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Phosphadiazine hcv polymerase inhibitors i and ii

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

AI Technical Summary

Benefits of technology

[0041]Provided is a compound disclosed herein, e.g., a compound of Formula I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, or a pharmaceutical composition thereof, for use in therapy. Also provided is a compound disclosed herein, e.g., a compound of Formula I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, 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 I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, 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 I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, 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 I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, or a pharmaceutical composition thereof, for manufacture of a medeicament for treating or preventing an HCV infection. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, or a pharmaceutical composition thereof, for manufacture of a medeicament 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 I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, 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 i and ii
  • Phosphadiazine hcv polymerase inhibitors i and ii
  • Phosphadiazine hcv polymerase inhibitors i and ii

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-(2-cyclopropylethyl)-(1-ethoxy-1-oxo-4H-benzo[1,2,4]phosphadiazine 3-yl)-6-fluoro-dihydro-4-hydroxy-2-oxoquinoline

[0502]

[0503]Intermediate 5 (90 mg, 0.18 mmol) was dissolved in dimethylacetamide (1 ml), heated under microwaves radiations to 200° C. for 4.5 hours. After cooling, the reaction mixture was added dropwise to 25 ml buffer pH 7 (0.1M). The product was extracted in ethyl acetate, after evaporation of the organic layer, the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give Example 1 (24.3 mg, 40%), which was a white powder. Example 1 was characterized by the following spectroscopic data: 1H NMR (d6-DMSO, 400 MHz) δ (ppm) 0.07-0.10 (m, 2H), 0.39-0.44 (m, 2H), 0.76-0.87 (m, 1H), 1.21 (t, J=6.99 Hz, 3H), 1.56 (q, J=7.36 Hz, 2H), 3.99-4.05 (m, 2H), 4.33-4.36 (m, 2H), 7.40-8.08 (m, 7H); 19F NMR (d6-DMSO, 376 MHz) δ (ppm) −120.47 (s, 1F); 31P NMR (d6-DMSO, 162 MHz) δ (ppm) −0.04 (s, 1P); and MS (ESI, EI+) m / z=456 (MH+).

example 2

1-(2-cyclopropylethyl)-(1-ethoxy-1-oxo-4H-benzo[1,2,4]phosphadiazine 3-yl)-6-fluoro-dihydro-4-hydroxy-2-oxoquinoline sodium salt

[0504]

[0505]Example 1 (10 mg, 0.0018 mmol), NaOH 0.1M (187 μl, 1 eq) were stirred in dioxane (2 ml) and water (2 ml) at 40° C. for 10 min and freeze dried to give Example 2, which was a white powder. Example 2 was characterized by the following spectroscopic data: 1H NMR (d6-DMSO, 400 MHz) δ (ppm) 0.06-0.15 (m, 2H), 0.40-0.46 (m, 2H), 0.73-0.82 (m, 1H), 1.08 (t, J=7.01 Hz, 3H), 1.43-1.49 (m, 2H), 3.45-3.56 (m, 1H), 3.63-3.73 (m, 1H), 4.01-4.22 (m, 2H), 7.10 (t, J=7.4 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.27-7.35 (m, 2H), 7.46-7.55 (m, 2H), 7.76 (dd, J=9.54 Hz and J=2.72 Hz, 1H), 14.9 (s, 1H); 19F NMR (d6-DMSO, 376 MHz) δ (ppm) −124.59 (s, 1F); 31P NMR (d6-DMSO, 162 MHz) δ (ppm) 3.24 (s, 1P); and MS (ESI, EI+) m / z=456 (MH+).

example 3

1-(2-cyclopropylethyl)-(1-hydroxy-1-oxo-4H-benzo[1,2,4]phosphadiazine 3-yl)-6-fluoro-dihydro-4-hydroxy-2-oxoquinoline

[0506]

[0507]The chromatography column of example 2 was flushed with methanol, the methanol was concentrated and the residue was precipitated in a minimum of methanol, filtered, washed with cold methanol and dried under reduced pressure, to give Example 3 (185 mg), which was a white powder. Example 3 was characterized by the following spectroscopic data: 1H NMR (d6-DMSO, 400 MHz) δ (ppm) 0.06-0.09 (m, 2H), 0.38-0.43 (m, 2H), 0.75-0.82 (m, 1H), 1.54 (q, J=7.22 Hz, 2H), 4.28 (t, J=7.22 Hz, 2H), 7.39-7.47 (m, 2H), 7.54-7.64 (m, 2H), 7.68 (t, J=7.72 Hz, 1H), 7.74-7.84 (m, 2H); 19F NMR (d6-DMSO, 376 MHz) δ (ppm) −120.77 (s, 1F); 31P NMR (d6-DMSO, 162 MHz) δ (ppm) −5.51 (s, 1P); and MS (ESI, EI+) m / z=428 (MH+).

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Abstract

Provided herein are phosphadiazine polymerase inhibitor, for example, of any of Formula I, II, III, I′, II′, I″, II″, Ia, IIa, or IIIa, 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 posttransfusion 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., Scientfic...

Claims

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Application Information

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IPC IPC(8): A61K38/20C07F9/60A61K31/675C07F9/6581C12N9/99C12N7/06A61K38/21A61P31/12
CPCC07F9/65848A61P1/16A61P31/12A61P31/14A61P43/00
Inventor DOUSSON, CYRILSURLERAUX, DOMINIQUEROLAND, ARLENEPIERRA, CLAIREDA COSTA, DANIEL
Owner INDENIX PHARM LLC
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