Nucleosides and nucleotides analogs as antiviral agents

Patent metadata

Field	Value
Publication number	US-2025114389-A1
Application number	US-202218285778-A
Country	US
Kind code	A1
Filing date	Apr 11, 2022
Priority date	Apr 9, 2021
Publication date	Apr 10, 2025
Grant date	—

Abstract

Compounds, compositions and methods for preventing, treating or curing a coronavirus infection in human subjects or other animal hosts. In one embodiment, the compounds can be used to treat an infection with a severe acute respiratory syndrome virus, such as human coronavirus 229E, SARS, MERS, SARS-CoV-1, OC43, and SARS-CoV-2. In another embodiment, the methods are used to treat a patient infected with a Flavivirus, Picornavus, Togavirus, or Bunyavirus.

First claim

1 . A method for treating or preventing a Coronaviridae, Flaviviridae, Picornaviridae, Bunyaviridae, or Togaviridae infection, comprising administering a treatment or preventative amount of a compound of Formula (A) to a patient in need of treatment or prevention thereof:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 4 is O, CH 2 , S, Se, or

R 1 and R 2 are independently selected from the group consisting of H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, (acyloxybenzyl)ester, (acyloxybenzyl)ether, optionally substituted bis-acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, an optionally substituted —C(O)—C 1-12 R′, an optionally substituted —C(O)O—R′, an optionally substituted —C(O)S—R′, an optionally substituted —C(S)S—R′, an optionally substituted —C(NR′)OR′, an optionally substituted —C(NR′)SR′, an optionally substituted —C(NR′)N(R′) 2 , and an optionally substituted —O—C(O)N(R′) 2 , PEG ester, PEG carbonate, an optionally substituted —CH 2 —O—C(O)—R′, an optionally substituted —CH 2 —O—C(O)O—R′, an optionally substituted —CH 2 —CH 2 —S—C(O)—R′, a lipid ester, a lipid carbonate, (in which the lipid is an optionally substituted C 12-22 alkyl, an optionally substituted C 12-22 alkenyl, an optionally substituted C 12-22 alkynyl or an optionally substituted C 12-22 alkoxy),
R′ is C 1-16 alkyl, C 2-16 alkenyl, C 2-16 alkynyl, or C 3-7 cycloalkyl,
wherein optional substituents are selected from the group consisting of halo, C 1-12 haloalkyl, C 1-16 alkyl, C 2-16 alkenyl, C 2-16 alkynyl, C 3-7 cycloalkyl, hydroxyl, carboxyl, C 1-12 acyl, aryl, heteroaryl, C 1-6 acyloxy, amino, amido, carboxyl derivatives, alkylamino, di-C 1-12 -alkylamino, arylamino, C 1-12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester;
R 3 is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, (acyloxybenzyl) ester, (acyloxybenzyl) ether, optionally substituted bis-acyloxybenzyl) ester, optionally substituted (acyloxybenzyl) ester, an optionally substituted —C(O)—R′, an optionally substituted —C(O)O—R′, an optionally substituted —C(O) SR′, an optionally substituted —C(S)SR′, PEG ester, PEG carbonate, an optionally substituted —CH 2 —O—C(O)—R′, an optionally substituted —CH 2 —O—C(O)O—R′, an optionally substituted —CH 2 —CH 2 —S—C(O)—R′, an optionally substituted —C(NR′)OR′, an optionally substituted —C(NR′)SR′, an optionally substituted —C(NR′)N(R′) 2 , an optionally substituted —O—C(O)N(R′) 2 , a lipid ester, a lipid carbonate (in which a lipid is an optionally substituted C 12-22 alkyl, an optionally substituted C 12-22 alkenyl, an optionally substituted C 12-22 alkynyl or an optionally substituted C 12-22 alkoxy), O—P(O)R 6 R 7 , or a mono-, di-, or triphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly or partially R p or S p or any mixture thereof,
R 6 and R 7 are independently selected from the group consisting of:
(a) OR 15 where R 15 selected from the group consisting of H,

Li, Na, K, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, optionally substituted —C(NR′)OR′, optionally substituted —C(NR′)SR′, optionally substituted —C(NR′)N(R′) 2 , optionally substituted —O—C(O)N(R′) 2 , C 1-4 (alkyl)aryl, benzyl, C 1-6 haloalkyl, C 2-3 (alkyl)OC 1-20 (alkyl, C 2-3 (alkyl)OC 1-20 alkene, C 2-3 (alkyl)OC 1-20 alkyne, aryl, and heteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionally substituted with zero to three substituents independently selected from the group consisting of (CH 2 ) 0-6 CO 2 R 16 and (CH 1 ) 0-6 CON(R′) 2 ;
where R 16 is independently H, substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 1-20 alkene, substituted or unsubstituted C 1-20 alkyne, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl-C 1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl: wherein the substituents are C 1-5 alkyl, C 1-5 alkene, C 1-5 alkyne, C 3-7 cycloalkyl or C 1-5 alkyl substituted with a C 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl; and
(b) the ester of a D- or L-amino acid

wherein R 17 and R 18 are, independently, H, C 1-20 (alkyl, C 1-20 alkene, C 1-20 alkyne, the carbon chain derived from a fatty alcohol or C 1-20 alkyl optionally substituted with a C 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl-C 1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a C 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl; and R 17A is H or C 1-2 alkyl;

R 9′ is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an (acyloxybenzyl)ester, an (acyloxybenzyl)ether, an optionally substituted bis-acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, an optionally substituted —C(O)—R′, an optionally substituted —C(O)O—R′, an optionally substituted —C(O)S—R′, an optionally substituted —C(S)S—R′, an optionally substituted C 1-12 -alkyl, an optionally substituted C 2-12 alkenyl, an optionally substituted C 2-12 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted —C(NR′)OR′, an optionally substituted —C(NR′)SR′, an optionally substituted —C(NR′)N(R′) 2 , an optionally substituted —O—C(O)N(R′) 2 , a PEG ester, a PEG carbonate, an optionally substituted —CH 2 —O—C(O)—R′, an optionally substituted —CH 2 —O—C(O)O—R′, an optionally substituted —CH 2 —CH 2 —S—C(O)—R′, a lipid ester, or a lipid carbonate,
wherein a lipid is an optionally substituted C 12-22 alkyl, an optionally substituted C 12-22 alkenyl, an optionally substituted C 12-22 alkynyl or an optionally substituted C 12-22 alkoxy),
R 10 and R 10′ are independently H, OH, an L-amino acid amide, a D-amino acid amide, (acyloxybenzyl)amide, (acyloxybenzyl)amine, optionally substituted (acyloxybenzyl)esters, an optionally substituted —C(O)—R′, an optionally substituted —C(O)O—R′, an optionally substituted —C(O)S—R′, an optionally substituted —C(S)S—R′, an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl, an optionally substituted C 2-12 alkynyl, an optionally substituted C 3-6 cycloalkyl, PEG amide, PEG carbamate, an optionally substituted —CH 2 —O—C(O)—R′, an optionally substituted —CH 2 —O—C(O)O—R′, an optionally substituted —CH 2 —CH 2 —S—C(O)—R′,

Assignees

• Univ Emory

Inventors

• Schinazi Raymond
• Amblard Franck
• Kasthuri Mahesh
• Biteau Nicolas
• Shi Junxing
• Zhou Longhu
• Zandi Keivan

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title