Phosphadiazine hcv polymerase inhibitors iii and vi

Inactive Publication Date: 2009-03-05
INDENIX PHARM LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0036]Provided is a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for use in therapy. Also provided is a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for use in treating or preventing an HCV infection. Also provided is a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for use in treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection. Also provided is a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for use in inhibiting replication of a virus in a host. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for manufacture of a medcicament for treating or preventing an HCV infection. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for manufacture of a medcicament for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula III, III′, I″, II″, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for manufacture of a medcicament for inhibiting replication of a virus in a host.

Problems solved by technology

However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load (Manns et al, Lancet 2001, 358, 958-965; Fried et al., N. Engl. J. Med.
Furthermore, research shows that using pegylated interferon and ribavirin to treat patients with HCV can cause significant side effects, such as alopecia, anorexia, depression, fatigue, myalgia, nausea and prunitus (Ward et al., American Family Physician.

Method used

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  • Phosphadiazine hcv polymerase inhibitors iii and vi
  • Phosphadiazine hcv polymerase inhibitors iii and vi
  • Phosphadiazine hcv polymerase inhibitors iii and vi

Examples

Experimental program
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examples

[0344]As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr (hours); min (minutes); TLC (thin layer chromatography); HPLC (high performance liquid chromatography); SCX (strong cation exchange); MS (mass spectrometry); ESI (electrospray ionization); Rt (retention time); SiO2 (silica); THF (tetrahydrofuran); CD3OD (deuterated methanol); CDCl3 (deuterated chloroform); DCE (dichloroethane); DCM (dichloromethane); DMF (dimethyformamide); D...

example 41

1-(1-ethoxy-1-oxo-4H-7-methanesulfonaminyl-benzo[1,2,4]phosphadiazine-3-yl)-1-N-(3,3-dimethylbutyl)-4-hydroxy-3-thiophenyl-pyridazin-6-one

[0486]

[0487]Example 41 was synthesized from intermediate 26 and intermediate 71. To a solution of intermediate 71 (0.140 mmol) in dioxane (2 ml) was added intermediate 26 (0.210 mmol). This mixture was treated dropwise with trimethyl aluminum (0.840 mmol) and stirred in a sealed tube at 80° C. for 4 hours. After, the reaction mixture was quenched with HCl 1N, diluted with TBDME or ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo after purification with preparative HPLC to give example 41, which was a white lyophilized powder. Example 41 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.96 (s, 9H), 1.15-1.18 (t, J=6.95 Hz, 3H), 1.58-1.62 (t, J=7.94 Hz, 2H), 3.04 (s, 3H), 3.94-3.90 (m, 2H), 3.99-4.01 (m, 2H), 7.47-7.52 (m, 4H), 7.58 (s, 1H), 8.46 (s, 1H), 10.15 (...

example 42

1-1-hydroxy-1-oxo-4H-7-methanesulfonaminyl-benzo[1,2,4]phosphadiazine-3-yl)-1-N-(3,3-dimethylbutyl)-4-hydroxy-3-thiophenyl-pyridazin-6-one

[0488]

[0489]Example 42 was synthesized from example 41. Example 41 (1 eq) and trimethylsilylbromide (10 eq) dissolved in 1,2-dichloroethane (10 ml), were stirred in sealed tube, at 60° C., for 2 hours. The reaction mixture was then evaporated, diluted in methanol (1 ml) and added to HCl 1N. (15 ml). The precipitate was filtered, washed with water and dried over P2O5 to give example 42, which was a white lyophilized powder. Example 42 was characterized by the following spectroscopic data; and MS (ESI, EI+) m / z=552 (MH+). Example 42 is equivalent to Compound III-21.

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Abstract

Provided herein are phosphadiazine polymerase inhibitor, for example, of Formula III, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 967,237, filed Aug. 31, 2007, the content of which is incorporated herein by reference in its entirety.FIELD[0002]Provided herein are phosphadiazine polymerase inhibitor compounds, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.BACKGROUND[0003]Hepatitis C virus (HCV) is known to cause at least 80% of posttransfiusion hepatitis and a substantial proportion of sporadic acute hepatitis (Houghton et al., Science 1989, 244, 362-364; Thomas, Curr. Top. Microbiol. Immunol 2000, 25-41). Preliminary evidence also implicates HCV in many cases of “idiopathic” chronic hepatitis, “cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as hepatitis B virus (Di Besceglie et al., Scientifi...

Claims

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Application Information

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IPC IPC(8): C07F9/6509A61K31/675A61K38/21A61K38/20A61K31/70A61P31/12
CPCC07F9/65848A61P1/16A61P31/12A61P31/14A61P43/00
Inventor DOUSSON, CYRILSURLERAUX, DOMINIQUEGRIFFON, JEAN-FRANCOISPIERRA, CLAIREROLAND, ARLENERAHALI, RACHID
Owner INDENIX PHARM LLC
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