6-aza-nucleoside prodrugs as antiviral agents for treating virus infections

Patent metadata

Field	Value
Publication number	US-11858956-B2
Application number	US-202117554979-A
Country	US
Kind code	B2
Filing date	Dec 17, 2021
Priority date	Dec 18, 2020
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

The present disclosure is concerned with 6-aza-nucleoside prodrugs that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, yellow fever virus, tick-borne encephalitis virus, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), Eastern equine encephalitis (EEEV), Western equine encephalitis (WEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV), Middle East Respiratory Syndromes (MERS), Severe Acute Respiratory Syndrome (SARS), and coronavirus disease 2019 (COVID-19), using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein R 1 is selected from —C(O)R 10 , —C(O)CH(R 11 )NH 2 , and —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 ;
wherein R 10 , when present, is selected from C1-C20 alkyl and C2-C20 alkenyl;
wherein R 11 , when present, is a side chain of an amino acid selected from arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan;
wherein R 12 , when present, is selected from C1-C6 alkyl and C3-C6 cycloalkyl;
wherein R 13 , when present, is selected from C1-C8 alkyl, C3-C8 cycloalkyl, Ar 2 , and —CH 2 Ar 2 ;
wherein Ar 2 , when present, is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

wherein each of R 14a and R 14b , when present, is independently C1-C8 alkyl; and
wherein Ar 1 , when present, is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halog'en, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and

wherein R 2 is a structure represented by a formula selected from:

 and
wherein R 15 , when present, is selected from hydrogen, —C(O)(C1-C20 alkyl), —C(O)(C3-C6 cycloalkyl), and —C(O)(C2-C20 alkenyl),

provided that when R 2 is

then R 1 is —C(O)CH(R 11 )NH 2 or —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 ,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 .

3. The compound of claim 1 , wherein R 1 is —C(O)CH(R 11 )NH 2 .

4. The compound of claim 1 , wherein R 2 is a structure represented by a formula:

5. The compound of claim 4 , wherein the compound has a structure represented by a formula selected from:

6. The compound of claim 4 , wherein the compound is selected from:

7. The compound of claim 1 , wherein R 2 is a structure represented by a formula:

8. The compound of claim 7 , wherein the compound has a structure represented by a formula selected from:

9. The compound of claim 7 , wherein the compound has a structure represented by a formula selected from:

10. The compound of claim 7 , wherein the compound is selected from:

11. The compound of claim 1 , wherein R 11 is selected from:

12. A compound having a structure represented by a formula:

wherein R 15 , when present, is selected from hydrogen, —C(O)(C1-C20 alkyl), —C(O)(C3-C6 cycloalkyl), and —C(O)(C2-C20 alkenyl).

13. A pharmaceutical composition comprising a therapeutically effective amount of compound having a structure represented by a formula:

wherein R 1 is selected from hydrogen, —C(O)R 10 , —C(O)CH(R 11 )NH 2 , —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 , and —P(O)(OR 14a )(OR 14b );
wherein R 10 , when present, is selected from C1-C20 alkyl and C2-C20 alkenyl;
wherein R 11 , when present, is a side chain of an amino acid selected from arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan;
wherein R 12 , when present, is selected from C1-C6 alkyl and C3-C6 cycloalkyl;
wherein R 13 , when present, is selected from C1-C8 alkyl, C3-C8 cycloalkyl, Ar 2 , and —CH 2 Ar 2 ;
wherein Ar 2 , when present, is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

wherein each of R 14a and R 14b , when present, is independently C1-C8 alkyl; and
wherein Ar 1 , when present, is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halog'en, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and

wherein R 2 is a structure represented by a formula selected from:

 and
wherein R 15 , when present, is selected from hydrogen, —C(O)(C1-C20 alkyl), —C(O)(C3-C6 cycloalkyl), and —C(O)(C2-C20 alkenyl),

provided that when R 2 is

then R 1 is —C(O)CH(R 11 )NH 2 , —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 , or —P(O)(OR 14a )(OR 14b ), and
provided that when IV is hydrogen, then R 15 is —C(O)(C1-C20 alkyl), —C(O)(C3-C6 cycloalkyl), or —C(O)(C2-C20 alkenyl),
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for treating a viral infection in a subject having the viral infection, the method comprising administering to the subject a compound having a structure represented by a formula:

wherein R 1 is selected from hydrogen, —C(O)R 10 , —C(O)CH(R 11 )NH 2 , —P(O)(OAr 1 )NHCH(R 12 )CO 2 R 13 , and —P(O)(OR 14a )(OR 14b );
wherein R 10 , when present, is selected from C1-C20 alkyl and C2-C20 alkenyl;
wherein R H, when present, is a residue of an amin

Assignees

• Southern Res Inst
• Univ Oregon Health & Science
• Washington University St Louis
• Univ Texas

Inventors

• Moukha-Chafiq Omar
• Pathak Ashish Kumar
• Karyakarte Shuklendu D
• Bratton Larry D
• Augelli-Szafran Corinne E
• Diamond Michael
• Shi Pei Yong
• Hirsch Alec Jay
• Smith Jessica Lee
• Streblow Daniel
• Haese Nicole
• Ying Baoling

Classifications

• C07H19/12 Primary

  Triazine radicals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P31/16 Primary

  for influenza or rhinoviruses · CPC title