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2'-disubstituted nucleoside analogs for treatment of the flaviviridae family of viruses and cancer

A compound, CH2 technology, applied in the direction of antiviral agents, drug combinations, sugar derivatives, etc., can solve the problems of pigmentation and edema, white blood cell and platelet reduction, etc.

Inactive Publication Date: 2017-03-22
COCRYSTAL PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 5-fluorouracil causes serious adverse reactions such as nausea, alopecia, diarrhea, stomatitis, leukocyte thrombocytopenia, anorexia, pigmentation, and edema

Method used

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  • 2'-disubstituted nucleoside analogs for treatment of the flaviviridae family of viruses and cancer
  • 2'-disubstituted nucleoside analogs for treatment of the flaviviridae family of viruses and cancer
  • 2'-disubstituted nucleoside analogs for treatment of the flaviviridae family of viruses and cancer

Examples

Experimental program
Comparison scheme
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specific Embodiment

[0312] Specific compounds representative of this invention were prepared according to the following examples and reaction sequences; the examples and schematic diagrams describing the reaction sequences are provided as illustrations to aid in the understanding of the invention, but are not to be construed as limiting in any way the ensuing claims The invention described in. Compounds of the invention can also be used as intermediates in subsequent examples to produce additional compounds of the invention. No attempt was made to optimize the yield obtained in any reaction. Those skilled in the art will know how to increase such yields by routine changes in reaction times, temperatures, solvents and / or reagents.

[0313] Anhydrous solvents were purchased from Aldrich Chemical Company (Milwaukee, WI) and EMD Chemicals (Gibbstown, NJ). Reagents were purchased from commercial sources. Unless otherwise indicated, materials used in the examples were obtained from readily available...

Embodiment 1

[0315] Preparation of nucleoside analog 12

[0316]

[0317] 2-Deoxyribonolactone (2)

[0318] To a solution of 2-deoxy-D-ribose (42.0 g, 313 mmol) in 800 mL of water was added Br 2 (42mL). The flask was sealed and the contents were stirred at room temperature for 5 days. The resulting mixture was neutralized until pH 7 by adding silver carbonate. The mixture was filtered and washed with water. After removal of water, the crude product was filtered through a pad of silica gel, eluting with ethyl acetate / MeOH (10:1 to 4:1). The filtrate was concentrated under reduced pressure to afford 2-deoxyribonolactone 2 as a colorless gum (31.1 g, 75%). 1 H NMR (DMSO-d 6,400MHz) δ(ppm): 2.17(dd, J=17.8 and 2.4Hz, 1H), 2.76(dd, J=17.8 and 6.4Hz, 1H), 3.48-3.54(m, 2H), 4.20-4.24(m , 2H), 5.06 (t, J=5.4Hz, 1H), 5.50 (d, J=4.0Hz, 1H).

[0319] 2-Deoxy-3,5-di-O-(tert-butyldiphenylsilyl)-D-ribonolactone (3)

[0320] To a solution of 2-deoxyribonolactone 2 (8.95 g, 66.80 mmol) in 300 ...

Embodiment 2

[0412] Cytotoxicity assay

[0413] Toxicity of compounds was assessed in Vera, human PBM, CEM (human lymphoblastoid), MT-2 and HepG2 cells as previously described (see Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob. Agents Chemother. 1990, 34, 1061-67). Cycloheximide was included as a positive cytotoxicity control and solvent-exposed untreated cells were included as a negative control. Cytotoxicity IC50 was obtained from the concentration-response curve using the previously described half efficient method (see Chou T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1 -11). The results are shown in Table 1 below.

[0414] Table 1

[0415]

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Abstract

The present invention is directed to compounds, compositions and methods for treating or preventing Flaviviridae family of viruses (including HCV, Yellow fever, Dengue, Chikungunya and West Nile virus), RSV and influenza infection and cancer in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment or prevention of HCV infection.

Description

technical field [0001] The present invention relates to compounds, methods and compositions useful in the treatment or prevention of hepatitis C virus (HCV) infection, as well as other flaviviruses, RSV, influenza and cancer. More specifically, the present invention describes certain nucleoside and nucleotide analogs, pharmaceutically acceptable salts or other derivatives thereof, and their use in the treatment of flaviviruses, respiratory syncytial virus (RSV), influenza and cancer the use of. Background technique [0002] Hepatitis C virus (HCV) has infected more than 170 million people worldwide. It is estimated that three to four million people are newly infected each year, 70% of whom will develop chronic hepatitis. HCV is responsible for 50-76% of all liver cancer cases and two-thirds of all liver transplants in developed countries. Standard of care (SOC) therapy [pegylated interferon alfa + ribavirin (nucleoside analog)] is only effective in 50-60% of patients and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H19/16A61K31/7076A61K31/7068A61P31/12A61P31/16A61P35/00
CPCA61K31/7068A61K31/7076C07H19/06C07H19/16C07H19/10A61K31/7072C07H19/12C07H19/14C07H19/207A61P31/12A61P31/16A61P35/00Y02A50/30A61K2300/00A61K31/706A61K45/06
Inventor 斯蒂文·J·科阿斯周少曼弗兰克·安布拉尔雷蒙德·F·斯基那兹艾哈迈德·卡里尔
Owner COCRYSTAL PHARMA INC
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