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Non nucleoside reverse transcriptase inhibitors

a reverse transcriptase inhibitor and nucleoside technology, applied in the field of compounds with antiviral activity, can solve the problems of limited usefulness of resistant strains, 30 to 50% of patients currently fail combination therapy, and major public health problems

Inactive Publication Date: 2006-06-15
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0874] Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.

Problems solved by technology

Human immunodeficiency virus (HIV) infection and related disease is 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.
Unfortunately, 30 to 50% of patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency.
Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory.
Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g. to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable.
This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs) that can be administered.
By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood / brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract.

Method used

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Examples

Experimental program
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accumulation embodiment

A Cellular Accumulation Embodiment

[0232] Another embodiment of the invention is directed toward a non-nucleoside reverse transcriptase inhibitor compound capable of accumulating in human PBMCs. Accumulation in human PBMCs is described in the examples herein. Typically, the compounds of this embodiment further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug has the structure A3 as described herein. Each of the preferred embodiments of A3 described herein is a preferred embodiment of A3 in the present embodiment.

[0233] Optionally, the compounds of this embodiment demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMCs when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug. Typically, the half-life is improved by at least about 50%, more typically at least in the range 50-100%, still more typically at least about 100%, more typic...

example 1

[0555] To a solution of 2-aminoethylphosphonic acid (810 where n=2, 1.26 g, 10.1 mmol) in 2N NaOH (10.1 mL, 20.2 mmol) was added benzyl chloroformate (1.7 mL, 12.1 mmol). See Scheme 5. After the reaction mixture was stirred for 2 d at room temperature, the mixture was partitioned between Et2O and water. The aqueous phase was acidified with 6N HCl until pH=2. The resulting colorless solid was dissolved in MeOH (75 mL) and treated with Dowex 50WX8-200 (7 g). After the mixture was stirred for 30 minutes, it was filtered and evaporated under reduced pressure to give carbamate 28 (2.37 g, 91%) as a colorless solid.

[0556] To a solution of carbamate 28 (2.35 g, 9.1 mmol) in pyridine (40 mL) was added phenol (8.53 g, 90.6 mmol) and 1,3-dicyclohexylcarbodiimide (7.47 g, 36.2 mmol). After the reaction mixture was warmed to 70° C. and stirred for 5 h, the mixture was diluted with CH3CN and filtered. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The organic phase...

example 10

[0570]

[0571] To a solution of alcohol 15 (42 mg, 0.10 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 μL, 0.17 mmol) and bis(4-nitrophenyl) carbonate (46 mg, 0.15 mmol). See Scheme 18. After the reaction mixture was stirred for 4 h at room temperature, the mixture was partitioned between CH2Cl2 and water. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 60-70% EtOAc / hexane) to give carbonic acid 5-(3,5-dichloro-phenylsulfanyl)-4-isopropyl-1-pyridin-4-ylmethyl-1H-imidazol-2-ylmethyl ester 4-nitro-phenyl ester 16 (47 mg, 82%) as a colorless oil.

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Abstract

Phosphorus-substituted imidazole compounds with anti-HIV properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit reverse transcriptase activity and are useful therapeutically for the inhibition of such enzymes, as well as in assays for the detection of such enzymes.

Description

[0001] This non-provisional application claims the benefit of Provisional Application No. 60 / 375,622, filed Apr. 26, 2002, Provisional Application No. 60 / 375,779 filed Apr. 26, 2002, Provisional Application No. 60 / 375,834 filed Apr. 26, 2002 and Provisional Application No. 60 / 375,665 filed Apr. 26, 2002, which are incorporated herein by reference. Additionally, copending applications Attorney Docket Nos. 257.P2C and 259.PC filed concurrently with this application are also incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The invention relates generally to compounds with antiviral activity and more specifically with anti-HIV properties. BACKGROUND OF THE INVENTION [0003] Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide. The retrovirus human immunodeficiency virus type 1 (HIV-1), a member of the primate lentivirus family (DeClercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/551A61K31/444A61K31/44C07D487/14C12N9/99A61K31/4155A61K31/66A61K31/665A61K31/675A61P31/18A61P43/00C07D213/75C07D213/85C07D231/12C07D231/20C07D233/42C07D239/48C07D239/80C07D243/04C07D265/18C07D307/68C07D401/06C07D403/06C07D471/14C07D491/04C07FC07F9/02C07F9/38C07F9/40C07F9/44C07F9/58C07F9/62C07F9/645C07F9/6506C07F9/6509C07F9/6512C07F9/653C07F9/6533C07F9/655C07F9/6558C07F9/6561C07F9/6584C12N9/16C12Q1/18C12Q1/37C12Q1/44C12Q1/70G01N33/04G01N33/50
CPCA61K31/66A61K31/675C07D213/75C07D213/85C07D231/12C07D231/20C07D233/42C07D239/49C07D239/80C07D243/04C07D265/18C07D307/68C07D401/06C07D403/06C07D471/14C07D491/04C07F9/4006C07F9/645C07F9/650947C07F9/65128C07F9/65335C07F9/65515C07F9/65583C07F9/6561C12N9/16C12Q1/18C12Q1/37C12Q1/44C40B40/04G01N33/5038G01N2333/16G01N2500/04C07F9/58C07F9/6506C07F9/650905C07F9/6512A61P31/18A61P43/00C07F9/38C07F9/40A61K31/4155
Inventor CHEN, JAMESCHEN, XIAOWUKIM, CHOUNGLEE, WILLIAMLEE, CHRISTOPHERNELSON, PETERTARIO, JAMESXU, LIANHONG
Owner GILEAD SCI INC
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