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Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

a technology of nucleosides and antibiotics, 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 flaviviridae polymeras

Inactive Publication Date: 2007-02-08
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 a biologically cleavable moiety at the 2' or 3' position and can be administered alone or in combination with other anti-Flaviviridae agents. The prodrugs can be natural or synthetic amino acid esters or alkyl esters. The invention also includes pharmaceutically acceptable salts of the nucleosides. The prodrugs have improved solubility and can be designed to release the nucleoside in a controlled and sustained manner. The technical effect of this invention is to provide new compounds that can prevent and treat Flaviviridae infections and related conditions."

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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  • Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
  • Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
  • Modified 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

[0566] 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-Methylribo-8-Methyladenine

[0570] 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 9).

[0571] 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 9b). 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-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2-one (500 mg, 1.95 mmol), 4-(dimethylamino)pyridine (25 mg, 0.195 mmol), t...

example 3

Preparation of 3′-C-Methylribo-8-Methyladenine

[0573] 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 10).

[0574] In a similar manner, but using the appropriate sugar and purine bases, the following nucleosides of Formula XXXVI are prepared.

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

Alternatively, the following nucleosides of Formula XXXVII are prepared, using the appropriate sugar and pyrimidine bases.

wherein R1, R2, R3, X1, X2, and Y are defined in Table 14.

Alternatively, the following nucleosides of Formula XXXVIII are prepared, using the appropriate sugar and pyrimidine or purine bases.

wherein R1, R2, R3, R6, X, and Base are defined in Table 15.

Alternatively, the following nucleosides of Formula XXXIX are prepared, using the appropriate sugar and pyrimidine or purine ...

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Abstract

2′ and / or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided 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 / 608,907, filed Jun. 27, 2003, which claims the benefit of priority to U.S. Provisional application No. 60 / 392,350, filed Jun. 28, 2002; U.S. Provisional Application No. 60 / 466,194, filed Apr. 28, 2003; and U.S. Provisional Application No. 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 6-modified, 1′, 2′, 3′ or 4′-branched pyrimidine nucleoside or 8-modified, 1′, 2′, 3′ or 4′-branched purine nucleoside 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: pestiviruses, which cause disease in cattle and pigs; flaviviruses...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7076A61K31/7072A61K31/522A61K31/513C07F9/6512C07F9/6521
CPCA61K31/675A61K47/48215A61K31/7076A61K38/21A61K45/06C07H19/00C07H19/04C07H19/048C07H19/22A61K31/7072A61K31/7056C07H19/16C07H19/06C07H19/056A61K38/212A61K31/708A61K31/7068A61K2300/00A61K47/60A61P31/14A61K9/20A61K9/48
Inventor LACOLLA, PAOLASTORER, RICHARDGOSSELIN, GILLESSOMMADOSSI, JEAN-PIERRE
Owner THE CENT NAT DEL LA RECH SCIQUE
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