MODULATORS OF TOLL-LIKE RECEPTOR 7

• US 20090202484A1
• Filed: 07/06/2007
• Published: 08/13/2009
• Est. Priority Date: 07/07/2006
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Gallagher, Brian, Graupe, Michael, Yang, Hong, Chong, Lee S., Desai, Manoj C., Halcomb, Randall L., Zhang, Jennifer R.
• Granted Patent: US 8,338,593 B2
• Time in Patent Office: Days
• US Class Current: 424/85.600
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The present application provides for a compound of Formula (I) or (II): or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods that include the administration of such compounds with at least one additional active agent.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein:

L² is —

NR⁵ or —

O—

; and

R³ is heteroalkyl or substituted heteroalkyl.

3. The compound of claim 1, wherein:

X¹ is alkylene or substituted alkylene;

L¹ is arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, or substituted carbocyclylene; and

X² is alkylene or substituted alkylene.

4. The compound of claim 1, wherein:

X¹ is alkylene or substituted alkylene;

L¹ is —

S—

, —

NR⁵—

, or —

O—

; and

X² is alkylene or substituted alkylene.

5. The compound of claim 1, wherein:

Y¹ is —

O—

or —

NR⁵—

;

Y² is a covalent bond;

R¹ is H, alkyl, or substituted alkyl; and

R² is alkyl or substituted alkyl.

6. The compound of claim 1, wherein:

Y¹ and Y² are each independently —

O—

or —

NR⁵—

; and

R¹ and R² are each independently H, alkyl, or substituted alkyl.

7. The compound of claim 1, wherein:

Y¹ and Y² are each independently —

O—

or —

NR⁵—

; and

R¹ and R² are each independently-alkylene-C(O)—

O—

R⁵, -(substituted alkylene)-C(O)—

O—

R⁵, -alkylene-O—

C(O)—

R⁵, -(substituted alkylene)-O—

C(O)—

R⁵, -alkylene-O—

C(O)—

O—

R⁵, or -(substituted alkylene)-O—

C(O)—

O—

R⁵.

8. The compound of claim 1, wherein:

Y¹ is —

O—

or —

NR⁵—

;

Y² is a covalent bond; and

R² is carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl.

39. The compound of claim 1 selected from the group consisting of:

54. A pharmaceutical composition comprising:

at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and

a pharmaceutically acceptable carrier or excipient.

57. The pharmaceutical composition of claim 54, further comprising:

at least one additional active agent.

60. The pharmaceutical composition of claim 57, wherein:

the additional active agent is selected from the group consisting of interferons, ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, or mixtures thereof.

63. The pharmaceutical composition of claim 60, wherein:

(1) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta;

(2) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);

(3) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;

(4) said 1HCV NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;

(5) said alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;

(6) said hepatoprotectants are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ;

(7) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, GS-9190, A-831, and A-689; and

(8) said other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

66. A method for treating or preventing a viral infection comprising:

administering, to a patient in need thereof, a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

69. The method of claim 66, wherein said viral infection is an HCV or HBV viral infection.

72. The method of claim 66, further comprising:

co-administering at least one additional active agent selected from the group consisting of interferons, ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, or mixtures thereof.

75. The method of claim 72, wherein:

(1) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta;

(2) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);

(3) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), 1HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;

(4) said HCV NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;

(5) said alpha-glucosidase I inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;

(6) said hepatoprotectants are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ;

(7) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, GS-9190, A-831, and A-689; and

(8) said other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-500S, ANA-975, XTL-6865, ANA 971, NOV-205, taivacin, EHC-18, NIM811, DEBIO-025, VCX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

78. A method of agonizing toll-like receptor 7, comprising:

contacting a cell having a toll-like receptor 7 with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

81. A combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and

b) a second pharmaceutical composition comprising at least one additional active agent selected from the group consisting of interferons, ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, or mixtures thereof.

9-38. -38. (canceled)

40-53. -53. (canceled)

55-56. -56. (canceled)

58-59. -59. (canceled)

61-62. -62. (canceled)

64-65. -65. (canceled)

67-68. -68. (canceled)

70-71. -71. (canceled)

73-74. -74. (canceled)

76-77. -77. (canceled)

79-80. -80. (canceled)

82-104. -104. (canceled)