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Nucleobase phosphonate analogs for antiviral treatment

a technology of nucleotide phosphonate and antiviral treatment, which is applied in the direction of biocide, group 5/15 element organic compounds, drug compositions, etc., can solve the problems and affecting the treatment effect of patients, so as to improve the therapeutic and diagnostic value, the effect of increasing the accumulation and retention of drug compounds

Inactive Publication Date: 2006-11-09
GILEAD SCI INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0019] This invention pertains to a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value.

Problems solved by technology

Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide.
Unfortunately, many 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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  • Nucleobase phosphonate analogs for antiviral treatment
  • Nucleobase phosphonate analogs for antiviral treatment
  • Nucleobase phosphonate analogs for antiviral treatment

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Section A

[0283]

[0284] Scheme A shows the general interconversions of certain phosphonate compounds: acids —P(O)(OH)2; mono-esters —P(O)(OR1)(OH); and diesters —P(O)(OR1)2 in which the R1 groups are independently selected, and defined herein before, and the phosphorus is attached through a carbon moiety (link, i.e. linker), which is attached to the rest of the molecule, e.g. drug or drug intermediate (R). The R1 groups attached to the phosphonate esters in Scheme 1 may be changed using established chemical transformations. The interconversions may be carried out in the precursor compounds or the final products using the methods described below. The methods employed for a given phosphonate transformation depend on the nature of the substituent R1. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.

[0285] The conversion of a phosphonate diester 27.1 into the corresponding phosphonate ...

preparation 1

Synthesis of SDS-1 S-(+)-N-Propenoylbornane-2,10-sultam

[0355] The acrylic acid (7.04 mL, 1.2 eq.) bought from Aldrich was dissolved in 120 ml of tetrahydrofuran (THF), 27.5 mL of triethyl amine (TEA) was added thereto and the resulting mixture was cooled to −20° C. To mixture 11.66 mL (1.2 eq.) of pivial chloride was added and stirred for 1 hour. To the reaction mixture add lithium chloride (3.7 g, 1.1 eq.) and bornane 2,10 sultam (17 g, 1 eq.), allow the mixture to warm to RT and stir another 4-6 hours. Reaction mixture was quenched with 10 mL 0.2 M hydrochloric acid (2 eq.). The mixture was reduced under vacuum to remove THF. Extract the aqueous mixture with ethyl acetate (EtOAc) washing the combined organic layers with saturated sodium bicarbonate 2× and brine 1×. Dry organic with sodium sulfate and concentrate in a large flask under reduced pressure to a dry solid. Dissolve the solid in minimum amount of toluene and add hexane until cloudy. Place mixture in freezer over night. ...

preparation 2

Synthesis of SDS-2 (2S,6S)-2,6-dimethyl-5-methylene-1,3-dioxan-4-one

[0356] The compound prepared in Preparation 1 (13.4 g) was dissolved in 65 mL of dichloromethane (DCM). The resulting solution was cooled to 0° C. using chiller. Methyl acrylate (41.49 mL, 14.5 eq.) and DABCO (2.74 mg, 0.5 eq) was added to the cold mixture. The solution was stirred over the weekend at 0° C. The mixture was concentrated under reduced pressure and purified by flash column chromatography to provide 6 g (86% yield) of the title compound as a colorless oil. 1H NMR(CDCl3) δ 1.48 (m, 6H), 4.64 (m, 1H), 5.50 (m, 1H), 5.59 (d, 1H), 6.49 (d, 1H); and ESI 142.8 (M+1)+, C7H10O3

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Abstract

The present invention provides novel compounds with activity against infectious viruses. The compounds of the invention may inhibit retroviral reverse transcriptases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and / or related diseases. The present invention also relates generally to the accumulation or retention of therapeutic compounds inside cells. The invention is more particularly related to attaining high concentrations of active metabolite molecules in HIV infected cells. Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.

Description

FIELD OF THE INVENTION [0001] The invention relates generally to compounds with antiviral activity and more specifically with anti-reverse transcriptase properties. BACKGROUND OF THE INVENTION [0002] Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide. The retrovirus human immunodeficiency virus type I (HIV-1), a member of the primate lentivirus family (DeClercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; Barre-Sinoussi F (1996) Lancet, 348:31-35), is generally accepted to be the causative agent of acquired immunodeficiency syndrome (AIDS) Tarrago et al FASEB Journal 1994, 8:497-503). AIDS is the result of repeated replication of HIV-1 and a decrease in immune capacity, most prominently a fall in the number of CD4+ lymphocytes. The mature virus has a single stranded RNA genome that encodes 15 proteins (Frankel et al (1998) Annual Review of Biochemistry, 67:1-25; Katz et al (1994) Annual Review of Biochemis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07F9/6512A61K31/675C07F9/6561
CPCC07F9/65616A61K31/675A61P31/12A61P31/14A61P31/18A61P43/00
Inventor KRAWCZYK, STEVEN H.
Owner GILEAD SCI INC
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