WO2003051306A2 - N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections - Google Patents

N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections Download PDF

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WO2003051306A2
WO2003051306A2 PCT/US2002/040090 US0240090W WO03051306A2 WO 2003051306 A2 WO2003051306 A2 WO 2003051306A2 US 0240090 W US0240090 W US 0240090W WO 03051306 A2 WO03051306 A2 WO 03051306A2
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hydrogen
dioxolane
fluorine
pharmaceutically acceptable
fluorocytidine
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PCT/US2002/040090
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French (fr)
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WO2003051306A3 (en
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Kyoichi A. Watanabe
Junxing Shi
Michael J. Otto
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Pharmasset Ltd.
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Publication of WO2003051306A3 publication Critical patent/WO2003051306A3/en

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    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • A61P31/22Antivirals for DNA viruses for herpes viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32Nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32Nitrogen atom
    • C07D473/34Nitrogen atom attached in position 6, e.g. adenine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16Purine radicals

Definitions

  • the present invention is directed to compounds, methods and compositions for the treatment or prevention of viral infections using nucleoside analogues. More specifically, the invention describes N 4 -acyl-substituted cytosine nucleoside analogues, pharmaceutically acceptable salts, prodrugs, or other derivatives thereof, and the use thereof in the treatment of a viral infection, and in particular a human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection.
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HBV infection can lead to acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which large sections of the liver are destroyed. Patients typically recover from the acute phase of HBV infection. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid- 1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
  • HBV infection In Western, industrialized countries, the high-risk group for HBV infection includes those in contact with HBV carriers or their blood samples.
  • the epidemiology of HBV is very similar to that of HIV/AIDS, which is a reason why HBV infection is common among patients infected with HIV or suffering from AIDS.
  • HBV is more contagious than HIV. '
  • these synthetic nucleosides After phosphorylation to the 5 '-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination, because they lack a 3 '-hydroxyl group. Some nucleosides also inhibit the viral enzyme reverse transcriptase.
  • 3TC (lamivudine) and interferon are currently the only FDA-approved drugs for the treatment of HBV infection. Viral resistance develops within 6 months of 3TC treatment in about 14% of patients.
  • Cis-2-hydroxymethyl-5-(5-fluorocytosin-l -yl)-l ,3-oxathiolane is currently in clinical trials for the treatment of HIV and separately for HBV by Triangle Pharmaceuticals, Inc. See Schinazi et al. (1992) Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-l-[2- (hydroxymethyl)-l,3-oxathiolane-5-yl]cytosine. Antimicrob. Agents Chemother. 36, 2423-2431; US Pat. Nos. 5,210,085; 5,914,331; 5,814,639; WO 91/11186; and WO 92/14743.
  • (+/-)- l-[(2- ⁇ , 4- ⁇ )-2-(hydroxymethyl)-4- dioxolanyl]thymine referred to as (+/-)-dioxolane-T
  • (+/-)-dioxolane-T exhibits a modest activity against HIV (EC 50 of 20 ⁇ M in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 ⁇ M.
  • 07/703,379 directed to a method to obtain the enantiomers of 1,3-dioxolane nucleosides using a stereoselective synthesis that includes condensing a 1,3-dioxolane intermediate covalently , bound to a chiral auxiliary with a silyl Lewis acid.
  • the corresponding application filed in Europe was EP 0 515 156.
  • R is O,H, CI, NH 2 , or H, or a pharmaceutically acceptable salt or derivative of the compounds Optionally in a pharmaceutically acceptable carrier or diluent.
  • the compound wherein R is chloro is referred to as (-)-(2R,4R)-2-amino-6-chloro-9-[(2- hydroxymethyl)-l,3-dioxolan-4-yl]purine.
  • the compound wherein R is hydroxy is (- )-(2R,4R)-9-[(2-hydroxy-methyl)-l,3-dioxolan-4-yl]guanine.
  • the compound wherein R is amino is (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-l,3-dioxolan-4-yl]adenine.
  • the compound wherein R is hydrogen is (-)-(2R,4R)-2-amino-9-[(2- hydroxymethyl)-l,3-dioxolan-4yl] ⁇ urine.
  • Kim et al. published an asymmetric synthesis for selected 1,3- dioxolane pyrimidine nucleosides from 1,6-anhydro-D-mannose. The specific synthesis resulted in ⁇ -D and ⁇ -D enantiomers of 1,3-dioxolane nucleosides.
  • Kim et al. 1 ,3-Dioxolanylpurine Nucleosides (2R,4R) and (2R,4S) with Selective Anti-HIV-1 Activity in Human Lymphocytes, J. Med. Chem., 1993 36, 30-37.
  • PCT/US92/01393 by Liotta et al. disclosed a method for the synthesis of 1,3-dioxolane nucleosides that includes condensing a 2-O-protected-5-O-acylated-l,3-dioxolane with a purine of pyrimidine base in the presence of a titanium containing Lewis acid to provide predominately the desired ⁇ -isomer in the Cl'-position of a 1,3-dioxolane nucleoside.
  • WO 92/14729 also disclosed a process for the resolution of a racemic mixture of 1,3-dioxolane nucleoside enantiomers.
  • Kim et al. published an article teaching how to obtain (-)-L- ⁇ - dioxolane-C and (+)-L- ⁇ -dioxolane-T from 1,6-anhydro-L- ⁇ -glucopyranose.
  • Kim et al. Potent anti-HIV and anti-HBV Activities of (-)-L- ⁇ -Dioxolane-C and (+)-L- ⁇ - Dioxolane-T and Their Asymmetric Syntheses, Tetrahedron Letters Vol 32(46), pp 5899-6902.
  • DAPD (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-l,3-dioxolari-4-yl]adenine
  • RTI reverse transcriptase inhibitor
  • DAPD is thought to be deaminated in vivo by adenosine deaminase,. a ubiquitous enzyme, to yield (-)- ⁇ -D-dioxolane guanine (DXG), which is subsequently converted to the corresponding 5'-tri-phosphate (DXG-TP).
  • DXG-TP 5'-tri-phosphate
  • Biochemical analysis has demonstrated thaf DXG-TP is a potent inhibitor " of the HIV reverse transcriptase (HIV-RT) with a Ki of 0.019 ⁇ M.
  • nucleosides that have been successful in anti-viral treatments include of 2',3'-dideoxy- and 2',3'-didehydro-2,'3'-dideoxy-nucleosides (referred to as a "ddN” or “d2N” nucleoside and a “d4N” nucleoside, respectively), particularly, these nucleosides inhibit the replication of HIV in vivo or in vitro, thus, has led a number of researchers to design and test a variety of modified d2- and d4-nucleosides.
  • Netherlands Pat. No. 8901258 discloses generally 5-halogeno-2',3'-dideoxy-2',3'-didehydrocytidine derivatives for use in treating HIV and HBV. ⁇ -D- and ⁇ -L-2',3'-didehydro-2',3 5 - dideoxy-5-fluorocytidine were further described in US Pat. Nos. 5,703,058; 5.905,070; 6,232,300; and 5,561,120. US Pat. No.
  • 5,703,058 claims a method for the treatment of HIV and/or HBV infection that includes administering an effective amount of ⁇ -L-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5- fluorocytosin- 1 -yl)- 1 ,3-oxathiolane, cis-2-hydroxymethyl-5 -(cytosin- 1 -yl)- 1,3- oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten-l-yl)-guanine (carbovir), 9-[(2- hydroxyethoxy)methyl]-guanine (acyclovir), interferon, 3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), (-)-2'-fluoro-5- methyl- ⁇ -L-ara-uridine (L-FMAU)
  • US Pat. No. 5,905,070 claims a method for the treatment of HIV and HBV infection that includes administering an effective amount " of ⁇ -D-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane, cis-2- hydroxymethyl-5-(cytosin-l -yl)-l ,3-oxathiolane, 9-[4-(hydroxy-methyl)-2- cyclopenten-1 -yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), (-)-2'-fluoro-5-methyl- ⁇ -L-ara-uridine (L-FM
  • N4-benzoyl- 2',3'-dideoxy-2',3'-didehydrocytidine as a prodrug of 2',3'-dideoxy-2',3'- didehydrocytidine (DDCN), Chem.' Pharm. Bull. (1989), 37(9), 2547-9), N 4 -benzoyl- 2',3'-dideoxycytidine (Gulbis et al. (1993) Structure of a dideoxynucleoside active against the HIV (AIDS) virus. Acta Cryst.
  • N 4 -acyl-cytosine 1,3-dioxolane nucleosides and in particular, N 4 -acyl-5-fluorocytidine-l,3-dioxolane, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of HIV and/or HBV infection in a host, and in particular, a human, is provided that includes administering an effective amount of a N 4 -acyl-cytosine nucleoside.
  • the active compound is of formula (A):
  • R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO , aryl, heteroaryl and acyl;
  • R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl ;
  • R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol; and
  • R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C O H J R where R is chosen from halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
  • R is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C O H J R where R is chosen from halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl
  • the compound of the present invention can be in the form of the isolated ⁇ -L- or ⁇ -D- configuration, or a mixture thereof, including but not limited to a racemic mixture.
  • the N 4 -acylcytosine-l,3-dioxolane nucleosides are inhibitors of HBV. Therefore, these compounds can also be used to treat patients that are co- infected with both HIV and HBV.
  • the present invention provides a compound, method and composition for treating an HIV infection in a host comprising administering a therapeutically
  • the present invention provides a compound, method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for treating an HBV ihfection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for
  • I preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a use of a compound for the treatment of HIV and/or HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a method of manufacture for a therapeutically effective compound for the treatment of an HIV and/or HBV infection.
  • a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient for the treatment of a host infected with HIV or HBV.
  • a compound, method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • N 4 -acyl-cytosine-l,3-dixolane nucleosides and in particular, N 4 -acyl-5-fluorocytidine-l,3-dioxolane, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of a host, and in particular, a human, infected with HIV and/or HBV, is provided that includes administering an effective amount of an N 4 -acyl-cytosine- 1,3-dioxolane nucleosides.
  • the present invention also provides a compouind, method and composition for treating an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for treating an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
  • a method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • the active compound is of formula (A):
  • R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl and acyl;
  • R and R are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;
  • R 4 is H, phosphate (including but not limited to mondphosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol; and R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl,
  • the compound of the present invention can be in the form of the isolated ⁇ -L- or ⁇ -D- configuration, or a mixture thereof, including but not limited to a racemic mixture.
  • the active compound is ⁇ -D-N 4 - p-iodobenzoyl-5-fluorocytidine-l,3-dioxolane, ⁇ -D-N 4 -p-fluoro-benzoyl-5- fluorocytidine-1 ,3-dioxolane, ⁇ -D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-l ,3- dioxolane, ⁇ -D-N 4 -p-bromobenzoyl-5 -fluorocytidine- 1 ,3 -dioxolane, ⁇ -D-N 4 -p-ethyl- benzoyl-5 -fluorocytidine- 1 ,3 -dioxolane, and ⁇ -D-N 4 -p-t-butylbenzoyl-5 -fluoro- cytidine-l,3-di
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the ortho position.
  • R 4 is hydrogen
  • R 1 is fluorine or hydrogen
  • R 3 and R 3 are independently hydrogen or fluorine
  • R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alk
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with Br in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with I in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with F in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CI in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 ' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted 1 with n-pentyl in the ortho position.
  • the active compound is of " formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine' or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with ⁇ isopentyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or. prodrugs thereof, wherein:
  • R is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CN in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; ' iii) R and R are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; ⁇ iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; ⁇ iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; '
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; ⁇ iii) R3 and R3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the ortho 'position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; > iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the ortho position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ' ii) R is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a pheny moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, a ⁇ kynyl, or aryl in the meta position.
  • halogen F, CI, Br, I
  • CN, CF 3 , N 3 , NO 2 alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, a ⁇ kynyl, or aryl in the meta position.
  • the active compound is of
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ' ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with Br in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with I in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with F in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CI in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 ⁇ are independently hydrogen or fluorine; and
  • R 2 is a phenyl moiety optionally substituted with methyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the meta position.
  • the active compound is of formula , its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: • i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally, substituted with tert-butyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrog ⁇ n; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ' ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the met'a position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted With a cyclohexyl in the meta
  • the active compound is of " formula " (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CN in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrpgen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted 1 with thioalkyl in the meta
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and
  • R 2 is a phenyl moiety optionally substituted with alkenyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted ' with naphthyl in the meta position. '
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the meta position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the para position.
  • halogen F, CI, Br, I
  • CN CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein:
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with Br in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluOrine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with I in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with F in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CI in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the para position.
  • the active compound is of formula (A), iis pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs' thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; I
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) Rf is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and
  • R 2 is a phenyl moiety optionally substituted with neopentyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: ' i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with CN in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 1 CF 3 in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the para position.
  • the active compound is of formula (A), its' pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and
  • R 2 is a phenyl moiety optionally substituted with alkynyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and ⁇ iv) R 2 is a phenyl moiety optionally substituted with aryl in the para position.
  • the active compound is of formula (A), its. pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and , iv) R 2 is a phenyl moiety optionally substituted with benzyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with thiophenyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the para position.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; '
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; , iii) R and R are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,4-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; , iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,6-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,5-dihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and
  • R 2 is a phenyl moiety optionally substituted with 2,3,5-trihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and ⁇ iv) R 2 is a phenyl moiety optionally substituted with 2,4,5-trihalo.
  • the active compound is of formula (A), its. pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and ⁇ iv) R 2 is a phenyl moiety optionally substituted with 2,4,6-trihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6-trihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5-trihalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentahalo.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl mqiety optionally substituted with 2,3-dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable- salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; ⁇ iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; . iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4- dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,5- dialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluoririe; and
  • R 2 is a ' phenyl moiety optionally substituted with 2,3,5- trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and , iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- trialkyl.
  • the active compound is of
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and , iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with 2,5,6- trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with 2,5,6- trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv
  • R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 'are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5- trialkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs. thereof, wherein:
  • R 4 is hydrogen; ii) R* is fluorine or hydrogen; iii) R 3 and ' ' R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetraalkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independe ⁇ tly.hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentaalkyl.
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-di-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- di-NO .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- di-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- di-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4- di-NO .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • R 4 is hydrogen; ii) R 1 is flu'orine or hydrogen;
  • R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,5- di-NO 2 .
  • the active compound is pf formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4- tri-N0 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5- tri-NO .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- tri-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- tri-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:-;. , i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- tri-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:-;. , i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- tri-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:-;. , i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; i
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5- tri-NO 2 .
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R l is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2- position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: ⁇ i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 3- position or the 4-position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a benzothiophenyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the benzene ring.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a benzothiophenyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the thienyl ring.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and > iv) R 2 is a cyclohexyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or 3-position.
  • the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R 4 is hydrogen; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; and iv) R 2 is a cyclohexyl moiety optionally substituted with alkyl, halo, alkenyl,
  • the active compound is ⁇ -D-5-fluoro-N 4 -(4-
  • the active compound is ⁇ -D-5-fluoro-N 4 -(4- fluorobenzoyl)cytidine-l,3-dioxolaneofthe structure:
  • the active compound is ⁇ -D-N 4 -(4- chlorobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-N 4 -(4- bromobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active conlpound is ⁇ -D-5-fluoro-N 4 -(3-
  • the active compound is ⁇ -D-N 4 -(3- chlorobe ⁇ zoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-N 4 -(3- bromobenzoyl)-5 -fluorocytidine- 1,3 -dioxolane of the structure:
  • the active compound is ⁇ -D-5-fluoro-N ⁇ 4 -(4- nitrobenzoyl)cytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-5-fluoro- N 4 -p-toluoylcj idine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-5-fluoro-N 4 -(w- toluoyl)cytidine- 1,3-dioxolane of the structure:
  • the active compound is ⁇ -D-N 4 -(4- ethylbenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-5-fluoro- N 4 -(4-propylbenzoyl)cytidine- 1,3 -dioxolane of the structure:
  • the active ⁇ ompound is ⁇ -D-N -(4-tert- butylbenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active compound is ' ⁇ -D-5-fluoro- N 4 -(2-thiophenecarbonyl)cytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-N 4 -(benzo-[b]- thiophene-2-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the active compound is ⁇ -D-N 4 - (cyclohexane-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
  • the compounds of the present invention have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention. Some compounds may exhibit polymorphism.
  • the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the
  • optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
  • Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a
  • simultaneous crystallization a technique whereby the individual enantiomers are separately crystallized from a 1 solution of the racemate, possible only if the latter is a conglomerate in the solid state;
  • enzymatic resolutions a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme;
  • enzymatic asymmetric synthesis a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;
  • chemical asymmetric synthesis a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries;
  • diastereomer separations a technique whereby a racemic compound is re
  • first- and second-order asymmetric transformations a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the
  • chiral liquid chromatography a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC).
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
  • chiral gas chromatography a technique whereby the racemate
  • I ⁇ is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
  • extraction with chiral solvents a technique whereby the i " " " " - enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
  • xiii) ' transport across chiral membranes a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one
  • Chiral chromatography including but not limited to simulated moving bed chromatography, is used in one embodiment.
  • a wide variety of chiral stationary phases are commercially available.
  • the term “substantially free of or “substantially in the absence of refers to a nucleoside composition that includes at least 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers.
  • isolated refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted alkyl groups.
  • the alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those
  • Alkyl groups include, but are not limited to the radicals of methane, ethane, propane, cyclopropane, 2-methylpropane (isobutane), »-butane, 2,2-dimethylpropane (neopentane), cytobutane, 1,1 dimethylcyclopropane, 2-methylbutane, trans-1,2- dimethylcyclopropane, ethylcyclopropane, n-pentane, methylcyclobutane, cis-1,2- dimethylcyclopropane, spiropentane, cyclopentane, 2,2-dimethylbutane, 1,1,2- trimethylcyclopropane, 2,3-dimethylbutane, 2-methylpentane, 3-methylpentane, 1,2,3-trimethylcyclopropane, w-hexane, ethylcyclobutane,, methylcyclopentane, 2,2dimethylpentane, 2,4-
  • alkenyl refers to an unsaturated, hydrocarbon radical, linear or branched, in so much as it contains one 1 or more double bonds.
  • the alkenyl group disclosed herein can be optionally substituted with any moiety that does riot adversely affect the reaction process, including but not limited to but not limited to alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,
  • Non-limiting examples of alkenyl groups include methylene, ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds.
  • the alkynyl group may be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to hydroxyl, halo (F, CI, Br, I), perfluoro alkyl including but not limited to trifluoromethyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, amido, carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al, Protective Groups in Organic Synthesis.
  • alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals.
  • alkylamino or "arylamino” refers toi an amino group that has one or two alkyl or aryl substituents, respectively.
  • protected refers to a group that is added to all oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other pu ⁇ oses.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or the following aromatic group that remains after the removal of a hydrogen from the aromatic ring: benzene, toluene, efhylbenzene, 1,4-xylene, 1,3-xylene, 1,2-xylene, isopropylbenzene (cumene), n-propylbenzene, l-ethyl-3- methylbenzene (m ⁇ ethyltoluene), l-ethyl-4-methylbenzene (p-ethyltoluene), 1,3,5- trimethylbenzene (mesitylene), l-ethyl-2-methylbenzene (o-ethyltoluene), tert
  • aryl includes both substituted and unsubstituted moieties.
  • the aryl group may be optionally substituted with any moiety that does not adversely affect the process, including but not limited to but not limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamirip, alkoxy, a yloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any
  • Non-limiting examples of substituted aryl include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino- N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyi, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially
  • halo includes chloro, bromo, iodo and fluoro.
  • acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but not limited to methoxymethyl, aralkyl including but not limited to benzyl, aryloxyalkyl suc ⁇ as phenoxymethyl, aryl including but not limited to phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to d, C 2 , C 3 , and C 4 ) or alkoxy (including but not limited to Cj, C 2 , C 3 , and C 4 ), sulfonate esters such as alkyl or aralkyl sulphonyl including but not limited to methanesulfonyl, the mono, di or
  • alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals having alkyl moieties, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • alkylamino denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
  • arylamino denotes “monparylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
  • aralkylamino embraces aralkyl radicals attached to an amino radical.
  • aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • heteroatom refers to oxygen, sulfur, nitrogen and phosphorus.
  • heteroaryl or “heteroaromatic,” ⁇ as used herein, refer to an aromatic that, includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
  • heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole
  • the heteroaromatic group can be optionally substituted as described above for aryl.
  • the heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen (F, CI, Br, I), haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino.
  • the heteroaromatic can be partially or totally hydrogenated as desired.
  • dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p- toluenelsulfonyl.
  • the heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to but not limited to those described above for aryl.
  • the term "host,” as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention.
  • the term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).
  • pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a nucleoside compound which, upon administration to a patient, provides the nucleoside compound.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
  • prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • the compounds of this invention possess antiviral activity against Flaviviridae, or are metabolized to a compound that exhibits such activity.
  • Prodrugs also include natural or unnatural amino acid esters of the disclosed nucleosides (see, e.g., European Patent Specification No. 99493, the text of which is inco ⁇ orated by reference, which describes amino acid esters of acyclovir, specifically the glycine and alanine esters which show improved water-solubility compared with acyclovir itself, and' US Pat. No. 4,957,924 (Beauchamp), which discloses the valine ester of acyclovir, characterized by side-chain branching adjacent to the ⁇ -carbon atom, which showed improved bioavailability after oral administration compared with the alanine and glycine esters).
  • a process for preparing such amino acid esters is disclosed in US Pat. No.
  • Suitable inorganic salts may also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • suitable acid affording a physiologically acceptable anion.
  • Alkali metal e.g., sodium, potassium or lithium
  • alkaline earth metal e.g., calcium
  • nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
  • a number of nucleotide prodrug ligands are known.
  • alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide.
  • substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including but not limited to sugars, 1,2- diacylglycerol and alcohols. Many are described in R. Jones & N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.
  • the active nucleoside can also be provided as a 5'-phosphoether lipid or a 5'- ether lipid, as disclosed in the following references, which are incorporated by reference: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi, "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation," AIDS Res. Hum. Retroviruses, 1990, 6, 491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S.
  • Nonlimiting examples of US patents that disclose suitable lipophilic substituents that can be covalently inco ⁇ orated into the nucleoside, preferably at the 5' -OH position of the nucleoside or lipophilic preparations, include US Pat. Nos.
  • the active compound or its prodrug or salt can be administered in combination or alternation with another antiviral agent, such as another active anti-HIV or anti-HBV agent, including but not lhnited to those of the formulae above, others listed below or known in the art.
  • another antiviral agent such as another active anti-HIV or anti-HBV agent, including but not lhnited to those of the formulae above, others listed below or known in the art.
  • effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially.
  • the dosage will depend on abso ⁇ tion, inactivation and excretion rates of the drug as well as other factors known to those of ' skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time
  • compositions I according to ihe individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein incl ⁇ de those in the tables below.
  • Hepsera (Adefovir Dipivoxi)" nucleotide analogue Gilead Sciences .. " .
  • NRTIs Inhibitors
  • NRTIs Transcriptase Inhibitors
  • the compounds of the invention may be employed together with at least one other antiviral agent chosen from reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors and polymerase inhibitors. i - - - .
  • compounds according to the present invention can be administered in combination or alternation with one or more anti-retrovirus, anti-HBV, anti-HCV or anti-he ⁇ etic agent or interferon, anti-cancer or antibacterial agents, including but not limited to other compounds of the present invention.
  • Certain compounds according to' the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or
  • Host including but not limited to humans, infected with a human immunodeficiency virus, a hepatitis virus, or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. .
  • a preferred dose of the compound for an HIV or HBV infection will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day.
  • the effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.
  • the compound is conveniently administered in unit any suitable dosage form, including but not limited to but not limited to one containing 7 to 3000 mg, preferably i I 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is usually convenient. ,
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 ⁇ M, preferably about 1.0 to 10 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
  • the concentration of active compound in the drug composition will depend on abso ⁇ tion, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein, are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the pu ⁇ ose of oral therapeutic administration, the active compound can be inco ⁇ orated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-
  • I inflammatories or other antivirals including but not limited to other nucleoside compounds.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. .
  • preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems.
  • a controlled release formulation including but not limited to implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
  • enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
  • Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (inco ⁇ orated by reference).
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • a process for the facile preparation of N 4 -acyl-cytosine- 1,3 -dioxolane nucleosides is also provided.
  • the method includes condensation of a 5'-O-silyl protected 5-fluorocytidine-l,3-dioxolane, with either a carboxylic acid chloride, or carboxylic acid anhydride, or a carboxylic acid, followed by desilylation.
  • the other N 4 -acyl-substituted cytosine nucleosides can be synthesized using the similar approaches.
  • N 4 -acyl-substituted 5-fluorocytidine-l,3-dioxolane disclosed herein can be prepared as described in detail below, or by other assays known to those skilled in the art.
  • the 1,3-dioxolane intermediate (i) of the present invention can be synthesized according to U.S. Patent No. 5,041,449, filed June 29, 1990; U.S. Patent No. 5,270,315, filed March7, 1991 ("2-Substituted-4-substituted-l,3-dioxolanes, synthesis and use thereof); PCT application CA 92/00209 , filed May 20, 1992; U.S. Patent No. 5,756,706, filed May 13, 1994; U.S. Patent No. 5,744,596, filed June 5, 1995 ("Processes for diastereoselective synthesis of nucleosides"); PCT Application CA 94/00311, filed June 7, 1994; U.S. Patent No.
  • 1,3-dioxolane intermediate can also be prepared according to the process as set forth in US Patent No. 5,444,063, filed October 28, 1992; US Patent No. 5,684,010, filed June 6, 1995; US Patent No. 5,834,474, filed April 15, 1997; US Patent No. 5,830,898, filed April 15, 1997; PCT Application WO 94/09793, filed October 28, 1993 ("Enantiomerically ⁇ -D-Dioxolane Nucleosides with Selective Anti-Hepatitis B Virus Activity"); US Patent No.
  • the 1,3-dioxolane intermediate (i) is protected at the 5'-hydroxyl with any known method known in the art.
  • the protected 1,3-dioxolane (ii) is then acylated and deprotected to form the N 4 -acylcytosine-l,3-dixolane nucleoside of formula (iv). See Scheme 1.
  • R 1 is hydrogen or F
  • P is an oxygen protecting group
  • R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C ⁇ FLR 6 where R 6 is chosen from halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
  • Anti-HIV- 1 activity of the compounds was determined in human peripheral blood mononuclear (PBM) cells as described previously (Schinazi R.F., McMillan A., Cannon D., Mathis R., Lloyd R.M. Jr., Peck A., Sommadossi J.-P., St. Clair M., Wilson J., Furman P.A., Painter G., Choi W.-B., Liotta D.C. Antimicrob. Agents Chemother. 1992, 36, 2423; Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D., Xie M.-Y., Hart G., Smith G., Hahn E. Antimicrob. Agents Chemother. 1990, 34,
  • the potency of the compounds was determined by measurement of viral RNA accumulation in HIV-I RF infected MT-2 cells (Bacheler LT, Paul M, Otto MJ, Jadhav PK, Stone BA & Miller JA (1994) An assay for HIV RNIn infected cell lysates, and its use for rapid evaluation of antiviral efficacy.
  • the virus titer was established to determine the dilution producing 15 to 30 ng/RNA per well of HIV RNIn 3 days of infection.
  • HTV-l RNA was quantified using biotinylated capture and alkaline phosphatase-derivatized reporter oligonucleotides as described previously (Charvet A-S, Camplo M, Faury P, Graciet JC, Mourier N, Chermann JC & Kraus JL (1994) Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates. J. Med. Chem. 37:2216-2223).
  • the anti-HBV activity of the compounds was determined by treating the AD- 38 cell line carrying wild type HBV under the control of tetracycline (Ladner S.K., Otto M.J., Barker C.S., Zaifert K., Wang G.H., Guo J.T., Seeger C. & King R.W. Antimicrob. Agents Chemother. 1997, 41, 1715-1720).
  • tetracycline Ladner S.K., Otto M.J., Barker C.S., Zaifert K., Wang G.H., Guo J.T., Seeger C. & King R.W. Antimicrob. Agents Chemother. 1997, 41, 1715-1720.
  • Tet (-)] results in the production of HBV.
  • the levels of HBV in the culture supernatant fluids from cells treated with the compounds were compared with that of the untreated controls. Control cultures with tetracycline [Tet (+)] were also maintained
  • the toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob Agents Chemother. 1990, 34, 1061-1067). Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls. The cytotoxicity IC 50 was obtained from the concentration-response curve using the median effective method described previously (Chou T.-C. & Talalay P. Adv. Enzyme Regul 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1-11).

Abstract

The present invention is directed to a comound, use and composition of treating or preventing viral infections, in particular, human immunodeficiency virus 8HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N4-acylcytosine-1,3-dioxolane and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

Description

N4-ACYLCYTOSINE-l,3-DIOXOLANE NUCLEOSIDES FOR TREATMENT
OF VIRAL INFECTIONS
The present application claims ipriority to U.S.S.N. 60/341,555 filed on December 14, 2001.
FIELD OF THE INVENTION
The present invention is directed to compounds, methods and compositions for the treatment or prevention of viral infections using nucleoside analogues. More specifically, the invention describes N4-acyl-substituted cytosine nucleoside analogues, pharmaceutically acceptable salts, prodrugs, or other derivatives thereof, and the use thereof in the treatment of a viral infection, and in particular a human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection.
BACKGROUND OF THE INVENTION
In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that without exception leads to death. In 1983, the etiological cause of AIDS was determined to be what is now known as human immunodeficiency virus (HIV).
Another virus that causes a serious human health problem is the hepatitis B virus (HBV). HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
After a 2- to 6-month incubation period, during which the host is typically unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which large sections of the liver are destroyed. Patients typically recover from the acute phase of HBV infection. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid- 1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
In Western, industrialized countries, the high-risk group for HBV infection includes those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of HIV/AIDS, which is a reason why HBV infection is common among patients infected with HIV or suffering from AIDS. However, HBV is more contagious than HIV. '
I
In 1985, it was reported that the synthetic nucleoside 3'-azido-3'- deoxythymidine (AZT) inhibited the replication of HIV. Since then, several other synthetic nucleosides, including but not limited to 2',3'-dideoxyinosine (ddl), 2',3'- dideoxycytidine (ddC), 2\3'-dideoxy-2',3'-didehydrothymidine (d4T), (-)-2',3'- dideoxy-3'-thiacytidine (3TC), and (-)-carbocyclic 2',3'-didehydro-2',3'- dideoxyguanosine (carbovir) and its prodrug abacavir, have proven effective against HIV. After phosphorylation to the 5 '-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination, because they lack a 3 '-hydroxyl group. Some nucleosides also inhibit the viral enzyme reverse transcriptase.
3TC (lamivudine) and interferon are currently the only FDA-approved drugs for the treatment of HBV infection. Viral resistance develops within 6 months of 3TC treatment in about 14% of patients.
Cis-2-hydroxymethyl-5-(5-fluorocytosin-l -yl)-l ,3-oxathiolane (FTC) is currently in clinical trials for the treatment of HIV and separately for HBV by Triangle Pharmaceuticals, Inc. See Schinazi et al. (1992) Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-l-[2- (hydroxymethyl)-l,3-oxathiolane-5-yl]cytosine. Antimicrob. Agents Chemother. 36, 2423-2431; US Pat. Nos. 5,210,085; 5,914,331; 5,814,639; WO 91/11186; and WO 92/14743.
There has also been a signficant amount of research on 1,3-dioxolane nucleosides and their use to treat viral infections. US Patent Nos. 5,210,085; 5,276,151; 5,852,027; and 5,179,104 disclose 5-fluorocytosine-l,3-dioxolane nucleoside and nucleoside analogues for the treatment of viral infections.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3'-position of the nucleoside. Norbeck, et al., disclosed that (+/-)- l-[(2-β, 4-β)-2-(hydroxymethyl)-4- dioxolanyl]thymine (referred to as (+/-)-dioxolane-T) exhibits a modest activity against HIV (EC50 of 20 μM in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 μM. Tetrahedron Letters 30 (46), 6246, (1989).
On April 11, 1988, Bernard Belleau, Dilip Dixit, and Nghe Nguyen-Ba at BioChem Pharma filed patent application U.S.S.N. 07/179,615 which disclosed a generic group of racemic 2-substituted-4-substituted-l,3-dioxolane nucleosides for the treatment of HIV. The '615 patent application matured into European Patent Publication No. 0 337 713; U.S. Pat. No. 5,041,449; and U.S. Patent No. 5,270,315 assigned to BioChem Pharma, Inc. '
On December 5, 1990, Chung K. Chu and Raymond F. Schinazi filed U.S.S.N. 07/622,762, which disclosed an asymmetric process for the preparation of enantiomerically pure β-D-l,3-dioxolane nucleosides via stereospecific synthesis, and certain nucleosides prepared thereby, including (-)-(2R,4R)-9-[(2-hydroxymethyl)- l,3-dioxolan-4-yl]guanine (DXG), and its use to treat HIV. This patent application issued as U.S. Patent No. 5,179,104.
Figure imgf000004_0001
DXG On May 21, 1991, Tarek Mansour, et al., at BioChem Pharma filed U.S.S.N.
I
07/703,379 directed to a method to obtain the enantiomers of 1,3-dioxolane nucleosides using a stereoselective synthesis that includes condensing a 1,3-dioxolane intermediate covalently , bound to a chiral auxiliary with a silyl Lewis acid. The corresponding application filed in Europe was EP 0 515 156.
On August 25, 1992, Chung K. Chu and Raymond F. Schinazi filed U.S.S.N. 07/935,515, disclosed certain enantiomerically pure β-D-dioxolanyl purine compounds for the treatment of humans infected with HIV of the formula:
Figure imgf000005_0001
wherein R is O,H, CI, NH2, or H, or a pharmaceutically acceptable salt or derivative of the compounds Optionally in a pharmaceutically acceptable carrier or diluent. The compound wherein R is chloro is referred to as (-)-(2R,4R)-2-amino-6-chloro-9-[(2- hydroxymethyl)-l,3-dioxolan-4-yl]purine. The compound wherein R is hydroxy is (- )-(2R,4R)-9-[(2-hydroxy-methyl)-l,3-dioxolan-4-yl]guanine. The compound wherein R is amino is (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-l,3-dioxolan-4-yl]adenine. The compound wherein R is hydrogen is (-)-(2R,4R)-2-amino-9-[(2- hydroxymethyl)-l,3-dioxolan-4yl]ρurine. This application issued as U.S. Patent Nos. 5,925,643.
In 1992, Kim et al., published an asymmetric synthesis for selected 1,3- dioxolane pyrimidine nucleosides from 1,6-anhydro-D-mannose. The specific synthesis resulted in β-D and α-D enantiomers of 1,3-dioxolane nucleosides. Kim et al., 1 ,3-Dioxolanylpurine Nucleosides (2R,4R) and (2R,4S) with Selective Anti-HIV-1 Activity in Human Lymphocytes, J. Med. Chem., 1993 36, 30-37.
In 1992, Belleau et al., at BioChem Pharma, published a method to obtain enantiomerically pure 1,3-dioxolane nucleosides via L-ascorbic acid as a chiral auxiliary in the process. L-ascorbic acid was used to produce a set of diastereomers which could be separated. Belleau, et al., Oxidative Degradation ofL-Ascorbic Acid Acetals to 2 ',3 '-Dideoxy-3 '-Oxaribofuranosides Synthesis of Enantiomerically Pure 2',3 '-Dideoxy-3 '-Oxaribofuranosides. Synthesis of Enantiomerically Pure 2 ',3'- Dideoxy-3 '-Oxacytidine Stereoisomers as Potential Antiviral Agents. Tetrahedron Lett. 1992, 33:6949.
On February 21, 1992, PCT/US92/01393 (WO 92/14729) by Liotta et al. disclosed a method for the synthesis of 1,3-dioxolane nucleosides that includes condensing a 2-O-protected-5-O-acylated-l,3-dioxolane with a purine of pyrimidine base in the presence of a titanium containing Lewis acid to provide predominately the desired β-isomer in the Cl'-position of a 1,3-dioxolane nucleoside. WO 92/14729 also disclosed a process for the resolution of a racemic mixture of 1,3-dioxolane nucleoside enantiomers.
In 1992, Kim et al., published an article teaching how to obtain (-)-L-β- dioxolane-C and (+)-L-β-dioxolane-T from 1,6-anhydro-L-β-glucopyranose. Kim et al., Potent anti-HIV and anti-HBV Activities of (-)-L-β-Dioxolane-C and (+)-L-β- Dioxolane-T and Their Asymmetric Syntheses, Tetrahedron Letters Vol 32(46), pp 5899-6902.
On October 28, 1992, Raymond Schinazi filed U.S.S.N. 07/967,460 directed to the use of the compounds disclosed in U.S.S.N. 07/935,515 for the treatment of hepatitis B. This application has issued as U.S. Patent Nos. 5,444,063; 5,684,010; 5,834,474; and 5,830,898.
In 1993, Jin et al., at BioChem Pharma published an article that concluded that Lewis acids play a crucial role in the preparation 1,3-dioxolane nucleosides. TiCl4 and SnCl4 promote the formation of dioxolane nucleosides with racemization in the
I coupling of enantiomerically pure -2'-deoxy-3'-oxaribosides with silylated N- acetylcytosine. The use of the Lewis acids trimethylsilyltriflate, trimethylsilyl iodide, and TiCl2(O-'Pr)2 furnished enantiomerically pure cytosine dioxolane nucleosides in low diastereoselectivity. Unexpected Effects of Lewis Acids in the Synthesis of Optically Pure 2 '-Deoxy-3' -Oxacytidine Nucleoside Analogs, Tetrahedron Asymmetry vol 4, No. 2 pp 211-214 (1993).
In 1993, Siddiqui, et al., at BioChem and Glaxo published that cis-2,6- diaminopurine dioxolane can be deaminated selectively using adenosine deaminase. Siddiqui, et al., Antiviral Optically Pure dioxolane Purine Nucleoside Analogues, Bioorganic & Medicinal Chemistry Letters, Vol. 3 (8), pp 1543-1546 (1993). (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-l,3-dioxolari-4-yl]adenine (DAPD) is a selective inhibitor of HTV-l replication in vitro as a reverse transcriptase inhibitor (RTI). DAPD is thought to be deaminated in vivo by adenosine deaminase,. a ubiquitous enzyme, to yield (-)-β-D-dioxolane guanine (DXG), which is subsequently converted to the corresponding 5'-tri-phosphate (DXG-TP). Biochemical analysis has demonstrated thaf DXG-TP is a potent inhibitor "of the HIV reverse transcriptase (HIV-RT) with a Ki of 0.019 μM.
Figure imgf000007_0001
Other nucleosides that have been successful in anti-viral treatments include of 2',3'-dideoxy- and 2',3'-didehydro-2,'3'-dideoxy-nucleosides (referred to as a "ddN" or "d2N" nucleoside and a "d4N" nucleoside, respectively), particularly, these nucleosides inhibit the replication of HIV in vivo or in vitro, thus, has led a number of researchers to design and test a variety of modified d2- and d4-nucleosides. One modification has been the replacement of the 5 -hydrogen on cytosine nucleosides with fluorine, resulting in several 5-fluorocytosine nucleosides with antiviral activity, including but not limited to β-D- and β-L-2',3'-dideoxy-5-fluorocytine (β-D-D2FC and β-L-D2FC) (US Pat. Nos. 4,788,181 and 6,156,737). β-D-2',3'-Dideoxy-2',3'-didehydro-5-fluorocytidine (d4FC) and its use to treat hepatitis B was first described in Example 2 of European Pat. Application No. 0 409 227 A2 (Ajinomoto Co., Inc.). Netherlands Pat. No. 8901258 (Stichting Rega V.Z.W.) discloses generally 5-halogeno-2',3'-dideoxy-2',3'-didehydrocytidine derivatives for use in treating HIV and HBV. β-D- and β-L-2',3'-didehydro-2',35- dideoxy-5-fluorocytidine were further described in US Pat. Nos. 5,703,058; 5.905,070; 6,232,300; and 5,561,120. US Pat. No. 5,703,058 claims a method for the treatment of HIV and/or HBV infection that includes administering an effective amount of β-L-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5- fluorocytosin- 1 -yl)- 1 ,3-oxathiolane, cis-2-hydroxymethyl-5 -(cytosin- 1 -yl)- 1,3- oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten-l-yl)-guanine (carbovir), 9-[(2- hydroxyethoxy)methyl]-guanine (acyclovir), interferon, 3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), (-)-2'-fluoro-5- methyl-β-L-ara-uridine (L-FMAU) or 2',3'-didehydro-2',3'-dideoxythymidine (d4T). US Pat. No. 5,905,070 claims a method for the treatment of HIV and HBV infection that includes administering an effective amount "of β-D-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane, cis-2- hydroxymethyl-5-(cytosin-l -yl)-l ,3-oxathiolane, 9-[4-(hydroxy-methyl)-2- cyclopenten-1 -yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3'-deoxy-3'-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), (-)-2'-fluoro-5-methyl-β-L-ara-uridine (L-FMAU) or 2',3'-didehydro-2',3'-dideoxythymidine (d4T). US Pat. No. 6,232,300 claims a method to treat HIV with β-D-d4FC.
Modification of the amino group of antiviral cytosine nucleosides has not been fully explored. Only a few N4-substituted cytosine 2',3'-dideoxy nucleosides and N4- substituted cytosine 2',3'-didehydro-2',3'-dideoxy nucleosides have been reported. These include N4-benzoyl-2',3'-didehydro-2,'3-dideoxycytidine (Kawaguchi et al, Studies on 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides. II. N4-benzoyl- 2',3'-dideoxy-2',3'-didehydrocytidine as a prodrug of 2',3'-dideoxy-2',3'- didehydrocytidine (DDCN), Chem.' Pharm. Bull. (1989), 37(9), 2547-9), N4-benzoyl- 2',3'-dideoxycytidine (Gulbis et al. (1993) Structure of a dideoxynucleoside active against the HIV (AIDS) virus. Acta Cryst. C49, 1095-1097), N4-acetyl-2\3'- didehydro-2 ' ,3 ' -dideoxy-5 -fluorocytidine, and N4-isopropyl-2 ' ,3 ' -didehydro-2 ' ,3 ' - dideoxy-5-fluorocytidine (Shi et al. (1999)) Synthesis and biological evaluation of 2',3'-didehydrό-2',3'-dideoxy-5-fluorocytidine (d4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase. J. Med. Chem. 42, 859-867). Of the sugar-modified cytosine nucleosides, some N4-acyl and imine-substituted 2',3'-dideoxy-3'-C- hydroxymethylcytidine analogues have been synthesized (Mauldin et al. (1998) Synthesis and antiviral activity of prodrugs of the nucleoside l-[2',3'-dideoxy-3'-C- (hydroxymethyl)-β-D-erythropentofuranosyl] cytosine. Bioorg. Med. Chem. 6, 577- 585), and some N4-acetyl- and phosphonoacetyl-2',3'-dideoxy-3'-thiacytidine nucleosides have been prepared (Charvet et al. (1993) Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and
I phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates. J. Med. Chem. 37, 2216- 2223).
Therefore, it is' an object of the present invention to provide a compound, method and composition for the treatment or prevention of HIV infection in human patients.
It is another object of the present invention to provide a compound, method and composition for the treatment or prevention of HBV infection in human patients or other host animals.
It is still another object of the present invention to provide a compound, method and composition for the treatment or prevention of HIV and HBV infection in human patients or other host animals. ι
SUMMARY OF THE INVENTION
It has been found that certain N4-acyl-cytosine 1,3-dioxolane nucleosides, and in particular, N4-acyl-5-fluorocytidine-l,3-dioxolane, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of HIV and/or HBV infection in a host, and in particular, a human, is provided that includes administering an effective amount of a N4-acyl-cytosine nucleoside.
In one embodiment of the present invention, the active compound is of formula (A):
Figure imgf000010_0001
wherein R1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO , aryl, heteroaryl and acyl;
R3 and R3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl ;
R4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R3 and R3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol; and
R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and COHJR where R is chosen from halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
The compound of the present invention can be in the form of the isolated β-L- or β-D- configuration, or a mixture thereof, including but not limited to a racemic mixture. In addition, the N4-acylcytosine-l,3-dioxolane nucleosides are inhibitors of HBV. Therefore, these compounds can also be used to treat patients that are co- infected with both HIV and HBV.
The present invention provides a compound, method and composition for treating an HIV infection in a host comprising administering a therapeutically
I effective amount of at least one compound as described in the present application.
The present invention provides a compound, method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a compound, method and composition for treating an HBV ihfection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application. I
The present invention provides a compound, method and composition for
I preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a use of a compound for the treatment of HIV and/or HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a method of manufacture for a therapeutically effective compound for the treatment of an HIV and/or HBV infection.
In another aspect, there is provided a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient for the treatment of a host infected with HIV or HBV.
In still another aspect, there is provided a compound, method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
In still another aspect, there is provided a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION .
It has been found that N4-acyl-cytosine-l,3-dixolane nucleosides, and in particular, N4-acyl-5-fluorocytidine-l,3-dioxolane, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of a host, and in particular, a human, infected with HIV and/or HBV, is provided that includes administering an effective amount of an N4-acyl-cytosine- 1,3-dioxolane nucleosides.
The present invention also provides a compouind, method and composition for treating an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a compound, method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a compound, method and composition for treating an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a compound, method and composition for preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
In another aspect, there is provided a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
In still another aspect, there is provided a method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
In still another aspect, there is provided a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
Active Compound
In one embodiment of the present invention, the active compound is of formula (A):
Figure imgf000013_0001
wherein R1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl and acyl;
R and R are chosen independently from H, halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
R4 is H, phosphate (including but not limited to mondphosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R3 and R3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol; and R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and CβlLR6 where R6 is chosen from halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
The compound of the present invention can be in the form of the isolated β-L- or β-D- configuration, or a mixture thereof, including but not limited to a racemic mixture.
In one embodiment of the present invention, the active compound is β-D-N4- p-iodobenzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-fluoro-benzoyl-5- fluorocytidine-1 ,3-dioxolane, β-D-N4-p-chlorobenzoyl-5-fluoro-cytidine-l ,3- dioxolane, β-D-N4-p-bromobenzoyl-5 -fluorocytidine- 1 ,3 -dioxolane, β-D-N4-p-ethyl- benzoyl-5 -fluorocytidine- 1 ,3 -dioxolane, and β-D-N4-p-t-butylbenzoyl-5 -fluoro- cytidine-l,3-dioxolane.
In one embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the ortho position. '
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the ortho position.
In yet another, embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with Br in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with I in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with F in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CI in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with NO2 in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with methyl in the ortho position. In yet another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 ' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with ethyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
I i) R4 is hydrogen; ii) R1 is fluorine or hydrogen;
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-propyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with iso-propyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-butyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with sec-butyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with tert-butyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted1 with n-pentyl in the ortho position. '
In yet another embodiment of the present invention, the active compound is of "formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine' or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with < isopentyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or. prodrugs thereof, wherein:
. I i) R is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with neopentyl in the ortho position. '
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with cyclopentyl in the ortho position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-hexyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with a cyclohexyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CN in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; ' iii) R and R are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CF3 in the ortho position.
I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; ι iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with N3 in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; ι iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with haloalkyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with aminoalkyl in the ortho position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkoxy in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with thioalkyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
I i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkenyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; '
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkynyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; ι iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with aryl in the ortho 'position.
I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; > iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with benzyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with thiophenyl in the ortho position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with furanyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with naphthyl in the ortho position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ' ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with benzoyl in the ortho position.
In one embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ' ii) R is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a pheny moiety optionally substituted with halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, aϊkynyl, or aryl in the meta position.
In another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ' ii) R1 is fluorine or hydrogen;
' iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with Br in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with I in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with F in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CI in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with NO2 in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkyl in the meta position. f ' -
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3^ are independently hydrogen or fluorine; and
I iv) R2 is a phenyl moiety optionally substituted with methyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with ethyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-propyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula , its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with iso-propyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: • i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-butyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with sec-butyl in the meta position. In yet another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally, substituted with tert-butyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogέn; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-pentyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with isopentyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with neopentyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with cyclopentyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ' ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-hexyl in the met'a position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted With a cyclohexyl in the meta
I position. '
In yet another embodiment of the present invention, the active compound is of "formula" (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CN in the meta position.
I
I
III yet ahother embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CF3 in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with N3 in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrpgen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with haloalkyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with aminoalkyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkoxy in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted1 with thioalkyl in the meta
I position. ι
In yet another .embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and
I iv) R2 is a phenyl moiety optionally substituted with alkenyl in the meta position.
I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkynyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with aryl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with benzyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with thiophenyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with furanyl in the meta position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted ' with naphthyl in the meta position. '
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with benzoyl in the meta position.
I
In one embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the para position. '
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the para position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein:
I i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with Br in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen;
1 I
I ii) R1 is fluOrine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with I in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with F in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CI in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with NO2 in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with methyl in the para position. In yet another embodiment of the present invention, the active compound is of formula (A), iis pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with ethyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs' thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-propyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with iso-propyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; I
iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-butyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with sec-butyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with tert-butyl in the para position.
. i i ' .. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-pentyl in the para position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with isopentyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) Rf is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and
I iv) R2 is a phenyl moiety optionally substituted with neopentyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: ' i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with cyclopentyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with n-hexyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with a cyclohexyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with CN in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with1 CF3 in the para position.
I I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with N3 in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its' pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with haloalkyl in the para position.
I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with aminoalkyl in the para position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkoxy in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with thioalkyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen;
I iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with alkenyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and
I iv) R2 is a phenyl moiety optionally substituted with alkynyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and ι iv) R2 is a phenyl moiety optionally substituted with aryl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its. pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and , iv) R2 is a phenyl moiety optionally substituted with benzyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with thiophenyl in the para position. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with furanyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with naphthyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with benzoyl in the para position.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; '
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3-dihalo.
- I In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; , iii) R and R are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,4-dihalo. ι
n yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; , iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,5-dihalo. ,
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,6-dihalo. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4-dihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,5-dihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen;
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4-trihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and
I iv) R2 is a phenyl moiety optionally substituted with 2,3,5-trihalo.
I
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and ι iv) R2 is a phenyl moiety optionally substituted with 2,4,5-trihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its. pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and ι iv) R2 is a phenyl moiety optionally substituted with 2,4,6-trihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,5,6-trihalo. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4,5-trihalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen;
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentahalo.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen;
I iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl mqiety optionally substituted with 2,3-dialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable- salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; ι iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,4- dialkyl. >
n yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; . iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,5- dialkyl. ,
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,6- dialkyl. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4- dialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,5- dialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4-trialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluoririe; and
I iv) R 2 is a ' phenyl moiety optionally substituted with 2,3,5- trialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and , iv) R2 is a phenyl moiety optionally substituted with 2,4,5- trialkyl.
I
In yet another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and , iv) R2 is a phenyl moiety optionally substituted with 2,4,6- trialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R is a phenyl moiety optionally substituted with 2,5,6- trialkyl. In yet another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 'are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4,5- trialkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs. thereof, wherein:
I i) R4 is hydrogen; ii) R* is fluorine or hydrogen; iii) R 3 and '' R 3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4,5-tetraalkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independeήtly.hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentaalkyl.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3-di-NO2.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,4- di-NO .
n yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,5- di-NO2.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,6- di-NO2. In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4- di-NO .
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
I i) R4 is hydrogen; ii) R1 is flu'orine or hydrogen;
|. iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,5- di-NO2.
In yet another embodiment of the present invention, the active compound is pf formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,4- tri-N02.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,3,5- tri-NO .
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,4,5- tri-NO2.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,4,6- tri-NO2.
In yet another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein:-;. , i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 2,5,6- tri-NO2. In yet another embodiment of the present invention, the active compound is of
I formula (A), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) R4 is hydrogen;
I ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a phenyl moiety optionally substituted with 3,4,5- tri-NO2.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) Rl is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2- position.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: ι i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 3- position or the 4-position.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a benzothiophenyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the benzene ring.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a benzothiophenyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the thienyl ring.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and > iv) R2 is a cyclohexyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or 3-position.
In another embodiment of the present invention, the active compound is of formula (A), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) R4 is hydrogen; ii) R1 is fluorine or hydrogen; iii) R3 and R3 are independently hydrogen or fluorine; and iv) R2 is a cyclohexyl moiety optionally substituted with alkyl, halo, alkenyl,
I alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 4-position.
In one preferred embodiment, the active compound is β-D-5-fluoro-N4-(4-
-iodobenzoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000059_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In another preferred embodiment, the active compound is β-D-5-fluoro-N4-(4- fluorobenzoyl)cytidine-l,3-dioxolaneofthe structure:
Figure imgf000059_0002
or a pharmaceutically acceptable salt or prodrug thereof. In still another preferred embodiment, the active compound is β-D-N4-(4- chlorobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000060_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In one preferred embodiment, the active compound is β-D-N4-(4- bromobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000060_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In another preferred embodiment, the active conlpound is β-D-5-fluoro-N4-(3-
I fluorobenzoyl)cytidine- 1,3 -dioxolane of the structure:
Figure imgf000061_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In still another preferred embodiment, the active compound is β-D-N4-(3- chlorobeήzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000061_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In one preferred embodiment, the active compound is β-D-N4-(3- bromobenzoyl)-5 -fluorocytidine- 1,3 -dioxolane of the structure:
Figure imgf000062_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In another preferred embodiment, the active compound is β-D-5-fluoro-N τ4 -(4- nitrobenzoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000062_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In still another preferred embodiment, the active compound is β-D-5-fluoro- N4-p-toluoylcj idine-l,3-dioxolane of the structure:
Figure imgf000063_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In one preferred embodiment, the active compound is β-D-5-fluoro-N4-(w- toluoyl)cytidine- 1,3-dioxolane of the structure:
Figure imgf000063_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In another preferred embodiment, the active compound is β-D-N4-(4- ethylbenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000064_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In still another preferred embodiment, the active compound is β-D-5-fluoro- N4-(4-propylbenzoyl)cytidine- 1,3 -dioxolane of the structure:
Figure imgf000064_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In one preferred embodiment, the active όompound is β-D-N -(4-tert- butylbenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000065_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In still another preferred embodiment, the active compound is 'β-D-5-fluoro- N4-(2-thiophenecarbonyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000065_0002
or a pharmaceutically acceptable salt or prodrug thereof.
In one preferred embodiment, the active compound is β-D-N4-(benzo-[b]- thiophene-2-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000066_0001
or a pharmaceutically acceptable salt or prodrug thereof.
In another preferred embodiment, the active compound is β-D-N4- (cyclohexane-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000066_0002
or a pharmaceutically acceptable salt or prodrug thereof.
II. Stereoisomerism and Polymorphism
The compounds of the present invention have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention. Some compounds may exhibit polymorphism. The present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the
I invention, which possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a
, ' conglomerate, and the crystals are visually distinct;
'ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a 1 solution of the racemate, possible only if the latter is a conglomerate in the solid state; ' iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated
I I by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations: a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the
'- l ' ' course of the synthesis; x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography: a technique whereby the racemate
I ι is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents: a technique whereby the i " " " - enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) ' transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier.
The barrier typically separates two miscible fluids, one
, containing the racemate, and a driving force such as concentration or pressure differential causes preferential
, ' transport across the membrane barrier. Separation occurs as a
,. result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
Chiral chromatography, including but not limited to simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available.
IH. Definitions
The term "independently" is used herein to indicate that the variable, which is independently applied, varies independently from application to application. Thus, in a compound such as R"XYR", wherein R" is "independently carbon or nitrogen," both R" can be carbon, both R" can be nitrogen, or one R" can be carbon and the other R" nitrogen.
As used herein, the term "substantially free of or "substantially in the absence of refers to a nucleoside composition that includes at least 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are substantially free of enantiomers. Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers. '
The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted alkyl groups. The alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incoφorated by reference. Specifically included are CF3 and CH2CF3.
Alkyl groups include, but are not limited to the radicals of methane, ethane, propane, cyclopropane, 2-methylpropane (isobutane), »-butane, 2,2-dimethylpropane (neopentane), cytobutane, 1,1 dimethylcyclopropane, 2-methylbutane, trans-1,2- dimethylcyclopropane, ethylcyclopropane, n-pentane, methylcyclobutane, cis-1,2- dimethylcyclopropane, spiropentane, cyclopentane, 2,2-dimethylbutane, 1,1,2- trimethylcyclopropane, 2,3-dimethylbutane, 2-methylpentane, 3-methylpentane, 1,2,3-trimethylcyclopropane, w-hexane, ethylcyclobutane,, methylcyclopentane, 2,2dimethylpentane, 2,4-dimethylpentane, cyclohexane, 2,2,3 -trimethylbutane, 3,3- dimethylpentane, 1,1-dimethylcyclopentane, 2,3-dimethylpentane, 2-methylhexane, trans-1 ,3-dimethylcyclopentane, cis-1 ,3-dimethylcyclopentane, 3-methylhexane, trans- 1,2-dimethylcyclopentane, 3-ethylpentane, quadricyclane (quadricyclo [2,2,1,026,035] heptane), «-heptane, 2,2,4-trimethylpentane, cis- 1,2- dimethylcyclopentane, methylcyclohexane, ethylcyclopentane, 1,1,3- trimethylcyclopentane, 2,2-dimethylhexane, 2,5-dimethylhexane, l,trans-2,cis- 4trimethylcyclopentane, 2,4-dimethylhexane, 2,2,3 -trimethylpentane, l,trans-2,cis-3- trimethylcyclopentane, 3,3-dimethylhexane, 2,3,4-trimethylpentane, 1,1,2- trimethylcycldpentane, 2,3,3-trimethylpentane, 2,3-dimethylhexane, 3-ethyl-2- methylpentane, 1 ,c/s-2,trøτ«-4-trimethylcyclopentane, 1 ,cis-2,trans-
3trimethylcyclopentanej 2-methylheptane, 4-methylheptane, 3,4-dimethylhexane, l,cz5-2,cz5-4trimethylcyclopentane, 3-ethyl-3-methylpentane, 3-ethylhexane, 3- methylheptane, cylotheptane (suberane), tran5-l,4-dimethylcyclohexane, 1,1- dimethylcyclohexane, cis- 1 ,3-dimethylcychohexane, trans- 1 -ethyl-3- methylcyclopentane, trans- 1 -ethyl-2-methylcyclopentane, cis- 1 -ethy 1-3 - methylcyclopentane, 1 -ethyl- 1-methylcyclopentane, 2,2,4,4-tetramethylpentane, l,cis- 2-cis-3 -trimethylcyclopentane, trans-1 ,2-dimethylcyclohexane, 2,2,5- trimethylhexane, trarø-l,3-dimethylcyclohexane, «-octane, κ isopropylcyclopentane, 2,2,4-trimethylhexafte, c is- 1 -ethyl-2-methylcyclopentane, cis- 1 ,2- dimethylcyclohexane, 2,4,4-trimethylhexane, «-propylcyclopentane, 2,3,5- trimethylhexane, ethylcyclohexane, 2,2-dimethylheptane, 2,2,3,4-tetramethylpentane, 2,4-dimethylhέptane, methylcycloheptane, 2,2,3 -trimethylhexane, 4-ethyl-2- methylhexane, 3-ethyl-2.2-dimethylpentane, . 4,4-dimethylheptane, 2,6- dimethylheptane,1 2,5-dimethylheptane, 3,5-dimethylheptane, bicyclo[4.2.0]octane, c/5-bicyclo[3.3.Ojoctane, 2,4-dimethyl-3-ethylpentane, 1 , 1 ,3-trimethylcyclohexane, 3,3-dimethylheptane, 2,2,5,5-tetramethylhexane, 2,3,3-trimethylhexane, 3-ethyl-2- methylhexane, tra«5-l,3,5-trimethylcyclohexane, 2,3,4-trimethylhexane, cis-1,3,5- trimethylcyclohexane, tra«5-l,2,4-trimethylcyclohexane, 2,2,3,3-tetramethylpentane, 4-ethyl-3-methylhexane, 3,3,4-trimethylhexane, 2,3-dimethylheptane, 3,4- dimethylheptane, 3-ethyl-3-methylhexane, 4-ethylheptane, 2,3,3,4- tetramethylpentane, 2,3-dimethyl-3-ethylpentane, tra«5-l,2,3-trimethylcyclohexane, 1-isopropyl-e-methylcyclopentane (pulegan), 4-methyloctane, l-isopropyl-2- methylcyclopentane, 3-ethylheptane, 2-methyloctane, cw-l,2,3-trimethylcyclohexane, 3-methyloctane, 2,4,6-trimethylheptane, cis- 1,2,4-trimethylcyclohexane, 3,3- diethylpentane, 2,2-dimethyl-4-ethylhexane, 2,2,4-trimethylheptane, 2,2,4,5- tetramethylhexane, 2,2,5-trimethylheptane, 2,2,6-trimethylheptane, 2,2,3,5- tetramethylhexane, nopinane (7,7-dimethylbicyclo[3.1.1]heptane), trø«s-l-ethyl-r- methylcyclohexane, cycloctane, l-ethyl-2-methylcyclohexane, «-nonane, 1,3,3- trimethylbicyclo[2.2.1]heptane(fenchane), trαrø-l-ethyl-4-methylcyclohexane, cis- 1,1,3,5-tetramethylcyclohexane, cώ-l-ethyl-4-methylcyclohexane, 2,5,5- trimethylheptane, 2,4,4-trimethylheptane, 2,3,3,5-tetramethylhexane, 2,2,4,4- tetramethylhexane, isopropylcyclohexane, 1,1,2,2-tetramethylcyclohexane, 2,2,3,4- tetramethylhexane, 2,2-dimethyloctane, 3-ethyl-2,2,4-trimethylpentane, 3,3,5- trimethylheptane, 2,3,5-trimethylheptane, 2,4-dimethyloctane, d,l-cis-l-εt yl-3- methylcyclohexane, J-2,5-dimethyloctane, 1,1,3,5-tetramethylcyclohexane, n- butylcyclopentane, ra-propylcyclohexane, 2,3,5-trimethylheptane, 2,5'-dimethyl-3- ethylhexane, 2,4,5-trimethylheptane, 2,4-dimethyl-3-isopropylpentane, 2,2,3- trimethylheptane, 2,4-dimethyl-4-ethylhexane, 2,2-dimethyl-3-ethylhexane, 2,2,3,4,4- pentamethylpentane, 1,1,3,4-tetramethylcyclohexane, 5-ethyl-2-methylheptane, 2,7- dimethyloctane, 3,6-dimethyloctane, 3,5-dimethyloctane, 4-isopropylheptane, 2,3,3- trimethylheptane, 4-ethyl-2-methylheptane, 2,6-dimethyloctane, 2,2,3,3- tetramethylhexane, trans- 1 -isopropyl-4-methylcyclohexane(p-menthane), 4,4- dimethyloctane, 2,3,4,5-tetramethylhexane, 5-ethyl-e-methylheptane, 3,3- dimethyloctne, 4,5-dimethyloctane, 3,4-diethylhexane, 4-propylheptane, 1,1,4- trimethylcycloheptane (eucarvane), trø«5-l,2,3,5-tetramethylcyclohexane, 2,3,4,4- tetramethylhexane, 2,3,4-trimethylheptane, 3-isopropyl-2-methylhexane, 2,2,7- trimethylbicyclo[2.2. l]heptane(α-frenchane), 3-methylheptane, 2,4-dimethyl-3- ethylhexane, 3,4,4-trimethylheptane, 3,3,4-trimethylheptane, 3,4,5-trimethylheptane, 2,3-dimemthyl-4-ethylhexane, 1-methyl-e-propylcyclohexane, 2,3-dimethyloctane, c -pinane, 2,3,3,4-tetramethylhexane, 3,3-dimethyl-4-ethylhexane, 5-methylnonane, 4-methylnonane, 3-ethyl-2-methylheptane, 3,4-dimethyloctane, d-opinane, d,l-l- isopropyl-3-methylcyclohexane(<i,/-w-menthane), 2,2,3,3,4-pentamethylpentane, tra«s-l,2,4,5-tetramethylcyclohexane, 3,3-diethylhexane, 2-methylnonane, d-1- isopropyl-3-methylcyclohexane (d-rø-menthane), 3-ethyl-4-methylheptane, 4-ethyl-3- methylheptane, 4-ethyl-4-methylheptane, 1-β-pi ne, 3-methylnonane, 3-e hyloctane, 4-ethyloctane, 3-ethyl-2,2,3-trimethylpentane, -l-isopropyl-3-methylcyclohexane (7- m-menthane)e«-l-isopropyl-4-m ethylcyclohexane (cw-p-menthane), c/s-1,2,3,5- tetramethylcyclohexane, 2,3-dimethyl-3-ethylhexane, 1 -isopropyl-4- methylcyclohexane (p-menthane), 3,4-dimethyl-3-ethylhexane, 3,3,4,4- tetramethylhexane, cyclononane, l-isopropyl-2-methylcyclohexane (ø-menthane), cis- 1, 2,4,5 -tetramethylcyclohexane, 1 -methyl- 1-propylcyclohexane, «-decane, 1-methyl- 4-propylcyclohexane, l-methyl-2-propylcyclohexane, π-pentrylcyclopentane, n- butylcyclohexane, trαws-decahydronaphthalene (trøws-decalin), isoamylcyclohexane, cw-decahydronaphthalene (cw-decalin), n-undecane (»-hendecane), cyclodecane, n- pentylcyclohexane, «-hexylcyclopentane, 9-methyl-trøra,-decahydronaphthalene, 1 , 10-dimethyl-trαws-decahydronaphthalene, 9-methyl-q/s-decahydronaphthalene, n- dodecane, ,1,10-dimethyl-cw-decahydronaphthalene, w-hexycyclohexane, n- heptylcyclopentane, 9-ethyl-trαrø-decahydronaphthalene, 9-ethyl-cw- decahydronaphthalene, 1 -methyl-tra«5-decahydronaphthalene, H-tridecane, bicyclohexyl, n-octylcyclopentane, H-heptylcyclohexane, n-tetradecane, n- nonylcyclopentane,, «-octylcyclohexane, w-pentadecane, n-decyclopentane, n- nonylcyclohexane, w-undecylcyclopentane (n-hendecylcyclopentane), n- decylcyclohexane, 2-methylheptadecane, H-dodecylcyclopentane, n- undecylcyclohexane ' (w-hendecylcyclohexane), n-tridecylcyclopentane, n- dodecylcyclohexane, H-tetradecylcyclopentane, pentadecyclcyclopentane, n- hexadecane (cetane), tridecylcyclohexane, hexadeclcyclopentane, «-heptadecane, tetradecylcyclohexane, heptadecylcyclopentane, «-octadecane, pentadecylcyclohexane, octadecylcyclopentane, n-nonadecane, hexadecyjcyclohexane, nonadecylcyclopentane, «-eicosane, heptadecylcyclohexane, eicosylcyclopentane, «-heneicosane, octadecylcyclohexane, heneicosylcyclopentane, n-docosane, ' docosylcyclopentane, nonadecylcyclohexane, «-tricosane, eicosylcyclohexane, tricosylcyclopentane, rc-tetracosane, tetracosylcyclopentane, heneicosylcyclohexane, n-pentacosane, pentacosylcyclopentane, docosylcyclohexane, hexacosylcyclopentane, notricyclene (tricyclo[2.2.1.02'6]heptane), n-hexacosane, cyclohexadecane, tricosylcyclohexane, heptacosylcyclopentane, »-heptacosane, tetracosylcyclohexane, cyclopentadecane, octacosylcyclopentane, «-octacosane, pentacosylcyclohexane, nonacosylcyclopentane, w-nonacosane, hexacosylcyclohexane, triacontylcyclopentane, d, 7-isobornane(2j2,3- trimethylbicyclo[2.2.2]heptane), π-triacontane, heptacosylcyclohexane, hentriacontylcyclopentane, «-hentriacontane, octacosylcyclohexane, dotriacontylcyclopentane, w-dotriacontane (bicetyl), noncosylcyclohexane, tritriacontylcyclopentane, tritriacontane, triacontylcyclohexane, tetratriacontylcyclopentane, tetratriacontane, 28-methylnonacosane, hentriacontylcyclohexane, pentatriacontylcyclopentane, pentatriacontane, dotriacontylcyclohexane, hexatriacontylcyclopentane, hexatriacontane, tritriacontylcyclohexane, heptatriacontane, tetratriacontylcyclohexane, octatriacontane, pentatriacontylcyclohexane, nonatriacontane, hexatriacontylcyclohexane, tetracontane, norbornane (bicyclo[2.2.1]heptane], 2,2,3,3- tetramethylbutane, bornane (camphane), and adamantane. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix "-ane" with the suffix "-yl".
The term "alkenyl" refers to an unsaturated, hydrocarbon radical, linear or branched, in so much as it contains one1 or more double bonds. The alkenyl group disclosed herein can be optionally substituted with any moiety that does riot adversely affect the reaction process, including but not limited to but not limited to alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al, Protective Groups in Organic Synthesis. John Wiley & Sons, Second Edition, 1991, hereby incoφorated by reference. Non-limiting examples of alkenyl groups include methylene, ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds. The alkynyl group may be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to hydroxyl, halo (F, CI, Br, I), perfluoro alkyl including but not limited to trifluoromethyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, amido, carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al, Protective Groups in Organic Synthesis. John Wiley & Sons, Second Edition, 1991, hereby incoφorated by reference. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals. The term "alkylamino" or "arylamino" refers toi an amino group that has one or two alkyl or aryl substituents, respectively.
The term "protected" as used herein and unless otherwise defined refers to a group that is added to all oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other puφoses. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or the following aromatic group that remains after the removal of a hydrogen from the aromatic ring: benzene, toluene, efhylbenzene, 1,4-xylene, 1,3-xylene, 1,2-xylene, isopropylbenzene (cumene), n-propylbenzene, l-ethyl-3- methylbenzene (m^ethyltoluene), l-ethyl-4-methylbenzene (p-ethyltoluene), 1,3,5- trimethylbenzene (mesitylene), l-ethyl-2-methylbenzene (o-ethyltoluene), tert- butylbenzene, 1,2,4-trimethylbenzene (pseudodocumene), isobutylbenzene, sec- butylbenzene, 3-isopropyl-methylbenzene (3-isopropyltoluene; wz-cymene), 1,2,3-
I trimethylbenzene (hemimellitene), ' tπ s-propenylbenzene, indane, 4-isopropyl-l- methylbenzene (4-isopropyltoluene; 4-cymene), 2-isopropyl-methylbenzene (2- isopropyltoluene; 2-cymene), 1,3-diethbenzene, 1 methyl-3 -proplybenzene (m- propyltoluene), indene, n-butylbenzene, l-methyl-4-propylbenzene (p-propyltoluene), 1,2-diethylbenzene, 1,4-diethylbenzene, l,3-dimethyl-5-ethylbenzene, l-methyl-2- propylbenzene (o-propyltoluene), 2,2-dimethyl-l-phenylpropane (neopentylbenzene), l,4-dimethyl-2-ethylbenzene, 2-methylindane, 3-methyl-2-phenylbutane, 1- methylindane, l,3-dimethyl-4-ethylbenzene, 3-tert-butyl-menthylbenzene, (3-tert- butyltoluene), l,2-dimethyl-4-ethylbenzene, l,3-dimethyl-2-ethylbenzene, 3- phenylpentane, l-ethyl-3-isopropylbenzene, 2-methyl-2-phenylbutane, 4-tert-butyll- methylbenzene (4-tert-butyltoluene), l-ethyl-2-isopropylbenzene, 2-phenylpentane, l,2-dimethyl-3-ethybenzene, 3 -sec-butyl-l -methylbenzene, (3-.sec-butylotoluene), 3- isobutyl-1 -methylbenzene, (3-isobutyltoluene), rf-2-methyl-l-phenylbutane, 1,3- dimethyl-5-isopropyl-benzene, 2-phenyl-cw-2-butene, 4-isobutyl-methylblenzene (p- isobutyltoluene), 2-^ec-butyl-l -methylbenzene (2-.sec-butyltoluene), 2-isobutyl-l- methylblenzene (o-isobutyltoluene), l,4-dimethyl-2-isopropyl -benzene, l-ethyl-4- isopropylbenzene, ,i-2-methyl-l-phenylbutane, 1,2,3, 5-tetramethylbenzene (isodurene), 3-methyl-l-phenylbutane (isopentylbenzene), l,3-dimethyl-2- isopropylbenzene, l,3-dimethyl-4-isopropylbenzene), 3-methylindene, 4-5ec-butyl-l- methylbenzene (p-sec-butyltoluene), 2-tert-butyl-l -methylbenzene (2-tert- butyltoluene), 3,5-diethyl-l-methylbenzene (3,5-diethyltoluene), 2-butyl-l- methylbenzene (2 butyltoluene), l-ethyl-3-propylbenzene, l,2 iinιethyl-4- isopropylbenzene, l,2-dimethyl-3-isopropylbenzene, l-ethyl-2-propylbenzene, 1,3-di- isopropyllbenzene, l,2-diethyl-4-methylbenzene, 1,2-di-isopropylbenzene, 1,4- dimethyl-2-proplybenzene, 1,2,3,4-tetramethylbenzene (prehnitene), l-ethyl-4- propylbenzene, 3-butyl-l-methlybenzene (wz-butyltoluene), 2,4-diethyl-l- methylbenzene (2,,4-diethyltoluene), «-pentylbenzene, 3 -methyl-3 -phenylpentane, l,3-dimethyl-5-tert-butylbenzene, l,3-dimethyl-4-propylbenzene, l,2-diethyl-3- methylbenzene, 4-butyl-l-methylbenzene, 4-butyl-l -methylbenzene, 1,2,3,4- tetrahydronaphthalene, 1 ,3-diethyl-2-propylbenzene, 2,6-diethyl-l -methylbenzene, 1 ,2-dimethyl-4-propylbenzene, 1 ,3-dimethyl 5-propylbenzene, 2-methyl-3- phenylpentane, 4-teπ'-butyl-l,3-dimethylbenzene, 1,4-di-isopropylbenzene, 1,2- dimethyl-3-propylbenzene, l-terz-butyl-4-ethylbenzene, d, 1 -3 -phenylhexane, 2- ethyly-l,3,5-trimethyl-benzene, 3-ethyly-4-isopropyl-l-methylbenzene, 5-ethyl- 1,2,4- trimethylbenzene, 6-ethyl-l-2,4-trimethylbenzene, 2-phenylhexane, 2-methyl-l- phenylpentane, 4-isopropyl-l-propylbenzene, 1,3-dipropylbenzene, 5-ethyl-l,2,3- trimethylbenzene, 1,2,4-triethylbenzene, 1,3,5-triethylbenzene, 2-methyl-l,2,3,4- tetrahydronaphthalene, 1 -methyl- 1, 2,3, 4-tetrahydronaphthalene, 4-ethyl-l,2,3- trimethylbenzene, 1,4-dipropylbenzene, 3-methyl-l -phenylpentane, 2-propyl-l,3,5- trimethylbenzene, 1 , 1 -dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene, 3-tert-butyl- 1 - isopropylbenzene, 1 -methyl-3 -pentylbenzene, 4-tert-butyl-l-isopropylbenzene, 2- methyl-2-phenylhexane, * 2,4-di-isopropyl-l -methylbenzene, 3-methyl-3- phenylhexane, «-hexylbenzene, 3-phenylheptane, 2,6-di-isopropyl-l -methylbenzene, 5-propyl-l,2,4-trimethylbenzene, 6-methyl-l,2,3,4-tetrahydronaphthalene, 2,2- dimethyl-l,2,3,4-tetrahydronaphthalene, 2-phenylheptane, 5-methyl- 1,2,3,4- tetrahydronaphthalene, 2-ethyl- 1,2,3, 4-tetrahydronaphthalene, cyclohexylbenzene, 1- ethyl-1 ,2,3,4-tetrahydronaphthalene, 2,5-dimethyl-l,2,3,4-tetrahydronaphthalene, 2,8- dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene, 2,7-dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene, 2,6-dimethyl- 1 ,2,3,4-tetrahydronaphthalene, 1 ,4-di-jec-butylbenzene, 1 ,5-dimethyl- 1,2,3,4-tetrahydronaphthalene, 3-ethyl-3-phenylhexane, 6-ethyl- 1,2,3,4- tetrahydronaphthalene, 2-methyl- 1 -phenyl- 1 -butene, 5-ethyl-l ,2,3,4- tetrahydronaphthalene, n-heptylbenzene, 1-methylnaphthalene, 5,6-dimethyl-l,2,3,4- tetrahydronaphthalene, 6,7-dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene, 5 ,7-dimethyl- 1,2,3, 4-tetrahydronaphthalene, 2-ethylnaphthalene, 1-7-dimethylnaphthalene, 1,6- dimethylnaphthalene, 1,3-dimethylnaphthalene, w-octylbenzene, 1-allylnaphthalene, 1-isopropylnaphthalene, 1,4-dimethylnaphthalene, 1,1-diphenylethane, 2- isopropylnaphthalene, 2-propylnaphthalene, 1-propylnaphthalene, 1,3,7- trimethylnaphthalene, l-isopropyl-7-methylnaphthalene, w-nonylbenzene, 2- butylnaphthalene, 2-tert-butylnaphthalene, 1-tert-butylnaphthalene, 1- butylnaphthalene, 4,5-benzindane, w-decylbenzene, 1-pentylnaphthalene, 2- pentylnaphthalene, »-undecylbenzene, 1-hexylnaphthalene, 2-hexylnaphthalene, n- dodecylbenzene, 1-heptylnaphthalene, 2-heptylnaphthalene, tridecylbenzene, 1- octylnaphthalene, 2-octylnaphthalene, 1-nonylnaphthalene, 2-nonylnaphthalene, 1- decylnaphthalene, 1,2,6-trimethylnaphthalene, diphenylmethane, 1,2,3- trimethylnaphthalerie, 1,6,7-trimethylnaphthalene, 2-isopropylazulene, 1,4-dimethyl- 7-isopropylazulene, 2,6-dimethylphenanthrene, 1,2,5-trimethylnaphthalene, 1- propylphenanthrene, 5-isopropylazulene, 5-isopropylazulene, 2-propylphenanthrene, 2-methylnaphthalene, l-ethyl-5-methylnaphthalene, 9-isopropylnaphthalene, 6- isopropylazulene, 2-ethyl-6-methylnaphthalene, 2-isopropylphenanthrene, 6- isopropyl-1-methylphenanthrene, 2-ethylazulene, 2,5,-dimethylphenanthrene, 1,3,5- trimethylnaphthalene, 3-ethyl-6-methylphenanthrene, 2-methylazulene, 1,3,8- trimethylnaphthalene, 4-methylphenanthrene, 1,4-dimethylphenanthrene, bibenzyl, methylenefluorene, 3,5-dimethylphenanthrene, 1,3-dimethylazulene, 7-methyl-3,4- benzphenanthrene, pentamethylbenzene, 1,2,4-trimethylnaphthalene, '3,3- dimethylstilbene, 1 ,4,5,7-tetramethylnaphthalene, 1 ,2,4,8-tetramethylnaphthalene, 2,9-dimethylphenanthrene, 1,5-dimethylphenanthrene, 2-benzylnaphthalene, 1- benzylnaphthalene, 1-benzylnaphthalene, 1,2-dimethylazulene, 9-propylphenanthrene, l,7-dimethyl-4-isopropylnaphthalene, 3-methylphenanthrene, 3,4- dimethylphenanthrene, 1-ethylphenanthrene, iywz-diphenylacetylene, 9- ethylphenanthrene, 1,4,5-trimethylnaphthalene, 4-methylfluorene, 1,4,6,7- tretramethylnaphthalene, 1,2,3-trimethylphenanthrene, 1,8-dimethylnaphthalene, 8- methyl-3,4-benzphenanthrene, 2-ethylphenanthrene, 3,4-benzphenanthrene, 1,3,7- trimethylphenanthrene, 4-isopropyl-l-methylphenanthrene, 4,8-dimethylazulene, biphenyl, 2-methyl-3,4-benzphenanthrene, 3-methylpyrene, 1,4,7- trimethylphenanthrene, 1 ,4-dimethylanthracene, 4,9-dimethyl-l ,2-benzanthracene, benzalfluorene, 1,3-dimethylphenanthrene, 1 -methyl-3 ,4-benzphenanthrene, 3- isopropyl-1 -methylphenanthrene, 1,2-binaphthyl, 2,3-dimethylphenanthrene, 1-ethyl- 2-methylphenanthrene, 1 ,5-dimethylnaphthalene, 6-methyl-3,4-benzphenanthrene, naphthalene, 1,3,6,8-tetramethylnaphthalene, l-ethyl-7methylphenanthrene, 9- methylanthracene, l-isopropyl-7-methylphenanthrene, 6-methylazulene, 1,3- dimethylanthracene, 2,2-dimethylstilbene, 1-methylanthracene, 1,7- dimethylphenanthrene, 1,6-diphenylnaphthalene, 1,6-dimethylphenanthrene, 1,9- dimethylphenanthrene, 9-methylphenanthrene, 1,2,10-trimethylanthracene, 7-ethyl-l- methylphenanthrene, triphenylmethane, 5-isopropylnaphthanthracene, 3,9-dimethyl- 1,2-benzanthracene, 5,6-benzindane, 12-isopropylnaphthanthracene, acenaphthene, 2,7-dimethylnaphthalene, 7-isopropyl-l-methylfluorene, azulene, retene, phenanthrene, 2,7-dimethfylphenanthrene, 2,3,6-trimethfylnaphthalene, 2- phenylnaphthalene, 1 ,2,3,4-tetrahydroanthracene, 2,3-dimethylnaphthalene, ethylidenefluorene,, 1,7-dimethylfuorene, 1,1-dinaphthylmethane, fluoranthrene, 2,6- dimethylnaphthalene, 2,4-dimethylphenanthrene, fluorene, 4,10-dimethyl- 1,2- benzanthracene, 4h-cyclopenta(def)phenanthrene, 1,3,8-trimethylphenanthrene, 11- methylnaphthanthracene, 5-methylchrysene, 1 ,2,5,6-tetramethylnaphthalene, cyclohept(fg)acenaphthene, 1 ,2,7-trimethylphenanthrene, 1 , 10-dimethyl- 1 ,2- dibenzanthracene, 9,10-dimethyl- 1,2-benzanthracene, benz(bc)aceanthrylene, 1- methylphenanthrene, 1,6,7-trimethylphenanthrene, 1,1-diacenaphthene, trø«s-stilbene, 3,4-benzflurorene, 9-isopropylnaphthanthracene, 6-methylnaphthanthracene, 5,8- dimethyl-1 ,2-bezanthracene, 8-isopropylnaphthanthracene, 1 ,4,5,8- tetramethylnaphthalene, 12-methylnaphthanthracene, 2-methyl-l,2-benzpyrene, 1,5- dimethylanthracene, 7-methylnaphthanthracene, 3,6-dimethylphenanthrene? 5-methyl- 3,4-benzphenanthrene, . 1,4-dimethylchrysene, 1,2-dimethylphenanthrene, 8,10- dimethy 1- 1 ,2-benzanthracene, 1,2, 8-trimethylphenanthrene, 3 -methyl- 1 ,2-benzpyrene, 9-methyl-l,2-benzpyrene, 9-phenylfluorene, 2-methylnaphthanthracene, pyrene, 9- methylnaphthanthracene, 4-methylchrysene, trans-trans- 1 ,4-diphenyl- 1 ,3 -butadiene, cinnamalfluorene, 5 -methylnaphthanthracene, 1,2-benzanthracene, 8- methylnaphthanthracene, 1,1-binaphthyl, di-1-naphthastibene, 6-methylchrysene, 3- methylnaphthanthracene, 2,6-dimethyl-l ,2-benzanthracene, cyclopentadienophenanthrene, 10,11-benzfluoranthene, hexamethylbenzene, 3- methylchrysene, cholanthrene, 6-methyl-l,2-benzpyrene, 6,7-dimethyl- 1,2- benzanthracene, 1,2-benzpyrene, 5,10-dimethyl- 1,2-benzanthracene, 4,5-benzpyrene, 9, 10-dimethylanthracene, 10-methylnaphthanthracene, 5,6-dimethyl-l ,2- benzanthracene, 2,2-binaphthyl, 1,2-benfluorene, 1,8-dimethylphenanthrene, 8- methyl-l,2-benzpyrene, bifluorenylidene, 1,2,7,8-dibenzanthracene, 4- methylnaphthanthracene, 1,2,3,4-dibenzanthracene, di-2-fluorenylmethane, 2,3- benzfluorene, 5-methyl-l,2-benzpyrene, anthracene, 11,12-benzfluoranthene, 4- methyl-l,2-benzpyrene, 2,8-dimethylchrysene, 2-methylchrysene, 6,12 dimethylchrysene, 1,2-benzphenanthrene, di-2-naphthastilbene, 1-methylchrysene, 2,3,6,7-dibenzphenanthrene, 2,3,5,6-dibenzphenanthrene, 1,2,5,6-dibenzanthracene, perylene, picene, 1,2,3,4,5,6,7,8-tetrabenzanthracene, and coronene. The term aryl includes both substituted and unsubstituted moieties. The aryl group may be optionally substituted with any moiety that does not adversely affect the process, including but not limited to but not limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamirip, alkoxy, a yloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al, Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incoφorated by reference. Non-limiting examples of substituted aryl include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino- N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyi, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, carboaralkoxy. The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent.
The term "halo," as used herein, includes chloro, bromo, iodo and fluoro. The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but not limited to methoxymethyl, aralkyl including but not limited to benzyl, aryloxyalkyl suc^ as phenoxymethyl, aryl including but not limited to phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to d, C2, C3, and C4) or alkoxy (including but not limited to Cj, C2, C3, and C4), sulfonate esters such as alkyl or aralkyl sulphonyl including but not limited to methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the esters optimally comprise a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals having alkyl moieties, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
The term "alkylamino" denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes "monparylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. The term "aralkylamino", embraces aralkyl radicals attached to an amino radical. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "heteroatom," as used herein, refers to oxygen, sulfur, nitrogen and phosphorus. The terms "heteroaryl" or "heteroaromatic," ιas used herein, refer to an aromatic that, includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
The term "heterocyclic" refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
I
Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole,
I
1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, moφholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridihyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines, N6-benzylpurine, N6-halopurine, N6-vinypurine, N6- acetylenic purine, N6-acyl purine,N6-hydroxyalkyl purine, N6-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidine, uracil, N5- alkylpyrimidines, N5-benzylpyrimidines, N5-halopyrimidines, N5-vinylpyrimidine, N5-acetylenic pyrimidine, N5-acyl pyrimidine, N5-hydroxyalkyl purine, andi N6- thioalkyl purine, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen (F, CI, Br, I), haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimiting example, dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p- toluenelsulfonyl. The heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to but not limited to those described above for aryl.
The term "host," as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).
The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a nucleoside compound which, upon administration to a patient, provides the nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of this invention possess antiviral activity against Flaviviridae, or are metabolized to a compound that exhibits such activity.
Prodrugs also include natural or unnatural amino acid esters of the disclosed nucleosides (see, e.g., European Patent Specification No. 99493, the text of which is incoφorated by reference, which describes amino acid esters of acyclovir, specifically the glycine and alanine esters which show improved water-solubility compared with acyclovir itself, and' US Pat. No. 4,957,924 (Beauchamp), which discloses the valine ester of acyclovir, characterized by side-chain branching adjacent to the α-carbon atom, which showed improved bioavailability after oral administration compared with the alanine and glycine esters). A process for preparing such amino acid esters is disclosed in US Pat. No. 4,957,924 (Beauchamp), the text of which is incoφorated by reference. As an alternative to the use of valine itself, a functional equivalent of the amino acid may be used (e.g., an acid halide such as the acid chloride, or an acid anhydride). In such a case, to avoid undesirable side-reactions, it may be is advantageous to use an amino-protected derivative.
IV. Nucleotide Salt or Prodrug Formulations
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid ιor base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid, addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.
Any of the nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside. A number of nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including but not limited to sugars, 1,2- diacylglycerol and alcohols. Many are described in R. Jones & N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.
The active nucleoside can also be provided as a 5'-phosphoether lipid or a 5'- ether lipid, as disclosed in the following references, which are incorporated by reference: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi, "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation," AIDS Res. Hum. Retroviruses, 1990, 6, 491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, CA. Wallen, S. Piantadosi, and E.J. Modest, "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity," J. Med. Chem., 1991, 34, 1408-1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch, "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine," Antimicrob. Agents Chemother., 1992, 36, 2025-2029; Hostetler, K.Y., L.M. Stuhmiller, H.B. Lenting, H. van den Bosch, and D.D. Richman, "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J. Biol Chem., 1990, 265, 61127.
Nonlimiting examples of US patents that disclose suitable lipophilic substituents that can be covalently incoφorated into the nucleoside, preferably at the 5' -OH position of the nucleoside or lipophilic preparations, include US Pat. Nos. 5,149,794 (Yatvin et al); 5,194,654 (Hostetler et al), 5,223,263 (Hostetler et al); 5,256,641 (Yatvin et al); 5,411,947 (Hostetler et al); 5,463,092 (Hostetler et al); 5,543,389 (Yatvin et al); 5,543,390 (Yatvin et al); 5,543,391 (Yatvin et al); and 5,554,728 (Basava et al), all of which are incoφorated by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350287, EP 93917054.4, and WO 91/19721. V. Combination or Alternation Therapy ι I
In another embodiment for the treatment of HIV or HBV infection, the active compound or its prodrug or salt can be administered in combination or alternation with another antiviral agent, such as another active anti-HIV or anti-HBV agent, including but not lhnited to those of the formulae above, others listed below or known in the art. In general, in combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially. The dosage will depend on absoφtion, inactivation and excretion rates of the drug as well as other factors known to those of ' skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time
, I according to ihe individual need and the professional judgment of the person administering or supervising the administration of the compositions.
Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein inclμde those in the tables below.
Hepatitis B Therapies
Drug Name Drug Class Company
Intron A (interferon alfa-2b) interferon Schering-Plough
Epivir-HBV (lamivudine; 3TC) nucleoside analogue GlaxoSmithKline
Hepsera (Adefovir Dipivoxi)" nucleotide analogue Gilead Sciences ..".
Coviracil (emtricitabine; FTC) nucleoside analogue Triangle Pharmaceuticals
Entecavir nucleoside analogue Bristol-Myers Squibb
Clevudine (L-FMAU) nucleoside analogue Triangle Pharmaceuticals
ACH 126, 443 (L-Fd4C) nucleoside analogue Achillion Pharmaceuticals
AM 365 nucleoside analogue A rad Amdoxovir (formerly DAPD) nucleoside analogue Triangle Pharmaceuticals
LdT (telbivudine) nucleoside analogue Idenix
XTL 001 monoclonal antibody XTL Biopharm
Theradigm Immune stimulant Epimmune
Zadaxin (thymosin) Immune stimulant SciClone
EHT 899 viral protein Enzo Biochem
HBV DNA vaccine Immune stimulant PowderJect (UK)
MCC 478 nucleoside analogue Eli Lilly
valLdC (valtorcitabine) nucleoside analogue Idenix
ICN 2001 nucleoside analogue ICN
Fluro L and D nucleosides nucleoside analogue Pharmasset
Racivir nucleoside analogue Pharmasset
Robustaflavone nucleoside analogue Advanced Life Sciences
Penciclovir
DXG
HDP-P-acyclovir
LM-019c
CS-109
PS-019
PS-018
ara-AMP prodrugs
HBV/MF59 Hammerhead ribozymes
Glycosidase Inhibitors
Pegylated Interferon
Human Monoclonal Antibodies
I
Famciclovir
HIV Therapies: Protease Inhibitors (Pis)
Figure imgf000087_0001
HIV Therapies: Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors (NRTIs)
Figure imgf000088_0001
HIV Therapies: Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
Figure imgf000089_0001
HIV Therapies: Other Classes of Drugs
Figure imgf000090_0001
Cellular Inhibitors
Figure imgf000090_0002
Entry Inhibitors (including Fusion Inhibitors)
Figure imgf000090_0003
HIV Therapies: Immune-Basedi Therapies
Figure imgf000091_0001
HIV Therapies: Treatments for Side Effects
Figure imgf000092_0001
Figure imgf000092_0002
In one embodiment, the compounds of the invention may be employed together with at least one other antiviral agent chosen from reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors and polymerase inhibitors. i - - - .
In addition, compounds according to the present invention can be administered in combination or alternation with one or more anti-retrovirus, anti-HBV, anti-HCV or anti-heφetic agent or interferon, anti-cancer or antibacterial agents, including but not limited to other compounds of the present invention. Certain compounds according to' the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or
I inactivation of other compounds and as such, are co-administered for this intended effect. ' i
VI. Pharmaceutical Compositions
Host, including but not limited to humans, infected with a human immunodeficiency virus, a hepatitis virus, or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. .
A preferred dose of the compound for an HIV or HBV infection will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art. The compound is conveniently administered in unit any suitable dosage form, including but not limited to but not limited to one containing 7 to 3000 mg, preferably i I 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is usually convenient. ,
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 μM, preferably about 1.0 to 10 μM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
The concentration of active compound in the drug composition will depend on absoφtion, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein, are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the puφose of oral therapeutic administration, the active compound can be incoφorated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can. contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-
, I inflammatories or other antivirals, including but not limited to other nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous,
|. or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. .
If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).
In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. For example, enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
Liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (incoφorated by reference). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
VII. Processes for the Preparation of Active Compound
A process for the facile preparation of N4-acyl-cytosine- 1,3 -dioxolane nucleosides is also provided. The method includes condensation of a 5'-O-silyl protected 5-fluorocytidine-l,3-dioxolane, with either a carboxylic acid chloride, or carboxylic acid anhydride, or a carboxylic acid, followed by desilylation. The other N4-acyl-substituted cytosine nucleosides can be synthesized using the similar approaches.
The N4-acyl-substituted 5-fluorocytidine-l,3-dioxolane disclosed herein can be prepared as described in detail below, or by other assays known to those skilled in the art.
The present invention is further illustrated in the following examples. It will be understood by one of ordinary skill in the art that these examples are in no way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention. EXAMPLES '
I I
Anhydrous solvents were purchased from Aldrich Chemical Company, Inc. (Milwaukee). Melting! points (mp) were determined on an Electrothermal digit melting point apparatus and are uncorrected. 1H and 13C NMR spectra were taken on a Varian Unity Plus 400 spectrometer at room temperature and reported in ppm downfield from internal tetramethylsilane. Deuterium exchange, decoupling experiments or 2D-COSY were performed to confirm proton assignments. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), bs (broad singlet), m (multiplet). All J-values are in Hz. Mass spectra were recorded on a JEOL JMS-SX/SX102A/E mass spectrometer. Ele ental analyses were performed by Atlantic Microlab Inc. (Norcross, GA). Analytic TLC was performed on Whatman LK6F silica gel plates, and preparative; TLC on Whatman PK5F silica gel plates. Column chromatography was carried ouf on Silica Gel (Fisher, S733-1) at atmospheric pressure.
Example 1
General Process for the Preparation of l,3-DioxolaneIntermediate(i)
The 1,3-dioxolane intermediate (i) of the present invention can be synthesized according to U.S. Patent No. 5,041,449, filed June 29, 1990; U.S. Patent No. 5,270,315, filed March7, 1991 ("2-Substituted-4-substituted-l,3-dioxolanes, synthesis and use thereof); PCT application CA 92/00209 , filed May 20, 1992; U.S. Patent No. 5,756,706, filed May 13, 1994; U.S. Patent No. 5,744,596, filed June 5, 1995 ("Processes for diastereoselective synthesis of nucleosides"); PCT Application CA 94/00311, filed June 7, 1994; U.S. Patent No. 5,763,606, filed February 2, 1995 ("Stereoselective synthesis of nucleoside analogues using bicyclic intermediate"); U.S. Patent Application 60/119,756, filed February 11, 1999; U.S. Patent Application 60/119,885, filed February 12, 1999; PCT Application CA 00/00144, filed February 11, 2000; U.S. Patent Application 09/890,283, filed February 11, 2000 (Stereoselective Synthesis Of Nucleoside Analogues); U.S. Patent Application 60/181,977, filed February 11, 2000; U.S. Patent Application 09/779,853, filed February 9, 2001; PCT Application CA 01/00117, filed February 2, 2001 (Stereoselective Synthesis Of Nucleoside Analogues); U.S. Patent Application 60/350968, filed January 25, 2002 (Process for producing dioxolane nucleoside analogues) or any manner known to those of ordinary skills in the art..
Additionally, the 1,3-dioxolane intermediate can also be prepared according to the process as set forth in US Patent No. 5,444,063, filed October 28, 1992; US Patent No. 5,684,010, filed June 6, 1995; US Patent No. 5,834,474, filed April 15, 1997; US Patent No. 5,830,898, filed April 15, 1997; PCT Application WO 94/09793, filed October 28, 1993 ("Enantiomerically β-D-Dioxolane Nucleosides with Selective Anti-Hepatitis B Virus Activity"); US Patent No. 5,179,104, filed December 5, 1990; PCT Application WO 92/10497, filed December 5, 1990 ("Process for the preparation of enantiomerically pure β-D-(-)-dioxolane"); US Patent No. 5,767,122, filed June 6, 1995 ("Enantiomerically pure β-D-(-)-dioxolane-nucleosides"); US Patent No. 5,276,151, filed December 6, 1991 ("Method of Synthesis of 1,3-Dioxolane Nucleosides"); U.S. Patent Application No. 09/669,806, filed September 26, 2000 ("Method of Manufacture of 1,3-Oxathiolane Nucleosides"); U.S. Patent Application No. 60/106,664, filed November 2, 1998; U.S. Patent Application No. 09/432,247, filed November 2, 1999; and PCT Application WO 00/25797, filed November 2, 1999 ("Combination Therapy to Treat Hepatitis B Virus"); U.S. Patent Application No. 10/023,636, filed December 17, 2001; PCT Application US 01/48817, filed December 17. 2001 ("DAPD Combination Therapy with Ribavirin or Mycophenolic Acid"); and U.S. Patent Application No. 60/393,935, filed July 3, 2002 ("Combination Therapy with 1,3,-Dioxolanes and Inosine Monophosphate Dehydrogenase Inhibitors"), all assigned to Emory University, Atlanta, GA, USA.
Example 2
General Process for Acylation of 1,3-Dioxolane
The 1,3-dioxolane intermediate (i) is protected at the 5'-hydroxyl with any known method known in the art. The protected 1,3-dioxolane (ii) is then acylated and deprotected to form the N4-acylcytosine-l,3-dixolane nucleoside of formula (iv). See Scheme 1. Scheme 1
Figure imgf000099_0001
Wherein are R1 is hydrogen or F; P is an oxygen protecting group; and R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and CβFLR6 where R6 is chosen from halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.
Example 3
β-D-5-fluoro-N4-(4-iodobenzoyl)cytidine-l ',3 '-dioxolane (vi)
To a solution of (ii) and DMAP in anhydrous CH2C12 and Et3N at 0°C was added 4-iodobenzoyl chloride. The reaction mixture was stirred at 0°C for 30 min, then at room temperature for another 3 h. After removal of the solvent by evaporation, the residue was mixed with THF, and TBAF was added. After stirring for 2 h at room temperature, the solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (96:4) to give, after recrystallization from CH2Cl2/hexane, the title compound vi as a yellow powder .
Example 4
β-D- 4 -Butyryl-5-fluorocytidine-l,3-dixolane (vii)
To a solution of ii and DMAP in anhydrous CH2C12 and Et3N at 0°C was added butyric anhydride. The reaction mixture was stirred at 0°C for 30 min, then at room temperature for another 2 h. After removal of the solvent by evaporation, the residue was mixed with THF, and TBAF was added. After stirring for 2 h at room temperature, the solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (96:4) to give, after recrystallization from CH2Cl2/hexane, the title compound vii.
Example 5
β-D-5-βuoro-N4 -(4-fluorobenzoyl)cytidine-l ,3-dioxolane (viii)
To a solution of ii and DMAP in anhydrous CH2C12 and Et3N at 0°C was added 4-fluorobenzoyl chloride. The reaction mixture was stirred at 0°C for 30 min, then at room temperature for another 2 h. After removal of the solvent by evaporation, the residue was mixed with THF, and TBAF was added. After stirring for 2 h at room temperature, the solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (96:4) to give, after recrystallization from CH2Cl /hexane, the title compound.
Example 6
Anti-HIV (in PBM cells) Assay
Anti-HIV- 1 activity of the compounds was determined in human peripheral blood mononuclear (PBM) cells as described previously (Schinazi R.F., McMillan A., Cannon D., Mathis R., Lloyd R.M. Jr., Peck A., Sommadossi J.-P., St. Clair M., Wilson J., Furman P.A., Painter G., Choi W.-B., Liotta D.C. Antimicrob. Agents Chemother. 1992, 36, 2423; Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D., Xie M.-Y., Hart G., Smith G., Hahn E. Antimicrob. Agents Chemother. 1990, 34,
I
1061). Stock solutions (20-40 mM) of the compounds were prepared in sterile DMSO and then diluted to the desired concentration in growth medium. Cells were infected with the prototype HIVΓ1LAI at a multiplicity of infection of 0.01. Virus obtained from the cell supernatant was quantified on day 6 after infection by a reverse transcriptase assay using (rA)n«(dT)i2-i8 as template-primer. The DMSO present in the diluted solution (< 0.1%) had no effect on the virus yield. AZT was included as positive control. The antiviral EC50 and EC90 were obtained from the concentration- response curve using the median effective method described previously (Chou T.-C. & Talalay P. Adv. Enzyme Regul 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1-11).
I
Example 7
, I
I
Anti-HIV (in MT-2 cells) Assay
In a second antiviral testing system, the potency of the compounds was determined by measurement of viral RNA accumulation in HIV-IRF infected MT-2 cells (Bacheler LT, Paul M, Otto MJ, Jadhav PK, Stone BA & Miller JA (1994) An assay for HIV RNIn infected cell lysates, and its use for rapid evaluation of antiviral efficacy. Antivir. Chem. Chemother. 5:111-121). The virus titer was established to determine the dilution producing 15 to 30 ng/RNA per well of HIV RNIn 3 days of infection. HTV-l RNA was quantified using biotinylated capture and alkaline phosphatase-derivatized reporter oligonucleotides as described previously (Charvet A-S, Camplo M, Faury P, Graciet JC, Mourier N, Chermann JC & Kraus JL (1994) Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates. J. Med. Chem. 37:2216-2223). In a third system, the effect of analogs on the replication of HIV- 1NM-3 was determined via the Intercompany Consortium consensus p24 assay as previously described (Jadhav PK & MacKay MF (1997) Cyclic urea amide: HIV-1 protease inhibitors with low nanomolar potency against both wild types and protease inhibitor resistant mutants of HIV. J. Med. Chem. 40:181-190). Recombinant viruses were recovered by transfecting the appropriate NL4-3 plasmid by lipofection. Virus stocks recovered 7 to 10 days post-transfection were titered on MT-4 cells to determine if the dilution produced 1,000 to 3,000 ng p24 in 4 days. This dilution was then used in drug susceptibility assays, where drug was added 24 h post infection of cells, and p24 quantified by ELISA 3 days later.
Example 8
I
Anti-HBV assay ,
The anti-HBV activity of the compounds was determined by treating the AD- 38 cell line carrying wild type HBV under the control of tetracycline (Ladner S.K., Otto M.J., Barker C.S., Zaifert K., Wang G.H., Guo J.T., Seeger C. & King R.W. Antimicrob. Agents Chemother. 1997, 41, 1715-1720). Removal of tetracycline from the medium [Tet (-)] results in the production of HBV. The levels of HBV in the culture supernatant fluids from cells treated with the compounds were compared with that of the untreated controls. Control cultures with tetracycline [Tet (+)] were also maintained to determine the basal levels of HBV expression. 3TC was included, as positive control.
Example 9
Cytotoxicity assay
The toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob Agents Chemother. 1990, 34, 1061-1067). Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls. The cytotoxicity IC50 was obtained from the concentration-response curve using the median effective method described previously (Chou T.-C. & Talalay P. Adv. Enzyme Regul 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1-11).

Claims

A compound of formula (A)
Figure imgf000103_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein i) R1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl and acyl;
ϋ) R2 is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and CδELtR6 where R6 is chosen from halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl; iii) R3 and R3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl; and iv) R4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R3 and R3 are H or phosphate, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.
2. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.
3. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 1 or 14 in a pharmaceutically acceptable carrier.
4. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of claim 1 or 14 in a pharmaceutically acceptable carrier.
5. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 1 or 14 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
6. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of claim 1 or 14 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
7. A compound of claim 1 or 14 for use in the treatment of host infected with HIV.
8. A compound of claim 1 or 14 for use in the treatment of a host infected with HBV infection.
9. The use of a compound of claim 1 or 14 in the manufacture of a medicament for the treatment of a host infected with HIV.
10. The use of a compound of claim 1 or 14 in the manufacture of a medicament for the treatment of a host infected with HBV.
11. The compound of claim 1 , 7 or 8 selected from the group consisting of β-D-N4-p- iodobenzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-fluoro-benzoyl-5- fluorocytidine-l,3-dioxolane, β-D-N4-p-chlorobenzoyl-5-fluoro-cytidine-l,3- dioxolane, β-D-N4-p-bromobenzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p- ethyl-benzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-t-butylbenzoyl-5-fluoro- cytidine- 1 ,3 -dioxolane.
12. The method of claims 2 or 3 wherein the compound is selected from the group consisting of β-D-N4-p-iodobenzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p- fluoro-benzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-chlorobenzoyl-5-fluoro- cytidine-l,3-dioxolane, β-D-N4-p-bromobenzoyl-5-fluorocytidine-l,3- dioxolane, β-D-N4-p-ethyl-benzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-t- butylbenzoyl-5-fluoro-cytidine-l,3-dioxolane.
13. The use of claims 9 or 10 wherein the compound is selected from the group consisting of β-D-N4-p-iodobenzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p- fluoro-benzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-chlorobenzoyl-5-fluoro- cytidine-l,3-dioxolane, β-D-N4-p-bromobenzoyl-5-fluorocytidine-l,3- dioxolane, β-D-N4-p-ethyl-benzoyl-5-fluorocytidine-l,3-dioxolane, β-D-N4-p-t- butylbenzoyl-5 -fluoro-cytidine- 1 ,3 -dioxolane .
14. A compound selected from the following, or its pharmaceutically acceptable salt or prodrug:
β-D-5-fιuoro-N τ -(4-iodobenzoyl)cytidine- 1,3-dioxolane of the structure:
Figure imgf000105_0001
β-D-5-fluoro-N -(4-fluorobenzoyl)cytidine-l,3-dioxolaneof the structure:
Figure imgf000106_0001
β-D-N -(4-chlorobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000106_0002
β-D-N -(4-bromobenzoyl)-5 -fluorocytidine- 1 ,3 -dioxolane of the structure :
Figure imgf000107_0001
β-D-5-fluoro-N -(3-fluorobenzoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000107_0002
β-D-N4-(3-chlorobenzoyl)-5 -fluorocytidine- 1 ,3-dioxolane of the structure:
Figure imgf000108_0001
β-D-N -(3-bromobenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000108_0002
β-D-5-fluoro-N τ4 -(4-nitrobenzoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000108_0003
β-D-5-fluoro-N4-/>-toluoylcytidine-l,3-dioxolane of the structure:
Figure imgf000109_0001
β-D-5-fluoro-N -(w-toluoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000109_0002
β-D-N -(4-ethylbenzoyl)-5-fluorocytidine- 1,3-dioxolane of the structure:
Figure imgf000109_0003
β-D-5-fluoro-N4-(4-propylbenzoyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000110_0001
β-D-N -(4-tert-butylbenzoyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000110_0002
β-D-5-fluoro-N -(2 -thiophenecarbonyl)cytidine-l,3-dioxolane of the structure:
Figure imgf000110_0003
β-D-N4-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000111_0001
and β-D-N -(cyclohexane-carbonyl)-5-fluorocytidine-l,3-dioxolane of the structure:
Figure imgf000111_0002
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Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6790228B2 (en) * 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US7094770B2 (en) 2000-04-13 2006-08-22 Pharmasset, Ltd. 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections
MY164523A (en) * 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
CN1315862C (en) 2000-05-26 2007-05-16 艾登尼科斯(开曼)有限公司 Methods and compositions for treating flaviviruses and pestiviruses
US7105527B2 (en) * 2001-12-14 2006-09-12 Otto Michael J N4-acylcytosine nucleosides for treatment of viral infections
US7608600B2 (en) * 2002-06-28 2009-10-27 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7456155B2 (en) * 2002-06-28 2008-11-25 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
NZ537662A (en) * 2002-06-28 2007-10-26 Idenix Cayman Ltd 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US8093380B2 (en) 2002-08-01 2012-01-10 Pharmasset, Inc. Compounds with the bicyclo[4.2.1]nonane system for the treatment of Flaviviridae infections
EP1576138B1 (en) * 2002-11-15 2017-02-01 Idenix Pharmaceuticals LLC. 2'-methyl nucleosides in combination with interferon and flaviviridae mutation
KR20050109918A (en) * 2002-12-12 2005-11-22 이데닉스 (케이만) 리미티드 Process for the production of 2'-branched nucleosides
CA2425031A1 (en) * 2003-04-01 2004-10-01 Smithkline Beecham Corporation Pharmaceutical compositions
ES2726998T3 (en) 2003-05-30 2019-10-11 Gilead Pharmasset Llc Modified fluorinated nucleoside analogs
US7741334B2 (en) * 2004-04-01 2010-06-22 Achillion Pharmaceuticals, Inc. Low dose therapy for treating viral infections
CN101023094B (en) * 2004-07-21 2011-05-18 法莫赛特股份有限公司 Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives
NZ554442A (en) 2004-09-14 2011-05-27 Pharmasset Inc Preparation of 2'fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US20060084628A1 (en) * 2004-10-19 2006-04-20 Achillion Pharmaceuticals Combination therapy for treating viral infections
US7968703B2 (en) * 2005-03-07 2011-06-28 Shire Canada Inc. Process and methods for the preparation of optically active cis-2-hydroxymethyl-4- (cytosin-1'-yl)-1,3-oxathiolane or pharmaceutically acceptable salts thereof
EP1976382B1 (en) * 2005-12-23 2013-04-24 IDENIX Pharmaceuticals, Inc. Process for preparing a synthetic intermediate for preparation of branched nucleosides
GB0623493D0 (en) 2006-11-24 2007-01-03 Univ Cardiff Chemical compounds
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
PA8855601A1 (en) 2008-12-23 2010-07-27 NUCLEOSID FORFORMIDATES
CN102325783A (en) 2008-12-23 2012-01-18 法莫赛特股份有限公司 Synthesis of purine nucleosides
CA2748034A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Purified 2'-deoxy'2'-fluoro-2'-c-methyl-nucleoside-phosphoramidate prodrugs for the treatment of viral infections
TWI576352B (en) 2009-05-20 2017-04-01 基利法瑪席特有限責任公司 Nucleoside phosphoramidates
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
SG184323A1 (en) 2010-03-31 2012-11-29 Gilead Pharmasett Llc Stereoselective synthesis of phosphorus containing actives
CA2818853A1 (en) 2010-11-30 2012-06-07 Gilead Pharmasset Llc 2'-spirocyclo-nucleosides for use in therapy of hcv or dengue virus
MX354958B (en) 2011-09-16 2018-03-27 Gilead Pharmasset Llc Methods for treating hcv.
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
CN103242400B (en) * 2012-02-08 2016-06-08 河南师范大学 There is 5-substituted pyrimidines nucleoside-thiazolidhybrid hybrid and its preparation method of HIV (human immunodeficiency virus)-resistant activity
PL2950786T3 (en) 2013-01-31 2020-05-18 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
PL3038601T3 (en) 2013-08-27 2020-08-24 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
UA124966C2 (en) 2015-03-06 2021-12-22 Атеа Фармасеутікалс, Інк. <font face="Symbol">b</font>-D-2'-DEOXY-2'α-FLUORO-2'-β-C-SUBSTITUTED-2-MODIFIED-N<sup>6</sup>-SUBSTITUTED PURINE NUCLEOTIDES FOR HCV TREATMENT
WO2018013937A1 (en) 2016-07-14 2018-01-18 Atea Pharmaceuticals, Inc. Beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-c-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection
AU2017324939B2 (en) 2016-09-07 2021-10-14 Atea Pharmaceuticals, Inc. 2'-substituted-N6-substituted purine nucleotides for RNA virus treatment
IL295609B2 (en) 2017-02-01 2023-11-01 Atea Pharmaceuticals Inc Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus
WO2019200005A1 (en) 2018-04-10 2019-10-17 Atea Pharmaceuticals, Inc. Treatment of hcv infected patients with cirrhosis
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922867A (en) * 1995-12-14 1999-07-13 Biochem Pharma Inc. Method and compositions for the synthesis of dioxolane nucleosides with β configuration
US20030013660A1 (en) * 2000-10-13 2003-01-16 Shire Biochem Inc. Dioxolane analogs for improved inter-cellular delivery

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US13660A (en) * 1855-10-09 Improvements
US3309359A (en) * 1965-10-22 1967-03-14 Hoffmann La Roche N-mono-acyl-5-fluorocytosine derivatives and process
NL8202626A (en) 1982-06-29 1984-01-16 Stichting Rega V Z W DERIVATIVES OF 9- (2-HYDROXYETHOXYMETHYL) GUANINE.
US4522811A (en) * 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
GB8719367D0 (en) * 1987-08-15 1987-09-23 Wellcome Found Therapeutic compounds
ZA886890B (en) * 1987-10-09 1989-05-30 Hoffmann La Roche Novel dideoxycytidine derivatives
US6350753B1 (en) * 1988-04-11 2002-02-26 Biochem Pharma Inc. 2-Substituted-4-substituted-1,3-dioxolanes and use thereof
NL8901258A (en) 1989-05-19 1990-12-17 Stichting Rega V Z W New 5-halo-2'-3'-di:deoxy-cytidine derivs. - useful as anti-retro-viral agents, esp. for treating HIV infections
DD293498A5 (en) 1989-07-20 1991-09-05 Zi Fuer Molekularbiologie Der Adw,De METHOD FOR PRODUCING A MEDIUM FOR THE TREATMENT OR PROPHYLAXIS OF HEPATITE INFECTIONS IN HUMANS AND ANIMALS
JPH05310777A (en) 1992-05-14 1993-11-22 Yoshitomi Pharmaceut Ind Ltd 2'-deoxy-2'-methylidynecytidine compound
TW254946B (en) * 1992-12-18 1995-08-21 Hoffmann La Roche
TW374087B (en) * 1993-05-25 1999-11-11 Univ Yale L-2',3'-dideoxy nucleotide analogs as anti-hepatitis B(HBV) and anti-HIV agents
TW530047B (en) 1994-06-08 2003-05-01 Pfizer Corticotropin releasing factor antagonists
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
WO1998017281A1 (en) * 1996-10-24 1998-04-30 Vion Pharmaceuticals, Inc. MONOPHOSPHATE PRODRUGS OF β-L-FD4C AND β-L-FddC AS POTENT ANTIVIRAL AGENTS
AU1412299A (en) * 1997-11-25 1999-06-15 Protarga, Inc. Nucleoside analog compositions and uses thereof
IL138037A0 (en) * 1998-02-25 2001-10-31 Univ Emory 2'-fluoronucleosides
CN1646141B (en) * 2000-10-18 2014-06-25 吉利德制药有限责任公司 Modified nucleosides for treatment of viral infections and abnormal cellular proliferation
US7105527B2 (en) * 2001-12-14 2006-09-12 Otto Michael J N4-acylcytosine nucleosides for treatment of viral infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922867A (en) * 1995-12-14 1999-07-13 Biochem Pharma Inc. Method and compositions for the synthesis of dioxolane nucleosides with β configuration
US20030013660A1 (en) * 2000-10-13 2003-01-16 Shire Biochem Inc. Dioxolane analogs for improved inter-cellular delivery

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