Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
  • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
  • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
  • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
  • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
  • C07F9/65719—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonous acid derivative

Definitions

• FIELD Provided herein are alkyl esters of phosphonate compounds.
• the compounds are esterified derivatives of biologically active phosphonates.
• provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders associated with viral infections, cell proliferation and bone metabolism using the compounds and compositions provided herein.
• BACKGROUND Phosphonate compounds have long been known to have antiviral, antiproliferative and other variety of therapeutic benefits.
• antiviral nucleotide phosphonates such as, for example, cidofovir, cyclic cidofovir, adefovir, tenofovir, and the like, as well as the 5 '-phosphonates and methylene phosphonates of azidothymidine (AZT), ganciclovir, acyclovir, and the like, hi these compounds, the 5'-hydroxyl of the sugar moiety, or its equivalent in acyclic nucleosides (ganciclovir, penciclovir, acyclovir) which do not contain a complete sugar moiety, is replaced with a phosphorus-carbon bond.
• antiviral nucleotide phosphonates such as, for example, cidofovir, cyclic cidofovir, adefovir, tenofovir, and the like
• 5 '-phosphonates and methylene phosphonates of azidothymidine (AZT) azidothymidine
• methylene phosphonates In the case of the methylene phosphonates, a methylene group replaces the 5'- hydroxyl or its equivalent, and its carbon atom is, in turn, covalently linked to the phosphonate.
• Such compounds may be active as antiviral or antiproliferative nucleotides. Upon cellular metabolism, two additional phosphorylations occur to form the nucleotide phosphonate diphosphate which represents the equivalent of nucleoside triphosphates.
• Antiviral nucleotide phosphonate diphosphates are selective inhibitors of viral RNA or DNA polymerases or reverse transcriptases.
• the antiproliferative nucleotide phosphonate diphosphates inhibit cancer cell DNA and RNA polymerases and may show much lower selectivity versus normal cellular DNA and RNA polymerases.
• Another class of therapeutically beneficial phosphonate compounds are the bisphosphonates, i.e., pyrophosphate analogs wherein the central oxygen atom of the pyrophosphate bond is replaced by carbon.
• Various substituent groups may be attached to this central carbon atom to produce derivatives of bisphosphonate compounds having various degrees of pharmacological potency.
• Bisphosphonates and their substituted derivatives have the intrinsic property of inhibiting bone resorption in vivo. Bisphosphonates also act by inhibiting apoptosis (programmed cell death) in bone-forming cells. Indications for their use therefore include the treatment and prevention of osteoporosis, treatment of Paget's disease, metastatic bone cancers, hyperparathyroidism, rheumatoid arthritis, algodistrophy, sterno-costo-clavicular hyperostosis, Gaucher's disease, Engleman's disease, and certain non-skeletal disorders.
• bisphosphonates Although bisphosphonates have therapeutically beneficial properties, they suffer from pharmacological disadvantages as orally administered agents.
• One drawback is low oral availability: as little as 0.7% to 5% of an orally administered dose is absorbed from the gastrointestinal tract. Oral absorption is further reduced when taken with food.
• some currently available bisphosphonates e.g., FOSAMAX® (Merck; alendronate sodium), SKELID® (Sanofi, tiludronate) and ACTONEL®(Procter and Gamble, risedronate) have local toxicity, causing esophageal irritation and ulceration.
• Other bisphosphonates like amino-olpadronate, lack anti-resorptive effects (Van Beek, E.
• phosphonate and bisphosphonate alkyl esters and compositions thereof for the treatment of various diseases.
• compounds and compositions provided herein have antiviral activity.
• compounds and compositions that are useful in the treatment, prevention, or amelioration of one or more symptoms associated with cell proliferation are provided herein.
• the compounds and compositions are for treating diseases associated with bone metabolism in a subject.
• chemically modified phosphonate derivatives of pharmacologically active agents e.g., antiviral and anti-neoplastic pharmaceutical agents that contain phosphonates.
• these modified derivatives increase the potency of the parent compound while minimizing deleterious side effects when administered to a subject in need thereof.
• the compounds are lipophilic esters of phosphonates. In certain embodiments, the lipophilic esters exhibit enhanced activity against cells infected with poxviruses and herpes viruses compared to non-esterified phosphonates.
• the compounds for use in the compositions and methods provided herein have formula I: P x o R wherein P x is a pharmacologically active phosphonate, O is an oxygen atom, and R is a substituted or unsubstituted C8-C24 alkyl, substituted or unsubstituted C8-C24 alkenyl having from 1 to 6 double bonds or substituted or unsubstituted C8-C24 alkynyl having from 1 to 6 triple bonds, wherein substituents when present are selected from one or more halogen, alkyl, -OR w , -SR W , cycloalkyl or epoxide, where R w is hydrogen or alkyl and where the alkyl, alkenyl, alkynyl groups may be further substituted or unsubstitued.
• compositions containing the compounds provided herein and a pharmaceutically acceptable carrier are provided.
• the pharmaceutical compositions are formulated for single dosage administration. Methods of treating, using the compounds and compositions provided herein are provided. Methods of treating, preventing, or ameliorating one or more symptoms of diseases associated with viral infections, cell proliferation and bone metabolism using the compounds and compositions provided herein are provided. In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered.
• Articles of manufacture are provided containing packaging material, a compound or composition provided herein which is useful for treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with viral infections, cell proliferation or bone metabolism using the compounds and compositions provided herein, and a label that indicates that the compound or composition is useful for treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with viral infections, cell proliferation or bone metabolism.
• DETAILED DESCRIPTION A Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety.
• Phosphonate compounds for use herein are biologically active derivatives of phosphonic acid that can be converted into alkyl esters as described herein.
• the phosphonate compounds for use herein are phosphonate-containing nucleotides or nucleosides which can be derivatized to their corresponding phosphonates.
• the phosphonate compounds for use herein are bisphosphonates. Bisphosphonates are synthetic phosphonic acid derivatives characterized by two carbon-phosphorus bonds.
• pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
• Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
• the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
• Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salt
• esters include, but are not limited to, alkyl, alkenyl, alkynyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxyhc acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
• Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
• treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating diseases or disorders in which ⁇ -synuclein fibril formation is implicated.
• amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
• EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
• a prodrug is a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
• the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
• the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
• Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof.
• the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. It is understood that the present invention encompasses any racemic, optically active, polymorphic, or steroisomeric form, or mixtures therof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms and how to determine antiproliferative activity using the standard tests described herein, or using other similar tests which are will known in the art.
• Examples of methods that can be used to obtain optical isomers of the compounds of the present invention include the following: i) physical separation of crystals- a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization- a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions — a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme iv) enzymatic asymmetric synthesis — a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enatiomerically pure or enriched synthetic precursor of the desired enantiomer;
• first- and second-order asymmetric transformations a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
• kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors — a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography — a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
• the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
• chiral gas chromatography a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
• extraction with chiral solvents a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
• xiii) transport across chiral membranes a technique whereby a racemate is placed in contact with a thin membrane barrier.
• the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
• amino acid residues such residues maybe of either the L- or D-form.
• the configuration for naturally occurring amino acid residues is generally L. When not specified the residue is the L form.
• amino acid refers to ⁇ -amino acids which are racemic, or of either the D- or L-configuration.
• the designation "d” preceding an amino acid designation refers to the D-isomer of the amino acid.
• the designation "dl” preceding an amino acid designation refers to a mixture of the L- and D-isomers of the amino acid. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.
• substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
• TLC thin layer chromatography
• HPLC high performance liquid chromatography
• MS mass spectrometry
• alkyl refers to a monovalent straight or branched chain or cyclic radical.
• the alkyl group contains from one to twenty-four carbon atoms, including methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, octadecyl, nonadecyl, eicosyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, and the like.
• lower alkyl refers to alkyl groups of 1 to 6 carbon atoms.
• substituted alkyl refers to alkyl groups further bearing one or more substituents, including, but not limited to substituents selected from lower alkyl, hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano,azido, nitro, nitrone, amino, amido, - C(O)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, and sulfuryl, which may be protected or unprotected as necessary, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Ed.
• alkenyl refers to straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds. In certain embodiments, the alkenyl group contains from 2 up to 24 carbon atoms, and “substituted alkenyl” refers to alkenyl groups further bearing one or more substituents as set forth above.
• alkynyl refers to straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds. In certain embodiments, the alkynyl group contains from 2 up to 24 carbon atoms, and "substituted alkynyl” refers to alkynyl groups further bearing one or more substituents as set forth above.
• aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl” refers to aryl groups further bearing one or more substituents as set forth above.
• heteroaryl refers to aromatic groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and “substituted heteroaryl” refers to heteroaryl groups further bearing one or more substituents as set forth above.
• heteroside refers to a molecule composed of a heterocyclic base and a carbohydrate.
• a nucleoside is composed of a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar.
• Nucleosides are recognized in the art to include natural bases (standard), and non-natural bases well known in the art.
• the carbohydrates include the true sugars found in natural nucleosides or a species replacing the ribofuranosyl moiety or acyclic sugars.
• the heterocyclic nitrogenous bases are generally located at the 1' position of a nucleoside sugar moiety. Nucleosides generally contain a base and sugar group.
• the nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non-standard nucleosides; see for example, Eckstein et al, International PCT Publication No. WO 92/07065 and Usman et al., International PCT Publication No. WO 93/15187).
• the heterocyclic base is typically thymine, uracil, cytosine, adenine or guanine.
• the carbohydrate shall be understood to mean the true sugar found in natural nucleosides or a species replacing the ribofuranosyl moiety or acyclic sugars.
• acyclic sugars contain 3-6 carbon atoms and include, for example, the acyclic sugar moieties present in acyclovir (-CH2-O-CH2 CH2- OH), ganciclovir (-CH2-O-CH(CH2 OH)-CH2-OH), and the like.
• Natural nucleosides have the ⁇ -D-configuration.
• the term "nucleoside" shall be understood to encompass unnatural configurations and species replacing the true sugar that lack an anomeric carbon. In natural nucleosides the heteocyclic base is attached to the carbohydrate through a carbon-nitrogen bond. The term
• nucleoside shall be understood to encompass species wherein the heterocyclic base and carbohydrate are attached through a carbon-carbon bond (C- nucleosides).
• subject is an animal, typically a mammal, including human, such as a patient.
• effective amount means an amount required for prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated including those associated with viral infection, cell proliferation and/or bone metabolism .
• substituents there may be one or more substituents present.
• haloalkyl may include one or more of the same or different halogens.
• parenteral includes subcutaneous, intravenous, intra-arterial, intramuscular or intravitreal injection, or infusion techniques.
• topically encompasses administration rectally and by inhalation spray, as well as the more common routes of the skin and mucous membranes of the mouth and nose and in toothpaste.
• abbreviations for any protective groups, amino acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. H:942-944).
• alkyl ester derivatives of known phosphonate compounds according to the methods provided herein, i certain embodiments, the alkyl ester derivatives of phosphonates provided herein have improved properties, such as improved pharmacologic activity, or increased oral absorption.
• cellular enzymes, but not plasma or digestive tract enzymes convert the compounds provided herein to a free phosphonates.
• the phosphonate compounds described herein reduce or eliminate the tendency of co-administered food to reduce or abolish phosphonate absorption, resulting in higher plasma levels of phosphonates and better compliance by patients.
• the alkyl ester compounds for use in the compositions and methods provided herein have formula I: px o R wherein P x is a pharmacologically active phosphonate, O is an oxygen atom, and R is a substituted or unsubstituted C 8 -C 24 alkyl, substituted or unsubstituted C 8 -C 24 alkenyl having from 1 to 6 double bonds or substituted or unsubstituted C 8 -C 24 alkynyl having from 1 to 6 triple bonds wherein substituents when present are selected from one or more halogen, alkyl, alkenyl, alkynyl, - OR w , -SR W , cycloalkyl or epoxide, where each R w is independently hydrogen or alkyl and where the alkyl, alkenyl, alkynyl groups may be substituted or unsubstitued.
• the compounds for use in the compositions and methods provided herein have formula I: P ⁇ o R wherein P x is a pharmacologically active phosphonate, O is an oxygen atom, and R is a substituted or unsubstituted C 8 -C 24 alkyl or substituted or unsubstituted C 8 -C 24 alkenyl having from 1 to 6 double bonds, wherein substituents when present are selected from one or more halogen, alkyl, -OH, - SH, cycloalkyl, or epoxide.
• the R group in the alkyl, alkenyl and alkynyl groups in the compounds of formula I contain 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms and can be straight or branched chain moieties.
• the R group is a C ⁇ 6 -C 23 straight or branched chain alkyl or C ⁇ 6 -C 23 straight or branched chain alkenyl.
• R is a C ⁇ -C ⁇ 9 straight or branched chain alkyl or C ⁇ 7 -C 19 straight or branched chain alkenyl.
• R is C ⁇ -alkyl, C ⁇ 8 -alkyl or C ⁇ 9 alkyl.
• R is C ⁇ -alkenyl, C ⁇ 8 -alkenyl or C 1 alkenyl. In other embodiments, R is C ⁇ 7 -C 22 alkyl. In other embodiments, R is alkyl, C ⁇ 8 alkyl, C 19 alkyl, C 2 o alkyl, C21 alkyl, or C 22 alkyl. hi certain embodiments, R is substituted with one or more groups selected from lower alkyl and halo. In certain embodiments, R is substituted with one or more methyl groups. In certain embodiments, R is substituted with one or more fluoro groups. In certain embodiments, R is C ⁇ 6 -C 23 alkyl and is substituted with one or more methyl or fluoro groups.
• the methyl group or the fluoro group substituent is present on the penultimate carbon of the alkyl, alkenyl, or alkynyl chain, hi certain embodiments, the R is 7-methyl-octyl, 8- methyl-nonyl, 9-methyl-decyl, 10-methyl-undecyl, 11-methyl-dodecyl, 12- methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl- hexadecyl, 16-methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8- fluoro-nonyl, 9- fluoro-decyl,
• Ri is an antiviral nucleoside or antiproliferative nucleoside, or a bisphosphonate
• R' is selected from an -H, a substituted or unsubstituted straight chain, branched or cyclic C8-C24 alkyl, substituted or unsubstituted C8- C24 alkenyl or C8-C24 alkynyl and wherein substituents when present are selected from one or more halogen, alkyl, alkenyl, alkynyl -OR3, -SR3, cycloalkyl, or epoxide and R3 is a -H or lower alkyl; is -H, or a physiologically acceptable monovalent cation.
• P x is represented by formula II O II Ri — P I OM , wherein Ri is an antiviral nucleoside or antiproliferative nucleoside, or a bisphosphonate, and M is -H, a physiologically acceptable monovalent cation, a substituted or unsubstituted straight chain, branched or cyclic C8-C24 alkyl, substituted or unsubstituted C8-C24 alkenyl or C8-C24 alkynyl and wherein substituents when present are selected from one or more halogen, alkyl, alkenyl, alkynyl, OR , -SR W , cycloalkyl or epoxide, where each R w is independently hydrogen or C 1-6 alkyl.
• M is -H, or a physiologically acceptable monovalent cation.
• P x is represented by formula II O II Ri — P I OM , wherein R ⁇ is an antiviral nucleoside or antiproliferative nucleoside, or a bisphosphonate, and M is -H, Na + , K , or a physiologically acceptable monovalent cation.
• the compounds provided herein have formula:
• R 3 , R 4 and R 5 are each H, hydroxy, halo, azido, Cl-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; B is a purine or pyrimidine base or analog thereof and P 1 is
• R 4 and R 5 are selected from hydrogen, halo and hydroxyalkyl. In certain embodiments, R 4 and R 5 are selected from halo and hydroxyalkyl. In certain embodiments, R 4 and R 5 are selected from fluoro and hydroxymethyl. In certain embodiments, R 4 is selected from fluoro and hydroxymethyl. In certain embodiments, R 5 is selected from fluoro and hydroxymethyl. hi certain embodiments, the compounds have formula:
• R 3x is H, azido, substituted or unsubstitued Cl-6 alkyl, substituted or unsubstitued C2-6 alkenyl or substituted or unsubstitued C2-6 alkynyl;
• R 4x is H, Cl-6 substituted or unsubstitued alkyl, C2-6 substituted or unsubstitued alkenyl or C2-6 substituted or unsubstitued alkynyl and other variables are as defined elsewhere herein.
• the compounds have formula:
• R 3z is H, Cl-6 alkyl, hydroxyl Cl-6 alkyl, halo Cl-6 alkyl, azido Cl-6 alkyl or OH and the other variables are as defined elsewhere herein.
• R 3z is hydrogen Cl-6 alkyl or hydroxyl Cl-6 alkyl.
• R 3z is hydrogen or hydroxy methyl.
• R 3z is hydroxy methyl.
• the OH groups are protected, for example as an ester.
• R 3z may be in S or R configuration.
• the compounds have formula:
• the compounds have formula:
• R 3y is H, substituted or unsubstitued Cl-6 alkyl, substituted or unsubstitued C2-6 alkenyl or substituted or unsubstitued C2-6 alkynyl; or OH and the other variables are as defined elsewhere herein.
• R 3y is hydrogen Cl-6 alkyl or hydroxyl Cl-6 alkyl.
• R 3y is hydrogen or hydroxy methyl.
• R 3y may be in S or R configuration.
• B is selected from a natural or non natural purine or pyrimidine base.
• the base is selected from pyrimidin- 1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl residue, hi certain embodiments, the base is thymin-1-yl, cytosine-1-yl, adenine-9-yl or guanine-9- yl. a).
• P as an antiviral phosphonate
• P is an antiviral phophonate, including, but not limited to adefovir, cidofovir, cyclic cidofovir, tenofovir, 9-(2- phosphonylmethoxyethyl)guanine (PMEG), 9-(2 phosphonyl- meth ⁇ xyethyl)adenine (PMEA), penciclovir, and 9-(3hydroxy-2- phosphonylmethoxypropyl)adenine (HPMPA).
• adefovir cidofovir
• cyclic cidofovir tenofovir
• PMEG 9-(2- phosphonylmethoxyethyl)guanine
• PMEA 9-(2 phosphonyl- meth ⁇ xyethyl)adenine
• HPMPA 9-(3hydroxy-2- phosphonylmethoxypropyl)adenine
• the phosphonates for use in the compounds provided herein contain either a phosphonate (-PO 3 H ) or a methylene phosphonate (-CH 2 -PO 3 H 2 ) group substituted for the 5'-hydroxyl of the antiviral nucleoside.
• P is a phosphonate derivative of azidothymidine (AZT).
• AZA azidothymidine
• P is cidofovir, cyclic cidofovir, tenofovir or 9-(3hydroxy-2- phosphonylmethoxypropyl)adenine (HPMPA).
• P is cidofovir or cyclic cidofovir.
• P is 9-(3hydroxy-2- phosphonylmethoxypropyl)adenine.
• P is an antiviral nucleoside, including cyclic and acyclic nucleosides, that can be converted to its corresponding 5 '-phosphonate.
• Such phosphonate analogs typically contain either a phosphonate (-PO 3 H 2 ) or a methylene phosphonate (-CH 2 -PO 3 H 2 ) group substituted for the 5'-hydroxyl of the antiviral nucleoside.
• antiviral phosphonates derived by substituting -CH 2 - PO 3 H 2 for the 5'-hydroxyl are: Huffman, et al. Ganciclovir phosphonate
• antiviral nucleotide phosphonates for use in the compounds provided herein are obtained 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.
• P as an anti-neoplastic
• P is an anti-neoplastic selected from a variety of phosphonate-containing nucleotides (or nucleosides which can be derivatized to their corresponding phosphonates).
• P is a phosphonate derivative of an anti-neoplastic nucleoside, including, but not limited to cytosine arabinoside, gemcitabine, 5- fluorodeoxyuridine riboside, 5-fluorodeoxyuridine deoxyriboside, 2- chlorodeoxyadenosine, fludarabine, 1- ⁇ -D-arabinofuranosyl-guanine, or pharmaceutically acceptable derivatives thereof.
• an anti-neoplastic nucleoside including, but not limited to cytosine arabinoside, gemcitabine, 5- fluorodeoxyuridine riboside, 5-fluorodeoxyuridine deoxyriboside, 2- chlorodeoxyadenosine, fludarabine, 1- ⁇ -D-arabinofuranosyl-guanine, or pharmaceutically acceptable derivatives thereof.
• P is a phosphonate derivative of an anti- neoplastic nucleoside, including, but not limited to 2-chloro-deoxyadenosine, 1- ⁇ -D-arabinofuranosyl-cytidine (cytarabine, ara-C), fluorouridine, fluorodeoxyuridine (floxuridine), gemcitabine, cladribine, fludarabine, pentostatin (2'-deoxycoformycin), 6-mercaptopurine, 6-thioguanine, and substituted or unsubstituted 1- ⁇ -D-arabinofuranosyl-guanine (ara-G), 1- ⁇ -D- arabinofuranosyl-adenosine (ara-A), 1- ⁇ -D-arabinofuranosyl-uridine (ara-U).
• 2-chloro-deoxyadenosine 1- ⁇ -D-arabinofuranosyl-cytidine
• fluorouridine fluorodeoxyuridine
• P is 9-(2-phosphonylmethoxyethyl)guanine (PMEG), 9-(2-(phosponomethoxy)ethyl)-2,6-diamino ⁇ urine (PMEDAP), 9-(2- (phosphonomethoxy)ethyl)adenine (adefovir), and the like. c).
• P is a bisphosphonate, such as for example, alendronate, etidronate, tiludronate, ibandronate, Disodium l-hydroxy-3-(l- pyrrolidinyl)-propylidene- 1 , 1 -bisphosphonate (EB- 1053), pamidronate, olpadronate, amino-olpadronate, clodronate, risedronate, and the like.
• the phosphonates for use in compounds of formula I provided herein are bisphosphonate compounds that have the ability to inhibit squalene synthase and to reduce serum cholesterol levels in a subject.
• bisphosphonate compounds that have the ability to inhibit squalene synthase are represented by formula:
• A is O, S, NR, SO, SO 2 or a bond
• B is (CR x R x ) ⁇ - 2 .
• R x N (CR x R , 7a C X R ,
• R x is hydrogen or alkyl
• R 1 and R" are independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl or phenyl; or R' and R" together may form a double bond
• each R z is independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl or phenyl
• R 3' , p, R 5' , R 6 ', R 7' , ⁇ ', and R > are independently hydrogen, alkyl, aryl, aralkyl or -CH 2 OCOR x
• Alk is bi- or tri-carbocycloalkane
• Ar I and Ar II are independently a mono- or di-aryl or heteroaryl
• a and b are independently 0-3; a+b is 0-4; d is 0-3; a+b+d is 1-3; e is 0-3;
• Phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases 5,183,815 (Bone acting agents), 5,196,409 (Bisphosphonates), 5,247,085 (Antiviral purine compounds), 5,300,671 (Gem-diphosphonic acids), 5,300,687 (Trifluoromethylbenzylphosphonates), 5,312,954 (Bis- and tetrakis- phosphonates), 5,395,826 (Guanidinealkyl- 1,1 -bisphosphonic acid derivatives), 5,428,181 (Bisphosponate derivatives), 5,442,101 (Methylenebisphosphonic acid derivatives), 5,532,226 (Trifluoromethybenzylphosphonates), 5,656,745 (Nucleotide analogs), 5,672,697 (Nuleoside-5' -methylene phosphonates),
• European Patent No. 753523 (Amino-substituted bisphosphonic acids); European Patent Application 186405 (geminal diphosphonates); and the like, hi addition, the compounds listed in the following publications can be derivatized according to the invention to improve their pharmacologic activity, or to increase their oral absorption; each of which are hereby incorporated by reference in their entirety: J. Med. Chem., 2002, 45:1918-1929; J. Med. Chem.., 2003, 46:5064-5073; Antimicrob. Agents Chemotherapy, 2002, 46:2185-2193.
• One of skill in the art would be able to select appropriate phosphonate compounds for use herein. The following U.S.
• Patents describe other nucleotide phosphonate analogs: U.S. Pat. No. 5,672,697 (Nucleoside-5 '-methylene phosphonates), U.S. Pat. No. 5,922,695 (Antiviral phosphonomethoxy nucleotide analogs), 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, U.S. Pat. No. 5,792,756 (Prodrugs of Phosphonates), U.S. Pat. No. 5,869,468 (Treatment of Conditions of Abnormally Increased Intraocular
• Ric -R ⁇ c can be the same or different and stand for hydrogen, a straight or branched aliphatic or alicyclic -do hydrocarbon radical, an aryl or an aryl- Ci -C 4 -alkyl radical; n is zero or one, and m is zero, one or two, or R 2c and R tc when taken together can form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted with one or more Ci -C -alkyl radicals.
• the phosphonates for use in the alkyl ester compounds provided herein are represented by formula 2: o B CH 2 -0 CH(CH 2 )n CHP(OH) 2
• the phosphonate compounds for use herein are represented by formula 3 : B 1 CH 2 CH OCH 2 P(0)(OH) 2
• R e is a hydrogen atom or a hydroxymethyl group and Bi is a pyrimidin- 1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl residue but not an adenin-9-yl residue, and the salts thereof with alkali metals, ammoma or amines.
• the phosphonate compounds for use herein are represented by formula 4: A2-B2-C2 wherein: A2 is a residue of a hydroxyl containing steroidal hormone possessing human bone resorption antagonist activity or bone formation stimulatory activity; C2 is a residue of an amino or hydroxy alkyl- 1,1 -bisphosphonate, possessing human bone affinity; and B2 is a covalent linkage, connecting A2 through the hydroxyl moiety and C2 through the respective amino or hydroxyl moiety, which linkage can hydrolyze in the human body in the vicimty of bone to release steroidal hormone A2, and pharmaceutically acceptable salts or esters thereof.
• the phosphonate compounds for use herein are represented by formula 5:
• Ri f represents hydrogen, a lower alkyl group, or an alkali metal cation
• R 2f represents hydrogen, a lower alkyl group or an alkali metal cation
• X is -(CH 2 ) p-(OCH 2 CH 2 ) q -O-(CH 2 )p'-, wherein p and p' are independently integers from 1 to 5 and q is an integer from 1 to 6; or
• X is -(CH 2 )t-O-(CH 2 )s-O-(CH 2 )f- wherein t and t' are independently integers from 1 to 6 and s is an integer from 2 to 12; or
• X is — B— A— B
• B represents a branched group or straight alkylene, or an alkenylene or alkynylene chain optionally substituted by one or more oxygen or nitrogen atoms
• A represents an aromatic group such as phenylene, naphthalenediyl, thiophenediyl or furandiyl.
• the phosphonate compounds for use herein are represented by formula 6:
• R ⁇ g is hydroxy, amino, chloro or OR 7g wherein R 7g is Cl-6 alkyl, phenyl or phenyl Cl-2 alkyl either of which phenyl moieties may be substituted by one or two substituents selected from halo, Cl-4 alkyl or C 1-4 alkoxy;
• R 2g is amino or, when R ⁇ g is hydroxy or amino, R 2g may also be hydrogen;
• R 3g is hydrogen, hydroxymethyl or acyloxymethyl; ig is a group of formula:
• R 5g and Rg g are independently selected from hydrogen, Cl-6 alkyl and optionally substituted phenyl; or R 3g and R g together are:
• Ri h and R 2 h which can be the same or different, are hydrogen or CI -C4 alkyl;
• A) is hydrogen, halogen, hydroxy, straight or branched CI -C12 alkyl;
• B is a covalent bond, a straight or branched CI -C8 alkylene or, together with the adjacent nitrogen atom, a group of formula
• the groups -N(R 3h )- and -(CH 2 )n h - may be in the 1 , 1 ; 1 ,2; 1 ,3 or
• R 7h and R 8 h which are the same or different, are hydrogen, straight or branched CI -C6 alkyl, phenyl, benzyl, p-methoxybenzyl, or one of R 7h and R 8h is as above defined and the other one is a group of formula R 9h ⁇ C(O)— in which R 9h is hydrogen, straight or branched CI -C4 alkyl, phenyl, benzyl, p-methoxyphenyl, straight or branched CI -C4 alkoxy, halo-Cl -C4 - alkoxy; R 5h and R h are haloethyl (2-chloroethyl, 2-bromoethyl, 2-iodoethyl) or R 5h and R 6 , together with the nitrogen atom to which they are bound, are a 1- aziridinyl residue of formula
• the phosphonate compounds for use here are hydrogen, straight or
• R J has the following meaning therein: I) a radical of the formula
• R , 11J o literally_r - Rr, 12J J has the following meaning: a) R — S(O)nj— or where R 13J is 1) (Cl-C6)-alkyl, 2) (C5-C7)-cycloalkyl, 3) cyclopentylmethyl, 4) cyclohexylmethyl, 5) phenyl, 6) phenyl substituted once to three times by fluorine atom, chlorine atom, methyl or methoxy, where nj is the integer zero, 1 or 2, where R 14J and R 15J are identical or different and have, independently of one another, the following meaning: 1) hydrogen atom, 2) (CI - C6)-alkyl, 3) phenyl, 4) phenyl substituted once or twice by fluorine atom, chlorine atom, methyl or methoxy, 5) -(CH2)mj -phenyl where mj is an integer from 1 to 4, or 6) -(CH2)m_ --pheny
• R 14J and R 15J have the abovementioned meaning, or II) a radical of the formula
• R 21J , R 22J or R 23J has the following meaning: a) hydrogen atom, b) halogen atom, such as fluorine, chlorine, bromine or iodine atom, or c) (CI -C12)-alkyl, where one of the substituents R 21J , R 22J or R 23J can also mean 1) N 3 , 2) CN, 3) OH, 4) (CI -C10)-alkoxy, 5) R 2 J -C nJ H.
• R 24J is 1) CpF 2p +l where p is the number 1, 2 or 3, as long as n is the number zero or 1, 2) (C3 -C12)-cycloalkyl, 3) phenyl, 4) pyridyl, 5) quinolyl or 6) isoquinolyl, where the ring system in the radicals 3) to 6) is unsubstituted or substituted by a radical from the group fluorine atom, chlorine atom, CF3, methyl, methoxy or NR 25J R 26J where R 25J and R 26J are identical or different and have, independently of one another, the meaning hydrogen atom or (CI -C.4)- alkyl, or III) a radical of the formula
• R , R , R or R has the following meaning: a) hydrogen atom, b) halogen atom, such as fluorine, chlorine, bromine or iodine atom, or c)- CN, d) -NO2, e) -N 3 , f)-(Cl -C6)-alkyl, straight-chain or branched or g) R 35J -Cn H 2n -Z-, where n is the number zero, 1, 2, 3, 4, 5 or 6, and the alkylene chain -Cn H2n- is straight-chain or branched, and one carbon atom can be replaced by an oxygen, sulfur or nitrogen atom, R 35J is 1) hydrogen atom, 2) (C3 -C6)-alkenyl, 3) (C5 -C8)-cycloalkyl, 4) (C5 -C8)-cycloalkyl, substituted by a hydroxyl group, or one methylene group is replaced by an oxygen, sulfur or nitrogen atom
• m is the number 1, 2 or 3; pyridyl; quinolyl or isoquinolyl, Y is CH 2 or NH; Z is 1) -CO-, 2) -CH 2 -, 3) -[CH(OH)]q -, where q is the number 1, 2 or 3, 4) - [C(CH 3 )(OH)]q -, where q is the number 1, 2 or 3, 5)-O-, 6) -NH-,7)-N(CH 3 )- 8) -S(O)x- 5 where x is zero, 1 or 2, 9) -SO2-NH- or 10) S0 2 — N
• X has the following meaning a) N or b) C-R 37J , where R 37J is hydrogen atom, (CI -C4)-alkyl or (C2 -C4)-alkenyl, has the following meaning a) NH, b)-N-(C2 -C6)-alkyl, c)-N-(C2 -C4)-alkenyl or d) R 35J --Cn H2n - -Z ⁇ , where R 35J , n and Z are defined as above, R 5J , R 6J , R 7J and R 8J , are identical or different and have, independently of one another, the following meaning a) hydrogen atom, b) (CI -C5)-alkyl, straight-chain or branched, or c) phenyl.
• the phosphonate compounds for use herein are represented by formula 10:
• Ak-O- denotes a residue of a compound having an estrogenic activity
• R ⁇ denotes H or a CI -C6 alkyl group
• Xk denotes a single bond, a CI CIO alkylene group or a group of the formula: wherein R 2k denotes H or a C1-C5 alkyl group; Zk denotes a nitro group or a halogen; n' is an integer of 3 to 12; k is an integer of 1 to 5; L is an integer of
• the phosphonate compounds for use herein are 5'- phosphonates of 3'-azido-2',3'-dideoxynucleosides that are represented by formula 11 :
• the phosphonate compounds for use herein are methylenebisphosphonic acid derivatives represented by formula 10: in which Wi, W , W 3 and W 4 are independently the group OR ⁇ m or the group NR 2m R 3m wherein R ⁇ m , R 2m and R 3m independently are hydrogen or straight or branched, optionally unsaturated C1-C22 -alkyl, optionally substituted, optionally unsaturated C3-C10-cycloalkyl, aryl, aralkyl or silyl SiR 3m , or the groups R 2m and R 3m form together with the adjacent nitrogen atom a 3 to 10- membered saturated, partly saturated or aromatic heterocyclic ring, wherein in addition to the nitrogen atom, there may be one or two heteroatoms from the group N, O and S, provided that in the formula I at
• each Ri n is independently hydrogen, hydroxyl, fluorine or methyl ester
• each Y n is independently OR 2n , N(R n ) or SR 2n wherein, each R 2n is independently hydrogen or alkyl (1-12 C)
• X is selected from oxygen and sulfur.
• the phosphonate compounds for use herein are represented by formula 12:
• R is hydrogen (H), alkyl, O-alkyl, -CHO, -C(O)OR 2 °, -C(O)R 2 °, - C(O)N(R 3o ) 2 or -S(O) 2 N(R 3o ) 2 ; each R° is independently hydrogen, cyano (CN), nitro (NO 2 ), halogen, alkyl, O-alkyl, -C(O)OR ,3 J o O , -C(O)R ,3 J o O , -S(O) 2 OH, ⁇ N(R 3 J c 0 ) 2 , -CHO or -OH; and each R 2 ° and each R 3 ° are independently hydrogen, alkyl, phenyl, alkyl substituted phenyl, -CH 2 C 6 H 5 or -CH 2 CH 2 C 6 H 5 .
• the phosphon is independently hydrogen, alkyl, phenyl, alkyl substituted
• R p is selected from the group consisting of
• R lp and R 2p are independently selected from the group consisting of hydrogen and lower alkyl, R 3p is lower alkyl or -(CH )n p -C 6 H 5 , and n p is an integer in the range of 0 to 6 inclusive; R' is selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, amino and halogen; and R" is hydrogen or a halogen substituent, or a pharmaceutically acceptable salt or ester thereof.
• the phosphonate compounds for use herein are represented by formula 15: O
• Zq is independently -OC(R 2q ) 2 OC(O)Xq(R q ) a , an ester, an amidate or -H, but at least one Zq is -OC(R 2q ) 2 OC(O)Xq(R q ) a ;
• a q is the residue of an antiviral phosphonomethoxy nucleotide analog;
• Xq is N or O;
• R 2q independently is -H, C1-C12 alkyl, C5 -C12 aryl, C2 -C12 alkenyl, C2 -C12 alkynyl, C7 -C12 alkenylaryl, C7 -C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or -OR 3q in which R 3q is
• the compounds herein are alkyl esters of cidofovir, cyclic cidofovir or HPMPA.
• the alkyl esters of CDN possess 16-22 carbon atoms.
• the alkyl esters of CDN possess 16, 17, 18, 19, 20, 21 or 22 carbon atoms.
• the alkyl esters of CDN possess 18, 19 or 20 carbon atoms
• the alkyl esters of cidofovir are selected from octyl cidofovir, dodecyl cidofovir, hexadecyl cidofovir, eicosyl cidofovir, docosyl cidofovir and tetracosyl cidofovir.
• the alkyl esters of cidofovir are selected from eicosyl cidofovir, docosyl cidofovir and tetracosyl cidofovir.
• the alkyl esters of cidofovir are selected from octyl cyclic cidofovir, dodecyl cyclic cidofovir, hexadecyl cyclic cidofovir, eicosyl cyclic cidofovir, docosyl cyclic cidofovir and cyclic cyclic tetracosyl cidofovir.
• the alkyl esters of cidofovir are selected from cyclic eicosyl cidofovir, docosyl cyclic cidofovir and tetracosyl cyclic cidofovir.
• the alkyl esters of HPMPA is eicosyl-(S)-HPMPA.
• the compounds provided herein are 7-methyl-octyl, 8-methyl- nonyl, 9-methyl-decyl, 10-methyl-undecyl, 11-methyl-dodecyl, 12-methyl- tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl-hexadecyl, 16- methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl- eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro- octyl, 8- fluoro-nonyl, 9- fluoro-decyl, 10- fluoro-undecyl, 11- fluoro-(S)
• a derivative of cyclic cidofovir which includes an alkyl ester, wherein the alkyl is a CI 8-22 straight, branched, or cyclic alkyl or alkenyl having 1 to 6 double bonds.
• the compounds provided herein possess one or more chiral centers, e.g. in the sugar moieties, and may thus exist in optically active forms.
• 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 tr /w-isomers are contemplated herein. All such isomers as well as mixtures thereof are intended to be included within the scope of the compounds provided herein. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific 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.
• C. Preparation of the Compounds The alkyl ester derivatives of phosphonates for use in the compositions and methods provided herein can be prepared by alkyl esterification of various phosphonate compounds.
• a phosphonate compound (1 eq), an appropriate alkanol (2 eq) and triphenyl phosphine (2 eq) are mixed in anhydrous DMF. The mixture is stirred under nitrogen. Diisopropyl azadicarboxylate (2 eq) is then added in three portions over 15 min before the mixture is allowed to stir overnight. The solvent is then evaporated under vacuum, and the residue is purified by methods known in the art.
• the alkyl esters of cyclic cidofovir analogs provided herein can be converted to their corresponding acyclic analogs by procedures known in the art. For example, an alkyl-cCDN analog is suspended in 2 M ⁇ aOH (25 ml/mmol).
• compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with viral infections, inappropriet cell proliferation or bone metabolism and a pharmaceutically acceptable carrier.
• compositions contain one or more compounds provided herein.
• suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
• the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).
• effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical carrier.
• the compoimds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above.
• the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with associated with viral infections, inappropriate cell proliferation or bone metabolism.
• the compositions are formulated for single dosage administration.
• the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.
• the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
• the therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems well known to those of skill in the art and then extrapolated therefrom for dosages for humans.
• concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
• the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with viral infections, inappropriate cell proliferation or bone metabolism, as described herein.
• a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-
• the pharmaceutical compositions in another embodiment, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
• Pharmaceutical dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500mg, 1000 mg or 2000 mg, and in one embodiment from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
• the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data.
• concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
• methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.
• Derivatives of the compounds such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
• the resulting mixture may be a solution, suspension, emulsion or the like.
• the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
• the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
• the pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
• the pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit-dosage forms or multiple- dosage forms.
• Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
• unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof.
• a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
• a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
• the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
• nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
• auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate
• compositions for oral administration are either solid, gel or liquid.
• the solid dosage forms are tablets, capsules, granules, and bulk powders.
• Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric- coated, sugar-coated or film-coated.
• Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. a.
• Solid compositions for oral administration are solid dosage forms, in one embodiment, capsules or tablets.
• the tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating.
• binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste.
• Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
• Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
• Glidants include, but are not limited to, colloidal silicon dioxide.
• Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
• Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
• Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors.
• Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
• Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
• Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
• Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
• the compound, or pharmaceutically acceptable derivative thereof could be provided in a composition that protects it from the acidic environment of the stomach.
• the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
• the composition may also be formulated in combination with an antacid or other such ingredient.
• the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
• dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
• the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
• a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
• the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
• the active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
• tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. b.
• Liquid compositions for oral administration include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
• Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations.
• Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative.
• An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid.
• Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives.
• Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.
• Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide.
• Coloring and flavoring agents are used in all of the above dosage forms.
• Solvents include glycerin, sorbitol, ethyl alcohol and syrup.
• preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.
• non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
• emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
• Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Neegum and acacia.
• Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin.
• Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
• Organic acids include citric and tartaric acid.
• Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
• Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
• Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
• the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is in one embodiment encapsulated in a gelatin capsule.
• the solution e.g., for example, in a polyethylene glycol
• a pharmaceutically acceptable liquid carrier e.g., water
• liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
• formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid,
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• antioxidants
• formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal.
• Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.
• Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal. 2.
• solutions and emulsions Parenteral administration, in one embodiment characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• the injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol.
• the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
• a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross- linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is sunounded by an outer polymeric membrane, e.g., polyethylene, poly
• parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations.
• Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
• the solutions may be either aqueous or nonaqueous.
• suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
• Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
• aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and
• Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
• Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
• Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate.
• Antioxidants include sodium bisulfate.
• Local anesthetics include procaine hydrochloride.
• Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
• Emulsifying agents include Polysorbate 80 (TWEEN® 80).
• a sequestering or chelating agent of metal ions include EDTA.
• Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
• the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. Injectables are designed for local and systemic administration.
• a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, in certain embodiments more than 1% w/w of the active compound to the treated tissue(s).
• the compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
• the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
• the effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. 3.
• Lyophilized powders of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.
• the sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent.
• the solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent.
• the solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH.
• a buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH.
• sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation, hi one embodiment, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound.
• the lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature. Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier.
• Topical administration Topical mixtures are prepared as described for the local and systemic administration.
• the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
• the compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos.
• formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a micro fine powder for insufflation, alone or in combination with an inert carrier such as lactose.
• the particles of the formulation will, in one embodiment, have diameters of less than 50 microns, in one embodiment less than 10 microns.
• the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
• Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.
• Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
• the preparation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application.
• the carrier may contain solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic solutions, pH about 5-7, with appropriate salts. 5. Compositions for other routes of administration Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein. Transdermal patches, including iotophoretic and electrophoretic devices, are well known to those of skill in the art. For example, such patches are disclosed in U.S. Patent Nos.
• rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
• Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
• bases examples include cocoa butter (theobroma oil), glycerin- gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases maybe used.
• Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. 6.
• Targeted Formulations may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Patent Nos.
• liposomal suspensions including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S . Patent No. 4,522,811.
• liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. 7.
• PBS phosphate buffered saline lacking divalent cations
• the compounds or pharmaceutically acceptable derivatives may be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with viral infections, inappropriate cell proliferation or bone metabolism, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable derivative thereof, is used for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with viral infections, inappropriate cell proliferation or bone metabolism.
• the articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252.
• Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• a wide array of formulations of the compoimds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder associated with viral infections, inappropriate cell proliferation or bone metabolism.
• E. Evaluation of the activity of the compounds The activity of the compounds as antivirals can be measured in standard assays known in the art. Exemplary assays are described herein. Determination of antiviral activity and drug cytotoxicity
• a Values are the means of two or more assays ( ⁇ standard deviation)
• b SI CC 5( EC 5 o c Values in parentheses are the numbers of atoms beyond tlie phosphate oxygen.
• HCMV and MCMV Activity i) Cell cultures and viruses Human foreskin fibroblast (HFF) cells and mouse embryo fibroblast (MEF) cells are prepared as primary cultures and used in the HCMV and MCMV assays. Cells are propagated in minimal essential medium (MEM) containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U of penicillin per ml and 25 ⁇ g of gentamicin per ml in T-175 cm2 tissue culture flasks (BD Falcon, Bedford, Mass.) until used in antiviral assays. HCMV strain AD-169 and MCMV strain Smith are propagated by using standard virological techniques. (ii) Neutral red uptake assay for cytotoxicity.
• HFF cells are seeded into 96-well tissue culture plates at 2.5 x 104 cells/well. After a 24-h incubation, medium is replaced with MEM containing 2% FBS, and an alkyl ester provided herein is added to the first row and then diluted serially fivefold from 100 to 0.03 ⁇ M. The plates are incubated for 7 days, and cells are stained with neutral red and incubated for 1 h. Plates are shaken on a plate shaker for 15 min, and neutral red is solubilized with 1% glacial acetic acid-50% ethanol. The optical density is read at 540 nm. The concentration of drug that reduced cell viability by 50% (CC 50 ) is calculated by using computer software.
• HFF or MEF cells are placed into 6- or 12-well plates and incubated at 37°C for 2 days (HFF) or 1 day (MEF).
• Ganciclovir and CDN are used as positive controls.
• Virus is diluted in MEM containing 10% FBS to provide 20 to 30 plaques per well. The medium is aspirated, and 0.2 ml of virus is added to each well in triplicate with 0.2 ml of medium added to drug toxicity wells.
• Nd not determined a Values are the means of two or more assays ( ⁇ standard deviation) Values in parentheses are the numbers of atoms beyond the phosphate oxygen; the number after the colon is the number of double bonds in the alkyl chain. Data are recorded as the means ⁇ standard deviations of at least two determinations. Values without a standard deviation represent a single determination. SI, selective index F. Methods of use of the compounds and compositions Methods of treating, preventing, or ameliorating one or more symptoms of diseases associated with viral infections, inappropriate cell proliferation and bone metabolism using the compounds and compositions provided herein are provided. In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered.
• the methods provided herein are for the preventing, or ameliorating one or more symptoms of diseases associated with viral infections, including, but not limited to influenza; hepatitis B and C virus; cytomegalovirus (CMV); herpes infections, such as those caused by Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus, Herpes type 6 (HHV-6) and type 8 (HHV-8); Varicella zoster virus infections such as shingles or chicken pox; Epstein Barr virus infections, including, but not limited to infectious mononucleosis/glandular; retroviral infections including, but not limited to SIN, HIV-l and HIV-2; ebola virus; adeno virus and papilloma virus.
• viruses such as those caused by Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus, Herpes type 6 (HHV-6) and type 8 (HHV-8); Varicella zoster virus infections such
• the methods provided herein are for the preventing, treating, or ameliorating one or more symptoms of diseases associated with viral infections caused by orthopox viruses, such as variola major and minor, vaccinia, smallpox, cowpox, camelpox, and monkeypox.
• a therapeutically effective dosage to treat such an orthopox infection should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50- 100 ⁇ g/ml.
• the pharmaceutical compositions in another embodiment, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
• Pharmaceutical dosage unit forms are prepared, e.g., to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500mg, 1000 mg or 2000 mg, and in one embodiment from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
• the methods provided herein are for the preventing, or ameliorating one or more symptoms of diseases associated with cell proliferation, including, but not limited to cancers.
• cancers include, but are not limited to, lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, and skin cancer.
• Such diseases include, but are not limited to osteoporosis, such as senile, post-menopausal or steroid-induced osteoporosis, metastatic bone cancers, Paget's disease, osteogenesis imperfecta, fibrous dysplasia, rheumatoid arthritis, hyperparathyroidism, algodystrophy, sterno- costoclavicular hyperostosis, Gaucher's disease, Engleman's disease, certain non- skeletal disorders and periodontal disease.
• osteoporosis such as senile, post-menopausal or steroid-induced osteoporosis, metastatic bone cancers, Paget's disease, osteogenesis imperfecta, fibrous dysplasia, rheumatoid arthritis, hyperparathyroidism, algodystrophy, sterno- costoclavicular hyperostosis, Gaucher's disease, Engleman's disease, certain non- skeletal disorders and periodontal disease.
• an effective amount is an amount that will prevent, attenuate, or reverse abnormal or excessive bone resorption or the bone resorption that occurs in the aged, particularly post- menopausal females or prevent or oppose bone metastasis and visceral metastasis in breast cancer.
• the compounds and compositions provided herein may also be used in combination with other active ingredients, hi certain embodiments, the compounds may be administered in combination, or sequentially, with another therapeutic agent.
• Such other therapeutic agents include those known for treatment, prevention, or amelioration of one or more symptoms associated with viral infections, inappropriate cell proliferation and bone metabolism .
• Such therapeutic agents include, but are not limited to, antiviral agents, anti-neoplastic agents and agents for the treatment and/or prevention of symptoms associated bone metabolism.
• the compounds provided herein may be administered in combination with one or more antiviral agents or anti-cancer agents.
• Anti-cancer agents for use in combination with the instant compounds include, but are not limited to, alkylating agents, toxins, antiproliferative agents and tubulin binding agents.
• Classes of cytotoxic agents for use herein include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the pteridine family of drugs, diynenes, the maytansinoids, the epothilones, the taxanes and the podophyllotoxins .
• any suitable combination of the compounds provided herein with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present disclosure.
• the compound provided herein is administered prior to or subsequent to the one or more additional active ingredients.
• HG-400 spectrometer with teframethylsilane (internal) and 85% D3PO4 in D2O (external) as references for IH and 3 IP (0.00 ppm), respectively.
• Electrospray ionization mass spectroscopy (ESI) was performed by HT Laboratories (San Diego, Calif). Chromatographic purification was done by the flash method with Merck silica gel 60 (240 to 400 mesh). All final products were homogeneous by thin-layer chromatography performed on Analtech 250- ⁇ m Silica Gel GF Uniplates visualized under UN light, with phospray(Supelco, Bellafonte, Pa.), and by charring (400°C).
• Cyclic cidofovir dihydrate was prepared by the method of Louie and Chapman (Nucleosides & Nucleic Acids, 20:1099-1102, 2001). Bromoalkanes and bromoalkoxyalkanes were either commercially available or synthesized from the corresponding alcohol. All other chemicals were of reagent quality and used as obtained from the suppliers. All reactions were carried out in an inert atmosphere (dry nitrogen).
• EXAMPLE 8 Octyl cidofovir, sodium salt.
• the octyl cyclic CDVanalog was suspended in 2 M NaOH (25 ml/mmol). The suspensions was heated to 80°C and stirred for 1 h, during which the mixtures became clear. After hydrolysis, the solution was cooled to 25°C and acidified with glacial acetic acid (pH approximately 5). The resulting precipitate was collected by vacuum filtration and dried under vacuum. The crude product was purified either by flash column chromatography (eluant, CH2C12-20% MeOH) and recrystallized to purity from ethanol (2).

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• 2005
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