Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides for the treatment of rna-dependent rna viral infection

A nucleoside compound, compound technology, applied in the direction of organic chemistry, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of limited clinical benefit and no HCV vaccine identified

Inactive Publication Date: 2007-09-26
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current treatment of HCV infection, limited to immunotherapy using recombinant interferon-α alone or in combination with the nucleoside analog ribavirin, has limited clinical benefit
Also, there is no definitive HCV vaccine

Method used

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  • Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides for the treatment of rna-dependent rna viral infection
  • Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides for the treatment of rna-dependent rna viral infection
  • Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides for the treatment of rna-dependent rna viral infection

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Experimental program
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Effect test

preparation example Construction

[0142] Preparation of compounds of the present invention:

[0143] The starting material for the preparation of the compounds of the present invention is 4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (1-9) , Scheme 1 describes its synthesis.

[0144] Flowchart 1

[0145]

[0146] Preparation of 5-fluoro-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1-4):

[0147] Step A: Preparation of 5-bromo-4chloro-7H-pyrrolo[2,3-d]pyrimidine (1-2)

[0148] To 4chloro-7H-pyrrolo[2,3-d]pyrimidine in DMF (20 mL) at 0 °C ( 1-1 ) (1.53 g, 10.0 mmol) was added dropwise a solution of N-bromosuccinimide (1.78 g, 10.0 mmol) in (10 mL). The reaction mixture was stirred at 0 °C for 30 minutes then at room temperature for 1 hour. Methanol (25 mL) was added and the reaction mixture was stirred for an additional 1 hour. Evaporation of the solvent and recrystallization of the residue from methanol gave the title compound as a white solid.

[0149] St...

Embodiment 1

[0170] 2,4-Diamino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2-4)

[0171] Step A: 4-Amino-5-fluoro-3-N-oxo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2 -1)

[0172] To 4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine in 50% methanol / water (20 mL) (268mg, 0.899mmol) was added m-chloroperoxybenzoic acid (444mg, 1.80mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was azeotroped twice with toluene to give the title compound as a beige solid.

[0173] Step B: 2,4-Diamino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2-4)

[0174] To a biological solution of cyanogen bromide in water (3 mL) was added 4-amino-5-fluoro-3-N-oxygen-7-(2-C-methyl-β-D A solution of -ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2-1 ) (160 mg, 0.509 mmol). The resulting solution was stirred at 0 °C for 1.5 hours. The solvent was eva...

Embodiment 2

[0179] 2-Amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (3-2 )

[0180] The compound was treated by treating the compound with 1,2-bis[(dimethylamino)-methylene]hydrazine in DMF 2-4 to provide compounds 3-1 , which was prepared by hydrolysis using aqueous 1 N NaOH in DMSO under the conditions described by K. Alarcon et al., Tetrahedron Lett, 41:7211-7215 (2000).

[0181] 2-fluoro-2-C-methyl ribonucleoside of the present invention (R in structural formula I 2 =F) can be prepared according to well-established synthetic methods practiced in nucleoside and nucleotide chemistry. provided the compound 6-3 The synthesis of is taken as an example, as described in Flowcharts 4-6. D-ribose ( 4-1 ) is protected first. In this case, esters such as acetate and benzoate provide suitable protecting groups, but alternative protecting groups may also be used. Esterification is achieved by reacting D-ribose with an appropriate acid halide or anhydri...

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Abstract

The present invention provides fluorinated pyrrolo[2,3,d]pyrimidine nucleoside compounds which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as precursors to inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors to inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaeutical compositions containing such fluorinated pyrrolo[2,3-d]pyrimidine nucleoside alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the fluorinated pyrrolo[2,3-d]pyrimidine nucleoside of the present invention.

Description

field of invention [0001] The present invention relates to fluorinated pyrrolo[2,3-d]pyrimidine nucleoside compounds and certain derivatives thereof, their synthesis and their use as inhibitors of RNA-dependent RNA viral polymerases. The compounds of the present invention are inhibitors of RNA-dependent RNA virus replication and are useful in the treatment of RNA-dependent RNA virus viral infections. In particular, they are useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication and for the treatment of hepatitis C virus infection. Background of the invention [0002] Review of the State of the Art in the Treatment of HCV Infection Hepatitis C virus (HCV) is a major health problem leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma in many infected individuals, estimated to be 2% of the world's population. -15%. The US Centers for Disease Control estimates that 3,900,000 people are infected in the US al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7052A61K31/7042C07H19/14
Inventor M·麦科斯D·B·奥尔森J·莱奥内P·L·杜雷特
Owner MERCK & CO INC
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