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US20050182252A1 - Novel 2'-C-methyl nucleoside derivatives - Google Patents

Novel 2'-C-methyl nucleoside derivatives Download PDF

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Publication number
US20050182252A1
US20050182252A1 US10/903,215 US90321504A US2005182252A1 US 20050182252 A1 US20050182252 A1 US 20050182252A1 US 90321504 A US90321504 A US 90321504A US 2005182252 A1 US2005182252 A1 US 2005182252A1
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group
compound
alkyl
phenyl
independently selected
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US10/903,215
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Inventor
K. Reddy
Mark Erion
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Metabasis Therapeutics Inc
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Individual
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Priority to US10/903,215 priority Critical patent/US20050182252A1/en
Priority to PCT/US2005/004447 priority patent/WO2005084192A2/fr
Priority to BRPI0507675-7A priority patent/BRPI0507675A/pt
Priority to EP05750052A priority patent/EP1720556A4/fr
Priority to EP07104279A priority patent/EP1905778A3/fr
Priority to JP2006553282A priority patent/JP2007522237A/ja
Priority to EP05807817A priority patent/EP1781101A2/fr
Priority to PCT/US2005/027235 priority patent/WO2006033709A2/fr
Priority to US11/572,785 priority patent/US20090131370A1/en
Priority to JP2007523879A priority patent/JP2008508319A/ja
Publication of US20050182252A1 publication Critical patent/US20050182252A1/en
Assigned to METABASIS THERAPEUTICS, INC. reassignment METABASIS THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: REDDY, K. RAJA, ERION, MARK D.
Priority to US11/589,363 priority patent/US7666855B2/en
Priority to US11/593,381 priority patent/US20070179114A1/en
Abandoned legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

  • the present invention is directed towards novel 2′-C-methyl nucleoside 5′-monophosphate derivatives, their preparation and their uses. More specifically, the novel compounds are useful to treat hepatitis C viral infections.
  • Hepatitis C is a viral disease that causes inflammation of the liver that may lead to cirrhosis, primary liver cancer and other long-term complications.
  • Nucleosides are a well-recognized class of compounds shown to be effective against a variety of viral infections, including hepatitis B, HIV, and herpes. A few nucleosides are reported to inhibit hepatitis C (HCV) virus replication, including ribavirin, which currently is marketed as a drug combination with various interferons, and nucleosides containing a 2′-C-methyl ribose sugar.
  • HCV hepatitis C
  • Nucleosides are generally effective as antiviral agents following conversion of the nucleoside to the corresponding nucleoside 5′-triphosphate (NTP). Conversion occurs inside cells through the action of various intracellular kinases.
  • the first step i.e. conversion of the nucleoside to the 5′-monophosphate (NMP) is generally the slow step and involves a nucleoside kinase, which is encoded by either the virus or host.
  • Conversion of the NMP to the NTP is generally catalyzed by host nucleotide kinases.
  • the NTP interferes with viral replication through inhibition of viral polymerases and/or via incorporation into a growing strand of DNA or RNA followed by chain termination.
  • nucleosides to treat viral liver infections are often complicated by one of two problems.
  • the desired nucleoside is a good kinase substrate and accordingly produces NTP in the liver as well as other cells and tissues throughout the body. Since NTP production is often associated with toxicity, efficacy can be limited by extrahepatic toxicities.
  • the desired nucleoside is a poor kinase substrate so is not efficiently converted into the NMP and ultimately into the NTP.
  • U.S. Pat. No. 6,312,662 discloses the use of certain phosphate prodrugs for the liver-specific delivery of various drugs including nucleosides for the treatment of patients with liver diseases such as hepatitis C, hepatitis B and hepatocellular carcinoma.
  • the present invention is directed towards novel 2′-C-methyl nucleoside 5′-monophosphate derivatives, their preparation and their uses for the treatment of hepatitis C viral infections.
  • the present invention relates to compounds of Formula I, and pharmaceutically acceptable salts and prodrugs thereof.
  • the invention relates to compounds of Formula I, and pharmaceutically acceptable salts and prodrugs thereof:
  • Some of the compounds of Formula I have asymmetric centers where the stereochemistry is unspecified, and the diastereomeric mixtures of these compounds are included, as well as the individual stereoisomers when referring to a compound of Formula I generally.
  • keto-enol tautomers may exist as tautomers such as keto-enol tautomers and imine-enamine tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
  • An example of keto-enol tautomers which are intended to be encompassed within the compounds of the present invention is illustrated below:
  • compositions comprising compounds of Formula I, pharmaceutically acceptable salts or prodrugs thereof; in association with pharmaceutically acceptable excipients or carriers.
  • Also provided are methods for inhibiting viral replication comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salts or prodrugs thereof.
  • Also provided are methods for inhibiting RNA-dependent RNA viral replication comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salts or prodrugs thereof.
  • Also provided are methods for inhibiting HCV replication comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salts or prodrugs thereof.
  • Also provided are methods for treating viral infections comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salts or prodrugs thereof.
  • Also provided are methods for treating viral infections of the liver comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salts or prodrugs thereof.
  • RNA-dependent RNA viral infection comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salts or prodrugs thereof.
  • Also provided are methods for treating HCV infection comprising the step of administering to a patient a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salts or prodrugs thereof.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups, up to and including 10 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and cyclopropyl. The alkyl may be optionally substituted with 1-3 substituents.
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • the aryl group may be optionally substituted with 1-6 substituents.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, indolyl and the like, all optionally substituted.
  • monocyclic aryl refers to aromatic groups which have 5-6 ring atoms and includes carbocyclic aryl and heterocyclic aryl. Suitable aryl groups include phenyl, furanyl, pyridyl, and thienyl. Aryl groups may be substituted.
  • monocyclic heteroaryl refers to aromatic groups which have 5-6 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
  • biasing represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
  • optionally substituted or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, lower alkylsulfonyl, lower-carboxamidoalkylaryl, lower-carbox
  • Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-6 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, and amino.
  • -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The aryl portion may have 5-14 ring atoms and the alkyl portion may have up to and including 10 carbon atoms. “Heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group.
  • alkylaryl- refers to an aryl group substituted with an alkyl group. “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl. The aryl portion may have 5-14 ring atoms and the alkyl portion may have up to and including 10 carbon atoms. The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, in one aspect up to and including 6, and in another aspect one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
  • heterocyclic refers to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6 atoms, containing at least one heteroatom, in a further aspect are 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring.
  • the heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
  • arylamino (a), and “aralkylamino” (b), respectively, refer to the group —NRR′ wherein respectively, (a) R is aryl and R′ is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R′ is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.
  • acyl refers to —C(O)R where R is alkyl, heterocycloalkyl, or aryl.
  • lower acyl refers to where R is lower alkyl.
  • C 1 -C 4 acyl refers to where R is C 1 -C 4 .
  • carboxy esters refers to —C(O)OR where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.
  • oxo refers to ⁇ O in an alkyl or heterocycloalkyl group.
  • amino refers to —NRR′ where R and R′ are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R′ can form a cyclic ring system.
  • -sulphonylamido or “-sulfonylamido” refers to —S( ⁇ O) 2 NR 2 where each R is independently hydrogen or alkyl.
  • halogen refers to —F, —Cl, —Br and —I.
  • alkylaminoalkylcarboxy refers to the group alkyl-NR-alk-C(O)—O— where “alk” is an alkylene group, and R is a H or lower alkyl.
  • sulphonyl or “sulfonyl” refers to —SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • sulphonate or “sulfonate” refers to —SO 2 OR, where R is —H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. “1-Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphate, it is attached at the first carbon.
  • alkynyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. “1-Alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphate, it is attached at the first carbon.
  • alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene chain contains up to and including 6 atoms. In a further aspect the alkylene groups contains up to and including 4 atoms.
  • the alkylene group can be either straight, branched or cyclic. The alkylene may be optionally substituted with 1-3 substituents.
  • acyloxy refers to the ester group —O—C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • aminoalkyl- refers to the group NR 2 -alk- wherein “alk” is an alkylene group and R is selected from —H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alkylaminoalkyl- refers to the group alkyl-NR-alk- wherein each “alk” is an independently selected alkylene, and R is H or lower alkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively.
  • arylaminoalkyl- refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is —H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkylene group is lower alkylene.
  • alkylaminoaryl- refers to the group alkyl-NR-aryl- wherein “aryl” is a divalent group and R is —H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylaminoaryl-”, the alkyl group is lower alkyl.
  • alkoxyaryl- refers to an aryl group substituted with an alkyloxy group.
  • the alkyl group is lower alkyl.
  • aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • aralkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • alkoxy- or “alkyloxy-” refers to the group alkyl-O—.
  • alkoxyalkyl- or “alkyloxyalkyl-” refer to the group alkyl-O-alk- wherein “alk” is an alkylene group. In “lower alkoxyalkyl-”, each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkylthio- refers to the group alkyl-S—.
  • alkylthioalkyl- refers to the group alkyl-S-alk- wherein “alk” is an alkylene group.
  • alk is an alkylene group.
  • lower alkylthioalkyl- each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkoxycarbonyloxy- refers to alkyl-O—C(O)—O—.
  • aryloxycarbonyloxy- refers to aryl-O—C(O)—O—.
  • alkylthiocarbonyloxy- refers to alkyl-S—C(O)—O—.
  • amido refers to the NR 2 group next to an acyl or sulfonyl group as in NR 2 —C(O)—, RC(O)—NR 1 —, NR 2 —S( ⁇ O) 2 — and RS( ⁇ O) 2 —NR 1 —, where R and R′ include —H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamido refer to NR 2 —C(O)— and RC(O)—NR 1 —, where R and R′ include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, —NR—C(O)—NR—.
  • sulphonamido or “sulfonamido” refer to NR 2 —S( ⁇ O) 2 — and RS( ⁇ O) 2 —NR 1 —, where R and R 1 include —H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include sulfonylurea, —NR—S( ⁇ O) 2 —NR—.
  • carboxamidoalkylaryl and “carboxamidoaryl” refers to an aryl-alk-NR 1 —C(O), and ar-NR 1 —C(O)-alk-, respectively where “ar” is aryl, “alk” is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • sulfonamidoalkylaryl and “sulfonamidoaryl” refers to an aryl-alk-NR 1 —S( ⁇ O) 2 —, and ar-NR 1 —S( ⁇ O) 2 —, respectively where “ar” is aryl, “alk” is alkylene, R 1 and R include —H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • hydroxyalkyl refers to an alkyl group substituted with one —OH.
  • haloalkyl refers to an alkyl group substituted with one halogen.
  • cyano refers to —C—N.
  • nitro refers to —NO 2 .
  • acylalkyl refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
  • aminocarboxamidoalkyl- refers to the group NR 2 —C(O)—N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups wherein “alk” is lower alkylene.
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • perhalo refers to groups wherein every C—H bond has been replaced with a C-halo bond on an aliphatic or aryl group.
  • Suitable perhaloalkyl groups include —CF 3 and —CFCl 2 .
  • heterocyclic base B refers to
  • terapéuticaally effective amount means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
  • L-amino acid refers to those amino acids routinely found as components of proteinaceous molecules in nature, including alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamio acid, lysine, arginine and histidine.
  • this term is intended to encompass L-amino acids having only the amine and carboxylic acid as charged functional groups, i.e., alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine and tyrosine.
  • they are alanine, valine, leucine, isoleucine, proline, phenylalanine, and glycine.
  • it is valine.
  • patient refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human. Another aspect includes a mammal, both male and female.
  • prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g. HO—, HS—, HOOC—, R 2 N—, associated with the drug, that cleave in vivo.
  • Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs.
  • Such prodrugs of the compounds of Formula I fall within this scope.
  • Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design of Prodrugs, edited by H.
  • prodrug herein also includes but is not limited to esterase cleavable prodrugs of the 2′ and 3′-hydroxy groups of compounds of Formula I (Anastasi et al., Curr. Med. Chem., 2003, 10, 1825). Standard groups include acyl and alkoxycarbonyl groups, and esters of natural L-amino acid derivatives (Perry, et al., Drugs, 1996, 52, 754). Also included is a cyclic carbonate derivative formed by carbonylation of the 2′ and 3′-hydroxy groups, which upon activation by esterase activity in vivo results in compounds of Formula I.
  • prodrugs are preferred at the 6-position of purine analogs. Such substitution may include H, halogen, amino, acetoxy or azido groups. Hydrogen substituted prodrugs at the 6-position of guanosine analogs undergo oxidation in vivo by aldehyde oxidase or xanthine oxidase to give the required functionality (Rashidi et al., Drug Metab. Dispos. 1997, 25, 805). While esterases unmask acetoxy groups, amine and halogen substituents are known to be substrates for deaminases. 6-Azido substituted compounds are also known to give the corresponding amino derivatives by the action of reductases (Koudriakova, et al., J. Med Chem., 1996, 39, 4676).
  • cyclic phosphate ester of 1,3-propanediol refers to the following:
  • V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group attached at the beta and gamma position to the O attached to the phosphorus” includes the following:
  • V and Z are connected via 4 additional atoms.
  • W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl” includes the following:
  • W and W′ are connected via an additional 2 atoms.
  • V aryl
  • a spiro-fused cyclopropyl group for W and W′ spiro-fused cyclopropyl group for W and W′.
  • cyclic phosphate refers to
  • the carbon attached to V must have a C—H bond.
  • the carbon attached to Z must also have a C—H bond.
  • cis stereochemistry refers to the spatial relationship of the V group and the substituent attached to the phosphorus atom via an exocyclic single bond on the six membered 2-oxo-phosphorinane ring.
  • the structures A and B below show two possible cis-isomers of 2- and 4-substituted 2-oxo-phosphorinane. Structure A shows cis-isomer of (2S,4R)-configuration whereas structure B shows cis-isomer of (2R,4S)-configuration.
  • trans stereochemistry refers to the spatial relationship of the V group and the substituent attached to the phosphorus atom via an exocyclic single bond on the six membered 2-oxo-phosphorinane ring.
  • the structures C and D below show two possible trans-isomers of 2- and 4-substituted 2-oxo-phosphorinane. Structure C shows trans-isomer of (2S,4S)-configuration whereas structure D shows trans-isomer of (2R,4R)-configuration.
  • enantioenriched or “enantiomerically enriched” refers to a sample of a chiral compound that consists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess.
  • liver refers to liver organ.
  • enhancing refers to increasing or improving a specific property.
  • liver specificity refers to the ratio: [ drug ⁇ ⁇ or ⁇ ⁇ a ⁇ ⁇ drug ⁇ ⁇ metabolite ⁇ ⁇ in ⁇ ⁇ liver ⁇ ⁇ tissue ] ⁇ [ drug ⁇ ⁇ or ⁇ ⁇ a ⁇ ⁇ drug ⁇ ⁇ metabolite ⁇ ⁇ in ⁇ ⁇ blood ⁇ ⁇ or ⁇ ⁇ another ⁇ ⁇ tissue ] ⁇ as measured in animals treated with the drug or a prodrug.
  • the ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
  • increased or enhanced liver specificity refers to an increase in the liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug.
  • the term “enhanced oral bioavailability” refers to an increase of at least 50% of the absorption of the dose of the parent drug. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100%, that is a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration.
  • therapeutic index refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.
  • sustained delivery refers to an increase in the period in which there is a prolongation of therapeutically-effective drug levels due to the presence of the prodrug.
  • bypassing drug resistance refers to the loss or partial loss of therapeutic effectiveness of a drug (drug resistance) due to changes in the biochemical pathways and cellular activities important for producing and maintaining the biological activity of the drug and the ability of an agent to bypass this resistance through the use of alternative pathways or the failure of the agent to induce changes that tend to resistance.
  • treating or “treatment” of a disease includes inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
  • the present invention relates to compounds of Formula I, stereoisomers, pharmaceutically acceptable salts or prodrugs thereof or pharmaceutically acceptable salts of the prodrugs as represented by Formula I:
  • the invention comprises compounds of Formula I:
  • the invention comprises compounds of Formula I:
  • the invention comprises compounds of Formula I:
  • the invention comprises compounds of Formula I:
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2 NR 2 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 2 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 t-but
  • V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 .
  • V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
  • V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OH, —OMe, —NH 2 , —NMe 2 , —OEt, —COOH, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN; monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OH, —OMe, —NH 2 , —NMe 2 , —OEt, —COOH, —CO 2 t
  • Z is selected from the group consisting of —H, —OMe, —OEt, phenyl, C 1 -C 3 alkyl, —NR 4 2 , —SR 4 , —(CH 2 ) p —OR 6 , —(CH 2 ) p —SR 6 and OCOR 5 ;
  • R 4 is C—C 4 alkyl;
  • R 5 is selected from the group consisting of C 1 -C 4 alkyl, monocyclic aryl, and monocyclic aralkyl; and
  • R 6 is C 1 -C 4 acyl.
  • Z is selected from the group consisting of —H, —OMe, —OEt, and phenyl.
  • W and W′ are independently selected from the group consisting of —H, C 1 -C 6 alkyl, and phenyl; or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group.
  • W and W′ are independently selected from the group consisting of —H, methyl, and V, or W and W′ are each methyl, with the proviso that when W is V, then W′ is H.
  • V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2 NR 2 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 2 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 Me, —
  • V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ;
  • V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; and
  • Z, W, and W′ are each —H.
  • V and W are the same and each is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl.
  • B is
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is
  • B is
  • a further aspect of this invention includes compounds of Formula V:
  • this invention includes compounds of Formula V:
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2 NR 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, —CF 3 , —OR 3 , —OR 12 , —COR 3 , —CO 2 R 3 , —NR 3 2 , —NR 12 2 , —CO 2 NR 2 2 , —SR 3 , —SO 2 R 3 , —SO 2
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 Me, —
  • V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, and —CF 3 .
  • V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
  • V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
  • this invention includes compounds of Formula II:
  • the invention comprises compounds of Formula II:
  • a further aspect of the invention comprises compounds of Formula III:
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 t-but
  • V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
  • the invention comprises compounds of Formula III:
  • V is selected from the group consisting of phenyl, substituted phenyl with 1-3 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 NH 2 and —CN, monocyclic heteroaryl, and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of —Cl, —Br, —F, C 1 -C 3 alkyl, —CF 3 , —COCH 3 , —OMe, —NMe 2 , —OEt, —CO 2 t-butyl, —CO 2 NH 2 , —SMe, —SO 2 Me, —SO 2 t-but
  • V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
  • the compounds of this invention are compounds of Formula VI:
  • the invention comprises compounds of Formula VII:
  • B is selected from the group consisting of:
  • B is selected from the groups consisting of:
  • X is NH 2 .
  • the invention comprises:
  • the invention comprises:
  • the invention comprises:
  • the invention comprises:
  • the invention comprises:
  • the compounds of this invention have R-stereochemistry at the V-attached carbon and have S-stereochemistry at the phosphorus center. In another aspect of the invention the compounds of this invention have S-stereochemistry at the V-attached carbon and have R-stereochemistry at the phosphorus center.
  • the following compounds are included in the invention but the compounds are not limited to these illustrative compounds.
  • the following prodrugs are preferred compounds of the invention.
  • the compounds are shown without depiction of stereochemistry since the compounds are biologically active as the diastereomeric mixture or as a single stereoisomer.
  • Compounds named in Table 1 are designated by numbers assigned to the variables of formula using the following convention: M1.V.L1.L2.
  • M1 is a variable that represents nucleosides of Formula I which are attached via 5′-hydroxyl group that is phosphorylated with a group P(O)(O—CH(V)CH 2 CH 2 —O) to make compounds of Formula VI.
  • V is an aryl or heteroaryl group that has 2 substituents, L1 and L2, at the designated positions. V may have additional substituents.
  • Variable V Group V1
  • Preferred compounds are compounds listed in Table 1 using variables M1 and V1 and L1 and L2 listed in that order.
  • compound 1.3.6.7 represents structure 1 of variable M1, i.e., 7-deaza-2′-methyl adenosine; structure 3 of group V1, i.e., 2-(L1)-5-(L2) phenyl; structure 6 of variable L1, i.e., trifluoromethyl; and structure 7 of variable L2, i.e., methoxy.
  • the compound 1.3.6.7 therefore is 7-deaza-2′-methyladenosine with the P(O)(O—CH(V)CH 2 CH 2 O) attached to the 5′-primary hydroxyl group being ⁇ [1-(2-trifluoromethyl-5-methoxyphenyl)-1,3-propyl]phosphoryl.
  • Preferred compounds are also compounds listed in Table 1 using variables M1 and V2 wherein the four digit number represents M1.V2.L1.L2.
  • Preferred compounds are also compounds listed in Table 1 using variables M1 and V3 wherein the four digit number represents M1.V3.L1.L2. TABLE 1 1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4 1.1.1.5 1.1.1.6 1.1.1.7 1.1.1.8 1.1.1.9 1.1.2.1 1.1.2.2 1.1.2.3 1.1.2.4 1.1.2.5 1.1.2.6 1.1.2.7 1.1.2.8 1.1.2.9 1.1.3.1 1.1.3.2 1.1.3.3 1.1.3.4 1.1.3.5 1.1.3.6 1.1.3.7 1.1.3.8 1.1.3.9 1.1.4.1 1.1.4.2 1.1.4.3 1.1.4.4 1.1.4.5 1.1.4.6 1.1.4.7 1.1.4.8 1.1.4.9 1.1.5.1 1.1.5.2 1.1.5.3 1.1.5.4 1.1.5.5 1.1.5.6 1.1.5.7 1.1.5.8 1.1.5.9 1.1.6.1 1.1.6.2 1.1.6.3 1.1.6.4 1.1.6.5 1.1.6.6 1.1.6.7 1.1.6.8 1.1.6.9 1.1
  • M1 is a variable that represents nucleosides of Formula I which are attached via 5′-hydroxyl group that is phosphorylated with a group P(O)(O—CH(V)CH(Z)C(WW′)—O) to make compounds of Formula I.
  • variable M1 The structures for variable M1 are the same as described above.
  • V/Z/W Group 1 of V/Z/W
  • Preferred compounds are compounds listed in Table 2 using groups M1 and Group 1 of V/Z/W.
  • the compound 1.3 therefore is 7-deaza-2′-methyladenosine with the P(O)(O—CH(4-pyridyl)CH(CH 3 )CH 2 O) attached to the primary hydroxyl.
  • Preferred compounds are also compounds listed in Table 2 using groups M1 and Group 2 of V/Z/W.
  • Preferred compounds are also compounds listed in Table 2 using groups M1 and Group 3 of V/Z/W. TABLE 2 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9
  • Preferred compounds are also compounds of Tables 1 and 2 of formulae VI-VIII where R 7 is an L-valinyl group attached via a carbonyl and R 7 and R 8 form a 5-membered cyclic carbonate.
  • the compounds of the present invention can be used for inhibiting viral replication.
  • the compounds of this invention can be used for inhibiting RNA-dependent RNA viral replication.
  • the compounds of this invention can be used for inhibiting HCV replication.
  • the compounds of the present invention can be used for treating viral infections.
  • compounds of this invention can be used for treating RNA-dependent RNA viral infection.
  • compounds of this invention can be used for treating HCV infection.
  • the compounds of the present invention can be used for treating viral infections of the liver.
  • compounds of this invention can be used for treating RNA-dependent RNA viral infection in the liver.
  • compounds of this invention can be used for treating HCV infection in the liver.
  • inhibition of viral replication is measured in serum. Increased viral titer reduction is associated with decreased generation of viral mutants which are associated with drug resistance.
  • the compounds of the present invention can be used for preventing the onset of symptoms associated with a viral infection.
  • NMP nucleoside monophosphate
  • NTP biologically active nucleoside triphosphate
  • Drug elimination from the hepatocyte typically entails degradation of phosphorylated metabolites back to a species capable of being transported out of the hepatocyte and into the blood for elimination by the kidney or into the bile for biliary excretion.
  • the phophorylated metabolites are dephosphorylated to the uncharged nucleoside.
  • nucleosides that leak back into the systemic circulation result in systemic exposure. If the nucleoside is active systemically, e.g. through entry into virally infected cells and phosphorylation to the active species, escape of the nucleoside from the liver leads to biological activity outside of the liver (i.e. extrahepatic tissues, blood cells).
  • prodrugs of the invention can be effective for treating diseases outside of the liver, e.g. viral infections. Since many nucleosides exhibit poor oral bioavailability due to breakdown in the gastrointestinal tract either enzymatically (e.g. deamination by adenosine deaminase) or chemically (e.g. acid instability), the prodrug can be used for oral drug delivery. Moreover, given that the prodrugs in some cases are broken down slowly relative to e.g. most ester based prodrugs, the prodrugs could advantageously result in slow, sustained systemic release of the nucleoside.
  • nucleosides that are preferentially excreted through the bile or nucleosides that are unable to undergo phosphorylation in tissues or nucleosides that undergo rapid intrahepatic metabolism to a biologically inactive metabolite.
  • Some enzymes in the hepatocyte are present that can degrade nucleosides and therefore minimize exposure (e.g. Phase I and Phase II enzymes).
  • adenosine deaminase which can deaminate some adenosine-based nucleosides to produce the corresponding inosine analogue. Rapid intracellular deamination of the nucleoside following its dephosphorylation to the nucleoside limits systemic exposure to the nucleoside and diminishes the risk of toxicity.
  • Example A-D Methods described in Examples A-D were used to test activation of compounds of this invention. Methods used in Example E were used to evaluate the ability of compounds of the invention to generate NTPs.
  • HCV replication in human liver tissue was evaluated as in Example F.
  • Liver specificity of the prodrugs relative to the nucleosides was measured by methods in Example G.
  • Tissue distribution can be determined according to methods in Example H.
  • Oral bioavailability was determined by methods described in Example I.
  • the susceptibility of nucleoside analogs to metabolism can be determined as in Example J.
  • the RNA-dependent RNA viral infection is a positive-sense single-stranded RNA-dependent viral infection.
  • the positive-sense single-stranded RNA-dependent RNA viral infection is Flaviviridae viral infection or Picornaviridae viral infection.
  • the Picornaviridae viral infection is rhinovirus infection, poliovirus infection, or hepatitis A virus infection.
  • the Flaviviridae viral infection is selected from the group consisting of hepatitis C virus infection, yellow fever virus infection, dengue virus infection, West Nile virus infection, Japanese encephalitis virus infection, Banzi virus infection, and bovine viral diarrhea virus infection.
  • the Flaviviridae viral infections hepatitis C virus infection.
  • compounds of the present invention can be used to enhance the oral bioavailability of the parent drug.
  • compounds of the present invention can be used to enhance the oral bioavailability of the parent drug by at least 5%.
  • compounds of the present invention can be used to enhance the oral bioavailability of the parent drug by at least 10%.
  • oral bioavailability is enhanced by 50% compared to the parent drug administered orally.
  • the oral bioavailability is enhanced by at least 100%.
  • compounds of the present invention can be used to increase the therapeutic index of a drug.
  • compounds of the present invention can be used to bypass drug resistance.
  • compounds of the present invention can be used to treat cancer.
  • Compounds of the invention are administered in a total daily dose of 0.01 to 1000 mg/kg. In one aspect the range is about 0.1 mg/kg to about 100 mg/kg. In another aspect the range is 0.5 to 20 mg/kg. The dose may be administered in as many divided doses as is convenient.
  • Compounds of this invention when used in combination with other antiviral agents may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). Administration of the prodrug may occur at or near the time in which the other antiviral is administered or at a different time.
  • the compounds of this invention may be used in a multidrug regimen, also known as combination or ‘cocktail’ therapy, wherein, multiple agents may be administered together, may be administered separately at the same time or at different intervals, or administered sequentially.
  • the compounds of this invention may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program.
  • the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Intravenous administration is generally preferred.
  • Pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as starch, ge
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monoo
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachid oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic
  • a time-release formulation intended for oral administration to humans may contain 20 to 2000 ⁇ mol (approximately 10 to 1000 mg) of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. It is preferred that the pharmaceutical composition be prepared which provides easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion should contain from about 0.05 to about 50 ⁇ mol (approximately 0.025 to 25 mg) of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/h can occur.
  • formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of Formula I when such compounds are susceptible to acid hydrolysis.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations suitable for parenteral administration may be administered in a continuous infusion manner via an indwelling pump or via a hospital bag.
  • Continuous infusion includes the infusion by an external pump.
  • the infusions may be done through a Hickman or PICC or any other suitable means of administering a formulation either parenterally or i.v.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • Another aspect of the present invention is concerned with a method of inhibiting HCV replication or treating HCV infection with a compound of the present invention in combination with one or more agents useful for treating HCV infection.
  • agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1, interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, N.J.), pegylated interferon- ⁇ 2a (PegasysTM), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, N.J.), pegylated interferon- ⁇ 2b (PegIntronTM), a recombinant consensus interferon (such as interferon alphacon-1), and a purified interferon- ⁇ product.
  • Amgen's recombinant consensus interferon has the brand name Infergen®.
  • Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin.
  • Viramidine is a liver-targeting prodrug analog of ribavirin disclosed in WO 01/60379 (assigned to ICN Pharmaceuticals).
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term “administering” is to be interpreted accordingly.
  • the scope of combinations of the compounds of this invention with other agents useful for treating HCV infection includes in principle any combination with any pharmaceutical composition for treating HCV infection.
  • the dose of each compound may be either the same as or different from the dose when the compound is used alone.
  • composition comprising a compound of Formula I or prodrug or pharmaceutically acceptable salt thereof and at least one agent useful for treating a viral infection, particularly an HCV infection.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
  • HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication.
  • Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, GB-2337262, WO 02/48116, WO 02/48172, U.S.
  • NS3 protease inhibitors for combination with the compounds of the present invention are BILN 2061 (Boehringer Ingelheim) and VX-950/LY-570310.
  • BILN 2061 Boehringer Ingelheim
  • VX-950/LY-570310 VX-950/LY-570310.
  • HCV NS3 protease as a target for the development of inhibitors of HCV replication and for the treatment of HCV infection is discussed in B. W. Dymock, “Emerging therapies for hepatitis C virus infection,” Emerging Drugs, 6: 13-42 (2001).
  • Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH).
  • IMPDH inosine monophosphate dehydrogenase
  • Ribavirin is readily phosphorylated intracellularly and the monophosphate derivative is an inhibitor of IMPDH.
  • inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication.
  • the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497 (merimepodib), which is disclosed in WO 97/41211 and WO 01/00622 (assigned to Vertex); another IMPDH inhibitor, such as that disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb); or mycophenolate mofetil [see A. C. Allison and E. M. Eugui, Agents Action, 44 (Suppl.): 165 (1993)].
  • an inhibitor of IMPDH such as VX-497 (merimepodib), which is disclosed in WO 97/41211 and WO 01/00622 (assigned to Vertex); another IMPDH inhibitor, such as that disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb); or mycophenolate mofetil [see A. C. Allison and E. M. Eugui, Agents Action, 44 (Suppl.): 165 (1993
  • the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) and its hydrochloride salt [for a comprehensive description of this agent, see J. Kirschbaum, Anal. Profiles Drug Subs. 12: 1-36 (1983)].
  • the compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 1′-C, 2′-C-, or 3′-C-branched ribonucleosides disclosed in R. E. Harry-O'kuru, et al., J. Org. Chem., 62: 1754-1759 (1997); M. S. Wolfe, et al., Tetrahedron Lett., 36: 7611-7614 (1995); U.S. Pat. No. 3,480,613 (Nov. 25, 1969); International Publication Number WO 01/90121 (29 Nov. 2001); International Publication Number WO 01/92282 (6 Dec. 2001); and International Publication Number WO 02/32920 (25 Apr.
  • Such branched ribonucleosides include, but are not limited to, 2′-C-methylcytidine, 2′-C-methyluridine, 2′-C-methyladenosine, 2′-C-methylguanosine, and 9-(2-C-methyl-O-D-ribofuranosyl)-2,6-diaminopurine, and prodrugs thereof.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in WO 02/51425 (4 Jul. 2002), assigned to Mitsubishi Pharma Corp.; WO 01/79246, WO 02/32920 (25 Apr. 2002), and WO 02/48165 (20 Jun. 2002), assigned to Pharmasset, Ltd.; WO 01/68663 (20 Sep. 2001), assigned to ICN Pharmaceuticals; WO 99/43691 (2 Sep. 1999); WO 02/18404 (7 Mar. 2002), assigned to Hoffmann-LaRoche; U.S. 2002/0019363 (14 Feb. 2002); WO 02/057287 (25 Jul. 2002), assigned to Merck & Co. and Isis Pharmaceuticals; and WO 02/057425 (25 Jul. 2002), assigned to Merck & Co. and Isis Pharmaceuticals.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in WO 01/77091 (18 Oct. 2001), assigned to Tularik, Inc.; WO 01/47883 (5 Jul. 2001), assigned to Japan Tobacco, Inc.; WO 02/04425 (17 Jan. 2002), assigned to Boehringer Ingelheim; WO 02/06246 (24 Jan. 2002), assigned to Istituto di Ricerche di Biologia Moleculare P. Angeletti S. P. A.; and WO 02/20497 (3 Mar. 2002).
  • WO 01/47883 discloses a large number of benzimidazole derivatives, such as JTK-003, which is claimed to be an orally active inhibitor of NS5B that is currently undergoing clinical evaluation.
  • NMP 5′-nucleoside monophosphate
  • Synthesis of phosphorylation precursors is attained in two stages: 1. Synthesis of 1, 3-diols and 2. Synthesis of phosphorylation precursor.
  • V, W, Z groups of Formula I can be introduced or modified either during synthesis of diols or after the synthesis of prodrugs.
  • 1,3-diols are divided into two types as following: 1) synthesis of racemic 1-(aryl)-propane-1,3-diols; 2) synthesis of enantioenriched 1-(aryl)-propane-1,3-diols.
  • 1,3-Dihydroxy compounds can be synthesized by several well-known methods from the literature.
  • Substituted aromatic aldehydes are utilized to synthesize racemic 1-(aryl)propane-1,3-diols via addition of lithium enolate of alkyl acetate followed by ester reduction (path A) (Turner, J. Org. Chem. 55:4744 (1990)).
  • path A Li enolate of alkyl acetate followed by ester reduction
  • aryl lithium or aryl Grignard additions to 1-hydroxy propan-3-al also give 1-(arylsubstituted)propane-1,3-diols (path B).
  • This method will enable conversion of various substituted aryl halides to 1-(arylsubstituted)-1,3-propane diols (Coppi, et al., J. Org. Chem. 53:911 (1988)).
  • Aryl halides can also be used to synthesize 1-substituted propane diols by Heck coupling of 1,3-diox-4-ene followed by reduction and hydrolysis (Sakamoto, et al., Tetrahedron Lett. 33:6845 (1992)).
  • Pyridyl-, quinolyl-, isoquinolyl-propan-3-ol derivatives can be hydroxylated to 1-substituted-1,3-diols by N-oxide formation followed by rearrangement in the presence of acetic anhydride (path C) (Yamamoto, et al., Tetrahedron 37:1871 (1981)).
  • a variety of aromatic aldehydes can also be converted to 1-substituted-1,3-diols by vinyl lithium or vinyl Grignard addition followed by hydroboration reaction (path D).
  • the ⁇ -keto acid or ester substrates for high pressure hydrogenation or hydrogen transfer reactions may be prepared by a variety of methods such as condensation of acetophenone with dimethylcarbonate in the presence of a base (Chu, et al., J. Het Chem. 22:1033 (1985)), by ester condensation (Turner, et al., J. Org. Chem. 54:4229 (1989)) or from aryl halides (Kobayashi, et al., Tetrahedron Lett. 27:4745 (1986)).
  • 1,3-diols of high enantiomeric purity can be obtained by enantioselective borane reduction of ⁇ -hydroxyethyl aryl ketone derivatives or ⁇ -keto acid derivatives (path B) (Ramachandran, et al., Tetrahedron Lett. 38:761 (1997)).
  • path B ⁇ -hydroxyethyl aryl ketone derivatives or ⁇ -keto acid derivatives
  • commercially available cinnamyl alcohols may be converted to epoxy alcohols under catalytic asymmetric epoxidation conditions. These epoxy alcohols are reduced by Red-A1 to result in 1,3-diols with high ee's (path C) (Gao, et al., J. Org. Chem. 53:4081 (1980)).
  • Enantioselective aldol condensation is another well-described method for synthesis of 1,3-oxygenated functionality with high ee's starting from aromatic aldehydes. (path D) (Mukaiyama, Org. React. 28:203 (1982)).
  • Various 2-substituted-1,3-diols can be made from commercially available 2-(hydroxymethyl)-1,3-propane-diol.
  • Pentaerythritol can be converted to triol via decarboxylation of diacid followed by reduction (path a) (Werle, et al., Liebigs. Ann. Chem., 1986, 944) or diol-monocarboxylic acid derivatives can also be obtained by decarboxylation under known conditions (Iwata, et. al., Tetrahedron Lett. 1987, 28, 3131).
  • Nitrotriol is also known to give triol by reductive elimination (path b) (Latour, et.
  • the triol can be derivatized by mono acylation or carbonate formation by treatment with alkanoyl chloride, or alkylchloroformate (path d) (Greene and Wuts, Protective groups in organic synthesis , John Wiley, New York, 1990).
  • Aryl substitution can be affected by oxidation to aldehyde and aryl Grignard additions (path c).
  • Aldehydes can also be converted to substituted amines by reductive amination reaction (path e).
  • Compounds of Formula 1 where V-Z or V-W are fused by four carbons are made from cyclohexane diol derivatives.
  • Commercially available cis, cis-1,3,5-cyclohexane-triol can be used as is or modified as described in case of 2-substituted propan-1,3-diols to give various analogues. These modifications can either be made before or after ester formation.
  • Various 1,3-cyclohexane-diols can be made by Diels-Alder methodology using pyrone as diene (Posner, et. al., Tetrahedron Lett., 1991, 32, 5295).
  • Cyclohexanediol derivatives are also made by nitrile oxide-olefin additions (Curran, et. al., J. Am. Chem. Soc., 1985, 107, 6023).
  • cyclohexyl precursors are also made from commercially available quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
  • 1,3-Diols described in the earlier section can be converted selectively to either hydroxy amines or to corresponding diamines by converting hydroxy functionality to a leaving group and treating with anhydrous ammonia or required primary or secondary amines (Corey, et al., Tetrahedron Lett., 1989, 30, 5207: Gao, et al., J. Org. Chem., 1988, 53, 4081).
  • a similar transformation may also be achieved directly from alcohols under Mitsunobu type of reaction conditions (Hughes, D. L., Org. React., 1992, 42).
  • a general synthetic procedure for 3-aryl-3-hydroxy-propan-1-amine type of prodrug moiety involves aldol type condensation of aryl esters with alkyl nitrites followed by reduction of resulting substituted benzoylacetonitrile (Shih et al., Heterocycles, 1986, 24, 1599).
  • the procedure can also be adapted for formation of 2-substituted aminopropanols by using substituted alkylnitrile.
  • 3-aryl-3-amino-propan-1-ol type of prodrug groups are synthesized from aryl aldehydes by condensation of malonic acid in presence of ammonium acetate followed by reduction of resulting substituted ⁇ -amino acids.
  • Substituted 1,3-diamines are synthesized starting from a variety of substrates.
  • Arylglutaronitriles can be transformed to 1-substituted diamines by hydrolysis to amide and Hofmann rearrangement conditions (Bertochio, et al., Bull. Soc. Chim. Fr, 1962, 1809).
  • malononitrile substitution will enable variety of Z substitution by electrophile introduction followed by hydride reduction to corresponding diamines.
  • cinnamaldehydes react with hydrazines or substituted hydrazines to give corresponding pyrazolines which upon catalytic hydrogenation result in substituted 1,3-diamines (Weinhardt, et al., J. Med.
  • 1,3-diimines obtained from corresponding 1,3-carbonyl compounds are another source of 1,3-diamine prodrug moiety which allows a wide variety of activating groups V and/or Z (Barluenga, et al., J. Org. Chem., 1983, 48, 2255).
  • Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are synthesized by CBS enantioselective catalytic reaction of ⁇ -chloropropiophenone followed by displacement of halo group to make secondary or primary amines as required (Corey, et al., Tetrahedron Lett., 1989, 30, 5207).
  • Chiral 3-aryl-3-amino propan-1-ol type of prodrug moiety may be obtained by 1,3-dipolar addition of chirally pure olefin and substituted nitrone of arylaldehyde followed by reduction of resulting isoxazolidine (Koizumi, et al., J. Org. Chem., 1982, 47, 4005).
  • Chiral induction in 1,3-polar additions to form substituted isoxazolidines is also attained by chiral phosphine palladium complexes resulting in enantioselective formation of amino alcohols (Hori, et al., J. Org. Chem., 1999, 64, 5017).
  • optically pure 1-aryl substituted amino alcohols are obtained by selective ring opening of corresponding chiral epoxy alcohols with desired amines (Canas et al., Tetrahedron Lett., 1991, 32, 6931).
  • Diastereoselective formation of 1,3-aminoalcohols is also achieved by reductive amination of optically pure 3-hydroxy ketones (Haddad et al., Tetrahedron Lett., 1997, 38, 5981).
  • 3-aminoketones are transformed to 1,3-disubstituted aminoalcohols in high stereoselectivity by a selective hydride reduction (Barluenga et al., J. Org. Chem., 1992, 57, 1219).
  • Synthesis of phosphorylation precursors is divided in to two sections: a. synthesis of P(III) phosphorylation precursor, b. stereoselective synthesis of P(V) phosphorylation precursors.
  • Phosphorylation of 5′-alcohol is achieved using cyclic 1′,3′-propanyl esters of phosphorylating agents where the agent is in the P(III) oxidation state.
  • Appropriately substituted phosphoramidites can be prepared by reacting cyclic chlorophospholanes with N,N-dialkylamine (Perich, et al., Aust. J. Chem., 1990, 43, 1623. Perich, et al, Synthesis, 1988, 2, 142) or by reaction of commercially available dialkylaminophosphorochloridate with substituted propane-1,3-diols.
  • the activated precursor can be prepared by several well known methods.
  • Chlorophosphates useful for synthesis of the prodrugs are prepared from the substituted-1,3-propanediol (Wissner, et al, J. Med Chem., 1992, 35, 1650). Chlorophosphates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, J. Org.
  • chlorophosphate agent is made by treating substituted-1,3-diols with phosphorus oxychloride (Patois, et al, J. Chem. Soc. Perkin Trans. I, 1990, 1577).
  • Chlorophosphate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., Tetrahedron Lett., 1996, 37, 771), which in turn can be either made from a chlorophospholane or phosphoramidate intermediate.
  • Phosphorofluoridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., Tetrahedron Lett., 1988, 29, 5763).
  • Monoalkyl or dialkylphosphoramidate (Watanabe, et al, Chem Pharm Bull., 1990, 38, 562), triazolophosphoramidate (Yamakage, et al., Tetrahedron, 1989, 45, 5459) and pyrrolidinophosphoramidate (Nakayama, et al, J. Am. Chem. Soc., 1990, 112, 6936) are some of the known intermediates used for the preparation of phosphate esters.
  • Another effective phosphorylating procedure is a metal catalyzed addition of cyclic chlorophosphate adduct of 2-oxazolone.
  • This intermediate attains high selectivity in phosphorylation of primary hydroxy group in presence of secondary hydroxyl group (Nagamatsu, et al, Tetrahedron Lett., 1987, 28, 2375).
  • These agents are obtained by reaction of a chlorophosphate with the amine or alternatively by formation of the corresponding phosphoramidite followed by oxidation.
  • the enantioenriched activated phosphorylating agent is synthesized by phosphorylation of an enantioenriched 1-(V)-1,3-propanediol with phosphorodichloridates of formula L-P(O)Cl 2 in the presence of a base (Ferroni, et al., J. Org. Chem. 64(13), 4943 (1999)). Phosphorylation of an enantiomerically pure substituted diol with, for example, a commercially available phosphorodichloridate R—OP(O)Cl 2 , where RO is a leaving group, preferably aryl substituted with electron withdrawing groups, such as a nitro or a chloro, produces two diastereomeric intermediates.
  • the relative configuration of the phosphorus atom is easily determined by comparison of the 31 P NMR spectra.
  • the chemical shift of the equatorial phosphoryloxy moiety (trans-isomer) is always more upfield than the one of the axial isomer (cis-isomer) (Verkade, et al, J. Org. Chem., 1977, 42, 1549).
  • These diastereomers can be further equilibrated to give a trans-2,4-substituted phosphorylating agents in presence of a base such as triethyl amine or DBU.
  • the equilibration to complete inversion of 2,4-cis-diastereomer is also achieved in presence of appropriately substituted sodium phenoxide.
  • the equilibration step results in greater than 95% ee of the isolated trans-phosphorylating agent.
  • nucleoside moieties of Formula I are well described in the literature.
  • 2′-C-methyl-adenosine and 2′-C-methyl-guanosine analogs are made by Lewis acid catalyzed reactions of the persilylated base and 1′-acetate or benzoate sugar intermediate (Walton et al., J. Am. Chem. Soc., 1966, 88, 4524; Harry-O'Kuru et al., J. Org. Chem., 1997, 62, 1754, WO01/90121).
  • the 7-deaza analogs are made as described earlier from 1′-bromo sugar intermediate via reaction of sodium salt of the bases (U.S. 2002-0147160A1 or WO02/057827).
  • the glycosylation products are subjected to deprotection and amination via ammonolysis reaction.
  • nucleoside moieties and derivatives thereof of Formulae VI-VIII of the present invention may be synthesized by many well-established general methods described in the nucleoside literature. Several nucleosides analogs described herein are synthesized as illustrated in WO04/046331 and by the methods cited therein. These compounds of the present invention can also be made from a wide variety of commercial bases utilizing the 2′-methyl riboglycosylation precursor (U.S. 2002-0147160A1 or WO02/057827) via a range of well-known glycosylation reactions (Vorbruggen and Ruh-Pohlenz, Handbook of Nucleoside Synthesis , Wiley, New York, 2001).
  • deaza and aza nucleoside analogs may be prepared utilizing the methods reported in the case of corresponding ribo-analogs by glycosylation with 2′-methyl glycosylation precursor (Robins, et al., Advances in Antiviral Drug Design, Vol. 1, p 39-85, De Clercq, ed., JAI Press, Greenwich, Conn., 1993).
  • new base analogs of the nucleosides can be synthesized by modification of the available nucleosides or via synthesis of new bases followed by glycosylation ( Chemistry of Nucleosides and Nucleotides , Vols. 1-3, Townsend, ed., Plenum, New York, 1988 and Nucleic Acid Chemistry , Vols. 1-4, Townsend and Tipson Eds., Wiley, New York, 1986).
  • prodrugs can be introduced at different stages of the synthesis. Most often they are made at a later stage, because of the general sensitivity of these groups to various reaction conditions.
  • Optically pure prodrugs containing single isomer at phosphorus center are made by coupling of enantiomerically enriched activated phosphate intermediates.
  • prodrugs are further organized into, 1) synthesis via P(III) intermediates, 2) synthesis via P(V) intermediates, and 3) miscellaneous methods.
  • Chlorophospholanes are used to phosphorylate alcohols on nucleosides in the presence of an organic base (e.g., triethylamine, pyridine).
  • an organic base e.g., triethylamine, pyridine.
  • the phosphite can be obtained by coupling the nucleoside with a phosphoramidate in the presence of a coupling promoter such as tetrazole or benzimidazolium triflate (Hayakawa et al., J. Org Chem., 1996, 61, 7996).
  • Phosphite diastereomers may be isolated by column chromatography or crystallization (Wang, et al, Tetrahedron Lett, 1997, 38, 3797; Bentridge et al., J. Am. Chem.
  • the resulting phosphites are subsequently oxidized to the corresponding phosphate prodrugs using an oxidant such as molecular oxygen or t-butylhydroperoxide (Meier et al., Bioorg, Med. Chem. Lett., 1997, 7, 1577). Oxidation of optically pure phosphites is expected to stereoselectively provide optically active prodrugs (Mikolajczyk, et al., J. Org. Chem., 1978, 43, 2132. Cullis, P. M. J. Chem. Soc., Chem Commun., 1984, 1510, Verfurth, et al., Chem. Ber., 1991, 129, 1627).
  • an oxidant such as molecular oxygen or t-butylhydroperoxide
  • the prodrug moiety can be introduced at different stages of the synthesis. Most often the cyclic phosphates are introduced at a later stage, because of the general sensitivity of these groups to various reaction conditions.
  • the synthesis can also proceed through using a protected or unprotected nucleoside or nucleoside analog depending on the reactivity of the functional groups present in the compound.
  • Single stereoisomers of the cis-prodrugs can be made either by separation of the diastereoisomers/enantiomers by a combination of column chromatography and/or crystallization, or by enantiospecific or enantioselective synthesis using enantioenriched activated phosphate intermediates.
  • the general procedure for the phosphorylation of protected nucleosides is accomplished by reacting a suitably protected nucleoside with a base and reacting the alkoxide generated with the phosphorylating reagent.
  • the protected nucleoside can be prepared by one skilled in the art using one of the many procedures described for the protection of nucleosides (Greene T. W., Protective Groups in Organic Chemistry, John Wiley & Sons, New York (1999)).
  • the nucleoside is protected in such a way as to expose the hydroxyl group on which to add the phosphate group while protecting all the remaining hydroxyls and other functional groups on the nucleoside that may interfere with the phosphorylation step or lead to regioisomers.
  • the protecting groups selected are resistant to strong bases, e.g., ethers, silyl ethers and ketals.
  • the protecting groups are optionally substituted MOM ethers, MEM ethers, trialkylsilyl ethers and symmetrical ketals.
  • the protecting groups are t-butyldimethylsilyl ether and isopropylidene. Further protection entails masking of the amino group of the base moiety, if present, so as to eliminate any acidic protons.
  • the selected N-protecting groups are selected from the groups of dialkyl formamidines, mono and dialkyl imines, mono and diaryl imines.
  • the N-protecting groups are selected from the groups of dialkyl formamidines and mono-alkyl imine and mono aryl imine.
  • the mono-alkyl imine is benzylimine and the mono-aryl imine is phenylimine.
  • the N-protecting group is a symmetrical dialkyl formamidine selected from the group of dimethyl formamidine and diethyl formamidine.
  • the alkoxide of the exposed hydroxyl group on the suitably protected nucleoside is accomplished with a base in an aprotic solvent that is not base sensitive such as THF, dialkyl and cyclic formamides, ether, toluene and mixtures of those solvents.
  • the solvents are DMF, DMA, DEF, N-methylpyrrolidinone, THF, and mixture of those solvents.
  • nucleosides and non-nucleoside compounds with cyclic and acyclic phosphorylating agents have been used for the phosphorylation of nucleosides and non-nucleoside compounds with cyclic and acyclic phosphorylating agents.
  • trialkylamines such as triethylamine (Roodsari et al., J. Org Chem. 64(21), 7727 (1999)) or N,N-diisopropylethylamine (Meek et al., J. Am. Chem. Soc. 110(7), 2317 (1988)
  • nitrogen containing heterocyclic amines such as pyridine (Hoefler et al., Tetrahedron 56(11), 1485 (2000)), N-methylimidazole (Vankayalapati et al., J.
  • Grignard reagents are alkyl and aryl Grignards.
  • the Grignard reagents are t-butyl magnesium halides and phenyl magnesium halides.
  • the Grignard reagents are t-butylmagnesium chloride and phenylmagnesium chloride.
  • magnesium alkoxides are used to generate the magnesium 5′-alkoxide of the nucleoside.
  • magnesium alkoxides are selected from the group of Mg(O-t-Bu) 2 , and Mg(O-iPr) 2 .
  • deprotection reagents include fluoride salts to remove silyl protecting groups, mineral or organic acids to remove acid labile protecting groups such as silyl and/or ketals and N-protecting groups, if present.
  • reagents are tetrabutylammonium fluoride (TBAF), hydrochloric acid solutions and aqueous TFA solutions. Isolation and purification of the final prodrugs, as well as all intermediates, are accomplished by a combination of column chromatography and/or crystallization.
  • the sequence provides methods to synthesize single isomers of compounds of Formula I. Due to the presence of a stereogenic center at the carbon where V is attached on the cyclic phosphate reagent, this carbon atom can have two distinct orientations, namely R or S.
  • the trans-phosphate reagent prepared from a racemic diol can exist as either the S-trans or R-trans configuration and results in a S-cis and R-cis prodrug mixture.
  • the reaction of the C′-S-trans-phosphate reagent generates the C′-S-cis-prodrug of the nucleoside while reaction with the C′-R-trans-phosphate reagent generates the C′-R-cis-prodrug.
  • Synthesis of 6-, 2′- and/or 3-′ substituted prodrugs of Formula II or III can be accomplished starting from compounds of Formula I.
  • selective 3′-acylation of nucleoside monophosphate cyclic prodrugs of Formula I may be achieved by several methods as described in the literature ( Protective groups in organic synthesis , Greene and Wuts, John Wiley, New York, 1991). Additionally, selective 3′-acylation can be attained by various esterification methods in the presence of tertiary hydroxy functionality at the 2′-position without protection. Acylation may also be accomplished efficiently by utilizing amine protected amino acids as described earlier (WO 04/002422, Hanson et al., Bioorg. Med Chem.
  • Prodrugs at 6-position may be prepared from the corresponding halo derivatives of the nucleosides.
  • the prodrug substitution is made at the nucleoside stage (before 5′-prodrug formation) from the corresponding chloro or hydroxy functionalities in case of compounds of Formula II or III where R 9 or R 10 is substituted (e.g., N 3 , H, —COR).
  • R 9 or R 10 is substituted (e.g., N 3 , H, —COR).
  • Synthesis of such nucleoside precursors are attained as described earlier (WO 02/057287).
  • Preparation of these purine analogs by azido displacement (Aso et al., J. Chem Soc Perkin Trans II, 2000, 8 1637) or hydrogention (Freer et al., Tetrahedron, 2000, 56, 45) are well known methods.
  • these prodrug functionality substituted nucleosides are transformed to corresponding monophosphate cyclic prodrugs of Formula II or
  • Coupling of activated phosphates with alcohols is accomplished in the presence of an organic base.
  • an organic base for example, chlorophosphates synthesized as described in the earlier section react with an alcohol in the presence of a base such as pyridine or N-methylimidazole.
  • phosphorylation is enhanced by in situ generation of iodophosphate from chlorophosphate (Stomberg, et al., Nucleosides & Nucleotides., 1987, 5: 815).
  • Phosphorofluoridate intermediates have also been used in phosphorylation reactions in the presence of a base such as CsF or n-BuLi to generate cyclic prodrugs (Watanabe et al., Tetrahedron Lett., 1988, 29, 5763). Phosphoramidate intermediates are known to couple by transition metal catalysis (Nagamatsu, et al., Tetrahedron Lett., 1987, 28, 2375).
  • reaction of the optically pure diastereomer of phosphoramidate intermediate with the hydroxyl of nucleoside in the presence of an acid produces the optically pure phosphate prodrug by direct S N 2(P) reaction (Nakayama, et al., J. Am. Chem. Soc., 1990, 112, 6936).
  • reaction of the optically pure phosphate precursor with a fluoride source preferably cesium fluoride or TBAF, produces the more reactive phosphorofluoridate which reacts with the hydroxyl of the nucleoside to give the optically pure prodrug by overall retention of configuration at the phosphorus atom (Ogilvie, et al., J. Am. Chem. Soc., 1977, 99, 1277).
  • Prodrugs of Formula I are synthesized by reaction of the corresponding phosphodichloridate and an alcohol (Khamnei, et al., J. Med. Chem., 1996, 39: 4109). For example, the reaction of a phosphodichloridate with substituted 1,3-diols in the presence of base (such as pyridine and triethylamine) yields compounds of Formula I.
  • base such as pyridine and triethylamine
  • Such reactive dichloridate intermediates can be prepared from the corresponding acids and the chlorinating agents such as thionyl chloride (Starrett, et al, J. Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al., Tetrahedron Lett., 1990, 31: 3261), and phosphorus pentachloride (Quast, et al., Synthesis, 1974, 490).
  • the chlorinating agents such as thionyl chloride (Starrett, et al, J. Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al., Tetrahedron Lett., 1990, 31: 3261), and phosphorus pentachloride (Quast, et al., Synthesis, 1974, 490).
  • Phosphorylation of an alcohol is also achieved under Mitsunobu reaction conditions using the cyclic 1′,3′-propanyl ester of phosphoric acid in the presence of triphenylphosphine and diethyl azodicarboxylate (Kimura et al., Bull. Chem. Soc. Jpn., 1979, 52, 1191). The procedure can be extended to prepare enantiomerically pure phosphates from the corresponding phosphoric acids. Phosphate prodrugs are also prepared from the free acid by Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org.
  • Cyclic-1,3-propanyl prodrugs of phosphates are also synthesized from NMP and substituted propane-1,3-diols using a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Phosphate prodrugs can be prepared by an alkylation reaction between the phosphate corresponding tetrabutylammonium salts and substituted-1,3-diiodopropanes made from 1,3-diols (Farquhar, et al., Tetrahedron Lett., 1995 36, 655). Furthermore, phosphate prodrugs can be made by conversion of nucleoside to the dichloridate intermediate with phosphoryl chloride in presence of triethylphosphite and quenching with substituted-1,3-propanediols (Farquhar et al., J. Org. Chem., 1983, 26, 1153).
  • Phosphorylation can also be achieved by making the mixed anhydride of the cyclic diester of phosphoric acid and a sulfonyl chloride, preferably 8-quinolinesulfonyl chloride, and reacting the hydroxyl of the nucleoside in the presence of a base, preferably N-methylimidazole (Takaku, et al., J. Org. Chem., 1982, 47, 4937).
  • a base preferably N-methylimidazole
  • Step A ( J. Org. Chem. 22:589 (1957))
  • Step A ( J. Org. Chem. 53:911 (1988))
  • Step A ( J. Org. Chem. 55:4744 (1990))
  • the crude hydroxyester was dissolved in ether (2.8 mL/mmol), cooled to ice bath temperature, and lithium aluminum hydride (3 mmol) was added batch wise. The reaction was stirred allowing the cooling bath to melt and the reaction to reach room temperature. After stirring overnight at room temperature, the reaction was cooled back to ice bath temperature and quenched with ethyl acetate. Aqueous work up (0.5 M HCl) afforded the crude diol, which was purified either by chromatography or distillation.
  • a pressure vessel was charged with 1-(3-bromophenyl)-1,3-propanediol (2 g, 8.6 mmol), methanol (30 mL), triethylamine (5 mL) and bis(triphenylphosphine)palladium dichloride (0.36 g, 05 mmol).
  • the sealed vessel was pressurize with carbon monoxide at 55 psi and heated at 85° C. for 24 h.
  • the cooled vessel was opened and the reaction mixture was filtered through Celite and rinsed with methanol.
  • the combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate 1/1) to afford the title compound (1.2 g).
  • Example 4 1-(4-bromophenyl)-1,3-propane diol was prepared as Example 4 and further derivatized as Example 4a.
  • Racemic diols synthesized as in Examples 1-4 may be resolved to yield both enantiomers as described in the following procedure.
  • the separated ketals were hydrolyzed by adding a catalytic amount of concentrated hydrochloric acid to a methanol (4.0 mL/mmol) solution of each. After stirring overnight at room temperature, the methanol was removed under vacuum and the residue was subjected to aqueous work up. The resolved diols were further purified by either chromatography or distillation.
  • Enantiomeric excesses were defined as diacetates (prepared by treatment of diols with acetic anhydride, triethylamine, cat.DMAP in dichloromethane) by HPLC ((S,S) Whelko-0, 250 cm ⁇ 4.0 mm ID purchased from Regis).
  • (+)Diisopropyltartrate provided >96% ee in (R)-1-(3′-chlorophenyl)-1,3-dihydroxypropane.
  • Step A Preparation of methyl 3-(3′-chlorophenyl)-3-oxo-propanoate:
  • a 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermowell/thermometer and nitrogen inlet (bubbler in-line). The flask was flushed with nitrogen and charged sequentially with THF (6 L), potassium t-butoxide (1451 g), and THF (0.5 L). The resulting mixture was stirred at ambient temperature for 15 min. and a 20° C. water bath was applied.
  • a 3 L round bottom flask was charged with 3′-chloroacetophenone (1000 g) and diethylcarbonate (1165 g), and the resulting yellow solution was added slowly to the stirred potassium t-butoxide solution, maintaining the temperature between 16 and 31° C.
  • Step B Preparation of methyl (S)-3-(3′-chlorophenyl)-3-hydroxypropionate:
  • a 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermometer, addition funnel (500 mL) and nitrogen inlet (bubbler in-line).
  • the flask was flushed with nitrogen and charged with formic acid (292 mL, 350 g).
  • Triethylamine (422 mL, 306 g) was charged to the addition funnel, then added slowly with stirring, maintaining the temperature less than 45° C. After the addition was complete (1 h, 30 min), the solution was stirred with the ice bath applied for 20 min., then at ambient temperature for an additional 1 h.
  • the flask was charged sequentially with methyl 3-(3-chlorophenyl)-3-oxo-propanoate (1260 g), DMF (2.77 L including rinsing volume) and (S,S)-Ts-DPEN-Ru-Cl-(p-cymene) (3.77 g).
  • the flask was equipped with a heating mantle and the addition funnel was replaced with a condenser (5 C circulating coolant for condenser).
  • the stirred reaction solution was slowly heated to 60° C. (90 min. to attain 60° C.) and the contents were maintained at 60° C. for 4.25 h. HPLC indicated 3% starting material remained.
  • the solution was stirred at 60° C.
  • the crude hydroxyester (10 mg, 0.046 mmol) was dissolved in dichloromethane (1 mL). Acetic anhydride (22 ⁇ L, 0.23 mmol) and 4-(dimethylamino)pyridine (22 mg, 0.18 mmol) were added and the solution was stirred at ambient temperature for 15 min. The solution was diluted with dichloromethane (10 mL) and washed with 1 M hydrochloric acid (3 ⁇ 3 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • Step C Preparation of (S)-3-(3′-chlorophenyl)-3-hydroxypropanoic acid:
  • a 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermowell/thermometer and nitrogen inlet (outlet to bubbler).
  • the flask was charged with 2 M borane-THF (3697 g, 4.2 L) and the stirred solution was cooled to 5° C.
  • a solution of (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (830 g) in THF (1245 mL) was prepared with stirring (slightly endothermic).
  • the reaction flask was equipped with an addition funnel (1 L) and the hydroxyacid solution was slowly added to the stirred borane solution, maintaining the temperature ⁇ 16° C.
  • the oil was purified by vacuum distillation and the fraction at 135-140° C./0.2 mm Hg was collected to provide 712.2 g of a colorless oil.
  • Step A Synthesis of methyl 3-oxo-3-(pyridin-4-yl)-propanoate
  • a 50 L, 3-neck flask was equipped with an overhead stirrer, heating mantle, and nitrogen inlet.
  • the flask was charged with THF (8 L), potassium t-butoxide (5 kg, 44.6 mol), and THF (18 L).
  • 4-Acetylpyridine (2.5 kg, 20.6 mol) was added, followed by dimethylcarbonate (3.75 L, 44.5 mol).
  • the reaction mixture was stirred without heating for 2.5 h then with heating to 57-60° C. for 3 h.
  • the heat was turned off and the mixture cooled slowly overnight (15 h).
  • the mixture was filtered through a 45 cm Buchner funnel.
  • the solid was returned to the 50 L flask and diluted with aqueous acetic acid (3 L acetic acid in 15 L of water).
  • the mixture was extracted with MTBE (1 ⁇ 16 L, 1 ⁇ 12 L).
  • the combined organic layers were washed with aqueous Na 2 CO 3 (1750 g in 12.5 L water), saturated aqueous NaHCO 3 (8 L), and brine (8 L) then dried over MgSO 4 (500 g) overnight (15 h).
  • the solution was filtered and the solvent removed by rotary evaporation to a mass of 6.4 kg.
  • the resulting suspension was cooled in an ice bath with stirring for 2 h.
  • the solid was collected by filtration, washed with MTBE (500 mL), and dried in a vacuum oven at 20° C. for 15 h, giving 2425 g of the keto ester as a pale yellow solid.
  • Step B Synthesis of S-methyl-3-hydroxy-3-(pyridin-4-yl)-propanoate
  • a 22 L, 3-neck round bottom flask was equipped with an overhead stirrer, thermowell/thermometer, addition funnel (1 L), and cooling vessel (empty).
  • the flask was flushed with nitrogen, charged with formic acid (877 g) and cooled with an ice bath.
  • Triethylamine (755 g) was charged to the addition funnel and added slowly over 50 min. to the stirred formic acid.
  • the cooling bath was removed and the reaction solution was diluted with DMF (5.0 L).
  • the ketoester (2648 g) was added in one portion, followed by an additional 0.5 L of DMF.
  • the flask was equipped with a heating mantle and the stirred mixture was heated gradually to 16° C. to dissolve all solids.
  • the catalyst (S,S)-Ts-DPEN-Ru-Cl-(p-cymene) (18.8 g) was added in one portion and the stirred mixture was heated to 55° C. over 1 h. The resulting dark solution was stirred at 55° C. for 16 h. TLC indicated the reaction was complete.
  • the oil was dissolved in dichloromethane (10 L) and transferred to a 5 gal. stationary separatory funnel.
  • the dark solution was washed with saturated sodium bicarbonate solution (3.0 L) and the aqueous phase was back extracted with dichloromethane (3.0 L).
  • the combined dichloromethane extracts were dried over MgSO 4 (300 g), filtered, and concentrated under reduced pressure to provide 3362 g of a brown oil.
  • a 22 L, 4-neck round bottom flask was equipped with an overhead stirrer, thermowell/thermometer, addition funnel (2 L), condenser and cooling vessel (empty).
  • the flask was flushed with nitrogen and charged sequentially with sodium borohydride (467 g, 12.3 mol), 1-butanol (9.0 L), and water (148 mL, 8.23 mol)
  • the crude hydroxyester was dissolved in 1-butanol (1.0 L) and the solution was charged to the addition funnel.
  • the solution was added over 3.25 h, using cooling as necessary to keep the temperature below 62° C.
  • the mixture was stirred for 0.5 h then the flask was equipped with a heating mantle and the stirred mixture was heated to 90° C.
  • Acetonitrile (3 L) was fed into the evaporator flask and the solvent was evaporated under reduced pressure.
  • Step A Preparation of 3-(3-chlorophenyl)-3-oxo-propanoic acid:
  • a 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer and addition funnel (2 L). The flask was flushed with nitrogen and charged with diisopropylamine (636 mL) and THF (1.80 L). A thermocouple probe was immersed in the reaction solution and the stirred contents were cooled to ⁇ 20° C. n-Butyllithium (1.81 L of a 2.5 M solution in hexanes) was charged to the addition funnel and added slowly with stirring, maintaining the temperature between ⁇ 20 and ⁇ 28° C. After the addition was complete (30 min), the addition funnel was rinsed with hexanes (30 mL) and the stirred solution was cooled to ⁇ 62° C.
  • Trimethylsilyl acetate 300 g was added slowly with stirring, maintaining the temperature ⁇ 60° C. After the addition was complete (30 min), the solution was stirred at ⁇ 60° C. for 15 min.
  • 3-Chlorobenzoyl chloride (295 mL) was added slowly with stirring, maintaining the temperature ⁇ 60° C. After the addition was complete (65 min), the cooling bath was removed and the reaction solution was stirred for 1.25 h, with gradual warming to 0° C.
  • the reaction flask was cooled with an ice bath, then water (1.8 L) was added to the stirred solution. The reaction mixture was stirred for 10 min., then diluted with t-butyl methyl ether (1.0 L).
  • the lower aqueous phase was separated and transferred to a 12 L, 3-neck round bottom flask equipped with a mechanical stirrer.
  • t-Butyl methyl ether was added (1.8 L) and the stirred mixture was cooled to ⁇ 10° C. (ice bath).
  • Concentrated HCl solution 300 mL of 12 M solution was added and the mixture was vigorously stirred.
  • the layers were separated and aqueous phase was further acidified with con. HCl (30 mL) and extracted again with t-butyl methyl ether (1.0 L).
  • the combined MTBE extracts were washed with brine (1 L), dried (MgSO4, 70 g), filtered and concentrated under reduced pressure to give 827 g of a yellow solid.
  • a 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer and addition funnel (1 L). The flask was flushed with nitrogen and charged with 3-(3-chlorophenyl)-3-oxo-propanoic acid (275.5 g) and dichloromethane (2.2 L). A thermocouple probe was immersed in the reaction slurry and the stirred contents were cooled to ⁇ 20° C. Triethylamine (211 mL) was added over 5 min. to the stirred slurry and all solids dissolved.
  • Beta-ketoester starting material was synthesized as described in Example 7, step A.
  • a solution containing beta-ketoester (1 mmol) in either methanol or ethanol (5-10 mL/mmol ketoester) was degassed through several pump/vent (N 2 ) cycles at room temperature.
  • the degassed solution was moved into a glove bag and under an atmosphere of N 2 was poured into a stainless steel bomb containing a stir bar and 1.0 mole % Ru-BINAP catalyst.
  • the bomb was sealed, removed from the glove bag and purged with H 2 prior to stirring 18-24 h at room temperature and 150 psi H 2 . After venting the hydrogen pressure, the bomb was opened and the reaction mixture was removed and concentrated.
  • the crude beta-hydroxyester was used for hydrolysis.
  • the reddish reaction mixture was cooled to room temperature and stirred at room temperature for 2 h then placed in the refrigerator overnight.
  • the final ratio was determined by HPLC to be 96/4 trans/cis.
  • the reaction mixture was quenched with a saturated solution of ammonium chloride and diluted with ethyl acetate. The layers were separated and the organics were washed 4 times with 0.3 N sodium hydroxide to remove the nitrophenol, then saturated sodium chloride and dried over sodium sulfate.
  • Example 13a Same as Example 11.1 starting with 1-(2,3-dichlorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and lithium hydride as in Example 13a.
  • Example 11.1 Same as Example 11.1 starting with 1-(2,3,5-trichlorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 13a Same as Example 11.1 starting with 1-(2-chlorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and lithium hydride as in Example 13a.
  • Example 11.1 Same as Example 11.1 starting with 1-(3,5-dimethoxyphenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-bromophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13a.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-bromo-5-ethoxyphenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-trifluoromethylphenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(4-chlorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-methylphenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(4-fluorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-fluorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-fluorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-[4-(4-chlorophenoxy)phenyl]-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-bromophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(3,4-ethylenedioxyphenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-fluoro-4-chlorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(2,6-dichlorophenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-fluoro-5-methoxyphenyl)-1,3-propanediol except that the trans-isomer was isolated from the cis/trans mixture without isomerization.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-fluoro-4-chlorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(3-chloro-4-fluorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(2-fluoro-5-bromophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(2,3,5,6-tetrafluorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • Example 11.1 Same as Example 11.1 starting with 1-(2,3,6-trifluorophenyl)-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • the 1,2-cis ketal (4.5 g, 17.5 mmol) was dissolved in 70% aq TFA (10 mL) and allowed to react overnight at room temperature. The reaction was diluted with acetonitrile (30 mL) and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (300 mL) and the organic layer was washed with saturated aq NaHCO 3 , water and dried (anhydrous Na 2 SO 4 ). The crude product was purified by column chromatography (1-5% MeOH—CH 2 Cl 2 ) to give 1,2-cis diol diastereomer (3.5 g).
  • the 1,2-trans ketal diastereomer was also hydrolyzed following the above procedure to give 1,2-trans-diol diastereomer.
  • 1,2-cis-diol diastereomer was subjected to phosphorylation using the procedure described in Example 11.1 without equilibration to give the following two isomers.
  • Phosphorus oxychloride (3.4 mL, 36.3 mmol) was added to a solution of 1-(3-chlorophenyl)-1,3-propanediol in dichloromethane at 0° C. followed by triethylamine (10.2 mL, 73 mmol). After 2 h, sodium 4-nitrophenoxide (10.63 g, 66 mmol) was added to the solution of cis/trans phosphorochloridate reagent and the orange reaction mixture was heated at reflux for 1 h. The cooled solution was partitioned with ethyl acetate and a saturated solution of ammonium chloride. The organics were separated and dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • a cis/trans mixture of 4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinanes was prepared as in Example 11, except that the cis and trans isomers were separated by column chromatography prior to the addition of 4-nitrophenol.
  • C is-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane was isomerized to the trans isomer by adding a solution of the cis-isomer to a solution of 4-nitrophenoxide prepared with the following bases.
  • Lithium hydride (19.4 mg, 2.44 mmol) was added to a solution of 4-nitrophenol in THF at room temperature. The yellow solution was stirred at room temperature for 30 min. A solution of cis-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane (300 mg, 0.813 mmol) in THF was added to the solution of lithium 4-nitrophenoxide. The orange reaction mixture was stirred a room temperature. After 5 h the ratio was 92.9/5.4 trans/cis (HPLC determination).
  • (+)-(R)-1-(3-chlorophenyl)-1,3-propanediol (3 g, 16.1 mmol) and triethylamine (6.03 ml, 59.6 mmol) in THF (80 mL) was added dropwise to a solution of 4-nitrophenoxyphosphorodichloridate (7.63 g, 29.8 mmol) in 150 mL of THF at 0° C. After about 2 h, the starting diol was consumed, with the formation of two isomeric 4-nitophenylphosphates, and additional triethylamine (8.31 mL) followed by of 4-nitrophenol (8.29 g, 59.6 mmol) were added.
  • Example 11.1 Same as Example 11.1 starting with S-( ⁇ )-1-phenyl-1,3-propanediol except that the isomerization was conducted with 4-nitrophenol and triethylamine as in Example 13b.
  • a 1 liter 3-neck round bottom flask was equipped with a mechanical stirrer, addition funnel, a thermometer and a N 2 inlet.
  • the flask is charged with S-( ⁇ )-1-(pyrid-4-yl)-propane-1,3-diol (25 g, 163.4 mmol) and ethyl acetate (250 mL) and the resulting suspension was treated slowly with a 4N HCl solution in dioxane (43 mL, 176 mmol) over a period of 15 min.
  • 4-nitrophenylphosphorodichloridate 41.81 g, 163.4 mmol
  • the internal temperature of the reaction mixture was adjusted to ⁇ 10° C. with the help of a dry ice-acetone cooling bath.
  • a solution of triethylamine (79 mL, 572 mmol) in ethyl acetate (100 mL) was added maintaining the reaction temperature at ⁇ 5° C.
  • the cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h.
  • the reaction mixture was filtered to remove triethylamine-hydrochloride salt, which is washed with ethyl acetate (3 ⁇ 30 mL) until the filtrate shows only faint absorption.
  • the filtrate was evaporated down to a volume of 150-175 mL under reduced pressure.
  • the prodrug (0.15 g, 0.27 mmol) obtained from the above step was dissolved in pre-cooled 75% TFA/H 2 O (20 mL) and allowed to stir at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by flash chromatography (1% aq.NH 4 OH in 10% MeOH in CH 2 Cl 2 ) to give 0.142 g of the title compound as an off-white solid.
  • the parent nucleoside 2-amino-7-(2-C-methyl-beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one was synthesized as described in U.S. 2002-0147160A1 and WO 02/057827.
  • the nucleoside was converted to corresponding prodrug following the procedures as in steps A, B and C of Example 16.
  • the nucleoside was converted to corresponding prodrug following the procedures as in steps A, B and C of Example 16.
  • Example 14 The compound was synthesized in a similar sequence as Example 19 using the phosphorylating agent whose preparation is described in Example 14.
  • the nucleoside was converted to corresponding prodrug following the procedures as in steps A, B and C of Example 16.
  • trans-phosphorylating agents utilized in step B are synthesized by the procedures as described in examples 1-15.

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Application Number Priority Date Filing Date Title
US10/903,215 US20050182252A1 (en) 2004-02-13 2004-07-29 Novel 2'-C-methyl nucleoside derivatives
PCT/US2005/004447 WO2005084192A2 (fr) 2004-02-13 2005-02-14 Nouveaux derives nucleosidiques de 2'-c-methyle
BRPI0507675-7A BRPI0507675A (pt) 2004-02-13 2005-02-14 derivados de 2'-c-metil nucleosìdeo
EP05750052A EP1720556A4 (fr) 2004-02-13 2005-02-14 Nouveaux derives nucleosidiques de 2'-c-methyle
EP07104279A EP1905778A3 (fr) 2004-02-13 2005-02-14 Nouveaux dérivés de nucléoside 2'-C-Methyl
JP2006553282A JP2007522237A (ja) 2004-02-13 2005-02-14 新規２’−ｃ−メチルヌクレオシド誘導体
PCT/US2005/027235 WO2006033709A2 (fr) 2004-07-29 2005-07-29 Nouveaux derives de nucleosides
EP05807817A EP1781101A2 (fr) 2004-07-29 2005-07-29 Nouveaux derives de nucleosides
US11/572,785 US20090131370A1 (en) 2004-02-13 2005-07-29 Novel Nucleoside Derivatives
JP2007523879A JP2008508319A (ja) 2004-07-29 2005-07-29 新規ヌクレオシド誘導体
US11/589,363 US7666855B2 (en) 2004-02-13 2006-10-30 2′-C-methyl nucleoside derivatives
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BRPI0507675A (pt) 2007-07-17
JP2007522237A (ja) 2007-08-09
US20070179114A1 (en) 2007-08-02
US20090131370A1 (en) 2009-05-21
WO2005084192A2 (fr) 2005-09-15
US20070042989A1 (en) 2007-02-22
WO2005084192A3 (fr) 2006-05-11
EP1720556A4 (fr) 2012-05-09
US7666855B2 (en) 2010-02-23
EP1720556A2 (fr) 2006-11-15

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