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Hiv-1 protease inhibitors

An alkyl, compound technology, applied in the direction of protease inhibitors, peptide/protein components, transferases, etc., can solve problems such as drug resistance mutations

Inactive Publication Date: 2010-05-05
UNIV OF MASSACHUSETTS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The HIV protease is a particularly attractive target because inhibition of its activity is clinically effective; however, it can evolve to allow a large number of mutations that confer resistance while retaining enzyme function

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0405] General method for CBZ protection of substituted anilines

[0406] Solid NaHCO 3 (32.65 g, 388.5 mmols) was added to an ice-cooled solution of the aniline derivative (185 mmols) in acetone-water mixture (2:1) (300 mL), followed by the slow addition of benzyl chloroformate (27 mL, 190 mmols). The resulting paste was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice, and the resulting precipitate was filtered, washed with water and dried. The product was purified by recrystallization from a mixture of hexane and ethyl acetate to give pure product as a crystalline solid. Compounds 4a-g were prepared following this general procedure.

Embodiment 2

[0408] A general method for the synthesis of 5-(hydroxymethyl)-oxazolidinones 7 and 8

[0409] in dry N 2 A solution of the CBZ-protected aniline derivative 4 (34.7 mmols) in anhydrous THF (150 mL) was cooled to -78 °C under atmospheric pressure. A solution of n-BuLi (1.6M in hexane; 25 mL, 40 mmols) was added slowly keeping the temperature below -70 °C. After stirring the reaction mixture for 45 minutes at -78°C, a solution of chiral monoglycidyl butyrate (5 g, 34.7 mmols) in anhydrous THF was added slowly. The resulting mixture was stirred at -78°C for 2 hours, then slowly warmed to room temperature and stirred overnight. Add saturated NH 4 Aqueous Cl solution quenched the reaction. Ethyl acetate and water were added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3 times). The combined organic extracts were washed with saturated aqueous NaCl, dried (NaCl 2 SO 4 ), filtered and evaporated to yield a pale yellow solid. The s...

Embodiment 3

[0411] A general method for the synthesis of phenyloxazolidinone-5-carboxylic acids 9 and 10

[0412] Ice-cooled NaIO 4 (35mmols) in water (75mL) was added to the mixture CH 3 CN and CCl 4 Alcohol 7 or 8 (10 mmols) in (1:1) (100 mL). Add solid RuCl 3 .H 2 O (0.5 mmol), the reaction mixture was stirred at 0 °C for 30 minutes, warmed to room temperature, and stirred for 4-6 hours. Join CH 2 Cl 2 The reaction was quenched and the layers were separated. Further use CH 2 Cl 2 The aqueous layer was extracted and the combined organic extracts were dried (Na 2 SO 4 ) and evaporated to give a sticky solid. adopted in CH 2 Cl 2 +1%HCO 2 25% CH in H 3 CN mixture was used as eluent and the crude product was purified by column chromatography on silica gel. This process provides the desired phenyloxazolidine-5-carboxylic acid as a solid in good yield. The following compounds were prepared according to this general procedure:

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Abstract

Described are novel protease inhibitors and methods for using said protease inhibitors in the treatment of human immunodeficiency virus (HIV) infection.

Description

[0001] related application [0002] This application claims U.S. Provisional Application Serial No. 60 / 919,896, filed March 23, 2007, U.S. Provisional Application Serial No. 60 / 919,819, filed March 23, 2007, U.S. Provisional Application Serial No., filed June 4, 2007 60 / 941,786 and the priority of US Provisional Application Serial No. 60 / 941,829, filed June 4, 2007, which are hereby incorporated by reference in their entirety. [0003] governmental support [0004] This invention was made with government support through Grant No. P01 GM 066524 awarded by the National Institutes of Health / National Institutes of Allergy and Infectious Diseases. The government has certain rights in this invention. Background of the invention [0005] The human immunodeficiency virus type 1 (HIV-1) protease plays a key role in the viral life cycle by processing the viral Gag and Gag-Pol polyproteins into structural and functional proteins necessary for viral maturation. Inhibition of HIV-1 prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/195A61K31/425C07K19/00
CPCC07D417/06C07D417/14C07D413/04C07D413/14C07D417/04C07D417/12C12N9/12C07D413/12C07D263/24C07D413/06C07K14/81
Inventor A·阿利M·D·阿尔特曼S·G·安朱姆H·曹S·谢拉潘M·X·费尔南德斯M·吉尔森V·凯里斯N·金E·纳利韦卡M·普拉布T·M·拉纳K·K·R·加鲁达马加里塞C·A·希菲尔B·蒂多尔M·N·L·纳拉姆
Owner UNIV OF MASSACHUSETTS
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