WO2011011710A1 - Methods of treating viral infections - Google Patents

Abstract

The present invention provides methods of treating human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection, including administering a compound described in the invention in an amount effective treat the HIV and/or HBV infection and at least substantially inhibit the development of resistance to said antiviral compounds in the subject. Pharmaceutical compositions are also provided.

Description

METHODS OF TREATING VIRAL INFECTIONS

Ernest Randall Lanier, Merrick R. Almond, George R, Painter

Related Applications

This application claims the benefit under 35 U. S. C. § 119(e) of United States Provisional Patent Application Serial Number 61/228,406, filed July 24, 2009, the disclosures of which are incorporated herein by reference in its entirety.

Background of the Invention

Human immunodeficiency virus type 1 (HIV-I) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Combination therapy with protease inhibitors and reverse transcriptase inhibitors has a long record of effectively treating HTV and integrase inhibitors are stalling to make significant contributions (See Palella, et al, N. Engl. J. Med,, 338, 853-860 (1998); Richman, Nature, 410, 995-1001(2001)). However, therapy frequently fails due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and/or lack of potency. Therefore, there is a continuing need for new therapies that are active against mutant HTV strains, have fewer side effects, and permit simpler dosing schedules.

Summary of the Invention

A first aspect of the invention is, in a method of treating a subject for human

immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection (in some embodiments thereof, said subject has not previously been administered an antiviral active agent for said HW or HBV infection), the method including: administering said subject an antiviral compound described herein, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof, in an amount effective to treat said viral infection and substantially inhibit the development of resistance to antiviral compounds in said subject.

A further aspect of the invention is, in a method of treating a subject for human

immunodeficiency virus (HlV) and/or hepatitis B virus (HBV) infection, where said subject has developed resistance, or a toxic response, to at least one antiviral compound in response to prior administration of at least one antiviral compound to said subject for said HlV or HBV infection, the method including: administering said subject an antiviral compound described herein, or a pharmaceutically acceptable salt, or a stereoisomer, a diastereomer, an enantiomer or racemate thereof, in an amount effective to treat said viral infection and inhibit the further development of resistance to antiviral compounds in said subject. The aforesaid methods may further include administering said subject one or more additional antiviral active agents in combination with said an antiviral compound.

In some embodiments of the foregoing, the subject is immunocompromised (hi some embodiments, the subject is immunocompromised due to infection of HIV.)

hi some embodiments of the foregoing, the virus is HBV (and in some embodiments thereof, the subject is afflicted with fulminant hepatitis or fulminant hepatic failure). In some embodiments, the virus is HTV.

In some embodiments of the foregoing, the subject is infected with both HBV and HTV, said antiviral compound is administered in an amount effective to treat both said HBV and HIV.

In some embodiments of the foregoing, the subject is in iiiero and said active compound is administered to the mother carrying said subject in utero.

A further aspect of the invention' is the use of an antiviral compound described herein as described herein for carrying out a method as described herein, and/or for the preparation of a medicament for carrying out a method as described herein.

A further aspect of the invention is a pharmaceutical composition comprising: (a) an antiviral compound described herein, or pharmaceutically acceptable salt, or a stereoisomer, a diastereomer, an enantiomer or racemate thereof, (b) one or more additional antiviral active agents (e.g., an anti HIV or an anti HBV antiviral compound); and (c) a pharmaceutically acceptable carrier.

Also described herein is the finding that active compounds described herein associate or bind directly to viruses such as HIV, making possible the delivery of the active compounds into cellular or tissue compartments (sometimes referred to as "privileged compartments") to which active compounds are not otherwise accessible, and making the active compounds useful as microbicides to inhibit the transmission (e.g., prophylactically) of viruses such as HIV. Compositions and devices for carrying out such methods, along with the use of active compounds as described herein for carrying out such methods, are also described.

In some embodiments, in the above methods, device, or compositions, the one or more additional antiviral agents can be selected from lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

Brief Description of the Drawings

Figure 1 shows for comparative purposes the virologic response to tenofovir in antiretroviral experienced patients at 24 weeks.

Figure 2 shows the in vitro efficacy of tenofovir (TFV) as compared to HDP-TFV

(CMXl 57). Figure 3 shows the in vitro efficacy of TFV as compared to HDP-TFV (CMX 157), this time with the IC50S for HDP-TFV multiplied by 100 for scaling.

Detailed Description

The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and encompasses any and all possible

combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, ail terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling,

As used herein, "alkyl" refers to a straight or branched chain hydrocarbon containing from 1 to 30 carbon atoms. In some embodiments, the alkyl group contains 2 to 25, 2 to 24, 1 to 10, or 1 to 8 carbon atoms. In some embodiments the alkyl group contains 1 to 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms. In still other embodiments, alkyl group contains 1-5 carbon atoms, and in yet other embodiments, alkyl group contain 1-4 or 1-3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-penryl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein. As used herein, "alkenyl," refers to a straight or branched chain hydrocarbon containing from 2 to 30 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. In some embodiments, the alkenyl group contains 2 to 25, 2 to 24, 2 to 10, 2 to 8 carbon atoms. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms. In still other embodiments, alkenyl groups contain 2-5 carbon atoms, and in yet other embodiments alkenyl groups contain 2-4 or 2-3 carbon atoms. Representative examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1- heptenyl, 3-decenyl and the like. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.

As used herein, "alkynyl," refers to a straight or branched chain hydrocarbon group containing from 2 to 30 carbon atoms and containing at least one carbon-carbon triple bond. In some embodiments, the alkynyl group contains 2 to 25, 2 to 24, 2 to 10 or 2 to 8 carbon atoms, hi some embodiments, the alkynyl group contains 2 to 6 carbon atoms, hi still other embodiments, alkynyi groups contain 2-5 carbon atoms, and in yet other embodiments, alkynyl groups contain 2-4 or 2-3 carbon atoms. Representative examples of alkynyl include, but are not limited, to ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.

As used herein, the term "alkoxy" refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. In some embodiments the alkyl group contains 1-30 carbon atoms. In other embodiment, the alkyl group contains 1 -20, 1-10 or 1-5 carbon atoms. In some embodiments, the alkoxyl group contains 1 to 8 carbon atoms, hi some embodiments, the alkoxyl group contains 1 to 6 carbon atoms. In some embodiments, the alkoxyl group contains 1 to 4 carbon atoms. In still other embodiments, alkoxyl group contains 1-5 carbon atoms, and in yet other embodiments, alkoxyl group contain 1-4 or 1-3 carbon atoms. Representative examples of alkoxyl include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, and n- pentoxy. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.

As used herein, "amino acid residue" refers to a compound consisting of a carbon atom which is bonded to a primary amino (-NH₂) group, a carboxylic acid (-COOH) group, a side chain, and a hydrogen atom. For example, the term "amino acid" includes, but is not limited to, Glycine, Alanine, Valine, Leucine, Isoleucine, Serine, Threonine, Aspartic acid and Glutamic acid. In the present invention, in Formula I or Ia, when R₂ is -NR¹H and R¹ is an amino acid residue, N is attached to the carbon atom as a side chain. Additionally, as used herein, "amino acid" also includes derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.

As used herein, "cycloalkyl" refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom, hi some embodiments, cycloalkyl contains 3 to 8 carbon atoms. In some embodiments, cycloalkyl contains 3 to 6 carbon atoms. Cycloalkyl groups may be optionally substituted with alkyl, alkoxy, halo, or hydroxy substituents. Representative examples of cycloalkyl include, but are not limited to, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclσheptyl, and cyclooctyl. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

As used herein, "heteroalkyl," "heteroalkenyl" or "heteroalkyiiyl" refer to alkyl, alkenyl or alkynyl groups which contain one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. In some embodiments, the heteroalkyl group contains 1-8 carbon atoms. In certain embodiments, the heteroalkenyl and heteralkynyl groups independently contain 2-8 carbon atoms. In still other embodiments, heteroalkyl, heteroalkenyl and heteralkynyl independently contain 2-5 carbon atoms, and in yet other embodiments, heteroalkyl, heteroalkenyl and heteralkynyl independently contain 2-4 or 2-3 carbon atoms.

The term "heterocycloalkyl" or "heterocycle", as used herein, refers to a non-aromatic, saturated or unsaturated, 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic having between one or more heteroatoms independently selected from oxygen, sulfur and nitrogen as part of the ring, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and/or (iv) any of the above heterocyclic rings may be fused to a benzene ring. Exemplary heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahy drofury 1.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals: fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-1).

As used herein, the term "haloalkyl" refers to a straight or branched chain alkyl group as defined herein containing at least one carbon atoms substituted with at least one halo group, halo being as defined herein. In some embodiments, the haloalkyl contains 1 to 30 carbon atoms. In some embodiments, the halkalkyl contains 1 to 8 or 1 to 6 carbon atoms. In other embodiments, the haloalkyl contains 1 to 4 carbon atoms. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein. As used herein, the term "aryl" refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term "aryl" is intended to include both substituted and unsubstituted aryl unless otherwise indicated. For example, an aryl may be substituted with one or more heteroatoms (e.g., oxygen, sulfur and/or nitrogen). Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.

In some embodiments, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,

heterocycloalkyl, aryl, heteroaryl, acyl, described herein include both substituted and unsubstituted moieties. Exemplary substituents include, but are not limited to, halo, hydroxyl, amino, amide, -SH, cyano, nitro, thioalkyl, carboxylic acid, -NI-1-C(=NH)-NH₂, alkyl, alkenyl, aikynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, in which alkyl, alkenyl, alkynyl, alkoxyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may be further substituted,

As used herein, the term "amino acid" refers to a compound comprising a primary amino (- NH₂) group and a carboxylic acid (-COOH) group. The amino acids used in the present invention include naturally occurring and synthetic α, β, γ or δ amino acids, and includes but are not limited to, amino acids found in proteins. Exemplary amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In some embodiments, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleuciiiyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lyshiyl, argininyl, histidinyl, β-alanyl, β-valinyl, β- leucinyl, β-iso leucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β- serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β- lysinyl, β-argininyl or β-histidinyl. Additionally, as used herein, "amino acids" also include derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.

As used herein, the term "natural α amino acid" refers to a naturally occurring α-amino acid comprising a carbon atom bonded to a primary amino (-NH₂) group, a carboxylic acid (-COOH) group, a side chain, and a hydrogen atom. Exemplary natural α amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophane, proline, serine, threonine, cysteine, tyrosine, asparaginate, giutaminate, aspartate, glutamate, lysine, arginine and histidine.

Subjects to be treated by the methods of the present invention are, in general, mammalian and primate subjects (e.g., human, monkey, ape, chimpanzee). Subjects may be male or female and may be of any age, including prenatal (i.e., in utero), neonatal, infant, juvenile, adolescent, adult, and geriatric subjects. Thus, in some cases the subjects may be pregnant female subjects. Treatment may be for any purpose, including the therapeutic treatment of previously infected subjects, as well as the prophylactic treatment of uninfected subjects (e.g., subjects identified as being at high risk for infection).

As used herein, "Human immunodeficiency virus" (or "HTV") as used herein is intended to include all subtypes thereof, including HIV subtypes A, B, C, D, E, F, G, and O, and HTV-2.

As used herein, "Hepatitis B virus" (or "HBV") as used herein is intended to include all subtypes (adw, adr, ayw, and ayr) and or genotypes (A, B, C, D, E, F, G, and H) thereof.

As used herein, "Multiple nucleoside resistant" or "multi-nucleoside resistant" as used herein refers to genotypic or phenotypic patterns which predict or indicate diminished efficacy for most or all nucleoside and nucleotide reverse transcriptase inhibitors. Genotypic examples include the Ql 5 IM complex, the T69SXX complex and multiple thymidine analog associated mutations. Phenotypic examples include patterns where few or no NRTIs test as "sensitive".

As used herein, "Toxic response" as used herein may be any deleterious toxic and/or undesired response to a treatment with an antiviral agent, including but not limited to nausea, vomiting, rash, diarrhea, nephrotoxicity, mitochondrial toxicity, etc. and combinations thereof.

As used herein, or "an amount effective¹" refers to an amount that will provide some alleviation, mitigation, and/or decrease in at least one clinical symptom in the subject. Those skilled in the ait will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

Unless otherwise stated, structures depicted herein are meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

As used herein, "prevention", "prevent", and "preventing" refer to eliminating or reducing the incidence or onset of a disorder or disease as described herein, as compared to that which would occur in the absence of the measure taken. Active compounds of the present invention may optionally be administered in combination (or in conjυction) with other active compounds and/or agents useful in the treatment of viral infections as described herein. The administration of two or more compounds "in combination" or "in conjunction" means that the two compounds are administered closely enough in time to have a combined effect, for example an additive and/or synergistic effect. The two compounds may be administered simultaneously (concurrently) or sequentially or it may be two or more events occurring within a short time period before or after each other. Simultaneous administration may be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration. In some embodiments, the other antiviral agent may optionally be administered concurrently.

A. Active compounds

According to some aspects of the present invention, compounds with a range of biological properties are provided. Compounds described herein have biological activities relevant for the treatment of HIV and/or HBV.

hi some embodiments, the compounds of the present invention have the structure of Formula I:

wherein:

R₁, Ri', R₂ and R₂' are independently— H, optionally substituted— O(C₁-C₂4)alkyl,— 0(C₂- C₂₄)alkenyl, -O(C₂-C₂₄)alkynyl, — O(C₁-C₂₄)acyl, — S(C₃-C₂₄)alkyl, — S(C₂-C₂₄)alkenyl, -S(C₂- C₂₄)alkynyl or— S(C,-C₂₄)acyl,— N(C₁-C₂₄)acyl,— NH(C₁-C₂₄)alkyl, ,— N(C₂-C₂₄)alkenyl, -N(C₂-C₂₄)alkynyl— N((d-C₂₄)alkyl)₂, oxo, halogen, -NH₂,—OH, or -SH;

wherein at least one of Ri and R_s' are not— H, and said alky 3, alkenyl, alkynyl or acyl moieties optionally have 1 to 6 double bonds or triple,

R₃ is a pharmaceutically active phosphonate, bisphosphonate or a phosphonate derivative of a pharmacologically active compound,;

X, when present, is:

and m is an integer from 0 to 6.

In some embodiments, the compound of the present invention (e.g. Formula I) is not

hi some embodiments, m is 0, 1 or 2. In one embodiment, R₂ and R₂' are H. In another embodiment, the compounds are ethanediol, propanediol or butanediol derivatives of a therapeutic phosphonate. In one embodiment, the compounds of the present invention are ethanediol phosphonate species has the structure: -

wherein R₁, R₁', and R₃ are as defined above.

In some embodiments, the compounds of the present invention are propanediol species that have the structure:

wherein m is 1 and R₁, R₁', and R₃ are as defined above in the general formula,

In one embodiment, the compounds of the present invention are glycerol species that have the structure:

wherein m is 1, R₂ is H, R₂' is OH, and R₂ and R₂' on C^α are both— H. Glycerol is an optically active molecule. Using the stereospecific numbering convention for glycerol, the sn-3 position is the position which is phosphorylated by glycerol kinase. Tn compounds of the invention having a glycerol residue, the R₃ moiety may be joined at either the sn-3 or sn-1 position of glycerol.

In some embodiments, R, is an alkoxy group having the formula— O— (CH₂)_t— CH₃, wherein t is 0-24. In one embodiment, t is 11-19. In another embodiment, t is 15 or 17. Additionally, antiviral phosphonates such as cidofovir, cyclic-cidofovir, adefovir, tenofovir, and the like, may be used as an R₃ group in accordance with the present invention.

According to one aspect of the present invention, the antiviral compounds have the structure of Formula A, A' or B

Formula A

Formula A'

or

Formula B wherein:

R] is a moiety selected from the group consisting of alkylglycerol, alkylpropanediol, 1-S-alkylthioglycerol, alkoxyalkanol and alkylethanediol, wherein Ri is linked to -P(=X)- via oxygen of an available -OH of the moiety (The "-OH" may be any available OH of the moiety. After R| is covalently linked to -P(=X>, the H of "-OH" cleaves and R, is bonded directly to -P(=X)- through O of the -OH. For example, formula a, b, and c shown below illustrate how R] is bonded to -P(=X)- when R] is alkylethanediol, alkylpropanediol, or alkylglycerol.) B is selected from the group consisting of hydrogen, F, CF₃, -CH₃, -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃, -CH₂F, -CH=CH₂, and -CH₂N₃,

X is selenium, sulphur, or oxygen (in some embodiments, oxygen);

R₂ is hydroxy, -OR_2a, -BH₃, C_{1- 8} alky], C_2-8 alkenyl, C_2-8 alkynyl, Q-g heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, or -NR'H (in some embodiments, R₂ is hydroxyl);

R_2a is C]-_S alkyl, C₂-& alkenyl, C_2-8 alkynyl, Cr₈ heteroalkyl, C_2-s heteroalkenyl, C_2-s heteroalkynyl, -P(=O)(OH)₂, or -P(=O)(OH)OP(=O)(OH)₂,

R' is C_{1 -8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C_2-8 heteroalkynyl, C_2-8 heteroalkenyl, C_6-10 aryl, or a substituted or unsubstituted amino acid residue, Z comprising a heterocyclic moiety comprising at least one N (in some embodiments, the heterocyclic moiety is purine or pyrimidine,), and

the symbol * indicates the point of attachment of the methylene moiety in Formula A, A' or B to Z is via an available nitrogen of the heterocyclic moiety,

or a pharmaceutically acceptable salt thereof,

In some embodiments, the antiviral compound is in the form of an enantiomer, diastereomer, racemate, stereoisomer, tautomer, rotamer or a mixture thereof.

In another embodiment, B is -CH₃.

In some embodiments, Ri is a moiety of alkylethanediol or alkylpropanediol. In one embodiment, Ri is a moiety of hexadecylpropanediol. In another embodiment, Ri is a moiety of octadecylpropanediol. Further, in one embodiment, Ri is -O-(CH₂)_a-O-(CH₂)₁-CH₃, wherein a is 2 to 4 and t is 11 to 19. In some embodiments, a is 2 or 3 and t is 15 or 17.

In one embodiment, Ri is a moiety of

wherein R^a and R^b are independently selected from the group consisting of— H, optionally substituted— O(d-C₂₄)alkyl,— O(C₂-C₂₄)alkenyl,— O(C₂-C₂₄)alkynyl,— O(C₃-C₂₄)acyl, -S(C,- C₂₄)alkyl, — S(C₂-C₂₄)alkenyl, — O(C₂-C₂₄)alkynyl, or -S(C₁-C₂₄)acyI, -N(C]-C₂₄)acyI, — NH(C₁-C₂₄)alkyl,— NH(C₂-C₂₄)alkeyl,— NH(C₂-C₂₄)alkynyl,— N((C₁-C₂₄)alkyl)₂, oxo, halogen,— NH₂,— OH and— SH. In some embodiments, at least one of R^a or R^b is not hydrogen. In some embodiments, R^a and R^b are independently selected from the group consisting of— H, optionally substituted — 0(C₁-C₂₄)alkyl, — O(C₂-C₂₄)alkenyl, -O(C₁-C₂₄)acyI, — S(C₁ -C₂₄)alkyl, — S(C₂- C₂₄)alkenyl, or— S(C,-C₂₄)acyI.

In some embodiments, Z is purine or pyriniidine, which may be optionally substituted by at least one substituent. In some embodiments, at least one substituent may be selected from the group consisting of halogen, hydroxyl, amino, substituted amino, di-substituted amino, sulfur, nitro, cyano, acetyl, acyl, aza, C_1-6alkyl, C_2-6alkenyl, C_2-6aIkynyl, C_6-10aryl, and carbony! substituted with a C_1- ealkyl, C_2-6alkenyl, C_2-6 alkynyl, or C_6-10aryl, haloalkyl and aminoalkyl.

In some embodiments, Z include, but are not limited to, adenine, 6-chloropurine, xanthine, hypoxanthine, guanine, 8-bromogυanine, 8-chloroguanine, 8-aminoguanine, 8-hydrazinoguanine, 8- hydroxyguanine, 8-methylguanine, 8-thioguanine, 2-aminopurine, 2,6-dianiinoρurine, thymine, cytosine, 5-fluorocytosine, uracil; 5-bromouracil, 5-iodouracil, 5-ethylιiracil, 5-ethynyluracil, 5- propynyluracil, 5-propyluracil, 5-vinyluracil, or 5-bromovinyluracil, .I some embodiments, Z is selected from guanin-9-yl_; adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3- deaza, 8-aza compounds, or cytosln-1-yl. In some embodiments, Z is guanin-9-yl or 2, 6- diaminopurin-9-yl.

In another embodiment, exemplary Z, includes, but is not limited to, 6-alkylpurine and N - alkylpurines, N⁶ -acylpurines, N⁶ -benzylpurine, 6-halopurine, N⁶ -acetylenic purine, N⁶ -acyl purine, N⁶ -hydroxyalkyl purine, 6-thioalkyl purine, N² -alkylpurines, N⁴ -alkylpyrimidines, N⁴ - acylpyrimidines, 4-halopyrimidines, N⁴ -acetylenic pyrimidines, 4-amino and N⁴ -acyl pyrimidines, 4- hydroxyalkyl pyrimidines, 4-thioalkyl pyrimidines, thymine, cytosine, 6-azapyrimidine, including 6- azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, C -alkylpyrimidines, C -benzylpyrimidines, C - halopyri mi dines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine, C⁵-aminopyrimidine, N²- alitylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyi-idinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

In one embodiment, Z is

Formula 1

Formula 2

Formula 3 or

Formula 4

wherein the symbol * in Formula 1-4 indicates the point of attachment of N to the methylene in Formula A, A¹ or B.

Additional examples of Z include, but are not limited to, moieties of the general formula:

and

where:

Y is N or CX; X is selected from the group consisting of H, halo, Crβ alkyl, C_2-6 alkenyl,,

C_2-S alkynyl, CN, CF₃, N₃, NO₂, C_ri0 aryl, C_6-10 heteroaryl, and COR_b;

R_b is selected from the group consisting of H, OH, SH, C_1-6alkyl, C_{1- 6}aminoalkyl, Q-

₆ alkoxy and C_1-6thioalkyl; and

Rn is selected from the group consisting of H, C_{1- 6}alkyl, C_2-6alkeπyl, Crβalkynyl, C₆-ιoaryl, and carbonyl substituted with a C_1-6alkyi, C_2-6alkenyl, C_{2- 6}alkynyi, C_3-6cycloalkyl, C₄, i₂alkyϊcycloalkyl, or C₆-ioaryl. The example of Z is further described in U.S. Patent No. 6,583,149, which is incorporated by reference in its entirety.

Additional examples of Y include, but are not limited to, compounds of the general formula:

where:

Y is -NR_aR_b, or -OR₃,

L₂ is a covalent bond (that is, is absent), -N(-R_[5)-, N(-Ri₅)C(=O)-, -0-, -S-, -S(=0)-, or is -

SC=O)_2-,

R₁₃ is H, C_{1- G} alkyl, C₁ -₆ heteroalkyl, C_2-6 alkenyl, C₆-I₀ aryl, C₇-I₆ arylalkyl, C₃-_!0 carbocyclyl, C₆-io heterocyclyl, or C₇-₁₆ heterocyclylalkyl;

Ri₄ is H, halo, hydroxy, alkoxy, -O(CH₂)_XOC(=O)OR_S5, or 0C(=0)0R_15; wherein x is 2 or 3 to 10, 15 or 20, and

R₁₅ is H, Cr₆ alkyl, C_{1- 6} heteroalkyl, C_2-6 alkenyl, C₆-_!0 aryl, C₇-is arylalltyl, C₃-_i0 cycloalkyl, C_6-10 heterocyclyl, or C₇-i_S heterocyclalkyl,

R₃, R_b are independently selected from the group consisting of hydrogen, C_1-6 alkyl, or C_3-6 cycloalkyi, and C_3-8 heterocyclyl, wherein C_3-6cycloalkyi and Csheterocyclyl can be optionally substituted with one or more C_1-S alkyl.

Additional examples of Z include, but are not limited to, moiety of the general formula:

R₁₆ and R₁₇ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, or C_3-6 cycloalkyl, or C_3-8 heterocyclyi, wherein C_3-6 cycloalkyl and C_3-8 heterocyciyl can be optionally substituted with one or more C_1-5 alkyl.

The exemplary compounds of the present invention include, but are not limited to,

or a phaπnaceutically acceptable salt thereof.

More exemplary compounds are shown below:

According to a further aspect of the present invention, a variety of lipid derivatives of acyclic nucleotide phosphonates such as cidofovir, tenofovir, cyclic-cidofovir and adefovir can also be used as active agents in the methods and compositions provided herein. In one embodiment, the active agents have the following structures:

wherein W¹, W², and W³ are each independently -O-, -S-, -SO-, -SO₂, -O(C=O)-, -(C=O)O-, -NH(C=O)-, -(C=O)NH- or -NH-; and in one embodiment are each independently O, S, or -0(C=O)-;

n is O or 1; m is O or 1 ; p is O or 1;

R¹ is an optionally substituted alkyi, alkenyl or alkynyl, e.g., C_1-30 alkyl, C_2-30 alkenyl, or C_2-30 alkynyl; or in one embodiment, R¹ is optionally substituted C₈.₃₀ alkyi, C_8-30 alkenyl or C_8-30 alkynyl, or R¹ is a C_3-24 alkyl, C_8-24 alkenyl or C_8-24 alkynyl (e.g., C₁₇, C₁₈, C₁₉, C₂₀, C_21, C₂₂, C₂₃, or C₂₄ alkyl, alkenyl, or alkynyl);

R² and R³ are each independently an optionally substituted C_1-2; alkyl, C2.25 alkenyl, or C_2-25 alkynyl;

D may be cidofovir, tenofovir, cyclic cidofovir or adefovir directly linked to a methylene group as depicted in Formulas V-X. For example, when D is tenofovir, D is a moiety of the formula:

When D is cidofovir, D is a moiety of the formula:

(e.g., Cidofovir or tenofovir is directly linked to the methylene group of formula V-X via the phosphonate hydroxyl group).

In some embodiments of formulas V-X:

W¹, W², and W³ are each independently -O-, -S-, or -O(CO)-; n is 0 or 1 ; m is 0 or 1 ; p is 0 or 1;

R¹ is optionally substituted C_12-24 alkyl or alkenyi (e.g., C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, or C₂₄ alkyl or alkenyi);

R² and R³ are each independently optionally substituted C_1-24 alkyl or C_2-24 alkenyi, or C_2-24 alkyoyl.

D is cidofovir, tenofovir, cyclic cidofovir or adefovir linked directly to a methylene group as depicted in Formulas V-X.

In another embodiment, the active compound of Formula V-X has one of the following structures: wherein R¹ is an optionally substituted C_8-24 alkyl, for example, C|_M4 alkyl, D is cidofovir, tenofovir, cyclic cidofovir or adefovir linked directly to a methylene group as depicted in Formulas V- X.

According to another aspect, 'compounds, compositions, formulations, and methods of treating subjects that can be used to carry out the present invention include, but are not limited to, those described in US Patent No. 6,716,825, 7,034,014, 7,094,772,7,098,197, 7,452,898 and 7,687,480, the disclosures of which are incorporated by reference herein in their entireties

In some embodiments, the active compounds have the structure Formula C:

Formula C

wherein:

R₁ and Ri' are independently -H, optionally substituted -O(C₁ -C₂₄)alkyl, -O(C₂ -C₂₄)alkenyl, — O(C₂ -C₂₄)alkynyl, 0(C₁ -C₂₄)aCyI, -S(C₁ -C₂₄)alkyl, -S(C₁ -C₂₄)alkenyl, -S(C₂ -C₂₄)alkynyl, or - S(C₁ -C₂₄)acyl, wherein at least one OfR₁ and R₁' are not -H, and wherein said alkenyl or acyl moieties optionally have 1 to 6 double bonds,

R₂ and R₂ ¹ are independently -H, optionally substituted -O(C₁ -C₂₄)alkyl, -O(C₂ - C₂₄)alkenyl, -O(C₂ -C₂₄)alkynyl, -O(C₁ - C₂₄)acyI, -S(C₁ -C₂₄)alkyl, -S(C₂ -C₂₄)alkenyl, -S(C₂ - C₂₄)alkynyl ,-S(C₁ -C₇)acyl, -N(C₁ -C₇)acyl, -NH(C₁ -C₂₄)alkyl, -N(C₂ -C₂₄)alkenyl, -N(C₂ - C₂₄)alkynyl, -N((C; -C₇)alkyl)₂, oxo, halogen, -NH₂, -OH, or -SH;

R₃ is a pharmaceutically active phosphonate, bisphosphonate or a phosphonate derivative of a pharmacologically active compound, linked to a functional group on optional linker L or to an available oxygen atom on C^α;

X, when present, is:

L is a valence bond or a bifunctional linking molecule of the formula -J-(CR₂)_t -G-, wherein t is an integer from 1 to 24, J and G are independently -O-, -S-, -C(O)O-, or -NH-, and R is -H, substituted or unsubstituted alkyl, or alkenyl;

m is an integer from 0 to 6; and

n is 0 or 1.

In some embodiments, m=0, 1 or 2. In some embodiments, R₂ and R₂' are H, and the prodrugs are then ethanedioi, propanediol or butanediol derivatives of a therapeutic phosphonate, A exemplary ethanedioi phosphonate species has the structure:

wherein Ri, R₁ ¹, R₃, L, and n are as defined above.

In some embodiments, propanediol species has the structure:

wherein m=l and Rl, Rl ', R3, L and n are as defined above in the general formula.

wherein m=l , R₂=H, R₂-OH, and R₂ and R₂' on C^α are both -H. Glycerol is an optically active molecule. Using the stereospecific numbering convention for glycerol, the sn-3 position is the position which is phosphorylated by glycerol kinase. In compounds of the invention having a glycerol residue, the -(L)_n -R₃ moiety may be joined at either the sn-3 or sn-1 position of glycerol. In another embodiment, R; is an alkoxy group having the formula -0-(CH₂)_I-CH₃, wherein t is 0-24. More preferably t is 11-19. Most preferably t is 15 or 17.

Exemplary R₃ groups include bisphosphonates that are known to be clinically useful, for example, the compounds:

Etidronate: 1-hydroxyethylidene bisphosphonic acid (EDHP);

Clodronate: dichloromethylene bisphosphonic acid (CI₂ MDP);

Tiludromate: chloro-4-phenylthiomethylene bisphosphonic acid;

Pamidronate: 3-amino-1-hydroxypiOpylidene bisphosphonic acid (ADP);

Alendronate: 4-amino-1-hydroxybutylidene bisphosphonic acid;

Olpadronate: 3dimethylamino-1-hydroxypiOpylidene bisphosphonic acid (dimethyl-APD);

Ibandronate: 3-methylpentylamino-1-hydroxypropylidene bisphosphonic acid (BM 21.0955);

EB-1053: 3-(l-pyrrolidinyl)-1-hydi'oxypiOpylidene bisphosphonic acid;

Risedmnate: 2-(3-pyridinyl)-1-hydroxy-ethylidene bisphosphonic acid;

Araino-Olpadronate: 3-(N,N-diimethylanino-1-aminopropyIidene)bisphosphonate (1G9402), and the like.

R₃ may also be selected from a variety of phosphonate-containing nucleotides (or nucleosides which can be derivatized to their corresponding phosphonates), which are also contemplated for use herein. Preferred nucleosides include those useful for treating disorders caused by inappropriate cell proliferation such as 2-chloro-deoxyadenosine, 1-β-D-arabinofuranosyl-cytidine (cytarabine, ara-C), fluorouridine, fluorodeoxyuridine (floxuridine), gemcitabine, cladribine, fiudarabine, pentostatin (T- deoxycoformycin), 6-mercaptopurine, 6-thioguanine, and substituted or unsubstituted 1-β-D- arabinofuranosyl-guanine (ara-G), 1-β-D-arabinofuranosyI-adenosine (ara-A), 1-β-D- arabinofuranosyl-uridine (ara-U), and the like.

Nucleosides useful for treating viral infections may also be converted to their corresponding 5 '-phosphonates for use as an R₃ group. Such phosphonate analogs typically contain either a phosphonate (-PO₃H₂) or a methylene phosphonate (-CH₂-PO₃H₂) group substituted for the 5'- hydroxyl of an antiviral nucleoside. Some examples of antiviral phosphonates derived by substituting -PO₃H₂ for the 5 '-hydroxy 1 are:

Some examples of antiviral phosphonates derived by substituting-CH₂-PO₃H₂ for the 5'- hydroxyl are:

Other exemplary antiviral nucleotide phosphonates are derived similarly from antiviral nucleosides including ddA, ddl, ddG, L-FMAU, DXG, DAPD, L-dA, L-dl, L-(d)T, L-dC, L-dG, FTC, penciclovir, and the like.

Additionally, antiviral phosphonates such as cidofovir, cyclic cidofovir, adefovir, tenofovir, and the like, may be used as an R₃ group in accordance with the present invention.

Many phosphonate compounds exist that can be derivatized according to the invention to improve their pharmacologic activity, or to increase their oral absorption, such as, for example, the compounds disclosed in the following patents, each of which are hereby incorporated by reference in their entirety: U.S. Pat. No. 3,468,935 (Etidronate), U.S. Pat. No. 4,327,039 (Pamidronate), U.S. Pat. No. 4,705,651 (Alendronate), U.S. Pat. No. 4,870,063 (Bisphosphonic acid derivatives), U.S. Pat. No. 4,927,814 (Diphosphonates), U.S. Pat. No. 5,043,437 (Phosphonates of azidodideoxynucleosides), U.S. Pat. No. 5,047,533 (Acyclic purine phosphonate nucleotide analogs), U.S. Pat. No. 5,142,051 (N-Phosphonyimethoxyalkyl derivatives of pyrimidine and purine bases), U.S. Pat. No. 5,183,815 (Bone acting agents), U.S. Pat. No. 5,196,409 (Bisphosphonates), U.S. Pat. No. 5,247,085 (Antivira! purine compounds), U.S. Pat. No. 5,300,671 (Gem-diphosphonic acids), U.S. Pat. No. 5,300,687 (Trifluoromethylbenzylphosphonates), U.S. Pat. No. 5,312,954 (Bis- and tetrakis-phosphonates), U.S. Pat. No. 5,395,826 (Guanidinealkyl- 1,1 -bisphosphonic acid derivatives), U.S. Pat. No. 5,428,181 (Bisphosponate derivatives), U.S. Pat. No. 5,442,101 (Methylenebisphosphonic acid derivatives), U.S. Pat. No. 5,532,226 (Trifluoromethybenzylphosphonates), U.S. Pat. No. 5,656,745 (Nucleotide analogs), U.S. Pat. No. 5,672,697 (Nucleoside-5 '-methylene phosphonates), U.S. Pat. No. 5,717,095 (Nucleotide analogs), U.S. Pat. No. 5,760,013 (Thymidylate analogs), U.S. Pat. No. 5,798,340 (Nucleotide analogs), U.S. Pat, No. 5,840,716 (Phosphonate nucleotide compounds), U.S. Pat. No. 5,856,314 (Thio-substituted, nitrogen-containing, heterocyclic phosphonate compounds), U.S. Pat. No. 5,885,973 (olpadronate), U.S. Pat. No. 5,886,179 (Nucleotide analogs), U.S. Pat. No. 5,877,166 (Enantiomerically pure 2-aminopurine phosphonate nucleotide analogs), U.S. Pat. No. 5,922,695 (Antiviral phosphonomethoxy nucleotide analogs), U.S. Pat. No. 5,922,696 (Ethylenic and allenic phosphonate derivatives of purines), U.S. Pat. No. 5,977,089 (Antiviral phosphonomethoxy nucleotide analogs), U.S. Pat. No. 6,043,230 (Antiviral phosphonomethoxy nucleotide analogs), U.S. Pat. No. 6,069,249 (Antiviral phosphonomethoxy nucleotide analogs); Belgium Patent No. 672205 (Clodronate); European Patent No. 753523 (Amino-substituted bisphosphonic acids); European Patent Application 186405 (geminal diphosphonates); and the like.

Certain bisphosphonate compounds have the ability to inhibit squalene synthase and to reduce serum cholesterol levels in mammals, including man. Examples of these bisphosphonates are disclosed, for example, in U.S. Pat. Nos. 5,441,946 and 5,563,128 to Pauls et al. Phosphonate derivatives of lipophilic amines, both of which are hereby incorporated by reference in their entirety. Analogs of these squalene synthase inhibiting compounds according to the invention, and their use in the treatment of lipid disorders in humans are within the scope of the present invention.

Bisphosphonates of the invention may be used orally or topically to prevent or treat periodontal disease as disclosed in U.S. Pat. No. 5,270,365, hereby incorporated by reference in its entirety.

In some embodiments, the active compounds have a phosphonate ester formed by a covalent linking of an antiviral compound selected from the group consisting of cidofovir, adefovir, cyclic cidofovir and tenofovir, to an alcohol selected from the group consisting of an alkylglycerol, alkylpropanediol, l-S-alkylthioglycerol, alkoxyalkanol or alkylethanediol, or a pharmaceutically acceptable salt thereof. In some embodiments, the active compounds comprise an antiviral nucleoside compound, wherein the 5'-hydroxyl group has been substituted for a phosphonate or methyl phosphonate that is covalently linked to an alkylethanedioi.

According to a further aspect of the invention, the compound having the structure of following Formula V:

wherein:

Ri is— O— (CH₂)_t— CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

or

Formula A Formula B and the symbol * indicates that -*CH_2- in Formula I is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of an enantiomer, diastereomer, racemate, or a mixture thereof. In another embodiment, the compound of formula V, a is 2 or 3. In another embodiment, t is 15 or 17. In one embodiment, B is -CH₃.

In some embodiments, the compound of Formula V has the following structure

or a pharmaceutically acceptable salt thereof.

Certain compounds of the invention possess one or more chiral centers, e.g. in the sugar moieties, and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl group or an unsaturated alkyl or acyl moiety there exists the possibility of cis- and trans- isomeric forms of the compounds. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers are contemplated by this invention. All such isomers as well as mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecifϊc reactions with starting materials that contain the asymmetric centers and are already resolved or, alternatively, by methods that lead to mixtures of the stereoisomers and resolution by known methods.

The active compounds disclosed herein can, as noted above, be provided in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.

Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from elemental anions such as chlorine, bromine, and iodine, and (c) salts derived from bases, such as ammonium salts, alkali metal salts such as those of lithium, sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases such as

dicyclohexylamine and N-methyl-D-glucamine.

Active compounds as described herein can be prepared in accordance with known procedures, or variations thereof that will be apparent to those skilled in the art. See, e.g., Painter et al., Evaluation of Hexadecyloxyρropyl-9-Jϊ-[2-(Phosphonomethoxy)Propyl]-Ademne, CMXl 57, as a Potential Treatment for Human Immunodeficiency Virus Type 1 and Hepatitis B Virus Infections,

Antimicrobial Agents and Chemotherapy 51, 3505-3509 (2007) and US Patent Application

Publication No. 2007/0003516 to Almond et al.

B. Additional antiviral agents/eompomids.

Additional antiviral active agents that may be used in carrying out the present invention include HTV-protease inhibitors, nucleoside reverse transcriptase inhibitors (this term herein including nucleotide reverse transcriptase inhibitors), non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entiy inhibitors, fusion inhibitors, maturation inhibitors, and combinations thereof.

Numerous examples are known and described in, for Example, US Patent Application Publication No. 2006/0234982 to Dahl et al. at Table A therein, and in Table A as set forth below. Additional examples include, but are not limited to the integrase inhibitor Isentress or raltegravir (MK-0518: Merck), the CCR5 inhibitor Maraviroc or selzentry (and K-427857, Pfizer) and others of these classes.

Additional examples are provided in US Patent No 7,094,413 to Bυelow et al.; US Patent No. 7,250,421 to Nair et al., US Patent Application Publication No. 2007/0265227 to Heneine et al and US Patent Application Publication No. 2007/0072831 to Cai et al.

The non-nυcleoside reverse transcriptase inhibitor ("NNRTT") 6~chloro-4-cyclopropylethynyl- 4-trifluorσmethyl4,4-dihydro-2H3,l-benzoxazin-2-one, and pharmaceutically acceptable salts thereof, are described in, for example, US Patent No. 5,519,021. Examples of the present invention include efavirenz.

The nucleoside reverse transcriptase inhibitor ("NRTI") 2-hydroxymethyl-5-(5-fluoiOCytosin- l-yl)-l, 3-oxathiolane ("FTC") and pharmaceutically acceptable salts thereof, are described in, for example, US Patent No. 6,642,245 to Liotta et al. Examples of the present invention include emtricitabine.

Integrase inhibitors include but are not limited to those described in US Patent Application Publication No. 2007/0072831, WO 02/30426, WO 02/30930, WO 02/30931, WO 02/055079, WO 02/36734, U.S. Patent No. 6,395,743; U.S. Patent No. 6,245,806; U.S. Patent No. 6,271,402; WO 00/039086; WO 00/075122; WO 99/62513; WO 99/62520; WO 01/00578; Jing, et al., Biochemistry, 41, 5397-5403, (2002); Pais, et al., J. Med. Chem., 45, 3184-94 (2002); Goldgur, et al., Proc. Natl. Acad. ScL U.S.A., 96, 13040-13043 (1999); Espeseth, et al., Proc. Natl. Acad. Sci. U.S.A., 97,11244- 11249, (2000); WO 2005/016927, WO 2004/096807, WO 2004/035577, WO 2004/035576 and US 2003/0055071.

C. Pharmaceutical formulations and administration

Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions include but are not limited to those described in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co. (1990) {See also US Patent Application US 2007/0072831).

The compounds of the invention may be formulated with conventional carriers, diluents and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders, diluents and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxy alkyl cellulose, hydroxyalkylmethylcellulose, stearic acid and the like.

Compounds of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.

While it is possible for the active ingredients to be administered alone it is preferably to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above defined, together with one or more pharmaceutically acceptable carriers (excipients, diluents, etc.) thereof and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

For infections of the eye or other external tissues e.g. mouth and skin, the formulations are, in some embodiments, applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), in some embodiments, 0.2 to 15% w/w and in other embodiments, 0,5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absoiption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, it includes both an oil and a fat.

Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween,TM.60, Span. TM. 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. In some embodiments, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. In some embodiments, the active ingredient is present in such formulations in a concentration of 0.5 to 20%. In some embodiments, the active ingredient is present in a concentration of 0.5 to 10%. In some embodiments, the active ingredient is present in a concentration of about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and

mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositoiy with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as pentamidine for treatment of Pneumocystis pneumonia.

Formulations suitable for vaginal administration may be presented as pessaries, rings, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods. Controlled release formulations may be employed for the treatment or prophylaxis of various microbial infections particularly human bacteria), human parasitic protozoan or human viral infections caused by microbial species including Plasmodium, Pneumocystis, herpes viruses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, adenoviruses and the like. The controlled release formulations can be used to treat HlV infections and related conditions such as tuberculosis, malaria, Pneumocystis pneumonia, CMV retinitis, AIDS, AIDS-related complex (ARC) and progressive generalized lymphadeopathy (PGL), and AIDS-related neurological conditions such as multiple sclerosis, and tropical spastic paraparesis. Other human retroviral infections that may be treated with the controlled release formulations according to the invention include Human T-cell Lymphotropic virus and HIV-2 infections. The invention accordingly provides pharmaceutical formuiations for use in the treatment or prophylaxis of the above-mentioned human or veterinary conditions and microbial infections.

Pharmacokinetic enhancers. The compounds of the invention may be employed in combination with pharmacokinetic enhancers (sometimes also referred to as "booster agents"). One aspect of the invention provides the use of an effective amount of an enhancer to enhance or "boost" the pharmacokinetics of a compound of the invention. An effective amount of an enhancer, for example, the amount required to enhance an active compound or additional active compound of the invention, is the amount necessaiy to improve the pharmacokinetic profile or activity of the compound when compared to its profile when used alone. The compound possesses a better efficacious pharmacokinetic profile than it would without the addition of the enhancer. The amount of pharmacokinetic enhancer used to enhance the potency of the compound is, preferably, subtherapeutic (e.g., dosages below the amount of booster agent conventionally used for therapeutically treating infection in a patient). An enhancing dose for the compounds of the invention is subtherapeutic for treating infection, yet high enough to effect modulation of the metabolism of the compounds of the invention, such that their exposure in a patient is boosted by increased bioavailability, increased blood levels, increased half life, increased time to peak plasma concentration, increased/faster inhibition of HIV integrase, RT or protease and/or reduced systematic clearance. One example of a

pharmacokinetic enhancer is RITONAVIR™ (Abbott Laboratories).

Combinations. As noted above, the compositions of the present invention can include the active compounds as described in section A above in combination with one or more (e.g., 1, 2, 3) additional active agents such as described in section B above, in analogous manner as known in the art. For example, combinations of efavirenz (an NRTI), emtricitabine (an NNRTI) and tenofovir DF (an NRTI) are described in, for example, DaM et al., US Patent Application Publication No.

2007/0099902 to Dahl et al. Specific examples of such combinations include, but are not limited to: CMXl 57 or a pharmaceutically acceptable salt) in combination with:

(a) FTC/Efavirenz;

(b) 3TC/Efavirenz;

(c) AZT/3TC;

(d) FTC;

(e) 3TC;

(f) FTC/Isentress;

(g) 3TC/Isentress;

(h) PPL-100;

(i) FTC/TMC278;

(k) 3TC/TMC278;

(l) FTC/TMC125; or

(m)3TC/TMC125.

D. Treatment of privileged compartment infections.

As noted above, it has also been found that active agents of the present invention surprisingly associate or bind to viral particles. Since viral particles migrate or permeate into cellular or tissue compartments that are not generally accessible to active therapeutic agents (thus creating a substantially untreated "reservoir" of infection when subjects are systemically administered such agents), this finding makes possible (a) the treatment of infection in such privileged compartments, and (b) the use of active agents in prophylactic or microbicidal treatments (where association or binding of the active agent to vims before infection occurs is of therapeutic benefit). In general, a privileged compartment is a cellular or tissue compartment to which said virus permeates in vivo, to which said active agent does not efficiently permeate in vivo in the absence of said virus, and to which said active agent is carried in vivo by said virus when said active agent binds to said virus. For example, when the privileged compartment is a tissue compartment, it may be brain (central nervous system), lymphoid, or testes. Examples of cellular privileged compartments include but are not limited to dendritic cells, microglia, monocyte/macrophages, and combinations thereof. Compositions and methods of treating privileged compartment infections may be prepared and carried out as described above. Prophylactic compositions, devices and methods are discussed in further detail below.

E. Topical compositions and microbicidal methods.

The present invention can take the form of a topical compositions containing the active agents described herein for inhibiting or combating viral infection, e.g., for prophylactic use. Such compositions (with active agents other than those disclosed herein) are known and described in, for example, US Patent No. 6,545,007, the disclosure of which is incorporated herein by reference in its entirety.

Such compositions can take several forms. Thus, in one embodiment the composition is in the form of a cream, lotion, gel, or foam that is applied to the affected skin or epithelial cavity, and preferably spread over the entire skin or epithelial surface which is at risk of contact with bodily fluids. Such formulations, which are suitable for vaginal or rectal administration, may be present as aqueous or oily suspensions, solutions or emulsions (liquid formulations) containing in addition to the active ingredient, such carriers as are known in the art to be appropriate. For "stand-alone" lubricants (i.e., lubricants that are not pre-packaged with condoms), gels and similar aqueous formulations are generally preferred, for various reasons (both scientific and economic) known to those skilled in the art. These formulations are useful to protect not only against sexual transmission of HIV, but also to prevent infection of a baby during passage through the birth canal. Thus the vaginal administration can take place prior to sexual intercourse, during sexual intercourse, and immediately prior to childbirth.

One method of applying an antiviral lubricant to the genitals, for the purposes disclosed herein, involves removing a small quantity (such as a teaspoon, or several milliliters) of a gel, cream, ointment, emulsion, or similar formulation from a plastic or metallic tube, jar, or similar container, or from, a sealed plastic, metallic or other packet containing a single dose of such composition, and spreading the composition across the surface of the penis immediately before intercourse. Alternate methods of emplacement include: (1) spreading the composition upon accessible surfaces inside the vagina or rectum shortly before intercourse; and (2) emplacing a condom, diaphragm, or similar device, which has already been coated or otherwise contacted with an anti-viral lubricant, upon the penis or inside the vagina. In a preferred embodiment, any of these methods of spreading an anti-viral lubricant across the surfaces of the genitals causes the lubricant to coat and remain in contact with the genital and epithelial surfaces throughout intercourse.

In one embodiment the compositions are used in conjunction with condoms, to enhance the risk-reducing effectiveness of condoms and provide maximum protection for users. The composition can either be coated onto condoms during manufacture, and enclosed within conventional watertight plastic or foil packages that contain one condom per package, or it can be manually applied by a user to either the inside or the outside of a condom, immediately before use,

As used herein, "condom" refers to a barrier device which is used to provide a watertight physical barrier between male and female genitalia during sexual intercourse, and which is removed after intercourse. This term includes conventional condoms that cover the penis; it also includes so- called "female condoms" which are inserted into the vaginal cavity prior to intercourse. The term "condom" does not include diaphragms, cervical caps or other barrier devices that cover only a portion of the epithelial membranes inside the vaginal cavity. Preferably, condoms should be made of latex or a synthetic plastic material such as polyurethane, since these provide a high degree of protection against viruses.

In another embodiment the composition is in the form of an infra-vaginal pill, an intra-rectal pill, or a suppository. The suppository or pill should be inserted into the vaginal or rectal cavity in a manner that permits the suppository or pill, as it dissolves or erodes, to coat the vaginal or rectal walls with a prophylactic layer of the anti-HIV agent.

In still another embodiment the composition is topically applied by release from an intravaginal device. Devices such as vaginal rings, vaginal sponges, diaphragms, cervical caps, female condoms, and the like can be readily adapted to release the composition into the vaginal cavity after insertion.

Compositions used in the methods of this invention may also comprise additional active agents, such as another agent(s) to prevent HTV infection, and agents that protect individuals from conception and other sexually transmitted diseases. Thus, in another embodiment, the compositions used in this invention further comprise one or more additional anti-HIV agents, vimcides effective against viral infections other than HIV, and/or spermicides.

In one particular embodiment, the composition contains nonoxynol, a widely-used spermicidal surfactant. The resulting composition could be regarded as a "bi-functional" composition, since it would have two active agents that provide two different desired functions, in a relatively inert carrier liquid; the nonoxynol would provide a spermicidal contraceptive agent, and the DABO would provide anti-viral properties. The nonoxynol is likely to cause some level of irritation, in at least some users; this is a regrettable but is a well-known side effect of spermicidal surfactants such as nonoxynol and octoxynol, which attack and destroy the lipid bilayer membranes that surround sperm cells and other mammalian cells. The compositions used in this invention may also contain a lubricant that facilitates application of the composition to the desired areas of skin and epithelial tissue, and reduces friction during sexual intercourse. In the case of a pill or suppository, the lubricant can be applied to the exterior of the dosage form to facilitate insertion.

In still another embodiment the invention provides a device for inhibiting the sexual transmission of HlV comprising (a) a barrier structure for insertion into the vaginal cavity, and (b) a composition comprising an active agent as described herein. As mentioned above, preferred devices which act as barrier structures, and which can be adapted to apply anti-HIV agent, include the vaginal sponge, diaphragm, cervical cap, or condom (male or female).

The methods, compositions and devices of this invention can be adapted generally to release active agent in a time sensitive manner that best corresponds to the timing of sexual activity. When topically applied as a lotion or gel, the compositions are preferably applied immediately prior to sexual activity. Other modes of application, such as devices and suppositories, can be designed to release active agent over a prolonged period of time, at a predetermined rate, depending upon the needs of the consumer.

The present invention will now be described in more detail with reference to the following examples. However, these examples are given for the purpose of illustration and are not to be construed as limiting the scope of the invention

EXAMPLE 1

In the following examples, CMX 157 has the following structure:

CMX 157

Figure 1 demonstrates, for comparative purposes, the virologic response to tenofovir in antiretroviral experienced patients at 24 weeks. Data is from M. Miller et al. J Infect Dis. 189: 837 (2004). The viral load response in monotherapy with TDF in naive patients is -1.51og (Louie et al, Determining the antiviral activity of tenofovir disoproxil fumarate in treatment-naive chronically HIV-I -infected individuals, AIDS, 17, 1151 (2003)).

Figures 2-3 show the in vitro efficacy of tenofovir (TFV) as compared to HDP-TFV (CMXl 57) in a PHENOSENSE™ HTV assay (service available from Monogram Biosciences, Inc., 345 Oyster Point Blvd., South San Francisco, CA 94080-1913 USA.) In Figure 3, the IC₅₀s for CMX157 are multiplied by 100 for scaling. Results are also shown in Table 1 below (where ABC is abacavir FTC is emtricitabine, ddl is didanosine, 3TC is lamivudine, d4T is stavudine, TFV is tenofovir and ZDV is zidovudine ).

TABLE 1: ASSAY RESULTS (IC50 shown in μM) PATIENT

TABLE 1: ASSAY RESULTS (IC50 shown in μM)

PATIENT

ID NOTES Results ABC CMX157 ddl FTC 3TC d4T TFV ZDV

TABLE 1: ASSAY RESULTS (IC50 shown in μM)

PATIENT

ID NOTES Results ABC CMX157 ddl FTC 3TC d4T TFV ZDV

TABLE 1: ASSAY RESULTS (IC50 shown in μM) PATIENT

TABLE 1: ASSAY RESULTS (IC50 shown in μM) PATIENT

The data shown in Tables 2 and 3 below demonstrate that CMXl 57 is active against all major HTV subtypes (A-G, O and HϊV-2) with IC50S ranging from 0,2-7.2 nanomolar.

Table 2. Activity of Chimerix Compound CMX157 Against HIV-I Subtype Isolates in PBMCs

Table 3. Activity of Chimerix Compound CMX157 against HIV-2 Isolates in PBMCs

Further, these data indicate that the IC50S for CMXl 57 against NRTI resistant HlV ranged from 1.2 to 57 nM, a median of 359-fold more potent than tenofovir (range 295-472x).

Finally, the data shown in Table 4 below indicates that the no-observed-adverse-effect level in rats for CMX 157 for 7 days is up to 100mg/kg/day, the highest dose tested.

Table 4. Toxicokinetic parameters on days 1 and 7 after oral administration of CMX157 to rats

a Plasma was obtained at 0,5, 1, 2, 4, 12, and 24 h after dosing and assayed for the prodrug and metabolite as described in Materials and Methods. Pharmacokinetic parameters were estimated using mean data from one male and one female in each group at each time point. AUC_0-24, AUC from 0 to 24h; t_1/2clim, elimination half-life; ND, not determined.

(See G. Painter et al, Evaluation of Hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)Propyl]- Adenine, CMXl 57, as a Potential Treatment for Human Immunodeficiency Vims Type I and Hepatitis B Virus Infections, Antimicrobial Agents and Chemotherapy 51, 3505-3509 (2007). )

EXAMPLE 2

To examine the potential of CMX157 to associate directly with virus, concentrated HIV-I _111B (approximately 9.7 x 10¹⁰ virus particles) is treated with 500 nM CMXl 57 or TFV for 2 hours.

Following incubation, virus is pelleted to remove unbound compound, lysed with 70% ice cold methanol and centrifuged. Supernatants are analyzed in triplicate using LC/MS/MS (liquid chromatography/mass spectrometry). TFV, TFV mono- and diphosphate are separated by gradient, reverse phase, ion-paring chromatography and detected by positive ion electrospray. The levels of CMXl 57 associated with the viral pellets (≈37,000 molecules/virion) are much higher than the levels of TFV associated with viral pellets (≈100 molecules/virion).

To evaluate the effect of exposing purified virus to drug on TCID₅₀, concentrated HIV- 1_IIIB virus (approximately 9.7 x 10¹⁰ virus particles) is treated with 1000, 500, 250 or 125 nM CMX157 or TFV for 2 hours. As shown in Table 5, CMX157 consistently reduce viral replication 2-4 fold across this dose range while TFV has no discernible effect even at the highest dose. Table 5: TCID₅₀ Determination of Treated HIV-Im_B (2 hours)

To determine the time dependence of compound incubation on loss of infectivity, concentrated fflV-l_mB is treated with 500 nM CMX157 for 1, 15, 30, 60, and 120 minutes. The TCID_5O results of these assays are summarized in Table 6. CMX157 decreases infectivity foliowing 1 minute incubation prior to centrifugation.

Table 6: TdD₅₀ Determination of Treated HIV-lπm

*VC=vehicle control

In the second experiment to determine the dose effect of CMX 157 treated HTV- Im_B on infectivity, concentrated virus is incubated for 15 minutes with eight concentrations ranging from 0.039 to 125 nM of test material and TCID₅₀ values are measured by XTT, RT and p24. HDP-ACV is evaluated in parallel to determine if a lipid-nucleotide of similar structure but without HIV activity would have any effect in this assay. The TdD₅₀ results of these assays are summarized in Table 7.

Evaluation of CMX 157 associated with H IV- Im_B using lower concentrations of test material yielded a dose response indicating concentrations of 3.9 nM and greater resulted in reduced infectivity. The XTT and p24 endpoints for measuring TCID₅₀ yielded greater fold decreases in infectivity compared to the RT endpoint as might be expected for a NRTI in this system. HDP-ACV had no effect on infectious virus when incubated with HIV- lnro at the concentrations evaluated.

Table 7: TCID₅₀ Determination of Treated HIV-l_mB (15 minutes)

Overall, these results indicate CMXl 57 associates directly with HTV and that this association reduces viral replication. Incubation of HIV with low nanomolar concentrations of CMX157 for short periods of time (1-15 minutes) resulted in decreased viral production in vitro. No effect on viral replication is seen for TFV or the lipid control, HDP-ACV. CMXl 57 may have advantages over TFV via this mechanism of cell targeting as any HIV exposed to CMXl 57 will then carry its own antiviral to whatever compartment or cell type it subsequently enters.

The mechanism suggested by the experiments presented here invokes direct association of the CMXl 57 lipid-TFV drug with HIV followed by delivery of CMXl 57 by the virus to the cell being infected. The data presented herein demonstrates a significant difference (approximate 300 fold) in the level of CMXl 57 directly associated with purified HIV versus TFV. Furthermore, pre-incubation of HIV with CMX157 inhibited replication of HTV in cells that are not exposed to drug except via the virus itself; pre-incubation of HIV with TFV has no inhibitory effect on subsequent HIV replication, consistent with the low levels of TFV associated with isolated virions.

This mechanism is distinct from inhibition of natural endogenous reverse transcription (NERT) within HIV virions. Inhibition of NERT has been demonstrated in vitro with high levels of AZT-triphosphate (lOuM) or Nevirapine (NVP) and in vivo with NVP (Zhang 1996, Zhang 2006). While there could be an element of NERT inhibition when cells are treated with CMXl 57, this mechanism presumably requires formation of TFV-PP which should not occur within isolated virions.

EXAMPLE 3

The anti-HIV-1 activity of CMX 157 is evaluated in two-drug combination studies with twenty-four different FDA- approved anti-HIV inhibitors. Each two-drug combination is tested three times in CEM T-lymphocytic cells or MAGI-CCR5 cells acutely infected with the laboratory-adapted strain HIV- l_πm or HTV- I_B3-_L, respectively. Viral growth/inhibition is evaluated by measuring virus- induced cytopathic effects (CPE) in CEM cells or by β-galactosidase reporter gene induction in MAGI-CCR5 cells at the experimental endpoint. The cytotoxicity of each two-drug combination is also evaluated in parallel with the antiviral evaluations. The concentrations of CMXl 57 used in these evaluations are selected in order to test a broad range of concentrations and to provide as complete a dose response curve as possible under the limitations of eight total concentrations. Similarly, the concentrations of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir are selected to provide as complete of a dose response curve as possible under the limitations of five total concentrations. The "positive antagonism control" of d4T (stavudine) in combination with RBV was tested in parallel with each of the assays that were performed. Analysis of drug interactions for each of the two-drug combinations is performed using the Prichard and Shipman MacSynergy II three- dimensional model for statistical evaluation of combination assays. The results from these experiments are summarized in Table 8 and interpretation of the results is provided in Table 9.

For these studies, synergy is defined as drug combinations yielding synergy volumes greater than 50. Slightly synergistic activity and highly synergistic activity have been operationally defined as yielding synergy volumes of 50-100 and > 100, respectively. Additive drug interactions have synergy volumes in the range of -50 to 50, while synergy volumes between -50 and -100 are considered slightly antagonistic and those < -100 are highly antagonistic. When assessing interactions at the 50% inhibitory concentrations (IC₅₀) for the two drugs, the average dose response from three experiments for each two-drug combination is determined and. the IC₅₀ range for the two drugs is assessed as the two drug concentrations that bracketed the IC₅₀ value (data not shown). If one of the concentrations for a particular drug yields an average percent inhibition of 50% ± 5%, then this concentration plus the two on either side were included in the IC50 range. Subsequently, the interactions within the IC₅₀ range of the two drugs were operationally defined as: 1) interactions with synergy volumes > 20 is considered synergistic; 2) interactions with synergy volumes in the range of - 20 to 20 are considered additive; and 3) interactions with synergy volumes < 20 are considered antagonistic.

Overall, CMX-157 is determined to have additive or synergistic interactions for all two-drug combinations performed with FDA-approved antiretroviral drugs. None of the interactions is found to be antagonistic. This conclusion of additive to synergistic interactions for ail combinations is also reached when assessing the interactions at the IC₅₀ range of the two drugs from each combination. In contrast, the positive antagonism control of stavudine in combination with ribavirin resulted in antagonistic interactions as expected.

Table 8 Antiviral Efficacy of CMX157 in Combination with Approved Antiretrovirals in CEM and MAGI-CCR5 CeUs (95% Confidence Values)

¹

The MacSynergy II program takes the raw data from individual experiments and calculates a positive (synergy) or negative (antagonism) value for each drug-drug combination. Positive values are summed to give a Volume of Synergy and negative values are summed to give a Volume of Antagonism (both values are reported for each experiment).

2 The Antiviral Synergy Plot (95%) datasets from multiple experiments (n = 3) are combined and arithmetic means are calculated for each drug-drug concentration. The positive and negative values are individually summed to respectively give Mean Volumes for synergistic and antagonistic interactions.

3 The antiviral efficacy results of CMX157 in combination with Maraviroc were performed in MAGI- CCR5 cells. All other evaluations were performed in CEM-SS cells.

Table 9 Interpretation of the MacSynergy Analysis for the Antiviral Efficacy of CMX157 in Combination with Approved Antiretroviral Drugs

No antagonistic interactions were observed within the concentration ranges examined for antiviral efficacy between CMXl 57 and the twenty-four FDA-approved antiretroviral drugs. A highly synergistic interaction is observed between CMXl 57 and zalcitabine, and slightly synergistic interactions were observed with lamivudine, emtricitabine, delavirdine, efavirenz, etravirine,, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir, and maraviroc, suggesting possible beneficial interactions with these drugs. CMX157 interactions with the remaining drugs resulted in strictly additive results. In contrast, the positive antagonism control of stavudine in combination with Ribavirin exhibited a highly antagonistic interaction in all experiments (mean antagonism volume = -330 μM²% in CEM cells and -111 μM²% in MAGI-R5 cells). Therefore, the overall interpretation of these data suggest that antagonism of the antiviral effects of the twenty-four FDA-approved antiretroviral drugs evaluated in this study should not be a problematic issue associated with the use of CMX157 in a clinical setting.

It is important to note there was no evidence of synergistic cytotoxicity within the drug concentrations examined for CMXl 57 (10 μM = highest test concentration). This is not unexpected because none of the drugs are cytotoxic within the concentration ranges evaluated. Much higher concentrations of all drugs (around the TC₅₀ concentration) would be required to correctly examine potential synergistic cytotoxicity interactions. However, it is important to document there are no notable synergistic cytotoxicities observed at concentrations where the FDA-approved drugs display potent antiviral properties.

Example 4

The signature mutation for tenofovir (TFV) is K65R, which is generally associated with a 2 to 4 fold increase in IC₅₀ for tenofovir and lack of clinical response to Viread. In vitro studies designed to select CMXl 57 resistant mutants use wild-type HTV-I as the primary inoculum and TFV as a positive control. These studies are conducted by serial passage of HTV-I _HIB and HIV-IRF in CEM- SS cells using increasing concentrations of TFV or CMX157. Drug levels are increased following detection of viral growth at each passage using procedures known to one skilled in the art. Upon completion of each passage, the reverse transcriptase coding region of the viral genome is sequenced to identify any possible resistance-associated mutations that may have emerged within the virus pool. As show in Tables 10 and 11, there is no resistance to CMX 157 through 9 passages. In contrast, K65R was selected by TFV by passage 8. These data indicates it may be more difficult for HIV to develop resistance to CMXl 57 than to TFV.

Table 10: Passaging of fflV-l_IIIB in CMX157

aDay post-infection when greatest level of virus was observed based on RT activity

Viinor = mutation is minor population in mix; major = mutation is major population; equal = equal peak heights

^"N/A = not applicable (vims replication not observed or RT not sequenced)

Table 11: Passaging of HIV-1_IIIB in Tenofovir

aDay post- infection when greatest level of virus was observed based on RT activity

bminor = mutation is minor population in mix; major = mutation is major population; equal = equal peak heights

N/A = not applicable (virus replication not observed or RT not sequenced)

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

THAT WHICH IS CLAIMED IS:

1. A method of treating a subject for human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection, wherein the subject has not been previously administered an antiviral active agent for said HIV or HBV infection, the method comprising:

administering said subject an antiviral compound of Formula A or Formula B or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

Formula B wherein:

Ri is a moiety selected from the group consisting of alkylglycerol, alkyipropanediol, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and R| is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F₃ CF₃, -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃, -CH₂F, -CH=CH₂, and— CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -0R_2a, -BH₃, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, or -NRΗ,

R_2a is C_{1 -8} alkyl, C_2-8 alkenyl, C_2-8 alkynyi, C_{1- 8} heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, -P(=O)(OH)₂, or -P(=O)(OH)OP(=O)(OH)₂;

R¹ is C_{1 -8} alkyl, C_{2- 8} alkenyl, C_2-8 alkynyl, C_{1 -8} heteroalkyl, C_2-8 heteroalkynyl, C_2-8 heteroalkenyl, C_6-10 aryl, or an substituted or unsubstituted amino acid residue;

Z comprising a heterocyclic moiety comprising at least one N, and

the symbol * indicates that the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety, in an amount effective to treat the HIV and/or HBV infection and at least substantially inhibit the development of resistance to said antiviral compounds in the subject.

2. The method of claim 1 , wherein X is oxygen.

3. The method of claim 1 or 2, wherein R₂ is hydroxyl.

4. The method of any of claims 1-3, wherein Z is guanin-9-yl, adenin-9-yl, 2, 6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

5. The method of any of claims 1-4, wherein R_t is a moiety of hexadecylpropasediol.

6. The method of any of claims 1-5, wherein R₁ is a moiety of octadecylpropanediol.

7. The method of any of claims 1-6, wherein Ri is -0-(CH₂VO-(CH₂VCH₃, wherein a is 2 to 4 and t is 11 to 19.

8. The method of claim 1, wherein a is 2 or 3 and t is 15 or 17.

9. The method of any of claims 1-8, wherein B is -CH₃,

10. The method of any of claims 1-9, wherein Z is

Formula 2

Formula 3 or

Formula 4

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B.

11. The method of any of claims 1-10, wherein the compound is

12. The method of claim 1, wherein the compound has the structure of formula V

wherein:

Ri is— O— (CH₂)_t—CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

Formula A Formula B and the symbol * indicates that -*CH_2- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, the compound has the structure of

HO

or a pharmaceutically acceptable salt thereof.

14. The method of any of claims 1-13, wherein said resistance is multi-nucleoside resistance.

15. The method of any of claims 1-14, wherein said subject is immunocompromised.

16. The method of any of claims 1-15, wherein said virus is HBV or HlV.

17. The method of any of claims 1-16, wherein said subject is infected with both HBV and HIV, and said antiviral compound is administered in an amount effective to treat both said HBV and HFV.

18. The method of any of claims 1-17, wherein said subject is in υtero and said antiviral compound is administered to the mother carrying said subject in utero.

19. The method any of claims 1-18, further comprising administering said subject one or more additional antiviral active agents in combination with said antiviral compound.

20. The method claim 19, wherein said virus is HIV and said one or more additional antiviral active agents are selected from the group consisting of HTV-protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, fusion inhibitors, maturation inhibitors, and combinations thereof.

21. The method of claim 19 or 20, wherein said at least one additional antiviral active agents are selected from the group consisting of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, deJavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

22. A method of treating a subject for human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection, wherein said subject has developed resistance or a toxic response to at least one other antiviral compound in response to prior administration of said at least one other antiviral compound to said subject for said HlV or HBV infection, the method comprising: administering said subject an antiviral compound of Formula A or Formula B, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

Formula B

wherein:

Ri is a moiety selected from the group consisting of alkylglycerol, alkylpropanediol, ] -S- alkylthioglycerol, alkoxyalkatiol and alkylethanediol, and Ri is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F, CF₃, -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃, -CH₂F, -CH=CH₂, and— CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -OR_2a, -BH₃, C_{1 -8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C₁-S heteroalkyl, C_{2- 8} heteroalkenyl, C_2-8 heteroalkynyl, or -NRΗ,

R-_2a is C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, -P(O)(OH)₂, or -P(=O)(OH)OP(=O)(OH)₂;

R¹ is C[-g alkyl, C_2-8 alkenyl, C_2-S alkynyl, C_1-8 heteroalkyl, C_2-8 heteroalkynyl, C_2-8 heteroalkenyl, C₆- ₁₀ aryl, or a substituted or unsubstituted amino acid residue;

Z comprises a heterocyclic moiety comprising at least one N, and

the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

in a amount effective to treat the HlV and/or HBV infection and at least substantially inhibit the further development of resistance to the other antiviral compounds in said subject.

23. The method of any of claims 22, wherein X is oxygen.

24. The method of claim 22 or 23, wherein R₂ is hydroxyl.

25. The method of any of claims 22-24, wherein Z is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9- yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

26. The method of any of claims 22-25, wherein Ri is a moiety of hexadecylpropanediol.

27. The method of any of claims 22-25, wherein Ri is a moiety of octadecylpropanediol.

28. The method of any of claims 22-25, wherein R₁ is -0-(CH₂VO-(CH₂)_I-CH₃, wherein a is 2 to 4 and t is 11 to 19.

29. The method of claim 22-28, wherein a is 2 or 3 and t is 15 or 17.

30. The method of claims 22-29, wherein B is -CH₃.

31. The method of claim 22, wherein Z is

Formula 4 wherein the symbol * in Formula 1, 2, 3 or 4 indicates the point of attachment of N to the methylene in Formula A or B.

32, The method of claim 22, wherein the compound is

or a pharmaceutically acceptable salt thereof.

32. The method of claim 22, wherein the compound has the structure of formula V

wherein:

Ri is— O— (CH₂),- CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

or

Formula A Formula B and the symbol * indicates that -*CH_2- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, the compound has the structure of

HO^'

or a pharmaceutically acceptable salt thereof.

34. The method of any of claims 22-33, wherein said resistance is multi-nucleoside resistance,

35. The method of any of claims 22-33, wherein said virus is HBV or HTV.

36. The method of any of claims 22-34, wherein said subject is infected with both HBV and HTV, and said antiviral compound is administered in an amount effective to treat both said HBV and HIV.

37. The method of any of claims 22-36, wherein said subject is in utero and said antiviral

compound is administered to the mother carrying said subject in utero.

38. The method any of claims 22-37, further comprising administering said subject one or more additional antiviral active agents in combination with said antiviral compound.

39. The method of claim 38, wherein said virus is HTV and said one or more additional antiviral active agents are selected from the group consisting of HIV-protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entiy inhibitors, fusion inhibitors, maturation inhibitors, and combinations thereof.

40. The method of claim 38 or 39, wherein said at least one additional antiviral active agents are selected from the group consisting of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

41. A pharmaceutical composition comprising:

(a) an antiviral compound of Formula A or Formula B

Formula A or

Formula B

wherein:

R₁ is a moiety selected from the group consisting of alkylglycerol, alkylpropanediol, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and Ri is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F, CF₃, -CH₂CH₃, -CFI₂OH, - CH₂CH₂OH, -CH(OH)CH₃, -CH₂F₃— CH=CH₂, and -CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -OR_2a, -BH₃, C_{1- 8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, or -NR'H ,

R_2a is C_{1- 8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 heteroalkyl, C_2-8 heteroalkenyl, C_2- heteroalkynyl, -P(=O)(OH)₂, or -P(=O)(OH)OP(=O)(OH)₂;

R¹ is C|-s alkyl, C_2-s alkenyl, C_2-8 alkynyl, C₁ -_g heteroalkyl, C_2-8 heteroalkynyi, C_2-8 heteroalkenyl, C₆-io aryl, or a substituted or unsubstituted amino acid residue; Z comprises a heterocyclic moiety at least one N, and the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

or a pharmaceutically acceptable salt, or a stereoisomer, a diastereomer, an enantiomer or racemate thereof;

(b) at least one additional antiviral active agent; and

(c) a pharmaceutically acceptable carrier.

42. The composition of claim 41, wherein X is oxygen.

43. The composition of claim 41 or 42, wherein R₂ is hydroxyl.

44. The composition of any of claims 41-43, wherein Z is guanin-9-yl, adenin-9-yl, 2, 6- diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or δ-aza compounds, or cytosin-1 -yl.

45. The composition of any of claims 41-44, wherein R₁ is a moiety of hexadecylpropanediol.

46. The composition of any of claims 41-44, wherein Ri is a moiety of octadecylpropanediol.

47. The composition of any of claims 41-44, wherein Ri is -0-(CH₂VO-(CH₂VCH₃, wherein a is 2 to 4 and t is 11 to 19.

48. The composition of claim 47, wherein a is 2 or 3 and t is 15 or 17.

49. The composition of any of claims 41-48, wherein B is -CH₃.

50. The composition of any of claims 41-49, wherein Z is

Formula 1

Formula 2

Formula 3 or

Formula A

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B.

51. The composition of any of claims 41-50, wherein the compound is

or a pharmaceutically acceptable salt thereof.

2. The composition of claim 41, wherein the compound has the structure of formula V

wherein:

R, is— O— (CH₂)_t—CH₃, wherein t is 1 1 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

Formula A Formula B

and the symbol * indicates that -*CH_2- in Formula V is attached to Z via ^"N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

53. The composition of claim 52, the compound has the structure of

or a pharmaceutically acceptable salt thereof.

54. The composition of any of claims 41-53, wherein said one or more additional antiviral active agents are selected from the group consisting of HTV-protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, fusion inhibitors, maturation inhibitors, and combinations thereof.

55. The composition of any of claims 41-54, wherein said one or more additional antiviral active agents are selected from the group consisting of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

56. A method of treating a subject for human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) infection, where said infection is in a privileged cellular or tissue compartment of said subject, the method comprising:administering said subject an antiviral compound of Formula_. A or Formula B, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

Formula B wherein:

R₁ is a moiety selected from the group consisting of alkylglycerol, alkylpropanedioi, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and Ri is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F, CF₃, -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃, -CH₂F, -CH=CH₂, and -CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -0R_2a, -BH₃, C_{1- g} alkyl, C_2-8 alkenyl, C_{2- ε} alkynyl, C_1-8 heteroalkyl, C_2-8 heteroalkenyl, C_2-s heteroalkynyl, or -NR¹H ,

R_2a is C_1-s alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C₂-_s heteroalkenyl, C_2- heteraalkynyl, -P(O)(OH)₂, or -P(0)(OH)OP(=0)(OH)₂; R¹ is Cs-g alkyl, C_2-s alkenyl, C_2-8 alkynyl, C_1-8 heteroalkyl, C_2-B heteroalkynyl, C_{2- 8} heteroalkenyl, C₃-_I0 aryl, or a substituted or υnsvtbstituted amino acid residue;

Z comprises a heterocyclic moiety, and

the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

in an amount effective to treat the HIV and/or HBV infection and at least substantially inhibit the development of resistance to antiviral compounds in said subject.

57. The method of claim 56, wherein X is oxygen.

58. The method of claim 56 or 57, wherein R₂ is hydroxyl.

59. The method of any of claims 56-58, wherein Z is guanin-9-yl, adenin-9-yl, 2, 6-diaminopurin-9- yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

60. The method of any of claims 56-59, wherein R₁ is a moiety of hexadecylpropanediol.

61. The method of any of claims 56-59, wherein Rj is a moiety of octadecylpropanediol.

62. The method of any of claims 56-59, wherein R₁ is -O-(CH₂)_a-O-(CH₂)rCH3, wherein a is 2 to 4 and t is 11 to 19.

63. The method of claim 62, wherein a is 2 or 3 and t is 15 or 17.

64. The method of any of claims 56-63, wherein B is -CH₃.

65. The method of any of claims 56-64, wherein Z is

Formula 1

Formula 3 _Or

Formula 4

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B.

66. The method of claim 56, wherein the compound is

or a pharmaceutically acceptable salt thereof. 67, The method of claim 56, wherein the compound has the structure of formula V

wherein:

Ri is— 0— (CH₂)_t— CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

and the symbol * indicates that -*CH_2- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, the compound has the structure of

-O(C H₂)₁₇CH₃

H

or a pharmaceutically acceptable salt thereof.

69. The method of any of claims 56-68, wherein said subject is immunocompromised.

70. The method of any of claims 56-69, wherein said virus is HBV or HlV.

71. The method of any of claim 56-69, wherein said subject is infected with both HBV and HTV, and said antiviral compound is administered in an amount effective to treat both said HBV and HTV.

72. The method of any of claims 56-71, wherein said subject is in utero and said antiviral compound is administered to the mother carrying said subject in utero.

73. The method of any of claims 56-72, wherein said privileged compartment is a cellular or tissue compartment to which said virus permeates in vivo, to which said antiviral does not permeate efficiently in vivo in the absence of said virus, and to which said antiviral is carried in vivo by said virus when said antiviral binds to said virus.

74. The method of any of claims 56-72, wherein said privileged compartment is a tissue

compartment selected from the group consisting of brain, lymphoid tissue, and testes,

75. The method of any of claims 56-74, wherein said privileged compartment is a cellular

compartment selected from the group consisting of dendritic cells, microglia,

monocyte/macrophages, combinations thereof, and other cell types ineffectively treated by the non-lipid-conjugated antiviral.

76. The method of any of claim 56-75, further comprising administering said subject one or more additional antiviral active agents in combination with said antiviral compound.

77. The method of claim 76, wherein said vims is HlV and said one or more additional antiviral active agent are selected from the group consisting of HTV-protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, fusion inhibitors, maturation inhibitors, and combinations thereof.

78. The method of claim 76 or 77, wherein said one or more additional antiviral active agents are selected from the group consisting of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfmavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

79. A method for inhibiting or preventing sexual transmission of HIV comprising topically

applying to the skin or epithelial tissue of a human an effective amount of a composition comprising an antiviral compound of Formula A or Formula B, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

wherein:

Ri is a moiety selected from the group consisting of alkylglycerol, aJkylpropanediol, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and Ri is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F, CF₃, -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃₃ -CH₂F, -CH=CH₂, and -CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -0R_2a, -BH₃, C_{1- 8} alky], C_2-8 alkenyl, C_2-8 alkynyl, C_{1- 8} heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, or -NR'H ,

R_2a is Cr₈ alkyi, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- s} heteroalkyl, C_2-8 heteroalkenyl, C_{2- s} heteroalkynyl, -P(O)(OH)₂, or -P(O)(OH)OP(O)(OH)₂;

R' is C_{1- 8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-s heteroalkyl, C_2-8 heteroalkynyl, C_2-s heteroalkenyl, C₆-_J0 aryl, or a unsubstituted or substituted amino acid residue;

Z comprising a heterocyclic moiety comprising at least one N, and

the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

in an amount effective to treat the HTV and/or HBV infection and at least substantially inhibit the development of resistance to antiviral compounds in said subject.

80. The method of claim 79, wherein X is oxygen.

81. The method of any of claims 79-80, wherein R₂ is hydroxy!.

82. The method of any of claims 79-81, wherein Z is guanin-9-yl, adenin-9-yI, 2, 6-diaminopurin-9- yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

83. The method of any of claims 79-82, wherein Ri is a moiety of hexadecylpropanediol.

84. The method of any of claims 79-82, wherein Ri is a moiety of octadecy (propanediol.

85. The method of any of claims 79-82, wherein R₁ is -O-(CH₂)_a-O-(CH₂)rCH₃, wherein a is 2 to 4 and t is 11 to 19.

86. The method of claim 85, wherein a is 2 or 3 and t is 15 or 17.

87. The method of any of claims 79-86 wherein B is -CH₃.

88. The method of any of claims 79-87, wherein Z is

Formula 3 or

Formula 4

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B.

89. The method of any of claims 79-88, wherein the compound is

or a pharmaceutically acceptable salt thereof.

90. The method of claim 79, wherein the compound has the structure of formula V

wherein:

R₁ is— O— <CH₂)_t— CH₃, wherein t is 1 1 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

Formula A Formula B and the symbol * indicates that -*CH₂- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

91, The method of claim 90, wherein the compound has the structure of

or a pharmaceutically acceptable salt thereof.

92. The method of any of claims 79-91, wherein the composition is applied intravaginally,

intrarectally or to the external male genitalia.

93. The method of any of claims 79-91, wherein the composition is in the form of a cream, lotion, gel, or foam.

94. The method of any of claims 79-91 , wherein the composition is in the form of an intra-vaginal pill, an intra-rectal pill, or a suppository.

95. The method of any of claims 79-91, wherein the composition can be topically applied by release from an intravaginal device selected from a vaginal ring, a vaginal sponge, a diaphragm, or a cervical cap.

96. The method of any of claims 79-91, wherein the composition is topically applied from the exterior surface of a condom or vaginal applicator.

97. The method of any of claims 79-96, wherein the composition further comprise one or more additional anti-HIV agents, a viracide effective against viral infections other than HIV, a spermicide, and/or a combination thereof.

98. The method of claim 97, wherein said one or more additiona! antiviral active agents are selected from the group consisting of lamivudine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

99. A topical composition in the form of a cream, lotion, gel, or foam, comprising a antiviral

compound of Formula A or Formula B, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

Formula B wherein:

R₁ is a moiety selected from the group consisting of alkylglycerol, alkylpropanediol, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and R_t is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, F, CF₃ -CH₂CH₃, -CH₂OH, - CH₂CH₂OH, -CH(OH)CH₃,— CH₂F, -CH=CH₂, and -CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -OR₂₃, -BH₃, C_1-8 alkyl, C_{2- 8} alkenyl, C_2-8 alkynyl, C₁-S heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, or -NR¹H , R_2a is Cr₈ alkyl, C_2-8 alkenyl, C_2-8 alkynyl, Q-g heteroalkyl, C_2-8 heteroalkenyl, C_2-8 heteroalkynyl, -P(=O)(OH)₂, or -P(=O)(OH)OP(=O)(OH)₂;

R' is C_{1 -8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 heteroalkyl, C_2-s heteroalkynyl, C_2-8 heteroalkenyl, Cg-io aryl, or a unsubstituted or substituted amino acid residue;

Z comprises a heterocyclic moiety comprising at least one N, and

the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

in am amount effective to treat the HIV and/or HBV infection and at least substantially inhibit the development of resistance to antiviral compounds in said subject.

100. The composition of claim 99, wherein X is oxygen.

101. The composition of any of claims 99- 100, wherein R₂ is hydroxyl .

102. The composition of any of claims 99-101, wherein Z is guanin-9-yl, adenin-9-yl, 2, 6- diaminopurin-9-yI, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

103. The composition of any of claims 99- 102, wherein Ri is a moiety of hexadecylpropanediol.

104. The composition of any of claims 99-103, wherein R₁ is a moiety of octadecylpropanediol.

105. The composition of any of claims 99- 103, wherein R₁ is -0-(CH₂X-O-(CH₂)_I-CH₃, wherein a is 2 to 4 and t is 11 to 19.

106. The composition of claim 105, wherein a is 2 or 3 and t is 15 or 17.

107. The composition of any of claims 99-106, wherein B is -CH₃.

108. The composition of any of claims 99-107, wherein Z is

Formula 1

Formula 4

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B,

109. The composition of any of claims 99, wherein the compound is

or a pharmaceutically acceptable salt thereof.

110. The method of claim 99, wherein the compound has the structure of Formula V

wherein:

R[ is— O— (CH₂)_t— CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

or

and the symbol * indicates that -*CH_2- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof. The method of claim 110, the compound has the structure of

or a pharmaceutically acceptable salt thereof,

112. The composition of any of claims 99-111 further comprising a viracide effective against viral infections other than HIV.

113. The composition of any of claims 99-112 further comprising a spermicide.

114. The composition of any of claims 99-113 further comprising one or more additional antiviral agents.

115. The composition of claim 114 further comprising one or more additional anti HTV agents.

116. The composition of claim 115, wherein said one or more additional antiviral active agents are selected from the group consisting of lamivυdine, abacavir, zidovudine, stavudine, zalcitabine, didanosine, emtricitabine, tenofovir, delavirdine, efavirenz, etravirine, nevirapine, amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, maraviroc, enfuvirtide, and raltegravir.

117. A device for inhibiting the sexual transmission of HtV comprising: a) a barrier structure for insertion into the vaginal cavity, and b) a composition comprising an antiviral compound of Formula A or Formula B, or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof,

Formula A or

Formula B wherein:

R₁ is a moiety selected from the group consisting of aikylglycerol, alkylpropanediol, 1-S- alkylthioglycerol, alkoxyalkanol and alkylethanediol, and R₁ is linked to -P(=X)- via oxygen of an available -OH of the moiety;

B is selected from the group consisting of hydrogen, -CH₃, -CH₂CH₃, -CH₂OH, -CH₂CH₂OH, -CH(OH)CH₃, -CH₂F, -CH=CH₂, and -CH₂N₃;

X is selenium, sulphur, or oxygen;

R₂ is hydroxy, -0R_2a, -BH₃, C_{1- s} alkyl, C_2-8 alkenyl, C_{2- s} alkynyl, C_{1- 8} heteroalkyϊ, C_{2- s} heteroalkenyl, C_2-8 heteroalkynyl, or -NRΗ ,

R_2ft is C_{1 -8} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_{1- s} heteroalkyl, C_{2- s} heteroalkenyl, C_2-8 heteroalkynyl, -P(O)(OH)₂, or -P(O)(OH)OPC=O)(OH)₂; R' is C_{1- S} alkyl, C_2-8 alkenyl, C_2-8 alkynyl, Cr₈ heteroalkyl, C_2-s heteroalkynyl, C_2-8 heteroalkenyl, C₆-, ₀ aryl, or an amino acid residue;

Z comprising a heterocyclic moiety comprising at least one N, and

the symbol * indicates the point of attachment of the methylene moiety in Formula (A) or (B) to Z is via an available nitrogen of the heterocyclic moiety,

in an amount effective to treat the HIV and/or HBV infection and at least substantially inhibit the development of resistance to antiviral compounds in said subject.

118. The device of claim 117, wherein X is oxygen.

119. The device of any of claims 117-118, wherein R₂ is hydroxyl.

120. The device of any of claims 117-119, wherein Z is guanin-9-yl, adenin-9-yl, 2, 6- diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza compounds, or cytosin-1-yl.

121. The device of any of claims 117, wherein R₁ is a moiety of hexadecylpropanediol.

122. The device of any of claims 117, wherein Ri is a moiety of octadecylpropanediol.

123. The device of any of claims 117, wherein R₁ is -O-(CH₂)_a-O-(CH₂)_rCH₃, wherein a is 2 to 4 and t is 11 to 19.

124. The device of claim 123, wherein a is 2 or 3 and t is 15 or 17.

125. The device of any of claims 117, wherein B is -CH₃.

126. The device of any of claims 117, wherein Z is

Formula 1

Formula 4

wherein the symbol * in Formula 1, 2, 3, or 4 indicates the point of attachment of N to the methylene in Formula A or B.

127. The device of any of claims 117-126, wherein the compound is

or a pharmaceutically acceptable salt thereof.

128. The method of claim 117, wherein the compound has the structure of Formula V

wherein:

R₁ is— O— (CH₂X- CH₃, wherein 1 is 1 3 to 19;

a is 2 to 4;

B is hydrogen, -CH₃, or -CH₂OH,

Z is

Formula A Formula B and the symbol * indicates that -*CH_2- in Formula V is attached to Z via N* in Formula A or

B;

or a pharmaceutically acceptable salt thereof.

129. The method of claim 117, the compound has the structure of

HO

HO^'

or a pharmaceutically acceptable salt thereof.

130. The device of any of claims 117-129, wherein the barrier structure is a vaginal sponge, diaphragm, cervical cap, or condom.

131. The device of any of claims 117-130 wherein the device further comprises additional anti- HIV agents, a viracide effective against viral infections other than HIV, and/or a spermicide,

132. A use an antiviral compound of Formula A or B or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof for the preparation of a medicament for carrying out a method of any of claims 1-40 and 56-98.

133. A use of a compound of Formula A or B or a pharmaceutically acceptable salt, a

stereoisomer, a diastereomer, an enantiomer or racemate thereof for carrying out a method of any of claims 1-40 and 56-98

134. A compound of Formula A or B or a pharmaceutically acceptable salt, a stereoisomer, a diastereomer, an enantiomer or racemate thereof for carrying out a method of any of claims 1- 40 and 56-98.