Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer
The present invention is directed to compounds, compositions and methods for treating or preventing Flaviviridae family of viruses (including HCV, Yellow fever, Dengue, Chikungunya and West Nile virus), RSV, HEV, and influenza infection and cancer in human subjects or other animal hosts.
1. A compound of Formula (A) or (B):
or a pharmaceutically acceptable salt, wherein:
R 1 is H or Me, wherein, when R 1 is Me it may be wholly or partially R or S or any mixture thereof;
R 2 is H, N 3 , F, (C 1-8 )alkyl, (C 2-8 )alkenyl or (C 2-8 )alkynyl;
R 4 is H or P(O)R 6 R 7 , 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 5 is O, CH 2 , S, Se, CHF, CF 2 , or C═CH 2 ,
R 3 is H or CN when R 5 is O, and
R 3 is selected from the group consisting of H, CN, (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and O—(C 1-8 ) alkyl when R 5 is CH 2 , CHF, CF 2 , or C═CH 2 ,
R 8 is selected from the group consisting of H, C(O)(C 1-8 )alkyl, C(O)(C 1-8 )branched alkyl, C(O)NH(C 1-8 )alkyl, C(O)NH(C 1-8 )branched alkyl, C(O)aryl C(O)(C 1-8 )alkyl-aryl, C(O)NH(C 1-8 )alkyl-aryl C(O)O(C 1-8 )alkyl, C(O)O(C 1-8 )branched alkyl, C(O)O(C 1-8 )alkyl-aryl or OR 8 as it appears in Formulas A or B is an ester derived from an alpha amino acid,
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, C 1-20 alkyl, 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, wherein phenyl and pyridinyl 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 ;
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 a D- or 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 6 and R 7 can come 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;
(e) R 6 and R 7 can come together to form a ring selected from the group consisting of
where
R 20 is O or NH, and
R 21 is selected from the group consisting of 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,
Base is selected from the group consisting of:
X 1 is CH, C—(C 1-6 )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,
R 22 is independently H, (C 1-10 )alkyl, (C 1-10 )haloalkyl or (C 3-7 )cycloalkyl,
R 9 is OH, NH 2 , O(C 1-10 )alkyl, O(C 3-7 )cycloalkyl, NH(C 1-10 )alkyl, N((C 1-10 )alkyl) 2 , NH(C 3-7 )cycloalkyl, NH(CO)(C 1-20 )alkyl, NH(CO)O(C 1-20 )alkyl, NHOH, NHO(CO)(C 1-20 )alkyl, NHO(CO)NH(C 1-20 )alkyl,
R 10 is H, F or CH 3 and
X 2 is H, F, Cl (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )hydroxyalkyl, OR 22 , SR 22 , N(R 22 ) 2 , NHC(O)OR 22 , NHC(O)N(R 22 ) 2 , NHC(O)R 22 , CN or NH 2 .
2. The compounds of claim 1 , wherein the compounds can be present in the β-D or β-L configuration.
3. The compounds of claim 1 , having one of the following formulas:
where R 4 and Base are as defined above in claim 1 .
4. A compound of claim 1 , having one of the following formulas:
or pharmaceutically acceptable salts thereof.
5. A compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , having the formula:
7. The compound of claim 1 wherein the sugar is partially deuterated.
8. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically-acceptable carrier.
9. The composition of claim 8 , wherein the composition is a transdermal composition or a nanoparticulate composition.
10. The pharmaceutical composition of claim 8 , further comprising a second antiviral agent.
11. The pharmaceutical composition of claim 10 , 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.
12. A method for treating a host infected with one or more viruses selected from the group consisting of HCV, Yellow fever, Dengue, Chikungunya and West Nile virus comprising administering an effective antiviral amount of a compound of claim 1 to a patient in need of treatment of one or more of an HCV, Yellow fever, Dengue, Chikungunya or West Nile virus infection.
13. The method of claim 12 , wherein the virus is selected from the group consisting of HCV, Yellow fever, Dengue, Chikungunya and West Nile virus.
14. The method of claim 12 , wherein the compound is administered in combination with another anti-Flaviviridae virus agent.
15. A method for treating a host infected with Norovirus or Saporovirus, comprising administering an effective antiviral amount of a compound of claim 1 to a patient in need of treatment of a Norovirus or Sapovirus infection.
16. A method for treating a host infected with RSV or influenza, comprising administering an effective antiviral amount of a compound of claim 1 to a patient in need of treatment of an RSV or influenza infection.
17. A method for treating a host infected with HEV, comprising administering an effective antiviral amount of a compound of claim 1 to a patient in need of treatment of an HEV infection.