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Deuterated nucleoside prodrugs useful for treating hcv

a nucleoside prodrug and hcv technology, applied in the direction of drug compositions, group 5/15 element organic compounds, peptide/protein ingredients, etc., can solve the problems of patient exhibiting serious adverse events such as vomiting/nausea, and reducing the efficacy, and achieve the effect of effective treatment against hepatitis

Inactive Publication Date: 2014-10-16
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent provides a novel class of deuterated nucleoside analogs that have shown promising anti-viral activity, particularly against HCV. These analogs can be used in combination with other direct-acting anti-HCV compounds. The deuterated nucleoside analogs have specific structures and can be further modified to improve their activity and selectivity. The technical effects of this patent include providing new compounds with improved anti-HCV activity and enhancing the effectiveness of combination therapies for the treatment of HCV.

Problems solved by technology

Lowering the dose of a nucleoside inhibitor to avoid toxicity can sometimes also compromise or lower efficacy.
One patient exhibited a serious adverse event of vomiting / nausea.
Despite progress in the area of hepatitis C treatment, there have also been a number of difficult setbacks.

Method used

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  • Deuterated nucleoside prodrugs useful for treating hcv
  • Deuterated nucleoside prodrugs useful for treating hcv
  • Deuterated nucleoside prodrugs useful for treating hcv

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of (S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(5-Deutero-2,4-Dioxo-3,4-Dihydropyrimidin-1(2H)-yl)-3,4-Dihydroxy-4-Methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (Prodrug of 2′-Methyl-5-Deutero-Uridine)

[0268]

[0269]Tetrabenzoylsugar (1, 2.44 g) and 5-Deutero-Uracil (2, 1.0 g) were reacted following the literature procedure described in Harry-Okuru et al. (J. Org. Chem. (1997) 62: 1754), followed by debenzylation using NaOMe / MeOH to give 2′-Methyl-S-D-Uridine (3, 0.8 g). Compound 3 (0.7 g) was converted to its phosphoramidate derivative 5 (0.63 g) following literature procedure described by Ross et al.

example 2

Preparation of (S)-Isopropyl 2-(((R)-(((2S,3R,4R,5R)-5-(2,4-Dioxo-3,4-Dihydropyrimidin-1(2H)-yl)-3,4-Dihydroxy-4-Methyltetrahydrofuran-2-yl)dideuteromethoxy)(phenoxy)phosphoryl)amino)propanoate (Prodrug of 2′-Methyl-5′,5′-DiDeutero-Uridine)

[0270]

[0271]Compound 6 was prepared from 2′-Me-Uridine (A) following procedure reported by Corey et al (J. Org. Chem. (1984) 49: 47350 with some modifications.

[0272]Lithium chloride (1.76 g) was stirred with NaBD4 (1.58 g) in EtOD for 1 h. Compound 6 (2.97 g) was added to this solution and stirred at room temperature for 3 h and quenched with acetic acid-d, diluted with ethyl acetate, washed with brine and evaporated to dryness. The residue was purified by chromatography over silica gel to give 5′-dideuterated compound 7 (2.1 g). Compound 7 (2.1 g) was treated with trifluoroacetic acid in presence of water to give the dideuterated nucleoside 8 (1.52 g). Compound 8 (1.0 g) was converted to its phosphoramidate derivative 9 (0.78 g) following literat...

example 3

Preparation of (2S)-Isopropyl 2-(((((2S,3R,4R,5R)-1-(6-Deutero-5-(trideuteromethyl)pyrimidine-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)dideuteromethoxy)(phenoxy)phosphoryl)amino)propanoate (Compound 16)

[0273]

[0274]Tetrabenzoyl sugar 1 and tetradeutero thymine 10 (2.1 equivalents; prepared according to the procedure in Heterocycles (2005) 66:361) were reacted following the literature procedure described in Harry-Okuru et al. (J. Org. Chem. (1997) 62: 1754), followed by debenzylation using NaOMe / MeOH to give compound 11.

[0275]Excess 2, 2-Dimethyl propane is added to compound 11 in acetone. The resulting mixture was cooled in an ice bath for 30 min, then p-Toluenesulfonic acid (1.3 equivalents) was added and the reaction mixture was stirred at room temperature for 24 hrs. After completion of the reaction (monitored by HPLC), the reaction mixture is cooled in an ice bath for 30 minutes and neutralized using cold aqueous potassium carbonate. The ...

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Abstract

Deuterated nucleoside analogs of Formula (I) and the pharmaceutically acceptable salts thereof are provided by this disclosureThe variables, e.g., B1, Y, R1, R2, R3, R3′, R4, R5, R6, R7, R8, and R9 carry definitions set forth in the disclosure. Compounds of Formula (I) are deuterated at one or more positions and the deuterium enrichment at each deuterated positions is at least 50%. Compounds and salts of Formula (I) are useful for treating viral infections, including HCV infections.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 811,464, filed Apr. 12, 2013, which is hereby incorporated by reference in its entirety.BACKGROUND[0002]An estimated 3% of the world's population is infected with the hepatitis C virus. Of those exposed to HCV, 80% to 85% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is us...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H19/10A61K45/06C07F9/24A61K31/7072
CPCC07H19/10A61K31/7072C07F9/242C07F9/2458A61K45/06C07H19/067C07B59/005C07F9/2429A61K31/4709C07F9/58A61P1/16A61P31/12A61P31/14A61P43/00Y02A50/30A61K2300/00C07H1/00
Inventor DESHPANDE, MILINDWILES, JASON ALLANHASHIMOTO, AKIHIROPHADKE, AVINASH
Owner ACHILLION PHARMA INC
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