Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus

1. A method of treating a hepatitis C virus infection in a patient comprising orally administering to the patient in need thereof a masked TLR7 ligand prodrug or a pharmaceutically acceptable salt thereof, wherein the oral administration of the masked TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of the TLR7 ligand, and wherein the masked TLR7 ligand prodrug is an analog of guanosine.

2. The method of claim 1 wherein the prodrug is selected from an (a) ester, ether, or aminal moiety after conversion of a TLR7 ligand alcohol substituent, or (b) deoxygenated moiety after conversion of a TLR7 ligand oxo substituent of guanosine or analog of guanosine.

3. The method of claim 1 wherein the masked TLR7 ligand prodrug is selected from

wherein:

each R 1 is H, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl, which may be interrupted by one or more O, S, or N heteroatoms, or a substituted or unsubstituted aryl or heteroaryl;

R 4 is a substituted or unsubstituted alkyl;

R 5 is independently H, —C(O)(C 1-8 alkyl), or a racemic, L-, or D-amino acid group —C(O)CHNH 2 R 9 ;

R 6 is H, OR 10 , or N(R 11 ) 2 ;

R 9 is H, or a substituted or unsubstituted alkyl, C(O)CH(C 1-6 alkyl)NH 2 , or —C(O)CH(CH 2 -aryl)NH 2 ;

R 10 is independently H, C 1-6 alkyl, C 3-7 alkenyl, C 3-7 alkynyl, —(CR 12 R 13 ) t (C 6 -C 10 aryl), —(CR 12 R 13 ) t (C 3 -C 10 cycloalkyl), —(CR 12 R 13 ) t (C 4 -C 10 heterocyclic), —(CR 12 R 13 ) t>1 OH, —(CR 12 R 13 ) t>0 CO 2 C 1-18 alkyl, and —(CR 12 R 13 ) t>0 N(R 14 )CO 2 C 1-18 alkyl, and SO 2 (aryl), wherein t is an integer from 0 to 6 unless otherwise indicated, and wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocyclic moieties of the foregoing groups are optionally substituted with substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH-aryl, —N(alkyl)(aryl), —N(aryl) 2 , —NHCHO,

—NHC(O)alkyl, —NHC(O)aryl, —N(alkyl)C(O)H, —N(alkyl)C(O)alkyl, —N(aryl)C(O)H, —N(aryl)C(O)alkyl, —NHCO 2 alkyl, —N(alkyl)CO 2 alkyl, —NHC(O)NH 2 , —N(alkyl)C(O)NH 2 , —NHC(O)NH-alkyl, —NHC(O)N(alkyl) 2 , —N(alkyl)C(O)NH-alkyl, N(alkyl)C(O)N(alkyl) 2 , —NHSO 2 -alkyl, —N(alkyl)SO 2 -alkyl, —C(O)alkyl, —C(O)aryl, —OC(O)alkyl, —OC(O)aryl, —CO 2 -alkyl, —CO 2 -aryl, —CO 2 H, —C(O)NH 2 , —C(O)NH-alkyl, —C(O)N(alkyl) 2 , —C(O)NH-aryl, —C(O)N(aryl) 2 , —C(O)N(alkyl)(aryl), —S(O)alkyl, —S(O)aryl, —SO 2 alkyl, —SO 2 aryl, —SO 2 NH 2 , —SO 2 NH-alkyl, and —SO 2 N(alkyl) 2 ;

R 11 is independently H, C 1-6 alkyl, C 3 -C 10 cycloalkyl, or together with nitrogen forms a 5- or 6-membered heterocyclic ring;

R 12 and R 13 are independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 14 is H, C 1-6 alkyl, or —CH 2 -aryl;

X is O or S;

Y is H, halo, OH, OR 4 , SH, SR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , or a substituted or unsubstituted alkyl or aryl; and

or stereoisomer or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 wherein R 1 is H or a substituted or unsubstituted alkyl, alkenyl, or alkynyl; R 5 is independently H, —C(O)(C 1-18 alkyl), or a racemic, L-, or D-amino acid group —C(O)CHNH 2 R 9 , wherein R 9 is an unsubstituted alkyl; R 6 is H or OR 10 , wherein R 10 is independently C 1-6 alkyl, C 3-7 alkenyl, C 3-7 alkynyl, —(CR 12 R 13 ) t (C 6 -C 10 aryl), —(CR 12 R 13 ) t (C 4 -C 10 heterocyclic), and —(CR 12 R 13 ) t>0 N(R 14 )CO 2 C 1-8 alkyl, wherein t is an integer from 0 to 4 unless otherwise indicated, and wherein the alkyl, alkenyl, aryl, and heterocyclic moieties of the foregoing groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, —CO 2 -alkyl, —CO 2 -aryl, —OC(O)alkyl, and —OC(O)aryl, and wherein R 12 and R 13 are independently H, C 1-6 alkyl, or C 2-6 alkenyl; and R 14 is H, —CH 3 , or —CH 2 CH 3 ; X is O or S; and Y is H, halo, OH, OR 4 , SH, or SR 4 .

5. The method of claim 1 wherein the masked TLR7 ligand prodrug is selected from

6. The method of claim 1 wherein the oral administration of the masked TLR7 ligand prodrug achieves an in vivo effective plasma concentration of the TLR7 ligand that is 10% to 500% of the effective in vivo exposure obtained upon oral administration of the TLR7 ligand alone.

7. The method of claim 1 wherein the oral administration of the masked TLR7 ligand prodrug achieves an in vivo effective plasma concentration of the TLR7 ligand that is 50% to 200% of the effective in vivo exposure obtained upon oral administration of the TLR7 ligand alone.

8. The method of claim 1 wherein the oral administration of the masked TLR7 ligand prodrug reduces undesirable side effects in a patient relative to the side effects upon oral administration of the TLR7 ligand alone.

9. The method of claim 1 wherein the oral administration of the masked TLR7 ligand prodrug reduces undesirable side effects by 50% in a patient relative to the side effects upon oral administration of the TLR7 ligand alone.

10. The method of claim 8 , wherein the side effect is gastrointestinal irritancy.

11. The method of claim 10 wherein the irritancy is hemorrhage.

12. The method of claim 10 wherein the irritancy is lesions.

13. The method of claim 10 wherein the irritancy is emesis.

14. The method of claim 1 wherein the patient is human.

15. The method of claim 1 further comprising administering a pharmaceutically acceptable excipient, carrier, or vehicle.

16. The method of claim 1 further comprising administering an additional therapeutic agent.

17. The method of claim 16 wherein the additional therapeutic agent is an antiviral agent.

18. The method of claim 1 wherein the therapeutically effective dose is 0.001 to 100 mg/kg per day.

19. The method of claim 18 wherein the therapeutically effective dose is about 0.1 to 25 mg/kg per day.

20. The method of claim 19 wherein the therapeutically effective dose is about 1 to 20 mg/kg per day.