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

• US 20050054590A1
• Filed: 09/01/2004
• Published: 03/10/2005
• Est. Priority Date: 09/05/2003
• Status: Active Grant

• Current Assignee: Anadys Pharmaceuticals Inc. (Roche Holding AG)
• Original Assignee: Anadys Pharmaceuticals Inc. (Roche Holding AG)
• Inventors: Averett, Devron R.
• Granted Patent: US 7,576,068 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to methods for treating or preventing hepatitis C virus infections in mammals using Toll-Like Receptor (TLR)7 ligands and prodrugs thereof. More particularly, this invention relates to methods of orally administering a therapeutically effective amount of one or more prodrugs of TLR7 ligands for the treatment or prevention of hepatitis C viral infection. Oral administration of these TLR7 immunomodulating ligands and prodrugs thereof to a mammal provides therapeutically effective amounts and reduced undesirable side effects.

Claims

1. A method of treating a hepatitis C virus infection in a patient comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of a TLR7 ligand or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.

29. 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.

2. A method of treating a hepatitis C virus infection in a patient comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of a TLR7 ligand or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein the TLR7 ligand is selected from analogs and derivatives of guanosine, imidazoquinoline, adenine, and pyrimidine.

3. The method of claim 2 wherein the TLR7 ligand is selected from

4. The method of claim 2 wherein the TLR7 ligand is selected from Formula Ia, Ib, Ic, Id, Ie, If, Ig, and Ih, wherein R¹ is H or a substituted or unsubstituted alkyl, alkenyl, or alkynyl;

R² is H, OH, halo, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or CH₂—

O-(alkyl);

R³ is H, OH, or SH, or a substituted or unsubstituted —

O-(alkyl), —

S-(alkyl), or —

NH(alkyl);

X is O or S;

Y is H, halo, OH, OR⁴, SH, or SR⁴; and

Z is H, halo, OH, OR⁴, SH, or SR4.

5. The method of claim 2 wherein the TLR7 ligand is selected from

6. The method of claim 2 wherein the patient is human.

7. The method of claim 2 further comprising administering a pharmaceutically acceptable excipient, carrier, or vehicle.

8. The method of claim 2 further comprising administering an additional therapeutic agent.

9. The method of claim 8 wherein the additional therapeutic agent is an antiviral agent.

10. The method of claim 2 wherein the therapeutically or prophylactically effective dose is 0.001 to 100 mg/kg per day.

11. The method of claim 10 wherein the therapeutically or prophylactically effective dose is about 0.01 to 50 mg/kg per day.

12. The method of claim 11 wherein the therapeutically or prophylactically effective dose is about 0.1 to 20 mg/kg per day.

13. The method of claim 2 wherein the TLR7 ligand is administered parenterally.

14. The method of claim 2 wherein the TLR7 ligand is administered intravenously.

15. The method of claim 2 wherein the TLR7 ligand is administered orally.

16. The method of claim 2 wherein the TLR7 ligand is administered mucosally.

17. A method of treating a hepatitis C virus infection in a patient comprising orally administering to the patient in need thereof a TLR7 ligand prodrug or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein the oral administration of the TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of the TLR7 ligand while reducing undesirable side effects associated with oral administration of TLR7 ligands.

18. 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, hydrate, or stereoisomer thereof, wherein the oral administration of the masked TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of the TLR7 ligand while reducing undesirable side effects associated with oral administration of TLR7 ligands.

19. The method of claim 18 wherein the masked TLR7 ligand prodrug is selected from analogs and derivatives of guanosine, imidazoquinoline, adenine, and pyrimidine.

20. The method of claim 19 wherein the prodrug is an (a) amide, carbamate, or amidine moiety after conversion of a TLR7 ligand amine substituent, (b) ester, carbonate, carbamate, ether, imidate, acetal, aminal, or ketal moiety after conversion of a TLR7 ligand alcohol substituent, (c) acetal or ketal moiety after conversion of a TLR7 ligand keto substituent, (d) imidate moiety after conversion of a TLR7 ligand carbonyl of an amido substituent, (e) deoxygenated moiety after conversion of a TLR7 ligand oxo substituent of pyrimidine or guanosine, or (f) amine.

21. The method of claim 20 wherein the prodrug is selected from an (a) carbamate moiety after conversion of a TLR7 ligand amine substituent, (b) ester, ether, or aminal moiety after conversion of a TLR7 ligand alcohol substituent, or (e) deoxygenated moiety after conversion of a TLR7 ligand oxo substituent of pyrimidine or guanosine.

22. The method of claim 18 wherein the prodrug of the masked TLR7 ligand is selected from

23. The method of claim 22 wherein R¹ is H or a substituted or unsubstituted alkyl, alkenyl, or alkynyl;

R² is H, OH, halo, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or —

CH₂—

O-(alkyl);

R³ is H, OH, or SH, or a substituted or unsubstituted —

O-(alkyl), —

S-(alkyl), or —

NH(alkyl);

R⁵ is independently H, —

C(O)(C_1-18alkyl), or a racemic, L-, or D-amino acid group —

C(O)CHNH₂R⁹, wherein R⁹ is an unsubstituted alkyl;

R⁶ is H or OR¹⁰, wherein R¹⁰ is independently C_1-6 alkyl, C_3-7 alkenyl, C_3-7 alkynyl, —

(CR¹²R¹³)_t(C₆-C₁₀ aryl), —

(CR¹²R¹³)_t(C₄-C₁₀ heterocyclic), and —

(CR¹²R¹³)<sub>t>

0</sub>N(R¹⁴)CO₂C_1-18 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy, C₁-C₆ alkoxy, —

CO₂-alkyl, —

CO₂-aryl, —

OC(O)alkyl, and —

OC(O)aryl, and wherein R¹² and R¹³ are independently H, C_1-6 alkyl, or C_2-6 alkenyl; and

R¹⁴ is H, CH₃, or —

CH₂CH₃;

R⁷ is independently H or a substituted or unsubstituted —

C(O)(C_1-18alkyl) or —

C(O)₂(C_1-18alkyl);

R⁸ is H, —

OH, —

O-(alkyl), —

OCO₂(C_1-18alkyl), or a racemic, L-, or D-amino acid group —

OC(O)CHNH₂R¹;

X is O or S;

Y is H, halo, OH, OR⁴, SH, or SR4; and

Z is H, halo, OH, OR⁴, SH, or SR⁴.

24. The method of claim 18 wherein the masked TLR7 ligand prodrug is selected from

25. The method of claim 18 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.

26. The method of claim 18 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.

27. The method of claim 25 wherein the oral administration of the masked TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of the corresponding TLR7 ligand without causing gastrointestinal irritation.

28. The method of claim 18 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.

30. The method of claim 18 wherein the side effect is gastrointestinal irritancy.

31. The method of claim 30 wherein the irritancy is hemorrhage.

32. The method of claim 30 wherein the irritancy is lesions.

33. The method of claim 30 wherein the irritancy is emesis.

34. The method of claim 18 wherein the patient is human.

35. The method of claim 18 further comprising administering a pharmaceutically acceptable excipient, carrier, or vehicle.

36. The method of claim 18 further comprising administering an additional therapeutic agent.

37. The method of claim 36 wherein the additional therapeutic agent is an antiviral agent.

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

39. The method of claim 38 wherein the therapeutically or prophylactically effective dose is about 0.1 to 25 mg/kg per day.

40. The method of claim 39 wherein the therapeutically or prophylactically effective dose is about 1 to 20 mg/kg per day.

41. The method of claim 18 wherein the masked TLR7 ligand prodrug is administered parenterally.

42. The method of claim 41 wherein the masked TLR7 ligand prodrug is administered intravenously.

43. The method of claim 18 wherein the masked TLR7 ligand prodrug is administered orally.

44. The method of claim 18 wherein the masked TLR7 ligand prodrug is administered mucosally.

45. A method for treating diseases responsive to immuno therapy while reducing undesirable side effects associated with immunologic agents, comprising orally administering a masked TLR7 ligand prodrug to a patient in need of immuno therapy, wherein the masked TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of a TLR7 ligand in the patient.

46. The method of claim 45 wherein the masked TLR7 ligand prodrug is selected from analogs and derivatives of guanosine, imidazoquinoline, adenine, and pyrimidine.

47. The method of claim 45 wherein the prodrug is an (a) amide, carbamate, or amidine moiety after conversion of a TLR7 ligand amine substituent, (b) ester, carbonate, carbamate, ether, imidate, acetal, aminal, or ketal moiety after conversion of a TLR7 ligand alcohol substituent, (c) acetal or ketal moiety after conversion of a TLR7 ligand keto substituent, (d) imidate moiety after conversion of a TLR7 ligand carbonyl of an amido substituent, (e) deoxygenated moiety after conversion of a TLR7 ligand oxo substituent of pyrimidine or guanosine, or (f) amine.

48. The method of claim 47 wherein the prodrug is selected from an (a) carbamate moiety after conversion of a TLR7 ligand amine substituent, (b) ester, ether, or animal moiety after conversion of a TLR7 ligand alcohol substituent, or (e) deoxygenated moiety after conversion of a TLR7 ligand oxo substituent of pyrimidine or guanosine.

49. The method of claim 45 wherein the masked TLR7 ligand prodrug is selected from

50. The method of claim 49 wherein R₁ is H or a substituted or unsubstituted alkyl, alkenyl, or alkynyl;

R² is H, OH, halo, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or —

CH₂—

O-(alkyl);

R³ is H. OH, or SH, or a substituted or unsubstituted —

O-(alkyl), —

S-(alkyl), or —

NH(alkyl);

R⁵ is independently H, —

C(O)(C_1-18alkyl), or a racemic, L-, or D-amino acid group —

C(O)CHNH₂R⁹, wherein R⁹ is an unsubstituted alkyl;

R⁶ is H or OR¹⁰, wherein R¹⁰ is independently C_1-6 alkyl, C_3-7 alkenyl, C_3-7 alkynyl, —

(CR¹²R¹³)_t(C₆-C₁₀ aryl), —

(CR ¹²R¹³)_t(C₄-C₁₀ heterocyclic), and —

(CR¹²R¹³)<sub>t>

0</sub>N(R¹⁴)CO₂C_1-18 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy, C₁-C₆ alkoxy, —

CO₂-alkyl, —

CO₂-aryl, —

OC(O)alkyl, and —

OC(O)aryl, and wherein R¹² and R¹³ are independently H, C_1-6 alkyl, or C_2-6 alkenyl; and

R¹⁴ is H, —

CH₃, or —

CH₂CH₃;

R⁷ is independently H or a substituted or unsubstituted (O)(C_1-18alkyl) or —

C(O)₂(C_1-18alkyl);

R⁸ is H, —

OH, —

O-(alkyl), —

OCO₂(C_1-18alkyl), or a racemic, L-, or D-amino acid group —

OC(O)CHNH₂R¹;

X is O or S;

Y is H, halo, OH, OR⁴, SH, or SR4; and

Z is H, halo, OH, OR⁴, SH, or SR4.

51. The method of claim 45 wherein the masked TLR7 ligand prodrug is selected from

52. The method of claim 45 wherein the disease is a viral infection.

53. The method of claim 52 wherein the viral infection is selected from an RNA or DNA virus including adenovirus, cytomegalovirus, hepatitis A virus (HAV), hepadnaviruses including hepatitis B virus (HBV), flaviviruses including Yellow Fever virus, hepaciviruses including hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes zoster, human herpesvirus 6, human immunodeficiency virus (HIV), human papilloma virus (HPV), influenza A virus, influenza B virus, measles, parainfluenza virus, pestivirus, poliovirus, poxvirus (including smallpox and monkeypox virus), rhinovirus, coronovirus, respiratory syncytial virus (RSV), multiple families of viruses that cause hemorrhagic fevers, including the Arenaviruses, the Bunyaviruses and Filoviruses, and a range of viral encephalitides caused by RNA and DNA viruses.

54. The method of claim 45 wherein the disease is a cancer.

55. The method of claim 45 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.

56. The method of claim 55 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.

57. The method of claim 56 wherein the oral administration of the masked TLR7 ligand prodrug achieves a therapeutically effective plasma concentration of the corresponding TLR7 ligand without causing gastrointestinal irritation.

58. The method of claim 45 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.

59. The method of claim 45 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.

60. The method of claim 45 wherein the side effect is gastrointestinal irritancy.

61. The method of claim 60 wherein the irritancy is hemorrhage.

62. The method of claim 60 wherein the irritancy is lesions.

63. The method of claim 60 wherein the irritancy is emesis.

64. The method of claim 45 wherein the patient is human.

65. The method of claim 45 further comprising administering a pharmaceutically acceptable excipient, carrier, or vehicle.

66. The method of claim 45 further comprising administering an additional therapeutic agent.

67. The method of claim 66 wherein the additional therapeutic agent is an antiviral agent.

68. The method of claim 45 wherein the therapeutically or prophylactically effective dose is 0.001 to 100 mg/kg per day.

69. The method of claim 68 wherein the therapeutically or prophylactically effective dose is about 0.01 to 50 mg/kg per day.

70. The method of claim 69 wherein the therapeutically or prophylactically effective dose is about 0.1 to 20 mg/kg per day.

71. The method of claim 45 wherein the masked TLR7 ligand prodrug is administered parenterally.

72. The method of claim 71 wherein the masked TLR7 ligand prodrug is administered intravenously.

73. The method of claim 45 wherein the masked TLR7 ligand prodrug is administered orally.

74. The method of claim 45 wherein the masked TLR7 ligand prodrug is administered mucosally.