WO2024016639A1 - 一种抗病毒感染的化合物及其制备方法和用途 - Google Patents

一种抗病毒感染的化合物及其制备方法和用途 Download PDF

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WO2024016639A1
WO2024016639A1 PCT/CN2023/075592 CN2023075592W WO2024016639A1 WO 2024016639 A1 WO2024016639 A1 WO 2024016639A1 CN 2023075592 W CN2023075592 W CN 2023075592W WO 2024016639 A1 WO2024016639 A1 WO 2024016639A1
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compound
alkyl
preparation
pharmaceutically acceptable
cycloalkyl
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PCT/CN2023/075592
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English (en)
French (fr)
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杨成
张起愿
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华创合成制药股份有限公司
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Publication of WO2024016639A1 publication Critical patent/WO2024016639A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention belongs to the field of virology and medicinal chemistry, and specifically relates to compounds that inhibit the replication of the novel coronavirus SARS-CoV-2 virus, the mechanism of the compound inhibiting the replication of the SARS-CoV-2 virus, and the use of the compound in the prevention and treatment of SARS-CoV-2.
  • coronavirus SARS-CoV-2 the Middle East respiratory syndrome coronavirus MERS-CoV, and the severe acute respiratory syndrome coronavirus SARS-CoV belong to the family Coronaviridae.
  • Coronaviruses are enveloped single-stranded positive viruses.
  • Stranded RNA viruses with genome lengths of approximately 26,000-32,000 bp, are the largest RNA viruses currently known.
  • Rendesivir an experimental anti-Ebola virus drug developed by Gilead Sciences, inhibits RNA synthase (RdRp) and is expected to inhibit the COVID-19 coronavirus. Therefore, there is an urgent need to find more safe and effective drugs to treat coronavirus.
  • the above-mentioned drugs have toxic side effects and may cause unnecessary damage to the patients themselves. Therefore, finding an anti-SARS-CoV-2 drug with low toxicity has become an urgent solution for the treatment of COVID-19.
  • the technical problem to be solved by the present invention is to provide a method for treating COVID-19 that avoids serious toxic and side effects and has a stable effect.
  • the invention provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, prodrugs or solvent compounds thereof:
  • R 1 is guanidine group
  • R 2 is hydrogen, deuterium or halogen
  • R 4 is OH, OD, halogen or
  • R 5 is OH, OD, halogen or
  • R 6 is H, D, CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 cycloalkyl, azido, C 1 -C 2 haloalkyl or halogen;
  • R 7 is H, D, CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 cycloalkyl, azido, C 1 -C 2 haloalkyl or halogen;
  • R 3 is selected from H
  • n is selected from 1, 2, 3 and 4;
  • R 8 is selected from C 1 -C 8 alkyl, -OC 1 -C 8 alkyl, benzyl, -O-benzyl, -CH 2 -C 3 -C 6 cycloalkyl, -O-CH 2 -C 3 -C 6 cycloalkyl and CF 3 ;
  • R 9 is selected from phenyl, 1-naphthyl, 2-naphthyl,
  • R 10 is selected from H and CH 3 ;
  • R 11 is selected from H or C 1 -C 6 alkyl
  • R 12 is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl and -CH 2 -C 3 -C 6 cycloalkyl;
  • R 13 is selected from H, C 1 -C 8 alkyl.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug or solvent compound thereof, wherein said compound
  • the items are selected from the following:
  • halogen and halogen refer to a halogen atom selected from F, CI, Br and I.
  • Azide refers to an azide group, that is, the group -N 3 .
  • the term “n” as used herein refers to an integer, such as an integer selected from 1, 2, 3, 4, that is, 1 to 4 or 1-4. In some cases, “n” refers to an integer group such as 1 to 3, 1 to 4, 1 to 6, 1 to 8, 2 to 4, 2 to 6, 2 to 8, etc.
  • the term “haloalkyl” refers to such as An alkyl group, as defined herein, in which one or more hydrogen atoms are each replaced by a halogen substituent.
  • a (C 1 -C 6 )haloalkyl group is a (C 1 -C 6 )alkyl group in which one or more hydrogen atoms are replaced by a halogen substituent.
  • Such range includes one halogen substituent on the alkyl group to complete halogenation of the alkyl group.
  • (C 1-n )haloalkyl as used herein, where n is an integer, alone or in combination with another group, is intended to mean a group as defined above in which one or more hydrogen atoms are each substituted by a halogen Replaced by an alkyl group having 1 to n carbon atoms.
  • Examples of (C 1-n ) haloalkyl groups in which n is 2 include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, dichloroethyl, Fluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
  • (C 1-n )alkyl as used herein, where n is an integer, alone or in combination with another group, is intended to mean a noncyclic, straight or branched chain containing from 1 to n carbon atoms. alkyl.
  • “(C 1-4 )alkyl” includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-medium ethyl (isopropyl), 1- Methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) and 1,1-dimethylethyl (tert-butyl).
  • Me represents a methyl group
  • Et represents an ethyl group
  • Pr represents a propyl group
  • iPr represents a 1-methylethyl group
  • Bu represents a butyl group
  • tBu represents 1,1-dimethylethyl group. base group.
  • alkyl refers to a hydrocarbon containing primary, secondary or tertiary atoms.
  • an alkyl group can have 1 to 4 carbon atoms (i.e., (C 1 -C 4 )alkyl), 1 to 3 carbon atoms (i.e., (C 1 -C 3 )alkyl), or 1 or 2 carbon atoms (ie, (C 1 -C 2 )alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH(CH 3 )2), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, sec-butyl, -CH(CH 3 ) CH 2 CH 3 ) and 2-methyl-9-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 ).
  • Alkyl also refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers resulting from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane.
  • Typical alkyl groups include, but are not limited to, dry methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl(-CH(CH 2 CH 3 )-), 1,9-propyl(-CH 2 CH(CH 3 )-), 1,3-propyl(-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • alkenyl is a straight or branched chain hydrocarbon containing primary, secondary or tertiary carbon atoms and having at least one site of unsaturation, a carbon-to-carbon sp-double bond.
  • an alkenyl group may have 2 to 4 carbon atoms (ie, C 2 -C 4 alkenyl) or 2 to 3 carbon atoms (ie, C 2 -C 3 alkenyl).
  • (C 2-n )alkenyl where n is an integer, alone or in combination with another group, is intended to mean a group containing from two to n carbon atoms in which at least two of the carbon atoms are connected through a double Unsaturated, non-cyclic linear or branched groups bonded to each other. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise indicated, the term “(C2 -n )alkenyl” is to be understood as encompassing the possible individual stereoisomers, including but not limited to the I and (Z) isomers, as well as mixtures thereof.
  • Alkynyl is a straight or branched chain hydrocarbon containing primary, secondary or tertiary carbon atoms and having at least one unsaturated site, a carbon-to-carbon sp-bond.
  • an alkynyl group can have 2 to 4 carbon atoms (ie, C 2 -C 4 alkynyl) or 2 to 3 carbon atoms (ie, C 2 -C 3 alkynyl).
  • suitable alkynyl groups include, but are not limited to, ethynyl (-C-CH), propynyl ( -CH2C -CH), and the like.
  • (C 2-n )alkynyl where n is an integer, alone or in combination with another group, is intended to mean a group containing from two to n carbon atoms, at least two of which are An unsaturated, non-cyclic linear or branched group with three bonds to each other.
  • Examples of such groups where n is 4 include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.
  • cycloalkyl refers to a cyclic aliphatic group.
  • a cycloalkyl group herein may be referred to by the number of carbon atoms in its ring, such as "C 3 -C 4 cycloalkyl” refers to a cycloalkyl group having 3 or 4 carbon ring atoms or "C 3 -C “6- Cycloalkyl” refers to a cycloalkyl group with 3, 4, 5 or 6 carbon ring atoms, that is, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • carbocycle refers to a saturated (i.e., cycloalkyl) or partially unsaturated ring having the specified number of carbon atoms such as 3 to 4 carbon atoms or 3 to 6 carbon atoms as a monocyclic ring system. Saturated (eg, cycloalkenyl, cyclodienyl, etc.) rings.
  • the carbocycle is a monocyclic ring containing 3-6 ring carbons (ie, a (C 3 -C 6 ) carbocycle).
  • Non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl base, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-9-enyl, 1-cyclohex-3-enyl and cyclohex-1,3-dienyl rings.
  • Each carbocyclyl group can be independently selected from 0, 1, 2 or 3 halogen, -OH, -CN, -NO 2 , -NH 2 , -NH (C 1 -C 6 alkyl), - Substituted with N(C 1 -C 6 alkyl) 2, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and -CF3 substituents.
  • a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof and/or a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof and/or a pharmaceutically acceptable carrier or excipient.
  • Separate pharmaceutical preparations are also provided, each containing a pharmaceutically effective amount of a compound of formula (I) or one of the specific compounds of the embodiments herein or a pharmaceutically acceptable salt, solvate and/or pharmaceutically acceptable salt thereof. carrier or excipient.
  • the compounds herein are formulated with conventional carriers and excipients selected according to common practice. Tablets will contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and will generally be isotonic when intended for parenteral delivery. All formulations optionally contain excipients such as those listed in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methylcellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, but is usually about 7 to 10.
  • active ingredients can be administered alone, they are preferably provided in the form of pharmaceutical preparations.
  • Formulations for both veterinary and human use comprise at least one active ingredient as defined above, together with one or more acceptable carriers and optionally other therapeutic ingredients, in particular those other therapeutic ingredients as discussed herein .
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof.
  • Formulations include those suitable for the aforementioned routes of administration.
  • the formulations are conveniently provided in unit dosage form and can be prepared by those well known in the pharmaceutical art. prepared by any method. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing together the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Preparations suitable for oral administration may be presented in the following dosage forms: discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; Or oil-in-water emulsion or water-in-oil emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • Tablets are made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent preparation.
  • Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may optionally be formulated to provide slow or controlled release of the active ingredient therefrom.
  • the formulation is preferably applied as a topical ointment or cream containing one or more active ingredients in an amount, for example, from 0.075 to 20% w/w (incl.
  • the active ingredient is between 0.1% and 20% in increments of 0.1% w/w, such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w, most preferably 0.5 to 10% weight/weight.
  • the active ingredients may be used with a paraffin or water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may comprise, for example, at least 30% w/w of polyols, i.e. alcohols with two or more hydroxyl groups such as propylene glycol, 1,3-butanediol, mannitol, sorbitol Alcohols, glycerol and polyethylene glycols (including PEG400) and mixtures thereof.
  • Topical formulations may desirably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of the emulsion can be composed in a known manner from known ingredients. Although this phase may contain emulsifiers alone, it ideally contains at least one emulsifier in a mixture with fat or oil or with both fat and oil. Preferably, the hydrophilic emulsifier is introduced together with a lipophilic emulsifier that acts as a stabilizer. It also preferably contains both oils and fats. Emulsifiers, with or without stabilizers, form so-called emulsifying waxes, which together with oils and fats form so-called emulsifying ointment bases, which form the oil dispersed phase of cream preparations.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulations include spermaceti, stearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • Suitable oils or fats for the formulation are selected on the basis of obtaining the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product, with a suitable consistency to avoid leakage from tubes or other containers.
  • Linear or branched chain, mono- or di-alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, etc. can be used.
  • a blend of isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a branched chain ester called Crodamol CAP is the preferred ester.
  • These can be used alone or in combination, depending on the properties required.
  • high melting point lipids such as white soft paraffin and/or rolling paraffin or other mineral oils are used.
  • compositions herein comprise combinations with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical preparations containing the active ingredients may be in any form suitable for the intended method of administration.
  • tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents, and preservatives , to provide palatable preparations.
  • Tablets are acceptable containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which may be suitable for the manufacture of tablets.
  • excipients may be, for example: inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or Gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used alone or with waxes.
  • Formulations for oral use may also be provided in hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin clay, or in soft gelatin capsules, in which the active ingredient is mixed with an aqueous or oily vehicle such as arachis oil, liquid paraffin or Olive oil mixture.
  • an inert solid diluent such as calcium phosphate or kaolin clay
  • an aqueous or oily vehicle such as arachis oil, liquid paraffin or Olive oil mixture.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents
  • examples include naturally occurring phospholipids (e.g., lecithin), condensation products of ethylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecan Condensation products of ethyleneoxycetyl alcohol), ethylene oxide and partial esters derived from fatty
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis, olive, sesame or coconut oil, or in a mineral oil, such as liquid paraffin.
  • Oral suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those described above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.
  • Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., a suspending agent
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.
  • Other excipients such as sweeteners, flavoring agents and coloring agents may also be present.
  • compositions may also be in the form of oil-in-water emulsions.
  • the oil phase can be vegetable oil such as olive oil or peanut oil, mineral oil such as liquid paraffin, or mixtures thereof.
  • Suitable emulsifiers include naturally occurring gums such as acacia and tragacanth, naturally occurring phospholipids such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate and these.
  • the condensation products of partial esters and ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • Lotions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such preparations may also contain demulcents, preservatives, flavoring or coloring agents.
  • compositions may be in the form of sterile injectable preparations or intravenous preparations such as sterile injectable aqueous or oleaginous suspensions.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those already mentioned above.
  • Sterile injectable preparations or intravenous preparations may also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or Prepared from freeze-dried powder.
  • the acceptable carriers and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can often be used as the solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- and diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables.
  • a sustained release formulation for oral administration to humans may contain from about 1 to 1000 mg of the active material formulated with a suitable and convenient amount of carrier material, which may be from about 5 to about 5% of the total composition. 95% (wt:wt).
  • Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain about 3 to 500 ug active ingredient per milliliter of solution so that an infusion of the appropriate volume can occur at a rate of about 30 Ml/hr.
  • Formulations suitable for topical application to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such preparations at a concentration of 0.5 to 20% w/w, advantageously 0.5 to 10% w/w, especially about 1.5% w/w.
  • Formulations suitable for topical administration into the mouth include those containing the active ingredient in a flavoring base, usually sucrose and acacia or tragacanth. Tablets; dragees containing the active ingredient in an inert base such as gelatin and glycerol, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as suppositories with a suitable base containing, for example, cocoa butter or salicylates.
  • Formulations suitable for intrapulmonary or nasal administration have, for example, particle sizes in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, etc., which are administered by rapid inhalation through the nasal passages or by oral inhalation to reach the alveoli. bag.
  • Suitable formulations include aqueous or oily solutions of the active ingredients.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used in the treatment or prevention of Pneumovirinae infections, as described below.
  • Another embodiment provides a novel, effective, safe, non-irritating and physiologically compatible inhalable composition suitable for accompanying bronchiolitis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof .
  • Preferred pharmaceutically acceptable salts are inorganic acid salts, including hydrochlorides, hydrobromides, sulfates or phosphates, as they may cause less pulmonary irritation.
  • the inhalable formulation is delivered to the endobronchial space in an aerosol containing particles having a mass median aerodynamic diameter (MMAD) of between about 1 and about 5 ⁇ m.
  • the compounds of formula (I) are formulated for delivery as an aerosol using a nebulizer, a pressurized metered dose inhaler (Pmdi) or a dry powder inhaler (DPI).
  • Non-limiting examples of nebulizers include atomizing, spraying, ultrasonic, pressurized, vibrating perforated plate or equivalent nebulizers, including those employing adaptive aerosol delivery technology.
  • Jet nebulizers use air pressure to break up a liquid solution into aerosol droplets.
  • Ultrasonic nebulizers work via piezoelectric crystals, which shear liquids into small aerosol droplets.
  • Pressurized spray systems force solutions through small pores under pressure to create aerosol droplets.
  • Vibrating porous plate equipment uses rapid vibrations to shear a stream of liquid into suitable droplet sizes.
  • the formulation for nebulization uses a nebulizer capable of aerosolizing the formulation of formula (I) into particles of the desired MMAD, such that the aerosol contains particles of MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m.
  • the agent is delivered into the endobronchial space.
  • most aerosolized particles should not have a MMAD greater than about 5 ⁇ m. If the aerosol contains a large number of particles with an MMAD greater than 5 ⁇ m, the particles will deposit in the upper airways reducing the amount of drug delivered to sites of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is less than about 1 ⁇ m, the particles have a tendency to remain suspended in the inhaled chamber air and are subsequently exhaled during exhalation.
  • aerosol formulations for nebulization will deliver a sufficient therapeutically effective dose of a compound of Formula (I) to the site of lung infection.
  • the amount of drug administered must be adjusted to reflect the efficiency of delivery of a therapeutically effective dose of the compound of formula (I).
  • the combination of an aqueous aerosol formulation with an atomizing, spraying, pressurizing, vibrating porous plate or ultrasonic nebulizer allows for the administration of a dose of the compound of formula (I) of from about 20 to about 90%, usually about 70%, is delivered into the airway.
  • at least about 30 to about 50% of the active compound is delivered. More preferably, from about 70 to about 90% of the active compound is delivered.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is delivered as an inhalable powder.
  • the compounds are administered intrabronchially in dry powder formulations using dry powder or metered dose inhalers to effectively deliver fine particles of the compound to the endobronchial space.
  • compounds of formula (I) are processed by grinding spray drying, critical fluid processing or precipitation from solution into particles with an MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m. Media milling, jet milling and spray drying equipment and procedures capable of producing MMAD particle sizes between about 1 ⁇ m and about 5 ⁇ m are well known in the art.
  • excipients are added to the compound of formula (I) prior to processing into particles of the desired size.
  • excipients are blended with particles of the desired size to aid dispersion of the drug particles, for example by using lactose as an excipient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be suitable.
  • Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents, and The preparations are solutes isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.
  • Formulations are provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (lyophilized) conditions requiring only the addition of a sterile liquid carrier such as water for injection immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof, of the active ingredient.
  • formulations may contain other agents conventional in the art for the type of formulation contemplated, for example those suitable for oral administration may include flavoring agents.
  • a veterinary carrier is a material intended for administration of the composition and may be a solid, liquid or gaseous material which is inherently inert or veterinary acceptable and is compatible with the active ingredient. These veterinary pharmaceutical compositions may be administered orally, parenterally or by any other desired route.
  • controlled release formulations in which the release of the active ingredients is controlled and regulated to allow for less frequent or improved dosing.
  • the pharmacokinetic or toxicological properties of a given active ingredient are used to provide controlled release pharmaceutical formulations containing one or more of the compounds as active ingredients ("controlled release formulations") in which the release of the active ingredients is controlled and regulated to allow for less frequent or improved dosing.
  • controlled release formulations The pharmacokinetic or toxicological properties of a given active ingredient.
  • the effective dose of the active ingredient will depend at least on the nature of the condition treated, toxicity, whether the compound is used prophylactically (lower doses) or to combat active viral infection, the method of delivery and pharmaceutical formulation, and will be determined by the clinician using routine dose escalation Research to determine. It can be expected to be from about 0.0001 to about 100 mg/kg body weight/day, typically from about 0.01 to about 10 mg/kg body weight/day, more typically from about 0.01 to about 5 mg/kg body weight/day, and most typically from about 0.05 to about 0.5 mg/kg. Weight/day.
  • a candidate daily dose for an adult weighing approximately 70 kg would be in the range of 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may be in single or multiple dose form.
  • One or more of the compounds are administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), among others. It is understood that the preferred route may vary depending, for example, on the recipient's condition.
  • An advantage of the compounds herein is that they are available as oral agents and can be administered orally.
  • compositions can also be used in combination with other active ingredients.
  • the other active therapeutic agent is against pneumovirinae viral infections.
  • Non-limiting examples of these other active therapeutics are ribavirin, palivizumab, movitizumab, RSV-IGIV (RespiGam), MEDI-557, A-60444 (also known as RSV604), MDT-637 , BMS-433771, ALN-RSVO, ALX-0171 and their mixtures.
  • Infections with many Pneumovirinae viruses are respiratory infections. Accordingly, other active therapeutic agents used to treat respiratory symptoms and sequelae of infection may be used in combination with compounds of formula (I).
  • the other therapeutic agents are preferably administered orally or by direct inhalation.
  • other preferred additional therapeutic agents for combination with compounds of formula (I) to treat viral respiratory tract infections include, but are not limited to, bronchodilators and corticosteroids.
  • Glucocorticoids originally introduced as asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most effective and consistently effective treatment for this disease, but their mechanism of action is not fully understood (Morris , J. Allergy Clin. Immunol., 75(1Pt)1-13, 1985).
  • oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit its use as a long-term therapeutic agent. The use of (Goodman and Gilman, 10th edition, 2001).
  • One solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation.
  • Inhaled corticosteroids have been developed to alleviate the severe side effects of oral steroids.
  • ICS Inhaled corticosteroids
  • Non-limiting examples of corticosteroids used in combination with compounds are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol ethyl carbonate, hydrocortisone, Prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluoxinandrolone, fluoxinandrolone acetone, flunisolide , flucodin-21-butylate, flumetasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone propionate
  • anti-inflammatory agents that act through anti-inflammatory cascade mechanisms may also be used as additional therapeutic agents in combination with compounds of formula (I) to treat viral respiratory tract infections.
  • Administration of "anti-inflammatory signaling modulators” referred to herein as AISTM
  • phosphodiesterase inhibitors e.g., PDE-4, PDE-5, or PDE-7 specific inhibitors
  • transcription factor inhibitors e.g., , blocking NFKB via IKK inhibition
  • kinase inhibitors e.g., blocking P38MAP, JNK, PI3K, EGFR, or Syk
  • Non-limiting other therapeutic agents include: 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl )-amide (P38Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-fluoromethoxy-benzamide ( PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-9-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP -840); N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-chloromonopyr
  • Combinations comprising an inhaled ⁇ 2-adrenoceptor agonist bronchodilator such as formoterol, albuterol or salmeterol and a compound of formula (I) are also suitable, but not limiting, combinations useful in the treatment of respiratory viral infections. .
  • Inhaled beta2-adrenoceptor agonist bronchodilators such as formoterol or salmeterol in combination with ICS have also been used to treat both bronchoconstriction and inflammation (Symbicort and Advair, respectively).
  • Combinations comprising these ICS and ⁇ 2-adrenoceptor agonist combinations and compounds of formula (I) are also suitable and non-limiting combinations useful in the treatment of respiratory viral infections.
  • Anticholinergic agents have potential use for the treatment or prevention of pulmonary bronchoconstriction and may therefore be used as other therapeutic agents in combination with compounds of formula (I) to treat viral respiratory tract infections.
  • These anticholinergics include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype), which have shown therapeutic efficacy in the control of cholinergic tone in human COPD (Witek, 1999) ;1- ⁇ 4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-9-carbonyl ⁇ -pyrrolidine-2-carboxylic acid (1- Methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-9-phenyl-propionyloxy]-8-isopropyl- 8-Methyl-8-nitrogen-bicyclo[3.2.1]octane (ipratropium-N
  • a mucolytic agent is ambroxol.
  • compounds of formula (I) can be combined with expectorants to treat both the infection and symptoms of respiratory tract infections.
  • an expectorant is guaiacol.
  • Nebulized hypertonic saline has been used to improve immediate and long-term clearance of small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266).
  • Compounds of formula (I) may also be combined with nebulized hypertonic saline, particularly when pneumovirinae virus infection is complicated by bronchiolitis.
  • the combination of the compound and hypertonic saline may also include any of the other agents discussed above.
  • nebulized hypertonic saline is used.
  • Any compound may also be combined with one or more other active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient.
  • Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.
  • Co-administration of a compound herein with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound and one or more other active therapeutic agents such that a therapeutically effective amount of the compound and one or more other active therapeutic agents is administered
  • the therapeutic agents are present in the patient's body.
  • Co-administration includes administration of a unit dose of the compound before or after administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of one or more other active therapeutic agents.
  • Administer the compound For example, a unit dose of the compound may be administered first, followed within seconds or minutes by a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by a unit dose of the compound administered over seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound first, followed a period of several hours (eg, 1-12 hours) by administering a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed a few hours (eg, 1-12 hours) later by administering a unit dose of a compound described herein.
  • Combination therapy may provide a "synergistic effect” or “synergistic effect,” whereby the effect obtained when the active ingredients are used together is greater than the sum of the effects produced by using the compounds individually.
  • Synergistic effects are obtained when the active ingredients are administered: (1) co-formulated in a combined formulation and administered or delivered simultaneously; (2) by alternating or delivered in parallel as separate formulations; or (3) by some other plan.
  • a synergistic effect may be obtained when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or by different injections in separate syringes.
  • a synergistic antiviral effect refers to an antiviral effect that is greater than the purely additive effect expected of the individual compounds of the combination.
  • the application provides a method of treating Pneumovirinae virus infection in a human, the method comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Solvates.
  • a method of treating Pneumovirinae viral infections in humans each comprising administering to the human a therapeutically effective pharmaceutically effective amount of a compound of formula (I) or one of the specific compounds of the embodiments herein, or a pharmaceutically effective method thereof.
  • a racemate, enantiomer, diastereomer, tautomer, polymorph of a compound of formula (I) by administering to a human a therapeutically effective amount of it.
  • the application provides a method of treating human respiratory viral infection in a human, said method comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof .
  • the present application provides a method of treating human respiratory viral infection in a human, said method comprising administering to the human a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvent thereof compound and at least one additional active therapeutic agent.
  • a therapeutically effective amount of a compound of formula (I) or an embodiment of the present invention comprising administering to the human a therapeutically effective amount of a compound of formula (I) or an embodiment of the present invention.
  • a compound of formula (I) or a specific embodiment of the embodiments herein.
  • Respiratory symptoms in people who are experiencing a respiratory viral infection can include a stuffy or runny nose, coughing, wheezing, sneezing, shortness of breath or difficulty breathing, choking, bronchitis, and pneumonia.
  • An embodiment is also provided, which includes the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of Pneumovirinae virus infection or respiratory virus infection.
  • a pharmaceutical preparation which contains a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical preparation comprising a pharmaceutically effective amount of a compound of formula (I) or one of the specific compounds of the embodiments herein, or a pharmaceutically acceptable salt, solvate and/or ester thereof and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical preparation which contains a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of at least one other of active therapeutic agents.
  • In vivo metabolite products of the compounds described herein are also within the scope of this document to the extent that such products are novel and non-obvious relative to the prior art. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds, mainly due to enzymatic processes. Accordingly, new and non-obvious compounds produced by a process involving contacting the compound with a mammal for a period of time sufficient to produce its metabolites are included in the present invention.
  • Such products are typically produced by preparing a radioactively labeled (e.g., 14C or 3H) compound and administering it parenterally to an animal such as a rat, mouse, guinea pig, monkey, or human at a detectable dose (e.g., greater than about 0.5 mg/kg). Sufficient time is allowed for metabolism to occur (usually about 30 seconds to 30 hours) and its transformation products to be identified by isolation from urine, blood or other biological samples. These products are easy to isolate because they are tagged (others are isolated by using antibodies capable of binding epitopes present in the metabolites separation). Metabolite structures are determined in a conventional manner, for example by MS or NMR analysis.
  • Transformation products so long as they are not otherwise found in the body, can be used in diagnostic assays at therapeutic doses of the compound, even if they do not possess HSV antiviral activity of their own.
  • Formulations and methods for determining the stability of compounds in alternative gastrointestinal secretions are known.
  • a compound is defined herein to be stable in the gastrointestinal tract when less than about 50 mole percent of the protected groups are deprotected in alternative intestinal or gastric juices upon incubation at 37°C for 1 hour. Just because compounds are stable to the gastrointestinal tract doesn't mean they won't hydrolyze in the body.
  • Prodrugs will generally be stable in the digestive system but may be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally within cells.
  • prodrug is understood to be a compound that is chemically designed to efficiently release the parent drug upon overcoming biological barriers to oral delivery.
  • lactone compound was prepared using the same procedure as for lactone compound C 1 except -azido-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluoro-tetrahydrofuran-2-ol. D1.
  • Intermediate 1 (5g, 9.2mmol) was dissolved in ammonia-methanol solution (80ml), sealed in a stainless steel tube, and heated to 110°C in an oil bath for 12 hours. After the reaction was completed, the reaction liquid was evaporated to dryness, and the residue was recrystallized with water to obtain intermediate 2 (4.0 g, 85% yield).
  • Compound 6 was prepared using the method of compound 5 in Example 25, replacing compound 1 with compound 2.
  • Compound 7 was prepared by using the method for compound 5 in Example 25, replacing compound 1 with compound 3.
  • Compound 8 was prepared using the method for compound 5 in Example 25, replacing compound 1 with compound 4.
  • Compound 10 was prepared by using the method of compound 9 in Example 29, replacing compound 1 with compound 2.
  • Compound 11 was prepared using the method of compound 9 in Example 29, except that compound 3 was substituted for compound 1.
  • Compound 12 was prepared using the method of compound 9 in Example 29, with compound 4 replacing compound 1.
  • Compound 13 was prepared using the method of compound 9 in Example 29, except that compound 5 was substituted for compound 1.
  • Compound 15 was prepared by using the method of compound 9 in Example 29, replacing compound 1 with compound 7.
  • Compound 16 was prepared by using the method of compound 9 in Example 29, replacing compound 1 with compound 8.
  • Compound 18 was prepared by using the method of compound 17 in Example 37, replacing compound 1 with compound 2.
  • Compound 19 was prepared by using the method of compound 17 in Example 37, replacing compound 1 with compound 3.
  • Compound 20 was prepared using the method of compound 17 in Example 37, replacing compound 1 with compound 4.
  • Compound 21 was prepared using the method of compound 17 in Example 37, except that compound 5 was substituted for compound 1.
  • Compound 22 was prepared by using the method of compound 17 in Example 37, replacing compound 1 with compound 6.
  • Compound 24 was prepared by using the method of compound 17 in Example 37, replacing compound 1 with compound 8.
  • reaction solution is added to 200 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution, extracted and separated, the organic layer is dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by column elution to obtain Compound 25 (13.9 g, 65% yield).
  • Compound 27 was prepared using the method of compound 25 in Example 45, except that compound 3 was substituted for compound 1.
  • Compound 28 was prepared using the method of compound 25 in Example 45, replacing compound 1 with compound 4.
  • Compound 29 was prepared using the method of compound 25 in Example 45, replacing compound 1 with compound 5.
  • Compound 30 was prepared by using the method of compound 25 in Example 45, replacing compound 1 with compound 6.
  • Compound 31 was prepared by using the method of compound 25 in Example 45, replacing compound 1 with compound 7.
  • Compound 33 was prepared using the method of compound 25 in Example 45, except that compound 8 was substituted for compound 1.
  • Compound 34 was prepared using the method of compound 33 in Example 52, except that compound 5 was substituted for compound 1.
  • Samples suspected of containing viruses considered in this article include natural or artificial materials such as living organisms, tissues or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc. ); laboratory samples; food, water or air samples; biological product samples such as cell extracts, especially recombinant cells that synthesize the required glycoproteins, etc.
  • samples are suspected of containing organisms that induce viral infection, often pathogenic organisms such as tumor viruses. Samples can be contained in any medium, including water and organic solvent/water mixtures. Samples include living organisms, such as humans, and artificial materials, such as cell cultures.
  • the antiviral activity of the compound upon administration of the composition may be observed by any method, including direct and indirect methods of detecting such activity. Quantitative, qualitative and semi-quantitative methods for detecting such activity are covered. Typically one of the above screening methods is used, however, any other method (eg observation of physiological properties of living organisms) is also suitable.
  • Known standard screening protocols can be used to measure the antiviral activity of compounds.
  • the following general scheme can be used to measure compounds antiviral activity.
  • Antiviral activity against 2019-nCoV was determined using an infectious cytopathic cell protection assay in Hep-2 cells.
  • compounds that inhibit viral infection and/or replication produce a cytoprotective effect against virus-induced cell killing that can be quantified using a cell viability reagent.
  • the technique used here is a new improvement of the method described in the published literature (Chapman et al., Antimicrob Agents Chemother. 2007, 51(9): 3346-53).
  • Hep-2 cells were obtained from ATCC (Manassas, VI) and maintained in MEM medium supplemented with 10% fetal calf serum and penicillin/streptomycin. Cells were passaged twice weekly and maintained at the subconfluent stage. Compound test stocks were titrated against 2019-nCoV strains to determine the appropriate dilution of the viral stock to produce the desired cytopathic effect in Hep-2 cells.
  • Hep-2 cells were grown in large cell culture flasks to near but not complete confluency.
  • Compounds to be tested were pre-diluted in DMSO in a standardized dose response of 8 or 40 samples/plate in 384-well compound dilution plates.
  • Serial dilutions of each test compound in threefold increments were prepared in plates and transferred at 100 nl/well into cell culture assay 384-well plates via an acoustic transfer device (Echo, Labcyte). Each compound dilution was transferred in single or quadruplicate samples to dry assay plates, which were stored until immediately before the start of the assay. Positive and negative controls were arranged in vertical blocks (1 column) at opposite ends of the plate.
  • an infectious mixture was prepared using a virus stock solution with a cell density of 50000/ml at the appropriate dilution previously determined by titration and added to the test plate with the compound at 20 Ul/well via automated equipment.
  • Each plate contained negative and positive controls (16 replicates per plate) to generate 0% and 100% viral inhibition standards, respectively.
  • 2019-nCoV the test plates were incubated in a 37°C cell culture incubator for 4 days.
  • cell viability reagent Cell TiterGIo Promega, Madison, WI was added to the assay plates, incubated briefly, and fluorescence readings (Envision, Perkin Elmer) were measured in all assay plates.
  • the percentage inhibition of the cytopathic effect induced by 2019-nCoV was determined from the remaining cell viability level. These numbers were calculated for each concentration tested relative to 0% and 100% inhibition controls, and the EC50 value was determined by nonlinear regression at the concentration that inhibited 50% of the 2019-nCoV-induced cytopathic effect. Use various potent anti-2019-nCoV tool compounds as positive controls for antiviral activity.
  • Cell viability reagents were used in parallel with antiviral activity in uninfected Hep- The cytotoxicity of the test compound was determined in 2 cells.
  • the same protocol as for the determination of antiviral activity was used, except that the cells were not infected by 2019-nCoV.
  • the same density of uninfected cell mixture was added at 20 ul/well to the plate containing the prediluted compound also at 100 nl/well. The plates were then incubated for 4 days before cell viability testing and fluorescence readings were measured using the same CeIITiter Glo reagent additions.
  • Untreated cells and cells treated with 2 Um puromycin served as 100% and 0% cell viability controls, respectively. Percent cell viability was calculated for each test compound concentration relative to 0% and 100% control, and the CC50 value was determined by nonlinear regression at the compound concentration that reduced cell viability by 50%.
  • the MT-4 cell line was obtained from the NIH AIDS Research and Reference Reagent Program (Germantown, MD) and maintained in RPMI-1640 supplemented with 10% FBS, 100 units/ml penicillin, 100 units/ml streptomycin, and 2mMl-glutamine. culture medium (Irvine Scientific, Santa Ana, CA, Cat#9160). Passage MT-4 cells twice weekly to maintain cell density below 0.6x10 cells/Ml. Black 384-tie plates were inoculated in quadruplicate in complete RPMI-1640 medium containing 100x concentration of 3-fold serial dilutions of compound (26 Nm to 530 Um).
  • the EC 50 , HEp-2CC 50 , and TM-4CC 50 concentrations of the compounds of the present invention are all better than those of the control compounds, indicating that the compounds of the present invention have stronger antibacterial ability than the control compounds and are less toxic to normal cells.
  • the 2019-nCoV ribonucleoprotein (RNP) complex was prepared according to the method modified by Mason et al (1).
  • HEp-2 cells were seeded in MEM + 10% fetal bovine serum (FBS) at a density of 7.1 ⁇ 10 4 cells/cm 2 and allowed to adhere overnight at 37°C (5% C 0 2). After attachment, cells were infected with 2019-nCoV in 35 mL MEM+2% FBS. At 20 hours post-infection, the medium was replaced with MEM + 2% FBS supplemented with 2ug/mL actinomycin D and returned to 37°C for one hour.
  • FBS fetal bovine serum
  • the cells were then washed once with PBS and treated with 35 mL PBS + 250 ug/mL lysolecithin for one minute, after which all liquid was aspirated. Collect cells by scraping them into 1.2 mL of Buffer A [50mM TRIS acetate (pH8.0), 100mM potassium acetate, 1mM DTT, and 2ug/mL actinomycin D] and pass them through repeatedly through an 18-gauge needle (10 times) to cause dissolution. Cell lysates were placed on ice for 10 minutes and then centrifuged at 2400 for 10 minutes at 4°C.
  • Buffer A 50mM TRIS acetate (pH8.0), 100mM potassium acetate, 1mM DTT, and 2ug/mL actinomycin D
  • the supernatant (S1) was removed and passed through repeated passages in 600uL buffer B [10mM TRIS acetate (pH8.0), 10mM potassium acetate and 1.5mM MgCl2] supplemented with 1% Triton X- 100 for 18 Pin (10 times) to break the clump (PI).
  • the resuspended pellet was placed on ice for 10 minutes and then centrifuged at 2400 for 10 minutes at 4°C.
  • the resuspended pellet was placed on ice for 10 minutes and then centrifuged at 2400 for 10 minutes at 4°C.
  • the supernatant (S3) fraction containing enriched 2019-nCoV RNP complexes was collected and protein concentration determined by UV absorbance at 280 nm. Aliquots of the 2019-nCoV RNP S3 fraction were stored at -80°C.
  • Transcription reactions were prepared in 30uL reaction buffer [50mM TRIS-acetate (pH 8.0), 120mM potassium acetate, 5% glycerol, 4.5mM MgCl 2 , 3mM DTT, 2mM ethylene glycol-bis(2-aminoethyl ether) - Contains 25ug crude RSV RNP complex in tetraacetic acid (EGTA), 50ug/mL BSA, 2.5U Rnasin (Promega), ATP, GTP, UTP, CTP and 1.5uCi [a- 32p ]NTP (3000Ci/mmol)] .
  • reaction buffer 50mM TRIS-acetate (pH 8.0), 120mM potassium acetate, 5% glycerol, 4.5mM MgCl 2 , 3mM DTT, 2mM ethylene glycol-bis(2-aminoethyl ether) - Contains 25ug crude RSV RNP complex in tetraace
  • the radiolabeled nucleotides used in the transcription assay were selected to match the nucleotide analogs used to evaluate transcriptional inhibition of the 2019-nCoV RNP.
  • the half inhibitory concentration of the compound of the present invention is better than that of the control compound, indicating that the antibacterial ability of the compound of the present invention is stronger than that of the control compound.

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Abstract

提供了一种抗病毒感染的化合物的制剂、方法和式(Ⅰ)的化合物以及用于合成式(Ⅰ)化合物的方法和中间体。该化合物能够抑制新型冠状病毒SARS-CoV-2病毒的复制且能够预防和治疗与SARS-CoV-2病毒引起的相关疾病。

Description

一种抗病毒感染的化合物及其制备方法和用途
本申请要求于2022年07月21日提交中国专利局、申请号为202210860718.2、发明名称为“一种抗病毒感染的化合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于病毒学领域和药物化学领域，具体地涉及抑制新型冠状病毒SARS-CoV-2病毒复制的化合物，该化合物抑制SARS-CoV-2病毒复制的机制，以及该化合物在预防和治疗与SARS-CoV-2病毒引起的相关疾病，尤其是与炎症，自身免疫相关疾病上的用途。
背景技术
新型冠状病毒SARS-CoV-2与中东呼吸综合征冠状病毒MERS-CoV,严重急性呼吸综合征冠状病毒SARS-CoV同属于冠状病毒科,冠状病毒(Coronavirus,CoVs)为有包膜的单股正链RNA病毒，其基因组长大约为26000-32000bp，是目前已知的最大的RNA病毒。
截止2022年4月15日，全球新冠肺炎确诊病例约5亿例，死亡约600万例。目前人们迫切需要有效的抗病毒药物来对抗SARS-CoV-2的感染，这不仅可以减轻患者的疾病负担，而且可以降低患者感染他人的风险。因此目前最快捷的方式是从FDA上市药物中筛选抵抗SARS-CoV-2感染的药物。目前，已在广泛应用抗病毒药物如：沙奎那韦(saquinavir)、带地那韦(indinavir)、利托那韦(ritonavir)、奈菲那韦(nelfinavir)、安普那韦(amprenavir)和洛匹那韦(lopinavir)主要用于人类免疫缺乏病毒(HIV)，一种导致获得性免疫缺陷综合征(AIDS)及其相关病变的病原性反转录病毒。吉利德科学公司研发的抗埃博拉病毒的试验药物瑞德西韦(rendesivir)，可抑制RNA合成酶(RdRp),有希望抑制COVID-19冠状病毒。因此，目前迫切需要找到更多安全、有效的治疗冠状病毒的药物。然而，上述药物具有毒副作用，可能对病人本身造成不必要的损伤，因此寻找一种毒性小的抗SARS-CoV-2的药物成为治疗COVID-19急需的解决方案。
发明内容
本发明所要解决的技术问题是，提供一种避免有严重毒副作用的药物，且具有稳定效果的治疗COVID-19方法。
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐、立体异构体、前药或溶剂化合物:
其中：
R1为胍基或
R2为氢、氘或卤素；
R4为OH、OD、卤素或
R5为OH、OD、卤素或
R6为H、D、CN、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C4环烷基、叠氮基、C1-C2卤代烷基或卤素；
R7为H、D、CN、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C4环烷基、叠氮基、C1-C2卤代烷基或卤素；
R3选自H、
其中：
n选自1、2、3和4；
R8选自C1-C8烷基、-O-C1-C8烷基、苄基、-O-苄基、-CH2-C3-C6环烷基、-O-CH2-C3-C6环烷基和CF3；
R9选自苯基、1-萘基、2-萘基、
R10选自H和CH3；
R11选自H或C1-C6烷基；
R12选自H、C1-C8烷基、苄基、C3-C6环烷基和-CH2-C3-C6环烷基；
R13选自H、C1-C8烷基。
本发明提供了式Ⅰ化合物或其药学上可接受的盐、立体异构体、前药或溶剂化合物，其中所述化合 物选自如下：







具体实施方式
定义
术语卤代和卤素指选自F、CI、Br和I的卤素原子。
“叠氮基”指叠氮基团，即基团-N3。本文所用术语“n”指整数，如选自1、2、3、4即1至4或1-4的整数。在一些情况下，“n”指整数组如1至3、1至4、1至6、1至8、2至4、2至6、2至8等如本文所用术语“卤代烷基”指如本文所定义的其中一个或多个氢原子各被卤素取代基所代替的烷基。例如，(C1-C6)卤代烷基为其中一个或多个氢原子被卤素取代基所代替的(C1-C6)烷基。这样的范围包括烷基基团上一个卤素取代基到烷基基团的完全卤化。
如本文所用术语“(C1-n)卤代烷基”，其中n为整数，单独地或与另一基团组合地意在指如上文所定义的其中一个或多个氢原子各被卤素取代基所代替的具有1至n个碳原子的烷基基团。其中n为2的(C1-n)卤代烷基的实例包括但不限于氯甲基、氯乙基、二氯乙基、溴甲基、溴乙基、二溴乙基、氟甲基、二氟甲基、三氟甲基、氟乙基和二氟乙基。
如本文所用术语“(C1-n)烷基”，其中n为整数，单独地或与另一基团组合地意在指含1至n个碳原子的非环状、直链或支链烷基。“(C1-4)烷基”包括但不限于甲基、乙基、丙基(正丙基)、丁基(正丁基)、1-中基乙基(异丙基)、1-甲基丙基(仲丁基)、2-甲基丙基(异丁基)和1,1-二甲基乙基(叔丁基)。缩写Me表示甲基基团，Et表示乙基基团，Pr表示丙基基团，iPr表示1-甲基乙基基团，Bu表示丁基基团，tBu表示1,1-二甲基乙基基团。
术语“烷基”指含伯、仲或叔原子的烃。例如，烷基基团可具有,1至4个碳原子(即，(C1-C4)烷基)、1至3个碳原子(即，(C1-C3)烷基)或者1或2个碳原子(即，(C1-C2)烷基)。合适的烷基基团的实例包括但不限于甲基(Me，-CH3)、乙基(Et，-CH2CH3)、1-丙基(n-Pr、正丙基、-CH2CH2CH3)、2-丙基(i-Pr、异丙基、-CH(CH3)2)、1-丁基(n-Bu、正丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu、异丁基、-CH2CH(CH3)2)、2-丁基(s-Bu、仲丁基、-CH(CH3)CH2CH3)和2-甲基-9-丙基(t-Bu、叔丁基、-C(CH3)3)。“烷基”还指具有通过从母体烷烃的同一或两个不同碳原子移除两个氢原子所得到的两个单价原子团中心的饱和、支链或直链烃基团。典型的烷基包括但不限干亚甲基(-CH2-)、1,1-乙基(-CH(CH3)-)、1,2-乙基(-CH2CH2-)、1,1-丙基(-CH(CH2CH3)-)、1,9-丙基(-CH2CH(CH3)-)、1,3-丙基(-CH2CH2CH2-)、1,4-丁基(-CH2CH2CH2CH2-)等。
“烯基”为包含伯、仲或叔碳原子的具有至少一个不饱和位点即碳一碳sp-双键的直链或支链烃。作为实例，烯基基团可具有2至4个碳原子(即，C2-C4烯基)或2至3个碳原子(即，C2-C3烯基)。合适的烯基基团的实例包括但不限于乙烯基(-CH＝CH2)和烯丙基(-CH2CH＝CH2)。
如本文所用术语“(C2-n)烯基”，其中n为整数，单独地或与另一基团组合地意在指含两个至n个碳原子的其至少两个碳原子通过双键彼此键合的不饱和、非环状直链或支链基团。这样的基团的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基和1-丁烯基。除非另有指出，否则术语“(C2-n)烯基”应理解为涵盖可能的单个立体异构体，包括但不限于I和(Z)异构体，以及它们的混合物。当(C2-n)烯基基团被取代时，应理解，除非另有指出，否则是在原本将携带氢原子的其任何碳原子上的取代，使得所述取代将导致化学稳定的化合物，如本领域技术人员认识到的那些。
“炔基”为含伯、仲或叔碳原子的具有至少一个不饱和位点即碳一碳sp-键的直链或支链烃。例如，炔基基团可具有2至4个碳原子(即，C2-C4炔基)或2至3个碳原子(即，C2-C3炔基)。合适的炔基基团的实例包括但不限于乙炔基(-C-CH)、丙炔基(-CH2C-CH)等。
如本文所用术语“(C2-n)炔基”，其中n为整数，单独地或与另一基团组合地意在指含两个至n个碳原子的、其至少两个碳原子通过三键彼此键合的不饱和、非环状直链或支链基团。其中n为4的此类基团的实例包括但不限于乙炔基、1-丙炔基、2-丙炔基和1-丁炔基。当(C2-n)炔基基团被取代时，应理解，除非另有指出，否则是在原本将携带氢原子的其任何碳原子上的取代，使得所述取代将导致化学稳定的化合物，如本领域技术人员认识到的那些。
术语环烷基指环状脂族基团。本文的环烷基基团可通过其环中的碳原子数被提及，如“C3-C4环烷基”指具有3或4个碳环原子的环烷基或“C3-C6环烷基”指具有3、4、5或6个碳环原子的环烷基，即环丙基、环丁基、环戊基或环己基环。
术语“碳环”或“碳环基”指具有指定的碳原子数如作为单环环系具有3至4个碳原子或3至6个碳原子的饱和(即，环烷基)或部分不饱和(例如，环烯基、环二烯基等)环。在一个实施方案中，碳环为包含3-6个环碳的单环(即，(C3-C6)碳环)。单环碳环的非限制性实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-9-烯基、1-环己-3-烯基和环已-1,3-二烯基环。
每一个碳环基基团可被0、1、2或3个独立地选自卤素、-OH、-CN、-NO2、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、C1-C6烷基、C1-C6烷氧基和-CF3的取代基所取代。
药物制剂
本文还提供了一种药物制剂，其包含药学有效量的式(I)化合物或其药学上可接受的盐、溶剂化物和/或药学可接受的载体或赋形剂。还提供了单独的药物制剂，每一者包含药学有效量的式(Ⅰ)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物和/或药学可接受的载体或赋形剂。
本文的化合物用常规的载体和赋形剂进行配制，所述载体和赋形剂根据通常的做法来选择。片剂将含赋形剂、助流剂、填料、粘结剂等。水性制剂以无菌形式制备并且当意在通过非口服递送时通常将是等渗的。所有制剂均任选地含赋形剂如“Handbook of Pharmaceutical Excipients”(1986)中列出的那些。赋形剂包括抗坏血酸和其它抗氧化剂、螯合剂如EDTA、碳水化合物如葡聚糖、羟烷基纤维素、羟烷基甲基纤维素、硬脂酸等。制剂的pH在约3至约11范围内，但通常为约7至10。
虽然活性成分可以单独施用，但优选以药物制剂的形式提供。用于兽的和用于人的制剂均包含至少一种如上所定义的活性成分，以及一种或多种可接受的载体和任选地其它治疗成分，特别是如本文讨论的那些其它治疗成分。载体必须是在与制剂的其它成分相容且对其接受者生理无害的意义上“可接受的”。
制剂包括适合于前述给药途径的那些。制剂可方便地以单位剂量形式提供并可通过药学领域中熟知 的任何方法制备。技术和制剂通常见于Remington’s Pharmaceutical Sciences(Mack Publishing Co.，Easton，PA)中。这样的方法包括使活性成分与构成一个或多个辅助成分的载体结合于一起的步骤。通常，制剂通过均匀且紧密地使活性成分与液体载体或细碎固体载体或二者结合于一起、并然后如果需要成型产品来制备。
适合于口服的制剂可以以下剂型提供：离散单元如胶囊剂、扁囊剂或片剂，各含预定量活性成分；粉末剂或颗粒剂；在水性或非水性液体中的溶液或混悬剂；或水包油乳液或油包水乳液。活性成分也可以大丸剂、药糖剂或糊剂施用。
片剂通过任选地与一种或多种辅助成分一起压制或模制来制成。压制片剂可通过在合适的机器中压制呈自由流动形式如粉末或颗粒的活性成分，其任选地与粘结剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合来制备。模制片剂可通过在合适的机器中模制经用惰性液体稀释剂润湿的粉状活性成分的混合物来制备。片剂可任选地被包衣或刻痕并可任选地配制为提供活性成分自其缓慢或受控释放。
对于眼或其它外部组织如口和皮肤的感染，制剂优选以局部软膏或霜剂施用，所述外用软膏或霜剂含一种或多种活性成分其量例如0.075至20％重量/重量(包括活性成分以0.1％重量/重量的增量在0.1％和20％之间，如0.6％重量/重量、0.7％重量/重量等)、优选0.2至15重量/重量％、最优选0.5至10％重量/重量。当配制软膏时，活性成分可与石蜡或可与水混溶的软膏基料一起使用。或者，活性成分可与水包油霜剂基料一起配制在霜剂中。
如果需要，霜剂基料的水相可包含例如至少30％重量/重量的多元醇，即具有两个或多个羟基基团的醇如丙二醇、1,3-丁二醇、甘露醇、山梨醇、甘油和聚乙二醇(包括PEG400)以及它们的混合物。局部制剂可理想地包含增强活性成分通过皮肤或其它受影响区域的吸收或渗逶的化合物。这样的皮肤渗透促进剂的实例包括二甲亚砜和相关类似物。
乳液的油相可由己知的成分以己知的方式构成。虽然该相可仅包含乳化剂，但其理想地包含至少一种乳化剂与脂肪或油或与脂肪和油二者的混合物。优选地，亲水乳化剂与充当稳定剂的亲脂乳化剂一起引入。其还优选包含油和脂肪二者。乳化剂与或不与稳定剂一起构成所谓的乳化蜡，所述蜡与油和脂肪一起构成所谓的乳化软膏基料，所述基料形成霜剂制剂的油分散相。
适合用于所述制剂中的乳化剂和乳液稳定剂包括鲸蜡、硬脂醇、苄醇、肉豆蔻醇、单硬脂酸甘油酯和十二烷基硫酸钠。
对于所述制剂合适的油或脂肪基于获得所需的化妆品性质来选择。霜剂应优选为不油腻、不染色并可洗的产品，具有合适的稠度以避免从管或其它容器渗漏。可使用直链或支链、一元或二元烷基酯如二异己二酸酯、硬脂酸异鲸蜡酯、椰油脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、棕榈酸2-乙基己酯或称为Crodamol CAP的支链酯的共混物，后三者为优选的酯。这些可单独或组合使用，取决于所需的性质。或者，使用高熔点脂质如白软石蜡和/或滚体石蜡或其它矿物油。
本文的药物制剂包含与一种或多种药学可接受的载体或赋形剂和任选地其它治疗剂的组合。含所述活性成分的药物制剂可呈任何适合预期的施用方法的形式。当例如用于口服使用时，可制备片剂、含片、锭剂、水性或油性混悬剂、可分散粉末或颗粒剂、乳剂、硬或软胶囊、溶液、糖浆或酏剂。旨在用于口服使用的组合物可根据药物组合物生产领域己知的任何方法来制备并且这样的组合物可含一种或多种试剂，包括增甜剂、调味剂、着色剂和防腐剂，以提供适口的制剂。包含与可适于制备片剂的无毒的药学可接受赋形剂的混合物中的活性成分的片剂是可接受的。这些赋形剂可为例如：惰性稀释剂，如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠；造粒和崩解剂，如玉米淀粉或海藻酸；粘合剂，如淀粉、明胶或 阿拉伯胶；和润滑剂，如硬脂酸镁、硬脂酸或滑石。片剂可无包衣或可通过包括微囊化在内的己知技术包衣以延迟在胃肠道中的崩解和吸收并由此在较长时间内提供持续的作用。例如，可单独地或与蜡一起采用延时材料如单硬脂酸甘油酯或二硬脂酸甘油酯。
用于口服使用的制剂也可以硬明胶胶囊提供，其中活性成分与惰性固体稀释剂如磷酸钙或高岭土混合，或以软明胶胶襄提供，其中活性成分与水或油介质如花生油、液体石蜡或橄榄油混合。
水性混悬剂包含与适于制备水性混悬剂的赋形剂的混合物中的活性材料。这样的赋形剂包括悬浮剂如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯树胶，以及分散或润湿剂如天然存在的磷脂(例如，卵磷脂)、环氧烷与脂肪酸的缩合产物(例如，聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂族醇的缩合产物(例如，十七乙烯氧基鲸蜡醇)、环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如，聚氧乙烯失水山梨醇单油酸酯)。水性混悬剂可还含一种或多种防腐剂如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂和一种或多种增甜剂，如蔗糖或糖精。
油混悬剂可通过悬浮活性成分于植物油如花生油、橄榄油、芝麻油或椰子油中，或者于矿物油如液体石蜡中来配制。口服混悬剂可含增稠剂如蜂蜡、硬石蜡或鲸蜡醇。可加入增甜剂如上述那些和调味剂来提供适口的口服制剂。这些组合物可通过加入抗氧化剂如抗坏血酸来保存。
适于通过加水来制备水性混悬剂的可分散粉末和颗粒提供了与分散或润湿剂、悬浮剂和一种或多种防腐剂的混合物中的活性成分。合适的分散或润温剂和悬浮剂以上面公开的那些为例。也可存在其它赋形剂，例如增甜剂、调味剂和着色剂。
药物组合物也可呈水包油乳液的形式。油相可为植物油如橄榄油或花生油、矿物油如液体石蜡、或它们的混合物。合适的乳化剂包括天然存在的树胶如阿拉伯树胶和黄蓍胶、天然存在的磷脂如大豆卵磷脂、衍生自脂肪酸和己糖醇酐的酯或偏酯，如失水山梨醇单油酸酯和这些偏酯与环氧乙烷的缩合产物如聚氧乙烯失水山梨醇单油酸酯。乳液可还含增甜剂和调味剂。糖浆和酏剂可用增甜剂如甘油、山梨糖醇或蔗糖配制。这样的制剂可还含缓和剂、防腐剂、调味剂或着色剂。
药物组合物可呈无菌可注射制剂或静脉制剂如无菌可注射水性或油质混悬剂的形式。此混悬剂可根据己知的技术使用上面己提及的那些合适的分散或润湿剂和悬浮剂配制。无菌可注射制剂或静脉制剂也可为在无毒的、肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬剂，如在1,3-丁二醇中的溶液或以冻干粉所制备。可采用的可接受载体和溶剂有水、林格氏溶液和等渗氯化钠溶液。另外，可通常采用无菌固定油作为溶剂或悬浮介质。就此目的而言，可采用任何温和的固定油，包括合成的甘油单酯和甘油二酯。另外，在注射剂的制各中同样可使用脂肪酸如油酸。
可与载体材料组合以产生单剂型的活性成分的量随被治疗的主体和特定的给药模式而异。例如，用于口服给药至人类的缓释制剂可含大约1至1000mg的与适宜且方便量的载体材料调配的活性材料，其中所述载体材料的量可为总组合物的约5至约95％(重量：重量)。药物组合物可制备为提供易于测量的量以便给药。例如，意在静脉输注的水性溶液可含约3至500ug活性成分/毫升溶液，以便可发生以约30Ml/hr的速率的合适体积的输注。
适合局部施用于眼的制剂还包括滴眼剂，其中活性成分溶解或悬浮在合适的载体中，尤其是用于活性成分的水性溶剂中。活性成分优选以0.5至20％重量/重量、有利地0.5至10％重量/重量、特别是约1.5％重量/重量的浓度存在于这样的制剂中。
适合局部施用于口中的制剂包括在调味基料通常是蔗糖和阿拉伯胶或黄蓍胶中包含活性成分的含 片；在惰性基料如明胶和甘油、或蔗糖和阿拉伯胶中包含活性成分的糖锭；和在合适的液体载体中包含活性成分的漱口剂。
用于直肠给药的制剂可提供为栓剂，其具有包含例如可可脂或水杨酸酯的合适基料。
适合肺内或经鼻给药的制剂具有例如在0.1至500微米的范围内如0.5、1、30、35等的颗粒尺寸，其通过经鼻道快速吸入或通过经口吸入给药以到达肺泡囊。合适的制剂包括活性成分的水性或油性溶液。适合气雾剂或干粉给药的制剂可根据常规方法制备并可与其它治疗剂如如下所述此前用于肺病毒亚科感染的治疗或预防中的化合物一起递送。
另一个实施方案提供了一种适于伴随细支气管炎的新型、有效、安全、无刺激且生理上相容的可吸入组合物，其包含式(I)的化合物或其药学上可接受的盐。优选的药学上可接受的盐为无机酸盐，包括盐酸盐、氢溴酸盐、硫酸盐或磷酸盐，因为它们可能引起较少的肺刺激。优选地，可吸入制剂在包含颗粒的气雾剂中递送到支气管内空间，所述颗粒具有约1和约5μm之间的质量中值空气动力学直径(MMAD)。优选地，式(I)的化合物配制为使用喷雾器、加压计量吸入器(Pmdi)或干粉吸入器(DPI)以气雾剂递送。
喷雾器的非限制性实例包括雾化、喷射、超声波、加压、振动多孔板或等效喷雾器，包括采用自适应气雾剂递送技术的那些喷雾器。喷射喷雾器采用空气压力来将液体溶液破碎成气雾剂小滴。超声波喷雾器通过压电晶体工作，其将液体剪切成小的气雾剂小滴。加压喷雾系统迫使溶液在压力下通过小孔隙以生成气雾剂小滴。振动多孔板设备利用快速振动来将液体的流剪切成适宜的小滴尺寸。
在一个优选的实施方案中，用于喷雾的制剂使用能够将式(I)的制剂气雾化成所需MMAD的颗粒的喷雾器，以将包含MMAD主要在约1μm和约5μm之间的颗粒的气雾剂递送到支气管内空间。为了最佳的治疗有效性和为了避免上呼吸道和全身性副作用，大多数气雾化的颗粒应不具有大于约5μm的MMAD。如果气雾剂含大量MMAD大于5μm的颗粒，则所述颗粒将沉积在上气道中而减少递送到下呼吸道中炎症和支气管收缩部位的药物的量。如果气雾剂的MMAD小于约1μm，则颗粒具有保持悬浮于吸入的室气中并随后在呼气过程中呼出的趋势。
当根据本文的方法配制和递送时，用于喷雾的气雾剂制剂将向肺感染部位递送足以治疗有效剂量的式(I)化合物。给予的药物的量必须被调整以反映式(I)化合物的治疗有效剂量的递送效率。在一个优选的实施方案中，水性气雾剂制剂与雾化、喷射、加压、振动多孔板或超声喷雾器(取决于喷雾器)的组合允许式(I)化合物的施用剂量的约至少20至约90％、通常约70％递送到气道中。在一个优选的实施方案中，至少约30至约50％的活性化合物被递送。更优选地，约70至约90％的活性化合物被递送。
在另一个实施方案中，式(I)的化合物或其药学上可接受的盐以可吸入粉末递送。所述化合物使用干粉或计量剂量吸入器以干粉制剂支气管内给药，以有效地递送化合物的细粒到支气管内空间。对于通过DPI的递送，通过研磨喷雾干燥、临界流体加工或从溶液沉淀将式(I)的化合物加工成MMAD主要在约1μm和约5μm之间的颗粒。能够产生MMAD介于约1μm和约5μm之间的颗粒尺寸的介质研磨、喷射研磨祁喷雾干燥设备及程序是本领域熟知的。
在一个实施方案中，在加工成所需尺寸的颗粒之前向式(I)的化合物中加入赋形剂。在另一个实施方案中，与所需尺寸的颗粒共混赋形剂以帮助药物颗粒的分散，例如通过使用乳糖作为赋形剂。
适于阴道给药的制剂可以阴道栓剂、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾制剂提供，其除所述活性成分外还含如本领域己知适宜的载体。
适于肠胃外给药的制剂包括水性和非水性无菌注射溶液，其可含抗氧化剂、缓冲液、抑菌剂和使得 制剂与预期接受者的血液等渗的溶质；及水性和非水性无菌混悬剂，其可包含悬浮剂和增稠剂。
制剂以单位剂量或多剂量容器提供，例如密封安瓿和小瓶，并可贮存在冻干(冷冻干燥)条件下，仅需要在使用前即刻加入无菌液体载体如水以便注射。临时注射溶液剂和混悬剂根据先前描述的种类的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂为含如上文所述日剂量或单位日亚剂量或其适宜分数的活性成分的那些。
应理解，除上面特别提到的成分外，制剂可还包含本领域中关于所考虑的制剂类型的常规的其它试剂，例如适于口服给药的那些可包含调味剂。
兽药载体为用于施用所述组合物的目的的材料并可为固体、液体或气体材料，其原本是惰性的或兽医领域申可接受的并与所述活性成分相容。这些兽药组合物可经口、肠胃外或通过任何其它期望的途径施用。
本文的化合物用来提供控释药物制剂，其含一种或多种所述化合物作为活性成分(“受控释放制剂”)，其中控制和调节活性成分的释放以允许较低的用药频率或改善给定活性成分的药代动力学或毒性特性。
活性成分的有效剂量至少取决于治疗的病症的性质、毒性、化合物是预防性地使用(较低剂量)还是用以对抗活动性病毒感染、递送方法和药物制剂，并由临床医生使用常规剂量递增研究来确定。其可预计为约0.0001至约100mg/kg体重/天，通常约0.01至约10mg/kg体重/天，更通常约0.01至约5mg/kg体重/天，最通常约0.05至约0.5mg/kg体重/天。
例如，体重大约70kg的成年人的日候选剂量将在1mg至1000mg的范围内，优选5mg和500mg之间，并可呈单剂量或多剂量的形式。
给药途径
一种或多种所述化合物(本文称活性成分)通过对被治疗的病症适宜的任何途径给药。合适的途径包括口、直肠、鼻、肺、局部(包括颊和舌下)、阴道和肠胃外(包括皮下、肌内、静脉内、皮内、鞘内和硬膜外)等。应理解，优选的途径可随例如接受者的情况而异。本文的化合物的优点在于其是口服主物可利用的并可口服给药。
联合疗法
也与其它活性成分组合地使用组合物。对于肺病毒感染的治疗，优选地，所述其它活性治疗剂对肺病毒亚科病毒感染。这些其它活性治疗剂的非限制性实例有利巴韦林、帕利珠单抗、莫维珠单抗、RSV-IGIV(RespiGam)、MEDI-557、A-60444(也称RSV604)、MDT-637、BMS-433771、ALN-RSVO、ALX-0171以及它们的混合物。
许多肺病毒亚科病毒的感染为呼吸道感染。因此，用来治疗呼吸道症状和感染后遗症的其它活性治疗剂可与式(I)的化合物组合地使用。所述其它治疗剂优选口服或通过直接吸入给药。例如，与式(I)的化合物组合以治疗病毒性呼吸道感染的其它优选的其它治疗剂包括但不限于支气管扩张剂和皮质类固醇。
糖皮质激素，最初作为哮喘疗法于1950年引入(Carryer，Journal ofAllergy，21，282-287，1950)，仍然是这种疾病最有效且持续有效的疗法，但它们的作用机制尚未完全理解(Morris，J.Allergy Clin。Immunol.，75(1Pt)1-13，1985)。不幸的是，口服糖皮质激素疗法伴有严重的不良副作用如躯干肥胖、高血压、青光眼、葡萄糖耐受不良、白内障形成加速、骨矿物质流失和心理影响，所有这些都限制其作为长期治疗剂的使用(Goodman and Gilman，10th edition，2001)。全身性副作用的一个解决方案是直接向炎症部位递送类固醇药物。己开发吸入用皮质类固醇(ICS)来缓解口服类固醇的严重副作用。可与式(I) 的化合物组合使用的皮质类固醇的非限制性实例有地塞米松、地塞米松磷酸钠、氟米龙、醋酸氟米龙、氯替泼诺、氯替泼诺碳酸乙酯、氢化可的松、泼尼松龙、氟氢可的松、曲安西龙、曲安奈德、倍他米松、倍氯米松二丙酸酯、甲泼尼龙、氟新诺龙、氟新诺龙丙酮、氟尼缩松、氟可丁-21-丁基化物、氟米松、氟米松新戊酸酯、布地奈德、卤倍他索丙酸酯、糠酸莫米松、丙酸氟替卡松、环索奈德；或它们的药学上可接受的盐。
通过抗炎级联机制起作用的其它抗炎剂也可用作与式(I)的化合物组合来治疗病毒性呼吸道感染的其它治疗剂。施用“抗炎信号转导调控剂”(在本文中称AISTM)妇磷酸二酯酶抑制剂(例如，PDE-4、PDE-5或PDE-7特异性抑制剂)、转录因子抑制剂(例如，通过IKK抑制阻断NFKB)或激酶抑制剂(例如，阻断P38MAP、JNK、PI3K、EGFR或Syk)是切断炎症的逻辑方法，因为这些小分子靶向有限数量的共同细胞内通路一对抗炎治疗干预为临界点的那些信号转导通路(参见P.J.Barnes，2006的综述)。这些非限制性的其它治疗剂包括：5-(2,4-二氟-苯氧基)-1-异丁基-1H-吲唑-6-羧酸(2-二甲基氨基-乙基)-酰胺(P38Map激酶抑制剂ARRY-797)；3-环丙基甲氧基-N-(3,5-二氯-吡啶-4-基)-4-氟甲氧基-苯甲酰胺(PDE-4抑制剂罗氟斯特)；4-[2-(3-环戊氧基-4-甲氧基苯基)-9-苯基-乙基]-吡啶(PDE-4抑制剂CDP-840)；N-(3,5-二氯-4-吡啶基)-4-(二氟甲氧基)-8-[(甲基磺酰)氨基]-1-二苯并呋喃甲酰胺(PDE-4抑制剂Oglemilast)；N-(3,5-氯一吡啶-4-基)-2-[1-(4-氟苄基)-5-羟基-IH-吲哚-3-基]-2-氧代-乙酰胺(PDE-4抑制剂AWD 12-281)；8-甲氧基-9-三氟甲基-喹啉-5-羧酸(3,5-二氯-1-氧-吡啶-4-墓)-酰胺(PDE-4抑制剂Sch351591)；4-[5-(4-氟苯基)-2-(4-甲烷亚硫酰基-苯基)-1H-咪唑-4-基]一吡啶(P38抑制剂SB-203850)；4-[4-(4-氟-苯基)-1-(3-苯基-丙基)-5-吡啶-4-基-1H-咪唑-9-基]-丁-3-炔-1-醇(P38抑制剂RWJ-67657)；4-氰基-4-(3-环戊氧基-4-甲氧基一苯基)-环己烷羧酸2-二乙基氨基-乙酯(西洛司特的9-二乙基-乙基酯前药，PDE-4抑制剂)；(3-氯-4-氟苯基)-[7-甲氧基-6-(3-吗啉-4-基-丙氧基)-喹唑啉-4-基]-胺(吉非替尼，EGFR抑制剂)；和4-(4-甲基一哌嗪-1-基甲基)-N-[4-甲基-3-(4-吡啶-3-基-嘧啶-2-基氨基)-苯基]-苯甲酰胺(伊马替尼，EGFR抑制剂)。
包含吸入用β2-肾上腺素受体激动剂支气管扩张剂如福莫特罗、沙丁胺醇或沙美特罗与式(I)的化合物的组合也是合适的但非限制性的可用于治疗呼吸道病毒感染的组合。
吸入用β2-肾上腺素受体激动剂支气管扩张剂如福莫特罗或沙美特罗与ICS的组合也被用来治疗支气管收缩和炎症二者(分别用。Sym bicort和Advair)。包含这些ICS和β2-肾上腺素受体激动剂组合以及式(I)的化合物的组合也是合适且非限制性的可用于治疗呼吸道病毒感染的组合。
对于肺支气管收缩的治疗或预防，抗胆碱能剂具有潜在的用途并因此可用作其它治疗剂与式(I)的化合物组合地使用来治疗病毒性呼吸道感染。这些抗胆碱能剂包括但不限于毒蕈碱性受体(特别是M3亚型)的拮抗剂，其已在人COPD中胆碱能紧张度的控制中显示出治疗效能(Witek，1999)；1-{4-羟基-1-[3,3,3-三-(4-氟-苯基)-丙酰]-吡咯烷-9-羰基}-吡咯烷-2-羧酸(1-甲基-哌啶-4-基甲基)-酰胺；3-[3-(2-二乙基氨基-乙酰氧基)-9-苯基-丙酰氧基]-8-异丙基-8-甲基-8-氮阳离子-双环[3.2.1]辛烷(异丙托铵-N，N-甘氨酸二乙酯)；1-环己基-3,4-二氢-1H-异喹啉-2-羧酸1-氮杂-双环[2.2.2]辛-3-基酯(索利那新)；2-羟甲基-4-甲烷亚硫酰基-2-苯基-丁酸1-氮杂-双环[2.2.2]辛-3-基酯(瑞伐托酯)式(I)的化合物还可与粘液溶解剂组合来治疗呼吸道感染的感染和症状。粘液溶解剂的一个非限制性实例为氨溴索。类似地，式(I)的化合物可与祛痰剂组合来治疗呼吸道感染的感染和症状二者。祛痰剂的一个非限制性实例为愈创木酚甘油醚。雾化高渗盐水被用来改善患肺病病人的小气道的即时和长期清除(Kuzik，J.Pediatrics 2007，266)。式(I)的化合物也可与雾化高渗盐水组合，特别是当肺病毒亚科病毒感染并发细支气管炎时。式(I)的化 合物与高渗盐水的组合可还包含任何上面讨论的其它试剂。在一个实施方案中，使用约3％的雾化高渗盐水。还可以以单一剂型组合任何化合物与一种或多种其它活性治疗剂以同时或依次施用给病人。联合疗法可作为同时或依次的方案施用。当依次施用时，组合可以两次或更多次给药进行施用。
本文的化合物与一种或多种其它活性治疗剂的联合给药通常指化合物和一种或多种其它活性治疗剂的同时或依次施用，以便治疗有效量的化合物和一种或多种其它活性治疗剂均存在于病人的身体中。
联合给药包括在施用单位剂量的一种或多种其它活性治疗剂之前或之后施用单位剂量的所述化合物，例如在施用一种或多种其它活性治疗剂的数秒、数分钟或数小时内施用所述化合物。例如，可首先施用单位剂量的所述化合物，然后在数秒或数分钟内施用单位剂量的一种或多种其它活性治疗剂。或者，可首先施用单位剂量的一种或多种其它治疗剂，然后在数秒或数分钟内施用单位剂量的化合物。在一些情况下，可能需要首先施用单位剂量的化合物，然后在数小时(例如，1-12小时)的时间后施用单位剂量的一种或多种其它活性治疗剂。在其它情况下，可能需要首先施用单位剂量的一种或多种其它活性治疗剂，然后在数小时(例如，1-12小时)的时问后施用单位剂量的本文所述化合物。
联合疗法可提供“协同作用”或“协同效应”，即当一起使用活性成分时获得的效应大于单独使用所述化合物产生的效应之和。当活性成分以如下方式施用时可获得协同效应：(1)共同配制在一种组合制剂中并且同时施用或递送；(2)通过作为单独的制剂交替或平行递送；或(3)通过一些其它方案。当以交替疗法递送时，当化合物例如在单独的片剂、丸剂或胶囊剂中，或通过在单独的注射器中的不同注射剂依次施用或递时可获得协同效应。
一般来说，在交替疗法过程中，依次即连续地施用有效剂量的各活性成分，而在联合疗法中，有效剂量的两种或更多种活性成分被一起施用。协同抗病毒效应指大于组合的单个化合物的预期的纯加和效应的抗病毒效应。
在又一个实施方案中，本申请提供了一种治疗人类中肺病毒亚科病毒感染的方法，所述方法包括向人施用治疗有效量的式(I)化合物或其药学上可接受的盐、溶剂化物。还提供了治疗人类中肺病毒亚科病毒感染的单独方法，每一者包括施用给人治疗有效的药学有效量的式(Ⅰ)化合物或本文的实施例的具体化合物中之一或其药学上可接受的盐、溶剂化物及药学可接受的载体或赋形剂。
在另一个实施方案中，提供了通过给予人治疗有效量的式(I)化合物的外消旋物、对映异构体、非对映异构体、互变异构体、多晶型物、假多晶型物、非晶形式、水合物或溶剂化物或者其药学上可接受的盐来治疗人的肺病毒亚科感染的方法。
还提供了治疗需要其的人的肺病毒亚科感染的单独方法，每一方法包括给予人治疗有效量的式(I)化合物的外消旋物、对映异构体、非对映异构体、互变异构体、多晶型物、假多晶型物、非晶形式、水合物或溶剂化物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物。
在还另一个实施方案中，本申请提供了一种治疗人的人呼吸道病毒感染的方法，所述方法包括给予人治疗有效量的式(I)化合物或其药学上可接受的盐、溶剂化物。
在还另一个实施方案中，本申请提供了一种治疗人的人呼吸道病毒感染的方法，所述方法包括给予人治疗有效量的式(I)化合物，或其药学上可接受的盐、溶剂化物及至少一种另外的活性治疗剂。
还提供了治疗需要其的人的人呼吸道病毒感染的单独方法，每一万法包括给予所述人治疗有效量的式(I)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物。
还提供了治疗有需要的人的人呼吸道病毒感染的单独方法，每一方法包括给予所述人治疗有效量的式(I)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物及至少一种另 外的活性治疗剂。
还提供了治疗有需要的人的人呼吸道病毒感染的单独方法，其中所述人还正在经受支气管炎，每一方法包括给予所述人治疗有效量的式(I)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物。
还提供了治疗有需要的人的人呼吸道病毒感染的单独方法，其中所述人还正在经受肺炎，每一方法包括给予所述人治疗有效量的式(I)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物。
还提供了改善正在经受人呼吸道病毒感染的人的呼吸道症状的单独方法，每一方法包括给予所述人治疗有效量的式(I)化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化合物。
正在经受呼吸道病毒感染的人的呼吸道症状可包括鼻塞不通或流鼻涕、咳嗽、喘息、打喷嚏、呼吸急促或呼吸困难、窒息、支气管炎和肺炎。
还提供了一个实施方案，其包括式(I)化合物或其药学上可接受的盐、溶剂化物在制备用于肺病毒亚科病毒感染或呼吸道病毒感染的治疗的药剂的用途。
还提供了一种药物制剂，其包含药学有效量的式(I)化合物或其药学上可接受的盐、溶剂化物，及药学可接受的载体或赋形剂。还提供了一种药物制剂，其包含药学有效量的式(I)化合物或者本文的实施例的具体化合物中之一，或者其药学上可接受的盐、溶剂化物和/或酯及药学可接受的载体或赋形剂。
还提供了一种药物制剂，其包含药学有效量的式(I)化合物或其药学上可接受的盐、溶剂化物，及药学可接受的载体或赋形剂和药学有效量的至少一种另外的活性治疗剂。
还提供了单独的实施方案，其包括式(I)的化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物，以用在人的肺病毒亚科病毒感染或呼吸道毒感染的治疗中。
还提供了单独的实施方案，其包括式(I)的化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物，以用作药剂。
还提供了单独的实施方案，其包括制备旨在治疗人的肺病毒亚科病毒感染或呼吸道病毒感染的药剂的方法，所述方法特征在于使用式(I)的化合物或者本文的实施例的具体化合物中之一或者其药学上可接受的盐、溶剂化物。
还提供了式(I)的化合物或其药学上可接受的盐、溶剂化物，以治疗人的的肺病毒亚科病毒感染或呼吸道病毒感染。
还提供了如本说明书中所述的化合物。还提供了如本说明书中所述的药物组合物。还提供了如本说明书中所述的使用式(I)化合物的方法。还提供了如本说明书中所述的制备式(I)化合物的方法。
化合物的代谢物
本文描述的化合物的体内代谢产物也落入本文的范围内，其程度使得此类产物相对于现有技术是新的且是非显而易见的。此类产物可产生自例如所施用化合物的氧化、还原、水解、酰胺化、酯化等，主要是由于酶解过程。相应地，通过包括使化合物与哺乳动物接触足以产生其代谢产物的时间段的过程产生的新的且非显而易见的化合物包括在本发明中。这样的产物通常通过制备放射性标记(例如，14C或3H)化合物、以可检测的剂量(例如，大于约0.5mg/kg)肠胃外施用给动物如大鼠、小鼠、豚鼠、猴或人.允许足够的时间以发生代谢(通常约30秒至30小时)并自尿、血液或其它生物样品分离其转化产物来识别。这些产物易于分离，因为它们是带标记的(其它的通过使用能够结合代谢物中存在的表位的抗体来 分离)。代谢物结构以常规方式确定，例如通过MS或NMR分析。一般来说，代谢物的分析以与本领域技术人员熟知的常规药物代谢研究相同的方式进行。转化产物只要它们未以其他方式见于体内，即可用于化合物的治疗剂量的诊断试验，即便它们不具有它们自身的HSV抗病毒活性。
测定化合物在替代的胃肠分泌物中的稳定性的配方和方法是己知的。当于37℃下保温1小时时少于约50摩尔％的受保护基团在替代的肠液或胃液中去保护时，化合物在本文中定义为在胃肠道中稳定。仅仅因为化合物对胃肠道稳定并不意味着它们不会在体内水解。前药通常将在消化系统中稳定，但可能在消化腔、肝、肺或其它代谢器官中或一般地在细胞内基本上水解为母体药物。如本文所用，前药理解为经化学设计以在克服口服递送的生物障碍后有效地释放母体药物的化合物。
化合物的制备
实施例1
(2S)-2-(氯代(苯氧基)磷酰基氨基)丙酸9-乙基丁酯(氯化物A1)
将2-乙基丁基丙氨酸酯盐酸盐(2.54g，12.1mmol)溶解在无水二氯甲烷(30ml)中并在N2下在搅拌下将混合物冷却至0℃。加入二氯磷酸苯基酯(2.23Ml，25mmol)，随后在10min内滴加三乙胺；然后将反应混合物缓慢地升温至室温并搅拌12h。加入无水乙酸酐(150Ml)，并搅拌混合物30min。通过过滤除去形成的固体，并在减压下浓缩滤液。对残留物采用硅胶色谱法洗脱，得氯化物A1(1.72g，41％)。
实施例2
S,S’-2,2’-((4-硝基苯氧基)磷酰)双(乙烷-2,1-二基)双(2,2-二甲基硫代丙酸酯)(中间体B1)
将氧氯化磷(4.72g，30.8mmol)溶于二氯甲烷50ml中并冷却溶液至-78℃，将硫代酯(10.0g 61.7mmol)溶于二氯甲烷50ml中并缓慢加到氧氯化磷溶液中。接下来逐滴加入三乙醇胺(9.19g，61.6mmol)并让冷搅拌30分钟。然后升温至室温并让搅拌2小时。一次性加入对-硝基苯酚(4.28g，30.8mmol)，然后缓慢加入三乙醇胺(4.59g，30.8mmol)于室温下搅拌30分钟。用TLC法测定反应结束后，用醚稀释溶液，通过过滤移除固体并弃去。浓缩母液并通过硅胶色谱纯化，得中间体B1(7.50g 48％)。
实施例3
内酯化合物C1
将(2R,3R,4R,5R)-3,4-双(苄氧基)-5-(苄氧基甲基)-四氢呋喃-2-醇(15g，35.7mmol)溶解在乙醇中(30Ml)中，加入甲酸(5Ml),再加入硫酸1ml并将所得到的反应混合物在回流下搅拌6h。在减压下浓缩。将残留物溶解二氯甲烷中，并对其进行硅胶色谱法洗脱，得内酯化合物C1(14.0g，94％)。
实施例4：内酯化合物D1
除了((2R,3R,4R,5R)-3,4-双(苄氧基)-5-(苄氧基甲基)-四氢呋喃-2-醇代替(2R,3R,4R,5R)-5-叠氮基-4-(苄氧基)-5-(苄氧基甲基)-3-氟-四氢呋喃-2-醇之外，使用与内酯化合物C1相同的程序来制备内酯化合物D1。
实施例5：中间体1的制备
将C1(10g，21.6mmol)、2,4-二乙氧基嘧啶(3.64g，21.6mmol)和对甲苯磺酸(2g，11.6mmol)加入反应瓶中，加入1,2-二氯乙烷(300ml)充分搅拌溶解，挥发干溶剂后至微波炉中设置功率为280W加热4分钟，反应完毕后加入热乙醇(400ml)，冷却结晶，过滤得中间体1(8.79g，75％收率)。
实施例6：中间体2的制备
将中间体1(5g,9.2mmol)溶解在氨-甲醇溶液(80ml)中，置不锈钢封管中密封，油浴加热至110℃反应12小时。反应完成后将反应液蒸干，残余物用水重结晶，得中间体2(4.0g，85％收率)。
实施例7：中间体3的制备
取中间体2(5g，9.7mmol)、DMF(50ml)、M1(2.95g，10.7mmol)和三乙胺(4.07g，40.3mmol)加入反应瓶中搅拌，然后室温分若干批加入氯化汞(3.16g，11.6mmol)，室温下搅拌过夜，过滤固体。用50ml水稀释滤液，然后用2×100ml乙酸乙酯萃取。经无水硫酸钠干燥合并有机层，然后在真空下浓缩，在硅胶柱上纯化残余物，得中间体3(6.6g，95％收率)
实施例8：中间体4的制备
将中间体3(5.0g，6.6mmol)溶解在二氯甲烷(50ml)中，加入三氟乙酸(7.5ml)。在40℃搅拌过夜，冷却，用100ml碳酸氢钠溶液洗涤二氯甲烷层，分层，二氯甲烷层干燥，减压浓缩，得中间体4(2.9g，80％收率)。
实施例9：中间体5的制备
采用实施例5中间体1的方法来制备中间体5，将D1代替C1。
实施例10：中间体6的制备
采用实施例6中间体2的方法来制备中间体6，将中间体5代替中间体1。
实施例11：中间体7的制备
采用实施例7中间体3的方法来制备中间体7，将中间体6代替中间体2。
实施例12：中间体8的制备
采用实施例8中间体4的方法来制备中间体8，将中间体7代替中间体3。
实施例13：中间体9的制备
采用实施例5中间体1的方法来制备中间体9，将2,4-二乙氧基-5-氟嘧啶代替2,4-二乙氧基嘧啶。
实施例14：中间体10的制备
采用实施例6中间体2的方法来制备中间体10，将中间体9代替中间体1。
实施例15：中间体11的制备
采用实施例7中间体3的方法来制备中间体11，将中间体10代替中间体2。
实施例16：中间体12的制备
采用实施例8中间体4的方法来制备中间体12，将中间体11代替中间体3。
实施例17：中间体13的制备
采用实施例5中间体1的方法来制备中间体13，将2,4-二乙氧基-5-氟嘧啶代替2,4-二乙氧基嘧啶；D1代替C1。
实施例18：中间体14的制备
采用实施例6中间体2的方法来制备中间体14，将中间体13代替中间体1。
实施例19：中间体15的制备
采用实施例7中间体3的方法来制备中间体15，将中间体14代替中间体2。
实施例20：中间体16的制备
采用实施例8中间体4的方法来制备中间体16，将中间体15代替中间体3。
实施例21：化合物1的制备
取中间体4(5.0g，9.0mmol)加入氢化反应釜，再加入乙醇(20ml)和钯碳(0.05g)。用氮气置换5遍，再用氢气置换5遍，升温至50℃反应4小时。反应结束后过滤反应液，减压浓缩滤液，得化合物1(2.3g，91％收率)。
实施例22：化合物2的制备
采用实施例21化合物1的方法来制备化合物2，将中间体8代替中间体4。
实施例23：化合物3的制备
采用实施例21化合物1的方法来制备化合物3，将中间体12代替中间体4。
实施例24：化合物4的制备
采用实施例21化合物1的方法来制备化合物4，将中间体16代替中间体4。
实施例25：化合物5的制备
取盐酸羟胺(38.97g，560.9mmol)在水(200ml)中的溶液，并用少量NaOH水溶液(10％w/w)将其调节至pH＝5。将该溶液和中间体5(10.0g，35mmol)加入反应瓶中，在55℃搅拌加热16h。将混合物冷却至室温，转移至圆底烧瓶中，减压浓缩。将残余物悬浮在甲醇中并固定在硅藻土上，过柱纯化，得化合物5(4.74g，收率45％)。
实施例26：化合物6的制备
采用实施例25化合物5的方法来制备化合物6，将化合物2代替化合物1。
实施例27：化合物7的制备
采用实施例25化合物5的方法来制备化合物7，将化合物3代替化合物1。
实施例28：化合物8的制备
采用实施例25化合物5的方法来制备化合物8，将化合物4代替化合物1。
实施例29：化合物9的制备
向反应瓶中加入化合物1(10g，35mmol)、三乙胺(7ml)和四氢呋喃(100ml)降温至-20℃，然后加入异丁酰氯(7.5g，70mmol)保温反应。反应完毕后减压浓缩，残余物中加入100ml乙酸乙酯和50ml水，用盐酸调节pH至5，萃取分液，有机相用硫酸钠干燥，加压浓缩，残余物采用柱洗脱纯化，得化合物9(9.45g，76％收率)。
实施例30：化合物10的制备
采用实施例29化合物9的方法来制备化合物10，将化合物2代替化合物1。
实施例31：化合物11的制备
采用实施例29化合物9的方法来制备化合物11，将化合物3代替化合物1。
实施例32：化合物12的制备
采用实施例29化合物9的方法来制备化合物12，将化合物4代替化合物1。
实施例33：化合物13的制备
采用实施例29化合物9的方法来制备化合物13，将化合物5代替化合物1。
实施例34：化合物14的制备
采用实施例29化合物9的方法来制备化合物14，将化合物6代替化合物1。
实施例35：化合物15的制备
采用实施例29化合物9的方法来制备化合物15，将化合物7代替化合物1。
实施例36：化合物16的制备
采用实施例29化合物9的方法来制备化合物16，将化合物8代替化合物1。
实施例37：化合物17的制备
取化合物1(10g，35mmol)和无水磷酸三甲酯(100ml)中并在N2下在0℃下搅拌溶液。将甲基咪唑(8.62g，105mmol)加入溶液中。将A1(18.25g，52.5mmol)溶解在无水四氢呋喃中滴加到反应液中，反应完成后，用乙酸乙酯稀释反应液，并用饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤，经无水硫酸钠干燥，过滤减压浓缩，残余物经柱洗脱纯化，得化合物17(8.14g，39％收率)。
实施例38：化合物18的制备
采用实施例37化合物17的方法来制备化合物18，将化合物2代替化合物1。
实施例39：化合物19的制备
采用实施例37化合物17的方法来制备化合物19，将化合物3代替化合物1。
实施例40：化合物20的制备
采用实施例37化合物17的方法来制备化合物20，将化合物4代替化合物1。
实施例41：化合物21的制备
采用实施例37化合物17的方法来制备化合物21，将化合物5代替化合物1。
实施例42：化合物22的制备
采用实施例37化合物17的方法来制备化合物22，将化合物6代替化合物1。
实施例43：化合物23的制备
采用实施例37化合物17的方法来制备化合物23，将化合物7代替化合物1。
实施例44：化合物24的制备
采用实施例37化合物17的方法来制备化合物24，将化合物8代替化合物1。
实施例45：化合物25的制备
向反应瓶中加入化合物1(10g，35mmol)和四氢呋喃(100ml)，冰浴冷却。缓慢滴加1M叔丁基氯化镁(40ml)。滴加完毕室温搅拌反应2小时。然后加入B1(26.6g，52.5mmol)，室温搅拌下反应24小时。反应完毕后将反应液加入到200ml乙酸乙酯中，用碳酸氢钠水溶液洗涤，萃取分层，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物采用柱洗脱纯化，得化合物25(13.9g，65％收率)。
实施例46：化合物26的制备
采用实施例45化合物25的方法来制备化合物26，将化合物2代替化合物1。实施例47：化合物27的制备
采用实施例45化合物25的方法来制备化合物27，将化合物3代替化合物1。
实施例48：化合物28的制备
采用实施例45化合物25的方法来制备化合物28，将化合物4代替化合物1。
实施例49：化合物29的制备
采用实施例45化合物25的方法来制备化合物29，将化合物5代替化合物1。
实施例50：化合物30的制备
采用实施例45化合物25的方法来制备化合物30，将化合物6代替化合物1。
实施例51：化合物31的制备
采用实施例45化合物25的方法来制备化合物31，将化合物7代替化合物1。
实施例52：化合物32的制备
采用实施例45化合物25的方法来制备化合物33，将化合物8代替化合物1。
实施例53：化合物33的制备
向反应瓶中加入化合物1(10g，35mmol)、三乙胺(7ml)和四氢呋喃(100ml)降温至20℃，然后加入异丁酰氯(7.5g，70mmol)保温反应。反应完毕后减压浓缩，残余物中加入100ml乙酸乙酯和50ml水，用盐酸调节pH至5，萃取分液，有机相用硫酸钠干燥，加压浓缩，残余物采用柱洗脱纯化，得化合物33(13.18g，76％收率)。
实施例54：化合物34的制备
采用实施例52化合物33的方法来制备化合物34，将化合物5代替化合物1。
实施例55：抗病毒活性
本文考虑的疑似含病毒的样品包括天然或人造材料如活生物体、组织或细胞培养物；生物样品如生物材料样品(血液、血清、尿、脑脊髓液、泪液、痰、唾液、组织样品等)；实验室样品；食品、水或空气样品；生物制品样品如细胞提取物，特别是合成所需糖蛋白的重组细胞等。通常，样品疑似含诱导病毒感染的生物体，常常是病原生物体如肿瘤病毒。可将样品包含在住何介质中，包括水和有机溶剂/水混合物。样品包括活生物体如人、及人造材料如细胞培养物。
如果需要，可通过任何方法来观察施用组合物后化合物的抗病毒活性，所述方法包括检测此类活性的直接和间接方法。检测此类活性的定量、定性和半定量方法均涵盖在内。通常采用上述筛选方法中之一，然而，任何其它方法(如观察活生物体的生理特性)也适用。
可使用己知的标准筛选方案来测量化合物的抗病毒活性。例如，可使用以下一般方案来测量化合物 的抗病毒活性。
呼吸道病毒(2019-nCoV)抗病毒活性和细胞毒性试验
抗2019-nCoV活性
对抗2019-nCoV的抗病毒活性在Hep-2细胞中使用感染性细胞病变细胞保护试验测定。在此试验中，抑制病毒感染和/或复制的化合物针对病毒诱导的细胞杀灭产生细胞保护作用，其可用细胞活力试剂定量。这里使用的技术为出版的文献(Chapman et al.，Antimicrob Agents Chemother.2007，51(9)：3346-53)中描述的方法的新的改进。
自ATCC(Manassas，VI)获得Hep-2细胞并保持在补充有10％胎牛血清和青霉素/链霉索的MEM培养基中。使细胞每周传代两次并保持在亚融合阶段。在化合物测试储备液2019-nCoV菌株进行滴定以确定在Hep-2细胞中生成所需细胞病变效应的病毒储备液的适宜稀释度。
为进行抗病毒试验，让Hep-2细胞在大的细胞培养瓶中生长到接近融合但未完全融合。将待测试的化合物在384-孔化合物稀释板中，以8或40个样品/板的标准化剂量响应形式预稀释于DMSO中。在板中制备各试验化合物的以三倍增量连续稀释的样品并经由声学转移装置(Echo，Labcyte)将试验样品以100nl/孔转移到细胞培养试验384-孔板中。每一化合物稀释液以单份或一式四份样品转移到干燥的试验板中，其被贮存直至试验即将开始。阳性和阴性对照以垂直的区块(1列)布置在板的相反端部。
随后，使用先前通过滴定确定的适宜稀释度的细胞密度为50000/ml的病毒储备液制备感染性混合物并经由自动化设备以20Ul/孔加到具有化合物的试验板。每一个板包含阴性和阳性对照(每一板16个平行样)以分别产生0％和100％病毒抑制标准。在用2019-nCoV感染后，将试验板于37℃细胞培养培育器中培育4天。培育后，向试验板加入细胞活力试剂Cell TiterGIo(Promega，Madison，WI)，将其短暂培育，然后在所有试验板中测量(Envision，Perkin Elmer)荧光读数。自剩余细胞活力水平确定2019-nCoV诱导细胞病变效应抑制百分数。相对于0％和100％抑制对照对每一受试浓度计算这些数，并通过非线性回归以抑制50％的2019-nCoV诱导细胞病变效应的浓度确定EC50值。使用各种有效的抗2019-nCoV工具化合物作为抗病毒活性的阳性对照。
在Hep-2细胞中的细胞毒性试验
使用细胞活力试剂以与先前针对其它细胞类型所述(Cihlar et al.，Antimicrob Agents Chemother.2008，52(2)：655-65)相似的方式与抗病毒活性平行地在未受感染的Hep-2细胞中测定受试化合物的细胞毒性。对于化合物细胞毒性的测量，采用与抗病毒活性的测定相同的方案，不同的是细胞不受2019-nCoV感染。相反，向也以100nl/样晶的包含预稀释化合物的板以20ul/孔加入相同密度的未受感染的细胞混合物。然后将试验板培育4天，随后使用相同的CeIITiter Glo试剂加入量进行细胞活力测试并测量荧光读数。未经处理的细胞和经2Um嘌呤霉素处理的细胞分别充当100％和0％细胞活力对照。相对于0％和100％对照，对每一受试化合物浓度计算细胞活力百分数，并通过非线性回归以将细胞活力降低50％的化合物浓度确定CC50值。
在MT-4细胞中的细胞毒性试验
自NIH AIDS Research and Reference Reagent Program(Germantown,MD)获得MT-4细胞系并在补充有10％FBS、100单位/Ml青霉素、100单位/ml链霉素和2mMl-谷氨酰胺的RPMI-1640培养基(Irvine Scientific，Santa Ana，CA，Cat#9160)中培养。使MT-4细胞每周传代两次以保持细胞密度低于0.6x106细胞/Ml。将含100x浓度的3倍连续稀释化合物(26Nm至530Um)的完全RPMI-1640培养基一式四份接种到黑色384-扎板中。化合物加入后，使用MicroFIo液体分配器(BioTek，Winooski，VT)向每一孔中 加入2x103MT-4细胞并将细胞于37℃下在5％CO2培育器中培育5天。培育后，让细胞平衡至25℃并通过加入25Ul Cell-Titer Glo活力试剂来测定细胞活力。将混合物于25℃下培育10分钟，并在Victor荧光板读数器上对荧光信号定量。CC50值定义为由Cell-Titer Glo信号所确定的将细胞活力降低50％的化合物浓度。使用Pipeline Pilot Plate Data Analytics Collection软件(版本7.0，Accelrys，San Diego，CA)分析数据。CC50值通过由非线性回归分析使用4-参数反曲剂量-响应公式计算：Y＝底+(顶-底)/(1+10[(LogCC50-X)*坡度])，其中“顶”和“底”分别固定在100％和0％细胞活力处。CC50值计算为3个独立实验的平均值±标准偏差。如以下表1所示。
表1
根据上述结果可知，本发明的化合物EC50、HEp-2CC50、TM-4CC50浓度均优于对照化合物，说明发明的化合物的抑菌能力强于对照化合物且对正常细胞毒性较小。
2019-nCoV RNP制备
自以Mason et al(1)改进的方法制备2019-nCoV核糖核蛋白(RNP)复合物。以7.1×104个细胞/cm2的密度接种HEp-2细胞于MEM+10％胎牛血清(FBS)中并让在37℃(5％C02)下贴壁过夜。贴壁后，用2019-nCoV在35mL MEM+2％FBS中感染细胞。在感染后20小时，用补充有2ug/mL放线菌素D的MEM+2％FBS更换培养基并返回到37℃达一小时。然后用PBS洗涤细胞一次并用35mL PBS+250ug/mL溶血卵磷脂处理一分钟，其后吸出所有液体。通过将它们刮到1.2mL缓冲液A[50mM TRIS乙酸盐(pH8.0)、100mM醋酸钾、ImM DTT和2ug/mL放线菌素D]中来收集细胞并通过反复穿过18号针(10次)来发生溶解。将细胞溶解产物置于冰中10分钟并然后于4℃下在2400下离心10分钟。移除上清液(S1)并在补充有1％Triton X-100的600uL缓冲液B[10mM TRIS乙酸盐(pH8.0)、10mM醋酸钾和1.5mM MgCl2]中通过反复穿过18号针(10次)来破坏团块(PI)。将再悬浮的团块置于冰中10分钟并然后于4℃下在2400下离心10分钟。移除上清液(S2)并在补充有0.50/脱氧胆酸盐和0.10/吐温40的600uL缓冲液B中破坏团块(P2)。将再悬浮的团块置于冰中10分钟并然后于4℃下在2400下离心10分钟。收集包含富集的2019-nCoV RNP复合物的上清液(S3)部分并在280nm下通过UV吸光度确定蛋白质浓度。将等分的2019-nCoV RNP S3部分贮存于-80℃下。
2019-nCoV RNP试验
转录反应物在30uL反应缓冲液[50mM TRIS-乙酸盐(pH 8.0)、120mM醋酸钾，5％甘油，4.5mM MgCl2，3mM DTT，2mM乙二醇-双(2-氨基乙基醚)-四乙酸(EGTA)、50ug/mL BSA、2.5U Rnasin(Promega)、ATP、GTP、UTP、CTP和1.5uCi[a-32p]NTP(3000Ci/mmol)]中包含25ug粗RSV RNP复合物。转录试验中使用的放射性标记核苷酸选择为与评价2019-nCoV RNP转录抑制的核苷酸类似物匹配。以其KⅢ的一半的最终浓度(ATP＝20uM、GTP＝12.5uM、UTP＝6uM和CTP＝2uM)加入冷的竞争性NTP。剩余的三种核苷酸以100uM的最终浓度加入。
为确定核苷酸类似物是否抑制了2019-nCoV RNP转隶，使用以5倍增量的6步连续稀释加入化合物。于30℃下培育90分钟后，用350uL Qiagen RLT裂解缓冲液停止RNP反应并使用Qiagen RNeasy 96试剂盒纯化RNA。将纯化的RNA在负载RNA样品的缓冲液(Sigma)中于65℃下变性10分钟并在含2M甲醛的1.20/琼脂糖/MOPS凝胶上试验。干燥琼脂糖凝胶，并暴露于Storm磷光成像屏并使用Storm磷光成像剂(GE Healthcare)显影。通过两个平行样的非线性回归分析计算将总放射性标记转录物减少50％的化合物浓度(IC50)。如以下表2所示。
表2

根据上述结果可知，本发明的化合物半数抑制浓度均优于对照化合物，说明发明的化合物的抑菌能力强于对照化合物。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述。然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (7)

  1. 式(Ⅰ)的化合物或其药学上可接受的盐、立体异构体、前药或溶剂化合物:
    其中：
    R1为胍基或
    R2为氢、氘或卤素；
    R4为OH、OD、卤素或
    R5为OH、OD、卤素或
    R6为H、D、CN、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C4环烷基、叠氮基、C1-C2卤代烷基或卤素；
    R7为H、D、CN、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C4环烷基、叠氮基、C1-C2卤代烷基或卤素；
    R3选自H、
    其中：
    n选自1、2、3和4；
    R8选自C1-C8烷基、-O-C1-C8烷基、苄基、-O-苄基、-CH2-C3-C6环烷基、-O-CH2-C3-C6环烷基和CF3；
    R9选自苯基、1-萘基、2-萘基、
    R10选自H和CH3；
    R11选自H或C1-C6烷基；
    R12选自H、C1-C8烷基、苄基、C3-C6环烷基和-CH2-C3-C6环烷基；
    R13选自H、C1-C8烷基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R6为H、D、CN、甲基、乙基、乙烯基、乙炔基、叠氮基、三氟甲基或氟。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R7为H、D、CN、甲基、乙基、乙烯基、乙炔基、叠氮基、三氟甲基或氟。
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R3选自：H、
    其中：
    n选自1、2、3和4；
    R8选自C1-C8烷基、-O-C1-C8烷基、苄基、-O-苄基、-CH2-C3-C6环烷 基、-O-CH2-C3-C6环烷基和CF3；
    R9选自苯基、1-萘基、2-萘基、
    R10选自H和CH3；
    R11选自H或C1-C6烷基；
    R12选自H、C1-C8烷基、苄基、C3-C6环烷基和-CH2-C3-C6环烷基；
    R13选自H、C1-C8烷基。
  5. 根据权利要求1-4所述的化合物，该化合物包括如下结构：






  6. 一种药物制剂，所述药物制剂包含药学有效量的根据权利要求1至5任一项所述的化合物或其药学上可接受的盐及药学可接受的载体或辅料。
  7. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐在用于制备治疗人的肺病毒亚科病毒感染或冠状病毒感染的药物中的用途。
PCT/CN2023/075592 2022-07-21 2023-02-13 一种抗病毒感染的化合物及其制备方法和用途 WO2024016639A1 (zh)

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