Thionucleosides as antiviral agents

Patent metadata

Field	Value
Publication number	US-2024216413-A1
Application number	US-202218285789-A
Country	US
Kind code	A1
Filing date	Apr 11, 2022
Priority date	Apr 9, 2021
Publication date	Jul 4, 2024
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) or Formula (A1) to a patient in need of treatment or prevention thereof:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Y and R are, independently, selected from the group consisting of H, OH, halo, an optionally substituted O-linked amino acid, substituted or unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, cyano, cyanoalkyl, azido, azidoalkyl, OR′, SR′, wherein each R′ is independently a —C(O)—C 1-12 alkyl, —C(O)—C 2-12 alkenyl, —C(O)—C 2-12 alkynyl, —C(O)—C 3-6 cycloalkyl, —C(O)O—C 1-12 alkyl, —C(O)O—C 2-12 alkenyl, —C(O)O—C 2-12 alkynyl, —C(O)O—C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, nitro, and cyano,
R 1 is and R 1A are, independently, H, CH 3 , CH 2 F, CHF 2 , or CF 3 , wherein, when R 1 is Me, the carbon to which it is attached may be wholly or partially R or S or any mixture thereof, or R 1 and R 1A can combine to form a C 3-7 cycloalkyl ring;
R 2 is H, CN, N 3 , F, CH 2 -halogen, CH 2 —N 3 , O—CH 2 —P—(OH); substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl or substituted or unsubstituted C 2-8 alkynyl;
R 3 is selected from the group consisting of H, F, N 3 , substituted or unsubstituted (C 1-8 )alkyl, substituted or unsubstituted (C 2-8 )alkenyl, substituted or unsubstituted (C 2-8 )alkynyl, O—(C 1-8 ) alkyl and N 3 ,
R 5 is S,
R 8 and R 8′ are independently selected from the group consisting of H, OH, halo, an optionally substituted O-linked amino acid, substituted or unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, cyano, cyanoalkyl, azido, azidoalkyl, OR′, SR′, wherein each R′ is independently a —C(O)—C 1-12 alkyl, —C(O)—C 2-12 alkenyl, —C(O)—C 2-12 alkynyl, —C(O)—C 3-6 cycloalkyl, —C(O)O—C 1-12 alkyl, —C(O)O—C 2-12 alkenyl, —C(O)O—C 2-12 alkynyl, —C(O)O—C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, nitro, and cyano,
R 4 is OH, an optionally substituted O-linked amino acid, —O—C(O)—C 1-12 alkyl, —O—C(O)—C 2-12 alkenyl, —O—C(O)—C 2-12 alkynyl, —O—C(O)—C 3-6 cycloalkyl, —O—C(O)O—C 1-12 alkyl, —O—C(O)O)—C 2-12 alkenyl, —O—C(O)O—C 2-12 alkynyl, —O—C(O)O—C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 1-6 alkoxy, OC 2-6 alkenyl, OC 2-6 alkynyl, OC 3-6 cycloalkyl, O—P(O)R 6 R 7 , O—CH 2 —P—(OH) 3 , O—CH 2 —P—(OH) 3 , or a mono-, di-, or triphosphate, wherein, when chirality exists at the phosphorous center of R 4 , 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, C 1-4 (alkyl)aryl, benzyl, C 1-6 haloalkyl, C 2-3 (alkyl)OC 1-20 alkyl, 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 2 ) 0-6 CON(R 16 ) 2 ;
where R 16 is independently H, substituted or unsubstituted C 1-20 alkyl, 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, 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;
(b) the ester of a D- or L-amino acid

R 17 and R 18 are independently H, C 1-20 alkyl, 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;
Base is selected from the group consisting of:

X 1 is CH, C—(Cis)alkyl, C—(C 2-6 )alkenyl, C—(C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, C—(C 1-6 )hydroxyalkyl, C—OR 22 , C—N(R 22 ) 2 , C-halo, C—CN or N,
X 1′ is CH, C—(C 1-6 )alkyl, C—(C 2-6 )alkenyl, C—(C 2-6 )alkynyl, C-halo, C—CN or N
R 9 and X 2 are independently H, OH, NH 2 , halo (i.e., F, Cl, Br, or I), SH, NHOH, O(C 1-10 )alkyl, O(C 2-10 )alkene, O(C 2-10 )alkyne, O(C 3-7 )cycloalkyl, —O—C(O)—C 1-12 alkyl, —O—C(O)—C 2-12 alkenyl, —O—C(O)—C 2-12 alkynyl, —O—C(O))—C 3-6 cycloalkyl, —O—C(O)O—C 2-12 alkyl, —O—C(O)O—C 2-12 alkenyl, —O—C(O)O—C 2-12 alkynyl, —O—C(O)O)—C 3-6 cycloalkyl, S(C 1-10 )alkyl, S(C 2-10 )alkene, S(C 2-10 )alkyne, S(C 3-7 )cycloalkyl, an optionally unsaturated NH(C 1-10 )alkyl, an optionally unsaturated N((C 1-10 )alkyl) 2 , NH(C 3-7 )cycloalkyl, an optionally unsaturated NH(CO)(C 1-20 )alkyl, an optionally unsaturated NH(CO)((C 1-20 )alkyl, NHOH, an optionally unsaturated NHO(CO)(C 1-20 )alkyl, or an optionally unsaturated NHO(CO)NH(C 1-20 )alkyl, (C 1-3 )alkyl,
R 9′ is OH, NH 2 , SH, NHOH, —O—C(O)—C 1-12 alkyl, —O—C(O)—C 2-12 alkenyl, —O—C(O)—C 2-12 alkynyl, —O—C(O)—C 3-6 cycloalkyl, —O—C(O)O—C 1-12 alkyl, —O—C(O)O—C 2-12 alkenyl, —O—C(O)O—C 2-12 alkynyl, or —O—C(O)O—C 3-6 cycloalkyl,
R 10 is H or F,
X 2′ is N or CH, and
W is O or S.

2 . The method of claim 1 , wherein R 2 is H or substituted or unsubstituted C 2-8 alkynyl.

3 . The method of claim 1 , wherein R 3 is H.

4 . The method of claim 1 , wherein R 1 is and R 1A are H.

5 . The method of claim 1 , wherein R 8 and R 8′ are OH.

6 . The method of claim 1 , wherein R 4 is OH or O—P(O)R 6 R 7 .

7 . The method of claim 1 , wherein Base is

8 . The method of claim 8 , wherein R 9′ is OH, NH 2 , or NHOH

9 . The method of claim 1 , wherein Base is

10 . The method of claim 10 , wherein X

Assignees

• Univ Emory

Inventors

• Schinazi Raymond
• Amblard Franck
• Chen Zhe
• Zandi Keivan

Classifications

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61K31/7072

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

• A61P31/14

  for RNA viruses · CPC title

• A61K45/06

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