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Methods for treating hcv

Inactive Publication Date: 2013-10-17
GILEAD PHARMASSET LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new methods and compositions for treating viral infections, specifically HCV. These methods have less side effects, can treat a wider range of genotypes, reduce the likelihood of resistance, and have simplified dosing schedules compared to existing treatments.

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

[0247]

[0248]Phosphinate ester 206 (23.7 g, 24.05 mmol) was dissolved in CH3CN (240 mL) and cooled to 0° C. Iodotrimethylsilane (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), 2.90-2.78m, 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

[0269]

[0270]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) * 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)

[0271]The intermediate compound 315 was prepared as follows.

a. Preparation of Compound 301

[0272]To a dry, argon purged three-neck round bottom flask...

example 4

Preparation of Compound 4

[0287]

[0288]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:

[0289]Column: Chiralcel OD-H, 2×25 cm

[0290]Solvent system: 70% heptane and 30% isopropanol

[0291]Flow rate: 6 mL / min.

[0292]Loading volume per run: 2.5 mL

[0293]Compound 4 had a retention time of 20 minutes. 1H NMR (300 MHz, CDCl3): * 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): * 2.72 (s). Compound 4 was subsequently recrystallized from MTBE for x-ray quality crystals.

[0294]Compound 4a had a retention time 50 min. 1H NMR (300 MHz, CDCl3): * 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 claims priority to U.S. Provisional Patent Application Nos. 61 / 425,194 filed 20 Dec. 2010 and 61 / 495,841 filed 10 Jun. 2011. The entire content of these applications are hereby incorporated herein by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created Feb. 29, 2012, is named 16923WO1.txt and is 798 bytes in size.FIELD OF THE INVENTION[0003]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[0004]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...

Claims

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Application Information

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IPC IPC(8): A61K31/501A61K31/5377A61K31/7056A61K31/4184A61K38/21A61K31/675A61K31/381
CPCA61K31/501A61K31/675A61K31/5377A61K31/381A61K31/4184A61K38/212A61K31/7056A61K31/40A61K31/401A61K31/4025A61K31/407A61K31/4178A61K31/4188A61K31/4353A61K31/4436A61K31/662A61K45/06A61K31/706A61K38/05A61P1/16A61K31/7068A61P31/12A61P31/14A61P43/00A61K2300/00
Inventor DELANEY, WILLIAM E.LINK, JOHN O.MO, HONGMEIOLDACH, DAVID W.RAY, ADRIAN S.WATKINS, WILLIAM J.YANG, CHENG YONGZHONG, WEIDONG
Owner GILEAD PHARMASSET LLC
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