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2' and 3'-nucleoside prodrugs for treating Flaviviridae infections

a technology of flaviviridae and nucleosides, applied in the field of pharmaceutical chemistry, can solve the problems of significant economic loss worldwide, severe flu-like symptoms, and significant pestivirus exposure, and achieve the effect of determining the activity spectrum and inhibiting the activity of hcv polymeras

Inactive Publication Date: 2007-02-15
THE CENT NAT DEL LA RECH SCIQUE +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes a method for treating Flaviviridae infections and related conditions using prodrugs of nucleosides. These prodrugs have biologically cleavable moieties at the 2' or 3' position and can be used alone or in combination with other anti-Flaviviridae agents. The prodrugs can be administered to prevent or treat Flaviviridae infections in humans. The invention also includes specific examples of prodrugs falling within the scope of the invention."

Problems solved by technology

Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide.
However, serological surveys indicate considerable pestivirus exposure in humans.
Unfortunately, the effect of IFN is temporary and a sustained response occurs in only 8%-9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).
Most patients, however, have difficulty tolerating interferon treatment, which causes severe flu-like symptoms, weight loss, and lack of energy and stamina.
Thus, ribavirin alone is not effective in reducing viral RNA levels.
Additionally, ribavirin has significant toxicity and is known to induce anemia.
However, as with monotherapy, significant side effects develop during combination therapy, including hemolysis, flu-like symptoms, anemia, and fatigue.

Method used

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  • 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections
  • 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections
  • 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 1′-C-methylriboadenine via 6-amino-9-(1-deoxy-β-D-psicofuranosyl)purine

[0444] Melting points were determined on a Mel-temp II apparatus and are uncorrected. NMR spectra were recorded on a Bruker 400 AMX spectrometer at 400 MHz for 1H NMR and 100 MHz for 13C NMR with TMS as internal standard. Chemical shifts (δ) are reported in parts per million (ppm), and signals are reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). IR spectra were measured on a Nicolet 510P FT-IR spectrometer. Mass spectra were recorded on a Micromass Autospec high-resolution mass spectrometer. TLC were performed on Uniplates (silica gel) purchased from Analtech Co. Column chromatography was performed using either silica gel-60 (220-440 mesh) for flash chromatography or silica gel G (TLC grade, >440 mesh) for vacuum flash column chromatography. UV spectra were obtained on a Beckman DU 650 spectrophotometer. Elemental analysis was performed by Atlan...

example 2

Preparation of 2′-C-methylriboadenine

[0449] The title compound was prepared according to a published procedure (R. E. Harry-O'kuru, J. M. Smith, and M. S. Wolfe, “A short, flexible route toward 2′-C-branched ribonucleosides”, J. Org. Chem. 1997, 62, 1754-1759) (Scheme 11). [0450] (a) Dess-Martin periodinane; (b) MeMgBr / TiCl4; (c) BzCl, DMAP, Et3N; (d) bis(trimethylsilyl)acetamide, N6-benzoyl adenine, TMSOTf; (e) NH3 / MeOH

[0451] The 3′-prodrug of the 2′-branched nucleoside was prepared according to published procedure (Synthetic Communications, 1978, 8(5), 327-333; J. Am. Chem. Soc., 1999, 121(24), 5661-5664). Alternatively, the 2′-branched nucleoside can be esterified without protection (Scheme 11b). Carbonyldiimidazole (377 mg, 2.33 mmol) was added to a solution of N-(tert-butoxycarbonyl)-L-valine (507 mg, 2.33 mmol) in 15 mL of anhydrous tetrahydrofuran. The mixture was stirred at 20° C. for one hour and at 50° C. for 10 minutes and then added to a solution of 4-Amino-1-(3,4-dih...

example 3

Preparation of 3′-C-methylriboadenine

[0461] The title compound can be prepared according to a published procedure (R. F. Nutt, M. J. Dickinson, F. W. Holly, and E. Walton, “Branched-chain sugar nucleosides. III. 3′-C-methyladenine”, J. Org. Chem. 1968, 33, 1789-1795) (Scheme 12).

(a) RuO2 / NaIO4; (b) MeMgI / TiCl4; (c) HCl / MeOH / H2O; (d) BzCl / pyridine; (e) AcBr, HBr / AcOH; (f) chloromercuri-6-benzamidopurine; (g) NH3 / MeOH.

[0462] In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula III are prepared.

wherein R1, R2, R3, X1, X2, and Y are defined in Table 13.

[0463] Alternatively, the following nucleosides of Formula VI are prepared, using the appropriate sugar and pyrimidine or purine bases.

wherein R1, R2, R3, X1, and Y are defined in Table 14.

[0464] Alternatively, the following nucleosides of Formula XI are prepared, using the appropriate sugar and pyrimidine or purine bases.

wherein R1, R2, R3, R6, X, and Ba...

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Abstract

2′ and 3′-Prodrugs of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts and derivatives are described, which are useful in the prevention and treatment of Flaviviridae infections and other related conditions. These modified nucleosides provide superior results against flaviviruses and pestiviruses, including hepatitis C virus and viruses generally that replicate through an RNA dependent RNA reverse transcriptase. Compounds, compositions, methods and uses are provided for the treatment of Flaviviridae infection, including HCV infection, that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Description

CROSS-REFERENCE To RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 609,298, filed Jun. 27, 2003, which claims the benefit of priority to U.S. Provisional application No. 60 / 392,351, filed Jun. 28, 2002; U.S. Provisional Application No. 60 / 466,194, filed Apr. 28, 2003; and U.S. Provisional application 60 / 470,949, filed May 14, 2003, the disclosures of each of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention is in the area of pharmaceutical chemistry, and is in particular, a 2′ and / or 3′ prodrug of a 1′, 2′, 3′ or 4′-branched nucleosides for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection. BACKGROUND OF THE INVENTION Flaviviridae Viruses [0003] The Flaviviridae family of viruses comprises at least three distinct genera: [0004] pestiviruses, which cause disease in cattle and pigs; flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fe...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H15/24C07J17/00A61K38/14A61K31/7076A61K9/20A61K9/48C07H19/067A61K31/7068A61K31/7072A61K38/21A61K45/00A61P1/16A61P31/14A61P43/00C07H19/06
CPCA61K38/00C07K9/003C07H19/067C07H19/06A61K31/7068A61K31/7072A61K45/06A61P1/16A61P31/12A61P31/14A61P43/00A61K2300/00
Inventor GOSSELIN, GILLESSTORER, RICHARDLACOLLA, PAOLASOMMADOSSI, JEAN-PIERRE
Owner THE CENT NAT DEL LA RECH SCIQUE
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