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EP-4112050-B1 - NUCLEOSIDE COMPOUND FOR USE IN THE TREATMENT OF COVID-19

EP4112050B1EP 4112050 B1EP4112050 B1EP 4112050B1EP-4112050-B1

Inventors

  • CHANG, JUNBIAO
  • DU, JINFA
  • JIANG, JIANDONG
  • LI, Yuhuan

Dates

Publication Date
20260506
Application Date
20210220

Claims (10)

  1. A compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease, wherein in the formula (I), R 1 is H, R 5 -CO-, or wherein Ar is phenyl, substituted phenyl, naphthyl, or substituted naphthyl, wherein the substituents are selected from the group consisting of C 1-6 alkyl, F, Cl, Br, I, CN, N 3 , OH, NH 2 , OR 5 , and NHR 5 ; R 2 is: azido; R 3 is H, optionally substituted R-CO-, optionally substituted R-O(C=O)-, or optionally substituted RNH-CO-, wherein R is C 1 -C 6 alkyl, wherein the substituents are selected from the group consisting of C 1 -C 6 alkyl, halogen, CN, N 3 , and OR 5 ; R 4 is H; B is wherein X 1 is -NH 2 ; Y is CH; Z is F; and R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, halo C 1 -C 6 alkyl, phenyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 , OH, NH 2 , or halogen, and naphthyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 , OH, NH 2 , or halogen; wherein the coronavirus infectious disease is a disease caused by infection with a virus of COVID-19.
  2. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to claim 1, wherein the compound represented by formula (I) is the following compound:
  3. The compound represented by formula (I)or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to claim 1 or 2, wherein the pharmaceutically acceptable salts of the compound represented by formula (I) include salts formed by the compound of formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, scorbic palmitatic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, or leucine.
  4. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to any one of claims 1 to 3, wherein the coronavirus infectious disease includes the diseases caused by infected humans or other animals.
  5. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to any one of claims 1 to 4, wherein the dosage form of the compound represented by formula (I) or its pharmaceutically acceptable salts is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, a granule, an emulsion, a syrup, an elixir, an injection, or a powder injection.
  6. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to claim 1, wherein a therapeutically or prophylactically effective amount of the compound represented by formula (I) or pharmaceutically acceptable salts thereof is administered to a patient in need thereof.
  7. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to claim 6, wherein the compound represented by formula (I) is the following compound:
  8. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to claim 6 or 7, wherein the pharmaceutically acceptable salts of the compound represented by formula (I) include salts formed by the compound of formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, scorbic palmitatic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, or leucine.
  9. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to any one of claims 6 to 8, wherein the coronavirus infectious disease includes the diseases caused by infected humans or other animals.
  10. The compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease according to any one of claims 6 to 8, wherein the dosage form of the compound represented by formula (I) or its pharmaceutically acceptable salts is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, a granule, an emulsion, a syrup, an elixir, an injection, or a powder injection.

Description

TECHNICAL FIELD The present disclosure relates to novel antiviral use of nucleoside compounds. BACKGROUND Coronavirus (CoV), a class of enveloped positive single-stranded RNA viruses, spreads widely in humans, other mammals, and birds, and may cause respiratory diseases, intestinal diseases, liver diseases, nervous system diseases, and the like. Seven CoVs are now known to cause human diseases, four of which, i.e., CoV-229E, -OC43, -NL63, and -HKU1, are prevalent in population and usually cause symptoms of the common cold. However, the other three CoVs, i.e., SARS-CoV, MERS-CoV, and 2019-nCoV (or known as COVID-19), all have severe hazards of quick onset, strong infectivity, and a high fatality rate. It is therefore very urgent to rapidly develop direct-acting antiviral drugs for use in treatment of novel coronavirus infection. Nucleotide analogues, such as sofosbuvir, have been suggested for the treatment of coronaviruses, including 2019-nCoV (Ju et al., 2020, Nucleotide Analogues as Inhibitors of Viral Polymerases, DOI: 10.1101/2020.01.30.927574). A virtual screening has revealed that velpatasvir and ledipasvir are particularly attractive as therapeutics to combat the 2019-nCoV (Chen et al., 2020, Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like Protease (3CLpro) Structure: Virtual Screening Reveals Velpatasvir, Ledipasvir, and Other Drug Repurposing Candidates, DOI: 10.26434/ chemrxiv.11831103.v2). SUMMARY Compound 1, as an anti-AIDS drug, has passed the phase II clinical trials and showed good safety. The inventors have determined the in vitro antiviral activity of Compound 1 in MRC-5 cells infected with the novel coronaviruses. The results show that Compound 1 has only a weak inhibitory activity against the novel coronaviruses (EC50 is 25 µM). However, when using the compound of formula (1) to directly conduct clinical trials for research, the inventors have surprisingly found that compared with the conventional treatment as a control, treating patients with novel coronavirus pneumonia with the compound of formula (1) shows obvious advantages in the clearance rate by viral nucleic acid test, the course of clearance, and the cure and discharge time. The inventors believe that Compound 1 does not show a significant inhibitory effect against the viruses, which may be because it cannot be effectively phosphorylated in vitro. In view of the above, on one aspect, there is provided herein a compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease, wherein the coronavirus infectious disease is a disease caused by infection with a virus of COVID-19, and on the other aspect, there is provided herein a compound represented by formula (I) or pharmaceutically acceptable salts thereof for use for preventing or treating a coronavirus infectious disease, wherein the coronavirus infectious disease is a disease caused by infection with a virus of COVID-19, and wherein a therapeutically or prophylactically effective amount of the compound represented by formula (I) or pharmaceutically acceptable salts thereof is administered to a patient in need thereof, wherein the formula (I) has the following structure: in the formula (I), R1 is any group that enables an OR1 group to be metabolized in vivo to release a hydroxyl group, or to form an O-phosphate group; OR1 is preferably an ester group, R1 is preferably H, R5-CO-, or wherein Ar is phenyl and substituted phenyl, naphthyl and substituted naphthyl, and the substituents are selected from the group consisting of C1-6 alkyl, F, Cl, Br, I, CN, N3, OH, NH2, OR5, and NHR5;R2 is azido;R3 is selected from the group consisting of H, optionally substituted R-CO-, optionally substituted R-O(C=O)-, and optionally substituted RNH-CO-, wherein R is selected from the group consisting of C1-C6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl), wherein the substituents are selected from the group consisting of C1-C6 alkyl, halogen (e.g. F or Cl), CN, N3, and OR5;R4 is H; B is wherein X1 is -NH2;Y is CH;Z is F; andR5 is selected from the group consisting of H, C1-C6 alkyl (e.g. methyl, ethyl, propyl, or isopropyl), C2-C6 alkynyl (e.g. ethynyl), C2-C6 alkenyl (e.g. ethenyl), halo C1-C6 alkyl (e.g. 2-chloroethyl, 2-fluoroethyl, or trifluoroethyl), phenyl optionally substituted with C1-6 alkyl, C1-6 alkoxy, CN, N3, OH, NH2, halogen (e.g. F, Cl, Br, or I), and naphthyl optionally substituted with C1-6 alkyl, C1-6 alkoxy, CN, N3, OH, NH2, halogen (e.g. F, Cl, Br, or I). The following compounds or pharmaceutically acceptable salts thereof are preferred: CL-236 The pharmaceutically acceptable salts of the compound represented by formula (I) include, but are not limited to, for example, salts formed by the compound of formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid,