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WO2023022231A1 - Inhibiteur de liaison covalente réversible pour le traitement ou la prévention d'une infection virale - Google Patents

Inhibiteur de liaison covalente réversible pour le traitement ou la prévention d'une infection virale Download PDF

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WO2023022231A1
WO2023022231A1 PCT/JP2022/031407 JP2022031407W WO2023022231A1 WO 2023022231 A1 WO2023022231 A1 WO 2023022231A1 JP 2022031407 W JP2022031407 W JP 2022031407W WO 2023022231 A1 WO2023022231 A1 WO 2023022231A1
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optionally substituted
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cycloalkyl
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英治 川西
彰夫 王子田
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Kyushu University NUC
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • SARS-CoV-2 which is known as the causative virus of the new coronavirus infection (COVID-19) (Non-Patent Document 3), which has caused a pandemic since 2019, is a SARS virus with a high fatality rate.
  • Non-Patent Document 3 has some homology with CoV. While rhinoviruses replicate via 3C protease, coronaviruses such as SARS-CoV, SARS-CoV-2 and MERS-CoV replicate using 3CL protease (3 chymotrypsin-like protease, hereinafter abbreviated as "3CLpro"). ) is known to replicate via (non-patent paper 4).
  • Viral replication inhibitors include remdesivir (GS-5734), favipiravir (T-705) and ribavirin, which target RdRp, and lopinavir and ritonavir, which target 3CLpro.
  • remdesivir GS-5734
  • favipiravir T-705
  • ribavirin which target RdRp
  • lopinavir and ritonavir which target 3CLpro.
  • lopinavir and ritonavir have in vitro inhibitory activity against SARS-CoV and MERS-CoV, but have little therapeutic effect alone in patients with COVID-19, and other agents such as ribavirin and interferon beta-1b It has been reported that it appears to be effective when used in combination with Thus, currently approved or clinically tested antiviral drugs cannot be said to have sufficient therapeutic effects.
  • R 1 is the formula: (wherein each R 5 is independently hydrogen, optionally substituted C1-C3 alkyl, or optionally substituted C3-C10 cycloalkyl, preferably C3-C10 cycloalkyl, R6 is hydrogen or C1-C3 alkyl, n is an integer from 0-2) is a group represented by Y is the formula: (wherein each R 7 is independently optionally substituted C1-C5 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted benzyl; p is an integer from 0-3) is a group represented by R3 is hydrogen or C1-C2 alkyl, R 4 is optionally substituted C1-C5 alkyloxy, optionally substituted C3-C10 cycloalkyl, optionally substituted heteroaryl, or an optionally substituted amino acid residue moiety; m is an integer
  • Each amino acid residue moiety in R2 is independently -(CH2)p (where p is an integer of 0-4), optionally substituted C1-C5 alkyl, optionally substituted nitrogen, hydroxy, optionally substituted thiol, optionally substituted carbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C5 alkenyl, optionally substituted C1- C5 alkynyl, halogen, optionally substituted C1-C5 alkoxyalkyl, optionally substituted formyl, optionally substituted C1-C5 alkoxycarbonyl, optionally substituted C1-C5 cycloalkyl, and optionally substituted
  • R 1 is the formula: (wherein each R 5 is independently hydrogen, optionally substituted C1-C3 alkyl, or optionally substituted C3-C10 cycloalkyl; R6 is hydrogen or C1-C3 alkyl, n is an integer from 0-2) is a group represented by Y is the formula: (wherein each R 7 is independently optionally substituted C1-C5 alkyl, optionally substituted C3-C10 cycloalkyl, or optionally substituted benzyl; p is an integer from 0-3) is a group represented by R3 is hydrogen or C1-C2 alkyl, R 4 is optionally substituted C1-C5 alkyloxy, optionally substituted C3-C10 cycloalkyl, optionally substituted heteroaryl, or an optionally substituted amino acid residue moiety; m is an integer of 2 or 3, and X is the formula: is a covalent substituent represented by ] The compound according to [1],
  • [8-2] A pharmaceutical composition containing the compound of [7-2], or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof.
  • the pharmaceutical composition of [9-2] wherein the viral infection is caused by a virus that replicates via cysteine protease or serine protease.
  • ⁇ Pharmaceutical composition> [102] A pharmaceutical composition containing the compound of either [100] or [101], or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof. [103] The pharmaceutical composition of [102] for treating or preventing viral infections. [104] [103] The pharmaceutical composition of [103], wherein the viral infection results from a virus that replicates via a cysteine protease or a serine protease. [105] The pharmaceutical composition of [104], wherein the viral infection results from a virus that replicates through cysteine proteases.
  • FIG. 1 is an NMR spectrum chart of compound 4af prepared in Reference Example 1.
  • FIG. 2 is an NMR spectrum chart of compound 4ag prepared in Reference Example 2.
  • FIG. 3 is an NMR spectrum chart of compound 4ah prepared in Reference Example 3.
  • FIG. 4 is an NMR spectrum chart of compound (S,S,R)-8a prepared in Example 106.
  • FIG. 5 is an NMR spectrum chart of compound (S,S,R)-8b prepared in Example 107.
  • FIG. 6 is an NMR spectrum chart of compound (S,R,R)-10a prepared in Example 108.
  • FIG. 7 is an NMR spectrum chart of compound (S,R,R)-10b prepared in Example 109.
  • the compounds of the present invention are characterized by having a covalent substituent group: X, and belong to a group of compounds called covalent drugs that inhibit protein function by forming covalent bonds. Due to the presence of the group: X, the compounds of the present invention function as reversible covalent bond inhibitors.
  • C1-C5 alkyl and “C1-C3 alkyl” in “optionally substituted C1-C5 alkyl” consist of the indicated number of carbon atoms and hydrogen atoms, It means a straight or branched hydrocarbon chain radical containing no saturation and connected to the remainder of the molecule by a single bond.
  • Examples are methyl, ethyl, n-propyl, isopropyl, isobutyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 3,3-dimethyl-1-butyl, t-butyl, pentyl, isopentyl and Examples include, but are not limited to, alkyl groups such as hexyl.
  • Preferred substituents are methyl, ethyl, n-propyl and isopropyl.
  • C3-C6 cycloalkyl in “optionally substituted C3-C6 cycloalkyl” refers to a non-aromatic monocyclic or polycyclic ring containing the indicated number of carbon atoms and hydrogen atoms. means a cyclic group.
  • a C3-C6 cycloalkyl group may contain one or more carbon-carbon double bonds in the ring, so long as the presence of the carbon-carbon double bonds does not render the ring aromatic.
  • Examples of C3-C6 cycloalkyl groups include C3-C6 fully saturated cycloalkyl groups (e.g.
  • cycloalkyl groups are monocyclic or bicyclic cyclic groups.
  • C3-C6 cycloalkyl in optionally substituted C3-C6 cycloalkyl also means a non-aromatic monocyclic or polycyclic group containing the indicated number of carbon and hydrogen atoms. Other meanings are the same as above.
  • amino acid residue moieties have conventional amino acid configurations, and each amino acid residue moieties can independently exist in the "L" or "D" stereoisomeric form. .
  • pharmaceutically acceptable salt means a salt that, when administered to a subject, can (directly or indirectly) provide the compounds described herein. Salt preparation can be performed by methods known in the art.
  • a “pharmaceutically acceptable salt” is physiologically tolerable and typically does not produce an allergic or similar untoward reaction (e.g., upset stomach, dizziness, etc.) when administered to humans. gives no molecular part.
  • Reference Example 10-1 TEA (1.15 mL, 8.49 mmol) was added to a THF (12 mL) solution of Cbz-Leu-OH (2.12 g, 7.99 mmol) and stirred at room temperature for 5 minutes. Then, the mixture was cooled to -10°C, a THF (12 mL) solution of ethyl chloroformate (789 ⁇ L, 8.29 mmol) was added, and the mixture was further stirred for 10 minutes. The white solid that formed was removed by filtration, and the filtrate was added to a solution of hydrazine monohydrate (757 ⁇ L, 15.8 mmol) in MeOH (20 mL) at 0° C. using a dropping funnel.
  • Step 1 Same reaction as in Reference Example 1-4, 3b (130.6 mg, 0.292 mmol) prepared in Example 2-3, HCl/dioxane (4.0 M, 4 mL, 16 mmol), DMF (2000 ⁇ L ), DIEA (289 ⁇ L, 0.462 mmol), T3P/DMF (1.6 M, 289 ⁇ L, 0.462 mmol), and 2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (64.0 mg, 0.277 mmol) to give compound 4bi (91.7 mg, 0.164 mmol, 71.1%).
  • Step 2 Same reaction as in Reference Example 1-4, 4ci (83.0 mg, 0.167 mmol), HCl/dioxane (4.0 M, 1.67 mL, 6.68 mmol) DMF (1000 ⁇ L), DIEA (139 ⁇ L, 0.798 mmol) , T3P/DMF (1.6 M, 203 ⁇ L, 0.325 mmol), and CF 3 COOH (15 ⁇ L, 0.195 mmol) to give compound 5ci (4.3 mg, 5.2%) MS (ESI, pos): m/z 528.1 (M+Na) +
  • Step 1 Compound 4di (30.0 mg, 0.057 mmol), HCl/dioxane (4.0 M, 0.57 mL, 2.28 mmol), DCM (285 ⁇ L), DIEA (58 ⁇ L, 0.333 mmol) ), T3P/DMF (1.6 M, 84 ⁇ L, 0.134 mmol) and trifluoroacetic anhydride (24 ⁇ L, 0.173 mmol) to give compound 5di (7.00 mg, 24%).
  • Example 7-3 Compound 2e (619 mg, 2.10 mmol) prepared in Example 7-2, DMF (6 mL), DIEA (1.79 mL, 4.20 mmol), sodium chlorofluoroacetate ( 429 mg, 3.15 mmol) and T3P/DMF (1.6 M, 2.60 mL, 4.20 mmol) to give compound 3e (503 mg, 61%).
  • Example 10 N-((2S)-1-(2-(3-amino-3-oxopropyl)-2-(2-hydroxyacetyl)hydrazinyl)-4-methyl-1-oxopentan-2-yl)-4 -Methoxy-1H-indole-2-carboxamide
  • methanol 5 mL
  • palladium on carbon 14.7 mg
  • Palladium on carbon 26.8 mg
  • Example 16 (S)-N-(1-(2-(3-amino-3-oxopropyl)-2-(vinylsulfonyl)hydrazinyl)-4-methyl-1-oxopentan-2-yl)-4-methoxy- 1H-indole-2-carboxamide (17af) HCl/dioxane (4.0 M, 2.0 mL) was added to 9af (110 mg, 0.225 mmol) prepared in Reference Example 10-4, and the mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was dissolved in DCM (1.5 mL) and ice-cooled to 0° C.
  • reaction mixture was concentrated in vacuo and the residue dissolved in DMF (6 mL) followed by (R)-CFA (45.7% in 1,4-dioxane, 140 ⁇ L, 0.722 mmol), TEA (453 ⁇ L, 3.25 mmol) and COMU (429 mg, 1.00 mmol) were added at 0 °C.
  • the reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of COMU (284 mg, 0.663 mmol and 57 mg, 0.133 mmol). After 20 minutes, the reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate.
  • reaction mixture was concentrated in vacuo and the residue dissolved in DMF (3 mL) followed by (R)-CFA (45.7% in 1,4-dioxane, 47 ⁇ L, 0.242 mmol), TEA (238 ⁇ L, 1.70 mmol) and COMU (131 mg, 0.306 mmol) were added at 0°C.
  • the reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of COMU (88 mg, 0.205 mmol, 44 mg, 0.103 mmol, and 44 mg, 0.103 mmol) and TEA (95 ⁇ L, 0.681 mmol). After 30 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate.
  • Example 117 N-((S)-1-(2-((R)-2-chloro-2-fluoroacetyl)-2-(((S)-2-oxopyrrolidin-3-yl)methyl)hydrazinyl)-1 -oxo-3-phenylpropan-2-yl)-4-fluoro-1H-indole-2-carboxamide ((S,S,R)-8pa) 8pa (83 mg, 83%) was obtained as a yellow solid from 7pa (101 mg, 0.188 mmol) in the same manner as in Example 106.
  • Example 118 tert-butyl 2-((4-fluoro-1H-indole-2-carbonyl)-L-phenylalanyl)-1-(((R)-2-oxopyrrolidin-3-yl)methyl)hydrazine-1- Carboxylate ((S,R)-14pa) (S,R)-14pa (120 mg, 84%) was obtained as a yellow solid from (S,R)-6p (100 mg, 0.26 mmol) in the same manner as in Example 102.
  • Example 119 N-((S)-1-(2-((R)-2-chloro-2-fluoroacetyl)-2-(((R)-2-oxopyrrolidin-3-yl)methyl)hydrazinyl)-1 -oxo-3-phenylpropan-2-yl)-4-fluoro-1H-indole-2-carboxamide ((S,R,R)-10pa) (S,R,R)-10pa (53 mg, 53%) was obtained as a yellow solid from (S,R)-14pa (100 mg, 0.188 mmol) in the same manner as in Example 106.
  • Example 122 tert-butyl 2-(((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-L-phenylalanyl)-1-(((R)-2 -oxopyrrolidin-3-yl)methyl)hydrazine-1-carboxylate ((S,S,R)-14pc) (2S)-3,3-Dimethyl-2-[(trifluoroacetyl)amino]butyric acid (80 mg, 0.35 mmol) and (S,S)-6p (120 mg, 0.319 mmol) were obtained in a similar manner to Example 120.
  • Example 123 (S)-N-((S)-1-(2-((R)-2-chloro-2-fluoroacetyl)-2-(((R)-2-oxopyrrolidin-3-yl)methyl) hydrazinyl)-1-oxo-3-phenylpropan-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamide ((S,S,R,R)-10pc ) (S,S,R,R)-10pc (63 mg, 64%) was obtained as a yellow solid from (S,S,R)-14pc (100 mg, 0.171 mmol) in the same manner as in Example 106.
  • Example 126 (S)-N-((S)-1-(2-((R)-2-chloro-2-fluoroacetyl)-2-(((S)-2-oxopyrrolidin-3-yl)methyl) hydrazinyl)-4-methyl-1-oxopentan-2-yl)-3-phenyl-2-(2,2,2-trifluoroacetamido)butanamide ((S,S,S,R)-18e) (S,S)-6 (173 mg, 0.505 mmol) and (2,2,2-trifluoroacetyl)-L-phenylalanine (147 mg, 0.561 mmol) were prepared from (S,S)-6 (173 mg, 0.505 mmol) and (S,S ,S)-17e (244 mg, 83%) was obtained.
  • Test example 1 3CL Protease Inhibitory Activity 3CL protease inhibitory activity was measured using the untagged 3CL protease (SARS-CoV-2) (BPS Bioscience 100823) and the fluorescent peptide substrate Ac-Abu-Tle-Leu-Gln-MCA (Peptide Institute 3250-v ) was used (Science 2020, 368, 409-412). Table 1 shows the results obtained.
  • Test example 2 X-ray crystal structure test of 3CLpro using example compound Example 2-1: Expression and purification of SARS-CoV-2 3CLpro (3C-like protease)
  • Expression plasmid (pGEX-5X-3-SARS-CoV-2-3CL) was a gift from Alejandro Chavez & David Ho & Sho Iketani (Addgene plasmid # 168457; http://n2t.net/addgene:168457 ; RRID: Addgene_168457).
  • the expression and purification of 3CLpro for SARS-CoV-2 is slightly different from the previously reported method (Iketani, S. et al. Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors.
  • Fractions containing 3CLpro were concentrated using a centrifugal filter (Amicon Ultra-15 centrifugal filter device with MWCO of 3 kDa) and equilibrated with 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA Superdex Increase 200 10/300 After column treatment, it was further purified by size exclusion chromatography. Collected fractions were analyzed by SDS-PAGE followed by Coomassie blue staining. Fractions containing 3CLpro were then dialyzed against 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, and 1 mM TCEP and concentrated to approximately 10 mg/mL for crystal screening.
  • Test Example 2-2 Crystallization of SARS-CoV-2 3CLpro with (S,S,R)-8a compound Crystals of 3CLpro complexed with (S,S,R)-8a compound are co-crystals It was obtained by the method of conversion. Prior to the crystallization step, complexes of protein and (S,S,R)-8a compounds were prepared at a protein concentration of 11 mg/mL and a protein:(S,S,R)-8a molar ratio of 1:2. . Crystals of this complex are mixed with an equal volume of solution composed of 16% (w:v) polyethylene glycol monomethyl ether, 20% glycerol, 80 mM TRIS (pH 8.5), and 8 mM NiCl using the sitting drop method.
  • the carboxamido oxygen of the CFA unit forms two hydrogen bonds with the backbone NH groups of residues Gly143 and Cys145, which stabilize the reversible covalent binding with the Cys145 residue.
  • residues Gly143 and Cys145 which stabilize the reversible covalent binding with the Cys145 residue.

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Abstract

La présente invention concerne un composé pour le traitement ou la prévention d'une infection virale.　La présente invention concerne un composé représenté par la formule (1) [dans laquelle : R1 est un groupe représenté par la formule (AA) ; Y est un groupe représenté par la formule (BB) ; et X est un substituant covalent représenté par la formule (CC)], un sel ou solvate pharmaceutiquement acceptable de celui-ci, ou un promédicament de celui-ci.
PCT/JP2022/031407 2021-08-20 2022-08-19 Inhibiteur de liaison covalente réversible pour le traitement ou la prévention d'une infection virale Ceased WO2023022231A1 (fr)

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