Azido nucleosides and nucleotide analogs
AssigneeAlios BioPharma, Inc.
InventorsLeonid Beigelman, Jerome Deval, David Bernard Smith, Guangyi Wang, Vivek Kumar Rajwanshi
Life of this patent
Estimating the term…
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. Examples of viral infections include a respiratory syncytial viral (RSV) and influenza infection.
Claims46
A method of ameliorating or treating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising administering a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject suffering from the viral infection, wherein the compound of Formula (II) has the structure:
- wherein:
- B1a is selected from the group consisting of an optionally substituted heterocyclic base and an optionally substituted heterocyclic base with a protected amino group;
- R1a is selected from the group consisting of hydrogen, an optionally substituted acyl,
- na is 0, 1, or 2;
- R2a and R3a are independently selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl;
- R4a is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl, —OR18a and —OC(═O)R19a;
- R5a is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl, —OR20a and —OC(═O)R21a;
- R6a is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl, —OR22a and —OC(═O)R23a;
- or R5a and R6a are both oxygen atoms and linked together by a carbonyl group;
- R7a is selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, —OR24a and —OC(═O)R25a;
- R8a is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl;
- R9a and R12a are independently absent or hydrogen;
- R10a is absent or hydrogen;
- each R11a is independently absent or hydrogen;
- R13a is absent or hydrogen;
- R14a is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R15a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R14a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R15a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R14a is O−, hydroxy or an —O-optionally substituted C1-6 alkyl, and R15a and R5a together are O;
- R16a is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R17a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R16a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R17a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R16a is O−, hydroxy or an —O-optionally substituted C1-6 alkyl, and R17a and R5a together are O;
- R18a, R20a, R22a and R24 are independently hydrogen or an optionally substituted C1-6 alkyl;
- and
- R19a, R21a, R23a and R25a are independently selected from the group consisting of an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl.
A method of inhibiting replication of a virus selected from paramyxovirus and orthomyxovirus comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
A method of ameliorating or treating a viral infection selected from paramyxovirus viral infection and orthomyxovirus viral infection comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
A method of ameliorating or treating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising administering a therapeutically effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in combination with one or more agents to a subject suffering from the viral infection.
A method of treating or ameliorating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in combination with one or more agents.
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein:
- B1 is selected from the group consisting of an optionally substituted heterocyclic base and an optionally substituted heterocyclic base with a protected amino group;
- R1 is selected from the group consisting of hydrogen, an optionally substituted acyl,
- n is 0, 1 or 2;
- R2 and R3 are independently selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl;
- R4 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, —OR18 and —OC(═O)R19;
- R5 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, —OR20 and —OC(═O)R21;
- R6 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, —OR22 and —OC(═O)R23;
- or R5 and R6 are both oxygen atoms and linked together by a carbonyl group;
- R7 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, —OR24 and —OC(═O)R25;
- R8 is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl and an optionally substituted C1-6 haloalkyl;
- R9, R10, each R11, R12 and R13 are independently absent or hydrogen;
- R14 is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R15 is
- or
- R14 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R15 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R14 is O−, hydroxy or an —O-optionally substituted C1-6 alkyl, and R15 and R5 together are O;
- R16 is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R17 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R16 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R17 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
- or
- R16 is O−, hydroxy or an —O-optionally substituted C1-6 alkyl, and R17 and R5 together are O;
- R18, R20, R22 and R24 are independently selected from the group consisting of hydrogen and an optionally substituted C1-6 alkyl;
- R19, R21, R23 and R25 are independently selected from the group consisting of an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl;
- R26 is hydrogen or an optionally substituted C1-4-alkyl;
- R27 is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted C10 aryl and an optionally substituted aryl(C1-6 alkyl);
- and
- R28 is selected from the group consisting of hydrogen, an optionally substituted C1-6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C1-6 alkyl) and an optionally substituted haloalkyl,
- or R26 and R27 are taken together to form an optionally substituted C3-6 cycloalkyl;
- provided that when R2, R3, R4, and R8 are all hydrogen, R1 cannot be hydrogen;
- provided that when R2 and R3 are both hydrogen, R5 is hydroxy, R4 and R6 are both hydrogen, R7 is halogen, R8 is hydrogen, and B1 is
- then R1 cannot be
- wherein n is 0 or 2;
- and R9, R10 and R11 are hydrogen;
- provided that when R1 is
- R2 and R3 are both hydrogen, R4 is hydrogen, R5 is OH, R6 is selected from the group consisting of halogen, hydrogen, and hydroxy, R7 is selected from the group consisting of halogen, hydrogen, methyl, and hydroxy, R8 is hydrogen, B1 selected from the group consisting of
- R14 is an —O-optionally substituted aryl, then R15 cannot be
- wherein R26 is hydrogen or an optionally substituted C1-4 alkyl;
- R27 is selected from the group consisting of hydrogen, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2CH2SCH3, —CH2CH2COOCH2CH3, —CH2C(═O)OCH2CH3, —CH2-indol-3-yl, —CH2-phenyl, unsubstituted cyclopentyl and —CH(CH2CH3)CH3;
- and R28 is selected from the group consisting of unsubstituted C1-4-alkyl, unsubstituted benzyl and CH2CF3;
- provided that when R1 is
- R2, R3, R4, R7 and R8 are all hydrogen, R5 is hydroxy, R6 is hydroxy, R14 is —O-naphthyl, R15 is
- wherein R26 is hydrogen, R27 is methyl and R28 is benzyl, then B1 cannot be
- provided that when R1 is
- R2, R3, R4, R7 and R8 are all hydrogen, R5 is hydroxy, R6 is hydroxy, R14 is —O-phenyl, R15 is
- wherein R26 and R27 are taken together to form an substituted cyclopentyl ring and R28 is an unsubstituted C1-4 alkyl or benzyl, then B1 cannot be
- provided that B1 cannot be adenine or an optionally substituted adenine when at least one of R2 and R3 is not hydrogen;
- and
- provided that a compound of Formula (I) cannot have the following structure:
Dependencies are inferred from the claim text.