US20080261913A1 - Compounds and pharmaceutical compositions for the treatment of liver disorders - Google Patents

Compounds and pharmaceutical compositions for the treatment of liver disorders Download PDF

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US20080261913A1
US20080261913A1 US12/005,938 US593807A US2008261913A1 US 20080261913 A1 US20080261913 A1 US 20080261913A1 US 593807 A US593807 A US 593807A US 2008261913 A1 US2008261913 A1 US 2008261913A1
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compound
alkyl
optionally substituted
aryl
amino
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Jean-Pierre Sommadossi
Gilles Gosselin
Claire Pierra
Christian Perigaud
Suzanne Peyrottes
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Centre National de la Recherche Scientifique CNRS
Universite de Montpellier
Idenix Pharmaceuticals LLC
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Universite de Montpellier
Idenix Pharmaceuticals LLC
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Assigned to L'UNIVERSITE MONTPELLIER II reassignment L'UNIVERSITE MONTPELLIER II ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PERIGAUD, CHRISTIAN
Assigned to IDENIX PHARMACEUTICALS, INC. reassignment IDENIX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SOMMADOSSI, JEAN-PIERRE
Assigned to IDENIX PHARMACEUTICALS, INC. reassignment IDENIX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PIERRA, CLAIRE
Assigned to IDENIX PHARMACEUTICALS, INC. reassignment IDENIX PHARMACEUTICALS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE DOCKET NUMBER PREVIOUSLY RECORDED ON REEL 021170 FRAME 0381. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST. Assignors: PIERRA, CLAIRE
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Definitions

  • the present invention relates to compounds, methods and pharmaceutical compositions, for use in treatment and prevention of disorders of the liver, including cancer.
  • Drug induced toxicities and pharmacological side effects are often associated with interactions by the drug or drug metabolite in tissues not associated with the pharmacological benefits of the drug therapy. In other cases, the desired pharmacological effect is poorly achieved either because of dose-limiting toxicities or inadequate drug levels in the target tissues.
  • High organ specificity can be achieved by a variety of mechanisms including local administration to the target organ and drug-protein conjugates. Local administration to the target organ is an invasive procedure. Drug-protein conjugates exhibit poor oral bioavailability, limitations in carrier manufacturing and drug loading, a potential for diminished liver uptake due to down regulation of the receptor in diseased tissue, and a high incidence of antibody induction.
  • a third approach entails use of prodrugs that are activated by enzymes highly enriched in the target organ.
  • Phosphoroamidate and phosphonoamidate compound forms of a variety of therapeutic agents are provided, as well as methods for their manufacture and use in the treatment of a variety of disorders including liver cancer, inflammation, fibrosis and metabolic disorders.
  • the compound is a S-pivaloyl-2-thioethyl phosphoroamidate, S-pivaloyl-2-thioethyl phosphonoamidate, S-hydroxypivaloyl-2-thioethyl phosphoroamidate or S-hydroxypivaloyl-2-thioethyl phosphonoamidate.
  • a “phosphoroamidate or phosphonoamidate compound of a therapeutic agent” includes a therapeutic agent derivatized to include a phosphoroamidate or phosphonoamidate group.
  • the therapeutic agent is, for example, an anti-cancer agent that includes, or has been derivatized to include, a reactive group, such as a hydroxyl, for attachment of the phosphoroamidate or phosphonoamidate moiety.
  • Such therapeutic agents include, but are not limited to nucleosides and nucleoside analogs including acyclic nucleosides.
  • phosphoroamidate or phosphonoamidate compounds of nucleotides and nucleotide analogs such as 2′-branched and 4′-branched nucleosides are provided.
  • Such compounds can be administered in an effective amount for the treatment of liver disorders, including cancer.
  • the parent drug is obtained from selective metabolism of the phosphoroamidate or phosphonoamidate compound in the liver and thus the parent drug provided herein is capable of accumulating in the liver. Accordingly, provided are methods of directing phosphoroamidate or phosphonoamidate compounds disclosed herein to the liver.
  • phosphoroamidate or phosphonoamidate compounds of pharmaceutical agents for the treatment of a liver disorder can be made and used therapeutically as described herein.
  • a variety of phosphoroamidate or phosphonoamidate compounds can be used in the treatment of liver disorders.
  • therapeutic agents for the treatment of liver cancer can be derivatized to form a phosphoroamidate or phosphonoamidate compound as described herein, and used for the treatment of liver cancers.
  • Liver cancers that can be treated include benign tumors, malignant tumors, hemangioma, hepatic adenomas, focal nodular hyperplasia, hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinomas, bile duct cancers, and other primary and metastatic cancers of the liver.
  • Phosphoroamidate and phosphonoamidate compounds of a variety of therapeutic agents are provided.
  • the compounds can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver.
  • the compound comprises an S-acyl-2-thioethyl phosphoroamidate or an S-acyl-2-thioethyl phosphonoamidate derivative, e.g., a S-pivaloyl-2-thioethyl phosphoroamidate or a S-hydroxypivaloyl-2-thioethyl phosphonoamidate derivative.
  • the phosphoroamidate or phosphonoamidate compounds, as well as salts thereof, and compositions comprising the compounds, provided herein are useful for treatment of disorders of the liver, including cancer.
  • the phosphoroamidate or phosphonoamidate compounds, as well as salts thereof, and compositions comprising the compounds, provided herein are useful for treatment of metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • the compounds, as well as salts thereof, and compositions comprising the compounds, provided herein are useful for treatment of liver fibrosis and inflammation.
  • the compound provided herein is a compound of Formula I:
  • Z is O or S
  • each W is independently O or S;
  • R y and R u each independently represent alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring;
  • R 1 is a moiety derivable by removal of a hydrogen from a group, such as a hydroxy group, of a therapeutic agent such as an anti-cancer drug.
  • Z is O, S, NH or NR w , where R w is, e.g., alkyl, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted;
  • each W is O, S, NH or NR w , where R w is, e.g., alkyl, alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted;
  • R y and R u each independently represent alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, alkoxy, heterocyclyl, or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring;
  • R 1 is a moiety derivable by removal of a hydrogen from a group, such as a hydroxy group, of a therapeutic agent such as an anti-cancer drug.
  • compounds of Formula I can be designed or prepared by reaction, e.g., at a hydroxy group of said drug, for example via condensation or dehydration.
  • exemplary substituents, such as R 1 groups are identified as a drug in a phosphoroamidate or phosphonoamidate compound, e.g. in a formula
  • the compound comprises a derivative, e.g. a radical of the anti-cancer drug.
  • Those derivatives can for example be prepared by elimination of a hydrogen radical from a hydroxy group of the drug, for instance in a dehydration reaction.
  • R 1 is a nucleoside comprising a cyclic or acyclic sugar or an analog thereof.
  • R 1 is an anti-cancer drug selected from clarubicin, decitabine, daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin, etoposide, fludarabine, 7-hydroxychlorpromazin, neplanocin A, podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin, vindesin, etoposide, teniposide, NK-611, camptothecin, irinotecan, 9-aminocamptothecin, GG-211, topotecan, paclitaxel, Azatoxin, coformycin, pirarubicin, nelarabine and losoxantrone.
  • clarubicin clarubicin, decitabine, daunorubicin, dihydro-5-azacytidine
  • doxorubicin epirubicin
  • R 1 is an immunosuppressant, such as pentostatin, combretastatin A-4, mycophenolic acid or mitoxantrone.
  • R y is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R y is —OR c , —C(R c ) 3 or —NHR c where each R c is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R a and R b are independently benzyl or substituted alkyl.
  • R y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R y is —C(CH 3 ) 2 CH 2 OH.
  • the compounds provided herein are selected such that R 1 is not 3′-azido-2′,3′-dideoxythymidine.
  • the compound provided herein is a compound of Formula IIa or IIb:
  • R y is alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, heterocyclyl or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R 1 is a drug such as an anti-cancer drug.
  • R y is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R a and R b are each independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R y is —OR c , —C(R c ) 3 or —NHR c where each R c is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R a and R b are each independently benzyl or substituted alkyl. In a further embodiment, R y is selected from the group consisting of alkyl and hydroxyalkyl. In certain embodiments, R y is —C(CH 3 ) 2 CH 2 OH.
  • provided herein are:
  • phosphoroamidate and phosphonoamidate formulas and compounds are provided, which optionally act as thyroid hormone receptor effectors:
  • each R if present, is independently alkyl, halogen or hydroxyl
  • X if present, is CH 2 , O or S;
  • R y is optionally substituted alkyl, wherein the substituted alkyl is optionally hydroxyalkyl or aminoalkyl, e.g., —C(CH 3 ) 2 CH 2 OH; and
  • R a and R b are independently hydrogen; unsubstituted alkyl; or alkyl substituted with aryl, amino, amido, hydroxyl, alkoxy, aminoalkyl, hydroxyalkyl, aryl, or heteroaryl, each optionally substituted; wherein, in one embodiment, R a and R b are independently H or a benzyl that is optionally substituted, for example, with hydroxy or amino.
  • R a is hydrogen
  • R b is —CH 2 —C 6 H 5
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • the thyroid hormone receptor effector compound provided herein has a formula selected from:
  • R x and R z are each independently hydrogen or alkyl
  • R w is alkyl
  • R y is alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, heterocyclyl or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring.
  • the thyroid hormone receptor effector provided herein is selected from:
  • R a is hydrogen
  • R b is —CH 2 —C 6 H 5
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • the compound or Formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b is derived from a phosphonate compound useful for inhibiting gluconeogenesis, optionally by inhibiting the enzyme fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the compound or Formula selected from IXa or b, Xa or b, XIa or b, XIIa or b, XIIIa or b and XIVa or b is derived from a compound useful for inhibiting gluconeogenesis, optionally by inhibiting the enzyme fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the compound or Formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b is a phosphonic acid-containing compound that binds to a thyroid receptor in the liver, and is optionally an agonist, antagonist, partial agonist or partial antagonist of T3. Inhibition of gluconeogenesis can result in blood glucose lowering in diabetic subjects. Such compounds can exhibit enhanced pharmacokinetics including oral bioavailability and liver drug levels.
  • a method of treatment of a subject in need thereof comprising administering to the subject a phosphoroamidate and phosphonoamidate compound or Formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b, IXa or b, X a or b, XIa or b, XIIa or b, XIIIa or b and XIVa or b or a pharmaceutically acceptable salt, enantiomer, ester or prodrug thereof, in an amount effective for one or more of the following:
  • thyroid disease thyroid cancer
  • depression glaucoma
  • cardiac arrhythmias heart failure
  • osteoporosis treating thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis
  • lipids e.g., cholesterol
  • glucose e.g., glucose
  • lipoproteins e.g., glucose
  • triglycerides e.g., glucose
  • T3-responsive genes e.g., T3-responsive genes
  • the compounds do not affect thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and/or the ratio of T3 to T4.
  • compositions comprising the compounds, e.g., in a dosage unit suitable for administration, e.g., oral administration.
  • FIG. 1 depicts depletion of B184 (NM108 hydroxySATE phosphoroamidate) after incubation with and without NADPH in monkey liver S9.
  • FIG. 2 depicts depletion of B102 (NM107 hydroxySATE phosphoroamidate) after incubation with and without NADPH in monkey liver S9.
  • liver disorders such as cancer
  • metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • dosage forms useful for such methods.
  • alkyl includes a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically C 1 to C 10 , and specifically includes methyl, CF 3 , CCl 3 , CFCl 2 , CF 2 Cl, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, cyclopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the term includes both substituted and unsubstituted alkyl groups, and particularly includes halogenated alkyl groups, and even more particularly fluorinated alkyl groups.
  • moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • lower alkyl includes a C to C 4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted moieties.
  • Alkylene includes divalent saturated aliphatic hydrocarbon groups particularly having up to about 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), the propylene isomers (e.g., —CH 2 CH 2 CH 2 — and —CH(CH 3 )CH 2 —) and the like.
  • Alkenyl includes monovalent olefinically unsaturated hydrocarbon groups, in certain embodiment, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation.
  • alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl (—C(CH 3 ) ⁇ CH 2 ), vinyl and substituted vinyl, and the like.
  • Alkenylene includes divalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (—CH ⁇ CH—), the propenylene isomers (e.g., —CH ⁇ CHCH 2 — and —C(CH 3 ) ⁇ CH— and —CH ⁇ C(CH 3 )—) and the like.
  • Alkynyl includes acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of alkynyl unsaturation.
  • alkynyl groups include acetylenic, ethynyl (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
  • aryl includes phenyl, biphenyl, or naphthyl, and preferably phenyl.
  • the term includes both substituted and unsubstituted moieties.
  • the aryl group can be substituted with any described moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), alkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991.
  • Alkoxy includes the group —OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkoxycarbonyl includes a radical —C(O)-alkoxy where alkoxy is as defined herein.
  • Amino includes the radical —NH 2 .
  • Carboxyl includes the radical —C(O)OH.
  • alkylamino or “arylamino” includes an amino group that has one or two alkyl or aryl substituents, respectively. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.
  • Halogen or “halo” includes chloro, bromo, fluoro or iodo.
  • “Monoalkylamino” includes the group alkyl-NR′—, wherein R′ is selected from hydrogen and alkyl.
  • Thioalkoxy includes the group —SR where R is alkyl.
  • protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • “Pharmaceutically acceptable salt” includes any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g.
  • alkaryl or “alkylaryl” includes an aryl group with an alkyl substituent.
  • aralkyl or arylalkyl includes an alkyl group with an aryl substituent.
  • purine or “pyrimidine” base includes, but is not limited to, adenine, N 6 -alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C
  • Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • acyl or “O-linked ester” includes a group of the formula C(O)R′, wherein R′ is an straight, branched, or cyclic alkyl (including lower alkyl), carboxylate reside of amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, sulfonate esters such as alkyl or arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl
  • Aryl groups in the esters optimally comprise a phenyl group.
  • acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, ⁇ -methoxy- ⁇ -trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluor
  • amino acid includes naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.
  • the amino acid is in the L-configuration.
  • the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl, ⁇ -serinyl, ⁇ -threoninyl, ⁇ -cysteinyl
  • nucleoside composition that includes at least 85 or 90% by weight, preferably 95%, 98%, 99% or 100% by weight, of the designated enantiomer of that nucleoside.
  • the compounds are substantially free of enantiomers.
  • nucleoside composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
  • Solidvate includes a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the terms “subject” and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human.
  • the subject is refractory or non-responsive to current treatments for cancer.
  • the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat).
  • the subject is a human.
  • terapéutica agent refers to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof.
  • therapeutic agent includes a compound provided herein.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.
  • “Therapeutically effective amount” includes an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • a “therapeutically effective amount” can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the disease or disorder.
  • prophylactic agent and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof.
  • the term “prophylactic agent” includes a compound provided herein.
  • the term “prophylactic agent” does not refer a compound provided herein.
  • a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to the prevent or impede the onset, development, progression and/or severity of a disorder.
  • prophylactically effective amount includes the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder (, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
  • a therapy e.g., prophylactic agent
  • another therapy e.g., another prophylactic agent
  • Phosphoroamidate and phosphonoamidate compounds of a variety of therapeutic agents can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver.
  • the compound is an S-acyl-2-thioethyl phosphoroamidate or an S-acyl-2-thioethyl phosphonoamidate derivative, e.g., a S-pivaloyl-2-thioethyl phosphoroamidate or a S-hydroxypivaloyl-2-thioethyl phosphonoamidate.
  • Therapeutic agents that can be derivatized to compound form include an anti-cancer agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoroamidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides.
  • Phosphoroamidate or phosphonoamidate compound forms of a variety of nucleosides can be formed from nucleosides disclosed herein and available in the art.
  • anti-cancer nucleosides can be derivatized to form a phosphoroamidate or phosphonoamidate compound that can enhance delivery to the liver.
  • the phosphoroamidate or phosphonoamidate compound provided herein is a compound of formula IIa or IIb:
  • R y is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R 1 is a drug such as an anti-cancer drug.
  • the compound of formula IIa or IIb is selected with a proviso that when R y is tert-butyl or hydroxy-tert-butyl, then R 1 is not 3′-azido-2′,3′-dideoxythymidine.
  • R 1 , R a , R b and R y are optionally substituted with one or more substituents as defined herein, e.g., in the definitions.
  • the compounds are of Formula IIa or IIb, wherein R y is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heterocyclyl or heteroaryl;
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; and
  • R 1 is an anti-cancer drug.
  • R 1 or R 1 —CH 2 — is a nucleoside comprising a cyclic or acyclic sugar or analog thereof, including any nucleoside or analogue thereof described herein or known in the art.
  • R y is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R y is —OR c , —C(R c ) 3 or —NHR c where each R c is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl. In a further embodiment, R a and R b are independently benzyl or substituted alkyl. In a further embodiment, R y is selected from the group consisting of alkyl and hydroxyalkyl.
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • R 2 and R 3 are each hydrogen, R a is hydrogen, R b is —CH 2 —C 6 H 5 and R y is —C(CH 3 ) 2 CH 2 OH.
  • R y is alkyl or hydroxyalkyl. In one embodiment, R y is methyl, tert-butyl, hydroxy-tert-butyl or hydroxyethyl. In certain embodiments, R y is —C(CH 3 ) 2 CH 2 OH.
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl or arylalkyl, wherein the alkyl groups can be further substituted with one or more substitutents.
  • at least one of R a or R b is other than hydrogen.
  • R a and R b are each independently hydrogen, methyl or benzyl.
  • R y is —C(CH 3 ) 2 CH 2 OH and R a and R b are each independently hydrogen, methyl or benzyl. In certain embodiments, R y is —C(CH 3 ) 2 CH 2 OH and R a is hydrogen and R b is benzyl.
  • the compound provided herein is a compound of formula:
  • R 1 and R y are as defined in formula IIa or IIb.
  • R y is alkyl or hydroxyalkyl.
  • R y is methyl, tert-butyl, hydroxy-tert-butyl or hydroxyethyl.
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • R y is substituted alkyl, e.g. hydroxyalkyl or aminoalkyl.
  • R y is —OR c , —C(R c ) 3 or —NHR c where each R c is independently alkyl, substituted alkyl, aryl or substituted aryl, for instance hydroxy- or amino-substituted alkyl or aryl.
  • R y is selected from the group consisting of alkyl and hydroxyalkyl.
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • the compound provided herein is a compound of formula:
  • R 1 is an anti-cancer drug, such as a nucleoside or nucleoside derivative
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; and
  • R a and R b is H and the other is alkyl optionally substituted with aryl, benzyl, or heteroaryl, each optionally substituted.
  • R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl, for instance hydroxy- or amino-substituted alkyl or benzyl.
  • R a and R b are independently benzyl or substituted alkyl.
  • the compound provided herein is a compound of formula:
  • R 1 is a drug such as an anti-cancer drug.
  • anti-cancer drugs that can be derivatized as described herein, for example via a free hydroxyl group, or after adding a hydroxylated linker, are:
  • immunosupressant drugs that can be derivatized as described herein are:
  • R 1 is an anti-cancer drug such as aclarubicin, decitabine, daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin, etoposide, fludarabine, 7-hydroxychlorpromazin, neplanocin A, podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin, vindesin, etoposide, teniposide, NK-611, camptothecin, irinotecan, 9-aminocamptothecin, GG-211, topotecan, paclitaxel, azatoxin, coformycin, pirarubicin and losoxantrone.
  • the anti-cancer drug is camptothecin or azotoxin.
  • R 1 is a purine nucleoside analog (see, e.g., Robak et al., Curr. Med. Chem. 2006, 13, 3165-3189).
  • R 1 is, for example, a cytotoxic agent such as fludarabine (9- ⁇ -D-arabinofuranosyl-2-fluoradenine), cladribine (2-chloro-2′-deoxyadenosine, CldA), pentostatin (2′-deoxycoformycin, DCF), clofarabine (CAFdA), nelabarine, immucillin H (BCX-1777, forodesine) or 8-chloroadenosine (8-Cl-Ado).
  • fludarabine (9- ⁇ -D-arabinofuranosyl-2-fluoradenine
  • cladribine (2-chloro-2′-deoxyadenosine, CldA
  • pentostatin (2′-deoxycoformycin
  • DCF
  • the anti-cancer drug also can be (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene- ⁇ -D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1- ⁇ -D-arabino-pentofuranosyl)cytosine (CNDAC) or 1-(3-C-ethynyl- ⁇ -D-ribo-pentofuranosyl)cytosine (ECyd).
  • SMDC 2-deoxy-2′-C-methylcytidine
  • DMDC 1-(2-deoxy-2-methylene- ⁇ -D-erythro-pentofuranosyl)cytosine
  • CNDAC 1-(2-C-cyano-2-deoxy-1- ⁇ -D-arabino-pentofuranosyl)cytosine
  • ECyd 1-(3-C-ethynyl- ⁇ -D-ribo-pentofur
  • R 1 is an immunosuppressant, such as combretastatin A-4, mycophenolic acid, pentostatin or mitoxantrone.
  • the anti-cancer drug can be derivatized to include the phosphoroamidate or phosphonoamidate at, e.g., a free OH or free carboxy group.
  • R 1 is ( ⁇ )-2′-Deoxy-3′-oxacytidine (BCH-4556, Troxacitabine):
  • R 1 is tezacitabine (2′-fluoromethylene-2′-deoxycytidine).
  • R 1 is a 5′-aza-pyrimidine, such as 5′-aza-cytidine, 5′-azadeoxycytidine (decytabine), or trasrabine.
  • R 1 is a 2′-deoxy-2′-methylidenepyrimidine nucleoside compound, disclosed, e.g. in U.S. Pat. No. 5,401,726, such as 2′-deoxy-2′-methylidene-5-fluorocytidine, 2′-deoxy-2′-methylidene-5-chlorocytidine, 2′-deoxy-2′-methylidene-5-bromocytidine, 2′-deoxy-2′-methylidene-5-iodocytidine, 2′-deoxy-2′-methylidene-5-methylcytidine, 2′-deoxy-2′-methylidene-5-ethylcytidine, 2′-deoxy-2′-methylidene-5-ethylcytidine, 2′-deoxy-2′-methylidene-5-ethyluridine, 2′-deoxy-2′-methylidene-5-ethynyluridine or 2′-deoxy-2′-methyl
  • R 1 also can be a pyrido[2,3-D]pyrimidine or pyrimido[4,5-D]pyrimidine nucleoside as described in U.S. Pat. No. 7,081,449, such as 4-amino-5-oxo-8-(4-C-hydroxymethyl- ⁇ -D-ribofuranosyl)pyrido-[2,3d]pyrimidine; 4-amino-5-oxo-8-(5(R)—C-methyl- ⁇ -D-ribofuranosyl)pyrido[2,3-d]pyrimidine; 4-amino-5-oxo-8-(5(R)—C-allyl- ⁇ -D-ribofuranosyl)pyrido[2,3-d]pyrimidine; 4-amino-5-oxo-8-(5(R,S)—C-ethynyl- ⁇ -D-ribofuranosyl)pyrido[2,3-d]pyrimidine; 4-Amino-5-
  • anti-cancer drugs include: dichloroacetal, Nexavar (sorafenib), cimetidine, adriamycin, Cytoxan (cyclophosphamide), methotrexate, vincristine, and 6-mercaptopurine.
  • the anti-cancer drug is selected from 2′,3-dideoxyinosine (ddl), or 2,3-didehydro-3-deoxythymidine (d4T). See, e.g., WO/2006/125166.
  • R 1 is an anti-inflammatory drug, such as a corticosteroid or a non-steroidal anti-inflammatory drugs (NSAID) that can be derivatized to include the phosphoroamidate or phosphonoamidate at, e.g., a free OH or free carboxy group.
  • NSAID non-steroidal anti-inflammatory drugs
  • corticosteroid drugs suitable for use herein are provided below:
  • NSAID drugs suitable for use herein are provided below:
  • compounds of Formula IIa are phosphonoamidates of an acyclic nucleoside phosphonate that have potential anti-cancer activity, such as (S)-9-[3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine (HPMPC, cidofovir), (S)-9- ⁇ 3-hydroxy-2-(phosphonomethoxy)-propyl]adenine ((S)-HPMPA), phosphonomethoxyethylguanine (PMEG), phosphonomethoxyethyl-adenine (PMEA, adefovir), phosphonomethoxy-propyladenine (PMPA, tenofovir), acyclovir, ganciclovir or penciclovir.
  • HPMPC cidofovir
  • S 9- ⁇ 3-hydroxy-2-(phosphonomethoxy)-propyl]adenine
  • (S)-HPMPA) phosphonomethoxyethylguanine
  • phosphoroamidate and phosphonoamidate formulas and compounds are provided, which optionally act as thyroid hormone receptor effectors:
  • each R if present, is independently alkyl, halogen or hydroxyl
  • X if present, is CH 2 , O or S;
  • R y is alkyl, alkenyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl, amino, aminoalkyl, heterocyclyl or heteroaryl, all optionally substituted;
  • R a and R b are selected as follows:
  • R a and R b are each independently hydrogen, alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, aryl alkyl, cycloalkyl, heteroaryl or heterocyclyl, all optionally substituted; or
  • R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring.
  • the compound provided herein has formula selected from IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa or VIIIb, wherein
  • each R if present, is independently alkyl, halogen or hydroxyl
  • X if present, is CH 2 , O or S;
  • R y is optionally substituted alkyl, wherein the substituted alkyl is optionally hydroxyalkyl or aminoalkyl, e.g., —C(CH 3 ) 2 CH 2 OH; and
  • R a and R b are independently hydrogen; unsubstituted alkyl; or alkyl substituted with aryl, amino, amido, hydroxyl, alkoxy, aminoalkyl, hydroxyalkyl, aryl, or heteroaryl, each optionally substituted; wherein, in one embodiment, R a and R b are independently H or a benzyl that is optionally substituted, for example, with hydroxy or amino; and
  • the compound provided herein has a formula selected from:
  • R x and R z are each independently hydrogen or alkyl
  • R w is alkyl
  • X 1 is O or S
  • R y is optionally substituted alkyl, wherein the substituents when present are selected from hydroxy and amino;
  • R a and R b are each independently hydrogen or optionally substituted alkyl; where the substituents when present are selected from one or more, in one embodiment, one, two or three groups selected from aryl, amino, amido, hydroxyl, alkoxy, aryl and heteroaryl, each optionally substituted with hydroxy or amino.
  • the compound provided herein is selected from:
  • R x and R z are each hydrogen.
  • R w is alkyl.
  • R w is isopropyl.
  • R y is optionally substituted alkyl, wherein the substituents when present are selected from hydroxy and amino.
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • R a and R b are each independently hydrogen or optionally substituted alkyl; where the substituents when present are selected from one or more, in one embodiment, one, two or three groups selected from aryl, amino, amido, hydroxyl, alkoxy, aryl and heteroaryl, each optionally substituted with hydroxy or amino.
  • R a is hydrogen and R b is benzyl.
  • R a is hydrogen
  • R b is —CH 2 —C 6 H 5
  • R y is —C(CH 3 ) 2 CH 2 OH.
  • the thyroid receptor effector compound has formula:
  • the compound or Formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b is derived from a phosphonate compound useful for inhibiting gluconeogenesis, optionally by inhibiting the enzyme fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the compound or Formula selected from IXa or b, X a or b, XIa or b, XIIa or b, XIIIa or b, XIVa or b and XVIIIa or b is derived from a compound useful for inhibiting gluconeogenesis, optionally by inhibiting the enzyme fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the compound or Formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b is a phosphonic acid-containing compound that binds to a thyroid receptor in the liver, and is optionally an agonist, antagonist, partial agonist or partial antagonist of T3. Inhibition of gluconeogenesis can result in blood glucose lowering in diabetic subjects. Such compounds can exhibit enhanced pharmacokinetics including oral bioavailability and liver drug levels.
  • a method of treatment of a subject in need thereof comprising administering to the subject a phosphoroamidate and phosphonoamidate compound or formula selected from IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b, VIII a or b, IXa or b, X a or b, XIa or b, XIIa or b, XIIIa or b, XIVa or b and XVIIIa or b or a pharmaceutically acceptable salt, enantiomer, ester or prodrug thereof thereof, in an amount effective for one or more of the following:
  • thyroid disease thyroid cancer
  • depression glaucoma
  • cardiac arrhythmias heart failure
  • osteoporosis treating thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis
  • lipids e.g., cholesterol
  • glucose e.g., glucose
  • lipoproteins e.g., glucose
  • triglycerides e.g., glucose
  • T3-responsive genes e.g., T3-responsive genes
  • the compounds do not affect thyroid function, thyroid production of circulating iodinated thyronines such as T3 and T4, and/or the ratio of T3 to T4.
  • provided herein is a method for treatment of liver fibrosis or inflammation by administering a compound provided herein.
  • compositions comprising the compounds, e.g., in a dosage unit suitable for administration, e.g., oral administration.
  • optically active materials examples include at least the following.
  • compounds provided herein can be prepared by coupling alcohols and H-phosphonate monoesters as illustrated in the reaction scheme below:
  • R 7 , R 8 , R 9 , R 10 are each independently hydrogen, hydroxy, alkyl or alkoxy. Any reactive function on R y , R 7 , R 8 , R 9 , R 10 or on the base should be protected during the coupling reaction. Any coupling agent known to one of skill in the art can be used.
  • Exemplary coupling agents for use in the reaction include, but are not limited to HOBt (N-Hydroxybenzotriazole), HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate), DCC (N,N′-dicyclohexylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) and others known to one of skill in the art.
  • HOBt N-Hydroxybenzotriazole
  • HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate
  • DCC N,N′-dicyclo
  • R H, Tr, MMTr or DMTr in case of reactive amine
  • R 1 , R 2 , R 4 , R 6 H, alkyl or halo
  • R 3 /R 5 are both H or isopropylidene.
  • nucleosides and analogs thereof and prodrugs thereof can be prepared according to methods known to one of skill in the art. Exemplary nucleosides and analogs are described in International Publication No. WO 06/125166, contents of which are hereby incorporated by reference in their entireties.
  • the compounds of formula IIIa or b, IVa or b, Va or b, VIa or b, VIIa or b and VIII a or b can be prepared by methods described herein and methods known to one of skill in the art, for example, see, Erion et al., Proc. Natl. Acad. Sci., 2007, 104, 15490-15495.
  • the compounds of formula IXa or b, X a or b, XIa or b, XIIa or b, XIIIa or b, XIVa or b and XVIIIa or b can be prepared by methods described herein and methods known to one of skill in the art, for example, see, Dang et al., Discovery of Potent and Specific Fructose-1,6-Bisphosphatase Inhibitors and a Series of orally-Bioavailable Phosphoramidase-Sensitive Prodrugs for the Treatment of Type 2 Diabetes, J. Am. Chem. Soc., 2007, Vol. 129, No. 50, pp. 15491-502.
  • Compounds can be assayed for accumulation in liver cells of a subject according to any assay known to those of skill in the art.
  • a compound can be administered to the subject, and a liver cell of the subject can be assayed for the compound or a derivative thereof.
  • a phosphoroamidate or phosphonoamidate nucleoside compound is administered to cells, such as liver cells, in vivo or in vitro, and the levels delivered intracellularly are measured, to indicate delivery of the compound in the cell.
  • Assays for other activities, including anti-cancer activity can be done as described in the art. Suitable in vitro assays can be used to preliminarily evaluate the efficacy of a compound in inhibiting growth of cancer cells. The compound can further be examined for its efficacy in treating cancer by in vivo assays known to those of skill in the art. For example, it can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effect can then assessed. Based on the results, an appropriate dosage range and administration route can also be determined. Exemplary assays are described in the paragraphs below.
  • Compounds provided herein can be shown to inhibit tumor cell proliferation, cell transformation and tumorigenesis in vitro and in vivo using a variety of assays known in the art, or described herein.
  • Such assays can use cells of a cancer cell line, or cells from a patient.
  • Many assays well-known in the art can be used to assess such survival and/or growth; for example, cell proliferation can be assayed by measuring ( 3 H)-thymidine incorporation, by direct cell count, by detecting changes in transcription, translation or activity of known genes such as proto-oncogenes (e.g., fos, myc) or cell cycle markers (Rb, cdc2, cyclin A, D1, D2, D3, E, etc.).
  • proto-oncogenes e.g., fos, myc
  • cell cycle markers Rb, cdc2, cyclin A, D1, D2, D3, E, etc.
  • protein can be quantitated by known immunodiagnostic methods such as Western blotting or immunoprecipitation using commercially available antibodies (for example, many cell cycle marker antibodies are available from Santa Cruz Biotechnology, Inc., Santa Cruz, Calif.).
  • mRNA can be quantitated by methods that are well known and routine in the art, for example, by Northern analysis, RNase protection, and the polymerase chain reaction in connection with the reverse transcription.
  • Cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art. Differentiation can be assessed, for example, visually based on changes in morphology, etc.
  • Cell proliferation analysis can be performed using a variety of techniques known in the art, including but not limited to the following:
  • bromodeoxyuridine (BRDU) incorporation may be used as an assay to identify proliferating cells.
  • the BRDU assay identifies a cell population undergoing DNA synthesis by incorporation of BRDU into newly synthesized DNA. Newly synthesized DNA can then be detected using an anti-BRDU antibody (see Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107, 79).
  • Cell proliferation can also be examined using (3H)-thymidine incorporation (see e.g., Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem. 270:18367-73).
  • This assay allows for quantitative characterization of S-phase DNA synthesis.
  • cells synthesizing DNA incorporate (3H)-thymidine into newly synthesized DNA.
  • Incorporation can then be measured using standard techniques in the art such as by counting of radioisotope in a Scintillation counter (e.g. Beckman LS 3800 Liquid Scintillation Counter).
  • PCNA proliferating cell nuclear antigen
  • Cell proliferation can be measured by counting samples of a cell population over time (e.g. daily cell counts). Cells may be counted using a hemacytometer and light microscopy (e.g. HyLite hemacytometer, Hausser Scientific). Cell number may be plotted against time in order to obtain a growth curve for the population of interest. In a preferred embodiment, cells counted by this method are first mixed with the dye Trypan-blue, such that living cells exclude the dye, and are counted as viable members of the population.
  • a hemacytometer and light microscopy e.g. HyLite hemacytometer, Hausser Scientific
  • DNA content and/or mitotic index of the cells can be measured, for example, based on the DNA ploidy value of the cell.
  • cells in the GI phase of the cell cycle generally contain a 2N DNA ploidy value.
  • Cells in which DNA has been replicated but have not progressed through mitosis e.g. cells in S-phase
  • Ploidy value and cell-cycle kinetics can be further measured using propidum iodide assay (see e.g. Turner, T., et al., 1998, Prostate 34:175-81).
  • the DNA ploidy can be determined by quantitation of DNA Feulgen staining (which binds to DNA in a stoichiometric manner) on a computerized microdensitometrystaining system (see e.g., Bacus, S., 1989, Am. J. Pathol. 135:783-92).
  • DNA content can be analyzed by preparation of a chromosomal spread (Zabalou, S., 1994, Hereditas. 120:127-40; Pardue, 1994, Meth. Cell Biol. 44:333-351).
  • cell-cycle proteins e.g., CycA, CycB, CycE, CycD, cdc2, Cdk4/6, Rb, p21, p27, etc.
  • identification in an anti-proliferation signaling pathway can be indicated by the induction of p21.
  • Increased levels of p21 expression in cells results in delayed entry into G1 of the cell cycle (Harper et al., 1993, Cell 75:805-816; Li et al., 1996, Curr. Biol. 6:189-199).
  • p21 induction can be identified by immunostaining using a specific anti-p21 antibody available commercially (e.g.
  • cell-cycle proteins may be examined by Western blot analysis using commercially available antibodies.
  • cell populations are synchronized prior to detection of a cell cycle protein.
  • Cell cycle proteins can also be detected by FACS (fluorescence-activated cell sorter) analysis using antibodies against the protein of interest.
  • Detection of changes in length of the cell cycle or speed of cell cycle can also be used to measure inhibition of cell proliferation by the compounds provided herein.
  • the length of the cell cycle is determined by the doubling time of a population of cells (e.g., using cells contacted or not contacted with one or more compounds identified using the pharmacophores of the present invention).
  • FACS analysis is used to analyze the phase of cell cycle progression, or purify G1, S, and G2/M fractions (see e.g., Delia, D. et al., 1997, Oncogene 14:2137-47).
  • the compounds useful in the methods of the present invention can also be demonstrated to inhibit cell transformation (or progression to malignant phenotype) in vitro.
  • cells with a transformed cell phenotype are contacted with one or more compounds of the present invention, and examined for change in characteristics associated with a transformed phenotype (a set of in vitro characteristics associated with a tumorigenic ability in vivo), for example, but not limited to, colony formation in soft agar, a more rounded cell morphology, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, release of proteases such as plasminogen activator, increased sugar transport, decreased serum requirement, or expression of fetal antigens, etc. (see Luria et al., 1978, General Virology, 3d Ed., John Wiley & Sons, New York, pp. 436-446).
  • Loss of invasiveness or decreased adhesion may also be used to demonstrate the anti-cancer effects of the compounds useful in the methods of the present invention.
  • a critical aspect of the formation of a metastatic cancer is the ability of a precancerous or cancerous cell to detach from primary site of disease and establish a novel colony of growth at a secondary site. The ability of a cell to invade peripheral sites is reflective of a potential for a cancerous state.
  • Loss of invasiveness may be measured by a variety of techniques known in the art including, for example, induction of E-cadherin-mediated cell-cell adhesion. Such E-cadherin-mediated adhesion can result in phenotypic reversion and loss of invasiveness (Hordijk et al., 1997, Science 278:1464-66).
  • Loss of invasiveness may further be examined by inhibition of cell migration.
  • a variety of 2-dimensional and 3-dimensional cellular matrices are commercially available (Calbiochem-Novabiochem Corp. San Diego, Calif.). Cell migration across or into a matrix may be examined by microscopy, time-lapsed photography or videography, or by any method in the art allowing measurement of cellular migration.
  • loss of invasiveness is examined by response to hepatocyte growth factor (HGF). HGF-induced cell scattering is correlated with invasiveness of cells such as Madin-Darby canine kidney (MDCK) cells. This assay identifies a cell population that has lost cell scattering activity in response to HGF (Hordijk et al., 1997, Science 278:1464-66).
  • HGF hepatocyte growth factor
  • loss of invasiveness may be measured by cell migration through a chemotaxis chamber (Neuroprobe/Precision Biochemicals Inc., Vancouver, BC).
  • a chemo-attractant agent is incubated on one side of the chamber (e.g., the bottom chamber) and cells are plated on a filter separating the opposite side (e.g., the top chamber).
  • the cells In order for cells to pass from the top chamber to the bottom chamber, the cells must actively migrate through small pores in the filter.
  • Checkerboard analysis of the number of cells that have migrated may then be correlated with invasiveness (see e.g., Ohnishi, T., 1993, Biochem. Biophys. Res. Commun. 193:518-25).
  • the compounds provided herein can also be demonstrated to inhibit tumor formation in vivo.
  • a number of animal models of hyperproliferative disorders, including tumorigenesis and metastatic spread, are known in the art (see Table 317-1, Chapter 317, “Principals of Neoplasia,” in Harrison's Principals of Internal Medicine, 13th Edition, Isselbacher et al., eds., McGraw-Hill, New York, p. 1814, and Lovejoy et al., 1997, J. Pathol. 181:130-135).
  • a compound provided herein can be administered to a test animal, preferably a test animal predisposed to develop a type of tumor, and the test animal subsequently examined for decreased incidence of tumor formation in comparison with controls not administered the compound identified using the pharmacophores of the present invention.
  • a compound useful in the methods of the present invention can be administered to test animals having tumors (e.g., animals in which tumors have been induced by introduction of malignant, neoplastic, or transformed cells, or by administration of a carcinogen) and subsequently examining the tumors in the test animals for tumor regression in comparison to controls that were not administered the compound.
  • Thyroid receptor binding activity that can serve as a mechanism for treatment of diseases sensitive thereto can be tested using assays available in the art.
  • Thyroid hormones are synthesized in the thyroid in response to thyroid stimulating hormone (TSH), which is secreted by the pituitary gland in response to various stimulants.
  • Thyroid hormones are iodinated O-aryl tyrosine analogues excreted into the circulation primarily as 3,3′,5,5′-tetraiodothyronine (T4).
  • T4 is rapidly deiodinated in local tissues by thyroxine 5′-deiodinase to 3,3′,5′-triiodothyronine (T3), which is the most potent TH.
  • T3 3,3′,5′-triiodothyronine
  • THs have profound physiological effects in animals and humans.
  • Hyper-thyroidism is associated with increased body temperature, general nervousness, weight loss despite increased appetite, muscle weakness and fatigue, increased bone resorption and enhanced calcification, and a variety of cardiovascular changes, including increased heart rate, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure.
  • Hypothyroidism is generally associated with the opposite effects.
  • TRs thyroid hormone receptors
  • T3 treatment increases oxygen consumption in isolated perfused liver and isolated hepatocytes.
  • THs also stimulate metabolism of cholesterol to bile acids. Hyperthyroidism leads to decreased plasma cholesterol levels, which is likely due to increased hepatic LDL receptor expression. Hypothyroidism is a well-established cause of hypercholesterolemia and elevated serum LDL. L-T3 is known to lower plasma cholesterol levels. In addition, THs are known to affect levels of other lipoproteins linked to atherosclerosis. THs stimulate apo AI and the secretion of apo AI in HDL while reducing apo B100. Accordingly, one would expect T3 and T3 mimetics to inhibit the atherosclerotic process in the cholesterol fed animal.
  • THs simultaneously increase de novo fatty acid synthesis and oxidation through effects on enzymes such as ACC, FAS, and spot-14.
  • THs increase circulating free fatty acids (FFA) levels in part by increasing production of FFAs from adipose tissue via TH-induced lipolysis.
  • FFA free fatty acids
  • THs increase mitochondrial enzyme levels involved in FFA oxidation, e.g., carnitine palmitoyltransferase 1 (CPT-1) and enzymes involved in energy storage and consumption.
  • CPT-1 carnitine palmitoyltransferase 1
  • the liver represents a major target organ of THs.
  • Microarray analysis of hepatic gene expression from livers of hypothyroid mice and mice treated with T3 showed changes in mRNA levels for 55 genes (14 positively regulated and 41 negatively regulated) (Feng et al., Mol. Endocrinol. 14(7): 947-55 (2000).
  • Others have estimated that approximately 8% of the hepatic genes are regulated by T3. Many of these genes are important to both fatty acid and cholesterol synthesis and metabolism.
  • T3 is also known to have other effects in liver, including effects on carbohydrates through increased glycogenolysis and gluconeogenesis and decreased insulin action.
  • T3 and T3 mimetics are thought to inhibit atherosclerosis by modulating the levels of certain lipoproteins known to be independent risk factors or potential risk factors of atherosclerosis, including low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, apoAI, which is a major apoprotein constituent of high density lipoprotein (HDL) particles and lipoprotein (a) or Lp(a).
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • apoAI which is a major apoprotein constituent of high density lipoprotein (HDL) particles and lipoprotein (a) or Lp(a).
  • TH therapy is reported to stimulate hepatic gluconeogenesis. Enzymes specific to gluconeogenesis and important for controlling the pathway and its physiological role of producing glucose are known to be influenced by TH therapy. Phosphoenolpyruvate carboxykinase (PEPCK) is upregulated by TH (Park et al, J. Biol. Chem. 274:211 (1999)) whereas others have found that glucose 6-phosphatase is upregulated (Feng et al., Mol. Endocrinol. 14:947 (2000)). TH therapy is also associated with reduced glycogen levels. TH therapy results in improved non insulin stimulated and insulin stimulated glucose utilization and decreased insulin resistance in the muscle of ob/ob mice. (Oh et al., J. Nutr. 125:125 (1995)).
  • thyromimetics potentially can be used to modulate cholesterol levels, to treat obesity, and other metabolic disorders especially with reduced undesirable effects.
  • SPA scintillation proximity assays
  • Subacute studies also can be conducted in cholesterol-fed rats.
  • the cholesterol-fed rat is an animal model of hypercholesterolemia generated by feeding the animals a diet with high cholesterol content.
  • the purpose of these studies is to evaluate the effects of compounds on serum cholesterol (an efficacy parameter) and on heart weight and heart mGPDH activity (potential toxicity parameters).
  • Compounds can be administered, e.g., IP, e.g., once-a-day for seven days.
  • Microsome/primary hepatocyte stability studies can be conducted using methods available in the art.
  • Prodrug activation in rat liver microsomes can be conducted to determine the kinetics of activation of prodrugs of thyromimetics in microsomal preparations.
  • Microsomes may contain P450 enzyme that may activate a prodrug.
  • the Km, Vmax, and intrinsic clearance values determined are measures of prodrug affinity for the microsomal enzymes, the rate at which the prodrug is activated, and the catalytic efficiency with which the prodrug is activated, respectively.
  • Prodrugs also can be tested for conversion to their respective parent compounds by human liver S9.
  • the S9 fraction is a fraction that contains both cytosolic and microsomal protein.
  • Uptake and activation of prodrug in isolated rat hepatocytes also can be conducted using methods known in the art.
  • Oral bioavailability and liver distribution following oral administration also can be measured using methods available in the art.
  • Thermogenesis is a measurement of energy consumption. Compounds that increase thermogenesis are likely to increase caloric expenditure and thereby cause body weight loss and its associated benefits to metabolic status (e.g., insulin sensitivity). Thermogenesis is assessed in subcellular fractions of various tissues, isolated cells, whole tissues, or in whole animals using changes in oxygen consumption as the endpoint. Oxygen is used up when calories are burned by various metabolic processes.
  • Mitochondrial thermogenesis is measured polarographically with a Clark-type oxygen electrode using mitochondria isolated from various tissues, including liver. Mitochondria are isolated by differential centrifugation. State 3 respiration or cytochrome c oxidase activity are measured in isolated mitochondria. (Iossa, S, FEBS Letters, 544: 133-7 (2003)). Oxygen consumption rates are measured in isolated hepatocytes using a portable Clark-type oxygen electrode placed in the hepatocyte medium. Hepatocytes are isolated from liver using a two-step collagenase perfusion (Berry, M. N., Friend, D. S. J. Cell Biol. 43: 506-520 (1969)) as modified by Groen (Groen, A.
  • Non-parenchymal cells are removed using a Percoll gradient and the cells are resuspended in tissue culture medium in a spinner flask. The oxygen consumption of the cells is measured over time once the system is sealed.
  • Oxygen consumption also can be measured in isolated perfused liver (Fernandez, V., Toxicol Lett. 69:205-10 (1993)). Liver is perfused in situ and oxygen consumption is calculated by measuring the difference between the oxygen saturation of the inflow buffer and the outflow buffer maintained at a constant flow. Whole animal oxygen consumption can be measured using an indirect calorimeter (Oxymax, Columbus Instruments, Columbus, Ohio). Animals are removed from their cages and placed in the chambers. The resting oxygen consumption is measured in animals during periods of inactivity as measured by activity monitors. The oxygen consumption is calculated based on the flow through the chamber and the difference in oxygen partial pressures at the inflow and outlet ports. Carbon dioxide efflux is also measured in parallel using a CO2 electrode.
  • Tissue distribution and the pharmacokinetics of compounds can be assessed following IP or oral administration to normal rats.
  • rats are made hypercholesterolemic by maintenance on a diet containing 1.5% cholesterol and 0.5% cholic acid for at least 2 weeks prior to initiation of treatment.
  • Plasma cholesterol values are assessed prior to and following treatment and the effects of compound are expressed as a percentage change from the pre-dose cholesterol levels.
  • Total cholesterol is analyzed using a commercially available enzymatic kit (Sigma Diagnostics, St. Louis, Mo.).
  • T3 mimetic compounds and prodrugs thereof in vivo on glucose can be measured in ZDF rats.
  • T3 and T3 mimetic mediated myosin heavy chain gene transcription in the heart can be measured.
  • An RT-PCR assay as disclosed in: Sara Danzi, Kaie Ojamaa, and Irwin Klein Am J Physiol Heart Circ Physiol 284: H2255-H2262, 2003 is used to study both the time course and the mechanism for the triiodothyronine (T3)-induced transcription of the ⁇ - and ⁇ -myosin heavy chain (MHC) genes in vivo on the basis of the quantity of specific heterogeneous nuclear RNA (hnRNA).
  • hnRNA specific heterogeneous nuclear RNA
  • the phosphoroamidate and phosphonoamidate compounds of a variety of therapeutic agents can be formed using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver.
  • the compound comprises a S-acyl-2-thioethyl phosphoroamidate or S-acyl-2-thioethyl phosphonoamidate, e.g., a S-pivaloyl-2-thioethyl phosphoroamidate or S-hydroxypivaloyl-2-thioethyl phosphonoamidate derivative.
  • Therapeutic agents that can be derivatized to phosphoroamidate or phosphonoamidate compound form include a therapeutic agent such as an anti-cancer agent or anti-diabetic agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoroamidate or phosphonoamidate moiety.
  • therapeutic agents for the treatment of liver cancer can be derivatized to form a phosphoroamidate or phosphonoamidate compound as described herein, and used for the treatment of liver cancers.
  • Liver cancers that can be treated include benign tumors, malignant tumors, hemangioma, hepatic adenomas, focal nodular hyperplasia, hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinomas, bile duct cancers, and other primary and metastatic cancers of the liver.
  • Exemplary therapeutic agents include anti-cancer agents having one or more hydroxy groups that can be derivatized as compounds described herein by removal of a hydrogen from one of the hydroxy groups.
  • Exemplary anti-cancer agents include, but are not limited to aclarubicin, decitabine, daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin, etoposide, fludarabine, 7-hydroxychlorpromazin, neplanocin A, podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin, vindesin, etoposide, teniposide, NK-611, camptothecin, irinotecan, 9-aminocamptothecin, GG-211, topotecan, paclitaxel, azatoxin, coformycin, pirarubicin, nelarabine and losoxan
  • Anti-cancer agents known in the art and described herein can be derivatized to form a phosphoramidate or phosphonoamidate compound as described herein.
  • Immunosuppressants such as combretastatin A-4, mycophenolic, pentostatin, or mitoxantrone, also can be derivatized to form a phosphoramidate or phosphonoamidate compound as described herein.
  • Such compounds can optionally be used in combination with another anti-cancer agent that is optionally in prodrug form.
  • the compounds provided herein are useful in methods for inhibiting gluconeogenesis, optionally by inhibiting the enzyme fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the compounds provided herein are useful in methods for inhibiting gluconeogenesis.
  • the compounds provided herein are useful in methods for treatment of metabolic diseases. In certain embodiments, the compounds provided herein are useful in methods for:
  • thyroid disease thyroid cancer
  • depression glaucoma
  • cardiac arrhythmias heart failure
  • osteoporosis treating thyroid disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias, heart failure, or osteoporosis
  • lipids e.g., cholesterol
  • glucose e.g., glucose
  • lipoproteins e.g., glucose
  • triglycerides e.g., glucose
  • T3-responsive genes e.g., T3-responsive genes
  • the compounds provided herein are useful in methods for lowering blood glucose levels, treating diabetes, impaired glucose tolerance, metabolic syndrome x, insulin resistance or hyperinsulinemia.
  • the compounds and compositions provided herein are useful in methods of treatment of a liver disorder, that comprises further administration of a second agent effective for the treatment of the disorder, such as liver cancer in a subject in need thereof.
  • a second agent effective for the treatment of the disorder, such as liver cancer in a subject in need thereof.
  • the second agent can be any agent known to those of skill in the art to be effective for the treatment of the disorder, including those currently approved by the FDA.
  • a compound provided herein is administered in combination with one second agent.
  • a second agent is administered in combination with two second agents.
  • a second agent is administered in combination with two or more second agents.
  • the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
  • the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • the active compounds provided herein can be administered in combination or alternation with another therapeutic agent, for example an anti-cancer agent.
  • the active compounds provided herein can be administered in combination or alternation with second agents useful in treating metabolic disorders such as diabetes, obesity, atherosclerosis, heart disease, metabolic syndrome x, nephrotic syndrome, thyroid disease, and symptoms associated therewith.
  • second agents useful in treating metabolic disorders such as diabetes, obesity, atherosclerosis, heart disease, metabolic syndrome x, nephrotic syndrome, thyroid disease, and symptoms associated therewith.
  • effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
  • the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art.
  • dosage values will 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 and schedules 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.
  • the second agent can be one of the agents disclosed herein.
  • contemplated additional pharmaceutically active substances include drugs commonly used as chemotherapy for treatment of cancer and immune modulator substances.
  • chemotherapeutic agents include anti-metabolites (e.g., Pentostatin®), DNA polymerase inhibitors (e.g, Gemzar®), RNA polymerase inhibitors (e.g., ECyd®), platinum derivatives (e.g., Paraplatin®), anti-estrogens (e.g., Nolvadex®), Taxanes (e.g., Taxotere®), GnRH analogs (e.g., Lupron®), DNA polymerase inhibitors (e.g., Gemzar®), topoisomerase inhibitors (e.g., Hycamptin®), biphosphonates (e.g., Aredia®), somatostatins (e.g., Sandostatin®), nucleoside analogs (e.g., Ribavirin®), and
  • Contemplated immunomodulatory substances include cytokines (e.g., interferon ⁇ and ⁇ , IL2, IL4, IL6, IL8, IL10, and IL12), cytokinins (e.g., kinetin), and chemokines (e.g., MIP-1).
  • cytokines e.g., interferon ⁇ and ⁇ , IL2, IL4, IL6, IL8, IL10, and IL12
  • cytokinins e.g., kinetin
  • chemokines e.g., MIP-1
  • the second agents for use in combination with the compounds provided herein include other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds provided herein are useful, such as treating metabolic diseases, including diabetes, obesity, atherosclerosis, heart disease, metabolic syndrome x, nephrotic syndrome, thyroid disease, and symptoms associated therewith.
  • Such second agents include, but are not limited to: sulfonylureas, for example, glibenclamide (DAONIL®), glimepiride (AMARYL®), glipizide (GLUCOTROL or MINODIAB), glyburide (MICRONASE®), tolbutamide (ORINASE®), acetohexamide (DYMELOR®), tolazamide (TOLINSE®) and chlorpropamide, (DIABINESE®); insulin and insulin mimetics; biguanides such as metformin (GLUCOPHAGE®); ⁇ -glucosidase inhibitors including acarbose (PRECOSE®) and miglitol (GLYSET®); meglitinides, for example, nateglinide (STARLIX®) and repaglinide (PRANDIN®); thiozolidinediones, for example, ciglitazone, englitazone, rosiglitazone (AVANDIA®),
  • Phosphoroamidate and phosphonoamidate compounds of a variety of therapeutic agents can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver.
  • the compound comprises a S-acyl-2-thioethyl phosphoroamidate or S-acyl-2-thioethyl phosphonoamidate, e.g., a S-pivaloyl-2-thioethyl phosphoroamidate or S-hydroxypivaloyl-2-thioethyl phosphonoamidate derivative.
  • therapeutic agents that can be derivatized to phosphoroamidate or phosphonoamidate compound form include any anti-cancer agent that includes, or has been derivatized to include a reactive group for attachment of the phosphoroamidate or phosphonoamidate moiety, including but not limited to nucleosides and nucleoside analogues including acyclic nucleosides.
  • therapeutic agents that can be derivatized to phosphoroamidate or phosphonoamidate compound form include any thyroid harmone receptor effector that includes, or has been derivatized to include a reactive group for attachment of the phosphoroamidate or phosphonoamidate moiety. Any of the phosphoroamidate or phosphonoamidate compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.
  • compositions containing at least one compound as described herein including a compound of general formula I, Ia, IIb, IIIa, IVa, IXa or IXb if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with other therapeutic agents, such as another anti-cancer or anti-diabetic agent.
  • a compatible and pharmaceutically acceptable carriers such as diluents or adjuvants
  • other therapeutic agents such as another anti-cancer or anti-diabetic agent.
  • the second agent can be formulated or packaged with the compound provided herein.
  • the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration.
  • the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
  • the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols).
  • the compound provided herein is administered orally.
  • compositions for oral administration of tablets, pills, hard gelatin capsules, powders or granules.
  • the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
  • a lubricant such as magnesium stearate
  • compositions for oral administration of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • inert diluents such as water or liquid paraffin.
  • These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
  • compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle.
  • the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, for example dextran, mannitol or lactose.
  • compositions provided herein is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients.
  • prophylactic or therapeutic agents e.g., a compound provided herein, or other prophylactic or therapeutic agent
  • typically one or more pharmaceutically acceptable carriers or excipients e.g., a typically one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable includes approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well-known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form.
  • the composition or single unit dosage form if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • Lactose free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI).
  • USP U.S. Pharmocopia
  • XXI U.S. Pharmocopia
  • NF NF
  • lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379 80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.
  • suspensions e.g., aqueous or non aque
  • compositions, shape, and type of dosage forms provided herein will typically vary depending on their use.
  • a dosage form used in the initial treatment of liver cancer may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same liver cancer.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa. (2000).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail in the sections above.
  • anhydrous ingredients as described in detail in the sections above.
  • the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof.
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R.
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each of which is
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
  • single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).
  • polymeric materials can be used.
  • a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).
  • the active ingredient can be 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 surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, ne
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th , 18th and 20 th eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
  • transdermal dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th , 18th and 20 th eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000).
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In certain embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult. In certain embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated.
  • the amount of the compound or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage administered to a subject is 0.140 mg/kg to 3 mg/kg of the subject's body weight, based on weight of the active compound.
  • the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the subject's body weight.
  • the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 10 mg to about 200 mg per day, in other embodiments, between about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
  • the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.
  • compositions provided herein are also encompassed by the above described dosage amounts and dose frequency schedules.
  • the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
  • the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject's body weight.
  • the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses.
  • the loading dose can be, for instance, about 60 to about 400 mg per day, or about 100 to about 200 mg per day for one day to five weeks.
  • the loading dose can be followed by one or more maintenance doses.
  • each maintenance does is, independently, about from about 10 mg to about 200 mg per day, between about 25 mg and about 150 mg per day, or between about 25 and about 80 mg per day.
  • Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.
  • a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject.
  • the steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.
  • a sufficient amount of a compound or composition provided herein is administered to achieve a steady-state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
  • loading doses can be administered to achieve steady-state blood or serum concentrations of about 1200 to about 8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days.
  • maintenance doses can be administered to achieve a steady-state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
  • administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail above.
  • the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active ingredient.
  • the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient.
  • Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
  • the dosages of the second agents are to be used in the combination therapies provided herein.
  • dosages lower than those which have been or are currently being used to prevent or treat the diseases described herein, for example, liver cancer and diabetes are used in the combination therapies provided herein.
  • the recommended dosages of second agents can be obtained from the knowledge of those of skill.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • the therapies are administered no more than 24 hours apart, less than 30 minutes apart, less than 1 hour apart, 1 hour apart, at about 1 hour apart, at
  • a compound provided herein and a second agent are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the compound provided herein and the second active agent exert their effect at times which overlap.
  • Each second active agent can be administered separately, in any appropriate form and by any suitable route.
  • the compound provided herein is administered before, concurrently or after administration of the second active agent.
  • the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • the compound provided herein and the second agent are cyclically administered to a patient.
  • Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agents) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • a first agent e.g., a first prophylactic or therapeutic agents
  • second agent and/or third agent e.g., a second and/or third prophylactic or therapeutic agents
  • the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • the second agent can act additively or synergistically with the compound provided herein.
  • the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition.
  • a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions.
  • a compound provided herein is administered prior to or subsequent to administration of a second agent.
  • administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral.
  • the second active agent when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • kits for use in methods of treatment of a liver disorder such as cancer or metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • the kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • a unit dose of a compound or composition provided herein, or a second agent or composition can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 days.
  • a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.
  • suitable packaging includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject.
  • materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • 1,1′-carbonyldiimidazole (830 mg, 5.12 mmol) was added to a stirring solution of carboxylic acid 2 in anhydrous PhMe/DMF (2/1, v/v, 2.7 mL) at room temperature and the reaction mixture turned turbid instantly. After 30 min, the medium was diluted by adding anhydrous PhMe/DMF (93/7, v/v, 17 mL) and cooled to ⁇ 10° C. 2-Mercaptoethanol (359 ⁇ L, 5.12 mmol) was then added dropwise and the solution was stirred for 1 h at this temperature. The reaction mixture was diluted with H 2 O (60 mL) and the product was extracted with Et 2 O (3 ⁇ 15 mL).
  • ⁇ -L-ddA (1.00 g, 4.25 mmol) was co-evaporated with anhydrous pyridine (3 ⁇ 10 mL) and then dissolved in anhydrous pyridine/DMF (1/1, v/v, 21 mL). Diphenyl phosphite (5.76 mL, 29.8 mmol) was then added dropwise to this solution at room temperature. The reaction mixture was stirred for 20 min upon which a mixture of Et 3 N/H 2 O (1/1, v/v, 8.5 mL) was added dropwise, and stirring was pursued for an additional 20 min.
  • H-Phosphonate monoester 4 (1.03 g, 2.57 mmol) and alcohol 3 (1.66 g, 3.45 mmol) were co-evaporated with anhydrous pyridine (3 ⁇ 5 mL) and then dissolved in anhydrous pyridine (5 mL).
  • PyBOP (1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1.60 g, 3.08 mmol) was then added in one portion and the reaction mixture was stirred for 15 min at room temperature. The solution was poured over saturated aqueous NaHCO 3 solution (30 mL) and the product was extracted with CH 2 Cl 2 (4 ⁇ 15 mL).
  • the resulting oil was dissolved in a mixture of dioxan (350 ml) and an aqueous solution of NaOH (30%, 350 ml). The heterogene mixture was refluxed for 16 hours. The reaction mixture was allowed to cool down to room temperature, the two phases were separated, and the organic phase carefully neutralized by dropwise addition of HCl (1M). The product was extracted with methylene chloride and the organic phases were evaporated under reduced pressure. The crude orange oil was recrystallized from methylene chloride to afford carboxylic acid 3 as white crystals (92%).
  • 1,1′-carbonyldiimidazole (1.3 eq, 1.17 g) was added to a stirring solution of carboxylic acid 3 (2 g, 5.56 mmol) in an anhydrous mixture of toluene and dimethylformamide (2/1, v/v, 4.5 ml) at room temperature, and the reaction mixture turned turbid instantly. After 30 min, the reaction mixture was diluted with a mixture of toluene and dimethylformamide (93/7, v/v, 28 ml), cooled to ⁇ 10° C., and 2-mercaptoethanol (1.3 eq, 500 ⁇ L) was added. The solution was stirred for 3 h at this temperature.
  • Phosphorus acid (10 eq, 4.1 g) was coevaporated two times with anhydrous pyridine, dissolved in that solvent (25 ml) and added to crude 4. The reaction mixture was stirred at room temperature and a white precipitate appeared after few minutes. The reaction mixture was cooled down to 0° C. and pivaloyl chloride (5.5 eq, 3.4 ml) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was stopped by addition of a solution of triethylammonium bicarbonate (TEAB 1M, 10 ml) and diluted with ethyl acetate (EtOAc).
  • TEAB 1M triethylammonium bicarbonate
  • EtOAc ethyl acetate
  • the crude mixture was purified by silica gel column chromatography (eluant: stepwise gradient of methanol [0-30%] in methylene chloride), followed by a purification on reverse phase chromatography (eluant: stepwise gradient of acetonitrile [0-50%] in water), to give the desired product 10 (B102) (1:1 mixture of diastereoisomers as judged by 31 P-NMR, 36%) which was lyophilized from a mixture of dioxan/water.
  • NM107 (10 g, 38.87 mmol) was dissolved in anhydrous pyridine (194 ml) and chlorotrimethylsilane (4.5 eq, 21.6 ml) was added. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2h30, then 4,4′-dimethoxytrityl chloride (1.5 eq, 19.8 g) and 4-dimethylaminopyridine (0.5 eq, 2.37 g) were successively added. The reaction mixture was stirred overnight at room temperature, then quenched with a saturated aqueous NaHCO 3 solution. The crude product was extracted with methylene chloride, washed with saturated aq NaHCO 3 solution, and water.
  • Compound 13 can be converted into the phosphoroamidate prodrug 10 (B102) following experimental conditions described for the last step of NM108- and NM105-OH-SATE phosphoroamidate synthesis, in Examples 3 and 4, respectively.
  • the crude mixture was purified on silica gel flash column chromatography (eluant: stepwise gradient [0-30%] of methanol in methylene chloride) and then, on reverse phase column chromatography (eluant: stepwise gradient [0-100%] of acetonitrile in water) to give the desired product 8 (B184) (1:1 mixture of diastereoisomers according to 31 P-NMR, 800 mg, 39%) which was lyophilized from a mixture of dioxan/water.
  • a anti-cancer drug, R—OH, such as an antiviral nucleoside, having a free OH group, is derivatized to form a phosphoramidate compound according to the following scheme. Reactive groups on the molecule, such as other hydroxyl groups, are protected using methods known in the art.
  • a phosphoroamidate of 5-azacytidine is prepared as follows:
  • Examples 6-10 illustrate by way of example the effect of the phosphoroamidate group on an antiviral compound to promote liver specific delivery of an active agent to liver cells.
  • Measurements of the concentration of 2′-3′-dideoxyadenosine-5′-triphosphate (ddATP) (the triphosphate nucleotide of 2′-3′-dideoxyadenosine (ddA) are performed by liquid chromatography tandem mass spectrometry (LC/MS/MS), e.g., of methanolic extracts of hepatocytes.
  • ddATP 2′-3′-dideoxyadenosine-5′-triphosphate
  • ddA the triphosphate nucleotide of 2′-3′-dideoxyadenosine
  • TP-ddA concentration of ddATP is measured by comparison to a standard curve.
  • Working stock solutions of TP-ddA are prepared from a 100 ⁇ mol/ ⁇ l stock solution in de-ionized water of ddATP (tetrasodium salt of >91% purity) purchased from Sigma Chemical Co as follows:
  • Working stock#1 Test compound TP-ddA 100 2000 2000 4000 50.0 500 2.
  • Working stock#2 Test article TP-ddA 100 1000 3000 4000 25.0 250 3.
  • Working stock#4 prepared from stock#1) TP-ddA 100 500 3500 4000 12.5 125 4.
  • Working stock#5 prepared from stock#1) TP-ddA 100 200 3800 4000 5.0 50 5.
  • Working stock#6 prepared from stock#1) TP-ddA 100 100 3900 4000 2.5 25 6.
  • Working stock#7 prepared from stock#1) TP-ddA 100 40 3960 4000 1.0 10
  • calibration standards are prepared as follows using liver
  • HPLC Tandem MS analysis instrument method e.g. HPLC Tandem MS analysis instrument method:
  • HPLC is conducted on Phenomenex Luna Amino 3 ⁇ m 100 A, 30 ⁇ 2 mm column, with a mobile phase: A: 70% 10 mM NH 4 OAc 30% ACN pH 6.0; and B: 70% 1 mM NH 4 OAc 30% ACN pH 10.5 as follows:
  • hepatocytes Primary hepatocytes (Rat, Cynomolgus Monkey or human) were seeded at 0.8 ⁇ 10 6 in a collagen-coated 12-well plate and allowed to attach 4-6 hours after which time the seeding medium was replaced with serum-free culture medium and cells allowed to acclimatize to the new medium overnight. On the next day, cells were exposed for 1, 4, 8 and 24 hours to test article A550 (NM204) at 10 and 50 ⁇ M prepared in fresh culture medium from stock solution in DMSO (final DMSO concentration was 0.1%). At each time point, an aliquot (500 ⁇ l) was collected and immediately added to 500 ⁇ l of acetonitrile and stored at ⁇ 20° C. until analysis.
  • LddA-TP formation in hepatocytes LddA TP Levels (pmol/million cells)
  • Rat Monkey Human A550 (Ex 1) 10 ⁇ M Time (hour) 1 159.5 287.5 161.5 4 388.0 978.0 312.5 8 468.5 1230.0 352.5 24 422.0 344.0 366.0
  • A550 (Ex 1) 50 ⁇ M Time (hour) 1 393.0 2085.0 682.5 4 1212.0 5690.0 1480.0 8 1590.0 6030.0 1930.0 24 1505.0 3030.0 2062.5
  • A550 (NM-204) (the compound of Example 1 (Hydroxy-tBuSATE N-benzylphosphoroamidate derivative of L-ddA) in the rat liver was evaluated following a single intravenous (I.V.) or oral administration of A550 (NM-204) at a dose of 20 (oral) or 10 (I.V.) mg/Kg body weight. The dose solutions were prepared on the same day prior to dose administration.
  • each animal was euthanized by CO 2 gas followed by exsanguination via the abdominal vein. Livers were collected immediately after sacrifice, flash frozen in liquid nitrogen, placed on dry ice, and later stored at ⁇ 70° C., before being analyzed.
  • Control rat liver samples were taken from whole frozen livers (Bioreclamation, Inc. Hicksville, N.Y.) with the aid of a tissue coring utensil (Harris Unicore, 8.0 mm, VWR). Each ⁇ 0.1 g sample was placed in individual 2 mL poly vials with 0.940 mL of 80% MeOH/20% DIH 2 O and homogenates were prepared using a mechanical tissue disruptor (Tissue Master, Omni-International, Inc, Marietta Ga.). The vials received a 10 ⁇ l aliquot of a working stock solution and a 50 ⁇ l aliquot of the ISTD before vortexing for ⁇ 30 sec. The mixtures were stored overnight at ⁇ 20° C.
  • NADPH Incubations Microsomal or S9 incubations were conducted in a final volume of 0.5 mL. Pooled liver microsomal or S9 protein (1.0 mg/mL), suspended in incubation buffer (100 mM potassium phosphate, pH 7.4, 5 mM MgCl 2 , and 0.1 mM EDTA) was preincubated for 5 min at 37° C. with 10-50 ⁇ M OHSATE phosphoroamidate compound from a stock solution in DMSO (final DMSO concentration was 0.1%); the reaction was initiated by the addition of NADPH (3 mM final concentration). Incubations with no NADPH served as controls.
  • incubation buffer 100 mM potassium phosphate, pH 7.4, 5 mM MgCl 2 , and 0.1 mM EDTA
  • FIGS. 1 and 2 depict depletion of NM108 SATE and NM107 SATE, respectively, after incubation with NADPH in monkey liver S9.
  • HPLC Agilent 1100 Column: Phenomenex Luna C18(2), 20 ⁇ 2 mm, Mobile phases (MP): MP(A) 10 mM K 2 HPO 4 pH5, MP(B) ACN Gradient elution: 20 to 63% MP(B) run from 0 to 30 min Runtime: 20 min Flow rate: 1 mL/min Injection volume: 10-20 ⁇ L UV: 252 nm-NM108SATE 272 nm-NM107SATE
  • the metabolism is NADPH dependent, it is possible that the phosphoroamidate compound is preferentially activated by Cytochrome P450 in the liver.
  • HPM hepatocyte culture medium
  • Hepatocyte incubations were conducted in a final volume of 1.0 mL HCM/well (0.8 million cells/mL). HCM from overnight incubation of cells was removed and replaced with fresh HCM, pre-warmed to 37° C., containing 10 ⁇ M test article from a stock solution in DMSO (final DMSO concentration was 0.1%). At specific times (up to 24 hrs), incubation medium was discarded and the cell monolayers were carefully washed two times with ice-cold PBS. Following the last wash, all PBS was carefully removed and 1 mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately following addition of methanol.
  • extraction buffer ice-cold 70% methanol
  • HepG2s or Huh7 cells were plated at 0.4 ⁇ 10 6 cells/well in collagen-coated 12-well plates. Cells were allowed to attach overnight. Culture medium from overnight incubation of cells was removed and replaced with fresh culture medium, pre-warmed to 37° C., containing 10 ⁇ M test article from a stock solution in DMSO (final DMSO concentration was 0.1%). After 24-72 hours, incubation medium was discarded and the cell monolayers were carefully washed two times with ice-cold PBS. Following the last wash, all PBS was carefully removed and 1 mL of extraction buffer (ice-cold 70% methanol) was added. Each well was sealed with parafilm immediately following addition of methanol.
  • extraction buffer ice-cold 70% methanol
  • Cellular extracts were prepared by transferring 0.9 mL of extract into 2 mL microfuge tubes followed by centrifugation for 5 min at 14,000 rpm. Approximately 100 ⁇ L of the supernatant was transferred to HPLC vials and triphosphate levels determined by LCMS/MS as described below.
  • NM107 triphosphate levels and B102 in cell extracts were observed as follows:

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