WO2022156693A1 - Inhibiteur de protéase virale contenant une structure acétamide n-(sulfonyl substitué) et son utilisation dans des médicaments antiviraux - Google Patents

Inhibiteur de protéase virale contenant une structure acétamide n-(sulfonyl substitué) et son utilisation dans des médicaments antiviraux Download PDF

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WO2022156693A1
WO2022156693A1 PCT/CN2022/072682 CN2022072682W WO2022156693A1 WO 2022156693 A1 WO2022156693 A1 WO 2022156693A1 CN 2022072682 W CN2022072682 W CN 2022072682W WO 2022156693 A1 WO2022156693 A1 WO 2022156693A1
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hcov
cov
compound
virus
pharmaceutically acceptable
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PCT/CN2022/072682
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Chinese (zh)
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李行舟
徐雷
李松
钟武
曹瑞源
肖军海
周辛波
郑志兵
李微
樊士勇
肖典
王子豪
谢菲
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中国人民解放军军事科学院军事医学研究院
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Priority to CN202280008016.XA priority Critical patent/CN116685573A/zh
Publication of WO2022156693A1 publication Critical patent/WO2022156693A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides

Definitions

  • the invention belongs to the field of medicine and chemical industry, and relates to a class of compounds having N-(substituted sulfonyl) acetamide structure as a viral protease inhibitor, and its application in the preparation of antiviral drugs.
  • the present invention relates to a class of viral protease inhibitors containing N-(substituted sulfonyl) acetamide structures, their pharmaceutically acceptable salts, their isomers, their hydrates or their solvates, and their effects in inhibiting virus Application of protease, prevention and/or treatment of protease in the virus life cycle, mainly including but not limited to picorna virus and coronavirus, and the application in infectious diseases.
  • Picornaviruses and coronaviruses are single positive-stranded RNA viruses.
  • the picornavirus family mainly includes enteroviruses [Coxsackievirus (Coxsackievirus, CV), poliovirus (PV), enterovirus 71 (EV71 virus), etc.], human rhinovirus (HRV) and A. Hepatitis virus (HAV) etc. Enterovirus 71 and Coxsackie virus infection can cause herpetic angina and hand, foot and mouth disease in children, which can be life-threatening in severe cases. Poliovirus (PV) and hepatitis A virus (HAV) can cause polio (usually polio) and hepatitis A, respectively.
  • RhV Human rhinovirus
  • Rhinovirus belongs to the genus and is the most serotyped virus among human viruses. Rhinovirus is the main pathogen that causes the common cold. The virus is the main culprit in causing acute respiratory disease, and nearly half of all acute respiratory disease infections are caused by rhinovirus infections.
  • Coronavirus Coronavirus belongs to the genus Coronavirus in the family Coronaviridae of the order Nidovirales in the systematic taxonomy. It is the seventh known coronavirus that can infect humans. Among them, the 2019 novel coronavirus (SARS-CoV-2), the most harmful one, can cause novel coronavirus pneumonia COVID-19 and complications, and has caused a global pandemic. The remaining 6 species are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (which causes severe acute respiratory syndrome) and MERS-CoV (which causes Middle East respiratory syndrome).
  • SARS-CoV-2 2019 novel coronavirus
  • MERS-CoV which causes Middle East respiratory syndrome
  • the genome of some viruses first encodes a large polymeric precursor protein, which is then hydrolyzed by the polyprotein to produce functional proteins. This hydrolysis process is mainly completed by proteases. Most of the precursor proteins produced by single-positive-strand RNA viruses can only undergo subsequent replication and encapsulation after being hydrolyzed by 3C or 3CL protease to form functional proteins. A core protease that plays a crucial role in the replication of single positive-stranded RNA viruses.
  • picornaviruses first encode a large multimeric precursor protein, which is then hydrolyzed by 3C protease, while coronaviruses first encode two multimeric proteins (pp1a and pp1ab), and then the same Hydrolysis produces functional protein, and the hydrolysis process is mainly completed by 3CL protease.
  • the non-structural protein NS3/4A is mainly responsible for the hydrolysis of polyproteins. Similar proteases are also involved in the life cycle of non-single positive-stranded RNA viruses, such as human transcriptovirus (HIV).
  • 3C or 3CL protease is an important target for single positive-stranded RNA viroid drug therapy research. Despite the diversity of single positive stranded RNA virus genes, the 3C and 3CL protease substrate binding sites are highly conserved and have similar catalytic mechanisms, which are highly similar proteases in single positive stranded RNA viruses. Therefore, the research on broad-spectrum anti-single positive-strand RNA virus inhibitors targeting 3C and 3CL proteases has received extensive attention.
  • Both 3C and 3CL proteases are cysteine proteases with highly conserved three-dimensional structures. Although 3C and 3CL proteases have low sequence homology, structural-based sequence analysis found that the two types of proteases have a highly conserved Gly-X-Cys-Gly-Gly-Gly/Ser sequence structure, and the catalytic triad of 3C proteases has a highly conserved Gly-X-Cys-Gly-Gly-Gly/Ser sequence structure. His-Cys is almost identical to that of 3CL protease, indicating that the two types of proteases have highly conserved substrate binding sites and have similar catalytic mechanisms.
  • Rupintrivir (AG7088, Rupintrivirvr) was originally developed by Agouton Pharmaceutical Company, it is an irreversible specific inhibitor of human rhinovirus, is a peptide drug, it has a similar spatial structure to 3C protease substrate Therefore, it can compete with the substrate to bind to 3C protease and exert its inhibitory effect on the enzyme.
  • Lupintravir inhibited replication of 48 different HRV serotypes in H1-HeLA and MRC-5 cytoprotection assays with a mean EC50 of 0.023 ⁇ M. Lupintravir has immunomodulatory effects. Lupintravir has been reported in the literature to have a therapeutic effect on EV71-infected animals.
  • anti-HIV drugs include nelfinavir, saquibonvir, indinavir, amprenavir, ritonavir, lopinavir Navir, etc.
  • anti-HCV drugs include traprevir and boceprevir.
  • ritonavir/lopinavir was tried to treat the new crown ("Diagnosis and Treatment Plan for Pneumonia Infected by Novel Coronavirus (Trial Fifth Edition)").
  • the compounds with the N-(substituted sulfonyl)acetamide structure represented by the formula I involved in the present invention are effective viral protease inhibitors.
  • the present invention provides compounds of formula I and pharmaceutically acceptable salts, isomers, solvates thereof, or proteases used as components of pharmaceutical compositions for inhibiting viruses, including but not limited to 3C/3CL proteases, or prophylactic/ Treat one or more symptoms of a viral infection.
  • a first aspect of the present invention relates to a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof.
  • R 1 is C 1 -C 6 alkyl or cycloalkyl
  • R 2 is C 1 -C 6 alkyl or cycloalkyl, or fluorine, chlorine, bromine, iodine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, nitro substituted aromatic alkane ;
  • R 3 is selected from substituted or unsubstituted alkyl, aralkyl, and alkoxy, wherein the substituent is C 1 -C 6 alkyl or cycloalkyl, C 1 -C 6 alkoxy, halogen (fluorine (fluorine) , chlorine, bromine, iodine), cyano, alkynyl, cyano, nitro;
  • n 1-3.
  • the compound of Formula I its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate,
  • R 1 is C 1 -C 3 alkyl or cycloalkyl
  • R 2 is C 1 -C 6 alkyl or cycloalkyl, or fluorine-substituted benzene ring;
  • R3 is selected from substituted or unsubstituted benzyloxy, phenyl, indol-2-yl, benzimidazol-2yl, oxazol-5yl, imidazolyl, benzyl.
  • the substituent is selected from C 1 -C 6 alkyl or cycloalkyl, C 1 -C 6 alkoxy, halogen (fluorine, chlorine, bromine, iodine), cyano, alkynyl, nitro;
  • n 1-2.
  • the compound of formula I a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate or a solvate thereof:
  • R 1 is selected from methyl, ethyl, propyl and cyclopropyl
  • R 2 is selected from cyclopropyl, cyclohexyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl;
  • R 3 is selected from
  • n 1-2.
  • the cycloalkyl group is a C3 - C6 cycloalkyl group.
  • R 1 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
  • R1 is selected from methyl, ethyl, isopropyl, and cyclopropyl.
  • R 2 is selected from C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl, or a fluoro-substituted benzene ring.
  • R 2 is selected from cyclopropyl, cyclohexyl, isopropyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl.
  • R 3 is selected from the following groups optionally substituted with substituents: C 1 -C 6 alkyl, aralkyl, C 1 -C 6 alkoxy selected from: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen (fluorine, chlorine, bromine, iodine), cyano, alkynyl, nitro.
  • the arylalkyl group is selected from the group consisting of: benzyloxy, phenyl, indol-2-yl, benzimidazol-2yl, oxazol-5yl, imidazolyl, benzyl, isoindyl dolyl, [1,2,3]triazolyl, methylene-2,3-dihydrobenzo[1,4]dioxanyl, pyridyl-S-CH 2 -phenyl, benzyl -isoindolyl, morpholinyl-SO2 - phenyl.
  • R 3 is selected from
  • n 1
  • n 2.
  • Compounds of the present invention include, but are not limited to, compounds having a structure selected from the group consisting of:
  • the application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention, its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate; optionally, said pharmaceutical composition Also included is at least one pharmaceutically acceptable excipient, carrier, medium or adjuvant.
  • the pharmaceutical composition further comprises an EV71 antiviral agent; in certain embodiments, the EV71 antiviral agent is an antiviral agent selected from the group consisting of 3D protease inhibitors and VP1 protein inhibitors.
  • the pharmaceutical composition is for preventing/treating a disease in a subject associated with a viral infection selected from the group consisting of picornaviruses (eg, Enteroviruses, Human Rhinoviruses (HRV) and Hepatitis A virus (HAV)), as well as coronaviruses.
  • a viral infection selected from the group consisting of picornaviruses (eg, Enteroviruses, Human Rhinoviruses (HRV) and Hepatitis A virus (HAV)), as well as coronaviruses.
  • the enteroviruses include but are not limited to enterovirus 71 (EV71), poliovirus, coxsackievirus A, coxsackievirus B, and the coronaviruses include but are not limited to SARS-CoV-2, HCoV- 229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV.
  • the pharmaceutical composition is used to prevent/treat a disease associated with enterovirus 71 (EV71) infection or a disease associated with SARS-CoV-2 infection in a subject.
  • the subject is a mammal, eg, bovine, equine, porcine, canine, feline, rodent, primate. Among them, particularly preferred subjects are humans.
  • the present application also provides the use of the compound of the present invention, its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate in the preparation of a medicament, the medicament being a viral protease inhibitor.
  • the virus is selected from the group consisting of picornaviruses (eg, enteroviruses (eg, coxsackievirus (CV), poliovirus (PV), enterovirus type 71), human rhinoviruses (HRV) and hepatitis A virus (HAV), and coronaviruses (e.g., SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, and MERS-CoV).
  • enteroviruses eg, coxsackievirus (CV), poliovirus (PV), enterovirus type 71
  • HRV human rhinoviruses
  • HAV hepatitis A virus
  • the protease is a 3C/3CL protease.
  • the application also provides the use of the compound of the present invention, its pharmaceutically acceptable salts, its isomers, its hydrates or its solvates in the preparation of medicines, the medicines being antiviral drugs;
  • the virus against which the antiviral drug is directed is selected from picornaviruses (eg, enteroviruses (eg, coxsackievirus (CV), poliovirus (PV), enterovirus type 71), human rhinoviruses genus (HRV) and hepatitis A virus (HAV), as well as coronaviruses (e.g. SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV) .
  • enteroviruses eg, coxsackievirus (CV), poliovirus (PV), enterovirus type 71
  • HRV human rhinoviruses genus
  • HAV hepatitis A virus
  • coronaviruses e.g. SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-
  • the present application also provides the use of the compound of the present invention, its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate in the preparation of a medicament for preventing/treating a subject's infection with a virus
  • the virus is selected from the group consisting of picornaviruses such as enteroviruses, human rhinoviruses (HRV) and hepatitis A virus (HAV), and coronaviruses.
  • the enteroviruses include but are not limited to enterovirus 71 (EV71), poliovirus, coxsackievirus A, coxsackievirus B, and the coronaviruses include but are not limited to SARS-CoV-2, HCoV- 229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV.
  • the subject is a mammal, eg, bovine, equine, porcine, canine, feline, rodent, primate. Among them, particularly preferred subjects are humans.
  • the present invention provides a method for preventing/treating a disease associated with viral infection in a subject, comprising the steps of: adding a prophylactically/therapeutic effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, Its isomer, its hydrate or its solvate, or the pharmaceutical composition of the present invention is administered to the subject, and the virus is selected from picornaviruses (such as enteroviruses (such as Coxsackie virus ( CV), poliovirus (PV), enterovirus 71), human rhinovirus (HRV) and hepatitis A virus (HAV), and coronaviruses (e.g.
  • picornaviruses such as enteroviruses (such as Coxsackie virus ( CV), poliovirus (PV), enterovirus 71), human rhinovirus (HRV) and hepatitis A virus (HAV), and coronaviruses (e.g.
  • the subject is a mammal, eg, bovine, equine, porcine, canine, feline, rodent, primate. Among them, particularly preferred subjects are humans.
  • the application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I according to any one of the first aspects of the present invention, its pharmaceutically acceptable salt, its isomer, its hydrate or solvate, preferably,
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, specifically, the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation, or a compound preparation.
  • the application also provides the compound of formula I according to any one of the first aspect of the present invention, its pharmaceutically acceptable salts, its isomers, its hydrates or solvates as viral protease inhibitors in the preparation of antiviral drugs application.
  • the medicine comprising at least one compound of formula I or a pharmaceutically acceptable salt, isomer, solvate and at least one other excipient thereof, for use in the preparation of a medicine for the treatment of enterovirus infection, wherein , the enterovirus includes: enterovirus 71 (EV71), poliovirus, coxsackie virus A, coxsackie virus B.
  • enterovirus 71 EV71
  • poliovirus poliovirus
  • coxsackie virus A coxsackie virus B.
  • It comprises the described medicine of at least one compound of formula I or its pharmaceutically acceptable salt, isomer, solvate and at least one other excipient, as viral protease inhibitor in preparation for picorna virus and coronavirus application of antiviral drugs.
  • Said medicine comprising at least one compound of formula I or a pharmaceutically acceptable salt, isomer, solvate and at least one other excipient, in preparation for EV71 virus, SARS-CoV-2 virus, SARS Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Antiviral Drug Application.
  • a pharmaceutical composition comprising an effective amount of the inhibitor of formula I and a pharmaceutically acceptable carrier medium or adjuvant thereof.
  • the pharmaceutical composition further comprises an EV71 antiviral agent, the EV71 antiviral agent is an antiviral agent selected from 3D protease inhibitors and VP1 protein inhibitors.
  • C 1 -C 6 alkyl refers to straight or branched chain alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, Tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, etc.; C1-C3 alkyl can also be similarly understood. Preferred are C1 - C3 alkyl groups.
  • cycloalkyl preferably refers to cycloalkyl groups having 3-6 carbon atoms.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-oxyhexyl, etc. ; C 1 -C 3 alkoxy can also be understood similarly. Preferred are C 1 -C 3 alkoxy groups.
  • solvate refers to a substance formed by the association of a compound with a solvent molecule, such as an organic solvent (eg, methanol, ethanol, propanol, acetonitrile, etc.), and the like.
  • a solvent molecule such as an organic solvent (eg, methanol, ethanol, propanol, acetonitrile, etc.), and the like.
  • hydrate refers to a substance formed by the association of a compound with a water molecule.
  • pharmaceutically acceptable salts refers to salts of compounds of formula I which are suitable for tissue contact in humans and animals without toxicity, irritation, allergic reactions, etc. in normal medical treatment. Generally water- or oil-soluble, or readily dispersible, and effective in their use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable acid addition salts refers to maintaining biological activity and the properties of a free base, and being non-biologically or otherwise undesirable, which interact with inorganic acids such as sulfuric, nitric, phosphoric, hydrochloric, hydrobromic Acid, sulfamic acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, cinnamic acid, citric acid, maleic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid Acid, glycolic acid, malic acid, lactic acid, malonic acid, oxalic acid, niacin, succinic acid, salicylic acid, stearic acid, tartaric acid, p-aminobenzenesulfonic acid, trimethylbenzenesulfonic acid, p-toluene Salts of sulfonic acid
  • pharmaceutically acceptable base addition salts refers to maintaining biological activity and properties of the free acid, and which are non-biologically or otherwise undesirable, formed with inorganic bases such as ammonia or ammonium or metal cations such as sodium , magnesium, copper, zinc, calcium, potassium, aluminum and other hydroxides or carbonates formed salts, particularly preferred are ammonium, potassium, sodium, calcium, magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, quaternary ammonium compounds, substituted amines including natural substituted amines, cyclic amines and base ion exchange resins, Such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tripropylamine, isopropylamine, tributylamine, ethanolamine, diethanolamine, diethanolamine Cyclohexylamine, Lysine, Arginine, Histidine, Caffeine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine.
  • methylamine dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tripropylamine, isopropylamine, tributylamine, ethanolamine, diethanolamine, diethanolamine Cyclohe
  • the present invention also relates to a medicament comprising at least one compound according to the invention, preferably together with one or more pharmacologically acceptable excipients or carriers, and also to its use for the aforementioned purposes.
  • Pharmaceutical carriers herein include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, saturated vegetable matter Partial glyceride mixtures of fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fibers Base material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • the active ingredient may have systemic and/or local action and, therefore, may be administered by a suitable route such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal Skin, conjunctiva, topical administration or in the form of implants.
  • a suitable route such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal Skin, conjunctiva, topical administration or in the form of implants.
  • the active ingredient can also be administered in administration forms suitable for these routes of administration.
  • Suitable for oral administration are the well-known forms of administration which can deliver the active ingredient rapidly and/or in a modified manner, such as solid preparations such as tablets (uncoated or coated, such as with an enteric coating or molybdenum). coated tablets), capsules, sugar-coated tablets, granules, pellets, powders, liquid preparations such as emulsions, suspensions, and aerosols.
  • parenteral administration it is possible to avoid the absorption step (intravenous, intraarterial, intracardiac, intraspinal or lumbar intramedullary administration) or to include absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration) .
  • Administration forms suitable for parenteral administration are especially formulations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders for injection and infusion.
  • Suitable for other routes of administration are, for example, medicaments for inhalation (especially powder inhalation, spray), nasal drops/solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, for Ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaker mixtures), lipophilic suspensions, ointments, creams, lotions, pastes, dusting powders, or implants such as stents mold.
  • the active ingredient can be converted into the stated administration forms by methods known per se. This can be accomplished with inert nontoxic suitable pharmaceutical excipients. It includes, inter alia, carriers (eg, microcrystalline cellulose), solvents (eg, liquid polyethylene glycols), emulsifiers (eg, sodium lauryl sulfate), dispersants (eg, polyvinylpyrrolidone), synthetic and natural biopolymers (eg proteins), stabilizers (eg antioxidants and ascorbic acid), colorants (eg inorganic pigments such as iron oxide) or flavoring and/or taste masking agents. Where appropriate, the active ingredient may be in microencapsulated form in one or more of the aforementioned carriers.
  • carriers eg, microcrystalline cellulose
  • solvents eg, liquid polyethylene glycols
  • emulsifiers eg, sodium lauryl sulfate
  • dispersants eg, polyvinylpyrrolidone
  • synthetic and natural biopolymers e
  • N-Boc-L-dimethyl glutamate 1-1 (12.0 g, 43.6 mmol) was dissolved in anhydrous THF (100 mL) solution, cooled to -78°C, and bis(trimethylsilyl) was added dropwise Lithium amide (LiHDMS) (94 mL, 1M in THF) solution, the mixture was stirred at -78 °C for 1 h, then bromoacetonitrile (3.24 mL, 46.6 mmol) was added dropwise to the reaction solution at -78 °C, at -78 °C The reaction was carried out for 4 hours.
  • LiHDMS Lithium amide
  • step 1 (3S,6S,8S)-2-[2-(1-(3-fluorobenzyl)-1H-indole-5-carboxamido)-1-carbonyl-3-(4-fluorophenyl) )]-propylamino-3-(2-carbonyl-3-pyridinyl)-propionic acid methyl ester (26-2) synthesis
  • step 1 (3S,6S,8S)-2-[2-(4-Fluoro-3-(morpholinosulfonyl)benzamido)-1-carbonyl-3-(4-fluorophenyl)]- Synthesis of propylamino-3-(2-carbonyl-3-pyridinyl)-propionic acid methyl ester (28-2)
  • MRC-5 cells were plated at 10,000 cells per well using phenol red-free MEM (Gibco). Various concentrations of compounds (320, 100, 33, 10, 3.3, 1.0, 0.3 or 0.1 ⁇ M) were added and cells were infected with a dose of SARS_CoV-2, or mock infection with vehicle alone. After 4 days, cell viability was determined using the XTT dye reduction method. Data are expressed as a percentage of neutral red or luminescent signal in compound-treated wells compared to the signal in uninfected compound-free wells. The EC 50 and CC 50 of the compounds were calculated accordingly.

Abstract

L'invention concerne un composé représenté par la formule I contenant une structure acétamide N-(sulfonyl substitué), un sel, un isomère, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci, et son utilisation en tant qu'inhibiteur de protéase virale dans la préparation de médicaments antiviraux. Le composé peptidique selon l'invention a des effets inhibiteurs forts sur la protéase 3CL du coronavirus et la protéase 3C des picornavirus (tels que le virus EV71 d'entérovirus). Des tests d'activité au niveau cellulaire montrent que le composé de structure acétamide N-(sulfonyl substitué) a un effet inhibiteur évident sur les picornavirus (tels que le virus EV71 d'entérovirus), les coronavirus, et analogues. Le composé représenté par la formule (I) contenant une structure acétamide N-(sulfonyl substitué) peut produire un effet inhibiteur viral au niveau cellulaire par inhibition de l'activité de protéases virales, et a de bonnes perspectives d'application dans des médicaments antiviraux.
PCT/CN2022/072682 2021-01-19 2022-01-19 Inhibiteur de protéase virale contenant une structure acétamide n-(sulfonyl substitué) et son utilisation dans des médicaments antiviraux WO2022156693A1 (fr)

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