PURINE MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS
The present invention is directed to compounds, compositions and methods for treating or preventing viral infections using nucleoside analog monophosphate prodrugs. More specifically, HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever in human patients or other animal hosts. The compounds are certain 2,6-diamino 2-C-methyl purine nucleoside monophosphate prodrugs and modified prodrug analogs, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever. This invention teaches how to modify the metabolic pathway of 2,6-diamino 2′-C-methyl purine and deliver nucleotide triphosphate(s) to polymerases at heretofore unobtainable therapeutically-relevant concentrations.
1 . A compound of Formula (A) or a compound of Formula (B):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
when chirality exists at the phosphorous center it may be wholly or partially R p or S p or any mixture thereof
R 1 is OH or F;
Y is O or S;
R 24 is selected from OR 15 ,
and fatty alcohols,
wherein R 15 , R 17 , and R 18 are as defined below;
R 2 and R 3 , when administered in vivo, are capable of providing the nucleoside monophosphate or thiomonophosphate that is either partially or fully resistant to 6-NH 2 deamination in a biological system and are independently selected from the group consisting of:
(a) OR 15 where R 15 selected from H, Li, Na, K, phenyl and pyridinyl; Phenyl and pyridinyl are substituted with one 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 ;
R 16 is independently H, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl 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 lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
(c) the ester of an L-amino acid
where R 17 is restricted to those occurring in natural L-amino acids, and R 18 is H, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl 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 lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
(d) R 2 and R 3 together to form a ring
where R 19 is H, C 1-20 alkyl, C 1-20 alkenyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl 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 lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl; and
(e) R 2 and R 3 together to form a ring selected from
where R 20 is O or NH and
R 21 is selected from H, C 1-20 alkyl, C 1-20 alkenyl, the carbon chain derived from a fatty acid, and C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl 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 lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl.
2 . The compounds of claim 1 , wherein the compounds are in the β-D configuration.
3 . The compounds of claim 1 , wherein the compounds are converted in a biological system to mixture C or D of 6-NH 2 and 6-OH purine triphosphates.
4 . The compounds of claim 1 , wherein the compounds are converted in a biological system to therapeutically-relevant concentrations of 2,6-diamino 2′-C-methyl purine triphosphate, E or 2,6-diamino 2′-C-methyl 2′-deoxy 2′-fluoro purine triphosphate, F.
5 . A compound of claim 1 of the formula:
wherein R 1 is as defined in claim 1 , and R 4 is C 1-6 alkyl or a carbon chain derived from a fatty alcohol.
6 . The compound of claim 5 , wherein the values of R 1 , R 4 , and R 5 are selected as follows:
R 1
R 4
R 5
OH
Me
Me
F
Me
Me
OH
Et
Et
F
Et
Et
OH
i-Pr
i-Pr
F
i-Pr
i-Pr
OH
oleyl
oleyl
F
oleyl
oleyl
7 . A compound of claim 1 of the formula:
wherein R 1 is as defined in claim 1 , R 6 is H or an alkali metal, and R 7 a carbon chain derived from a fatty alcohol.
8 . A compound of claim 7 , wherein the values for R 1 , R 6 , and R 7 are as provided below:
R 1
R 6
R 7
OH
Na +
linoleyl
F
Na
linoleyl
OH
K
linoleyl
F
K
linoleyl
OH
Na
oleyl
F
Na
oleyl
OH
K
oleyl
F
K
oleyl
9 . A compound of claim 1 of the formula:
wherein R 1 is as defined in claim 1 , and R 8 is a fatty acid radical.
10 . A compound of claim 9 , wherein the values for R 1 and R 8 are as provided below:
R 1
R 8
OH
linoleyl
F
linoleyl
OH
oleyl
F
oleyl
11 . A compound of claim 1 of the formulas:
wherein R 1 is as defined in claim 1 , and R 9 is O or NH, and R 10 is a C 1-6 alkyl or a carbon chain derived from a fatty alcohol.
12 . A compound of claim 11 , wherein the values for R 1 , R 9 , and R 10 are as provided below:
R 1
R 9
R 10
OH
O
Me
F
O
Me
OH
NH
Me
F
NH
Me
OH
O
Et
F
O
Et
OH
NH
Et
F
NH
Et
OH
O
i-Pr
F
O
i-Pr
OH
NH
i-Pr
F
NH
i-Pr
13 . A compound of claim 1 having the formulas:
wherein R 1 is as defined in claim 1 , and R 11 is a C 1-6 alkyl or a carbon chain derived from a fatty alcohol.
14 . A compound of claim 13 , wherein the values of R 1 and R 11 are as provided below:
R 1
R 11
OH
Me
F
Me
OH
Et
F
Et
OH
i-Pr
F
i-Pr
15 . A compound of claim 1 of the formulas:
wherein R 1 is as defined in claim 1 , and R 12 and R 13 are, independently, O or NH.
16 . A compound of claim 15 , wherein the values of R 1 , R 12 , and R 13 are as provided below:
R 1
R 12
R 13
OH
O
O
F
O
O
OH
O
NH
F
O
NH
OH
NH
NH
F
NH
NH
17 . A compound of claim 1 having the formula:
wherein R 1 is as defined in claim 1 , R 4 is C 1-6 alkyl or a carbon chain derived from a fatty alcohol, and R 12 is O or NH.
18 . A compound of claim 17 , wherein the values of R 1 , R 4 , and R 12 are as provided below:
R 1
R 4
R 12
OH
Me
O
F
Me
O
OH
Et
O
F
Et
O
OH
i-Pr
O
F
i-Pr
O
OH
oleyl
O
OH
Me
NH
F
Me
NH
OH
Et
NH
F
Et
NH
OH
i-Pr
NH
F
i-Pr
NH
OH
oleyl
NH
F
oleyl
NH
19 . A compound of claim 1 of the formula:
wherein
and R 11 , R 7 and R 13 are as defined above.
20 . A process for preparing compounds of claim 1 wherein the phosphorous-5′-oxygen bond is formed by reaction with a reagent of general formulas G or H:
wherein:
the chirality at the phosphorous center of formulas G or H can be wholly or partially R p or S p or any mixture thereof,
Y, R 2 and R 3 are as defined above, and
R 22 is, independently, H, C 1-20 alkyl, CF 3 , aryl, heteroaryl, substituted aryl, or substituted heteroaryl, or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, chloro, fluoro, aryl, such as phenyl, heteroaryl, substituted aryl, or substituted heteroaryl.
21 - 32 . (canceled)
33 . A method for treating a host infected with Flaviviridae family of viruses, or for reducing the biological activity of an infection with Flaviviridae family of viruses, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
34 - 35 . (canceled)
36 . The method of claim 33 , wherein the compound is administered in combination with another anti-Flaviviridae virus agent.
37 . (canceled)
38 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically-acceptable carrier.
39 . The method of claim 34 , for treating a host infected with wherein the Flaviviridae virus is Norovirus or Saporovirus, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
40 - 43 . (canceled)
44 . The pharmaceutical composition of claim 38 , further comprising a second antiviral agent.
45 . The pharmaceutical composition of claim 44 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an NS3 protease inhibitor, an NS5A inhibitor, a non-nucleoside polymerase inhibitor, a helicase inhibitor, a polymerase inhibitor, a nucleotide or nucleoside analogue, an inhibitor of IRES dependent translation, and combinations thereof.