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WO2013187978A1 - Promédicaments de phosphoramidate et phosphonoamidate à double ciblage hépatique - Google Patents

Promédicaments de phosphoramidate et phosphonoamidate à double ciblage hépatique Download PDF

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Publication number
WO2013187978A1
WO2013187978A1 PCT/US2013/032128 US2013032128W WO2013187978A1 WO 2013187978 A1 WO2013187978 A1 WO 2013187978A1 US 2013032128 W US2013032128 W US 2013032128W WO 2013187978 A1 WO2013187978 A1 WO 2013187978A1
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compound
pharmaceutically acceptable
solvate
acceptable salt
prodrug
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PCT/US2013/032128
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English (en)
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Runcong LIU
Qiang Huang
Zheng Wang
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Nanjing Molecular Research, Inc.
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Priority to CN201380030061.6A priority Critical patent/CN104640444B/zh
Publication of WO2013187978A1 publication Critical patent/WO2013187978A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Definitions

  • the present invention relates to double-liver-targeting phosphoramidate or phosphonoamidate prodrugs, and therapeutic use and preparation methods thereof.
  • Nucleoside analogues have been developed as antiviral and anticancer agents.
  • Nucleotide kinases phosphorylate nucleosides to their corresponding 5 '-monophosphates which are further converted into their di- and tri-phosphates by cellular nucleotide kinases.
  • nucleosides are weakly active because they cannot be efficiently phosphorylated by kinases or are not substrates of kinases at all, as evidenced by the observation that some inactive nucleosides, when converted chemically to triphosphates, become potently active against certain viruses in vitro.
  • Nucleoside phosphates (nucleotides) per se cannot be used as drugs often because they are de-phosphorylated by membrane nucleotides and/or other hydrolases before entering the cells or are too polar to enter the cells.
  • their phosphate prodrugs have been intensively studied because they can potentially bypass the rate-limiting first step of phosphorylation.
  • phosphoramidate prodrug approach has been reported to be an effective method to convert biologically inactive nucleosides to their active nucleoside monophosphates bypassing the rate-limiting first step of phosphorylation (see, e.g., J. Med. Chem. 2007, 50, 5463; WO 2008/121634; WO 2008/082601; and WO 2008/082602).
  • nucleoside monophosphates can be further phosphorylated to diphosphates and then the corresponding biologically active triphosphates.
  • phosphoramidate of nucleoside usually can demonstrate maximum biological activity in cell line assays because it can release nucleoside or nucleotide quickly in the cells. It was reported that phosphoramidate prodrug of d4T could not be detected in plasma after oral administration immediately (Drug Metab. Dispos. 2001, 29, 1035). Phosphoramidate is stable in gastric fluid and may be absorbed in the stomach. On the other hand, phosphoramidate may decompose readily in intestinal fluid to ala-d4T-MP which may not be absorbed efficiently in intestine due to its polar nature.
  • bioavailability of this type of phosphoramidate prodrugs usually is low, probably due to its hydrolysis catalyzed by esterase followed by releasing phenol.
  • bioavailability of GS-7340 an isopropylalanyl monoamidate phenyl monoester of tenofovir, was only 17% in male beagle dogs (Antimicrob. Agents Chemother. 2005, 49, 1898).
  • Phosphoramidate prodrug of 2'-C-methylguanosine only delivered about 10% - 20% of active triphosphate delivered into the liver from free nucleoside (J. Med. Chem. 2010, 53, 4949).
  • Erion et al. disclosed that cyclic phosphate or phosphonate prodrugs which are stable in the presence of esterase can enhance liver specific drug delivery (Erion, M., et al., US 7,303,739 and reference thereof). Erion's prodrugs are activated by P450 enriched in the liver.
  • clinical application of this approach may be limited by potentially adverse side effects caused by ⁇ , ⁇ -unsaturated ketone metabolites from prodrugs.
  • R a is aminoacid ester resdue while R b is an aryl group including phenyl or nathphyl.
  • R b would be simultaneously released after ester of aminoacid residue was hydrolyzed by esterase.
  • Sofia US 7,964,580
  • R b was defined as an alkyl group, such as Me, Et, iPr, and t-Bu, there is no phosphoramidate prodrug with R b as alkyl group that has actually been prepared.
  • WO 2012/142075 also reported phosphoramidates with R b as benzyl groups with no substitution on phenyl group. However, no biological activity for any of such compounds was reported. Therefore, phosphoramidates with R b as alkyl or benzyl group without substitution on phenyl ring have never demonstrated biological usefulness, probably because these groups (alkyl or benzyl group) in phosphoramidate prodrugs of nucleoside are too stable to be cleaved efficiently to produce active nucleoside phosphate.
  • the phosphoramidate prodrug of F5 which contains an aminoacid ester moiety and the 2-methylbenzyl group had significantly improved oral bioavailability as compared with the phosphoramidate of formula F4.
  • the phosphoramidate prodrug of formula F5 is the first example that has demonstrated excellent ability to deliver nucleoside phosphoramidate into the liver in rats after oral administration (see Example 17). Therefore, this novel phosphoramidate prodrug containing the aminoacid ester and substituted benzyl groups can be used as liver- targeting prodrug to deliver active nucleoside phosphoramidate into the liver for treating liver diseases, by which the systemic toxicity can be significantly reduced due to the reduced concentration of the active drug in the circulation system.
  • the working mechanisms of the prodrug disclosed herein may include hydrolysis of the ester group by an esterase enriched in the liver while the substituted benzyl group is degraded through hydroxylation by P450, which is also highly enriched in the liver. Therefore, the phosphoramidate prodrugs of the present invention can be considered as double-liver- targeting prodrugs.
  • Compound F5 was synthesized as a single isomer. The chirality of F5 was tentatively assigned based on the similar chemistry and will be confirmed by X-ray crystallography.
  • a stable DGX-intermediate prodrug of formula F7 was prepared and isolated as a carboxylic acid or its salt (only salt form shown in FIG. 1). Even if the DGX-prodrug of formula F5 is hydrolyzed by esterases in organs other than the liver, the stable intermediate prodrug (F7) formed could still be delivered into the liver by rich monocarboxylate transporters. While McGuigan's prodrug (F6) would be converted to a polar diacid (F9) after hydrolysis of the ester group by esterases followed by simultaneous release of phenol, the stable DGX-intermediate prodrug of formula F7 can be prepared as a water-soluble phosphoramidate prodrug.
  • the present invention provides prodrug forms of small molecule drug substances, in particular, nucleosides, nucleotides, C-nucleosides, C-nucleotides, nucleoside phosphonates.
  • the prodrugs with aminoacid ester and substituted benzyl groups disclosed herein are activated by both esterases and P450 enriched in the liver, and deliver the active drugs, or nucleoside phosphoramidate or phosphonoamidates, into the liver efficiently, which have demonstrated double-liver- targeting nature and usefulness particularly as prodrugs for treating liver diseases, including but not limited to liver cancers and hepatitis infections.
  • the present invention also provides prodrug forms administered orally for small molecules that cannot be taken orally due to their metabolic instability in gastrointestinal track.
  • the present invention provides a compound of formula I:
  • X is oxygen (O) or -CH 2 -;
  • Y is a nucleoside, acyclonucleoside, or C-nucleoside moiety
  • R', R 1 , R2", and R 3 J are independently selected from the group consisting of hydrogen and substituted and unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, wherein the heterocyclyl and heteroaryl group each comprises one to three heteroatoms independently selected from O, S, and N, or alternativerly R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-, preferably 3- to 6-, membered ring;
  • R 4 is selected from the group consisting of hydrogen, and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, metal ions, and ammonium ions;
  • Ar is optionally substituted aryl or heteroaryl, wherein the heteroaryl comprises one to three heteroatoms independently selected from O, S, and N, wherein said optionally substituted aryl is preferably C6-C 10 aryl, in particular phenyl or naphthyl, and said optionally substituted heteroaryl is preferably a 5- to 10-membered heteroaryl; andthe "linker" is selected from a bond and optionally substituted C C 3 alkylene, vinyl, ethynyl, arylene and heteroarylene groups, optionally substituted vinyl, or ethynyl or aromatic or heteroaromatic moiety, wherein the heteroarylene comprises one to three heteroatoms independently selected from O, S, and N.
  • the formulas of Y-XH or Y-OH according to the present invention would represent a nucleoside, acyclonucleoside, or C-nucleoside drug; the formula Y-0-P(0)(OH) 2 would represent a biologically active monophosphate of a nucleoside, acyclonucleoside, or C-nucleoside drug; and the formula Y-CH 2 -P(0)(OH) 2 would represent a biologically active phosphonate analog of a nucleoside, acyclonucleoside, or C-nucleoside drug.
  • prodrugs disclosed herein can also be prepared and used as water soluble salts, which possess unique useful properties as compared with any other phosphoramidate prodrugs reported in the literature.
  • Salt forms of phosphoramidate prodrugs herein can be salts formed with organic or inorganic bases.
  • R 4 when R 4 is an ammonium ion, it can be NH 4 + or an organic ammonium ion, including but not limited to monoalkyl, dialkyl, trialkyl, and tetraalkyl ammonium ions, for example, RNH 3 + , R 2 NH 2 + , R 3 NH + , or R 4 N + , wherein R represents a lower alkyl group, preferably comprising one to six carbons, more preferably comprising one to four carbons.
  • R 4 when R 4 is a metal ion, it can be any pharmaceutically acceptable metal ion, preferably K + , Na + , Ca 2+ , Mg 2+ , or the like.
  • carboxylic acid intermidates of typical McGuigan's phosphoramidate prodrugs are unstable and readily decompose to very polar diacids after simultaneously releasing phenol under ester hydrolysis or physiological conditions.
  • the present invention provides a method for efficient delivery of nucleoside phosphates or phosphonates into cells, particularly into the liver, through use of the phosphoramidate and phosphonoamidate prodrugs disclosed herein.
  • the present invention provides use of a compound as described herein as a prodrug of nucleoside, acyclic nucleoside, C-nucleoside, nucleotide, or a phosphonate analog thereof.
  • the compounds of the present invention can be used in combination with other therapeutically active agents.
  • the present invention provides a pharmaceutical composition comprising any compound disclosed herein, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of treating diseases, such as a viral infection or cancer, comprising administration of any compound as disclosed herein, or a pharmaceutically acceptable prodrug thereof, to a patient in need of the treatment.
  • diseases such as a viral infection or cancer
  • the present invention provides a method of treating diseases, such as a viral infection or cancer, comprising administration of a pharmaceutical composition as disclosed herein to a patient in need of the treatment.
  • diseases such as a viral infection or cancer
  • the present invention provides use of any compound disclosed herein in the manufacture of a medicament for treatment of diseases, such as viral infections or cancers.
  • the present invention provides processes and intermediates for the preparation of the phosphoramidate prodrugs disclosed herein as a diastereomerically enriched isomer.
  • FIG. 1 illustrates prodrug activation pathways.
  • FIG. 2 illustrates mechanisms of activation of known phosphoramidate prodrugs.
  • FIG. 3 illustrates proposed mechanisms of activation of phosphoramidate prodrugs according to one embodiment of the present invention.
  • FIG. 4 illustrates proposed mechanism of action of prodrug F5 (FDURPAE).
  • the present invention relates to chemical compounds that have enhanced therapeutic potency, particularly potency with respect to cancers (such as leukaemia), viral infections (including HIV, HBV and HCV), liver disorders (including liver cancer), and metabolic diseases (such as diabetes, hyperlipidemia, atherosclerosis, and obesity).
  • cancers such as leukaemia
  • viral infections including HIV, HBV and HCV
  • liver disorders including liver cancer
  • metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity
  • the present invention provides phosphoramidate or phosphonoamidate prodrugs of a variety of therapeutic agents, including nucleosides, nucleotides, C-nucleosides, C-nucleotides, and other alcohol-containing drugs, or phosphonate analogs thereof.
  • the phosphoramidate and phophonoramidate prodrug comprises optionally substituted benzyl group and aminoacid moiety, the benzyl group preferably substituted by one or more substituents independently selected from CrC 4 alkyl, CrC 4 alkoxy, CrC 4 haloalkoxy, hydroxy, halogen, substituted amino, acylamino.
  • the parent drug compound is mainly obtained from selective metabolism of a phosphoramidate or phosphonoamidate compound in the liver; thus, the parent drug is capable of accumulating in the liver, for example, of humans.
  • the parent drug is capable of accumulating in the liver, for example, of humans.
  • the prodrugs of the present invention may become biologically active, since the prodrugs directly deliver nucleoside monophosphate bypassing the rate-limiting first step of phosphorylation.
  • a method for the treatment of a liver disorder includes administering an effective amount of a compound provided herein, either alone or in combination or alternation with another therapeutically effective agent, optionally in a pharmaceutically acceptable carrier.
  • Prodrugs with high lipophilicity of the present invention readily penetrate cell membranes so as to improve pharmacokinetics and/or bioavailability of parent drugs.
  • These prodrugs may be activated by P450 and/or other enzymes enriched in the liver.
  • bioavailability of the prodrugs disclosed herein can be further improved because the monocarboxylic acid or its salt intermediate generated from hydrolysis of ester of prodrug herein is stable and can be delivered into the tissues or cells by monocarboxylate transporters.
  • the prodrugs disclosed herein can be used for the treatment of diseases that the corresponding parent drugs are used for.
  • the prodrugs disclosed herein may also be used for the treatment of diseases resistant to the corresponding parent drugs.
  • the present invention provides a method of enhancing bioavailability and/or liver-targeting property of an alcohol drug, comprising protecting at least one of the hydroxyl groups of said alcohol-containing drug with a phosphoramidate moiety of formula:
  • R', R 1 , R2", and R 3 J are each independently selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, wherein the heterocyclyl and heteroaryl group each comprises one to three heteroatoms independently selected from O, S, and N, or, alternatively, R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-, preferably 3- to 6-, membered ring;
  • R 4 is selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, metal ions, and ammonium ions;
  • Ar is optionally substituted C 6 -C 10 aryl or optionally substituted 5- to 10- membered heteroaryl comprising one to three heteroatoms independently selected from O, S, and N;
  • the "linker” is selected from a bond and optionally substituted CrC 3 alkylene, vinyl, ethynyl, arylene and heteroarylene, wherein the heteroaryl comprises one to three heteroatoms independently selected from O, S, and N.
  • alcohol-containing drug is a nucleoside, acyclonucleoside, or C-nucleoside.
  • Ar is substituted aryl, in particular, 2-methylphenyl group.
  • the present invention provides a compound of formula I:
  • X is oxygen (O) or methylene (-CH 2 -);
  • Y is a nucleoside, acyclonucleoside, C-nucleoside, or other alcohol-containing drug molecule moiety
  • R', R 1 , R2", and R 3 J are independently selected from the group consisting of hydrogen and substituted and unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, wherein the heterocyclyl and heteroaryl group each comprises one to three heteroatoms independently selected from O, S, and N, or altemativerly R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-, preferably 3- to 6-, membered ring;
  • R 4 is selected from the group consisting of hydrogen, and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, metal ions, and ammonium ions;
  • Ar is optionally substituted aryl or heteroaryl, wherein the heteroaryl comprises one to three heteroatoms independently selected from O, S, and N, wherein said optionally substituted aryl is preferably C6-C 10 aryl, in particular phenyl or naphthyl, and said optionally substituted heteroaryl is preferably a 5- to 10-membered heteroaryl; and the "linker" is selected from a bond and optionally substituted C C 3 alkylene, vinyl, ethynyl, arylene and heteroarylene groups, optionally substituted vinyl, or ethynyl or aromatic or heteroaromatic moiety, wherein the heteroarylene comprises one to three heteroatoms independently selected from O, S, and N.
  • Ar is not an unsubstituted phenyl.
  • Ar is a substituted C6-Q0 aryl, more preferably, 2-methylphenyl group.
  • the present invention provides a compound of formula II:
  • n 0, 1, 2, 3, 4, or 5;
  • R 5 at each occurrence is independently selected from halogen (F, CI, Br, I), and substituted or unsubstituted acyloxy, acyl-NH-, CH 3 , methoxy, alkyl, alkyloxyl, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, aryl, aryloxy, arylamino, and arylalkyl.
  • n is 1 or 2
  • R 5 is preferably at 2 and/or 4-position(s).
  • Y is a nucleoside moiety comprising a sugar group and a base group.
  • the base group of the nucleoside moiety is selected from adenine, guanine, uracil, thymine, cytosine, and derivatives thereof.
  • Any amino or hydroxyl group in the Y-X moiety can be optionally protected.
  • a compound of formula II is one or a mixture of diastereomers of formula III:
  • R 4 , X and Y-XH are defined as above, and wherein P* is a phosphorus atom having either R- or S- configuration.
  • a compound of formula III is one or a mixture of diastereomers of formula IVa or IVb:
  • R 4 , Y and Y-OH are defined as above, and wherein P* is a phosphorus stereogenic center (P) having either an R- or S-configuration.
  • the present invention provides a compound selected from the group consisting of formulas:
  • the compound is diastereomerically enriched with the phosphorus stereogenic center (P) being in (R)- or (S)-configuration.
  • the present invention provides a compound selected from the group consisting of formulas:
  • the compound is diastereomerically enriched with the phosphorus stereogenic center (P) being in (R)- or (S)-configuration.
  • the present invention provides a compound selected from the group consisting of formulas: ⁇
  • the compound provided may comprise two diastereomers having phosphorus (P) in either (R)- or (S)-configuration.
  • such compound is enriched with one of such two diastereomers with phosphorus in either (R)- or (S)-configuration.
  • such compound is a pure diastereomer with phosphorus (P) in only (R)-configuration, or substantially free of the corresponding "(S)-P” diastereomer.
  • such compound is a pure disastereomer with phosphorus (P) in only (S)- configuration, or substantially free of the corresponding "(R)-P” diastereomer.
  • the present invention provides the compounds, or compositions thereof, for use in the treatment of a disease or disorder that is modulated or otherwise affected by liver function, in particular, hepatitis infections (e.g., HCV and HBV), liver disorders (e.g., cancers), and metabolic diseases (such as diabetes, hyperlipidemia, atherosclerosis, and obesity).
  • hepatitis infections e.g., HCV and HBV
  • liver disorders e.g., cancers
  • metabolic diseases such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • the prodrugs disclosed herein are prepared and used as water soluble salts, which possess useful properties different from those of any other phosphoramidate prodrugs as reported in the literature.
  • These salts can be formed by treatment of a prodrug in carboxylic acid form with base, including organic or inorganic bases, or by hydrolysis of the ester group of a prodrug with bases.
  • the preferred prodrug salt forms of the present invention are salts formed with cations such as NH 4 + , K + , Na + , Ca 2+ , and Mg 2+ .
  • typical McGuigan's phosphoramidate prodrugs are unstable and readily decompose to the corresponding very polar diacid after simultaneously releasing phenol under ester hydrolysis conditions.
  • the present invention provides the use of phosphoramidate and phosphonoamidate compounds as prodrugs of nucleoside, nucleotide, C-nucleoside, C- nucleotide, or other alcohol-containing drugs, or phosphonate analogs thereof, for the treatment of a variety of diseases or disorders, including, but not limited to, liver diseases or disorders.
  • the compounds of the present invention can be used in combination with other therapeutically active drug.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any compound disclosed herein, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of treating human diseases, such as viral infection or cancers, comprising administration of any compound as described herein, or a pharmaceutically acceptable prodrug thereof, to a patient in need of the treatment.
  • the present invention provides a method of treating human diseases, such as a viral infection or cancer, comprising administration of a pharmaceutical composition as described herein to a patient in need of the treatment alone or in combination with other drug(s).
  • the present invention provides the use of any compound described herein in the manufacture of medicaments for treatment of human diseases, such as viral infections or cancers.
  • the present invention provides methods for manufacture of these phosphoramidate and phosphonoamidate compounds.
  • the compounds of formula I-IV can be prepared by reaction of, e.g., a hydroxyl group of the parent drug with chlorophosphoramide or chlorophosphonoamidate, for example, via condensation or dehydration.
  • HBV and HCV hepatitis infections
  • liver disorders such as cancers, or metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • the activation mechanism of the phosphoramidate prodrugs disclosed herein involves both esterase and P450 enzymes, through a pathway different from any phosphoramidate prodrugs reported in the literature.
  • the latter simultaneously cyclizes to release phenol to form unstable cyclophosphoramidate E which is subsequently hydrolyzed to a very polar diacid F.
  • the diacid F then releases active nucleoside monophosphate by phosphoramidase.
  • Esterases in the intestine also can degrade the prodrug to diacid F, which may be too polar to readily pass through intestine wall and result in low bioavailability.
  • the ester of phosphoramidate prodrug of nucleoside has demonstrated excellent stability in human plasma and instability in human liver S9, which demonstrated its liver-targeting property (J. Med. Chem. 2010, 53, 7202).
  • the phosphoramidate prodrugs disclosed herein may be activated through different mechanistic pathway involving both esterase and P450 enzymes (Erion, M. et al US 7303739 and references cited therein).
  • the ester group of benzylic phophoramidate prodrug G is hydrolyzed by esterase enriched in the liver to provide stable prodrug H and trapped in the liver (FIG. 3), which demonstrated its liver-targeting property. Again, potentially the ester group can also be hydrolyzed in intestine.
  • compound H is much less polar than diacid F and can be transported into the liver by monocarboxylate transporter.
  • the phosphoramidate prodrug disclosed herein also can be prepared and used in a stable salt form of intermediate prodrug H for injectable formulation, whereas intermediates at the same stage from other phosphoramidate prodrugs reported in the literature and patent applications are unstable and decompose to a very polar diacid after simultaneously releasing phenol.
  • alkyl refers to a saturated straight or branched hydrocarbon radical of typically C to C 2 o, preferably C to C 6 , and specifically includes methyl, CF 3 , CC1 3 , CFC1 2 , CF 2 C1, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, cyclopropyl, and the like.
  • Non-limiting examples of 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 and the like.
  • Alkynyl includes acetylenic unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms, which can be straight-chained or branched and having at least 1 or 2 sites of alkynyl unsaturation (i.e., C ⁇ C bond).
  • alkynyl groups include acetylenic, ethynyl, propargyl, 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, sulfono, sulfato, phosphono, phosphato, or phosphonoxy, either unprotected, or protected as necessary.
  • halogen fluoro, chloro, bromo or iodo
  • Cyclic alkyl or “cycloalkyl” includes 3-7 membered rings of hydrocarbon, such as cyclopropyl, cyclopentyl, cyclohexyl, etc., all optionally substituted.
  • Heteroaromatic group or “heteroaryl” refers to a aromatic ring radical which consists of carbon atoms and from one to five, preferably one to three, heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic or bicyclic and preferably 5- to 10- membered.
  • Examples include, but are not limited to, furanyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophenyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, and benzotriazolyl.
  • heterocyclyl is intended to mean a 3- to 10-membered monocyclic or bicyclic, heterocyclic non-aromatic group which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S.
  • heterocyclyl radicals include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, oxazolidinyl, 4-piperidonyl, pyrazolidinyl, thiazolidinyl, or the like.
  • alkyl, alkenyl, "cycloalkyl,” “aryl,” “heterocyclyl,” or “heteroaryl” is said to be “optionally substituted,” it means that the group is or is not substituted by from one to five, preferably one to three, substituents independently selected from halogen, C -C alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, hydroxy, oxo, Ci-Cy acyl, cyano, nitro, and amino group, or the like.
  • substituents independently selected from halogen, C -C alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, hydroxy, oxo, Ci-Cy acyl, cyano, nitro, and amino group, or the like.
  • Alkoxy or alkyloxy includes the group -OR where R is alkyl.
  • Amino includes the radical -NH 2 .
  • alkylamino or arylamino includes an amino group that has one or two alkyl or aryl substituents, respectively.
  • Halogen or “halo” includes chloro (CI), bromo (Br), fluoro (F) or iodo (I).
  • “Monoalkylamino” includes the group alkyl-NHR'— , wherein R' is selected from alkyl or aryl.
  • Alkylthio and arylthio refer to the group -SR, where R is alkyl or aryl, respectively.
  • any hydroxyl or amino groups can be either protected or unprotected.
  • a hydroxyl or amino group is called to be “protected,” it means that the group is protected by a removable group, such as acyl, phosphonyl, phosphate, or the like, as understood by a person of skill in the art.
  • Suitbale protecting groups for prodrugs are preferably hydrolysable under physiological conditions in vivo.
  • nucleoside includes natural or modified nucleoside, acyclic nucleoside and C-nucleoside.
  • C-nucleoside referred to nucleoside in which glycosyl bond is attached to carbon on modified nucleic bases instead of nitrogen in normal nucleoside (see reference for C-nucleoside review: Chemistry of Nucleosides and Nucleotides by Leroy B Townsend 1994, Science, Chapter 5 The Chemistry of C-nucleosides, Kyoichi A Watanabe pp421). C-nucleoside is not limited to compound cited in the review.
  • “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.
  • prodrug refers to any compound that generates a biologically active compound when administered to a biological system as the result of spontaneous chemical reaction(s), enzyme catalyzed reactions(s), and/or metabolic process(es) or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g. -OH, -NH 2 , associated with the drug, that cleave in vivo.
  • the prodrugs described in the present invention are exemplary, but not limited to, and one skilled in the art could prepare other known varieties of prodrugs.
  • L-nucleoside refers to enantiomer of the natural and modified ⁇ -D- nucleoside analogs.
  • arabinofuranosyl nucleoside refers to nucleoside analogues containing an arabinofuranosyl sugar, i.e. where the 2'-hydroxyl of ribofuranosyl sugars of natural (normal) nucleoside is on the opposite face of the sugar ring.
  • dioxolane sugar refers to sugars that contain an oxygen atom in place of the 3' carbon of the ribofuranosyl sugar.
  • fluorinated sugars refers to sugars that have 1-3 fluorine atoms attached to sugar carbons.
  • nucleoside refers to a purine or pyrimidine base, or analogs thereof, connected to a sugar, including heterocyclic and carbocyclic analogues thereof.
  • terapéuticaally effective amount refers to an amount that has any beneficial effect in treating a disease or condition.
  • phosphate refers to -O-PO 3 " .
  • phosphoramidate refers to -N-PO 3 " .
  • phosphonate refers to -CHR-PO 3 2 -.
  • nucleoside phosphoramidate or phosphonoamidate as a therapeutic agent includes a nucleoside (including acyclonucleoside and C-nucleoside) therapeutic agent derivatized to a phosphoramidate and phosphonoamidate having a benzyl group containing one or more substituents selected from, but not limited to, amino, Ci-C2o acyloxy, C C 2 o alkyl, aryl, C C 2 o alkyloxy, aryloxy or aralkyloxy group, all optionally substituted.
  • the therapeutic agent is, for example, an antiviral agent that includes, or has been derivatized to include, a reactive group, such as a hydroxyl, for attachment of the phosphoramidate or phosphonoamidate moiety.
  • a reactive group such as a hydroxyl
  • therapeutic agents include, but are not limited to, nucleosides, nucleoside analogs including acyclonucleosides, C-nucleosides, and alcohol-containing drugs.
  • phosphoramidates of nucleoside and nucleotide analogues are also provided, such as phosphoramidates of ⁇ -, 2'-, 3'- and 4'-branched or disubstituted nucleosides.
  • Such compounds can be administered in a therapeutically effective amount for the treatment of infectious diseases, liver disorders, including cancers and infectious diseases, such as hepatitis B and hepatitis C infections, including resistant strains thereof.
  • infectious diseases such as hepatitis B and hepatitis C infections, including resistant strains thereof.
  • the phosphoramidate or phosphonoamidate prodrugs of present invention may also generally be referred to as "phosphate prodrugs" in this application, which meanings should be well understood by a person of skill in the art by taking into consideration the context in which such references are made.
  • nucleosides acyclonucleoside and their monophosphate drugs (Y-O-PO 3 2 ).
  • parent drug also refers to phosphonate-containing drugs [Y-CH 2 - P(0)(OH) 2 ].
  • biolgically active agents refer to nucleoside (Y-OH), nucleoside mono-phosphates (Y-O-PO 3 " ), nucleoside diphosphates ( ⁇ -0- ⁇ 2 ⁇ 6 3 ), nucleoside triphosphates (Y-O-P3O9 4 ), nucleoside phosphonate [Y- CH 2 P(0)(OH) 2 , Y-CH2PO3H, non-nucleoside phosphonate, monophosphate (Y- CH 2 P 2 0 6 3 ⁇ ) or its diphosphate (Y-CH ⁇ Og 4 ), alcohol-containing compound.
  • 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 - alkyl-6-aminopurines, N 6 -acyl-6-aminopurines (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzyl-6-aminopurine, N 6 -vinyl-6-aminopurine, N 6 -ethynyl-6- aminopurine, 6-cycloaminopurine, 7-deazapurine, modified 7-deazapurine, thymine, cytosine, N 4 -acylcytosine, 5-fluorocytosine, 5-methylcytosine, 6-azacytosine, uracil, 5- fluorouracil, 5-alkyluracil, 5-vinylpyrimidine, 5-ethynyluracil, 5-hydroxymethyluracil, 5- amidouracil, 5-cyanouracil, 5-i
  • Purine bases include, but are not limited to, guanine, adenine, 2-fluoroadenine, 2-chloroadenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine, and 6-chloropurine, 6-alkoxypurine, 6-deoxyguanine, 6-alkylthiopurine. 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(0)R', wherein R' is a straight, branched, or cyclic alkyl or aryl.
  • 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
  • Diastereomerically enriched diastereomer means that the material contains greater than 80% of major diastereomer and less than 20% of minor diastereomer, in particular with regard to (R)- and (S)-configurations of the phosphorus stereogenic center in the phosphoramidate and phosphonoamidate prodrugs.
  • 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.
  • moiety refers to a partial structure of a molecule, often a significant portion of a molecule retaining characteristic features of the molecule. In some instances, it is exchangeable with the term “group” or "substituent.”
  • group or "substituent.”
  • a “sugar moiety” means a sugar group attached to a structure of interest by a covalent bond through an oxygen atom of the sugar molecule after losing a hydrogen atom from a hydroxyl group or through a carbon atom after losing a hydroxyl group from the carbon atom.
  • the terms “subject” and “patient” are used interchangeably.
  • the terms “subject” refers to an animal, such as a mammal including a non-primate (e.g., cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee).
  • the subject is a human.
  • the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof.
  • the term “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.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “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.
  • “treating” or “treatment” includes delaying the onset of the disease or disorder.
  • the prodrug protecting group be attached to a hydroxyl group on the parent drug.
  • the parent drug may have many such functional groups.
  • the preferred group selected for attachment of the prodrug is the one that is most important for biological activity and is chemically suitable for attachment to the prodrug.
  • the phosphoric prodrug moiety will prevent the prodrug from having biological activity.
  • An inactive prodrug should reduce systemic side effects because higher drug concentrations will be in the target organ (liver) relative to non-hepatic tissues.
  • nucleoside or non-nucleoside containing hydroxyl functional group which can be used to be derivatized to phosphoramidate or phosphonoamidate prodrugs of the present invention.
  • These compounds include nucleoside, C-nucleoside, nucleotide, phosphonate and other alconol-containing compounds.
  • Prodrugs disclosed herein derivatized from these compounds are considered to fall within the scope of the present invention.
  • nucleoside drugs D- and L-
  • Y- OH a compound of formula V:
  • R 6 and R 7 are selected independently from, but are not limited to, H, OH, CH 3 0, F, CI, Br, I, CN, N 3 , methyl, ethyl, vinyl, ethynyl, chloro vinyl, fluoromethyl, difluoromethyl, and trifluoromethyl, or alternatively R 6 and R 7 together form a vinylidene
  • R 1 ' group F R 12 wherein R 11 and R 12 are independently selected from hydrogen, halogen
  • R is selected from but is not limited to, H, methyl, ethyl, vinyl, ethynyl, chlorovinyl, fluoromethyl, difluoromethyl, and trifluoromethyl;
  • R 9 is selected from but is not limited to, H, CN, N 3 , methyl, ethyl, vinyl, ethynyl, chlorovinyl, fluoromethyl, difluoromethyl, and trifluoromethyl;
  • R 10 is selected from, but is not limited to, H, OH, F, cyano, and azido.
  • B is selected from, but is not limited to, pyrimidine and purine and derivatives thereof selected from formulas -1 and B-2:
  • X is selected from, but not limited to, H, NH 2 , NHMe, NMe 2 , and halogen (I, Br, CI, F);
  • X 4 is NH 2 or OH
  • X 5 is selected from, but not limited to, halogen (I, Br, CI, F), OH, NH 2 , methyl, vinyl, alkyl, 2-bromovinyl, and ethynyl;
  • X 6 is selected from, but not limited to, H, OH, and optionally substituted alkyloxy (preferably OMe and OEt,), aryloxy, cyclic alkyloxy, alkylthio (preferably SMe and SEt), arylthio, cyclic alkylthio, thienyl, furyl, alkylamino, dialkylamino, arylamino, arylalkylamino, cyclic alkylamino, and cyclopropylamino;
  • Z is Nitrogen (N) or CX 7 ;
  • X is selected from, but not limited to, H, and optionally substituted vinyl, ethynyl, and halogen (I, Br, CI, F);
  • modified pyrimidines or purines such as 5-azapyrimidine, 6-azapyrimidine, 3-deazapyridine, 3-fluoro-3-deazapyrimidine, and 8-aza-7-deazapurine, and modified bases for C-nucleoside, or the like, are also considered to fall within the scope of the present invention.
  • nucleoside drugs D- and L-
  • Another class of exemplary nucleoside drugs (D- and L-) therapeutically useful and suitable to be derivatized to prodrugs of the present invention is selected from compounds of formula VI:
  • R 11 and R 12 are independently selected from, but are not limited to, H, N 3 , F, CN, and optionally substituted alkyl (preferably methyl) and vinyl.
  • parent drugs suitable for the prodrug derivatization of the present invention include compounds of formulas (D- and L-isomers) VII and VIII:
  • B is a base group defined as above.
  • Another class of parent drugs suitable for the prodrug modification of the present invention is selected from, but is not limited to, nucleoside phosphonates (Biochem. Pharmacol. 2007, 73, 911, which is hereby incorporated by reference).
  • Another class of parent drugs suitable for the prodrug derivatization of the present invention is seleted from acyclic nucleosides, including, but not limited to, acyclovir, ganciclovir and pencyclovir.
  • Another class of parent drug suitable for the prodrug derivatization of the present invention is selected from C-nucleosides, a special class of nucleosides (see reference for C-nucleoside review: Chemistry of Nucleosides and Nucleotides by Leroy B Townsend 1994, Science, Chapter 5, The Chemistry of C-nucleosides, Kyoichi A Watanabe, p. 421, which is hereby incorporated by reference).
  • C-Nucleosides suitable for the present invention include, but are not limited to, the compounds cited in the review.
  • nucleoside monophosphates When some of nucleosides are not good substrates for kinases and show no biological activity while their nucleotides or nucleoside monophosphates are biologically active, the parent drugs are referred to the corresponding nucleoside monophosphates.
  • compounds suitable for prodrug derivatization herein include, but are not limited to, nucleosides (including prodrugs thereof) of formulas described in Table 1.
  • prodrugs herein are provided for the treatment of viral infections, cancers and other liver disorders. These prodrugs can be used to improve bioavailability and/or pharmacokinetics of parent drugs. These prodrugs and compositions disclosed herein can be administered either alone or in combination with other therapeutically effective agents.
  • prodrugs disclosed herein can be prepared and used as water soluble salts.
  • the water solubility is a useful property different from any other phosphoramidate prodrugs reported in the literature. Therefore, the prodrug technology provided herein is more versatile and useful than the phosphoramidate technologies reported in the literature.
  • the phosphoramidate and phosphonoamidate compounds of a variety of therapeutic agents disclosed herein can be used for the treatment of such diseases that the corresponding parent drugs are used for.
  • the prodrugs disclosed herein can also be used for the treatment of viruses resistant to parent drugs.
  • Such phosphoramidate and phosphonoamidate compounds can advantageously enhance drug delivery to the liver.
  • the compounds permit delivery of an active 5'-monophosphate of a nucleoside to the liver, which can enhance the formation of active triphosphorylated compound.
  • the present invention provides methods for the treatment of liver disorders, the methods comprising the administration of an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof to an individual host.
  • the methods encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment of liver disorders in combination with other agent(s) effective for the treatment of the diseases.
  • the compound can be any compound as described herein, and the other agent can be any agent(s) known to those of skill in the art.
  • Prodrug technologies of the present invention can be applied in conversion of a large number of inactive nucleosides into prodrugs of therapeutically useful nucleotides.
  • Therapeutic use of the prodrugs disclosed herein is also provided for the treatment of hepatitis infections (including HBV and HCV) and liver disorders including liver cancer and metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • hepatitis infections including HBV and HCV
  • liver disorders including liver cancer and metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity.
  • compositions comprising a compound selected from compounds of formulae I, II, III, IVa and IVb, or pharmaceutically acceptable salts (acid or basic addition salts)and solvates (preferably hydrates) thereof, and a pharmaceutically acceptable medium selected from excipients, carriers, diluents, and equivalent media.
  • formulation of the above embodiment can contain any of the compounds of formulae I, II, III, IVa, IVb and those exemplified herein, either alone or in combination with another compound of the present invention.
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration dosage forms include, but are not limited to, tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present invention are efficacious when administered by suppository administration, among other routes of administration.
  • the most convenient manner of administration is generally oral using a convenient daily dosing regimen that can be adjusted according to the severity of the disease and the patient's response to the antiviral or anticancer medication.
  • a compound or compounds of the present invention, as well as their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for human pharmaceutical use.
  • the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Solid form preparations include powders, tablets, pills, capsules, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa., which is hereby incorporated by reference.
  • the compounds of the present invention can also be encapsulated in liposomes, such as those disclosed in U.S. Pat. Nos. 6,180,134, 5,192,549, 5,376,380, 6,060,080, and 6,132,763, each of which is incorporated by reference.
  • a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (e.g., salt formulation), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • the compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art based on the present disclosure. Exemplary methods of preparation are described in detail in the Examples Section below.
  • Active is a nucleoside or drug moiety
  • Group is an amine moiety or S-containing moiety for IDX-prodrug or aminoacid residue
  • W is an aryl group (preferably phenyl and naphthyl), or -(CH 2 ) felicit'SC(0)C(CH 3 ) m CH 2 OH) wherein n * is 2 or 3 and m' is 0, 1, 2, or 3; and LG is a leaving group.
  • diastereomerically enriched benzylic phosphoramidate reagent 4 could also be prepared by recrystallization from a mixture of diastereomers (Scheme 1).
  • Phosphoramidate ester prodrug F5 was obtained by deprotection of 6 with tetrabutylammonium fluoride (TBAF).
  • a phosphoramidate prodrug in sodium salt form (7) was also prepared by the treatment of compound F5 with IN NaOH (Scheme 4).
  • prodrugs of other nucleosides or nucleotides can be prepared by those of skill in the art based on the present disclosure.
  • the compounds synthesized as anti-cancer agents can each be tested in leukaemic cell lines to assess their anticancer efficacy.
  • the compounds can be tested using the MTS assay reagents from Pro mega (CellTiter96 Aqueous One solution proliferation assay). Such testings can be done by a person of ordinary skill in the art following the common testing procedures as described in the literature. For example, the compounds can be tested at 5 ⁇ concentration (see, e.g., WO 2006/100439).
  • Anti-HCV activity and cytotoxicity of compounds disclosed herein were assayed following the method described in WO 2007/027248.
  • Compounds of the present invention can be assayed for anti-HBV activity according to any assay known to those of skill in the art.
  • liver cells of the subject can be used to assay for the liver accumulation of the compound(s) or derivatives thereof, e.g., a nucleoside, nucleoside phosphate or nucleoside triphosphate derivative thereof.
  • Compounds can be assayed for accumulation of active metabolites in the liver of animals according to any assay known to those of skill in the art.
  • a mixture of compound 3 was prepared as in Example 1 in 20 mmol scale. To the mixture was added a solution of pentafluorophenol (20 mmol) and triethylamine (20 mmol). To the mixture was added an additional triethylamine (20 mmol) and the mixture was stirred at room temperature for 4h. EtOAc (200 mL) was added and the mixtue was washed with water and brine and dried over Na 2 S0 4 . Solvent was removed and the residue was purified by silica gel column chromatography (5-50% EtOAc in hexane) to give crude compound as a mixture of diastereomers.
  • Diastereomers of 4 and 4' can also be recovered from the filtration mother liquor by chromatographic methods or any other available separation methods, respectively.
  • Example 11 By following the above procedure using corresponding nucleoside or reagent, the following prodrugs (Table 2) of typical nucleosides in Table 1 can be prepared. Table 2. Structures of the selected prodrugs
  • Compounds synthesized as anti-cancer agents can each be each tested in leukaemic cell lines to assess their anticancer efficacy.
  • the compounds can be tested using the MTS assay reagents from Promega (CellTiter96 Aqueous One solution proliferation assay).
  • the compounds can be tested 5 ⁇ (WO 2006/100439). Symbol, (+) indicates that the compound tested inhibits cellar growth greater than 50%.
  • the anti-HCV activity and toxicity of the exemplary compounds can be tested in two biological assays -a cell-based HCV replicon assay and cytotoxicity assay (WO
  • a human hepatoma cell line (Huh-7) containing replicating HCV subgenomic replicon with a luciferase reporter gene (luc-ubi-neo) was used to evaluate anti-HCV activity of the compounds.
  • level of luciferase signal correlates with the viral
  • the HCV replicon-reporter cell line (NK/luc-ubi-neo) was cultured in DMEM medium supplemented with 10% fetal bovine serum and 0.5 mg/ml
  • HCV replicon RNA synthesis To evaluate the antiviral activity of compounds, serial dilutions were prepared with concentrations ranging from 0.14 to 300 ⁇ . Diluted compounds were transferred to a 96-well plate followed by the addition of replicon cells (6000 cells per well). Cells were incubated with the compounds for 48 h after which luciferase activity was measured. Reduction of luciferase signal reflected the decrease of HCV replicon RNA in the treated cells and used to determine the EC 50 value (concentration which yielded a 50% reduction in luciferase activity).
  • a Huh-7 cell line carrying a luciferase reporter gene (driven by a HIV LTR promoter ) stably integrated into the chromosome was used to analyze the cytotoxic effect of the selected compounds.
  • This cell line (LTR-luc) was maintained in DMEM medium with 10% FBS.
  • Design of the cytotoxicity assay was similar to that of the HCV replicon assay. Reduction of luciferase activity in the treated cells correlated with the cytotoxic effect of the test compound and was used to calculate the CC 50 value (concentration that inhibited cell growth by 50%).
  • Compounds of the present invention can be assayed for anti-HBV activity according to any assay known to those of skill in the art.
  • Example 16 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 liver cell of the subject can be used to assay for the liver accumulation of compound or a derivative thereof, e.g. a nucleoside, nucleoside phosphate or nucleoside triphosphate derivative thereof.
  • FDURPAN (0.096 mmol, 23.7 mg/kg) were dosed orally by gavage with a single dose of each compound to rats in a volume of 5 mL/kg in 0.5% carboxymethylcellulose sodium.
  • FDURPAN (0.096 mmol, 50.24 mg) was dosed both orally or iv by gavage with a single dose to rats in a volume of 5 mL/kg in water.
  • the animal was restrained manually at designated time points. Approximately 500 ⁇ ⁇ of blood/time point was collected into K 2 EDTA tube via cardiac puncture for terminal bleeding under anesthesia with Isoflurane. Blood samples were put on ice after collection and then centrifuged to obtain plasma sample (2000 g, 5 min, 4 °C) within 15 minutes of sampling.
  • Plasma samples were then centrifuged to obtain plasma sample (2000 g, 5 min, 4 °C). All the plasma samples were immediately quenched for protein precipitation. Liver samples were removed at designated time points by first sacrificing the animal by C0 2 inhalation, then perfusing the liver with ice cold saline and removing the left middle liver lobe, which was then snap frozen in dry ice. Liver samples were stored at approximately -80 °C until analysis. The liver homogenate was then processed for further analysis by LC/MS-MS. Plasma and liver samples were stored at approximately -80 °C until analysis.
  • FDURPAE FDURPAN 234 0.25 316 3673 0.25 5509 (po) FDUR 17 0.25 26 747 0.25 1541 (0.096 mmol) 5FU NA NA NA 139 0.25 257
  • NA Not analyzed due to concentration below quantitation level.
  • Ester of prodrug F5 was rapidly hydrolyzed to more stable secondary prodrug F7 (FDURPAN) mediated by esterases so that FDURPAN instead of FDURPAE was monitered.
  • Ester prodrug F5 (FDURPAE) can efficiently deliver drug substances including stable metabolte F7 (FDURPAN), parent drug (FDUR), metabolites (5FU and FDUR-MP) into the liver after oral administration. Only minimum secondary prodrug (FDURPAN), and parent drug (FDUR) could be detected in plasma. Ratio of C max for FDURPAN and FDUR in liver/plasma were 17 and 59, respectively. While metabolites 5FU and active drug FDUR-MP could not be detected in plasma at all. FDURPAE demonstrated excellent liver-targeting nature. Concentration of active drug (FDUR-MP) in the liver is comparable to that from iv administration of prodrug (FDURPAN) in sodium salt form.
  • PK Data for parent drug (FDUR) in Table 3 indicated that very limited drug- related compouds including parent drug (FDUR), metabolites (5FU and FDUR-MP) were detected in the liver after orally administration of FDUR. More drug substances including FDUR, 5FU and FDUR-MP were detected in plasma than in the liver. Overall, FDUR could not deliver drug substances into the liver target efficiently.
  • Prodrug (FDURPAN) in sodium salt form was dosed to rats both by oral or iv.
  • Data in Table 3 indicated that FDURPAN could not deliver drug substances including FDURPAN, FDUR, 5FU and FDUR-MP to the liver target efficiently after oral administration probably due to its high clearance of water soluble drug.
  • FDURPAN did deliver high levels of drug substances, in particular active monophosphate-FDUR-MP in the liver target after iv administration.
  • ester prodrug of the present invention can be useful for the development of drugs for oral administration while prodrug in salt form can be better applied for development of drugs for iv administration for the treatment of liver associated diseases, such as hepatitis infection or liver cancer.
  • FIG. 4 illustrates prossible metabolic pathway for benzylic phosphoramidate or phosphonoamidate of the present invention.
  • Ester prodrug F5 (FDURPAE) is hydrolyzed to a secondary prodrug F7 (FDURPAN) mediated by esterases.
  • the FDURPAN is hydroxylated in the presence of P450 followed by releasing benzaldehyde and diacid which is further converted to the desired active nucleoside monophosphate mediated by phosphoramidase.
  • the floxuridine (FDUR) monophosphate demonstrates anticancer activity by inhibiting activity of thymidylate synthase.
  • Prodrug technology disclosed herein can be applied in drug development to improve properties of parent drugs.
  • Prodrug technology disclosed in the present invention is particularly useful for the development of drugs for the treatment of liver diseases, such as liver cancers, liver infections including hepatitis infections.
  • the present monophosphate prodrugs of nucleosides for the first time demonstrated the ability to deliver nucleoside phosphate into the liver selectively after oral administration.
  • the technology of the present monophosphate prodrugs of nucleosides can be used to convert drugs that previously can only be administered via injection to orally available drugs.
  • the present monophosphate prodrugs of nucleosides were for the first time prepared as single isomers through asymmetric synthesis, which may find general practical utility for the drug design and development.
  • the present monophosphate prodrugs of nucleosides were designed and discovered to be activated by esterase and P450 enzymes in the liver, which can be considered as double-liver-targeting prodrugs and will be particularly useful for the development of orally available drugs for treating liver diseases including hepatitis infections and liver cancers.
  • Monocarboxylic acids and salts of nucleoside phosphoramidate prodrugs were prepared for the first time as stable water soluble drug substances.

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Abstract

La présente invention concerne des promédicaments de phosphoramidate et de phosphonoamidate d'agents thérapeutiques à base d'alcool, tels que des nucléosides, des nucléotides, des acyclonucléosides, des C-nucléosides, et des C-nucléotides, et l'utilisation de ces promédicaments pour le traitement de maladies ou troubles, comprenant des maladies infectieuses et des cancers. La présente invention concerne en outre un procédé général pour augmenter la biodisponibilité et/ou la propriété de ciblage hépatique de médicaments à base d'alcool par conversion des médicaments à base d'alcool en promédicaments phosphoramidates ou phosphonoamidates, et des procédés de préparation de ces promédicaments.
PCT/US2013/032128 2012-06-16 2013-03-15 Promédicaments de phosphoramidate et phosphonoamidate à double ciblage hépatique WO2013187978A1 (fr)

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US9675632B2 (en) 2014-08-26 2017-06-13 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
US9718851B2 (en) 2014-11-06 2017-08-01 Enanta Pharmaceuticals, Inc. Deuterated nucleoside/tide derivatives
US9732110B2 (en) 2014-12-05 2017-08-15 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
WO2017162169A1 (fr) * 2016-03-25 2017-09-28 江苏天士力帝益药业有限公司 Promédicament de phosphoramidate d'uridine, procédé de préparation de ce dernier, et utilisations médicinales de ce dernier
US9828410B2 (en) 2015-03-06 2017-11-28 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
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KR20180053320A (ko) * 2015-09-16 2018-05-21 브라이트제네 바이오-메디컬 테크놀로지 코., 엘티디. 뉴클레오시드 포스포아미데이트 프로드러그의 제조방법 및 이의 중간체
US10034893B2 (en) 2013-02-01 2018-07-31 Enanta Pharmaceuticals, Inc. 5, 6-D2 uridine nucleoside/tide derivatives
JP2018532718A (ja) * 2015-09-16 2018-11-08 ブライトジーン バイオ−メディカル テクノロジー カンパニー リミテッド ホスホルアミダート化合物及びその製造方法並びに結晶
US10202412B2 (en) 2016-07-08 2019-02-12 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections
US10519186B2 (en) 2017-02-01 2019-12-31 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US10774104B2 (en) 2015-12-11 2020-09-15 Laurus Labs Private Ltd Diastereoselective synthesis of phosphate derivatives
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US10946033B2 (en) 2016-09-07 2021-03-16 Atea Pharmaceuticals, Inc. 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment
US10987372B2 (en) 2016-03-11 2021-04-27 Kagoshima University Anti-hepatoma-virus agent
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US10034893B2 (en) 2013-02-01 2018-07-31 Enanta Pharmaceuticals, Inc. 5, 6-D2 uridine nucleoside/tide derivatives
CN114404427A (zh) * 2014-02-13 2022-04-29 配体药物公司 前药化合物及其用途
US9675632B2 (en) 2014-08-26 2017-06-13 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
US9718851B2 (en) 2014-11-06 2017-08-01 Enanta Pharmaceuticals, Inc. Deuterated nucleoside/tide derivatives
US9732110B2 (en) 2014-12-05 2017-08-15 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
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US10870672B2 (en) 2015-03-06 2020-12-22 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
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US10946033B2 (en) 2016-09-07 2021-03-16 Atea Pharmaceuticals, Inc. 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment
US11975016B2 (en) 2016-09-07 2024-05-07 Atea Pharmaceuticals, Inc. 2′-substituted-N6-substituted purine nucleotides for RNA virus treatment
US10519186B2 (en) 2017-02-01 2019-12-31 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus
US12006340B2 (en) 2017-02-01 2024-06-11 Atea Pharmaceuticals, Inc. Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus
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US11690860B2 (en) 2018-04-10 2023-07-04 Atea Pharmaceuticals, Inc. Treatment of HCV infected patients with cirrhosis
US12060380B2 (en) 2018-07-06 2024-08-13 Kancera Ab Phosphate and phosphonate derivatives of 7-amino-5-thio-thiazolo[4,5-d]pyrimidines and their use in treating conditions associated with elevated levels of CX3CR1 and/or CX3CL1
US11738038B2 (en) 2020-02-27 2023-08-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
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