WO2023226822A1 - Procédé d'utilisation d'un dérivé d'azétidine pour traiter des infections virales et utilisation - Google Patents

Procédé d'utilisation d'un dérivé d'azétidine pour traiter des infections virales et utilisation Download PDF

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WO2023226822A1
WO2023226822A1 PCT/CN2023/094492 CN2023094492W WO2023226822A1 WO 2023226822 A1 WO2023226822 A1 WO 2023226822A1 CN 2023094492 W CN2023094492 W CN 2023094492W WO 2023226822 A1 WO2023226822 A1 WO 2023226822A1
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methyl
independently selected
compound
once
patient
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PCT/CN2023/094492
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English (en)
Chinese (zh)
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唐夕岚
苏东海
袁晓曦
和成华
宋宏梅
蔡晓莉
欧阳学农
葛均友
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四川科伦博泰生物医药股份有限公司
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Publication of WO2023226822A1 publication Critical patent/WO2023226822A1/fr

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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • 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

Definitions

  • the present invention relates to the use of azetidine derivatives as Janus kinase (JAK) inhibitors in the treatment of viral infection-related diseases, particularly the use of azetidine derivatives as Janus kinase (JAK) inhibitors in the treatment of coronavirus. Use in diseases related to viral infections.
  • JK Janus kinase
  • Viral infection seriously threatens human health. Viruses can invade the body through multiple ways, such as respiratory tract infection, genitourinary system infection, and digestive tract infection, and proliferate in susceptible host cells. Viral infection is a process of interaction between the virus and the body, and between the virus and susceptible cells. Viral infection produces varying degrees of damage or viral diseases depending on the type of virus and individual differences in the human body.
  • Coronaviruses are single-stranded RNA enveloped viruses, which are divided into four categories: ⁇ , ⁇ , ⁇ and ⁇ .
  • the ⁇ category can be divided into four subgroups A-D. So far, 6 viral molecules (except SARS-CoV-2) have been discovered, each of which can cause different types of diseases.
  • the main clinical manifestations are upper respiratory tract and gastrointestinal tract infections. SARS and MERS virus infections can cause pneumonia, kidney failure and other serious organ damage and death. According to statistics, the patient mortality rates caused by SARS and MERS are 9% and 36% respectively.
  • Coronavirus particles are covered with a fatty membrane, and there are three types of glycoproteins on the membrane surface: spike glycoprotein (S protein, which is the receptor binding site, cell lysis and main antigenic site), small envelope glycoprotein ( E protein, Envelope protein, a smaller protein that binds to the envelope), M protein, Membrane protein, which is responsible for the transport of nutrients across the membrane and the budding of new viruses. release and formation of the viral envelope).
  • S protein spike glycoprotein
  • E protein Envelope protein, a smaller protein that binds to the envelope
  • M protein Small envelope glycoprotein
  • Membrane protein which is responsible for the transport of nutrients across the membrane and the budding of new viruses. release and formation of the viral envelope.
  • the envelope of the beta group A coronavirus also has a shorter spike protein, namely hemagglutininesterase (HE protein).
  • HE protein hemagglutininesterase
  • N protein nulceocapsid phosphor protein
  • a first aspect of the present invention provides compounds of formula (I), pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof for the preparation of preventive and/or therapeutic Use in medicines for viral infections,
  • R 1 is selected from C(O)R 8 and S(O) 2 R 9 ;
  • R 2 is selected from H, CN, halogen and C 1-6 alkyl
  • R 5 , R 6 and R 7 are each independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy and C(O)NR 10 R 11 ;
  • a third aspect of the present invention provides compounds of the above formula (I), pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof, which are used for prevention and/or Treat related diseases caused by viral infections.
  • R2 is selected from H, CN, F and methyl.
  • R2 is selected from H and methyl.
  • R 3 and R 4 are each independently selected from H, F, Cl and CN.
  • R 3 and R 4 are H.
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, CN, methyl, ethyl, methoxy and C(O )NH 2 .
  • R 5 is H, F, Cl, CN, methyl or C(O)NH 2 ;
  • R 6 is H, Cl, CN, methyl or methoxy
  • R 8 and R 9 are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl group, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl and N(CH 3 ) 2 , wherein each of the above groups is optionally selected from 1, 2 or 3 independently from F, CN Substituted with methyl substituents.
  • each occurrence of R 10 and R 11 is independently selected from H, methyl and ethyl.
  • the present invention provides compounds, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof in the preparation of compounds for the prevention and/or treatment of viral infections.
  • said compound is selected from:
  • the compound of formula (I) is:
  • the pharmaceutically acceptable salts include selected from the group consisting of aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclic Hexamethonate Salt, ethanesulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethyl sulfonate Acid, lactate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, naphthalene Acid, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glycosate, stearate, tannin, xinafoate, aluminum salt, arginine Salt, benza
  • the virus is a coronavirus.
  • the coronavirus is selected from any one of SARS-CoV-1, SARS-CoV-2, MERS, 229E, NL63, OC43, HKU1 or a combination thereof.
  • the coronavirus is SARS-CoV-2.
  • the medicine of the present invention also includes pharmaceutically acceptable excipients.
  • the excipients include any one or a combination of two of excipients, diluents, carriers, flavoring agents, binders or fillers.
  • the carriers include liposomes. , micelles, microspheres or microcapsules, etc.
  • the dosage form of the medicine of the present invention includes tablets, capsules, granules, powders or injections.
  • Each dosage form of medicine can be prepared according to conventional methods in the pharmaceutical field.
  • the pharmaceutical dosage form of the present invention is a capsule.
  • the pharmaceutical dosage form of the present invention is a capsule
  • the capsule specifications i.e., the compound of formula I contained in each capsule, its pharmaceutically acceptable salts, stereoisomers, polymorphs form, solvate, metabolite or prodrug
  • 0.1-50 mg such as 0.1-20 mg, e.g.
  • 0.2-10 mg such as 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg, such as 0.5 mg, 1 mg or 2 mg.
  • the drug also includes one or more other therapeutic drugs.
  • the one or more other therapeutic drugs are selected from one or more of antiviral drugs, hormonal drugs, immune drugs, anticoagulant drugs, Chinese herbal medicines, etc.
  • the antiviral drugs include Imdevimab, Casirivimab, Monupivir, Remdesivir, Lopinavir, Ritonavir, Nematvir, Hydroxychloroquine, Chloroquine Phosphate, Azizumab One or more of vudine, alpha-interferon, ribavirin, arbidol, tofacitinib, etc.
  • the hormonal drugs include corticosteroids and the like, such as methylprednisolone, dexamethasone and the like.
  • the immune drugs include COVID-19 human immunoglobulin, tocilizumab, etc.
  • the anticoagulant drug includes low molecular weight heparin, unfractionated heparin, etc.
  • the Chinese herbal medicine includes one or more of Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Shufeng Jiedu Capsules, Qingfei Paidu Decoction, etc.
  • the compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is present in an amount of less than about 100 nM, for example less than about 90 nM , 80nM, 70nM, 60nM, 50nM, 40nM, 30nM, 20nM, 19nM, 18nM, 17nM, 16nM, 15nM, 14nM, 13nM, 12nM, 11nM, 10nM or less inhibit AAK1 with IC50 .
  • the compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is present in an amount of less than about 1000 nM, for example less than about IC50 inhibits GAK at 950nM, 900nM, 850nM, 800nM, 750nM, 700nM, 650nM, 600nM, 550nM, 500nM, 450nM, 400nM, 350nM, 340nM, 330nM, 320nM, 310nM, 300nM or less.
  • the prevention and/or treatment includes administering to the patient a prophylactically or therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, polymorphs, solvents
  • the compound, metabolite or prodrug is preferably administered at a daily dose of 0.0001-100mg/kg body weight, and the preferred dose is 0.0001-100mg/kg, 0.0001-90mg/kg, 0.0001-80mg/kg, 0.0001-70mg daily /kg, 0.0001-60mg/kg, 0.0001-50mg/kg, 0.0001-40mg/kg, 0.0001-30mg/kg, 0.0001-20mg/kg, 0.001-100mg/kg, 0.001-90mg/kg, 0.001-80mg/kg , 0.001-70mg/kg, 0.001-60mg/kg, 0.001-50mg/kg, 0.001-40mg/kg, 0.001-30mg
  • the frequency of administration is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, once every five weeks, or once every six weeks.
  • the dosing cycle is 1-200d, such as 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d, 11d, 12d, 13d, 14d, 21d, 28d, 60d, 90d, 180d.
  • administration routes include oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is combined with one or more other therapeutic agents Combined administration.
  • the one or more other therapeutic drugs are selected from one or more of antiviral drugs, hormonal drugs, immune drugs, anticoagulant drugs, Chinese herbal medicines, etc.
  • the antiviral drugs include Imdevimab, Casirivimab, Monupivir, Remdesivir, Lopinavir, Ritonavir, Nematvir, Hydroxychloroquine, Chloroquine Phosphate, Azizumab One or more of vudine, alpha-interferon, ribavirin, arbidol, tofacitinib, etc.
  • the hormonal drugs include corticosteroids and the like, such as methylprednisolone, dexamethasone and the like.
  • the immune drugs include COVID-19 human immunoglobulin, tocilizumab, etc.
  • the anticoagulant drug includes low molecular weight heparin, unfractionated heparin, etc.
  • the Chinese herbal medicine includes one or more of Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Shufeng Jiedu Capsules, Qingfei Paidu Decoction, etc.
  • the patient is a COVID-19 patient.
  • the COVID-19 patients are asymptomatic, mild, common, severe, or critical patients.
  • the COVID-19 patient is a hospitalized COVID-19 adult patient requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
  • ECMO extracorporeal membrane oxygenation
  • the COVID-19 patient has at least one elevated inflammatory marker, such as CRP, D-dimer, LHD, ferritin, etc.
  • references to "or” herein mean the term “and/or” and may be used interchangeably with the term “and/or”.
  • alkyl is defined to include saturated aliphatic hydrocarbons, including straight and branched chains.
  • an alkyl group has 1 to 6, such as 1 to 4 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl (isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (e.g.
  • C 1-4 alkyl refers to a linear or branched fat of 1 to 4 carbon atoms Family hydrocarbon chain (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkoxy refers to a linear, branched or cyclic saturated monovalent hydrocarbon radical of the formula -O-alkyl, where the term “alkyl” is as defined above or as defined below "Cycloalkyl", such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentyloxy, isopentyloxy or n-hexyloxy, or their isomers.
  • cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl,
  • C 3-10 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms ( for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.
  • 3-10 membered heterocyclyl groups have 3-10 carbon atoms and heteroatoms in the ring.
  • Groups such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( dioxolinyl), pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • Aryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, additionally In each case it may be benzo-fused.
  • the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, etc. and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • aralkyl preferably means an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6 to 14 carbon atoms
  • the alkyl group may have 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted refers to one or more (e.g., one, two, three or four) hydrogens are replaced by a selection from the groups indicated, provided that the normal valencies of the atoms indicated in the present case are not exceeded and that said substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • the compounds of the invention may also contain one or more (eg one, two, three or four) isotopic substitutions.
  • H can be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C can be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O can be in any isotope form, including 16 O, 18 O, etc.
  • stereoisomer means an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers they may give rise to racemates, racemic mixtures, single enantiomers, diastereomers Conformational mixtures and individual diastereomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers).
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. wait. It is to be understood that the scope of this application encompasses all such products in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99 %) isomers or mixtures thereof.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs that, upon administration to a patient in need thereof, can directly or Compounds of the invention or metabolites or residues thereof are indirectly provided.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclamate, ethylenedisulfonate, ethanesulfonate , fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethionate, lactate, methyl sulfate, Naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/diphosphate Hydrogen salts, pyroglutamate, glycolates, stearates, tannins and xinofoate.
  • Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • the compounds of the invention may exist in the form of hydrates or solvates, wherein the compounds of the invention comprise as a structural element of the crystal lattice of the compound a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention ie compounds formed in the body upon administration of the drug.
  • the prodrugs of the invention can be prepared, for example, by using certain groups known to those skilled in the art (e.g. "pro-moieties” as described in H. Bundgaard, Design of Prodrugs (Elsevier, 1985)) are produced by replacing the appropriate functional groups present in the compounds of formula I.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered with a therapeutic agent and is suitable for contact with humans and/or within the scope of reasonable medical judgment. Tissues from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • compositions/medicines of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, Mineral oil, sesame oil, etc.
  • Water is an exemplary carrier when the pharmaceutical composition is administered intravenously.
  • Physiological saline and aqueous glucose and glycerol solutions may also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol etc.
  • the compositions may also, if desired, contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the compounds/compositions/drugs of the present invention may act systemically and/or locally.
  • they may be administered by suitable routes, for example by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, Administered as an ophthalmic preparation or by inhalation.
  • the compounds/compositions/medicaments of the invention may be administered in suitable dosage forms.
  • the dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, and aqueous suspensions. , injectable solutions, elixirs, syrups.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered, alleviates to a certain extent one or more symptoms of the condition being treated.
  • Dosage regimens can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
  • the amount of a compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day.
  • dosage levels no higher than the lower end of the foregoing ranges may be sufficient, while in other cases, larger dosages may still be employed without causing any deleterious side effects, provided that the larger dosage is first
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition/drug may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.1-300 mg, more preferably 0.1-150 mg, particularly preferably 0.3-50 mg, such as 0.5 mg, 1mg, 1.5mg, 2mg, 4mg, 10mg, 25mg wait.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Preventing such a disease or condition or one or more symptoms of such a disease or condition.
  • Subject as used herein includes humans or non-human animals.
  • exemplary human subjects include human individuals (referred to as patients) suffering from a disease, such as a disease described herein, or normal individuals.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • the terms "subject” and “patient” are used interchangeably herein.
  • PaO 2 /FiO 2 should be corrected according to the following formula: PaO 2 /FiO 2 ⁇ [760/atmosphere (mmHg)].
  • the structure of the compound is confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
  • the reaction is monitored by thin layer chromatography (TLC) or LC-MS.
  • TLC thin layer chromatography
  • the developing solvent systems used are: methylene chloride and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.
  • the eluent system includes: methylene chloride and methanol system and n-hexane and ethyl acetate system.
  • reaction temperature is room temperature (20°C to 30°C).
  • Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company Or companies like Tebo Chemical.
  • Step 1 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (8b)
  • Step 2 4-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b] Pyridine(8c)
  • Step 3 2-(1-(ethylsulfonyl)-3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (8d)
  • Step 4 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl) nitrogen Hetetane-3-yl)acetonitrile (8)
  • AAK1 and GAK are activated, thereby mediating virus entry into cells.
  • AAK1 and GAK Inhibitors prevent viruses from entering host cells.
  • AAK1 kinase (Tag-tagged), GAK kinase (Tag-tagged), Eu-tagged anti-Tag antibody, Alexa 647 dye-labeled tracers, etc., are all from Thermo Fisher Scientific.
  • compound 8 prepared in Example 1 and the control compound baricitinib were added to the 384-well plate respectively, so that the final concentrations were 10000nM, 3330nM, 1110nM, 370nM, 123nM, 41.2nM, 13.7nM, 4.57nM, and 1.52nM respectively. ,0.5nM.
  • kinase buffer and kinase/Eu-labeled anti-Tag antibody mixture The final concentration of GAK kinase is 5nM.
  • Alexa Tracer 236 labeled with 647 dye the final concentration is 100nM. After incubation at room temperature for 60 minutes, read using a fluorescence plate reader.
  • the 0% substitution rate control well did not add any inhibitor.
  • the GAK inhibitor Staurosporine was added to the 100% substitution rate control well.
  • Compound 8 prepared in Example 1 was added to a 384-well plate to a final concentration of 10000 nM, 3330 nM, 1110 nM, 370 nM, 123 nM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, and 0.5 nM. Then add kinase buffer and kinase/Eu-labeled anti-Tag antibody mixture. The final concentration of AAK1 kinase is 5nM. Then join Alexa 647 dye-labeled tracer Tracer222, the final concentration is 100nM. After incubation at room temperature for 60 minutes, read using a fluorescence plate reader.
  • the 0% substitution rate control well did not add any inhibitor.
  • the AAK1 inhibitor sunitinib was added to the 100% substitution rate control well.
  • IDBS XFfit was used to perform curve fitting on the substitution rate (the results are shown in Figure 1), and the IC 50 value of compound 8 for inhibiting kinase AAK1 was calculated to be 11.5nM.

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Abstract

La présente invention concerne le traitement d'infections virales, en particulier d'infections à coronavirus. Plus précisément, l'invention concerne un composé de formule I, un sel pharmaceutiquement acceptable, un stéréoisomère, un polymorphe, un solvate, un métabolite ou un promédicament de celui-ci, ou l'utilisation d'une composition le comprenant dans la préparation d'un médicament pour le traitement d'infections virales. La présente invention a un mécanisme d'action clair, une efficacité claire et une bonne inocuité, et offre davantage d'options de médication pour des patients.
PCT/CN2023/094492 2022-05-26 2023-05-16 Procédé d'utilisation d'un dérivé d'azétidine pour traiter des infections virales et utilisation WO2023226822A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017097224A1 (fr) * 2015-12-11 2017-06-15 四川科伦博泰生物医药股份有限公司 Dérivé d'azétidine, son procédé de préparation et son utilisation
WO2019090143A1 (fr) * 2017-11-03 2019-05-09 Aclaris Therapeutics, Inc. Analogues de pyrrolo[2,3-b]pyrimidine-5-carboxylate de pyrazolyle et leurs procédés de préparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017097224A1 (fr) * 2015-12-11 2017-06-15 四川科伦博泰生物医药股份有限公司 Dérivé d'azétidine, son procédé de préparation et son utilisation
WO2019090143A1 (fr) * 2017-11-03 2019-05-09 Aclaris Therapeutics, Inc. Analogues de pyrrolo[2,3-b]pyrimidine-5-carboxylate de pyrazolyle et leurs procédés de préparation

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Title
CHEN, CHONGXIANG ET AL.: "JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis", LEUKEMIA, vol. 35, 14 May 2021 (2021-05-14), XP037553405, DOI: 10.1038/s41375-021-01266-6 *
ELY E WESLEY, RAMANAN ATHIMALAIPET V, KARTMAN CYNTHIA E, DE BONO STEPHANIE, LIAO RAN, PIRUZELI MARIA LUCIA B, GOLDMAN JASON D, SAR: "Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial", THE LANCET. RESPIRATORY MEDICINE, ELSEVIER, OXFORD, vol. 10, no. 4, 11 February 2022 (2022-02-11), Oxford , pages 327 - 336, XP093111621, ISSN: 2213-2600, DOI: 10.1016/S2213-2600(22)00006-6 *
LIMEN RONAL YOSUA, SEDONO RUDYANTO, SUGIARTO ADHRIE, HARIYANTO TIMOTIUS IVAN: "Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis", EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, FUTURE DRUGS, LONDON, GB, vol. 20, no. 3, 4 March 2022 (2022-03-04), GB , pages 425 - 434, XP009550818, ISSN: 1478-7210, DOI: 10.1080/14787210.2021.1982695 *
STEBBING JUSTIN; PHELAN ANNE; GRIFFIN IVAN; TUCKER CATHERINE; OECHSLE OLLY; SMITH DAN; RICHARDSON PETER: "COVID-19: combining antiviral and anti-inflammatory treatments", THE LANCET INFECTIOUS DISEASES, ELSEVIER, AMSTERDAM, NL, vol. 20, no. 4, 27 February 2020 (2020-02-27), AMSTERDAM, NL , pages 400 - 402, XP086103993, ISSN: 1473-3099, DOI: 10.1016/S1473-3099(20)30132-8 *

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