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Pyridinone diketo acids: inhibitors of HIV replication in combination therapy

A technology of composition and compound, which is applied in the field of treatment of human HIV infection and combination therapy, and can solve problems such as no described compound

Inactive Publication Date: 2009-08-26
UNIV OF GEORGIA RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some of the patents cited above are more relevant than others, but none of the patents or publications describe this class of compounds of the present invention

Method used

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  • Pyridinone diketo acids: inhibitors of HIV replication in combination therapy
  • Pyridinone diketo acids: inhibitors of HIV replication in combination therapy
  • Pyridinone diketo acids: inhibitors of HIV replication in combination therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0938] 4-(1,5-Dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2enoic acid (8).

[0939] The related process (1) is as follows.

[0940]

[0941] Process 1

[0942]Step 1: 5-Benzylpyridin-2-amine (2).

[0943]

[0944] A mixture of pyridin-2-amine 1 (14.1 g, 149.8 mmol) and benzyl chloride (36.0 g, 284.6 mmol) was heated to 180° C. until the mixture boiled [Kowalski, J. Heterocycl. Chem. 28, 875-879 (1991 )]. The temperature was then ramped up to 250°C over 3 hours and held there for 24 hours. After cooling, the reaction mixture was washed out of the flask with MeOH (60 mL) and washed with 10% NH 4 Aqueous OH solution (40 mL) was used for treatment. After adding water (200mL), with CHCl 3 (2×200mL) extracted the resulting oil with anhydrous Na 2 SO 4 dried, and distilled off CHCl 3 . The residue was separated by distillation under reduced pressure. Fractions collected at 130-135 °C / 1 mm Hg were further purified by flash chromatography on silica gel...

Embodiment 2

[0964] 4-(1,5-Dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2enoic acid (16).

[0965] The related process (2) is shown below.

[0966]

[0967] Process 2

[0968] Step 1: 3,5-Dibromo-pyridin-4-one (10)

[0969]

[0970] To an ice-cold solution of pyridin-4-one 9 (6.98 g, 73.4 mmol) and KOH (9.52 g, 146.8 mmol) in water (140 mL) was added bromine (7.58 mL, 147.5 mmol) dropwise over 30 minutes [Spivey, et al. , J. Org. Chem. 65, 3154-3159 (2000)]. 30 minutes after the addition, the precipitate was filtered, washed with copious amounts of water, and dried in vacuo. Yield 16.17 g (87%), yellow solid, mp 320°C (sublimation). 1 H NMR (DMSO-d 6 , 500MHz): δ12.3(s, 1H), 8.26(s, 2H). 13 C NMR (DMSO-d 6 , 125MHz): δ167.5, 138.2, 138.2, 111.8, 111.8.

[0971] Step 2: 3-Bromo-5-(hydroxy-phenyl-methyl)-pyridin-4-one (11)

[0972]

[0973] To a heterogeneous mixture of 3,5-dibromo-pyridin-4-one 10 (0.313 g, 1.24 mmol) in anhydrous THF (4 mL) was added phenylm...

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Abstract

A new class of diketo acids constructed on pyridinone scaffolds, designed as inhibitors of HTV replication through inhibition of HIV integrase, is described. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti- HIV compounds (including other anti-HIV integrase agents), which can be used to create combination anti-HIV cocktails. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described. Compounds of the present application include those of formula I and include tautomers, regioisomers, geometric isomers, and pharmaceutically acceptable salts thereof, wherein the pyridinone scaffold and R groups are as otherwise defined in the specification. These are combined, with any number of typical other anti-HIV agents (including other integrase-based anti-HIV agents) and other combination therapeutic agents described herein, to provide an effective treatment modality for HIV infections, including AIDS and ARC.

Description

field of invention [0001] The present invention relates to the field of antiviral therapy, especially the treatment of human HIV infection, preferably combined therapy. [0002] Related applications and financial support [0003] This application claims provisional applications US 60 / 831,990, filed July 19, 2006, US 60 / 920,196, filed March 27, 2007, both titled "Pyridone diketoacids: Inhibitors of HIV Replication," and titled " Priority to provisional application 60 / 920,197, filed March 27, 2007, to Pyridonediketoacids: HIV Replication Inhibitors for Combination Therapy, which is incorporated by reference in its entirety. [0004] Work on this patent application was supported in part by funding from the National Institutes of Health under award number A143181. Accordingly, the US Government reserves certain rights in this invention. Background of the invention [0005] Human immunodeficiency virus, namely HIV, encodes three key viral enzymes through its pol gene and these...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4412C07D211/86
Inventor 瓦瑟·奈尔徐炳益维诺德·R·尤奇尔迟国臣
Owner UNIV OF GEORGIA RES FOUND INC
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