INHIBITORS OF MTOR KINASE AS ANTI -VIRAL AGENT

• US 20140206678A1
• Filed: 01/27/2012
• Published: 07/24/2014
• Est. Priority Date: 01/27/2011
• Status: Abandoned Application

• Current Assignee: The Trustees of Princeton University (Princeton University), Kadmon Corporation, LLC (Sanofi )
• Original Assignee: The Trustees of Princeton University (Princeton University), Kadmon Corporation, LLC (Sanofi )
• Inventors: Shenk, Thomas, Kim, Ji-In
• Application Number:
  US13/982,331
• Publication Number:
  US 20140206678A1
• Time in Patent Office: Days
• US Class Current: 514/230.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5386 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods for treating or preventing viral infections using modulators of host cell enzymes relating to mTOR. The invention also provides methods for treating or preventing viral infections using modulators of host cell enzymes relating to mTOR and modulators of the unfolded protein response.

Claims

1. A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula VIII

2. The method of claim 1, wherein the compound of formula VIII is GNE-493.

3. The method of claim 1, wherein the compound of formula VIII is GNE-0941.

4. The method of claim 1, wherein the compound is an inhibitor of mTORC1.

5. The method of claim 1, wherein the compound is an inhibitor of mTORC2.

6. The method of claim 1, wherein the viral infection is by a herpesvirus.

7. The method of claim 1, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

8. The method of claim 1, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

9. The method of claim 8 wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

10. The method of claim 8 wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

11. A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug;

and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula VIII;

12. The pharmaceutical composition of claim 11, wherein the compound of formula VIII is GNE-493.

13. The pharmaceutical composition of claim 11, wherein the compound of formula VIII is GNE-0941.

14. The pharmaceutical composition of claim 11, wherein the compound is an inhibitor of mTORC1.

15. The pharmaceutical composition of claim 11, wherein the compound is an inhibitor of mTORC2.

16. The pharmaceutical composition of claim 11, wherein the viral infection is by a herpesvirus.

17. The pharmaceutical composition of claim 11, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

18. The pharmaceutical composition of claim 11, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

19. The pharmaceutical composition of claim 18 wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

20. The pharmaceutical composition of claim 18 wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

21-40. -40. (canceled)

41. A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula IX

42. The method of claim 41, wherein the compound of Formula IX is Wyeth BMCL 20102644-13.

43. The method of claim 41, wherein the compound of Formula IX is Wyeth BMCL 20102648-27.

44. The method of claim 41, wherein the compound is an inhibitor of mTORC1.

45. The method of claim 41, wherein the compound is an inhibitor of mTORC2.

46. The method of claim 41, wherein the viral infection is by a herpesvirus.

47. The method of claim 41, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

48. The method of claim 41, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

49. The method of claim 48, wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

50. The method of claim 48, wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

52. The pharmaceutical composition of claim 50, wherein the compound of Formula IX is Wyeth BMCL 20102644-13.

53. The pharmaceutical composition of claim 50, wherein the compound of Formula IX is Wyeth BMCL 20102648-27.

54. The pharmaceutical composition of claim 50, wherein the compound is an inhibitor of mTORC1.

55. The pharmaceutical composition of claim 50, wherein the compound is an inhibitor of mTORC2.

56. The pharmaceutical composition of claim 50, wherein the viral infection is by a herpesvirus.

57. The pharmaceutical composition of claim 50, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

58. The pharmaceutical composition of claim 50, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

59. The pharmaceutical composition of claim 58, wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

60. The pharmaceutical composition of claim 58, wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

51. A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug;

and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula IX

61-80. -80. (canceled)

81. A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula X:

82. The method of claim 81, wherein the compound of Formula X is NVP-BEZ235.

83. The method of claim 81, wherein the compound is an inhibitor of mTORC1.

84. The method of claim 81, wherein the compound is an inhibitor of mTORC2.

85. The method of claim 81, wherein the viral infection is by a herpesvirus.

86. The method of claim 81, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

87. The method of claim 81, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

88. The method of claim 87, wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

89. The method of claim 87, wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

90. A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug;

and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula X;

91. The pharmaceutical composition of claim 90, wherein the compound of Formula X is NVP-BEZ235.

92. The pharmaceutical composition of claim 90, wherein the compound is an inhibitor of mTORC1.

93. The pharmaceutical composition of claim 90, wherein the compound is an inhibitor of mTORC2.

94. The pharmaceutical composition of claim 90, wherein the viral infection is by a herpesvirus.

95. The pharmaceutical composition of claim 90, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

96. The pharmaceutical composition of claim 90, further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.

97. The pharmaceutical composition of claim 96, wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.

98. The pharmaceutical composition of claim 96, wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.

99-116. -116. (canceled)

117. A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is selected from AZD2014, CC-223 (TORKi), SB-2015, NVP-BGT-226, LY294002, GSK2126458, XL147, XL765, PF-04691502, P-2281, GDC-0980, ETP-45658, WJD008, PKI-179, PKI-402, PKI-587, OXA-01, Compound 401, ZSTK-474, PI-103, and Palomid-529.

118. The method of claim 117, wherein the viral infection is by a herpesvirus.

119. The method of claim 117, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

120. A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug;

and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is selected from AZD2014, CC-223 (TORKi), SB-2015, NVP-BGT-226, LY294002, GSK2126458, XL147, XL765, PF-04691502, P-2281, GDC-0980, ETP-45658, WJD008, PKI-179, PKI-402, PKI-587, OXA-01, Compound 401, ZSTK-474, PI-103, and Palomid-529.

121. The pharmaceutical composition of claim 120, wherein the viral infection is by a herpesvirus.

122. The pharmaceutical composition of claim 120, wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.

123-128. -128. (canceled)