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Thieno[3,2‑d]pyrimidines, furo[3,2‑d]pyrimidines, and pyrrolo[3,2‑d]pyrimidines for the treatment of respiratory syncytial virus infection

A compound, C2-C8 technology, applied in the direction of respiratory diseases, antiviral agents, drug combinations, etc., can solve the problems of high cost and limited curative effect

Active Publication Date: 2017-04-19
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The monoclonal antibody palivizumab is available for immunoprophylaxis, but its use is limited to high-risk infants, eg, premature infants or infants with congenital heart or lung disease, and is often cost prohibitive for general use
In addition, the nucleoside analogue ribavirin has been approved as the only antiviral agent for the treatment of HRSV infection with limited efficacy

Method used

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  • Thieno[3,2‑d]pyrimidines, furo[3,2‑d]pyrimidines, and pyrrolo[3,2‑d]pyrimidines for the treatment of respiratory syncytial virus infection
  • Thieno[3,2‑d]pyrimidines, furo[3,2‑d]pyrimidines, and pyrrolo[3,2‑d]pyrimidines for the treatment of respiratory syncytial virus infection
  • Thieno[3,2‑d]pyrimidines, furo[3,2‑d]pyrimidines, and pyrrolo[3,2‑d]pyrimidines for the treatment of respiratory syncytial virus infection

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0355] Scheme 3 shows the general synthesis of intermediates of the invention via the preparation of alcohol S2c. Deoxygenation of alcohol S2c (e.g. PPh 3 , I 2 , then Bu 3 SnH, AIBN) and X 1 group to -NH 2 transformation (e.g. NH 4 OH) to give the final compound of type S3a. Methylation of alcohol S2c (e.g. MeI) and X 1 group to -NH 2 transformation (e.g. NH 4 OH) to give the final compound of type S3b. Chlorination of alcohol S2c (e.g. POCl 3 ) and X 1 group to -NH 2 transformation (e.g. NH 4 OH) to give the final compound of type S3c. Fluorination of Alcohols S2c (eg DAST) and X 1 group to -NH 2 transformation (e.g. NH 4 OH) to give the final compound of type S3d.

[0356]

[0357] Equation 4 shows the general synthesis of intermediates of the invention by the preparation of aldehyde S2d. Alkenylation of aldehyde S2d (e.g. Ph 3 PCH 2 ) and X 1 group to -NH 2 transformation (e.g. NH 4 OH) to give the final compound of type S4a. Reduction of alkenes...

Embodiment

[0401] Example 1-(2R,3R,4R,5S)-5-(4-aminothieno[3,2-d]pyrimidin-7-yl)-2-azido-4-fluoro-2-(hydroxy Methyl)-tetrahydrofuran-3-ol

[0402] Intermediate 1l (135mg, 0.237mmol) and NH 4 A solution of OH (28%, 3 mL) in MeOH (3 mL) was stirred at 45 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Example 1 (54 mg, 70%).

[0403] 1 H NMR (400MHz, DMSO-d 6 )δ8.40(s, 1H), 8.24(s, 1H), 7.67(wide s, 2H), 5.85(wide s, 1H), 5.62(d, J=23.6Hz, 1H), 5.14(ddd, J = 55.2, 4.8, 2Hz, 1H), 4.46 (dd, J = 24.0, 4.8Hz, 1H), 3.70 (d, J = 12Hz, 1H), 3.56 (d, J = 12Hz, 1H). 19 F NMR (376MHz, DMSO-d 6 ) δ -197.67 to -197.94 (m). MS m / z = 327.0 [M+1].

[0404]

[0405]

[0406] Intermediate 2a-N-(7-((2S,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro- 4-Hydroxytetrahydrofuran-2-yl)thieno[3,2-d]pyrimidin-4-yl)benzamide

[0407] To a solution of intermediate 1h (2.0 g, 5.14 mmol) in pyridine (20 mL) w...

Embodiment 3

[0483] Example 3-(2R,3S,4R,5S)-5-(4-aminothieno[3,2-d]pyrimidin-7-yl)-3,4-dihydroxy-2-(hydroxymethyl) Tetrahydrofuran-2-carbonitrile

[0484] Intermediate 3n (88 mg, 0.156 mmol) was dissolved in 5 mL TFA / H2O solution (1:1). After 20 h, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in 20 mM triethylamine bicarbonate solution and purified by prep-HPLC (2-70% acetonitrile in water) to give Example 3 (39 mg, 81%).

[0485] 1 H NMR (400MHz, CD 3 OD) δ8.41(s, 1H), 8.14(s, 1H), 5.27(d, J=7.2Hz, 1H), 4.47(dd, J=7.2, 5.4Hz, 1H), 4.37(d, J= 5.4Hz, 1H), 4.04-3.85(m, 2H). MS m / z = 309.1 [M+1], 307.1 [M-1].

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Abstract

The application provides preparations, methods and substituted thieno[3,2-d]pyrimidines, furo[3,2-d]pyrimidines and pyrrolo[ 3,2‑d]pyrimidine compounds, wherein the pneumovirinae virus infection includes respiratory syncytial virus infection, and thieno[3,2‑d]pyrimidine, furo[3,2 Processes and intermediates for ‑d]pyrimidine and pyrrolo[3,2‑d]pyrimidine compounds.

Description

technical field [0001] The application provides substituted thieno[3,2-d]pyrimidines, furo[3,2-d]pyrimidines for use in the treatment of Pneumovirinae virus infections, including respiratory syncytial virus infections in particular and pyrrolo[3,2-d]pyrimidine compounds, methods and pharmaceutical formulations, and methods and intermediates for the preparation of said compounds. Background technique [0002] Pneumovirinae viruses are negative-sense, single-stranded RNA viruses that are responsible for many prevalent human and animal diseases. The Pneumovirinae subfamily of viruses is part of the Paramyxoviridae family and includes the human respiratory syncytial virus (HRSV). Almost all children will be infected with HRSV by their first two years of age. HRSV is a leading cause of lower respiratory tract infections in infants and children, with 0.5%-2% of those infected requiring hospitalization. Older adults and adults with chronic heart disease, lung disease, or those w...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/675A61K31/519A61P31/14
CPCC07D495/04C07D519/00C07H7/06C07H11/04A61P11/00A61P31/12A61P31/14A61P31/16C07F9/6561A61K31/519A61K31/706C07D487/04C07D491/048
Inventor M.O.H.克拉克R.L.马克曼D.西格尔
Owner GILEAD SCI INC
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