Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-9441007-B2
Application number	US-201314386294-A
Country	US
Kind code	B2
Filing date	Mar 19, 2013
Priority date	Mar 21, 2012
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.

First claim

What is claimed is:

1. A method for ameliorating or treating a viral infection caused by a virus comprising administering to or contacting a cell in a subject with an effective amount of a compound selected from Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt of the foregoing, wherein the virus is selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus and a metapneumovirus, and wherein the compound is selected from Formula (I), Formula (II), and Formula (III) has one of the following structures:

wherein:
B 1A B 1B and B 1C are independently an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;
R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid,

the dashed line (------)of Formula (I) is absent;
R 2A is selected from the group consisting of an unsubstituted C 1-6 alkyl, a halogen substituted C 1-6 alkyl, a hydroxy substituted C 1-6 alkyl, an alkoloxy substituted C 1-6 alkyl, a sulfenyl substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted —O—C 1-6 alkyl, an optionally substituted —O—C 3-6 alkenyl, an optionally substituted —O—C 3-6 alkynyl and cyano;
R 3A is selected from the group consisting of OH, —OC(═O)R″ A and an optionally substituted O-linked amino acid;
R 1B is selected from the group consisting of O − , OH,

 an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
R 1C and R 2C are independently selected from the group consisting of O − , OH, an optionally substituted C 1-6 alkoxy,

 an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; or
R 1C is

 and R 2C is O − or OH;
R 2B and R 3 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted —O—C 1-6 alkyl, an optionally substituted —O—C 3-6 alkenyl, an optionally substituted —O—C 3-6 alkynyl and cyano;
R 4C is selected from the group consisting of OH, —OC(═O)R″ C and an optionally substituted O-linked amino acid;
R 4A , R 3B and R 5C are independently a halogen;
R 5A , R 4B and R 6C are independently hydrogen or halogen;
R 6A , R 7A and R 8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted *—(CR 15A R 16A ) p —O—C 1-24 alkyl, an optionally substituted *—(CR 17A R 18A ) q —O—C 1-24 alkenyl,

 or
R 6A is

 and R 7A is absent or hydrogen; or
R 6A and R 7A are taken together to form a moiety selected from the group consisting of an optionally substituted

 and an optionally substituted

 wherein the oxygens connected to R 6A and R 7A , the phosphorus and the moiety form a six-membered to ten-membered ring system;
R 9A is independently selected from the group consisting of an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, NR 3OA R 31A , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
R 10A and R 11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
R 12A , R 13A and R 14A are independently absent or hydrogen;
each R 15A , each R 16A , each R 17A and each R 18A are independently hydrogen, an optionally substituted C 1-24 alkyl or alkoxy;
R 19A , R 20A , R 22A , R 23A , R 5B , R 6B , R 8B , R 9B , R 9C , R 10C , R 12C and R 13C are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 21A , R 24A , R 7B , R 10B , R 11C and R 14C are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl and an optionally substituted —O-aryl;
R 25A , R 29A , R 11B and R 15C are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 16C , R 17C and R 18C are independently absent or hydrogen;
R 26A and R 27A are independently —C≡N or an optionally substituted substituent selected from the group consisting of C 2-8 organylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 organylaminocarbonyl;
R 28A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 -alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl;
R 30A and R 31A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 -alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl;
for Formula (III), ------- is a single bond or a double bond;
when ------- is a single bond, each R 7C and each R 8C is independently hydrogen or halogen; and
when ------- is a double bond, each R 7C is absent and each R 8C is independently hydrogen or halogen;

R″ A and R″ C are independently an optionally substituted C 1-24 -alkyl;
m and n are independently 0 or 1;
p and q are independently selected from the group consisting of 1, 2 and 3;
r is 1 or 2;
Z 1A , Z 2A , Z 3A , Z 4A , Z 1B , Z 2B and Z 1C are independently O or S; and
provided that when R 1A is

 wherein R 8A is an unsubstituted C 1-4 alkyl or phenyl optionally para-substituted with a halogen or methyl and R 9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester o

Assignees

• Alios Biopharma Inc

Inventors

• Wang Guangyi
• Smith David Bernard
• Beigelman Leonid
• Deval Jerome
• Prhavc Marija

Classifications

• C07H19/207

  the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide · CPC title

• A61K31/7076

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

• A61K31/708 Primary

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H19/20 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title