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Integrase inhibitors

a technology of integrase inhibitors and inhibitors, which is applied in the field of compounds having antiviral activity, can solve the problems of inability to inhibit the activity of integrase inhibitors, the inability to fully integrate preintegration complexes, and the inability to inhibit the inhibitory potency of fully assembled preintegration complexes

Inactive Publication Date: 2009-12-10
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The new compounds demonstrate improved potency and prolonged activity against HIV integrase, effectively inhibiting viral integration and prolonging intracellular half-life, addressing limitations of existing inhibitors by enhancing bioavailability and resistance to metabolic degradation.

Problems solved by technology

Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide.
Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med.
Although numerous agents potently inhibit 3′-P and ST in extracellular assays that employ recombinant integrase and viral long-terminal-repeat oligonucleotide sequences, often such inhibitors lack inhibitory potency when assayed using fully assembled preintegration complexes or fail to show antiviral effects against HIV-infected cells (Pommier, et al Adv.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0331]

[0332]Compound (1) (107 mg, 213 μmol) was dissolved in 5 mL of pyridine and flashed with nitrogen, It was cold to 0° C. and added sulfonyl chloride (200 μl) and stirred for 2 h under nitrogen. It became dark. The reaction was diluted with 20 mL of EtOAc, washed with 0.1N HCl, brine, sat'd NaHCO3 and brine again. It was dried over Na2SO4 and filtered through a pile of Celite, then concentrated in vacuum to give crude product (2). The crude product was purified by flash chromatography with 30% EtOAc / Hexane to yield 81 mg of desired product in 62%.

General Procedure for the Deprotection of DPM Group at C8-OH:

[0333]The compound (2) (20 mg) was dissolved in 1 mL of DCM and treated with TFA (100 μl) and triethylsilane (200 μl). After stirring for 30 minutes at room temperature, the reaction mixture was azeotroped with toluene once. The resulting residue was then purified by reverse-phase prep HPLC to provide 11.5 mg of (3), as the TFA salt.

[0334]General HPLC conditions: mobile phase ...

example 2

[0336]

[0337]9 (100 mg, 0.18 mmol) was dissolved in 1.0 ml of THF. Cyclopropylmethanol (21.3 ul, 0.27 mmol), Triphenylphosphine (71 mg, 0.27 mmol), and DIAD (53 uL, 0.27 mmol) were then added to this solution successively and the reaction was allowed to stir at room temperature for 45 minutes. The reaction was then diluted with Ethyl Acetate and the organic was washed once with sat. NaHCO3, twice with water, and once with Brine. The organic was then dried over Magnesium Sulfate and concentrated in vacuo to afford a crude residue which was then purified by silica gel chromatography (3:1—Hexane:EthylAcetate) to afford 10 (90 mg, 81%).

example 3

[0338]

[0339]9 (100 mg, 0.18 mmol) was dissolved in 1.0 ml of THF. N,N-Dimethylaminoethanol (81 ul, 0.8 mmol), Triphenylphosphine (210 mg, 0.8 mmol), and DIAD (155 ul, 0.8 mmol) were then added to this solution successively and the reaction was allowed to stir at room temperature for 45 minutes. The reaction was then diluted with Ethyl Acetate and the organic was washed once with sat. NaHCO3, twice with water, and once with Brine. The organic was then dried over Magnesium Sulfate and concentrated in vacuo to afford a crude residue which was then purified by silica gel chromatography (1% Triethylamine in EthylAcetate) to afford 13 (84 mg, 72%).

[0340]13 (84 mg, 0.13 mmol) was dissolved in 1 ml of THF and 100 ul of water. LiBH4 (22 mg, 1.05 mmol) was then added and the reaction then stirred at room temperature for 1 hour. The reaction was then diluted with Ethyl Acetate and the organic was washed once with water and once with Brine. The organic was then dried over Mg2SO4 and concentrate...

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Abstract

Tricyclic compounds of formulae I-III, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

Description

FIELD OF THE INVENTION[0001]The invention relates generally to compounds having antiviral activity, and more specifically, compounds having HIV-integrase inhibitory properties.BACKGROUND OF THE INVENTION[0002]Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. A virally encoded integrase protein mediates specific incorporation and integration of viral DNA into the host genome. Integration is necessary for viral replication. Accordingly, inhibition of HIV integrase is an important therapeutic pursuit for treatment of HIV infection of the related diseases.[0003]Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their us...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C07D471/04A61K31/551A61K31/5377A61P31/18
CPCC07D471/04A61P31/12A61P31/18A61P37/04A61P43/00
Inventor CAI, ZHENHONG R.JABRI, SALMAN Y.JIN, HAOLUNLANSDOWN, RACHEL A.METOBO, SAMUEL E.MISH, MICHAEL R.PASTOR, RICHARD M.
Owner GILEAD SCI INC
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