Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication
A pyridyl, compound technology, applied in the directions of antiviral agents, drug delivery, aerosol delivery, etc., can solve problems such as insertion errors of subnucleotides
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example 1
[0438] Example 1: Side chain preparation
[0439] Some of the compounds described herein contain relatively long side chain moieties. The synthesis of precursors to some of these side chains is shown below.
[0440] sidechain-1
[0441] 2-(2-(2-Ethoxyethoxy)ethoxy)acetic acid (side chain-1)
[0442]
[0443] To a stirred solution of 2-(2-ethoxyethoxy)ethan-1-ol 1 (2.68 g, 20 mmol) in 1,4-dioxane (60 mL) was added NaOH (1.2 g , 30mmol). The mixture was stirred at room temperature for 15 minutes. After cooling to 0 °C, tert-butyl 2-bromoacetate 2 (7.8 g, 40 mmol) and 18-crown ether (250 mg) were added to the reaction mixture and stirred at room temperature for 16 h. After the starting material was consumed, the mixture was diluted with ice water (200 mL) and extracted with diethyl ether (2 x 100 mL). The separated aqueous layer was acidified (pH~2) with concentrated HCl (30 mL) and extracted with dichloromethane (2 x 250 mL). The organic layer was washed with water (2 ...
example 2
[0780] Example 2: Compound Preparation
[0781] Representative examples of the synthesis of some of the compounds described herein, as well as intermediates used to prepare these compounds, are shown below. Certain terms used in the reaction schemes presented below are defined as follows: SFC = preparative supercritical fluid chiral separation; Borsm = intermediate-013 based on recovered starting material
[0782]
[0783] 5-Fluoro-3-iodopyridin-2-amine (2)
[0784]
[0785] To 5-fluoropyridin-2-amine (1) (10g, 89.28mmol) in 2M H at 0°C 2 SO 4 To a stirred solution in aqueous solution (150 mL) was added sodium metaperiodate (7.5 g, 35 mmol) and heated at 100 °C. Then, an aqueous solution (30 mL) of sodium iodide (13.5 g, 89.28 mmol) was added dropwise at the same temperature for 3 h. After the starting material was consumed, the mixture was poured into ice water (300 mL) and washed with solid NaHCO 3 Basified (pH~8) and extracted with ethyl acetate (2 x 500 mL). Th...
example 3
[0995] Example 3: Data on selected compounds
[0996] As can be seen below, many of the compounds described herein exhibit positive effects on the survival of A / PR / 8 / 34 infected cells and inhibitory effects on the replication of A / PR / 8 / 34 influenza virus.
[0997] In vitro antiviral assay
[0998] Influenza Antiviral Test:
[0999] Inhibition of virus-induced cytopathic effect (CPE) was measured by XTT dye reduction and MDCK cells (female cocker spaniel kidney epithelial cells, ATCC CCL-34) in influenza A (strain A / PR / 8 / 34, ATCC VR-95) or influenza B (for cell cultures of strain B / Lee / 40, ATCC VR-1535) replication (Appleyard et al., Journal of Antimicrobial Chemotherapy 1(4 Suppl. ): 49-53,1975 (J AntimicrobChemother.1 (4Suppl): 49-53,1975) " and Shigeta et al's "Antimicrob Agents Chemotherapy 41 (7): 1423-1427, 1997 (Antimicrob Agents Chemother.41 (7):1423-1427, 1997) "). Use Dulbecco's minimal essential medium supplemented with 10% heat-inactivated fetal bovine serum (FB...
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