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WO2005087788A2 - Elaboration de phorphonates-esters nucleosidiques - Google Patents

Elaboration de phorphonates-esters nucleosidiques Download PDF

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Publication number
WO2005087788A2
WO2005087788A2 PCT/US2005/007187 US2005007187W WO2005087788A2 WO 2005087788 A2 WO2005087788 A2 WO 2005087788A2 US 2005007187 W US2005007187 W US 2005007187W WO 2005087788 A2 WO2005087788 A2 WO 2005087788A2
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formula
compound
alkyl
substituted
alkenyl
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PCT/US2005/007187
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WO2005087788A3 (fr
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James R. Beadle
Karl Hostetler
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The Regents Of The University Of California
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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
    • 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
    • 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

Definitions

  • CDV has been reported to be active against all double stranded DNA viruses. It has also been reported that the in vitro activity of long chain alkoxyalkyl esters of CDV, for example hexadecyloxypropyl-CDV (HDP- CDV) and octadecyloxypropyl CDV, (ODE-CD V) against herpes group viruses (HCMV and HSV), orthopoxviruses (vaccinia and cowpox) and others is increased when compared to unmodified CDV.
  • HDP- CDV hexadecyloxypropyl-CDV
  • ODE-CD V octadecyloxypropyl CDV
  • HCMV and HSV herpes group viruses
  • orthopoxviruses vaccinia and cowpox
  • alkoxyalkyl esters of CDV have been shown to have good oral bioavailability. Oral administration of the alkoxyalkyl analogs provides decreased exposure to the kidneys versus when unmodified drug is given intravenously. This is expected to improve tolerance to drug exposure. Preliminary studies in lethal ectromelia, cowpox and vaccinia virus challenge in mice indicate that HDP-CDV and ODE-CDV are effective in preventing death when given orally. CDV itself is not effective orally.
  • the in vitro antiviral activity and oral bioavailability of many other nucleoside phosphonates such as 9-(2-phosphonomethoxyethyl)- guanine (PMEG), 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir), and (S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine ((S)-HPMPA), (R)-9-(2- phosphonomethoxypropyl)adenine (PMPA, tenofovir), and 9- (phosphonopropoxymethyl)guanine (PPMG) can be improved by derivitazation with a lipophilic group.
  • nucleoside phosphonates such as 9-(2-phosphonomethoxyethyl)- guanine (PMEG), 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir), and (S)-9-(3-hydroxy-2-phospho
  • nucleoside phosphonate monoesters Several procedures for the preparation of nucleoside phosphonate monoesters have been reported in the literature. Alkylation of cyclic cidofovir (cCDV) using alkoxyalkyl bromides followed by basic hydrolysis is known in the art. However, this approach gave very poor yields of product and required difficult isolation procedures because regioisomers are formed.
  • cCDV cyclic cidofovir
  • cyclic cidofovir N,N'-dicyclohexyl 4-mo holinecarboxamidine salt
  • 3-alkoxy-l-bromoalkanes N,N-DMF, 80 °C
  • esters of cCDV See, Beadle et al, Antimicrobial Agents and Chemotherapy 46(8), 2381- 2386, 2002 and Kern et al, Antimicrobial Agents and Chemotherapy 46(4), 991- 995, 2002
  • the yields in this reaction are low and careful chromatography is required to avoid contamination with N-dialkylated compound.
  • the processes provided herein include the steps of providing a lipophilic phosphonate monoester; reacting the lipophilic phosphonate monoester with an antiviral nucleoside or antiproliferative nucleoside having a free -OH group; and isolating the lipophilic phosphonate monoester of the antiviral nucleoside or antiproliferative nucleoside.
  • the process is for the preparation of lipophilic nucleoside phosphonate monoesters of formula 3, including their stereoisomers,
  • n 1 to 3. In one embodiment, n is 1.
  • the reactive sites in the nucleosides for use in the processes provided herein can be protected by suitable protecting groups known in the art. The protecting groups can be then removed by deprotection reactions known in the art. Certain of the antiviral and anticancer nucleoside phosphonates that can be prepared using the processes provided herein are described by Hostetler et al. in International Patent Application No. WO 01/39721.
  • the processess provided herein give lipophilic nucleoside phosphonate monoesters in high purity and good yields within a commercially feasible amount of time in a minimum number of process steps. In certain embodiments, the processes provided herein do not need difficult separation processes in the preparation of lipophilic esters of nucleoside phosphonate monoesters. In certain embodiments, provided herein are lipophilic phosphonate monoesters of formula 1 used in the processes provided herein. DETAILED DESCRIPTION A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety.
  • nucleoside refers to a molecule composed of a heterocyclic base and a carbohydrate. Typically, a nucleoside is composed of a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and non-natural bases well known in the art. The carbohydrates include the true sugars found in natural nucleosides or a species replacing the ribofuranosyl moiety or acyclic sugars.
  • the heterocyclic nitrogenous bases are generally located at the 1' position of a nucleoside sugar moiety.
  • Nucleosides generally contain a base and sugar group.
  • the nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non-standard nucleosides; see for example, Eckstein et al, International PCT Publication No. WO 92/07065 and Usman et al, International PCT Publication No. WO 93/15187).
  • the heterocyclic base is typically thymine, uracil, cytosine, adenine or guanine.
  • acyclic sugars contain 3-6 carbon atoms and include, for example, the acyclic sugar moieties present in acyclovir (-CH 2 -O-CH 2 CH 2 -OH), ganciclovir (-CH 2 -O-CH(CH 2 OH)-CH 2 -OH), and the like.
  • Natural nucleosides have the ⁇ -D-configuration. The term "nucleoside” shall be understood to encompass unnatural configurations and species replacing the true sugar that lack an anomeric carbon. In natural nucleosides the heterocyclic base is attached to the carbohydrate through a carbon-nitrogen bond.
  • nucleoside shall be understood to encompass species wherein the heterocyclic base and carbohydrate are attached through a carbon-carbon bond (C-nucleosides).
  • the nucleoside contains 1 or more functional groups that may be reactive to form undesired products under the reaction conditions of the present process, for example, the amino groups of cytosine and adenine and the 2-amino and 4-oxo groups of guanine, such functional groups may be blocked using the protecting groups commonly employed in nucleoside chemistry.
  • the amino group of adenine and cytosine may be protected by benzoyl; the 4-oxo and 2-amino groups of guanine may be protected by the triphenylmethyl (trityl) group.
  • lipophilic refers to the cyclic, branched or straight chain chemical groups that when covalently linked to a phosphonic acid to form a phosphonate monoester increase oral bioavailability and enhance activity of the nucleoside phosphonates as compared with the parent nucleoside phosphonates.
  • lipophilic groups include, but are not limited to alkyl, alkoxyalkyl, and alkylglyceryl.
  • nucleoside phosphonate and “acyclic nucleoside phosphonate” refer to the group of phosphonomethoxyalkyl or phosphono substituted nucleoside derivatives that are biologically active, for example, as anti-viral, anti-cancer or anti-parasitic drugs.
  • methylene phosphonate refers to compounds of the formula
  • lipophilic monoesters of nucleoside phosphonates refers to compound where a lipophilic group is covalently attached to a nucleoside phosphonate via an ester linkage.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, nitrates, borates, me
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • a prodrug is a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • prodrugs of the compound see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
  • Other prodrugs for use herein are described elsewhere herein.
  • the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. It is understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms and how to determine antiproliferative activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • alkyl refers to a monovalent straight or branched chain or cyclic radical.
  • the alkyl group contains from one to twenty-four carbon atoms, including methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, octadecyl, nonadecyl, eicosyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, and the like.
  • lower alkyl refers to alkyl groups of 1 to 6 carbon atoms.
  • substituted alkyl refers to alkyl groups further bearing one or more substituents, including, but not limited to substituents selected from lower alkyl, hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano,azido, nitro, nitrone, amino, amido, - C(O)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, and sulfuryl, which may be protected or unprotected as necessary, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Ed.
  • alkenyl refers to straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds. In certain embodiments, the alkenyl group contains from 2 up to 24 carbon atoms, and “substituted alkenyl” refers to alkenyl groups further bearing one or more substituents as set forth above.
  • alkynyl refers to straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds, h certain embodiments, the alkynyl group contains from 2 up to 24 carbon atoms, and "substituted alkynyl” refers to alkynyl groups further bearing one or more substituents as set forth above.
  • aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl” refers to aryl groups further bearing one or more substituents as set forth above.
  • heteroaryl refers to aromatic groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and “substituted heteroaryl” refers to heteroaryl groups further bearing one or more substituents as set forth above.
  • subject is an animal, typically a mammal, including human, such as a patient.
  • haloalkyl means an amount required for prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated including those associated with viral infection, parasitic infections and cell proliferation.
  • substituents e.g., haloalkyl
  • haloalkyl may include one or more of the same or different halogens.
  • the abbreviations for any protective groups, amino acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. ⁇ :942-944).
  • n 1 c) isolating the compound of formula 3; wherein M is -H, or a physiologically acceptable monovalent cation; L is a lipophilic group; R is a nucleoside or a pharmaceutically acceptable derivative thereof; X is a leaving group; and n is 1 to 3. In one embodiment, n is 1.
  • aprotic solvents known to those of skill in the art can be used in the process. Exemplary aprotic solvents include, but are not limited to N,N- dimethylformamide (N,N-DMF), tetrahydrofuran (THF) and triethyamine.
  • X is selected from halogen, toluenesulfonyloxy, and methylsulfonyloxy. In certain embodiments, X is bromo or iodo. In certain embodiments, X is toluenesulfonyloxy.
  • M is -H, Na , K , or NH 4 + . In other embodiments, M is -H or Na + . In other embodiments, M is -H. In other embodiments, M is Na + .
  • the compounds of formula 2 in the processes provided herein have formula:
  • R 3 , R 4 and R 5 are each independently H, hydroxy, halo, azido, C ⁇ . 6 alkyl,
  • R 3x is H, azido, substituted or unsubstituted d- 6 alkyl, substituted or unsubstituted C 2 . 6 alkenyl or substituted or unsubstituted C 2 . 6 alkynyl;
  • R 4x is H, Ci_ 6 substituted or unsubstituted alkyl, C 2 . 6 substituted or unsubstituted alkenyl or C 2 _ 6 substituted or unsubstituted alkynyl; and
  • R >3z is H, d- 6 alkyl, hydroxylC 1 . 6 alkyl, halod- 6 alkyl, azidod. 6 alkyl or
  • R is H, azido, substituted or unsubstituted C ⁇ . 6 alkyl, substituted or unsubstituted C 2 . 6 alkenyl or substituted or unsubstituted C 2 . 6 alkynyl.
  • R 3 is H, azido, substituted or unsubstituted d. 6 alkyl.
  • R is H or azido.
  • R is azido.
  • R 3 is H.
  • R 4 and R 5 are each independently selected from hydrogen, halo and hydroxyalkyl.
  • R 4 and R 5 are each independently selected from halo and hydroxyalkyl. In certain embodiments, R 4 and R 5 are each independently selected from fluoro and hydroxymethyl. In certain embodiments, R 4 is selected from fluoro and hydroxymethyl. In certain embodiments, R 5 is selected from fluoro and hydroxymethyl. In certain embodiments, the compounds of formula 2 in the processes provided herein have formula:
  • R 3x is H, azido, substituted or unsubstituted C ⁇ . 6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl or substituted or unsubstituted C . 6 alkynyl; R 4x is H, d- 6 substituted or unsubstituted alkyl, C 2 . 6 substituted or unsubstituted alkenyl or C 2 . 6 substituted or unsubstituted alkynyl and other variables are as defined elsewhere herein.
  • R 3x is H, azido or substituted or unsubstituted d- 6 alkyl.
  • R 4x is H, d_ 6 substituted or unsubstituted alkyl, C 2 . 6 substituted or unsubstituted alkenyl or C 2 _ 6 substituted or unsubstituted alkynyl. In certain embodiments, R 4x is H, or C ⁇ -6 alkyl. In certain embodiments, the compounds of formula 2 in the processes provided herein have formula:
  • R 3z is H, d- 6 alkyl, hydroxyl C ⁇ . 6 alkyl, halo d- 6 alkyl, azido d- 6 alkyl or OH and the other variables are as defined elsewhere herein.
  • R 3z is hydrogen C ⁇ _ 6 alkyl or hydroxyl d- 6 alkyl.
  • R 3z is hydrogen or hydroxy methyl.
  • R 3z is hydroxy methyl.
  • the OH groups are protected, for example as an ester or an ether.
  • R 3z may be in S or R configuration.
  • the compounds of formula 2 in the processes provided herein have formula:
  • R 3y is H, substituted or unsubstituted d- 6 alkyl, substituted or unsubstituted C 2 . 6 alkenyl or substituted or unsubstituted C 2 . 6 alkynyl; or OH and the other variables are as defined elsewhere herein.
  • R 3y is hydrogen d- 6 alkyl or hydroxyl d- 6 alkyl.
  • R 3y is hydrogen or hydroxy methyl, hi certain embodiments, R 3y may be in S or R configuration.
  • the compounds of formula 2 in the processes provided herein have formula:
  • L is a substituted or unsubstituted C 8 -C 24 alkyl or substituted or unsubstituted C 8 -C 24 alkenyl having from 1 to 6 double bonds, wherein substituents when present are selected from one or more halogen, alkyl, - OH, -SH, cycloalkyl, or epoxide; or L has formula:
  • R 1 and R la are independently -H, optionally substituted -O(C 1 -C 24 )alkyl, -O(d-C 2 )alkenyl, -O(C ⁇ -C 24 )acyl, -S(d-C 2 )alkyi, -S(d-C 2 )alkenyl, or-S(C ⁇ - C 24 )acyl, wherein at least one of R 1 and R la are not -H, and wherein the alkenyl or acyl moieties optionally have 1 to 6 double bonds
  • R 2 and R 2a are independently -H, optionally substituted-O(C 1 -C 7 )alkyl, - O(d-C 7 )alkenyl, -S(d-C 7 )alkyl, -S(d-C 7 )alkenyl, -O(d-C 7 )acyl, -S(d- C 7 )acyl, -N(d-C
  • R 1 , R la , and L 1 ⁇ and n are as defined elsewhere herein.
  • L has formula:
  • R , 1 , ⁇ R > la , and Li , and n are as defined elsewhere herein.
  • L is hexadecyloxypropyl, octadecyloxypropyl, or octadecyloxyethyl.
  • the glycerol residue has the -(L ⁇ ) n - moiety joined at the sn-3 position of glycerol.
  • the glycerol residue has the -(L ⁇ ) n - moiety j oined at the sn- 1 position of glycerol.
  • R 1 is an alkoxy group having the formula -O- (CH 2 ) t -CH 3 wherein t is 0-24.
  • t is 8, 10, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • t is 13, 14, 15, 16, 17, 18, 19 or 20.
  • t is 15, 16, 17, 18, 19 or 20.
  • t is 17, 18, 19 or 20.
  • t is 15 or 17.
  • L is a substituted or unsubstituted C 8 -C 24 alkyl, substituted or unsubstituted C 8 -C 24 alkenyl having from 1 to 6 double bonds or substituted or unsubstituted C 8 -C 24 alkynyl having from 1 to 6 triple bonds, wherein substituents when present are selected from one or more halogen, alkyl, - OR w , -SR W , cycloalkyl or epoxide, where R w is hydrogen or alkyl and where the alkyl, alkenyl, alkynyl groups may be further substituted or unsubstituted.
  • L is an alkyl, alkenyl or alkynyl group and contains 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms and can be straight or branched chain moieties.
  • L is a C 16 -C 23 straight or branched chain alkyl or C 16 -C 23 straight or branched chain alkenyl.
  • L is a C 1 -C 19 straight or branched chain alkyl or C 17 -C 19 straight or branched chain alkenyl.
  • L is C 17 -alkyl, C 18 -alkyl or C 19 alkyl.
  • L is C 17 -alkenyl, C 18 -alkenyl or C 19 alkenyl. In other embodiments, L is C 1 -C 2 2 alkyl. h other embodiments, L is C 17 alkyl, C 18 alkyl, C 19 alkyl, C 20 alkyl, C 21 alkyl, or C 22 alkyl. In certain embodiments, L is substituted with one or more groups selected from lower alkyl and halo. In certain embodiments, L is substituted with one or more methyl groups. In certain embodiments, L is substituted with one or more fluoro groups. In certain embodiments, L is C 16 -C 23 alkyl and is substituted with one or more methyl or fluoro groups.
  • the methyl group or the fluoro group substituent is present on the penultimate carbon of the alkyl, alkenyl, or alkynyl chain.
  • the L is 7-methyl-octyl, 8- methyl-nonyl, 9-methyl-decyl, 10-methyl-undecyl, 11-methyl-dodecyl, 12- methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl- hexadecyl, 16-methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8- fluoro-nonyl, 9- fluoro-decyl,
  • L is selected from alkyl, alkenyl and alkynyl groups that contain 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms and can be straight or branched chain moieties, hi certain embodiments, the L group is a C 16 -C 23 straight or branched chain alkyl or C 16 -C 23 straight or branched chain alkenyl. In other embodiments, L is a C 17 -C 19 straight or branched chain alkyl or C 17 -C 19 straight or branched chain alkenyl. In other embodiments, L is C 17 -alkyl, C 18 -alkyl or C 19 alkyl.
  • L is C 17 -alkenyl, C 18 -alkenyl or C 19 alkenyl. In other embodiments, L is C 17 -C 22 alkyl. In other embodiments, L is C 17 alkyl, C 18 alkyl, C 19 alkyl, C 2 o alkyl, C 21 alkyl, or C 22 alkyl. In certain embodiments, L is C 16 -C 23 alkyl that is substituted with one or more groups selected from lower alkyl and halo. In certain embodiments, L is substituted with one or more methyl groups. In certain embodiments, L is substituted with one or more fluoro groups.
  • L is C 16 -C 23 alkyl and is substituted with one or more methyl or fluoro groups.
  • the methyl group or the fluoro group substituent is present on the penultimate carbon of the alkyl, alkenyl, or alkynyl chain.
  • the L is 7-methyl-octyl, 8-methyl-nonyl, 9-methyl-decyl, 10- methyl-undecyl, 11-methyl-dodecyl, 12-methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl-hexadecyl, 16-methyl-heptadecyl, 17-methyl- octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21- methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8- fluoro-nonyl, 9- fluoro- decyl, 10- fluoro-undecyl, 11- fluoro-dodecyl, 12- fluoro-tridecyl, 13-fluoro- tetrade
  • B is selected from a natural or non natural purine or pyrimidine base.
  • the base is selected from pyrimidin- 1-yl, pyrimidin-3-yl, ⁇ urin-3-yl, purin-7-yl or purin-9-yl residue.
  • the base is thymin-1-yl, cytosine-1-yl, adenine-9-yl or guanine-9- yi-
  • provided herein is a process for making lipophilic nucleoside phosphonate monoesters of formula 6, including their stereoisomers,
  • the processes provided herein include a step of preparing the methylene phosphonate lipophilic monoesters of formula 1.
  • the preparation of compound of formula 1, in some embodiments, include the steps of activation of phosphonic acid by reaction with an activating agent, such as thionyl chloride or oxalyl chloride followed by coupling with a lipophilic alcohol of formula L-OH.
  • the coupling reaction is carried out using condensation reactions known in the art including, but not limited to coupling in presence of N,N-dicyclohexylcarbodiimide (DCC); 1,1- carbonyldiimidazole (GDI); 2,4,6-triisopropylbenzenesulfonyl chloride (TIPS- Cl); trichloroacetonitrile; alkylation with alkyl halide; Mitsunobo alkylation (diethylazodicarboxylate/ triphenylphosphine).
  • DCC N,N-dicyclohexylcarbodiimide
  • GDI 1,1- carbonyldiimidazole
  • TIPS- Cl 2,4,6-triisopropylbenzenesulfonyl chloride
  • trichloroacetonitrile alkylation with alkyl halide
  • Mitsunobo alkylation diethylazodicarboxylate/ triphenylphos
  • the compound of formula 8 is obtained from the dialkyl esters of phosphonic acid by dealkylatmg the alkyl groups, as shown in an exemplary reaction with diethyl ester of formula 9a.
  • the dealkylation reaction conditions are known in the art.
  • the compound of formula 9a is diethyl p- toluenesulfonyloxymethylphosphonate.
  • Diethyl p-toluenesulfonyloxy- methylphosphonate can be prepared by methods known in the art, such as by treatment of diethyl hydroxymethylphosphonate (commercially available) with p-toluenesulfonyl chloride, in the presence of a base.
  • the diester is treated with halotrialkylsilane, such as bromotrimethylsilane or boron trihalide, such as boron tribromide to cleave both ethyl groups.
  • the resulting p-toluenesulfonyloxy- methyl phosphonic acid is conveniently isolated as the crystalline pyridinium salt or used as a free acid.
  • the phosphonic acid is then activated by reaction with oxalyl chloride (catalyzed by N,N-DMF); followed by treatment with a desired lipophilic alcohol. After hydrolysis, (aqueous NaHCO 3 ) the esters are isolated as the sodium salts.
  • Exemplary methylene phosphonate monoesters with various leaving groups for use herein are provided below: O O O O — OL HsC. H/O, ,R — OL B ⁇ ,P. — OL ,P ⁇ ⁇ ⁇ 0 ' Na + O " Na + O " Na + o Synthesis of N-substituted derivatives of heterocyclic bases
  • the methods provided herein are used for the preparation of lipophilic esters of acyclic nucleoside phosphonates.
  • the starting compounds for these reactions for example, hydroxyalkyl derivatives of purine and pyriniidine bases are prepared by methods known in the art.
  • Exemplary acyclic nucleosides that can be derivatized to lipophilic monoesters of phosphonates according to the methods provided herein are shown below in Table 2.
  • the acyclic nucleosides have general formula:
  • N 4 -monomethoxytriyl-O 3' -(trityl)-dihydroxy- propylcytosine or N 4 ,O 3' -ditrityl-dihydroxypropylcytosine are prepared as intermediates in the synthesis of cidofovir monoesters.
  • the antiviral nucleosides that can be derived according to the process provided herein have free 5'-hydroxy group.
  • antiviral nucleosides include:
  • antiviral nucleosides for use in the processes provided herein include ddA, ddl, ddG, L-FMAU, DXG, DAPD, L-dA, L-dl, L- (d)T, L-dC, L-dG, FTC, penciclovir, and the like.
  • Exemplary processes for the preparation of alkoxyalkyl esters of adefovir, tenofovir, HPMPA and PMPMG are illustrated in the reactions below: i) Alkoxyalkyl esters of adefovir and tenofovir
  • the compound has formula:
  • the compound has formula: wherein the variables are described elsewhere herein.
  • provided herein is a compound selected from N 4 - monomethoxytrityl-O 3 -(trityl)-dihydroxypropylcytosine and N 4 ,O 3 -ditrityl- dihydroxypropylcytosine.
  • the compounds prepared by the methods provided herein are useful for the prevention, or amelioration one or more symptoms of diseases associated with viral infections, including, but not limited to influenza; hepatitis B and C virus; cytomegalovirus (CMV); herpes infections, such as those caused by Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus, Herpes type 6 (HHV-6) and type 8 (HHV-8); Varicella zoster virus infections such as shingles or chicken pox; Epstein Barr virus infections, including, but not limited to infectious mononucleosis/glandular; retroviral infections including, but not limited to SIV, HIV-1 and HIV-2; ebola virus; adenovirus and papilloma virus.
  • viruses such as those caused by Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus, Herpes type 6 (HHV-6) and type 8 (HHV-8); Varicella zoster
  • the disease is drug resistant hepatitis B.
  • the following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.
  • EXAMPLES The isolation and purification of the compounds and intermediates described in the examples can be effected, if desired, by any suitable separation or purification procedure such as , for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick layer preparative chromatography, distillation, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures are in the examples below. Other equivalent separation or isolation procedures can of course also be used.
  • EXAMPLE 1 Synthesis of Hexadecyloxypropyl- cidofovir SCHEME
  • N -monomethoxytrityl-O 3 -trityl-dihydroxy- propylcytosine A mixture of N ⁇ monomethoxytritylcytosine (3.44 g, 8.9 mmol) and sodium hydride (0.043 g, 1.78 mmol) in dry N,N-DMF (50 mL) was stirred at room temperature for 1 hr. (S)-Trityl glycidyl ether (2.5 g, 8.0 mmol) was added to the mixture and it was stirred at 105 °C for 7 hours. The mixture was allowed to cool to room temperature. N,N-DMF was evaporated.
  • EXAMPLE 2 Synthesis of Hexadecyloxypropyl-adefovir, sodium salt (HDP-ADV) Hydroxyethyladenine (2.15 g, 12 mmol) was suspended in dry N,N-DMF (25 mL) and sodium hydride (144, mg, 6mmol) was added and the mixture was stirred 15 min. To the mixture was added HDP-TsOMPA (1.0 g, 1.8 mmol) and stirring continued for 36 hours. The mixture was evaporated, then adsorbed on silica gel and purified by flash column chromatography. Product eluted with 35% MeOH/CH 2 Cl 2 .
  • HDP-ADV Hydroxyethyladenine
  • EXAMPLE 4 Synthesis of HexadecyIoxypropyl-(S)-HPMPA 1 Synthesis of N 6 -O 3 '-ditrityl- HDP-(S)-HPMPA N6,O3'-ditrityl-(S)-dihydroxypropyladenine (9.2 g, 13.3 mmol) was dissolved in anhydrous trriethylamine (75 mL) with gentle heating, then NaH (3.7 g, 153 mmol) was added and the mixture stirred for 30 min under a nitrogen atmosphere. To the mixture was added a solution of HDP-TsOMPA (9.0 g, 15.4 mmol) in THF (25 L).

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Abstract

La présente invention concerne un procédé destiné à l'élaboration de monoesters lipophiles représentés par la formule (III) et de leurs stéréoisomères. En l'occurrence, on commence par l'estérification d'un phosphonate avec un alcool lipophile, et on fait réagir le produit résultant avec un nucléoside convenablement protégé en présence d'une base forte. Pour certains modes de réalisation, le traitement sert à l'élaboration de monoesters de lipide-éthers alkylés ou alcoxyalkylés de phosphonates nucléosidiques convenant comme antiviraux, anticancéreux ou antiparasites.
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