WO2006042478A1 - Inhibiteurs de petites molecules de la protease principale des coronavirus, leur preparation et utilisation - Google Patents

Inhibiteurs de petites molecules de la protease principale des coronavirus, leur preparation et utilisation Download PDF

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WO2006042478A1
WO2006042478A1 PCT/CN2005/001748 CN2005001748W WO2006042478A1 WO 2006042478 A1 WO2006042478 A1 WO 2006042478A1 CN 2005001748 W CN2005001748 W CN 2005001748W WO 2006042478 A1 WO2006042478 A1 WO 2006042478A1
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group
compound
optionally substituted
aryl
formula
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PCT/CN2005/001748
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Chinese (zh)
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WO2006042478A8 (fr
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Zihe Rao
Haitao Yang
Xiaoyu Xue
Mark Bartlam
Kailin Yang
Dawei Ma
Weiqing Xie
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Tsinghua University
Shanghai Institute Of Organic Chemistry Chinese Academy Of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention provides a series of small molecule inhibitors designed based on the crystal structure of SARS coronavirus main protease, a preparation method thereof, a pharmaceutical composition comprising the same, and use thereof for preparing a medicament for treating or preventing various coronavirus infections .
  • Background technique
  • SARS Coronavirus A new type of coronavirus has been identified as the culprit of the Severe Acute Respiratory Sydrome (SARS) and is named SARS Coronavirus (abbreviated as SARS-CoV).
  • SARS coronavirus belongs to the genus “Nidovirales”, “Coronaviridae”, and “Coronavirus” in the species classification. It is a new variant of the coronavirus family, with a total length of 29,736 bp (Urbani Strain) o SARS is a potent infectious disease that poses a great threat to humans. There are no specific drugs and vaccines available.
  • the coronavirus family includes four types (Group).
  • Type I includes porcine transmissible gastroenteritis virus (TGEV), human coronavirus (HCoV) strain 229E, and feline infectious peritonitis virus (FIPV).
  • Type II includes Bovine coronavirus (BCoV), Murine hepatitis virus (MHV), etc.
  • Type III currently includes only three viruses, one of which is called avian infectious.
  • Avian Infectious Bronchitis Virus abbreviated as AIBV
  • SARS-CoV belongs to type IV.
  • Various coronaviruses pose a huge threat to the health of people and animals.
  • the genome of the SARS coronavirus encodes two large replicase polyproteins (replicase polyproteins) ppla (486 kDa) and pplab (790 kDa), these two proteins are encoded by the genome of 2/3 to 3/4 of the coronavirus. These two proteins are hydrolyzed to produce many functional subunits of the viral replication complex.
  • the main proteolytic enzyme of SARS coronavirus (main protease, abbreviated as M pro , molecular weight 33.8 kDa, sometimes called 3C-Like Protein) plays a very important role.
  • the main protease is also a segment of ppla and pplab, its release is achieved by autocatalytic hydrolysis, and autocatalytic hydrolysis occurs at the Gln S er , Al a ) site beside the protease, by trans-splicing (bi-molecular reaction) carry out.
  • the replicase polyproteins ppla and pplab are hydrolyzed into more than a dozen functional peptides, which further play a role. If it can inhibit the hydrolysis of SARS coronavirus main protease, it will effectively resist the infection of SARS coronavirus. Therefore, SARS coronavirus primary protease is an ideal target for anti-SARS drug design. Summary of invention
  • Another object of the present invention is to provide a process for the preparation of the small molecule inhibitor.
  • the invention provides a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof:
  • U is Wherein X is NH or CH 2; R, groups selected from the group consisting of: optionally substituted by halogen (6 ⁇ 0 ⁇ (preferably C 3 ⁇ C 6) alkyl with a carbonyl group, C 3 ⁇ C 6 cycloalkyl embankment a carbonyl group, optionally substituted by a C 6 ⁇ C 1() aryl group ( ⁇ 05 ⁇ oxycarbonyl, C 6 ⁇ .
  • halogen 6 ⁇ 0 ⁇ (preferably C 3 ⁇ C 6) alkyl with a carbonyl group, C 3 ⁇ C 6 cycloalkyl embankment a carbonyl group, optionally substituted by a C 6 ⁇ C 1() aryl group ( ⁇ 05 ⁇ oxycarbonyl, C 6 ⁇ .
  • R 2 is selected from the group consisting of: -C 6 (preferably -C 4 )alkyl and C 6 wherein the aryl group is optionally substituted by halogen, optionally substituted by C 6 -C 1Q aryl ⁇ C 1Q aryl
  • R 3 is selected from the group consisting of: -C 6 (preferably C, ⁇ C 4 ) wherein the aryl group is optionally substituted by halogen, optionally substituted by C 6 -C 1 () aryl a fluorenyl group, optionally ( ⁇ ( 4 alkyl-substituted C 6 -C 1Q aryl; group selected from the group consisting of: wherein the aryl group is optionally substituted by halogen, optionally C 6 -C 1 Q aryl substituted ⁇ C 6 (preferably ( ⁇ ( fluorenyl, C, optional
  • the invention also provides a process for the preparation of a compound of formula (I), which comprises the steps of:
  • step (b) condensing the product of step (a) with a compound of formula (III) in the presence of a condensing reagent to provide a compound of formula (I),
  • the definitions of the formulas, R 2 , R 4 and U are the same as defined in the above formula (I).
  • the invention provides a pharmaceutical composition comprising a compound of the above formula (I), or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.
  • the invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a coronavirus infection.
  • the test proves that the compound of the present invention can significantly inhibit the activity of the main protease of coronavirus such as TGEV, HCoV, FIPV, AIBV, SARS-CoV, and has a good application prospect in the preparation of a medicament for treating or preventing coronavirus infection.
  • the main protease of coronavirus such as TGEV, HCoV, FIPV, AIBV, SARS-CoV
  • Figure 1 is a surface view of the small molecule inhibitor N1 of the present invention combined with SARS-CoV M pro monomer A;
  • Figure 2 is a graph showing the activity of the small molecule inhibitor N1 of the present invention and the SARS-CoV M pro monomer A Electronic density map of sexual pockets;
  • Figure 3 shows the small molecule inhibitors Nl, N2, N3 and N4 of the present invention versus SARS-CoV M p r .
  • Inhibitory activity curve wherein SARS-3CL represents SARS coronavirus main protease, ie SARS-CoV M p r° ;
  • FIG 4 is a graph showing the inhibitory activity curve of the small molecule inhibitor N1 of the present invention against the main protease of Transmissible Gastroenteritis Virus (TGEV) (abbreviated as TGEV-3CL);
  • TGEV Transmissible Gastroenteritis Virus
  • Figure 5 is a graph showing the inhibitory activity curve of the small molecule inhibitor N1 of the present invention against the human coronavirus (HCoV) 229 main protease (abbreviated as HCoV-3CL in the figure);
  • HoV human coronavirus
  • HCoV-3CL main protease
  • FIG. 6 is a graph showing the inhibitory activity curve of the small molecule inhibitor N1 of the present invention against Feline Infectious Peritonitis Virus (FIPV) main protease (abbreviated as FIPV_3CL in the figure);
  • FIPV_3CL Feline Infectious Peritonitis Virus
  • Fig. 7 is a graph showing the inhibitory activity curve of the small molecule inhibitor N1 of the present invention against the Avian Infectious Bronchitis Virus (AIBV) main protease (abbreviated as AIBV-3CL). Detailed description of the invention
  • Nl is particularly preferred small molecule inhibitors of the present invention, the structural formulas of which are:
  • main proteolytic enzymes of SARS coronavirus are used herein to refer to the main SARS coronavirus. Proteolytic enzymes.
  • C, ⁇ C 6 fluorenyl means a straight or branched alkyl group having from 1 to 6 carbon atoms, which includes but is not limited to: methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl Base, tert-butyl, n-pentyl, n-hexyl, and the like.
  • ⁇ 0 ⁇ alkyl means a straight or branched fluorenyl group having from 1 to 4 carbon atoms, which includes: methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl and the like.
  • C 3 -C 6 cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, and includes: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
  • C 6 -C 1Q aryl means a hetero atom-free (monocyclic and bicyclic) aromatic ring having from 6 to 10 carbon atoms, which includes: phenyl, naphthyl such as 1-naphthyl or 2-naphthyl.
  • the "C 5 -C 1Q heteroaryl group” means an aromatic 5- to 10-membered (monocyclic or bicyclic) heterocyclic ring containing 1 to 3 hetero atoms each selected from an oxygen atom, a sulfur atom and a nitrogen atom, and includes: Oxazolyl, isoxazolyl, furyl, imidazolyl, pyridyl, quinolyl, isoquinolyl and benzimidazolyl, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Fluorobenzyl includes p-fluorobenzyl, m-fluorobenzyl, o-fluorobenzyl and the like.
  • Fluorophenyl includes p-fluorophenyl, m-fluorophenyl, o-fluorophenyl and the like.
  • Methods includes p-methylphenyl, m-methylphenyl, o-methylphenyl and the like. Abbreviation
  • Pr represents an isopropyl group
  • Et represents an ethyl group
  • ⁇ represents a phenyl group
  • Boc represents a tert-butoxycarbonyl group
  • THF trifluoroacetic acid
  • DMF tetrahydrofuran
  • DSO dimethyl sulfoxide
  • PhH benzene
  • ipr 2 NEt stands for two Isopropylethylamine
  • NEt 3 stands for triethylamine
  • DCC dicyclohexylcarbodiimide
  • DIEA diisopropylethylamine
  • DMAP stands for 4- ⁇ , ⁇ -dimethyl Aminopyridine
  • EDCI stands for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HATU stands for N-[(dimethylamino)(3//-1 , 2,3-triazolo(4,5-b)pyridin-3-oxy)methylene]methylammonium hex
  • a group consisting of the following groups is selected: trifluoromethylcarbonyl, tert-butoxycarbonyl, isoxazolylcarbonyl, furyl
  • R 2 is methyl, isopropyl, phenyl, benzyl, fluorobenzyl
  • R 3 is selected from the group consisting of methyl, isopropyl, benzyl, fluorobenzyl (especially Fluorobenzyl), phenyl and methylphenyl (especially p-methylphenyl)
  • R4 is selected from the group consisting of ethyl, phenyl, benzyl, methylphenyl (especially Rhenyl) and fluorobenzyl
  • R 5 is isobutyl, phenyl, benzyl, methylphenyl (especially p-methylphenyl), fluorobenzyl (especially p-fluorobenzyl) and Fluorophenyl.
  • the compound of the present invention may be in the form of a pharmaceutically acceptable acid addition salt thereof, which may be combined with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and an organic acid such as acetic acid, trifluoroacetic acid, Propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, a salt formed of toluenesulfonic acid, salicylic acid or the like.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • an organic acid such as acetic acid, trifluoroacetic acid, Propionic acid, glycolic
  • the preparation method of the compound of the formula (I) provided by the invention comprises the following steps:
  • step (b) condensing the product of step (a) with a compound of formula (III) in the presence of a condensing reagent to provide a compound of formula (I),
  • R 2 , R 4 and U are the same as defined in the above formula (I).
  • the synthesis of compounds of the formula ( ⁇ ) can be found in the literature: Qingping Tian, Naresh K. Nayyar, Srinivasan Babu, Lijian Chen, Junhua Tao, Steven Lee, Anthony Tibbetts, Terence Moran, Jason Liou, Ming Guo and Timothy P. Kennedy Ze i. 2001, 42, 6808-6809.
  • the synthesis of compounds of formula (III) can be found in the literature: Dawei Ma, Weiqing Xie, Bin Zou, Qiong Lei and Duanqing Pei Tetrahedron Lett. 2004, 45, 8103-8105.
  • the compound of the formula ( ⁇ ) is reacted with an acid (for example, a mixture of dichloromethane and trifluoroacetic acid in a volume ratio of 1 to 4:1) in an organic solvent at room temperature for 1 to 4 Hour solvent; dissolve the product with a compound of formula (III) in an aprotic solvent (eg CH 2 C1 2 , THF, CHCI3), add a condensation reagent (eg HATU, HBTU or EDCI), then add an organic base ( The reaction is carried out at room temperature for 8 to 24 hours, such as ipr 2 Net or NEt 3 ), to give a compound of the formula (I).
  • an acid for example, a mixture of dichloromethane and trifluoroacetic acid in a volume ratio of 1 to 4:1
  • an organic solvent at room temperature for 1 to 4 Hour solvent
  • aprotic solvent eg CH 2 C1 2 , THF, CHCI3
  • a condensation reagent eg HATU, HBTU or
  • arylcarbonyl and optionally substituted by C, ⁇ C 4 alkyl C 5 ⁇ d.
  • the compound of formula (I) to be derivatized is reacted in an organic solvent with an acid (for example, a mixture of dichloromethane and trifluoroacetic acid in a volume ratio of from 1 to 4:1) at room temperature. 1 ⁇ 4 hours; remove the solvent, dissolve the product with the carboxylic acid R-OH in an aprotic solvent (such as CH 2 C1 2 , THF, CHC1 3 ), add a condensation reagent (such as HATU, HBTU or EDCI), then add An organic base (e.g., ipr 2 Net or NEt 3 ) is allowed to react at room temperature for 8 to 24 hours to provide a series of derivatives of the compound of formula (I).
  • an organic solvent for example, a mixture of dichloromethane and trifluoroacetic acid in a volume ratio of from 1 to 4:1
  • the acid described above is preferably trifluoroacetic acid or hydrochloric acid; a preferred organic solvent is selected from the group consisting of CH 2 C1 2 , tetrahydrofuran, CHC1 3 , N,N-dimethylformamide and dioxane Ring; preferred aprotic solvent is selected from the group consisting of CH 2 C1 2 , tetrahydrofuran, CHC1 3 , hydrazine, hydrazine-dimethylformamide, dimethyl sulfoxide and benzene; preferred condensation reagents are selected from the following members Groups constituted: HATU, HBTU and EDCI; preferred organic bases are selected from the group consisting of diisopropylethylamine and triethylamine.
  • compositions of the present invention comprise a small molecule inhibitor of the invention together with one or more pharmaceutically acceptable carriers.
  • the compositions may take a wide variety of formulations, and the pharmaceutically acceptable carrier may be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules and capsules.
  • the solid carrier can be one or more substances which may also act as a diluent, a flavoring agent, a solubilizer, a lubricant, a suspending agent, a binder or a tablet disintegrating agent; it may also be an encapsulating material.
  • the preparation of various preparations can be carried out in accordance with a conventional method in the field of pharmacy.
  • the pharmaceutical preparation is in unit dosage form, such as a packaged preparation, the package containing discrete amounts of preparation such as packaged tablets, capsules and vials or powders in ampoules.
  • the dosage can vary depending on the needs of the patient, the severity of the disease, and the particular compound employed. For convenience, the total daily dose can be divided into several doses throughout the day. The skilled person in the medical field is able to determine the appropriate dosage depending on the specific situation.
  • specific embodiments of the present invention will be described below in conjunction with the accompanying drawings. In describing the embodiments, well-known experimental methods, apparatus, reagents, materials, and the like have not been described in detail to avoid the disadvantages of the present invention.
  • the substrate is dissolved in 2 ml CH 2 C1 2 and 12 mg is added. Then add 48 ⁇ ipr 2 NEt and then add 44 mg HATU. The reaction at room temperature for 12 hours, washed with 1 M HC saturated NaHCO ⁇ solution, saturated brine, dried with Na 2 S0 4. Over The solvent was evaporated under reduced pressure and flash column chromatography afforded
  • Example 1 and Example 2 can be briefly summarized by the following reaction formula:
  • Boc-depleted substrate was dissolved in 2 ml of CH 2 C1 2 , 62 mg of compound 11 was added, and 97 ⁇ M of 'P ⁇ NEt was added, followed by 75 mg of HATU.
  • N1 binds to the substrate binding pocket of the enzyme.
  • C 3 in N1 forms a covalent bond with S 7 of A145-Cys having a bond length of 1.8A.
  • the carbonyl oxygen in the N1 ester group forms a hydrogen bond with the amino group on the A145-Cys main carbon chain; the ethyl group in the ester forms a hydrophobic interaction with the side chains of A27-Len His-A41 and Thr-A25.
  • the oxygen in the five-membered ring of the lactam forms a 2.6A hydrogen bond with NE2 of His-163.
  • a water molecule near the lactam ring can form a 2.6A 3.2A, 2.6 person and 2.7 human hydrogen bond with NE2 of N His-172 on the lactam ring of N1 and carbonyl oxygen of 140-Phe and Ser-Bl, respectively. , allowing the lactam ring to be firmly bonded in the S1 pocket.
  • P1 due to the major protease of the entire coronavirus family The site is very conserved and always appears in the form of Q, therefore, occupying the corresponding substrate binding pocket S1 is a key to inhibiting protease activity.
  • the small molecule Leu side chain is easily inserted into the side chain of His-41, Met-49 and Phe-181, and the alkyl moiety of the side chain of Gln-189 and Asp-187. In the hydrophobic pocket.
  • the carbonyl oxygen in His-164 forms a hydrogen bond of 2.9A with N in the peptide bond near the ester group side in N1, and the carbonyl oxygen of Val in N1 forms a 2.9A hydrogen bond with N in GKI-A166, Val N in the peptide bond forms a hydrogen bond of 3.0A with the G1U-A166 carbonyl oxygen, and N in the Ala peptide bond in N1 forms a hydrogen bond of 3.2A with the carbonyl oxygen of Thr-190.
  • the side chain of Ala is inserted into a hydrophobic pocket consisting of Phe-185, Glu-192, Leu-167, Met-165 side chains.
  • the heterocyclic ring at the end of N1 has a hydrophobic interaction with the five-membered ring of Pro-168. All of these covalent bonds, hydrogen bonds, and hydrophobic interactions allow the inhibitor compound N1 to bind tightly to the substrate active pocket of the enzyme, thereby causing inactivation of the enzyme.
  • the method for measuring the inhibitory activities of ⁇ 2, ⁇ 3 and ⁇ 4 is basically the same as that of N1.
  • Nl, N2, N3 and N4 have inhibitory activities against SARS-CoV M pro , and N1 has the strongest inhibitory activity.
  • N1 From the inhibition activity of N1 against other coronavirus main proteases (ie, Fig. 4 to Fig. 7), N1 has an inhibitory activity against the main proteases of TGEV, HCoV, FIPV and AIBV, and the most inhibitory activity against the main protease of TGEV. Strong, under the condition of ⁇ ⁇ , N1 still has inhibitory activity against TGEV main protease.
  • TGEV, HCoV, and FIPV belong to the type I (serotype) of the Coronavirus family
  • AIBV belongs to type III
  • SARS-CoV belongs to type IV. Therefore, it can be inferred that N1 has inhibitory activity against the major protease of the entire coronavirus family.

Abstract

La présente invention a trait à une série d’inhibiteurs de petites molécules de formule générale (I), qui sont construits sur la structure cristalline de la protéase principale du coronavirus du SARS. L’invention concerne également la préparation desdits inhibiteurs de petites molécules, la composition pharmaceutique les contenant ainsi que leur utilisation pour la fabrication d’un médicament destiné à traiter ou à prévenir diverses infections induites par des coronavirus.
PCT/CN2005/001748 2004-10-22 2005-10-24 Inhibiteurs de petites molecules de la protease principale des coronavirus, leur preparation et utilisation WO2006042478A1 (fr)

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CNB2004100877217A CN100363346C (zh) 2004-10-22 2004-10-22 冠状病毒主蛋白酶的小分子抑制剂、制备方法及其应用
CN200410087721.7 2004-10-22

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EP3455205A4 (fr) * 2016-05-13 2020-01-01 Emory University Peptidomimétiques pour le traitement d'une infection à norovirus
US11021513B2 (en) 2016-05-13 2021-06-01 Emory University Peptidomimetics for the treatment of norovirus infection
EP3912628A1 (fr) * 2020-05-20 2021-11-24 Institut de Recherche en Semiochimie et Ethologie Appliquée Analogues de nucléoside pour inhiber la protéase principale d'un coronavirus
WO2021234128A1 (fr) * 2020-05-20 2021-11-25 Institut de Recherche en Semiochimie et Ethologie Appliquee Analogues nucléosidiques pour inhiber la protéase principale d'un coronavirus
WO2021234127A1 (fr) * 2020-05-20 2021-11-25 Institut de Recherche en Semiochimie et Ethologie Appliquee Analogue de nucléoside pour inhiber la protéase principale du virus de sars-cov-2

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