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Methods for treating hcv

a technology for hepatitis c virus and therapeutic molecules, applied in the field of methods for treating hcv, can solve the problems of inability to start therapy, poor tolerance of treatment with peg-ifn+rbv, and many patients' refusal to start therapy, so as to reduce the potential for viral rebound, and shorten the less complicated dosing schedule

Inactive Publication Date: 2016-12-08
GILEAD PHARMASSET LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new compositions and methods for treating viral infections, particularly HCV. These compositions have fewer side-effects, are more effective, and have shorter treatment schedules compared to current therapies. Additionally, the invention provides a method for reducing the emergence of HCV with resistance to oral antiviral agents. The use of certain compounds in combination can achieve a "synergy" or "synergistic effect" that is greater than the sum of the effects of using each compound separately. This is important because it suggests that these compounds may work better together to treat viral infections.

Problems solved by technology

In addition, treatment with PEG-IFN+RBV is not well tolerated, with an adverse event profile that includes flu-like symptoms, thrombocytopenia, anemia, and serious psychiatric side effects.
While treatment with the current standard of care is suboptimal, many patients are precluded from ever starting therapy due to comorbidities common in HCV-infected populations, including psychiatric disorders, advanced liver disease, and substance abuse.
IMPDH inhibitors also interfere with the reproduction of rapidly proliferating cells and cells with a high rate of protein turnover.
Treatment with ribavirin monotherapy has little effect on HCV RNA levels, but is associated with a decline in serum alanine transferase (ALT).
Unfortunately, different genotypes of HCV respond differently to PEG-IFN / ribavirin therapy; for example, HCV genotype 1 is more resistant to therapy than types 2 and 3.
Additionally, many current treatments for HCV produce unwanted side effects.

Method used

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  • Methods for treating hcv
  • Methods for treating hcv
  • Methods for treating hcv

Examples

Experimental program
Comparison scheme
Effect test

example 2

Preparation of Compound 2

[0271]

[0272]Phosphinate ester 206 (23.7 g, 24.05 mmol) was dissolved in CH3CN (240 mL) and cooled to 0° C. lodotrimethylsilane (17.4 mL, 122.3 mmol) was added at a fast drop-wise pace followed by, after 10 min, 2,6-lutidine (17.0 mL, 146.4 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h then cooled back down to 0° C. and 2,6-lutidine (11.1 mL, 95.6 mmol) followed by MeOH (24 mL) were added. The solution was concentrated in vacuo and the crude residue was purified by HPLC to afford 12.68 g of Compound 2 in 55% yield. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=9.3 Hz, 1H), 8.28 (s, 1H), 7.85 (s, 1H), 7.64 (d, J=9.6 Hz, 1H), 7.35-7.22 (m, 1H), 7.02-6.89 (m, 2H), 5.85 (bs, 1H), 4.82-4.71 (m, 2H), 4.33 (bs, 1H), 4.28-3.99 (m, 3H), 4.16 (s, 3H), 3.57-3.28 (m, 2H), 2.90-2.78 m, 1H), 2.63-2.50 (m, 1H), 2.08-1.91 (m, 1H), 1.91-170 (m, 2H), 1.70-1.13 (m, 22H), 1.37 (d, J=6.9 Hz, 6H); 31P NMR (121.4 MHz, CD3OD) δ 42.4; LCMS (M+1): 957.35...

example 3

Preparation of Compound 3

[0293]

[0294]Compound 315 (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 hours. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give compound 3 as a yellow solid (11 g, 93%). LC / MS=911.52 (M++1). 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 1H), 7.90 (s, 1H), 7.48 (s, 1H), 7.31 (d, 1H), 5.42 (s, 1H), 4.37 (dd, 1H), 4.20 (m, 2H), 3.83-3.56 (m, 7H), 3.50 (m, 2H), 3.39 (m, 2H), 2.45 (m, 1H), 2.27 (m, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.33 (m, 2H), 1.18 (m, 1H), 1.05 (m, 8H), 0.90 (m, 3H), 0.76 (m, 11H), 0.14-0.04 (m, 2H)

[0295]The intermediate compound 315 was prepared as follows.

a. Preparation of Compound 301

[0296]To a dry, argon purged three-neck round bottom flask...

example 4

Preparation of Compound 4

[0311]

[0312]Diastereomeric mixture 414 was dissolved in heptane and isopropanol (70%:30%, 230 mg in 4.5 mL of the mixed solvents) and subjected to chiral column separation under the following conditions:

[0313]Column: Chiralcel OD-H, 2×25 cm

[0314]Solvent system: 70% heptane and 30% isopropanol

[0315]Flow rate: 6 mL / min.

[0316]Loading volume per run: 2.5 mL

[0317]Compound 4 had a retention time of 20 minutes. 1H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.1-7.3 (m, 5H), 6.83 (d, 1H), 6.71 (d, 1H), 6.09 (brs, 2H), 5.95 (s, 1H), 5.04 (m, 2H), 4.67 (q, 1H), 4.35-4.52 (m, 2H), 4.00 (m, 2H), 2.74 (m, 1H), 1.40 (d, 3H), 1.2-1.3 (12H), 0.98 (s, 3H). 31P NMR (121.4 MHz, CDCl3): δ 2.72 (s). Compound 4 was subsequently recrystallized from MTBE for x-ray quality crystals.

[0318]Compound 4a had a retention time 50 min. 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.1-7.3 (m, 5H), 6.83 (d, 1H), 6.73 (d, 1H), 6.02 (brs, 2H), 5.95 (s, 1H), 5.08 (d, 1H), 5.00 (m, 1H), 4.68 (q, 1H), 4.38-...

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Abstract

This invention relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.

Description

PRIORITY OF INVENTION[0001]This application is a continuation application of U.S. application Ser. No. 13 / 875,252, filed May 1, 2013, which application is a continuation of PCT / US2012 / 055621, filed Sep. 14, 2012, which claims priority to U.S. Application No. 61 / 535,885, filed Sep. 16, 2011, and to U.S. Application No. 61 / 561,753, filed Nov. 18, 2011. The entire content of each of these applications is hereby incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.BACKGROUND OF THE INVENTION[0003]Hepatitis is a disease occurring throughout the world. Hepatitis is generally of viral nature, although, if considered a state of chronic inflammation of the liver, there are other known, non-infectious causes. Viral hepatitis is by far the most common form of hepatitis. The U.S. Centers for Dis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/06A61K9/20A61K9/00A61K31/4184A61K31/7052
CPCA61K38/06A61K31/4184A61K9/20A61K9/0053A61K31/7052A61K31/381A61K31/4196A61K31/7072A61K2300/00A61K31/513A61K45/06A61K31/7056A61K38/212A61P1/16A61P31/00A61P31/12A61P31/14A61P31/22A61P43/00
Inventor DELANEY, IV, WILLIAM E.LINK, JOHN O.MO, HONGMEIOLDACH, DAVID W.RAY, ADRIAN S.WATKINS, WILLIAM J.YANG, CHENG YONG
Owner GILEAD PHARMASSET LLC
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