Patent Grant
10363265
This invention is in the area of pharmaceutical chemistry, and is in particular, is a compound, method and composition for the treatment of hepatitis C virus.
The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85, (1999); Boyer, N. et al. J. Hepatol. 32:98-112, 2000). An estimated 170 million persons are infected with HCV worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplant.
HCV is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of “idiopathic” chronic hepatitis, “cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as Hepatitis B Virus (HBV). A small proportion of healthy persons appear to be chronic HCV carriers, varying with geography and other epidemiological factors. The numbers may substantially exceed those for HBV, though information is still preliminary; how many of these persons have subclinical chronic liver disease is unclear. (The Merck Manual, ch. 69, p. 901, 16th ed., (1992)).
HCV has been classified as a member of the virus family Flaviviridae that includes the genera flaviviruses, pestiviruses, and hapaceiviruses which includes hepatitis C viruses (Rice, C. M., Flaviviridae: The viruses and their replication. In: Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb. The viral genome consists of a 5′ untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3′ UTR. The 5′ UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a cap-independent mechanism known as internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). An RNA pseudoknot structure has recently been determined to be an essential structural element of the HCV IRES. Viral structural proteins include a nucleocapsid core protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine proteinase encoded in the NS3 region. These proteinases are required for cleavage of specific regions of the precursor polyprotein into mature peptides. The carboxyl half of nonstructural protein 5, NS5B, contains the RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins, NS4A and NS4B, and that of NS5A (the amino-terminal half of nonstructural protein 5) remain unknown.
A significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85, (1999)). Currently, there are two primary antiviral compounds, Ribavirin and interferon-alpha, which are used for the treatment of chronic HCV infections in humans.
Treatment of HCV Infection with Ribivarin
Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a synthetic, non-interferon-inducing, broad spectrum antiviral nucleoside analog sold under the trade name, Virazole (The Merck Index, 11th edition, Editor: Budavari, S., Merck & Co., Inc., Rahway, N.J., p 1304, 1989). U.S. Pat. No. 3,798,209 and RE29,835 disclose and claim Ribavirin. Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).
Ribavirin reduces serum amino transferase levels to normal in 40% or patients, but it does not lower serum levels of HCV-RNA (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Thus, Ribavirin alone is not effective in reducing viral RNA levels. Additionally, Ribavirin has significant toxicity and is known to induce anemia.
Treatment of HCV Infection with Interferon
Interferons (IFNs) are compounds that have been commercially available for the treatment of chronic hepatitis for nearly a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, including HCV, and when used as the sole treatment for hepatitis C infection, IFN suppresses serum HCV-RNA to undetectable levels. Additionally, IFN normalizes serum amino transferase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8%-9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).
A number of patents disclose HCV treatments using interferon-based therapies. For example, U.S. Pat. No. 5,980,884 to Blatt et al. discloses methods for retreatment of patients afflicted with HCV using consensus interferon. U.S. Pat. No. 5,942,223 to Bazer et al. discloses an anti-HCV therapy using ovine or bovine interferon-tau. U.S. Pat. No. 5,928,636 to Alber et al. discloses the combination therapy of interleukin-12 and interferon alpha for the treatment of infectious diseases including HCV. U.S. Pat. No. 5,908,621 to Glue et al. discloses the use of polyethylene glycol modified interferon for the treatment of HCV. U.S. Pat. No. 5,849,696 to Chretien et al. discloses the use of thymosins, alone or in combination with interferon, for treating HCV. U.S. Pat. No. 5,830,455 to Valtuena et al. discloses a combination HCV therapy employing interferon and a free radical scavenger. U.S. Pat. No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins for treating HCV. Other interferon-based treatments for HCV are disclosed in U.S. Pat. No. 5,676,942 to Testa et al., U.S. Pat. No. 5,372,808 to Blatt et al., and U.S. Pat. No. 5,849,696.
Combination of Interferon and Ribavirin
The combination of IFN and Ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of IFN naïve patients (Battaglia, A. M. et al., Ann. Pharmacother. 34:487-494, 2000). Results are promising for this combination treatment both before hepatitis develops or when histological disease is present (Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998). Side effects of combination therapy include hemolysis, flu-like symptoms, anemia, and fatigue. (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).
Additional References Disclosing Methods to Treat HCV Infections
A number of HCV treatments are reviewed by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000).
Several substrate-based NS3 protease inhibitors have been identified in the literature, in which the scissile amide bond of a cleaved substrate is replaced by an electrophile, which interacts with the catalytic serine. Attwood et al. (1998) Antiviral peptide derivatives, 98/22496; Attwood et al. (1999), Antiviral Chemistry and Chemotherapy 10.259-273; Attwood et al. (1999) Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. (1998) Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, WO 98/17679. The reported inhibitors terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al. (1999) Hepatitis C inhibitor peptide analogues, WO 99/07734. Two classes of electrophile-based inhibitors have been described, alphaketoamides and hydrazinoureas.
The literature has also described a number of non-substrate-based inhibitors. For example, evaluation of the inhibitory effects of 2,4,6-trihydroxy-3-nitro-benzamide derivatives against HCV protease and other serine proteases has been reported. Sudo, K. et al., (1997) Biochemical and Biophysical Research Communications, 238:643-647; Sudo, K. et al. (1998) Antiviral Chemistry and Chemotherapy 9:186. Using a reverse-phase HPLC assay, the two most potent compounds identified were RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group.
Thiazolidine derivatives have been identified as micromolar inhibitors, using a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate. Sudo, K. et al. (1996) Antiviral Research 32:9-18. Compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, was the most potent against the isolated enzyme. Two other active examples were RD4 6205 and RD4 6193.
Other literature reports screening of a relatively small library using an ELISA assay and the identification of three compounds as potent inhibitors, a thiazolidine and two benzanilides. Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al., Analytical Biochemistry 247:242-246, 1997. Several U.S. patents disclose protease inhibitors for the treatment of HCV. For example, U.S. Pat. No. 6,004,933 to Spruce et al. discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2. U.S. Pat. No. 5,990,276 to Zhang et al. discloses synthetic inhibitors of hepatitis C virus NS3 protease. The inhibitor is a subsequence of a substrate of the NS3 protease or a substrate of the NS4A cofactor. The use of restriction enzymes to treat HCV is disclosed in U.S. Pat. No. 5,538,865 to Reyes et al.
Isolated from the fermentation culture broth of Streptomyces sp., Sch 68631, a phenan-threnequinone, possessed micromolar activity against HCV protease in a SDS-PAGE and autoradiography assay. Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996. In another example by the same authors, Sch 351633, isolated from the fungus Penicillium griscofuluum, demonstrated micromolar activity in a scintillation proximity assay. Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952. Nanomolar potency against the HCV NS3 protease enzyme has been achieved by the design of selective inhibitors based on the macromolecule eglin c. Eglin c, isolated from leech, is a potent inhibitor of several serine proteases such as S. griseus proteases A and B, α-chymotrypsin, chymase and subtilisin. Qasim M. A. et al., Biochemistry 36:1598-1607, 1997.
HCV helicase inhibitors have also been reported. U.S. Pat. No. 5,633,358 to Diana G. D. et al.; PCT Publication No. WO 97/36554 of Diana G. D. et al. There are a few reports of HCV polymerase inhibitors: some nucleotide analogues, gliotoxin and the natural product cerulenin. Ferrari R. et al., Journal of Virology 73:1649-1654, 1999; Lohmann V. et al., Virology 249:108-118, 1998.
Antisense phosphorothioate oligodeoxynucleotides complementary to sequence stretches in the 5′ non-coding region of the HCV, are reported as efficient inhibitors of HCV gene expression in in vitro translation and IIcpG2 IICV-luciferase cell culture systems. Alt M. et al., Hepatology 22:707-717, 1995. Recent work has demonstrated that nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA are effective targets for antisense-mediated inhibition of viral translation. Alt M. et al., Archives of Virology 142:589-599, 1997. U.S. Pat. No. 6,001,990 to Wands et al. discloses oligonucleotides for inhibiting the replication of HCV. PCT Publication No. WO 99/29350 discloses compositions and methods of treatment for hepatitis C infection comprising the administration of antisense oligonucleotides that are complementary and hybridizable to HCV-RNA. U.S. Pat. No. 5,922,857 to Han et al. disclose nucleic acids corresponding to the sequence of the pestivirus homology box IV area for controlling the translation of HCV. Antisense oligonucleotides as therapeutic agents have been recently reviewed (Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999).
Other compounds have been reported as inhibitors of IRES-dependent translation in HCV. Japanese Patent Publication JP-08268890 of Ikeda N et al.; Japanese Patent Publication JP-10101591 of Kai, Y. et al. Nuclease-resistant ribozymes have been targeted at the IRES and recently reported as inhibitors in an HCV-poliovirus chimera plaque assay. Maccjak D. J. et al., Hepatology 30 abstract 995, 1999. The use of ribozymes to treat HCV is also disclosed in U.S. Pat. No. 6,043,077 to Barber et al., and U.S. Pat. Nos. 5,869,253 and 5,610,054 to Draper et al.
Other patents disclose the use of immune system potentiating compounds for the treatment of HCV. For example, U.S. Pat. No. 6,001,799 to Chretien et al. discloses a method of treating hepatitis C in non-responders to interferon treatment by administering an immune system potentiating dose of thymosin or a thymosin fragment. U.S. Pat. No. 5,972,347 to Eder et al. and U.S. Pat. No. 5,969,109 to Bona et al. disclose antibody-based treatments for treating HCV.
U.S. Pat. No. 6,034,134 to Gold et al. discloses certain NMDA receptor agonists having immunodulatory, antimalarial, anti-Boma virus and anti-Hepatitis C activities. The disclosed NMDA receptor agonists belong to a family of 1-amino-alkylcyclohexanes. U.S. Pat. No. 6,030,960 to Morris-Natschke et al. discloses the use of certain alkyl lipids to inhibit the production of hepatitis-induced antigens, including those produced by the HCV virus. U.S. Pat. No. 5,922,757 to Chojkier et al. discloses the use of vitamin E and other antioxidants to treat hepatic disorders including HCV. U.S. Pat. No. 5,858,389 to Elsherbi et al. discloses the use of squalene for treating hepatitis C. U.S. Pat. No. 5,849,800 to Smith et al discloses the use of amantadine for treatment of Hepatitis C. U.S. Pat. No. 5,846,964 to Ozeki et al. discloses the use of bile acids for treating HCV. U.S. Pat. No. 5,491,135 to Blough et al. discloses the use of N-(phosphonoacetyl)-L-aspartic acid to treat flaviviruses such as HCV.
Other compounds proposed for treating HCV include plant extracts (U.S. Pat. No. 5,837,257 to Tsai et al., U.S. Pat. No. 5,725,859 to Omer et al., and U.S. Pat. No. 6,056,961), piperidenes (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang et al.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.).
In light of the fact that the hepatitis C virus has reached epidemic levels worldwide, and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that has low toxicity to the host.
Therefore, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with hepatitis C virus.
Compounds, methods and compositions for the treatment of hepatitis C infection are described that include an effective hepatitis C treatment amount of a β-D- or β-L-nucleoside of the Formulas (I)-(XVIII), or a pharmaceutically acceptable salt or prodrug thereof.
In a first principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a second principal embodiment, a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a third principal embodiment, a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a fourth principal embodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a fifth principal embodiment, a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a sixth principal embodiment, a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a seventh principal embodiment, a compound selected from Formulas VII, VIII and IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2; and
X is O, S, SO2 or CH2.
In a eighth principal embodiment, a compound of Formulas X, XI and XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 is hydrogen, OR3, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2i and
X is O, S, SO2 or CH2.
In a ninth principal embodiment a compound selected from Formulas XIII, XIV and XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2; and
X is O, S, SO2 or CH2.
In a tenth principal embodiment the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, R7 and R10, R8 and R9, or R8 and R10 can come together to form a pi bond; and
X is O, S, SO2 or CH2.
In a eleventh principal embodiment the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R7 and R10 can come together to form a pi bond; and
X is O, S, SO2 or CH2.
In an twelfth principal embodiment, the invention provides a compound of Formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 and R2 independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(lower-alkyl)amino;
R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R8 and R9 can come together to form a pi bond;
X is O, S, SO2 or CH2.
The β-D- and β-L-nucleosides of this invention may inhibit HCV polymerase activity. Nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay.
In one embodiment the efficacy of the anti-HCV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound's EC50). In preferred embodiments the compound exhibits an EC50 of less than 25, 15, 10, 5, or 1 micromolar.
In another embodiment, the active compound can be administered in combination or alternation with another anti-HCV agent. In combination therapy, an effective dosage of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, 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 according to the 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 include:
(1) an interferon and/or ribavirin (Battaglia, A. M. et al., Ann. Pharmacother. 34:487-494, 2000); Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998);
(2) Substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.
(3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et al. Antiviral Chemistry and Chemotherapy 9:186, 1998), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group;
(4) Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research 32:9-18, 1996), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;
(5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997;
(6) A phenan-threnequinone possessing activity against HCV protease in a SDS-PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952);
(7) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M. A. et al., Biochemistry 36:1598-1607, 1997);
(8) HCV helicase inhibitors (Diana G. D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G. D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554);
(9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and the natural product cerulenin (Lohmann V. et al., Virology 249:108-118, 1998);
(10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5′ non-coding region (NCR) of the HCV (Alt M. et al., Hepatology 22:707-717, 1995), or nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of the IICV RNA (Alt M. et al., Archives of Virology 142:589-599, 1997; Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999);
(11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP-10101591);
(12) Nuclease-resistant ribozymes (Maccjak D. J. et al., Hepatology 30 abstract 995, 1999); and
(13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang et al.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.), and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.).
The invention as disclosed herein is a compound, method and composition for the treatment of hepatitis C in humans or other host animals, that includes administering an effective HCV treatment amount of a β-D- or β-L-nucleoside as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HCV) activity, or are metabolized to a compound that exhibits such activity.
In summary, the present invention includes the following features:
(a) β-D- and β-L-nucleosides, as described herein, and pharmaceutically acceptable salts and prodrugs thereof;
(b) β-D- and β-L-nucleosides as described herein, and pharmaceutically acceptable salts and prodrugs thereof for use in the treatment or prophylaxis of an HCV infection, especially in individuals diagnosed as having an HCV infection or being at risk for becoming infected by HCV;
(c) use of these β-D- and β-L-nucleosides, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for treatment of an HCV infection;
(d) pharmaceutical formulations comprising the β-D- or β-L-nucleosides or pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier or diluent;
(e) β-D- and β-L-nucleosides as described herein substantially in the absence of enantiomers of the described nucleoside, or substantially isolated from other chemical entities;
(f) processes for the preparation of β-D- and β-L-nucleosides, as described in more detail below; and
(g) processes for the preparation of β-D- and β-L-nucleosides substantially in the absence of enantiomers of the described nucleoside, or substantially isolated from other chemical entities.
I. Active Compound, and Physiologically Acceptable Salts and Prodrugs Thereof
In a first principal embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H;
X2 is H or NH2; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a second principal embodiment, a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula II, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H;
X2 is H or NH2; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a third principal embodiment, a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H;
X2 is H or NH2; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a fourth principal embodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H, phosphate (including mono-, di- or triphosphate and a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H or CH3; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a fifth principal embodiment, a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H or CH3; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a sixth principal embodiment, a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate; and
Y is hydrogen, bromo, chloro, fluoro, iodo, OR4, NR4R5 or SR4;
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4NR5 or SR5; and
R4 and R5 are independently hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl).
In a preferred subembodiment, a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
R1, R2 and R3 are independently H or phosphate (preferably H);
X1 is H or CH3; and
Y is hydrogen, bromo, chloro, fluoro, iodo, NH2 or OH.
In a seventh principal embodiment, a compound selected from Formulas VII, VIII and IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), CF3, chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2; and
X is O, S, SO2, or CH2.
In a first preferred subembodiment, a compound of Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently hydrogen or phosphate;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a second preferred subembodiment, a compound of Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are hydrogens;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula VII, VIII or IX, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently hydrogen or phosphate;
R6 is alkyl; and
X is O.
In a eighth principal embodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 is hydrogen, OR3, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(loweralkyl)2, —N(acyl)2; and
X is O, S, SO2 or CH2.
In a first preferred subembodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently hydrogen or phosphate;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a second preferred subembodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are hydrogens;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula X, XI or XII, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H or phosphate;
R6 is alkyl; and
X is O.
In even more preferred subembodiments, a compound of Formula XI, or its pharmaceutically acceptable salt or prodrug, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein; optionally substituted with an amine or cyclopropyl (e.g., 2-amino, 2,6-diamino or cyclopropyl guanosine); and
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate.
In a ninth principal embodiment a compound selected from Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1, R2 or R3 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2; and
X is O, S, SO2 or CH2.
In a first preferred subembodiment, a compound of Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently hydrogen or phosphate;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a second preferred subembodiment, a compound of Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are hydrogens;
R6 is alkyl; and
X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula XIII, XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, is provided wherein:
Base is a purine or pyrimidine base as defined herein;
R1, R2 and R3 are independently hydrogen or phosphate;
R6 is alkyl; and
X is O.
In a tenth principal embodiment the invention provides a compound of Formula XVI, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 and R2 are independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, R7 and R10, R8 and R9, or R8 and R10 can come together to form a pi bond; and
X is O, S, SO2 or CH2.
In a first preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO2 or CH2.
In a second preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R8 and R10 are H; and (6) X is O, S, SO2 or CH2.
In a fourth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O.
In a fifth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OW; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO2 or CH2.
In a sixth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 and R10 are H; and (6) X is O, S, SO2, or CH2.
In a seventh preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.
In a eighth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 and R10 are hydrogen; and (6) X is O, S, SO2 or CH2.
In a ninth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.
In a tenth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 and R10 are hydrogen; and (6) X is O.
In an eleventh preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 and R10 are hydrogen; and (6) X is O, S, SO2 or CH2.
In a twelfth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2; (5) R8 and R10 are hydrogen; and (6) X is O, S, SO2, or CH2.
In a thirteenth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2; (5) R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O.
In a fourteenth preferred subembodiment, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R8 and R10 are hydrogen; and (6) X is O.
In even more preferred subembodiments, a compound of Formula XVI, or its pharmaceutically acceptable salt or prodrug, is provided in which:
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is guanine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is cytosine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is thymine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is uracil; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is phosphate; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is ethyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is propyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is butyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 is hydrogen and R9 is hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is S;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is SO2;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 and R10 are hydrogen; and (6) X is CH2;
In a eleventh principal embodiment the invention provides a compound of Formula XVII, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 is H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R10 is H alkyl (including lower alkyl), chlorine, bromine, or iodine;
alternatively, R7 and R9, or R7 and R10 can come together to form a pi bond; and
X is O, S, SO2 or CH2.
In a first preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)-amino; (5) R10 is H; and (6) X is O, S, SO2, or CH2.
In a second preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R10 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)-amino; (5) R10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.
In a fourth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R10 is H; and (6) X is O, S, SO2 or CH2.
In a fifth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O.
In a sixth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R10 is H; and (6) X is O.
In a seventh preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R10 is H; and (6) X is O.
In an eighth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)-amino; (5) R10 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO2, or CH2.
In a ninth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R10 is H; and (6) X is O, S, SO2, or CH2.
In a tenth preferred subembodiment, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2; (5) R10 is H; and (6) X is O, S, SO2, or CH2.
In even more preferred subembodiments, a compound of Formula XVII, or its pharmaceutically acceptable salt or prodrug, is provided in which:
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is guanine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is cytosine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is thymine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is uracil; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is phosphate; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is ethyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is propyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is butyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is S;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is SO2; or
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R10 is hydrogen; and (6) X is CH2.
In an twelfth principal embodiment the invention provides a compound of Formula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base as defined herein;
R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate;
R6 is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino, or di(loweralkyl)amino;
R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R8 and R9 can come together to form a pi bond;
X is O, S, SO2 or CH2.
In a first preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino or di(loweralkyl)amino; (5) R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO2 or CH2.
In a second preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di-(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO2 or CH2.
In a third preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(lower-alkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 is H; and (6) X is O, S, SO2 or CH2.
In a fourth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O.
In a fifth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 is H; and (6) X is O, S, SO2, or CH2.
In a sixth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 is H, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6) X is O.
In a seventh preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (4) R7 and R9 are independently hydrogen, OR2, alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, loweralkylamino, or di(loweralkyl)amino; (5) R8 is H; and (6) X is O.
In an eighth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO2, amino, loweralkylamino or di(loweralkyl)amino; (4) R7 and R9 are independently OR2; (5) R8 is H; and (6) X is O, S, SO2 or CH2.
In a ninth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2; (5) R8 is H; and (6) X is O, S, SO2, or CH2.
In a tenth preferred subembodiment, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which: (1) Base is a purine or pyrimidine base as defined herein; (2) R1 is independently H or phosphate; (3) R6 is alkyl; (4) R7 and R9 are independently OR2; (5) R8 is H; and (6) X is O.
In even more preferred subembodiments, a compound of Formula XVIII, or its pharmaceutically acceptable salt or prodrug, is provided in which:
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is guanine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is cytosine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is thymine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is uracil; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is phosphate; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is ethyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is propyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is butyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is O;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is S;
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is SO2; or
(1) Base is adenine; (2) R1 is hydrogen; (3) R6 is methyl; (4) R7 and R9 are hydroxyl; (5) R8 is hydrogen; and (6) X is CH2.
The β-D- and β-L-nucleosides of this invention may inhibit HCV polymerase activity. Nucleosides can be screened for their ability to inhibit HCV polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay.
In one embodiment the efficacy of the anti-HCV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound's EC50). In preferred embodiments the compound exhibits an EC50 of less than 15 or 10 micromolar, when measured according to the polymerase assay described in Ferrari et al., Jnl. of Vir., 73:1649-1654, 1999; Ishii et al., Hepatology, 29:1227-1235, 1999; Lohmann et al., Jnl. of Bio. Chem., 274:10807-10815, 1999; or Yamashita et al, Jnl. of Bio. Chem., 273:15479-15486, 1998.
The active compound can be administered as any salt or prodrug that upon administration to the recipient is capable of providing directly or indirectly the parent compound, or that exhibits activity itself. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as “physiologically acceptable salts”), and a compound that has been alkylated or acylated at the 5′-position or on the purine or pyrimidine base (a type of “pharmaceutically acceptable prodrug”). Further, the modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the salt or prodrug and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art.
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically C1 to C10, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. Moieties with which the alkyl group can be substituted are selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
The term lower alkyl, as used herein, and unless otherwise specified, refers to a C1 to C4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.
The term alkylamino or arylamino refers to 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 an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties. The aryl group can be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
The term alkaryl or alkylaryl refers to an alkyl group with an aryl substituent. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.
The term halo, as used herein, includes chloro, bromo, iodo, and fluoro.
The term purine or pyrimidine base includes, but is not limited to, adenine, N6-alkylpurines, N6-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurines, N2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
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 methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C1 to C4 alkyl or C1 to C4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including 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 a lower alkyl.
As used herein, the term “substantially free of” or “substantially in the absence of” 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 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 “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.
The term host, as used herein, refers to an unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the hepatitis C 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 HCV genome and animals, in particular, primates (including 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 HCV, or are metabolized to a compound that exhibits such activity.
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or 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, 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 (for example, sodium, potassium or lithium) or alkaline earth metal (for example 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 sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and 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 herein: Kucera, L. S., N. Iyer, E. Leake, A. Raben, Modest E. K., D. L. W., and C. Piantadosi. 1990. “Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.” AIDS Res. Hum. Retro Viruses. 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, C. A. Wallen, S. Piantadosi, and E. J. Modest. 1991. “Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity.” J. Med. Chem. 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. 1992. “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. 36:2025.2029; Hosetler, K. Y., L. M. Stuhmiller, H. B. Lenting, H. van den Bosch, and D. D. Richman, 1990. “Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides.” J. Biol. Chem. 265:61127.
Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5′-OH position of the nucleoside or lipophilic preparations, include U.S. Pat. No. 5,149,794 (Sep. 22, 1992, Yatvin et al.); U.S. Pat. No. 5,194,654 (Mar. 16, 1993, Hostetler et al., U.S. Pat. No. 5,223,263 (Jun. 29, 1993, Hostetler et al.); U.S. Pat. No. 5,256,641 (Oct. 26, 1993, Yatvin et al.); U.S. Pat. No. 5,411,947 (May 2, 1995, Hostetler et al.); U.S. Pat. No. 5,463,092 (Oct. 31, 1995, Hostetler et al.); U.S. Pat. No. 5,543,389 (Aug. 6, 1996, Yatvin et al.); U.S. Pat. No. 5,543,390 (Aug. 6, 1996, Yatvin et al.); U.S. Pat. No. 5,543,391 (Aug. 6, 1996, Yatvin et al.); and U.S. Pat. No. 5,554,728 (Sep. 10, 1996; Basava et al.), all of which are incorporated herein by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to the 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 0 350 287, EP 93917054.4, and WO 91/19721.
It has been recognized that drug-resistant variants of HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against HCV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include:
(1) an interferon and/or ribavirin (Battaglia, A. M. et al., Ann. Pharmacother. 34:487-494, 2000); Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998);
(2) Substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate. Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.
(3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647, 1997; Sudo K. et al. Antiviral Chemistry and Chemotherapy 9:186, 1998), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group;
(4) Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research 32:9-18, 1996), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;
(5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry 247:242-246, 1997;
(6) A phenan-threnequinone possessing activity against HCV protease in a SDS-PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952);
(7) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M. A. et al., Biochemistry 36:1598-1607, 1997);
(8) HCV helicase inhibitors (Diana G. D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G. D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554);
(9) HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and the natural product cerulenin (Lohmann V. et al., Virology 249:108-118, 1998);
(10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5′ non-coding region (NCR) of the HCV (Alt M. et al., Hepatology 22:707-717, 1995), or nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of the IICV RNA (Alt M. et al., Archives of Virology 142:589-599, 1997; Galderisi U. et al., Journal of Cellular Physiology 181:251-257, 1999);
(11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP-10101591);
(12) Nuclease-resistant ribozymes. (Maccjak D. J. et al., Hepatology 30 abstract 995, 1999); and
(13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang et al.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.), and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.).
Hosts, including humans, infected with HCV, 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 HCV 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 one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. A 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 absorption, 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 purpose of oral therapeutic administration, the active compound can be incorporated 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 corn 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, dosage unit forms can contain various other materials which 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 compounds, 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-inflammatories, or other antivirals, including 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 implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation.
Liposomal suspensions (including 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 U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). 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.
The nucleosides of the present invention can be synthesized by any means known in the art. In particular, the synthesis of the present nucleosides can be achieved by either alkylating the appropriately modified sugar, followed by glycosylation or glycosylation followed by alkylation of the nucleoside. The following non-limiting embodiments illustrate some general methodology to obtain the nucleosides of the present invention.
A. General Synthesis of 1′-C-Branched Nucleosides
1′-C-Branched ribonucleosides of the following structure:
wherein BASE is a purine or pyrimidine base as defined herein;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R8 and R10 are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, R7 and R10, R8 and R9, or R8 and R10 can come together to form a pi bond;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is an alkyl, chloro-, bromo-, fluoro-, or iodo-alkyl (i.e. CF3), alkenyl, or alkynyl (i.e. allyl); and
X is O, S, SO2 or CH2
can be prepared by one of the following general methods.
1) Modification from the Lactone
The key starting material for this process is an appropriately substituted lactone. The lactone can be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques. The lactone can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The protected lactone can then be coupled with a suitable coupling agent, such as an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R6—SiMe3 in TBAF with the appropriate non-protic solvent at a suitable temperature, to give the 1′-alkylated sugar.
The optionally activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature.
Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
In a particular embodiment, the 1′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
2. Alternative Method for the Preparation of 1′-C-Branched Nucleosides
The key starting material for this process is an appropriately substituted hexose. The hexose can be purchased or can be prepared by any known means including standard epimerization, such as alkaline treatment, substitution and coupling techniques. The hexose can be selectively protected to give the appropriate hexa-furanose, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.
The 1′-hydroxyl can be optionally activated to a suitable leaving group such as an acyl group or a chloro, bromo, fluoro, iodo via acylation or halogenation, respectively. The optionally activated sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.
The 1′-CH2—OH, if protected, can be selectively deprotected by methods well known in the art. The resultant primary hydroxyl can be functionalized to yield various C-branched nucleosides. For example, the primary hydroxyl can be reduced to give the methyl, using a suitable reducing agent. Alternatively, the hydroxyl can be activated prior to reduction to facilitate the reaction; i.e. via the Barton reduction. In an alternate embodiment, the primary hydroxyl can be oxidized to the aldehyde, then coupled with a carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R6—SiMe3 in TBAF with the appropriate non-protic solvent at a suitable temperature.
In a particular embodiment, the 1′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
In addition, the L-enantiomers corresponding to the compounds of the invention can be prepared following the same general methods (1 or 2), beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material.
B. General Synthesis of 2′-C-Branched Nucleosides
2′-C-Branched ribonucleosides of the following structure:
wherein BASE is a purine or pyrimidine base as defined herein;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R10 is H, H alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R7 and R10 can come together to form a pi bond;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is an alkyl, chloro-, bromo-, fluoro-, iodo-alkyl (i.e. CF3), alkenyl, or alkynyl (i.e. allyl); and
X is O, S, SO2 or CH2
can be prepared by one of the following general methods.
1. Glycosylation of the Nucleobase with an Appropriately Modified Sugar
The key starting material for this process is an appropriately substituted sugar with a 2′-OH and 2′-H, with the appropriate leaving group (LG), for example an acyl group or a chloro, bromo, fluoro or iodo. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2′-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H2O2-ammonium molybdate, NaBrO2—CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.
Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R6—SiMe3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 2′-alkylated sugar. The alkylated sugar can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
The optionally protected sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.
Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
In a particular embodiment, the 2′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
2. Modification of a Pre-Formed Nucleoside
The key starting material for this process is an appropriately substituted nucleoside with a 2′-OH and 2′-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can be optionally protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2′-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H2O2-ammonium molybdate, NaBrO2—CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.
Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by GreeneGreene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
In a particular embodiment, the 2′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 4. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
In another embodiment of the invention, the L-enantiomers are desired. Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material.
C. General Synthesis of 3′-C-Branched Nucleosides
3′-C-Branched ribonucleosides of the following structure:
wherein BASE is a purine or pyrimidine base as defined herein;
R7 and R9 are independently hydrogen, OR2, hydroxy, alkyl (including lower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO2, NH2, —NH(lower alkyl), —NH(acyl), —N(lower alkyl)2, —N(acyl)2;
R8 is H, alkyl (including lower alkyl), chlorine, bromine or iodine;
alternatively, R7 and R9, or R8 and R9 can come together to form a pi bond;
R1 and R2 are independently H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given herein; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R1 or R2 is independently H or phosphate;
R6 is an alkyl, chloro-, fluoro-, bromo-, iodo-alkyl (i.e. CF3), alkenyl, or alkynyl (i.e. allyl); and
X is O, S, SO2 or CH2
can be prepared by one of the following general methods.
1. Glycosylation of the Nucleobase with an Appropriately Modified Sugar
The key starting material for this process is an appropriately substituted sugar with a 3′-OH and 3′-H, with the appropriate leaving group (LG), for example an acyl group or a chloro, bromo, fluoro, iodo. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 3′-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H2O2-ammonium molybdate, NaBrO2—CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.
Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R6—SiMe3 in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 3′-C-branched sugar. The 3′-C-branched sugar can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
The optionally protected sugar can then be coupled to the BASE by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a lewis acid, such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.
Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
In a particular embodiment, the 3′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 5. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
2. Modification of a Pre-Formed Nucleoside
The key starting material for this process is an appropriately substituted nucleoside with a 3′-OH and 3′-H. The nucleoside can be purchased or can be prepared by any known means including standard coupling techniques. The nucleoside can be optionally protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
The appropriately protected nucleoside can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2′-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H2O2-ammonium molybdate, NaBrO2—CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.
Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by GreeneGreene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
In a particular embodiment, the 3′-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 6. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2′-OH can be reduced with a suitable reducing agent. Optionally, the 2′-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction.
In another embodiment of the invention, the L-enantiomers are desired. Therefore, the L-enantiomers can be corresponding to the compounds of the invention can be prepared following the same foregoing general methods, beginning with the corresponding L-sugar or nucleoside L-enantiomer as starting material.
As another alternative method of preparation, the title compound could also be prepared according to a published procedure (J. Farkas, and F. Sorm, “Nucleic acid components and their analogues. XCIV. Synthesis of 6-amino-9-(1-deoxy-β-D-psicofuranosyl)purine”, Collect. Czech. Chem. Commun. 1967, 32, 2663-2667. J. Farkas”, Collect. Czech. Chem. Commun. 1966, 31, 1535) (Scheme 7).
In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula I are prepared.
Alternatively, the following nucleosides of Formula IV are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula VII are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula VIII are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula IX are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XVI are prepared, using the appropriate sugar and pyrimidine or purine bases.
The title compound was prepared according to a published procedure (R. E. Harry-O'kuru, J. M. Smith, and M. S. Wolfe, “A short, flexible route toward 2′-C-branched ribonucleosides”, J. Org. Chem. 1997, 62, 1754-1759) (Scheme 8).
In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula II are prepared.
Alternatively, the following nucleosides of Formula V are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula X are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XI are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XII are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XVII are prepared, using the appropriate sugar and pyrimidine or purine bases.
The title compound can be prepared according to a published procedure (R. F. Nutt, M. J. Dickinson, F. W. Holly, and E. Walton, “Branched-chain sugar nucleosides. III. 3′-C-methyladenine”, J. Org. Chem. 1968, 33, 1789-1795) (Scheme 9).
In a similar manner, but using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of Formula III are prepared.
Alternatively, the following nucleosides of Formula VI are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XIII are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XIV are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XV are prepared, using the appropriate sugar and pyrimidine or purine bases.
Alternatively, the following nucleosides of Formula XVIII are prepared, using the appropriate sugar and pyrimidine or purine bases.
Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes needed in the replication cycle, or by other pathways. A number of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture is disclosed in U.S. Pat. No. 5,738,985 to Miles et al. In vitro assays have been reported in Ferrari et al., Jnl. of Vir., 73:1649-1654, 1999; Ishii et al., Hepatology, 29:1227-1235, 1999; Lohmann et al., Jnl. of Bio. Chem., 274:10807-10815, 1999; and Yamashita et al, Jnl. of Bio. Chem., 273:15479-15486, 1998.
WO 97/12033, filed on Sep. 27, 1996, by Emory University, listing C. Hagedorn and A. Reinoldus as inventors, and which claims priority to U.S. Ser. No. 60/004,383, filed on September 1995, describes an HCV polymerase assay that can be used to evaluate the activity of the compounds described herein. Another HCV polymerase assay has been reported by Bartholomeusz, et al., Hepatitis C virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996:1(Supp 4) 18-24.
Screens that measure reductions in kinase activity from HCV drugs are disclosed in U.S. Pat. No. 6,030,785, to Katze et al., U.S. Pat. No. 6,010,848 to Delvecchio et al, and U.S. Pat. No. 5,759,795 to Jubin et al. Screens that measure the protease inhibiting activity of proposed HCV drugs are disclosed in U.S. Pat. No. 5,861,267 to Su et al, U.S. Pat. No. 5,739,002 to De Francesco et al, and U.S. Pat. No. 5,597,691 to Houghton et al.
To determine the cellular metabolism of the compounds, HepG2 cells were obtained from the American Type Culture Collection (Rockville, Md.), and were grown in 225 cm2 tissue culture flasks in minimal essential medium supplemented with non-essential amino acids, 1% penicillin-streptomycin. The medium was renewed every three days, and the cells were subcultured once a week. After detachment of the adherent monolayer with a 10 minute exposure to 30 mL of trypsin-EDTA and three consecutive washes with medium, confluent HepG2 cells were seeded at a density of 2.5×106 cells per well in a 6-well plate and exposed to 10 μM of [3H] labeled active compound (500 dpm/μmol) for the specified time periods. The cells were maintained at 37° C. under a 5% CO2 atmosphere. At the selected time points, the cells were washed three times with ice-cold phosphate-buffered saline (PBS). Intracellular active compound and its respective metabolites were extracted by incubating the cell pellet overnight at −20° C. with 60% methanol followed by extraction with an additional 20 μL of cold methanol for one hour in an ice bath. The extracts were then combined, dried under gentle filtered air flow and stored at −20° C. until HPLC analysis. The preliminary results of the HPLC analysis are tabulated in Table 1.
Within 1 week prior to the study initiation, the cynomolgus monkey was surgically implanted with a chronic venous catheter and subcutaneous venous access port (VAP) to facilitate blood collection and underwent a physical examination including hematology and serum chemistry evaluations and the body weight was recorded. Each monkey (six total), received approximately 250 uCi of 3H activity with each dose of active compound, namely β-D-2′-CH3-riboG at a dose level of 10 mg/kg at a dose concentration of 5 mg/mL, either via an intravenous bolus (3 monkeys, IV), or via oral gavage (3 monkeys, PO). Each dosing syringe was weighed before dosing to gravimetrically determine the quantity of formulation administered. Urine samples were collected via pan catch at the designated intervals (approximately 18-0 hours pre-dose, 0-4, 4-8 and 8-12 hours post-dosage) and processed. Blood samples were collected as well (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours post-dosage) via the chronic venous catheter and VAP or from a peripheral vessel if the chronic venous catheter procedure should not be possible. The blood and urine samples were analyzed for the maximum concentration (Cmax), time when the maximum concentration was achieved (Tmax), area under the curve (AUC), half life of the dosage concentration (T1/2), clearance (CL), steady state volume and distribution (Vss) and bioavailability (F), which are tabulated in Tables 2 and 3, and graphically illustrated in
Human bone marrow cells were collected from normal healthy volunteers and the mononuclear population was separated by Ficoll-Hypaque gradient centrifugation as described previously by Sommadossi J-P, Carlisle R. “Toxicity of 3′-azido-3′-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro” Antimicrobial Agents and Chemotherapy 1987; 31:452-454; and Sommadossi J-P, Schinazi R F, Chu C K, Xie M-Y. “Comparison of cytotoxicity of the (−)- and (+)-enantiomer of 2′,3′-dideoxy-3′-thiacytidine in normal human bone marrow progenitor cells” Biochemical Pharmacology 1992; 44:1921-1925. The culture assays for CFU-GM and BFU-E were performed using a bilayer soft agar or methylcellulose method. Drugs were diluted in tissue culture medium and filtered. After 14 to 18 days at 37° C. in a humidified atmosphere of 5% CO2 in air, colonies of greater than 50 cells were counted using an inverted microscope. The results in Table 4 are presented as the percent inhibition of colony formation in the presence of drug compared to solvent control cultures.
HepG2 cells were cultured in 12-well plates as described above and exposed to various concentrations of drugs as taught by Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer V M. “Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells” Antimicrob Agents Chemother 2000; 44:496-503. Lactic acid levels in the culture medium after 4 day drug exposure was measured using a Boehringer lactic acid assay kit. Lactic acid levels were normalized by cell number as measured by hemocytometer count. The preliminary results from this assay are tabulated in Table 5.
This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention, will be obvious to those skilled in the art from the foregoing detailed description of the invention.
This application is a continuation of U.S. application Ser. No. 13/623,674, filed on Sep. 20, 2012, which is a continuation of U.S. application Ser. No. 12/504,601, filed on Jul. 16, 2009, which is a continuation of U.S. application Ser. No. 10/602,691, filed on Jun. 20, 2003, which is a continuation of U.S. application Ser. No. 09/864,078, filed on May 23, 2001, which claims the benefit of priority to U.S. Provisional Application No. 60/206,585, filed on May 23, 2000, the disclosure of each of which is incorporated herein by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3074929 | Hitchings et al. | Jan 1963 | A |
| 3116282 | Hunter | Dec 1963 | A |
| 3480613 | Walton et al. | Nov 1969 | A |
| 3798209 | Wilkowski et al. | Mar 1974 | A |
| 3891623 | Vorbruggen et al. | Jun 1975 | A |
| 4022889 | Bannister et al. | May 1977 | A |
| 4058602 | Beisler et al. | Nov 1977 | A |
| RE29835 | Witkowski et al. | Nov 1978 | E |
| 4209613 | Vorbruggen | Jun 1980 | A |
| 4239753 | Skulnick et al. | Dec 1980 | A |
| 4294766 | Schmidt et al. | Oct 1981 | A |
| 4522811 | Eppstein et al. | Jun 1985 | A |
| 4605659 | Verheyden et al. | Aug 1986 | A |
| 4689404 | Kawada et al. | Aug 1987 | A |
| 4754026 | Kawada et al. | Jun 1988 | A |
| 4814477 | Wijnberg et al. | Mar 1989 | A |
| 4880784 | Robins et al. | Nov 1989 | A |
| 4952740 | Juge et al. | Aug 1990 | A |
| 4957924 | Beauchamp | Sep 1990 | A |
| 5034394 | Daluge | Jul 1991 | A |
| 5118672 | Schinazi et al. | Jun 1992 | A |
| 5122517 | Vince et al. | Jun 1992 | A |
| 5149794 | Yatvin et al. | Sep 1992 | A |
| 5157027 | Biller et al. | Oct 1992 | A |
| 5194654 | Hostetler et al. | Mar 1993 | A |
| 5200514 | Chu | Apr 1993 | A |
| 5223263 | Hostetler et al. | Jun 1993 | A |
| 5246924 | Fox et al. | Sep 1993 | A |
| 5256641 | Yatvin et al. | Oct 1993 | A |
| 5256797 | Chou et al. | Oct 1993 | A |
| 5322955 | Matsumoto et al. | Jun 1994 | A |
| 5371210 | Chou et al. | Dec 1994 | A |
| 5372808 | Blatt et al. | Dec 1994 | A |
| 5391769 | Matsumoto et al. | Feb 1995 | A |
| 5401861 | Chou et al. | Mar 1995 | A |
| 5411947 | Hostetler et al. | May 1995 | A |
| 5455339 | Chu et al. | Oct 1995 | A |
| 5463092 | Hostetler et al. | Oct 1995 | A |
| 5539116 | Liotta et al. | Jul 1996 | A |
| 5543389 | Yatvin et al. | Aug 1996 | A |
| 5543390 | Yatvin et al. | Aug 1996 | A |
| 5543391 | Yatvin et al. | Aug 1996 | A |
| 5554728 | Basava et al. | Sep 1996 | A |
| 5565438 | Chu et al. | Oct 1996 | A |
| 5567688 | Chu et al. | Oct 1996 | A |
| 5587362 | Chu et al. | Dec 1996 | A |
| 5606048 | Chou et al. | Feb 1997 | A |
| 5676942 | Testa et al. | Oct 1997 | A |
| 5696277 | Hostetler et al. | Dec 1997 | A |
| 5738845 | Imakawa | Apr 1998 | A |
| 5744600 | Mansuri et al. | Apr 1998 | A |
| 5750676 | Vorbruggen et al. | May 1998 | A |
| 5763418 | Matsuda et al. | Jun 1998 | A |
| 5780617 | Van den Bosch et al. | Jul 1998 | A |
| 5789608 | Glazier | Aug 1998 | A |
| 5821357 | Chou et al. | Oct 1998 | A |
| 5830455 | Valtuena et al. | Nov 1998 | A |
| 5849696 | Chretien et al. | Dec 1998 | A |
| 5908621 | Glue et al. | Jun 1999 | A |
| 5928636 | Alber et al. | Jul 1999 | A |
| 5942223 | Bazer et al. | Aug 1999 | A |
| 5977061 | De Clerq | Nov 1999 | A |
| 5977325 | McCarthy et al. | Nov 1999 | A |
| 5980884 | Blatt et al. | Nov 1999 | A |
| 6002029 | Hostetler et al. | Dec 1999 | A |
| 6063628 | Loeb et al. | May 2000 | A |
| 6071922 | Schinazi et al. | Jun 2000 | A |
| 6140310 | Glazier | Oct 2000 | A |
| 6153594 | Borretzen et al. | Nov 2000 | A |
| 6156501 | McGall et al. | Dec 2000 | A |
| 6172046 | Albrecht | Jan 2001 | B1 |
| 6174868 | Anderson et al. | Jan 2001 | B1 |
| 6248878 | Matulic-Adamic et al. | Jun 2001 | B1 |
| 6252060 | Hostetler | Jun 2001 | B1 |
| 6271212 | Chu et al. | Aug 2001 | B1 |
| 6277830 | Ganguly et al. | Aug 2001 | B1 |
| 6284458 | Anderson et al. | Sep 2001 | B1 |
| 6312662 | Erion et al. | Nov 2001 | B1 |
| 6340690 | Bachand et al. | Jan 2002 | B1 |
| 6348587 | Schinazi et al. | Feb 2002 | B1 |
| 6369040 | Acevedo et al. | Apr 2002 | B1 |
| 6391542 | Anderson et al. | May 2002 | B1 |
| 6395716 | Gosselin et al. | May 2002 | B1 |
| 6423489 | Anderson et al. | Jul 2002 | B1 |
| 6433159 | Anderson | Aug 2002 | B1 |
| 6436437 | Yatvin et al. | Aug 2002 | B1 |
| 6444652 | Gosselin et al. | Sep 2002 | B1 |
| 6448392 | Hostetler et al. | Sep 2002 | B1 |
| 6455508 | Ramasamy et al. | Sep 2002 | B1 |
| 6455513 | McGuigan et al. | Sep 2002 | B1 |
| 6458772 | Zhou et al. | Oct 2002 | B1 |
| 6458773 | Gosselin et al. | Oct 2002 | B1 |
| 6472373 | Albrecht | Oct 2002 | B1 |
| 6495677 | Ramasamy et al. | Dec 2002 | B1 |
| 6566344 | Gosselin et al. | May 2003 | B1 |
| 6566365 | Storer | May 2003 | B1 |
| 6569837 | Gosselin et al. | May 2003 | B1 |
| 6573248 | Ramasamy et al. | Jun 2003 | B2 |
| 6596700 | Sommadossi et al. | Jul 2003 | B2 |
| 6599887 | Hostetler et al. | Jul 2003 | B2 |
| 6605614 | Bachand et al. | Aug 2003 | B2 |
| 6642206 | Ramasamy et al. | Nov 2003 | B2 |
| 6660721 | Devos et al. | Dec 2003 | B2 |
| 6752981 | Erion et al. | Jun 2004 | B1 |
| 6777395 | Bhat et al. | Aug 2004 | B2 |
| 6784161 | Ismaili et al. | Aug 2004 | B2 |
| 6784166 | Devos et al. | Aug 2004 | B2 |
| 6787526 | Bryant et al. | Sep 2004 | B1 |
| 6812219 | LaColla | Nov 2004 | B2 |
| 6815542 | Hong et al. | Nov 2004 | B2 |
| 6831069 | Tam et al. | Dec 2004 | B2 |
| 6833361 | Hong et al. | Dec 2004 | B2 |
| 6846810 | Martin et al. | Jan 2005 | B2 |
| 6875751 | Imbach et al. | Apr 2005 | B2 |
| 6908924 | Watanabe et al. | Jun 2005 | B2 |
| 6911424 | Schinazi et al. | Jun 2005 | B2 |
| 6914054 | Sommadossi | Jul 2005 | B2 |
| 6927291 | Jin et al. | Aug 2005 | B2 |
| 6946115 | Erion et al. | Sep 2005 | B2 |
| 6946450 | Gosselin et al. | Sep 2005 | B2 |
| 6949522 | Otto et al. | Sep 2005 | B2 |
| 6965033 | Jiang et al. | Nov 2005 | B2 |
| 7018989 | McGuigan et al. | Mar 2006 | B2 |
| 7019135 | McGuigan et al. | Mar 2006 | B2 |
| 7056895 | Ramasamy et al. | Jun 2006 | B2 |
| 7094770 | Watanabe et al. | Aug 2006 | B2 |
| 7101861 | Sommadossi et al. | Sep 2006 | B2 |
| 7105493 | Sommadossi | Sep 2006 | B2 |
| 7105499 | Carroll et al. | Sep 2006 | B2 |
| 7125855 | Bhat et al. | Oct 2006 | B2 |
| 7138376 | Gosselin et al. | Nov 2006 | B2 |
| 7144868 | Roberts et al. | Dec 2006 | B2 |
| 7148206 | Sommadossi et al. | Dec 2006 | B2 |
| 7151089 | Roberts et al. | Dec 2006 | B2 |
| 7157434 | Keicher et al. | Jan 2007 | B2 |
| 7157441 | Sommadossi et al. | Jan 2007 | B2 |
| 7163929 | Sommadossi et al. | Jan 2007 | B2 |
| 7169766 | Sommadossi et al. | Jan 2007 | B2 |
| 7192936 | LaColla et al. | Mar 2007 | B2 |
| 7202224 | Eldrup et al. | Apr 2007 | B2 |
| 7285658 | Cook et al. | Oct 2007 | B2 |
| 7307065 | Schinazi et al. | Dec 2007 | B2 |
| 7323449 | Olsen et al. | Jan 2008 | B2 |
| 7323453 | Olsen et al. | Jan 2008 | B2 |
| 7339054 | Xu et al. | Mar 2008 | B2 |
| 7365057 | LaColla et al. | Apr 2008 | B2 |
| 7384924 | LaColla et al. | Jun 2008 | B2 |
| 7429572 | Clark | Sep 2008 | B2 |
| 7452901 | Boojamra et al. | Nov 2008 | B2 |
| 7456155 | Sommadossi et al. | Nov 2008 | B2 |
| 7534767 | Butora et al. | May 2009 | B2 |
| 7547704 | LaColla et al. | Jun 2009 | B2 |
| 7582618 | Sommadossi et al. | Sep 2009 | B2 |
| 7598230 | Cook et al. | Oct 2009 | B2 |
| 7598373 | Storer et al. | Oct 2009 | B2 |
| 7601820 | Wang et al. | Oct 2009 | B2 |
| 7608597 | Sommadossi | Oct 2009 | B2 |
| 7608600 | Storer et al. | Oct 2009 | B2 |
| 7625875 | Gosselin et al. | Dec 2009 | B2 |
| 7632821 | Butora et al. | Dec 2009 | B2 |
| 7635689 | LaColla et al. | Dec 2009 | B2 |
| 7645747 | Boojamra et al. | Jan 2010 | B2 |
| 7662798 | LaColla et al. | Feb 2010 | B2 |
| 7754699 | Chun et al. | Jul 2010 | B2 |
| 7772208 | Schinazi et al. | Aug 2010 | B2 |
| 7781576 | Mayes et al. | Aug 2010 | B2 |
| 7807653 | Cook et al. | Oct 2010 | B2 |
| 7820631 | McGuigan et al. | Oct 2010 | B2 |
| 7824851 | Sommadossi | Nov 2010 | B2 |
| 7842672 | Boojamra et al. | Nov 2010 | B2 |
| 7871991 | Boojamra et al. | Jan 2011 | B2 |
| 7879815 | MacCoss et al. | Feb 2011 | B2 |
| 7902202 | Sommadossi et al. | Mar 2011 | B2 |
| 7951787 | McGuigan | May 2011 | B2 |
| 7951789 | Sommadossi et al. | May 2011 | B2 |
| 7964580 | Sofia et al. | Jun 2011 | B2 |
| 7973013 | Cho et al. | Jul 2011 | B2 |
| 8008264 | Butler et al. | Aug 2011 | B2 |
| 8012941 | Cho et al. | Sep 2011 | B2 |
| 8012942 | Butler et al. | Sep 2011 | B2 |
| 8022083 | Boojamra et al. | Sep 2011 | B2 |
| 8119779 | McGuigan et al. | Feb 2012 | B2 |
| 8148349 | Meppen et al. | Apr 2012 | B2 |
| 8173621 | Du et al. | May 2012 | B2 |
| 8183216 | DiFrancesco et al. | May 2012 | B2 |
| 8299038 | Sommadossi | Oct 2012 | B2 |
| 8318682 | Butler et al. | Nov 2012 | B2 |
| 8318701 | Boojamra et al. | Nov 2012 | B2 |
| 8324179 | Chen et al. | Dec 2012 | B2 |
| 8329926 | Boojamra et al. | Dec 2012 | B2 |
| 8334270 | Sofia et al. | Dec 2012 | B2 |
| 8343937 | Sommadossi | Jan 2013 | B2 |
| 8415308 | Cho et al. | Apr 2013 | B2 |
| 8415322 | Clark | Apr 2013 | B2 |
| 8455451 | Cho et al. | Jun 2013 | B2 |
| 8481713 | Wang et al. | Jul 2013 | B2 |
| 8507460 | Surleraux et al. | Aug 2013 | B2 |
| 8551973 | Bao et al. | Oct 2013 | B2 |
| 8563530 | Chang et al. | Oct 2013 | B2 |
| 8569478 | Du et al. | Oct 2013 | B2 |
| 8575119 | Wang et al. | Nov 2013 | B2 |
| 8580765 | Sofia et al. | Nov 2013 | B2 |
| 8609627 | Cho et al. | Dec 2013 | B2 |
| 8618076 | Ross et al. | Dec 2013 | B2 |
| 8637475 | Storer et al. | Jan 2014 | B1 |
| 8642756 | Ross et al. | Feb 2014 | B2 |
| 8658616 | McGuigan et al. | Feb 2014 | B2 |
| 8680071 | Surleraux et al. | Mar 2014 | B2 |
| 8691788 | Sommadossi et al. | Apr 2014 | B2 |
| 8716262 | Sofia et al. | May 2014 | B2 |
| 8716263 | Chun et al. | May 2014 | B2 |
| 8735372 | Du et al. | May 2014 | B2 |
| 8759510 | Du et al. | Jun 2014 | B2 |
| 8765710 | Sofia et al. | Jul 2014 | B2 |
| 8765935 | Wagner | Jul 2014 | B2 |
| 8816074 | Chu et al. | Aug 2014 | B2 |
| 8841275 | Du et al. | Sep 2014 | B2 |
| 8859756 | Ross et al. | Oct 2014 | B2 |
| 8877733 | Cho et al. | Nov 2014 | B2 |
| 8889159 | Cleary et al. | Nov 2014 | B2 |
| 8906880 | Du et al. | Dec 2014 | B2 |
| 8946244 | Chu et al. | Feb 2015 | B2 |
| 20020019363 | Ismaili et al. | Feb 2002 | A1 |
| 20020035085 | Somadossi et al. | Mar 2002 | A1 |
| 20020052345 | Erion et al. | May 2002 | A1 |
| 20020055473 | Ganguly et al. | May 2002 | A1 |
| 20020055483 | Watanabe et al. | May 2002 | A1 |
| 20020095033 | Ramasamy et al. | Jul 2002 | A1 |
| 20020099072 | Bachand et al. | Jul 2002 | A1 |
| 20020120129 | Beigelman et al. | Aug 2002 | A1 |
| 20020127203 | Albrecht | Sep 2002 | A1 |
| 20020147160 | Bhat et al. | Oct 2002 | A1 |
| 20020156030 | Ramasamy et al. | Oct 2002 | A1 |
| 20020173490 | Jiang et al. | Nov 2002 | A1 |
| 20020198171 | Schinazi et al. | Dec 2002 | A1 |
| 20030008841 | Devos et al. | Jan 2003 | A1 |
| 20030028013 | Wang et al. | Feb 2003 | A1 |
| 20030039630 | Albrecht | Feb 2003 | A1 |
| 20030050229 | Sommadossi et al. | Mar 2003 | A1 |
| 20030053986 | Zahm | Mar 2003 | A1 |
| 20030055013 | Brass | Mar 2003 | A1 |
| 20030060400 | LaColla et al. | Mar 2003 | A1 |
| 20030083306 | Imbach et al. | May 2003 | A1 |
| 20030083307 | Devos et al. | May 2003 | A1 |
| 20030087873 | Stuyver et al. | May 2003 | A1 |
| 20030124512 | Styuver | Jul 2003 | A1 |
| 20030220290 | Gosselin et al. | Nov 2003 | A1 |
| 20030225028 | Gosselin et al. | Dec 2003 | A1 |
| 20030225029 | Stuyver et al. | Dec 2003 | A1 |
| 20030225037 | Storer et al. | Dec 2003 | A1 |
| 20030236216 | Devos et al. | Dec 2003 | A1 |
| 20040002476 | Stuyver et al. | Jan 2004 | A1 |
| 20040002596 | Hong et al. | Jan 2004 | A1 |
| 20040006002 | Sommadossi et al. | Jan 2004 | A1 |
| 20040014108 | Eldrup et al. | Jan 2004 | A1 |
| 20040023921 | Hong et al. | Feb 2004 | A1 |
| 20040059104 | Cook et al. | Mar 2004 | A1 |
| 20040063622 | Sommadossi et al. | Apr 2004 | A1 |
| 20040063658 | Roberts et al. | Apr 2004 | A1 |
| 20040067901 | Bhat et al. | Apr 2004 | A1 |
| 20040072788 | Bhat et al. | Apr 2004 | A1 |
| 20040077587 | Sommadossi et al. | Apr 2004 | A1 |
| 20040097461 | Sommadossi et al. | May 2004 | A1 |
| 20040097462 | Sommadossi et al. | May 2004 | A1 |
| 20040101535 | Sommadossi et al. | May 2004 | A1 |
| 20040102414 | Sommadossi et al. | May 2004 | A1 |
| 20040110717 | Bhat et al. | Jun 2004 | A1 |
| 20040110718 | Devos et al. | Jun 2004 | A1 |
| 20040121980 | Martin et al. | Jun 2004 | A1 |
| 20040147464 | Roberts et al. | Jul 2004 | A1 |
| 20040229839 | Babu et al. | Nov 2004 | A1 |
| 20040229840 | Bhat et al. | Nov 2004 | A1 |
| 20040248844 | Ismaili et al. | Dec 2004 | A1 |
| 20040259934 | Olsen et al. | Dec 2004 | A1 |
| 20040266722 | Devos et al. | Dec 2004 | A1 |
| 20040266723 | Otto et al. | Dec 2004 | A1 |
| 20040266996 | Rabi | Dec 2004 | A1 |
| 20050009737 | Clark et al. | Jan 2005 | A1 |
| 20050020825 | Storer et al. | Jan 2005 | A1 |
| 20050031588 | Sommadossi et al. | Feb 2005 | A1 |
| 20050038240 | Connolly et al. | Feb 2005 | A1 |
| 20050090463 | Roberts et al. | Apr 2005 | A1 |
| 20050101550 | Roberts et al. | May 2005 | A1 |
| 20050107312 | Keicher et al. | May 2005 | A1 |
| 20050113330 | Imbach et al. | May 2005 | A1 |
| 20050119200 | Roberts et al. | Jun 2005 | A1 |
| 20050124532 | Sommadossi et al. | Jun 2005 | A1 |
| 20050137141 | Hilfinger et al. | Jun 2005 | A1 |
| 20050137161 | Sommadossi et al. | Jun 2005 | A1 |
| 20050215511 | Roberts et al. | Sep 2005 | A1 |
| 20060040890 | Martin et al. | Feb 2006 | A1 |
| 20060040944 | Gosselin et al. | Feb 2006 | A1 |
| 20060111311 | Keicher et al. | May 2006 | A1 |
| 20060166865 | Sommadossi et al. | Jul 2006 | A1 |
| 20060194835 | Dugourd et al. | Aug 2006 | A1 |
| 20060199783 | Wang et al. | Sep 2006 | A1 |
| 20060234962 | Olsen et al. | Oct 2006 | A1 |
| 20060241064 | Roberts et al. | Oct 2006 | A1 |
| 20060264389 | Bhat et al. | Nov 2006 | A1 |
| 20070004669 | Carroll et al. | Jan 2007 | A1 |
| 20070015905 | LaColla et al. | Jan 2007 | A1 |
| 20070027065 | LaColla et al. | Feb 2007 | A1 |
| 20070027104 | LaColla et al. | Feb 2007 | A1 |
| 20070032449 | LaColla et al. | Feb 2007 | A1 |
| 20070037735 | Gosselin et al. | Feb 2007 | A1 |
| 20070042990 | Gosselin et al. | Feb 2007 | A1 |
| 20070060503 | Gosselin et al. | Mar 2007 | A1 |
| 20070060504 | Gosselin et al. | Mar 2007 | A1 |
| 20070060505 | Gosselin et al. | Mar 2007 | A1 |
| 20070060541 | Gosselin et al. | Mar 2007 | A1 |
| 20070203334 | Mayes et al. | Aug 2007 | A1 |
| 20070265222 | MacCoss et al. | Nov 2007 | A1 |
| 20070275883 | Sommadossi et al. | Nov 2007 | A1 |
| 20080070861 | Clark | Mar 2008 | A1 |
| 20080139802 | Axt et al. | Jun 2008 | A1 |
| 20080253995 | Clark | Oct 2008 | A1 |
| 20080261913 | Sommadossi et al. | Oct 2008 | A1 |
| 20080280842 | MacCoss et al. | Nov 2008 | A1 |
| 20090004135 | Clark | Jan 2009 | A1 |
| 20090036666 | Clark | Feb 2009 | A1 |
| 20090118223 | Erion et al. | May 2009 | A1 |
| 20100279969 | Schinazi et al. | Nov 2010 | A1 |
| 20100279974 | Pierra et al. | Nov 2010 | A1 |
| 20100316594 | Sommadossi et al. | Dec 2010 | A1 |
| 20110269707 | Stuyver et al. | Nov 2011 | A1 |
| 20110306541 | Delaney, IV et al. | Dec 2011 | A1 |
| 20110306573 | Avolio et al. | Dec 2011 | A1 |
| 20120010164 | Summa et al. | Jan 2012 | A1 |
| 20120107274 | Clarke et al. | May 2012 | A1 |
| 20120245335 | Clark | Sep 2012 | A1 |
| 20120251487 | Surleraux | Oct 2012 | A1 |
| 20130017171 | Sommadossi et al. | Jan 2013 | A1 |
| 20130064794 | Surlereaux et al. | Mar 2013 | A1 |
| 20130149283 | Sommadossi et al. | Jun 2013 | A1 |
| 20130273005 | Delaney et al. | Oct 2013 | A1 |
| 20130281686 | Cho et al. | Oct 2013 | A1 |
| 20130315862 | Sommadossi et al. | Nov 2013 | A1 |
| 20130315866 | Parsy et al. | Nov 2013 | A1 |
| 20130315867 | Parsy et al. | Nov 2013 | A1 |
| 20130315868 | Mayes et al. | Nov 2013 | A1 |
| 20130330297 | Storer et al. | Dec 2013 | A1 |
| 20140038916 | Chang et al. | Feb 2014 | A1 |
| 20140086873 | Mayes et al. | Mar 2014 | A1 |
| 20140099283 | Gosselin et al. | Apr 2014 | A1 |
| 20140112886 | Moussa et al. | Apr 2014 | A1 |
| 20140112887 | Mayes et al. | Apr 2014 | A1 |
| 20140113880 | Storer et al. | Apr 2014 | A1 |
| 20140128339 | Girijavallabhan et al. | May 2014 | A1 |
| 20140140951 | Moussa et al. | May 2014 | A1 |
| 20140140952 | Moussa et al. | May 2014 | A1 |
| 20140140955 | McGuigan et al. | May 2014 | A1 |
| 20140154211 | Girijavallabhan et al. | Jun 2014 | A1 |
| 20140161770 | Girijavallabhan et al. | Jun 2014 | A1 |
| 20140178338 | Mayes et al. | Jun 2014 | A1 |
| 20140205566 | Liao et al. | Jul 2014 | A1 |
| 20140206640 | Girijavallabhan et al. | Jul 2014 | A1 |
| 20140212382 | Schinazi et al. | Jul 2014 | A1 |
| 20140248241 | Stewart et al. | Sep 2014 | A1 |
| 20140248242 | Dousson et al. | Sep 2014 | A1 |
| 20140271547 | Dukhan et al. | Sep 2014 | A1 |
| 20140294769 | Mayes et al. | Oct 2014 | A1 |
| 20140364446 | Dukhan et al. | Dec 2014 | A1 |
| 20150037282 | Mayes et al. | Feb 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| 2252144 | Apr 2000 | CA |
| 1919307 | Jan 1971 | DE |
| 2122991 | Nov 1972 | DE |
| 2508312 | Sep 1976 | DE |
| 140254 | Feb 1980 | DE |
| 3512781 | Oct 1985 | DE |
| 4224737 | Feb 1994 | DE |
| 102005012681 | Sep 2006 | DE |
| 0 288 847 | Apr 1988 | EP |
| 0 180 276 | Dec 1988 | EP |
| 0 352 248 | Jan 1990 | EP |
| 0 494 119 | Jan 1992 | EP |
| 0 526 655 | Feb 1993 | EP |
| 0 553 358 | Aug 1993 | EP |
| 0 587 364 | Mar 1994 | EP |
| 0 742 287 | Nov 1996 | EP |
| 0 747 389 | Dec 1996 | EP |
| 0 350 287 | Sep 2000 | EP |
| 0 650 371 | Nov 2000 | EP |
| 1521076 | Apr 1968 | FR |
| 1581628 | Sep 1969 | FR |
| 2662165 | Nov 1991 | FR |
| 0924246 | Apr 1963 | GB |
| 0984877 | Mar 1965 | GB |
| 1163102 | Sep 1969 | GB |
| 1163103 | Sep 1969 | GB |
| 1187824 | Apr 1970 | GB |
| 1209654 | Oct 1970 | GB |
| 1542442 | Mar 1979 | GB |
| 46021872 | Jun 1971 | JP |
| 48048495 | Sep 1971 | JP |
| 61212592 | Sep 1986 | JP |
| 61263995 | Nov 1986 | JP |
| 61263996 | Nov 1986 | JP |
| 63215694 | Sep 1988 | JP |
| 2091022 | Mar 1990 | JP |
| 06135988 | May 1994 | JP |
| 06211890 | Aug 1994 | JP |
| 06228186 | Aug 1994 | JP |
| 06293645 | Oct 1994 | JP |
| 09059292 | Mar 1997 | JP |
| WO 89002733 | Apr 1989 | WO |
| WO 90000555 | Jan 1990 | WO |
| WO 91016920 | Nov 1991 | WO |
| WO 91018914 | Dec 1991 | WO |
| WO 91019721 | Dec 1991 | WO |
| WO 92015308 | Sep 1992 | WO |
| WO 92018517 | Oct 1992 | WO |
| WO 93000910 | Jan 1993 | WO |
| WO 94001117 | Jan 1994 | WO |
| WO 94026273 | Nov 1994 | WO |
| WO 96015132 | May 1996 | WO |
| WO 9712033 | Apr 1997 | WO |
| WO 98016184 | Apr 1998 | WO |
| WO 9830223 | Jul 1998 | WO |
| WO 99015194 | Apr 1999 | WO |
| WO 99023104 | May 1999 | WO |
| WO 99043691 | Sep 1999 | WO |
| WO 99045016 | Sep 1999 | WO |
| WO 99052514 | Oct 1999 | WO |
| WO 99059621 | Nov 1999 | WO |
| WO 99064016 | Dec 1999 | WO |
| WO 00009531 | Feb 2000 | WO |
| WO 00025799 | May 2000 | WO |
| WO 00037110 | Jun 2000 | WO |
| WO 00052015 | Sep 2000 | WO |
| WO 01018013 | Mar 2001 | WO |
| WO 01032153 | May 2001 | WO |
| WO 01047935 | Jul 2001 | WO |
| WO 01049700 | Jul 2001 | WO |
| WO 01060315 | Aug 2001 | WO |
| WO 01068663 | Sep 2001 | WO |
| WO 01079246 | Oct 2001 | WO |
| WO 01081359 | Nov 2001 | WO |
| WO 01090121 | Nov 2001 | WO |
| WO 01091737 | Dec 2001 | WO |
| WO 01092282 | Dec 2001 | WO |
| WO 01096353 | Dec 2001 | WO |
| WO 02003997 | Jan 2002 | WO |
| WO 0218369 | Mar 2002 | WO |
| WO 02018404 | Mar 2002 | WO |
| WO 02032414 | Apr 2002 | WO |
| WO 02032920 | Apr 2002 | WO |
| WO 02048165 | Jun 2002 | WO |
| WO 02057287 | Jul 2002 | WO |
| WO 02057425 | Jul 2002 | WO |
| WO 02070533 | Sep 2002 | WO |
| WO 02094289 | Nov 2002 | WO |
| WO 02100415 | Dec 2002 | WO |
| WO 03024461 | Mar 2003 | WO |
| WO 03026589 | Apr 2003 | WO |
| WO 03026675 | Apr 2003 | WO |
| WO 03039523 | May 2003 | WO |
| WO 03051899 | Jun 2003 | WO |
| WO 03061385 | Jul 2003 | WO |
| WO 03061576 | Jul 2003 | WO |
| WO 03062255 | Jul 2003 | WO |
| WO 03062256 | Jul 2003 | WO |
| WO 03062257 | Jul 2003 | WO |
| WO 03063771 | Aug 2003 | WO |
| WO 03068162 | Aug 2003 | WO |
| WO 03068164 | Aug 2003 | WO |
| WO 03068244 | Aug 2003 | WO |
| WO 03072757 | Sep 2003 | WO |
| WO 03093290 | Nov 2003 | WO |
| WO 03099840 | Dec 2003 | WO |
| WO 03100017 | Dec 2003 | WO |
| WO 03105770 | Dec 2003 | WO |
| WO 03106577 | Dec 2003 | WO |
| WO 04000858 | Dec 2003 | WO |
| WO 04002422 | Jan 2004 | WO |
| WO 04002999 | Jan 2004 | WO |
| WO 04003000 | Jan 2004 | WO |
| WO 04003138 | Jan 2004 | WO |
| WO 04007512 | Jan 2004 | WO |
| WO 04009020 | Jan 2004 | WO |
| WO 04023921 | Mar 2004 | WO |
| WO 04028481 | Apr 2004 | WO |
| WO 04041203 | May 2004 | WO |
| WO 04043977 | May 2004 | WO |
| WO 04043978 | May 2004 | WO |
| WO 04044132 | May 2004 | WO |
| WO 04046159 | Jun 2004 | WO |
| WO 04046331 | Jun 2004 | WO |
| WO 04052899 | Jun 2004 | WO |
| WO 04058792 | Jul 2004 | WO |
| WO 04065398 | Aug 2004 | WO |
| WO 04072090 | Aug 2004 | WO |
| WO 04080466 | Sep 2004 | WO |
| WO 04084796 | Oct 2004 | WO |
| WO 04096149 | Nov 2004 | WO |
| WO 04106356 | Dec 2004 | WO |
| WO 05003147 | Jan 2005 | WO |
| WO 05012327 | Feb 2005 | WO |
| WO 05020884 | Mar 2005 | WO |
| WO 05020885 | Mar 2005 | WO |
| WO 05021568 | Mar 2005 | WO |
| WO 05030258 | Apr 2005 | WO |
| WO 05042556 | May 2005 | WO |
| WO 05123087 | Dec 2005 | WO |
| WO 06002231 | Jan 2006 | WO |
| WO 06012078 | Feb 2006 | WO |
| WO 06012440 | Feb 2006 | WO |
| WO 06016930 | Feb 2006 | WO |
| WO 06037028 | Apr 2006 | WO |
| WO 06037227 | Apr 2006 | WO |
| WO 06063717 | Jun 2006 | WO |
| WO 06065335 | Jun 2006 | WO |
| WO 06097323 | Sep 2006 | WO |
| WO 06100087 | Sep 2006 | WO |
| WO 06121820 | Nov 2006 | WO |
| WO 06130532 | Dec 2006 | WO |
| WO 07011777 | Jan 2007 | WO |
| WO 07025304 | Jan 2007 | WO |
| WO 14059901 | Apr 2014 | WO |
| WO 14059902 | Apr 2014 | WO |
| WO 14204831 | Dec 2014 | WO |
| Entry |
|---|
| Thornber et al., Chemical Society reviews, vol. 8(4), 1979, pp. 563-580. |
| Afdhal, et al., “Enhanced Antiviral Efficacy for Valopicitabine Plus PEG-Interferon in Hepatitis C Patients with HCV Genotype-1 Infection,” J. Hepatol., 42:39-40 (2005). |
| Alt, et al., “Specific Inhibition of Hepatitis C Viral Gene Expression by Antisense Phosphorothioate Oligodeoxynucleotides,” Hepatology, 22:707-717 (1995). |
| Alt, et al., “Core Specific Antisense Phosphorothioate Oligodeoxynucleotides as Potent and Specific Inhibitors of Hepatitis C Viral Translation,” Arch. Virol., 142:589-599 (1997). |
| Aparicio, et al., “Synthesis of Saccarinic Acid Derivatives,” Carbohydrate Res., 129:99-109 (1984). |
| Awano, et al., “Synthesis and Antiviral Activity of 5-Substituted (2′S)-2′-Deoxy-2′-C-Methylcytidines and -Uridines,” Arch. Pharm. 329:66-72 (1996). |
| Baginski, et al., “Mechanism of Action of a Pestivirus Antiviral Compound,” Proc. Natl. Acad. Sci. U.S.A., 97:7981-7986 (2000). |
| Battaglia, et al., “Combination Therapy with Interferon and Ribavirin in the Treatment of Chronic Hepatitis C Infection,” Ann. Pharmacother, 34:487-494 (2000). |
| Beigelman et al., “Epimerization During the Acetolysis of 3-O-Acetyl-5-O-Benzoyl-1,2-O-Isopropylidene-3-C-Methyl-α-D-Ribofuranose. Synthesis of 3′-C-Methylnucleosides with the β-D-ribo-and α-D-arabino Configurations,” Carbohydrate Res., 181:77-88 (1988). |
| Beigelman, et al., “New Synthesis of 2′-C-Methylnucleosides Starting from D-Glucose and D-Ribose,” Carbohydrate Res., 166:219-232 (1987). |
| Beigelman, et al., “A General Method for Synthesis of 3′-Alkylnucleosides,” Nucleic Acids Symp. Ser., 9:115-118 (1981). |
| Beigelman, et al., “Functionally Complete Analogs of Nucleosides. The Use of D-Glucose for the Synthesis of 2-C-Methyl-D-Ribose Derivatives and Related Nucleosides,” Bioorg. Khim., 12:1359-1365 (1986). |
| Berenguer, et al., “Hepatitis B and C Viruses: Molecular Identification and Targeted Antiviral Therapies,” Proc. Asso. Am. Physicians, 110:98-112 (1998). |
| Berenguer, et al., “Hepatitis C Virus in the Transplant Setting,” Antivir. Ther., 3:125-136 (1998). |
| Berman, et al., “Synergistic Cytotoxic Effect of Azidothymidine and Recombinant Interferon Alpha on Normal Human Bone Marrow Progenitor Cells,” Blood, 74:1281-1286 (1989). |
| 16th International Conference on Antiviral Research (Apr. 27, 2003), Savannah, Ga., pp. A75-A77. |
| Bhopale, et al., “Emerging Drugs for Chronic Hepatitis C,” Hepatol. Res. 32:146-153 (2005). |
| Bianco, et al., “Synthesis of a New Carbocyclic Nucleoside Analog,” Tetrahedron Lett., 38:6433-6436 (1997). |
| Billich, et al., “Nucleoside Phosphotransferase from Malt Sprouts,” Biol. Chem. Hoppe-Seyler, 367:267-278 (1986). |
| Bio, et al., “Practical Synthesis of a Potent Hepatitis C Virus RNA Replication Inhibitor,” J. Org. Chem., 69:6257-6266 (2004). |
| Bloch, A., et al., “The Role of the 5′-Hydroxyl Group of Adenosine in Determining Substrate Specificity for Adenosine Deaminase,” J. Med. Chem., 10:908-12 (1967). |
| Browne, et al., “2′,3′-Didehydro-3′-Deoxythymidine (d4T) in Patients with AIDS or AIDS-Related Complex: A Phase I Trial,” J. Infect. Dis., 167:21-29 (1993). |
| Bryant, et al., “Antiviral L-Nucleosides Specific for Hepatitis B Virus Infection,” Antimicrob. Agents Chemother., 45:229-235 (2001). |
| Cappellacci, et al., “Synthesis, Biological Evaluation, and Molecular Modeling of Ribose-Modified Adenosine Analogues as Adenosine Receptor Agonists,” J. Med. Chem., 48:1550-1562 (2005). |
| Cappellacci, et al., “Ribose-Modified Nucleosides as Ligands for Adenosine Receptors: Synthesis, Conformational Analysis, and Biological Evaluation of 1′-C-Methyl Adenosine Analogues,” J. Med. Chem., 45:1196-1202 (2002). |
| Carroll, et al., “Inhibition of Hepatitis C Virus RNA Replication by 2′-Modified Nucleoside Analogs,” J. Biol. Chem., 278 11979-11984 (2003). |
| Carroll, “Nucleoside Analog Inhibitors of Hepatitis C Virus Replication,” Infectious Disord. Drug Targets 6:17-29 (2006). |
| Cavelier, et al., “Studies of Selective Boc Removal in the Presence of Silyl Ethers,” Tetrahedron Lett., 37:5131-5134 (1996). |
| Chand, et al., “Synthesis of (2S,3S,4R,5R)-2-(4-Amino-5H-Pyrrolo[3,2-d]Pyrimidin-7-yl)-5-(Hydroxymethyl)-3-Methylpyrrolidine-3,4-Diol, An Analog of Potent HCV Inhibitor,” Collection Symposium Series 7 (Chemistry of Nucleic Acid Components), pp. 329-332 (2005). |
| Chiacchio, et al., “Stereoselective Synthesis of 2′-Amino-2′,3′-Dideoxynucleosides by Nitrone 1,3-Dipolar Cycloaddition: A New Efficient Entry Toward d4T and its 2-Methyl Analogue,” J. Org. Chem., 64:28-36 (1999). |
| Chiaramonte, et al., “Inhibition of CMP-Sialic Acid Transport into Golgi Vesicles by Nucleoside Monophates,” Biochemistry, 40:14260-14267 (2001). |
| Clark, et al., “Design, Synthesis, and Antiviral Activity of 2′-Deoxy-2′-Fluoro-2′-C-Methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication,” J. Med. Chem., 48:5504-5508 (2005). |
| Clark, et al., “Synthesis and Antiviral Activity of 2′-Deoxy-2′-Fluoro-2′-C-Methyl purine Nucleosides as Inhibitors of Hepatitis C Virus RNA Replication.,” Bioorg. Med. Chem. Lett., 16:1712-1715 (2006). |
| Coelmont, et al., “Ribavirin Antagonizes the In Vitro Anti-Hepatitis C Virus Activity of 2′-C-Methylcytidine, The Active Component of Valopicitabine,” Antimicrob. Agents Chemother., 50:3444-3446 (2006). |
| Colacino, “Mechanisms for the Anti-Hepatitis B Virus Activity and Mitochondrial Toxicity of Fialuridine (FIAU),” Antiviral Res., 29:125-139 (1996). |
| Cook, “Improving the Treatment of Hepatitis C Infection in the UK,” Expert Opin. Pharmacother., 8:183-191 (2007). |
| Cornberg, et al., “Present and Future Therapy for Hepatitis C Virus,” Expert Rev. Antiinfect. Ther., 4:781-793 (2006). |
| Cretton-Scott, et al., “Pharmacokinetics of β-L-2′-Deoxycytidine Prodrugs in Monkeys,” Antiviral Res., 50:A44 (2001). |
| Cui, et al., “Cellular and Molecular Events Leading to Mitochondrial Toxicity of 1-(2-Deoxy-2-Fluoro-1-β-D-Arabinofuranosyl)-5-Iodouracil in Human Liver Cells,” J. Clin. Invest., 95:555-563 (1995). |
| Czernecki, et al., “Synthesis of Various 3′-Branched 2′,3′-Unsaturated Pyrimidine Nucleosides as Potential Anti-HIV Agents,” J. Org. Chem., 57:7325-7328 (1992). |
| Czernecki, et al., “Synthesis of 2′-Deoxy-2′-Spirocyclopropyl Cytidine as Potential Inhibitor of Ribonucleotide Diphosphate Reductase,” Can. J. Chem., 71:413-416 (1993). |
| Dalpiaz, et al., “Temperature Dependence of the Affinity Enhancement of Selective Adenosine A1 Receptor Agonism: A Thermodynamic Analysis,” Eur. J. Pharmacol., 448:123-131 (2002). |
| Daniels et al., “Tautomerism of Uracil and Thymine in Aqueous Solution: Spectroscopic Evidence,” Proc. Nat. Acad. Sci. U.S.A., 69:2488-2491 (1972). |
| Davis, “Current Therapy for Chronic Hepatitis C,” Gastroenterology 118:S104-S114 (2000). |
| Davis, “New Therapies: Oral Inhibitors and Immune Modulators,” Clin. Liver Dis., 10:867-880 (2006). |
| Davisson, et al., “Synthesis of Nucleotide 5′-Diphosphates from 5′-O-Tosyl Nucleosides,” J. Org. Chem., 52:1794-1801 (1987). |
| De Francesco, et al., “Approaching a New Era for Hepatitis C Virus Therapy: Inhibitors of the NS3-4A Serine Protease and the NS5B RNA-Dependent RNA Polymerase,” Antiviral Res., 58:1-16 (2003). |
| Delombaert, et al., “N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors,” J. Med. Chem., 37:498-511 (1994). |
| Ding, et al., “Synthesis of 2′-β-C-Methyl Toyocamycin and Sangivamycin Analogs as Potential HCV Inhibitors,” Bioorg. Med. Chem. Lett., 15:725-727 (2005). |
| Ding, et al., “Synthesis of 9-(2-β-C-Methyl-β-D-Ribofuranosyl)-6-Substituted Purine Derivatives as Inhibitors of HCV RNA Replication,” Bioorg. Med. Chem. Lett., 15:709-713 (2005). |
| Dornsife, et al., “In Vitro Potency of Inhibition by Antiviral Drugs of Hematopoietic Progenitor Colony Formation Correlates with Exposure at Hemotoxic Levels in Human Immunodeficiency Virus-Positive Human,” Antimicrob. Agents Chemother., 40:514-519 (1996). |
| Dutartre, et al., “General Catalytic Deficiency of Hepatitis C Virus RNA Polymerase with an S282T Mutation and Mutually Exclusive Resistance towards 2′-Modified Nucleotide Analogues,” Antimicrob. Agents Chemother., 50:4161-4169 (2006). |
| Dymock, et al., “Novel Approaches to the Treatment of Hepatitis C Virus Infection,” Antiviral Chem. Chemother., 11:79-95 (2000). |
| Eldrup, et al., “Structure-Activity Relationship of Heterobase-Modified 2′-C-Methyl Ribonucleosides as Inhibitors of Hepatitis C Virus RNA Replication,” J. Med. Chem. 47:5284-5297 (2004). |
| Eldrup, et al., “Structure-Activity Relationship of Purine Ribonucleosides for Inhibition of Hepatitis C Virus RNA-Dependent RNA Polymerase,”, J. Med. Chem., 47:2283-2295 (2004). |
| Faivre-Buet, et al., “Synthesis of 1′-Deoxypsicofuanosyl-Deoxynucleosides as Potential Anti-HIV Agents,” Nucleosides Nucleotides, 11:1411-1424 (1992). |
| Farkas, et al., “Nucleic acid Components and Their Analogues. LXXIX. Synthesis of Methyl 1-Deoxy-D-Psicofuranosides Substituted at C(1) With Halo Atoms or a Mercapto Group,” Collect. Czech. Chem. Commun., 31:1535-1543 (1996). |
| Farkas, et al., “Nucleic Acid Components and Their Analogues. XCIV. Synthesis of 6-Amino-9-(1-Deoxy-β-D-Psicofuranosyl)purine,” Collect. Czech. Chem. Commun., 32:2663-2667 (1967). |
| Farquhar et al., “Biologically Reversible Phosphate-Protective Groups,” J. Pharm. Sci., 72(3):324 (1983). |
| Farquhar, et al., “Synthesis and Biological Evaluation of 9-[5′-(2-Oxo-1,3,2-Oxazaphosphorinan-2-yl-)-β-D-Arabinosyl]Adenine and 9-[5′-(2-Oxo-1,3,2-Dioxazaphosphorinan-2-yl)-β-D-Arabinosyl]Adenine: Potential Neutral Precursors of 9-[β-D-Arabinofuranosyl]Adenine 5′-Monophosphate,” J. Med. Chem., 28:1358-1381 (1985). |
| Farquhar, et al., “Synthesis and Biological Evaluation of Neutral Derivatives of 3-Fluoro-2′-Deoxyuridine 5′-Phosphate,” J. Med. Chem., 26:1153-1158 (1983). |
| Feast, et al., “Studies on the D-Glucosaccharinic Acids,” Acta Chem. Scand., 19(5):1127-1134 (1965). |
| Fedorov, et al., “3′-C-Branched 2′-Deoxy-5-Methyluridines: Synthesis, Enzyme Inhibition, and Antiviral Properties,” J. Med. Chem., 35:4567-4575 (1992). |
| Ferrari, et al., “Characterization of Soluble Hepatitis C Virus RNA-Dependent RNA Polymerase Expressed in Escherichia coli,” J. Virol., 73:1649-1654 (1999). |
| Fischl, et al., “Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy,” Ann. Intern. Med., 18:762-769 (1993). |
| Fox, et al., “Thiolation of Nucleosides. II. Synthesis of 5-Methyl-2′-Deoxycytidine and Related Pyrimidine Nucleosides,” J. Am. Chem. Soc., 81:178-187 (1959). |
| Franchetti, et al., “2′-C-Methyl Analogues of Selective Adenosine Receptor Agonists: Synthesis and Binding Studies,” J. Med. Chem., 41:1708-1715 (1998). |
| Franchetti, et al., “Antitumor Activity of C-Methyl-β-D-Ribofuranosyladenine Nucleoside Ribonucleotide Reductase Inhibitors,” J. Med. Chem., 48, 4983-4989 (2005). |
| Freed, et al., “Evidence for Acyloxymethyl Esters of Pyrimidine 5′-Deoxyribonucleotides as Extracellular Sources of Active 5′-Deoxyribonucleotides in Cultured Cells,” Biochem. Pharmacol., 38:3193-3198 (1989). |
| Fujimori, et al., “A Convenient and Stereoselective Synthesis of 2′-Deoxy-β-L-Nucleosides,” Nucleosides Nucleotides, 11:341-349 (1992). |
| Furukawa, et al.,. “A Novel Method for Synthesis of Purine Nucleosides Using Friedel-Crafts Catalysts,” Chem. Pharm. Bull., 16:1076-1080 (1968). |
| Galderisi, et al., “Antisense Oligonucleotides as Therapeutic Agents,” J. Cell. Physiol., 181:251-257 (1999). |
| Gallo, et al., “2′-C-Methyluridine Phosphoramidite: A New Building Block for the Preparation of RNA Analogues Carrying the 2′-Hydroxyl Group,” Tetrahedron, 57:5707-5713 (2001). |
| Gerotto, et al., “Effect of Retreatment with Interferon Alone or Interferon Plus Ribavirin on Hepatitis C Virus Quasispecies Diversification in Nonresponder Patients with Chronic Hepatitis C,” J. Virol., 73:7241-7247 (1999). |
| Girardet, et al., “Synthesis and Cytotoxicity of 4-Amino-5-Oxopyrido[2,3-d]Pyrimidine Nucleosides,” J. Med. Chem., 43:3704-3713 (2000). |
| Gretch, “Use and Interpretation of HCV Diagnostic Tests in the Clinical Setting,” Clinics in Live Disease, 1:547-557 (1997). |
| Grouiller, et al., “Novel-p-Toluenesulfonylation and Thionocarbonylation of Unprotected Thymine Nucleosides,” Synlett, 1993:221-222 (1993). |
| Grouiller, et al., “Structural Studies on a Psicofuranosyl Nucleoside, a Potential Antiviral Agent,” J. Pharm. Belg., 47:381-383 (1992). |
| Grunnagel, et al., “Preparation of D-Tagatose,” Justus Liebigs Annalen der Chemie, 721:234-235 (1969). |
| Gunic, et al., “Synthesis and Cytotoxity of 4′-C-and 5′-C-Substituted Toyocamycins,” Bioorg. Med. Chem., 9:163-170 (2001). |
| Haraguchi, et al., Preparation and Reactions of 2′-and 3′-Vinyl Bromides of Uracil Nucleosides: Versatile Synthons for Anti-HIV Agents, Tetrahedron Lett., 32:3391-3394 (1991). |
| Haraguchi, et al., “Stereoselective Synthesis of 1′-C-Branched Uracil Nucleosides from Uridine,” Nucleotides Nucleosides , 14:417-420 (1995). |
| Harry-O'Kuru, et al., “2′-C-alkylribonucleosides: Design, Synthesis and Conformation,” Nucleosides Nucleotides, 6:1457-1460 (1997). |
| Harry-O'Kuru, et al., “A Short, Flexible Route Toward 2′-C-Branched Ribonucleosides,” J. Org. Chem., 62:1754-1759 (1997). |
| Hassan, et al., “Nucleosides and Nucleotides 151: Conversion of (Z)-2′-(Cyanomethylene)-2′-Deoxyuridines into Their (E)-Isomers via Addition of Thiophenol to the Cyanomethylene Moiety Followed by Oxidative Syn-Elimination Reactions,” J. Org. Chem., 61. 6261-6267 (1996). |
| Hassan, et al., “Nucleosides and Nucleotides 156: Chelation-Controlled and Nonchelation-Controlled Diastereofacial Selective Thiophenol Addition Reactions at the 2′-Position of 2′-[(Alkoxycarbonyl)Methylene]-2′-Deoxyuridines: Conversion of (Z)-2′[(Alkoxycarbonyl)Methylene]-2′-Deoxyuridines into Their (E)-Isomers,” J. Org. Chem., 62:11-17 (1997). |
| Hattori, et al., “Nucleosides and Nucleotides 175. Structural Requirements of the Sugar Moiety for the Antitumor Activities of New Nucleoside Antimetabolites, 1-(3-C-Ethynyl-β-D-Ribo-Pentofuranosyl)Cytosine and -Uracil,” J. Med. Chem., 41:2892-2902 (1998). |
| Hattori, et al., “Nucleosides and Nucleotides 158. 1-(3-C-Ethynyl-β-D-Ribo-Pentofuranosyl)-Cytosine, 1-(3-C-Ethynyl-β-D-Ribo-Pentofuranosyl)Uracil, and Their Nucleobase Analogues as New Potential Multifunctional Antitumor Nucleosides with a Broad Spectrum of Activity,” J. Med. Chem., 39:5005-5001 (1996). |
| Hayakawa, et al., “Reaction of Organometallic Reagents with 2′- and 3′-Ketouridine Derivatives: Synthesis of Uracil Nucleosides Branched at the 2′- and 3′-Positions,” Chem. Pharm. Bull., 35:2605-2608 (1987). |
| Hoard, et al., “Conversion of Mono- and Oligodeoxyribonucleotides to 5′-Triphosphates,” J. Am. Chem. Soc., 87:1785-1788 (1965). |
| Hodge, et al., “Amadori Rearrangement Products,” Meth. Carbohydrate Chem., 2:99-107 (1963). |
| Holy, “Nucleic Acid Components and Their Analogs. CLIII. Preparation of 2′Deoxy-L-Ribonucleosides for the Pyrimidine Series,” Collect. Czech. Chem. Commun., 37:4072-4087 (1972). |
| Hossain, et al., “Synthesis of 2′- and 3′-Spiro-Isoxazolidine Derivatives of Thymidine & Their Conversions to 2′,3′-Dideoxy-2′,3′-Didehydro-3′-C-Substituted Nucleosides by Radical Promoted Fragmentation,” Tetrahedron, 49:10133-10156 (1993). |
| Hostetler, et al., “Greatly Enhanced Inhibition of Human Immunodeficiency Virus Type I Replication in CEM and HT4-6C Cells by 3′-Deoxythymidine Diphosphate Dimyristoylglycerol, a Lipid Prodrug of 3′-Deoxythymidin,” Antimicrob. Agents Chemother., 36:2025-2029 (1992). |
| Hostetler, et al., “Synthesis and Antiretroviral Activity of Phospholipids Analogs of Azidothymidine and Other Antiviral Nucleosides,” J. Biol. Chem., 265:6112-6117 (1990). |
| Hrebabecky, et al., “Nucleic Acid Components and Their Analogs: CXLIX: Synthesis of Pyrimidine Nucleosides Derived from 1-Deoxy-D-Psicose,” Collect. Czech. Chem. Commun., 37:2059-2064 (1974). |
| Hrebabecky, et al., “Synthesis of 7- and 9β-D-Psicofuranosylguanine and Their 1′-Deoxy Derivatives,” Collect. Czech. Chem. Commun., 39:2115-2123 (1974). |
| Hu, et al., “Viral, Host and Interferon-Related Factors Modulating the Effect of Interferon Therapy for Hepatitis C Virus Infection,” J. Viral Hepatitis, 8:1-18 (2001). |
| Hunston, et al., “Synthesis and Biological Properties of Some Cyclic Phosphotriesters Derived from 2′-Deoxy-5-Fluorouridine,” J. Med. Chem., 27:440-444 (1984). |
| Iglesias, et al., “Complete and Regioselective Deacetylation of Peracetylated Uridines Using a Lipase,” Biotech. Lett., 22:361-365 (2000). |
| Iimori, et al., “2′-C-, 3′-C-, and 5′-C-Methylsangivamycins: Conformational Lock with the Methyl Group,” Tetrahedron Lett., 32, 7273-7276 (1991). |
| Iino et al., “Nucleosides and Nucleotides 139. Stereoselective Synthesis of (2′S)-2′-C-Alkyl-2′-Deoxyuridines,” Nucleosides Nucleotides, 15:169-181 (1996). |
| Ikegashira, et al., “Discovery of Conformationally Constrained Tetracylic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors,” J. Med. Chem., 449:6950-6953 (2006). |
| Imai, K., et al., “Studies on Phosphorylation. IV. Selective Phosphorylation of the Primary Hydroxyl Group in Nucleosides,” J. Org. Chem., 34:1547-1550 (1969). |
| Itoh, et al., “Divergent and Stereocontrolled Approach to the Synthesis of Uracil Nucleosides Branched at the Anomeric Position,” J. Org. Chem., 60:656-662 (1995). |
| Johnson, et al., “3′-C-Trifluoromethyl Ribonucleosides,” Nucleoside Nucleosides, 14:185-194 (1995). |
| Jones, et al., “4′-Substituted Nucleosides. 5. Hydroxymehylation of Nucleoside 5′-Aldehydes,” J. Org. Chem., 44:1309-1317 (1979). |
| Jones, et al., “Oxidation of Carbohydrates by the Sulfoxide-Carbodiimide and Related Methods,” Meth. Carbohydrate Chem., 6:315-322 (1972). |
| Kakefuda, et al., “Nucleosides and Nucleotides. 120. Stereoselective Radical Deoxygenation of Tert-Alcohols in the Sugar Moiety of Nucleosides: Synthesis of 2′,3′-Dideoxy-2′ -C-Methyl- and -2′-C-Ethynyl-β-D-Threo-Pentofuranosyl Pyrimidines and Adenine as Potential Antiviral and Antitumor Agents,” Tetrahedron, 49:8513-8528 (1993). |
| Kamaike, et al., “An Efficient Method for the Synthesis of [4-15N]Cytidine, 2′-Deoxy[4-15N]Cytidine, [6-15N]Adenosine, and 2′-Deoxy[6-15N]Adenosine Derivatives,” Nucleosides Nucleotides, 15:749-769 (1996). |
| Kaneko, et al., “A Convenient Synthesis of Cytosine Nucleosides,” Chem. Pharm. Bull., 20:1050-1053 (1972). |
| Kawana, et al., “The Deoxygenations of Tosylated Adenosine Derivatives with Grignard Reagents,” Nucleic Acids Symp Ser., 17:37-40 (1986). |
| Kempe, et al., “Selective 2′-Benzoylation at the Cis 2′,3′-Diols of Protected Ribonucleosides. New Solid Phase Synthesis of RNA and DNA-RNA Mixtures,” Nucleic Acids Res., 10:6695-6714 (1982). |
| Kerr, et al., “N-(Dialkylamino)Methylene Derivatives of 2′-Deoxycytidine and Arabinocytidine: Physicochemical Studies for Potential Prodrug Applications,” J. Pharm. Sci., 83:582-586 (1994). |
| Khamnei, “Neighboring Group Catalysis in the Design of Nucleotide Prodrugs,” J. Med. Chem., 39:4109-4115 (1996). |
| Kim, et al., “A Novel Nucleoside Prodrug-Activating Enzyme: Substrate Specificity of Biphenyl Hydrolase-like Protein,” Mol. Pharm., 1:117-127 (2004). |
| Klumpp, et al., “The Novel Nucleoside Analog R1479 (4′-Azidocytidine) Is a Potent Inhibitor of NS5B-Dependent RNA Synthesis and Hepatitis C Virus Replication in Cell Culture,” J. Biol. Chem., 281:3793-3799 (2006). |
| Kohn, et al., “A New Method for the Synthesis of Furanose Derivatives of Aldohexoses,” J. Am. Chem. Soc., 87:5475-5480 (1965). |
| Kotra, et al., “Structure-Activity Relationships of 2′-Deoxy-2′,2′-Difluoro-L-Erythro-Pentofuranosyl Nucleosides,” J. Med. Chem., 40:3635-3644 (1997). |
| Kucera, et al., “Novel Membrane-Interactive Ether Lipid Analogs that Inhibit Infectious HIV-1 Production and Induce Defective Virus Formation,” AIDS Res. Hum. Retro Viruses, 6:491-501 (1990). |
| Kuhn, et al., “Uber eine Molekulare Umlagerung von N-Glucosiden,” Jahrg., 69:1745-1754 (1936). |
| Kurtzberg, et al., “Differential Toxicity of Carbovir and AZT to Human Bone Marrow Hematopoietic Progenitor Cells in Vitro,” Exp. Hematol., 18:1094-1095 (1990). |
| Lai, et al., “Mutational Analysis of Bovine Viral Diarrhea Virus RNA-Dependant RNA Polymerase,” J. Virol., 73:10129-101136 (1999). |
| Landowski, “Nucleoside Ester Prodrug Substrate Specificity of Liver Carboxylesterase,” J. Pharmacol. Exp. Ther., 316:572-580 (2006). |
| Lavaire, et al., “3′-Deoxy-3′-C-Trifluoromethyl Nucleosides: Synthesis and Antiviral Evaluation,” Nucleosides Nucleotides, 17:2267-2280 (1998). |
| Le Pogam, et al., “In Vitro Selected Con1 Subgenomic Replicons Resistant to 2′-C-Methyl-Cytidine or to R1479 Show Lack of Cross Resistance,” Virology, 351:349-359 (2006). |
| Le Pogam, et al., “Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus,” J. Virology, 80:6146-6154 (2006). |
| Leonard, et al., “5-Amino-5-deoxyribose Derivatives. Synthesis and Use in the Preparation of ‘Reversed’ Nucleosides (1a),” J. Heterocycl. Chem., 3:485-489 (1966). |
| Lerza, et al., “In Vitro Synergistic Inhibition of Human Bone Marrow Hemopoietic Progenitor Growth by a 3′-Azido-3′ -Deoxy-Thymidine, 2′,3′-Dideoxycytidine Combination,” Exp. Hematol., 25:252-255 (1997). |
| Lewis, et al., “Fialuridine and its Metabolites Inhibit DNA Polymerase y at Sites of Multiple Adjacent Analog Incorporating, Decrease mtDNA Abundance, and Cause Mitochondrial Structural Defects in Cultured Hepatoblasts,” Proc. Natl. Acad. Sci. U.S.A., 93:3592-3597 (1996). |
| Lewis, et al., “Ultrastructural Changes Associated with Reduced Mitochondrial DNA and Impaired Mitochondrial Function in the Presence of 2′,3′-Dideoxycytidine,” Antimicrob. Agents Chemother., 36:2061-2065 (1992). |
| Lewis, et al., “Zidovudine Induces Molecular, Biochemical, and Ultrastructural Changes in Rat Skeletal Muscle Mitochondria,” J. Clin. Invest., 89:1354-1360 (1992). |
| Leyssen, et al., “Perspectives for the Treatment of Infections with Flaviviridae,” Clin. Microbiol. Rev., 13:67-82 (2000). |
| Li, et al., “2′-C-Branched Ribonucleosides. 2. Synthesis of 2′-C-β-Trifluormethyl Pyrimidine Ribonucleosides,” Org. Lett., 3:1025-1028 (2001). |
| Lin, et al., “Synthesis of Several Pyrimidine L-Nucleoside Analogues as Potential Antiviral Agents,” Tetrahedron Lett., 51:1055-1068 (1995). |
| Lohmann, et al., “Biochemical and Kinetic Analyses of NS5B RNA-Dependent RNA Polymerase of the Hepatitis C Virus,” Virology, 249:108-118 (1998). |
| Lopez-Herrera, et al., “A New Synthesis of 2-C-Methyl-D-Ribono-1,4-Lactone and the C-9/C-13 Fragment of Methynolide,” J. Carbohydrate Chem., 13:767-775 (1994). |
| Luh, et al., “A Convenient Method for the Selective Esterification of Amino-Alcohols,” Synth. Commun., 8:327-333 (1978). |
| Maga, et al., “Lack of Stereospecificity of Suid Pseudorabies Virus Thymidine Kinase,” Biochem. J., 294:381-385 (1993). |
| Mahmoudian, et al., “A Versatile Procedure for the Generation of Nucleoside 5′-Carboxylic Acids Using Nucleoside Oxidase,” Tetrahedron, 54:8171-8182 (1998). |
| Mansour, et al., “Editorial,” Antiinfec. Agents Med. Chem., 6:1 (2007). |
| Markland, et al., “Broad-Spectrum Antiviral Activity of the IMP Dehydrogenase Inhibitor VX-497: A Comparison with Ribavirin and Demonstration of Antiviral Additivity with Alpha Interferon,” Antimicrob. Agents Chemother., 44:859-866 (2000). |
| Martin, et al., “Intramolecular Hydrogen Bonding in Primary Hydroxyl of Thymine 1-(1-Deoxy-β-D-Piscofuranosyl)Nucleoside,” Tetrahedron, 50:6689-6694 (1994). |
| Martin, et al., “Synthesis and Antiviral Activity of Monofluoro and Difluoro Analogues of Pyrimidine Deoxyribonucleosides against Human Immnodeficiency Virus (HIV-1),” J. Med. Chem., 33:2137-2145 (1990). |
| Matsuda, et al., “Alkyl Addition Reaction of Pyrimidine 2′-Ketaonucleosides: Synthesis of 2′-Branched-Chain Sugar Pyrimidine Nucleosides (Nucleosides and Nucleotides. LXXXI),” Chem. Pharm. Bull., 36:945-53 (1988). |
| Matsuda, et al., “Nucleosides and Nucleotides 104. Radical and Palladium-Catalyzed Deoxygenation of the Allylic Alcohol Systems in the Sugar Moiety of Pyrimidine Nucleosides,” Nucleosides Nucleotides, 11:197-226 (1992). |
| Matsuda, et al., “Nucleosides and Nucleotides 94. Radical Deoxygenation of Tert-Alcohols in 1-(2-C-Alkylpentafuranosyl)Pyrimidines: Synthesis of (2′S)-2-Deoxy-2′-C-Methylcytidine, and Antileukemic Nucleoside,” J. Med. Chem., 34:234-239 (1991). |
| Matsuda, et al., “Radical Deoxygenation of Tert-Alcohols in 2′-Branched-Chain Sugar Pyrimidine Nucleosides: Synthesis and Antileukemic Activity of 2′-Deoxy-2′(S)-Methylcytidine,” Chem. Pharm. Bull., 35: 3967-3970 (1987). |
| McCormick, J., et al., “Structure and Total Synthesis of HF-7, a Neuroactive Glyconucleoside Disulfate from the Funnel-Web Spider Hololena Curta,” J. Am. Chem. Soc., 121:5661-5665 (1999). |
| McFarlin, et al., “The Reaction of Lithium Aluminum Hydride with Alcohols. Lithium Tri-t-Butoxy-Aluminohydride as a New Selective Reducing Agent,” J. Am. Chem. Soc., 80:5372-5376 (1958). |
| McKenzie, et al., “Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B,” N. Engl. J. Med., 333:1099-1105 (1995). |
| Medina, et al., “Comparison of Mitochondrial Morphology, Mitochondrial DNA Content, and Cell Viability in Cultured Cell Treated with Three Anti-Human Immunodeficiency Virus Dideoxynucleosides,” Antimicrob. Agents Chemother., 38:1824-8 (1994). |
| Meier, et al., “Cyclic Saligenyl Phosphotriesters of 2′,3′-Dideoxy-2′,3′-Didehydrothymidine (d4T)—A New Pro-Nucleic Approach,” Bioorg. Med. Chem. Lett., 7:99-104 (1997). |
| Meyer, et al., “2′-O-Acyl-6-Thioinosine Cyclic 3′,5′-Phosphates as Prodrugs of Thioinosinic Acid,” J. Med. Chem., 22:811-815 (1979). |
| Mikhailov, et al., “Hydrolysis of 2′- and 3′-C-Methyluridine 2′,3′-Cyclic Monophosphates and Interconversion and Dephosphorylation of the Resulting 2′- and 3′-Monophosphates: Comparison with the Reactions of Uridine Monophosphates,” J. Org. Chem., 57:4122-4126 (1992). |
| Mikhailov, et al., “Substrate Properties of C'-Methylnucleoside and C'-Methyl-2′-Deoxynucleoside 5′-Triphosphates in RNA and DNA Synthesis Reactions Catalyzed by RNA and DNA polymerases,” Nucleosides Nucleotides, 10:339-343 (1991). |
| Mikhailov, et al., “Synthesis and Properties of 3′-C-Methylnucleosides and Their Phosphoric Esters,” Carbohydrate Res., 124:75-96 (1983). |
| Miles, et al., “Circular Dichroism of Nucleoside Derivatives. IX. Vicinal Effects on the Circular Dichroism of Pyrimidine Nucleosides,” J. Am. Chem. Soc., 92:3872-3881 (1970). |
| Moiseyev, et al., “Determination of the Nucleotide Conformation in the Productive Enzyme-Substrate Complexes of RNA-Depolymerases,” FEBS Lett., 404:169-172 (1997). |
| Moore, et al., “Synthesis of Nucleotide Analogues that Potently and Selectively Inhibit Human DNA Primase,” Biochemistry, 41:14066-14075 (2002). |
| Murai, et al., “A Synthesis and an X-Ray Analysis of 2′-C-, 3′-C- and 5′-C-Methylsangivamycins,” Heterocycles, 33:391-404 (1992). |
| Neidlein, et al., “Mild Preparation of 1-Benzyloxyiminoalkylphosphonic Dichlorides: Application to the Synthesis of Cyclic Phosphonic Diesters and Cyclic Monoester Amides,” Heterocycles, 35:1185-1203 (1993). |
| Nishiguchi, et al., “Methods to Detect Substitutions in the Interferon-Sensitivity-Determining Region of Hepatitis C Virus 1b for Prediction of Response to Interferon Therapy,” Hepatology, 33:241-247 (2001). |
| Nishimura, et al., “Studies on Synthetic Nucleosides. Trimethylsilyl Derivatives of Pyrimidines and Purines,” Chem. Pharm. Bul., 12:352-356 (1964). |
| Novak, et al., “Nucleic Acid Components and Their Analogues. CXX. 2-C-Methyl-D-Ribose and Its Derivatives,” Collect. Czech. Chem. Commun., 34:857-866 (1969). |
| Novak, “Chiroptical Properties of 2-Methyl-1,4-Lactones; Revised Absolute Configuration of 2-Deoxy-2-C-Methyl-Erythro-D-Pentono-1,4-Lactones,” Collect. Czech. Chem. Commun., 39:869-882 (1974). |
| Nutt, et al., “Branched-Chain Sugar Nucleosides. III. 3′-C-Methyladenine,” J. Org. Chem., 33:1789-1795 (1968). |
| Oivanen, et al., “Additional Evidence for the Exceptional Mechanism of the Acid-Catalyzed Hydrolysis of 4-Oxopyrimidine Nucleosides: Hydrolysis of 1-(1-Alkoxyalky)uracils, Seconucleosides, 3′-C-Alkyl nucleosides and Nucleoside 3′,5′-Cyclic Monophosphates,” J. Chem. Soc. Perkin Trans. 2, 309-314 (1994). |
| Ong, et al., “Synthesis of 3′-C-Methyladenosine and 3′-C-Methyluridine Diphosphates and Their Interaction with the Ribonucleoside Diphosphate Reductase from Corynebacterium Nephridii,” Biochemistry, 31:11210-11215 (1992). |
| Pagliaro, et al., “Epatologia: Ieri, Oggi E (Forse) Domani,” Recenti Progressi in Medicina, 97:741-750 (2006). |
| Pan-Zhou, et al., “Differential Effects of Antiretroviral Nucleoside Analogs on Mitochondrial Function in HepG2 Cells,” Antimicrob. Agents Chemother., 44:496-503 (2000). |
| Piantadosi, et al., “Synthesis and Evaluation of Novel Ether Lipid Nucleoside Conjugates for Anti-HIV-1 Activity,” J. Med. Chem., 34:1408-1414 (1991). |
| Pierra., et al., “Comparative Studies of Selected Potential Prodrugs of B-L-dC, a Potent and Selective Anti-HBV Agent,” Antiviral. Res., 50:A79 (2001). |
| Pierra, et al., “NM 283, an Efficient Prodrug of the Potent Anti-HCV Agent 2′-C-Methylcytidine,” Nucleosides, Nucleotides Nucleic Acids, 24:767-770 (2005). |
| Pierra, et al., “Synthesis and Pharmacokinetics of Valopicitabine (NM283), an Efficient Prodrug of the Potent Anti-HCV Agent 2′-C-Methylcytidine,” J. Med. Chem., 49:6614-6620 (2006). |
| Reist, et al., “Potential Anticancer Agents. LXXVII. Synthesis of Nucleosides of Purine-6-Thiol(6-Mercaptopurine) Containing ‘Fraudulent’ Sugars,” J. Org. Chem., 27:3279-3283 (1962). |
| Richman, et al., “The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex,” N. Engl. J. Med., 317:192-197 (1987). |
| Robins, et al., “Purine Nucleosides. XXIX. The Synthesis of 2′-Deoxy-L-Adenosine and 2′-Deoxy-L-Guanosine and Their α Anomers,” J. Org. Chem., 35:636-639 (1970). |
| Rong, et al., “The Synthesis and Conformation of 2′-and 3′-Hypermodified Tricyclic Nucleosides and Their Use in the Synthesis of Novel 2′- or 3′-Isomeric 4(7)-Substituted Isoxazolidine-Nucleosides,” Tetrahedron, 50:4921-4936. (1994). |
| Roque-Afonso, et al., “Performance of TRUGENE™ Hepatitis C Virus 5′ Noncoding Genotyping Kit, a New CLIP™ Sequencing-Based Assay for Hepatitis C Virus Genotype Determination,” J. Viral Hepatitis., 9:385-389 (2002). |
| Rosenthal, et al., “Branched-Chain Sugar Nucleosides. Synthesis of 3′-C-Ethyl (and 3′-C-Butyl)Uridine,” Carbohydrate Res., 79:235-242 (1980). |
| Sakthivel, et al., “Electrophilic Fluorination of 5-(Cyanomethyl)Imidazole-4-Carboxylate Nucleosides: Facile Entry to 3-Fluoro-3-Deazaguanosine Analogues,” Synlett, 1586-1590 (2005). |
| Sakthivel, et al., “Direct SNAr Amination of Fluorinated Imidazo[4,5-c]Pyridine Nucleosides: Efficient Syntheses of 3-Fluoro-3-Deazaadenosine Analogs,” Tetrahedron Lett., 46:3883-3887 (2005). |
| Saladino, et al., “A New and Efficient Synthesis of Cytidine and Adenosine Derivatives by Dimethyldioxirane Oxidation of Thiopyrimidine and Thiopurine Nucleosides,” J. Chem. Soc., Perkin Trans. I, 21:3053-3054 (1994). |
| Samano, et al., “Nucleic Acid Related Compounds. 77. 2′,3′-Didehydro-2′,3′-Dideoxy-2′(and 3′)-Methylnucleosides via [3,3]-Sigmatropic Rearrangements of 2′(and 3′)-Methylene-3′(and 2′)-O-Thiocarbonyl Derivatives and Radical Reduction of a 2′-Chloro-3′-Methylene Analogue,” Can. J. Chem., 71:186-191 (1993). |
| Samano, et al., “Synthesis and Radical-Induced Ring-Opening Reactions of 2′-Deoxyadenosine-2′-Spirocyclopropane and its Uridine Analogue. Mechanistic Probes for Ribonucleotide Reductases,” J. Am. Chem. Soc. 114:4007-4008 (1992). |
| Sandhu, et al., “Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development: Demonstration of Linear Pharmacokinetics in Dogs of a Nucleoside Analog over a 50-Fold Dose Range,” Drug Metab. Dispos., 32:1254-1259 (2004). |
| Sato, et al., “C-Nucleoside Synthesis. 10. Synthesis of 2′-Methylated Pyrimidine C-Nucleosides,” Tetrahedron Lett., 21:1971-1974 (1980). |
| Sato, et al., “C-Nucleoside Synthesis. 19. Stereocontrolled General Synthesis of Pyrimidine C-Nucleosides Having Branched-Chain Sugar Moieties,” Bull. Chem. Soc. Jpn., 56:2680-99 (1983). |
| Savochkina, et al., “Substrate Properties of C—Methylnucleoside Triphosphates in RNA Syntheses Catalyzed by E. coli RNA—Polymerase,” Mol. Biol., 23:1700-1710 (1989). |
| Scheibler, “Ueber das Saccharin und die Saccharinsaure,” Chem. Ber., 13:2212-2217 (1880). |
| Schiff, “Emerging Strategies for Pegylated Interferon Combination Therapy,” Nat. re Clin. Pract. Gastoenterol. Hepatol., 4:S17-S21 (2007). |
| Schmit, et al., “Synthesis of 2′-Deoxy-2′-Alpha-Monofluoromethyl and Trifluoromethylnucleosides,” Synlett, 4:241-242 (1994). |
| Schmit, et al., “The Effects of 2′- and 3′-Alkyl Substituents on Oligonucleotide Hybridization and Stability,” Bioorg. Med. Chem. Lett., 4:1969-1974 (1994). |
| Serafinowski, et al., “New Method for the Preparation of Some 2′- and 3′-Trifluoromethyl-2′,3′-Dideoxyuridine Derivatives,” Tetrahedron, 56:333-339 (1999). |
| Shalaby, et al., “Conformations and Structure Studies of Sugar Lactones in the Solid State. Part II. The Molecular Structure of α-D-Glucosaccharino-γ-Lactone: 2-C-Mehtyl-D-Ribo-Pentono-1,4-Lactone,” Carbohydrate Res., 264:191-198 (1994). |
| Sharma, et al., “Synthesis of 3′-Trifluoromethyl Nucleosides as Potential Antiviral Agents,” Nucleosides, Nucleotides Nucleic Acids, 19:757-774 (2000). |
| Shi, et al., “Synthesis and in vitro Anti-HCV Activity of β-d- and 1-2′-Deoxy-2′-Fluororibonucleosides,” Nucleosides, Nucleotides Nucleic Acids, 23:875-879 (2005). |
| Shim, “Recent Patents on Nucleoside and Nucleotide Inhibitors for HCV,” Recent Pat. Antiinfect. Drug Discov., 1:323-331 (2006). |
| Sinko, et al., “Carrier-Mediated Intestinal Absorption of Valacyclovir, the L-Valyl Ester Prodrug of Acyclovir,” Biopharm. Drug Dispos., 19:209-217 (1998). |
| Sinkula, et al., “Rationale for Design of Biologically Reversible Drug Derivatives: Prodrugs,” J. Pharm. Sci., 64:181-210 (1975). |
| Smith, et al., “Synthesis of New 2′β-C-Methyl Related Triciribine Analogues as Anti-HCV Agents,” Bioorg. Med. Chem. Lett., 14:3517-3520 (2004). |
| Sommadossi, et al., “Comparison of Cytotoxicity of the (−)- and (+)-Enantiomer of 2′,3′-Dideoxy-3′-Thiacytidine in Normal Human Bone Marrow Progenitor Cells,” Biochem. Pharmacol., 44:1921-1925 (1992). |
| Sommadossi, et al., “Toxicity of 3′-Azido-3′-Deoxythymidine and 9-(1,3-Dihydroxy-2-Propoxymethyl)Guanine for Normal Human Hematopoietic Progenitor Cells In Vitro,” Antimicrob. Agents Chemother., 31:452-454 (1987). |
| Song, et al., “Amino Acid Ester Prodrugs of the Anticancer Agent Gemcitabine: Synthesis, Bioconversion, Metabolic Bioevasion, and hPEPT1-Medicated Transport,” Mol. Pharm., 2:157-167 (2005). |
| Sorbera, et al., “Valopicitabine: Anti-Hepatitis C Virus Drug RNA—Directed RNA Polymerase (NS5B) Inhibitor,” Drugs of the Future, 31:320-324 (2006). |
| Sowden, “The Saccharinic Acids,” Adv. Carbohydrate Chem., 12:43-46 (1957). |
| Spardari, et al., “L-Thymidine Is Phosphorylated by Herpes Simplex Virus Type 1 Thymidine Kinase and Inhibits Viral Growth,” J. Med. Chem., 35:4214-4220 (1992). |
| Standring, et al., “Antiviral β-L-Nucleosides Specific for Hepatitis B Virus Infection,” Antiviral Chem. Chemother., 12 :119-129 (2001). |
| Starrett, et al., “Synthesis, Oral Bioavailability Determination, and In Vitro Evaluation of Prodrugs of the Antiviral Agents 9-(2-(Phosphonomethoxy)Ethyl)Adenine (PMEA),” J. Med. Chem., 37:1857-1864 (1994). |
| Stuyver, et al., “Ribonucleoside Analogue that Block Replication of Bovine Viral Diarrhea and Hepatitis C Viruses in Culture,” Antimicrob. Agents Chemother., 47:244-254 (2003). |
| Sundberg, et al., Advanced Organic Chemistry, Part B, pp. 232 and 236 (1990). |
| Takenuki, et al., “Nucleosides and Nucleotides. XLIII. On the Stereoselectivity of Alkyl Addition Reaction of Pyrimidine 2′-Ketonucleosides,” Chem. Pharm. Bull., 38:2947-2952 (1990). |
| Tang, et al., “2′-C-Branched Ribonucleosides: Synthesis of the Phophoramidite Derivatives of 2′-C-B-Methylcytidine and Their Incorporation into Oligonucleotides,” J. Org. Chem., 64:747-754 (1999). |
| The Merck Index, 12th edition, p. 275 (1996). |
| Tritsch, et al., “3′β-Ethynyl and 2′-Deoxy-3 ′-β-Ethynyl Adenosines: First 3′-β-Branched Adenosine Substrates of Adenosine Deaminase,” Bioorg. Med. Chem. Lett., 10:139-141 (2000). |
| Tronchet, et al., “72. Synthese et Desamination Enzymatique Des C-Hydroxymethyl-3′-et C-Methyl-3′β-D-Xylofurannosyl-9-Adenines,” Helv. Chim. Acta, 62:689-695 (1979). |
| Tunitskaya, et al., “Substrate Properties of C′-Methyl UTP Derivatives in T7 RNA Polymerase Reactions. Evidence for N-Type NTP Conformation,” FEBS Lett., 400:263-266 (1997). |
| Tyrsted, et al., “Inhibition of the Synthesis of 5-Phosphoribosyl-1-Pyrophosphate by 3′-Deoxyadenosine and Structurally Related Nucleoside Analogs,” Biochem. Biophys. Acta., 155:619-622 (1968). |
| Usui, et al., “Synthesis of 2′-Deoxy-8,2′-Ethanoadenosine and 3′-Deoxy-8,3′-Ethanoadenosine (Nucleotides & Nucleosides. LXIV),” Chem. Pharm. Bull., 34:15-23 (1986). |
| Vassilev, et al., “Bovine Viral Diarrhea Virus Induced Apoptosis Correlates with Increased Intracellular Viral RNA Accumulation,” Virus Res., 69:95-107 (2000). |
| Velazquez, et al., “Synthesis of [1-[3′,5′-Bis-O-(Tert-Butyldimethylsily)-β-D-Arabino- and β-D-Ribofuransoyl]Cytosine]-2′—Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide). Analogues of the Highly Specific Anti-HIV-1 Agent TSAO-T,” Tetrahedron, 50:11013-11022 (1994). |
| Verri, et al., “Relaxed Enantioselectivity of Human Mitochondrial Thymidine Kinase and Chemotherapeutic Uses of L-Nucleoside Analogues,” Biochem. J., 328:317-320 (1997). |
| Verri, et al., “Lack of Enantiospecificity of Human 2′-Deoxycytidine Kinase: Relevance for the Activation of B-L-Deoxycytidine Analogs as Antineolastic and Antiviral Agents,” Mol. Pharmacol., 51:132-138 (1997). |
| Von Buren, et al., “Branched Oligodeoxynucleotides: Automated Synthesis and Triple Helical Hybridization Studies,” Tetrahedron, 51:8491-8506 (1995). |
| Von Janta-Lipiniski, et al., “Newly Synthesized L-Enantiomers of 3′-Fluoro-Modified β-2′-Deoxyribonucleoside 5′-Triphosphates Inhibit Hepatitis B DNA Polymerase but Not the Five Cellular DNA Polymerases α, β, γ,δ,and ε Nor HIV-1 Reverse Transcriptase,” J. Med. Chem., 41:2040-2046 (1998). |
| Wagner, et al., “Preparation and Synthetic Utility of Some Organotin Derivatives of Nucleosides,” J. Org. Chem., 39:24-30 (1974). |
| Walczak, et al., “Synthesis of 1-(3-Alkyl-2,3-Dideoxy-D-Pentofuranosyl)Uracils with Potential Anti-HIV Activity,” Acta Chem. Scand., 45:930-934 (1991). |
| Walton et al., “Branched-Chain Sugar Nucleosides. A New Type of Biologically Active Nucleoside,” J. Am. Chem. Soc., 88:4524-4525 (1966). |
| Walton, et al., “Branched-Chain Sugar Nucleosides: V. Synthesis and Antiviral Properties of Several Branched-Chain Sugar Nucleosides,” J. Med. Chem. 12:306-309 (1969). |
| Wang et al., “Reactions of N-Acylimidazole with Nucleosides and Nucleotides,” Heterocycles, 28:593-601 (1989). |
| Weinberg, et al., “Effect of Antiviral Drugs and Hematopoietic Growth Factors on In Vitro Erythropoiesis,” Mt. Sinai J. Med.; 65:5-13 (1998). |
| Whistler, et al., “‘α’-D-Glucosaccharino-1,4-Lactone,” Methods in Carbohydrate Chemistry, 2:484-485 (1963). |
| Wohnsland, et al., “Viral Determinants of Resistance to Treatment in Patients with Hepatitis C,” Clin. Microbiol. Rev., 20:23-38 (2007). |
| Wolf, et al., “New 2′-C-Branched-Chain Sugar Nucleoside Analogs with Potential Antiviral or Antitumor Activity,” Synthesis, 8:773-778 (1992). |
| Wolfe, et al., “A Concise Synthesis of 2′-C-Methylribonucleosides,” Tetrahedron Lett., 36:7611-7614 (1995). |
| Wu, et al., “A New Stereospecific Synthesis of [3.1.0] Bicyclic Cyclopropano Analog of 2′,3′-Dideoxyuridine,” Tetrahedron, 46:2587-2592 (1990). |
| Wu, et al., “Targeting NS5B RNA-Dependent RNA Polymerase for Anti-HCV Chemotherapy,” Curr. Drug Targets Infect. Disord., 3:207-219 (2003). |
| Yarchoan, et al., “Long-Term Toxicity/Activity Profile of 2′,3′-Dideoxyinosine in AIDS or AIDS-Related Complex,” Lancet, 336:526-529 (1990). |
| Yoshida, et al., “Reversal of Azidothymidine-Induced Bone Marrow Suppression by 2′,3′-Dideoxythymidine as Studied by Hemopoietic Clonal Culture,” AIDS Res. Hum. Retroviruses, 6:929-932 (1990). |
| Zedeck, et al., “Inhibition of the Steroid Induced Synthesis of Δ5-3-Ketosteroid Isomerase in Pseudomonas Testosteroni by a New Purine Deoxyribonucleoside Analog: 6-Chloro-8-Aza-9-Cyclopentylpurine,” Mol. Phys., 3:386-395 (1967). |
| Zemlicka, et al., “Aminoacyl Derivatives of Nucleosides, Nucleotides, and Polynucleotides. VIII. The Preparation of 2′(3′)-O-L-Phenylalanyluridine, -Cytidine, -Adenosine, -Inosine, -Guanosine and 2′-Deoxy-3′-O-L-Phenylalanyladenosine,” Collect. Czech. Chem. Commun., 43:3755-3768 (1969). |
| Zemlicka, et al., “Substrate Specificity of Ribosomal Peptidyltransferase. Effect of Modifications in the Heterocyclic, Carbohydrate and Amino Acid Moiety of 2′(3)-O-L-Phenylalanyladenosine,” Biochemistry., 14:5239-5279 (1975). |
| Zhou, et al., “Pharmacokinetics and Pharmacodynamics of Valopicitabine,”. J. Hepatology, 42:229 (2005). |
| Zinchenko, et al., “[2′-, 3′- & .5′—Methyl Analogs of Uridine in the Reaction of Microbiologic Transglycosylation],” Dokl. Akad. Nauk. S.S.S.R., 297:731-734 (1987). |
| Zintchenko, et al., “Substrate Specificity of Uridine and Purine Nucleoside Phosphorylases of the Whole Cells of Escherichia coli,” Nucleic Acids Symp. Ser., 18:137-140 (1987). |
| Zintchenko, et al., “Substrate Specificity of Uridine and Purine Nucleoside Phosphorylases in Whole Cells of E. coli,” Biopolymers & a cell, v. 4, No. 6 (1988). |
| Zon, “Cyclophosphamide Analogues,” Chapter 4 in Progress in Medicinal Chemistry, vol. 19, G. P., Ellis and G. B. West, Eds., pp. 205-246 (1982). |
| Office Action dated Oct. 1, 2003 from U.S. Appl. No. 09/863,816. |
| Notice of Allowance dated Jun. 23, 2004 from U.S. Appl. No. 09/863,816. |
| Office Action dated Aug. 27, 2003 from U.S. Appl. No. 09/864,078. |
| Notice of Allowance dated Feb. 19, 2004 from U.S. Appl. No. 09/864,078. |
| Notice of Allowance dated May 17, 2005 from U.S. Appl. No. 10/602,135. |
| Office Action dated Apr. 5, 2005 from U.S. Appl. No. 10/602,135. |
| Notice of Allowance dated Mar. 9, 2006 from U.S. Appl. No. 10/602,136. |
| Office Action dated Jul. 28, 2006 from U.S. Appl. No. 10/602,142. |
| Office Action dated Sep. 20, 2007 from U.S. Appl. No. 10/602,142. |
| Office Action dated Dec. 10, 2008 from U.S. Appl. No. 10/602,142. |
| Office Action dated Nov. 15, 2005 from U.S. Appl. No. 10/602,142. |
| Office Action dated Mar. 29, 2007 from U.S. Appl. No. 10/602,142. |
| Office Action dated Feb. 26, 2008 from U.S. Appl. No. 10/602,142. |
| Notice of Allowance dated Dec. 28, 2005 from U.S. Appl. No. 10/602,692. |
| Office Action dated Apr. 5, 2005 from U.S. Appl. No. 10/602,692. |
| Notice of Allowance dated Dec. 27, 2005 from U.S. Appl. No. 10/602,693. |
| Office Action dated Apr. 6, 2005 from U.S. Appl. No. 10/602,693. |
| Notice of Allowance dated Dec. 27, 2005 from U.S. Appl. No. 10/602,694. |
| Office Action dated Apr. 6, 2005 from U.S. Appl. No. 10/602,694. |
| Office Action dated Sep. 10, 2004 from U.S. Appl. No. 10/602,976. |
| Office Action dated May 19, 2005 from U.S. Appl. No. 10/602,976. |
| Notice of Allowance dated Oct. 13, 2005 from U.S. Appl. No. 10/602,976. |
| Office Action dated Aug. 15, 2006 from U.S. Appl. No. 10/608,907. |
| Office Action dated May 31, 2007 from U.S. Appl. No. 10/608,907. |
| Office Action dated Jan. 28, 2008 from U.S. Appl. No. 10/608,907. |
| Office Action dated Nov. 26, 2008 from U.S. Appl. No. 10/608,907. |
| Office Action dated Aug. 2, 2006 from U.S. Appl. No. 10/609,298. |
| Office Action dated Jul. 10, 2008 from U.S. Appl. No. 10/609,298. |
| Office Action dated Oct. 5, 2005 from U.S. Appl. No. 11/005,440. |
| Office Action dated Dec. 5, 2006 from U.S. Appl. No. 11/005,440. |
| Office Action dated Jun. 13, 2007 from U.S. Appl. No. 11/005,440. |
| Office Action dated Oct. 16, 2007 from U.S. Appl. No. 11/005,440. |
| Office Action dated Aug. 21, 2006 from U.S. Appl. No. 11/005,441. |
| Notice of Allowance dated Jun. 22, 2007 from U.S. Appl. No. 11/005,441. |
| Notice of Allowance dated Jan. 8, 2008 from U.S. Appl. No. 11/005,441. |
| Office Action dated Aug. 7, 2006 from U.S. Appl. No. 11/005,442. |
| Office Action dated May 16, 2007 from U.S. Appl. No. 11/005,442. |
| Office Action dated Nov. 28, 2007 from U.S. Appl. No. 11/005,442. |
| Office Action dated Nov. 7, 2005 from U.S. Appl. No. 10/602,691. |
| Office Action dated May 30, 2006 from U.S. Appl. No. 10/602,691. |
| Office Action dated Dec. 29, 2006 from U.S. Appl. No. 10/602,691. |
| Final Office Action dated Aug. 22, 2007 from U.S. Appl. No. 10/602,691. |
| Office Action dated Feb. 26, 2008 from U.S. Appl. No. 10/602,691. |
| Final Office Action dated Oct. 7, 2008 from U.S. Appl. No. 10/602,691. |
| Notice of Allowance dated Jun. 15, 2009 from U.S. Appl. No. 10/602,691. |
| Non-Final Office Action dated Jan. 5, 2011 from U.S. Appl. No. 12/504,601. |
| Final Office Action dated Aug. 29, 2011 from U.S. Appl. No. 12/504,601. |
| Notice of Allowance dated Jun. 21, 2012 from U.S. Appl. No. 12/504,601. |
| U.S. Appl. No. 60/392,350, filed Jun. 28, 2002, Sommadossi. |
| U.S. Appl. No. 60/466,194, filed Apr. 28, 2003, Sommadossi. |
| U.S. Appl. No. 60/470,949, filed May 14, 2003, Sommadossi. |
| U.S. Appl. No. 60/474,368, filed May 30, 2003, Clark. |
| U.S. Appl. No. 10/608,907, filed Jun. 27, 2003, Sommadossi. |
| U.S. Appl. No. 11/854,218, filed Sep. 12, 2007, Clark. |
| U.S. Appl. No. 12/131,868, filed Jun. 2, 2008, Sommadossi. |
| U.S. Appl. No. 12/878,262, filed Sep. 9, 2010, Clark. |
| 2nd Declaration of Christoph Seeger, Ph.D. dated Nov. 28, 2012. |
| 2nd Declaration of Victor E. Marquez, Ph.D. dated Nov. 28, 2012. |
| Apath.com webpage at http://www.apath.com/Blazing_Blight_7.htm. |
| Awad, Laila Fathy, et al., A Synthesis of Methyl 3-O-(β-D-Mannopyranosyl)-α-Dmannopyranoside from Sulfonate Intermediates, Bull. Chem. Soc. Jpn., vol. 59, pp. 1587-1592 (1986). |
| Bartenschlager and Lohmann, Antiviral Res. 52: 1-17 (2001). |
| Beard et al., Hepatology 30: 316-24 (1999). |
| Beauchamp, L.M., et al., Amino Acid Ester Prodrugs of Acyclovir, Antiviral Chemistry & Chemotherapy, vol. 3, No. 3, pp. 157-164 (1992). |
| Behrens et al., EMBO J. 15: 12-22 (1996). |
| Blight et al., Science 290: 1972-74 (2000). |
| Bourne, Nigel, et al., Screening for Hepatitis C Virus Antiviral SctivityWith a Cell-based Secreted Alkaline Phosphatase Reporter Replicon System, Antiviral Research, vol. 67, pp. 76-82 (2005). |
| Briot, Anne, et al., Benzylsulfonyl: A Valuable Protecting and Deactivating Group in Phenol Chemistry, Tetrahedron Letters, vol. 44, pp. 965-967 (2003). |
| Buckwold, et al., “Bovine viral diarrhea virus as a surrogate model of hepatitis C virus for the evaluation of antiviral agents.” Antiviral Research, 60: 1-15 (2003). |
| Calif. Inst. of Technol. v. Enzo Life Sciences, Inc., Interference 105,496, Paper 120 (BPAI Sep. 22, 2010). |
| Carroll and LaFemina, Antiviral Research: Strategies in Antiviral Drug Discovery 153-166 (Robert L. LaFemina, Ph.D., ed., 2009). |
| Choi, Yongseok, et al., A Conformationally Locked Analogue of the Anti-HIV Agent Stavudine. An Important Correlation between Pseudorotation and Maximum Amplitude, J. Med. Chem., vol. 46, pp. 3292-3299 (2003). |
| Chu et al., FEMS Microbiology Letters 202: 9-15 (2001). |
| Clark, Jeremy L., et al., Synthesis of 2-Deoxy-2-Fluoro-2-C-Methyl-DRibofuranoses, Journal of Carbohydrate Chemistry, vol. 25, pp. 461-470 (2006). |
| Clarke, Baillière's Clin. Gastroenterol. 14: 293-305 (2000). |
| Cohen, Science 285: 26-30 (1999). |
| Commentary, Science 285: 9 (1999). |
| Condit, R.C., Principles of Virology (Chapter 2), in Knipe, D.M. et al., eds., Fields Virology, Fourth Edition, Philadelphia, Lippincott Williams & Wilkins (2001). |
| Condit, R.C., Principles of Virology (Chapter 2), in Knipe, D.M. et al., eds., Fields Virology, Fifth Edition, Philadelphia, Lippincott Williams & Wilkins (2007). |
| Cox et al., Principles of Biochemistry, p. 330 (1993). |
| Cramer and Pfleiderer, Helvetica Chimica Acta 79: 2114-2136 (1996). |
| Damha et al., Curr. Protocols in Nucleic Acid Chem.: 1.7.1-1.7.19 (2002). |
| Damha et al., J. Org. Chem., 71(3): 921-925 (2006). |
| Damha et al., Nucleosides, Nucleotides & Nucleic Acids 22: 1343-1346 (2003). |
| De Clercq, J. Clin. Viology 22:73-89 (2001). |
| Declaration and Curriculum Vitae of Jean-Pierre Sommadossi, Ph.D., Interference No. 103,906, Apr. 3, 1998. |
| Désiré and Prandi, Carbohydrate Research 317: 110-118 (1999). |
| Dhanak, D., et al., Identification and Biological Characterization of Heterocyclic Inhibitors of the Hepatitis C Virus RNA-dependent RNA Polymerase, J. Biol. Chem. vol. 277, No. 41, pp. 38322-38327 (2002). |
| Di Bisceglie and Bacon, Sci. Am. 281: 80-85 (1999). |
| Di Bisceglie, Hepatology 35:224-31 (2002). |
| Diamond et al., J. Virol. 74: 4957-66 (2000). |
| European Patent Appln. No. 03761744 Office Action dated Apr. 16, 2012. |
| Ferrari et al., J. Virol. 73: 1649-54 (1999). |
| Fournier-Caruana et al., Biologicals 28: 33-40 (2000). |
| Frese et al., Hepatology 35:694-703 (2002). |
| Frese et al., J. Gen. Virol. 82: 723-33 (2001). |
| Friebe et al., J. Viro1.75: 12047-57 (2001). |
| Furman et al., Antiviral Res. 91: 120-132 (2011). |
| GenBank accession No. AJ242652 at http://www.ncbi.nlm.nih.gov/nuccore/5441834?sat=8&satkey=803423. |
| Genentech, Inc. v. Chiron Corp., Interference 105,048, Paper 258 (BPAI Nov. 30, 2004) (non-precedential). |
| Goeddel v. Sugano Interference 105,334, Paper 109, at 40-42 (BPAI Sep. 29, 2008), rev'd on other grounds, 617 F.3d 1350 (Fed. Cir. 2010). |
| Goldman, Bruce, Potential New Class of Drugs to Combat Hepatitis C Identified by Scientists, Stanford School of Medicine, http://med.stanford.edu/ism/2010/january/glenn.html (Jan. 20, 2010). |
| Grakoui et al., Hepatology 33: 489-95 (2001). |
| Greene and Wuts, Protective Groups in Organic Synthesis (3rd ed.): 76-81, 95-96, 102-106, 150, 173-176 and 197-198 (1999). |
| Guo, J.-T., Bichko, V.V., Seeger, C., Effect of Alpha Interferon on the Hepatitis C Virus Replicon, J. Virol., vol. 75, pp. 8516-8523 (2001). |
| Harrison, Steadman D., et al., Therapeutic Synergism of Tiazofurin and Selected Antitumor Drugs against Sensitive and Resistant P388 Leukemia in Mice, Cancer Research, vol. 46, pp. 3396-3400 (1986). |
| Hirooka et al., Bull. Chem. Soc. Jpn. 74(9): 1679-1694 (2001). |
| Hong et al., Virology 256: 36-44 (1999). |
| Hostetler, Karl Y., et al., Synthesis and Antiretroviral Activity of Phospholipid Analogs of Azidothymidine and Other Antiviral Nucelosides, The Journal of Biological Chemistry, vol. 265, No. 11, pp. 6112-6117 (1990). |
| Hudziak v. Ring, Interference 105,266, 2005 WL 3694322 (BPAI 2005). |
| Husson van Vilet, Biologicals 18: 25-27 (1990). |
| Ikeda et al., J. Virol. 76: 2997-3006 (2002 (received Oct. 3, 2001, accepted for publication Dec. 20, 2001). |
| Interference 105,871, Sommadossi Responses to Material Facts of Clark Reply 3 ated Oct. 18, 2012. |
| Interference 105,871, Appearance record dated Jan. 7, 2014. |
| Interference 105,871, Clark Clean Copy of Claims dated Mar. 7, 2012. |
| Interference 105,871, Clark Corrected Reply 1 dated Oct. 11, 2012. |
| Interference 105,871, Clark Corrected Reply 6 dated Oct. 11, 2012. |
| Interference 105,871, Clark exhibit list 9 dated Jun. 10, 2013. |
| Interference 105,871, Clark exhibit list for priority record dated Dec. 4, 2013. |
| Interference 105,871, Clark filing of demonstrative exhibits dated Jan. 3, 2014. |
| Interference 105,871, Clark Final Exhibit List dated Nov. 28, 2012. |
| Interference 105,871, Clark final exhibit list-priority phase dated Nov. 7, 2013. |
| Interference 105,871, Clark List of Intended Motions dated Apr. 11, 2012. |
| Interference 105,871, Clark miscellaneous motion 10 dated Oct. 18, 2013. |
| Interference 105,871, Clark Miscellaneous Motion 7 dated Oct. 23, 2012. |
| Interference 105,871, Clark miscellaneous motion 8 dated Jun. 10, 2013. |
| Interference 105,871, Clark Notice 2 dated Aug. 14, 2012. |
| Interference 105,871, Clark Notice dated May 31, 2012. |
| Interference 105,871, Clark Notice of Change in Related Proceedings dated Jul. 6, 2012. |
| Interference 105,871, Clark notice of judicial review dated Mar. 31, 2014. |
| Interference 105,871, Clark notice of related proceedings 2 dated Apr. 11, 2013. |
| Interference 105,871, Clark Notice of Related Proceedings dated Mar. 7, 2012. |
| Interference 105,871, Clark notice of service of supplemental evidence 4 dated Jul. 10, 2013. |
| Interference 105,871, Clark notice of service of supplemental evidence 5 dated Jul. 12, 2013. |
| Interference 105,871, Clark notice of service of supplemental evidence 6 dated Jul. 17, 2013. |
| Interference 105,871, Clark notice regarding exhibit 2136 dated Jul. 22, 2013. |
| Interference 105,871, Clark Notice Regarding Filing Priority Statement dated Jun. 5, 2012. |
| Interference 105,871, Clark Opposition 1 dated Aug. 17, 2012. |
| Interference 105,871, Clark opposition 10 dated Nov. 8, 2013. |
| Interference 105,871, Clark Opposition 19 dated Jul. 25, 2012. |
| Interference 105,871, Clark Opposition 6 dated Aug. 17, 2012. |
| Interference 105,871, Clark Opposition 8 dated Nov. 13, 2012. |
| Interference 105,871, Clark opposition dated Jul. 26, 2013. |
| Interference 105,871, Clark Priority Statement dated Jun. 5, 2012. |
| Interference 105,871, Clark Real Party-In-Interest dated Mar. 7, 2012. |
| Interference 105,871, Clark Reply 1 dated Oct. 11, 2012. |
| Interference 105,871, Clark reply 10 dated Nov. 22, 2013. |
| Interference 105,871, Clark Reply 2 dated Oct. 11, 2012. |
| Interference 105,871, Clark Reply 3 dated Oct. 11, 2012. |
| Interference 105,871, Clark Reply 6 dated Oct. 11, 2012. |
| Interference 105,871, Clark Reply 7 dated Nov. 19, 2012. |
| Interference 105,871, Clark reply 9 dated Sep. 6, 2013. |
| Interference 105,871, Clark Request for File Copies dated Mar. 7, 2012. |
| Interference 105,871, Clark request for oral argument 2 and list of issues dated Oct. 18, 2013. |
| Interference 105,871, Clark Request for Oral Arguments dated Oct. 23, 2012. |
| Interference 105,871, Clark response to Sommadossi reply 9 alleged material facts dated Sep. 17, 2013. |
| Interference 105,871, Clark Submission of Corrected Replies 1 and 6 dated Oct. 11, 2012. |
| Interference 105,871, Clark submission of DVD dated Dec. 23, 2013. |
| Interference 105,871, Clark submission of priority phase exhibits dated Nov. 7, 2013. |
| Interference 105,871, Clark submission of record 2 dated Dec. 4, 2013. |
| Interference 105,871, Clark Submission of Record dated Nov. 28, 2012. |
| Interference 105,871, Clark Submission of Sommadossi Declarations dated Jun. 28, 2012. |
| Interference 105,871, Clark Substantive Motion 1 dated Jun. 5, 2012. |
| Interference 105,871, Clark Substantive Motion 2 dated Jun. 5, 2012. |
| Interference 105,871, Clark Substantive Motion 3 dated Jun. 5, 2012. |
| Interference 105,871, Clark Substantive Motion 6 dated Jun. 5, 2012. |
| Interference 105,871, Clark substantive motion 9 dated Jun. 28, 2013. |
| Interference 105,871, Decision dated Jan. 29, 2014. |
| Interference 105,871, Decision on Motions dated Mar. 22, 2013. |
| Interference 105,871, Decision on Request for Rehearing dated Apr. 23, 2013. |
| Interference 105,871, email communication dated Jul. 22, 2013. |
| Interference 105,871, Judgement dated Jan. 29, 2014. |
| Interference 105,871, Notice Regarding Sommadossi Substantive Motion 5 dated Jun. 22, 2012. |
| Interference 105,871, Notice to Declare Interference dated Feb. 22, 2012. |
| Interference 105,871, Order Authorizing Miscellaneous Motion dated Jul. 16, 2012. |
| Interference 105,871, Order Authorizing Motions dated Apr. 24, 2012. |
| Interference 105,871, Order Authorizing Responsive Motion dated Jun. 18, 2012. |
| Interference 105,871, Order Cross Examination of Marquez dated Sep. 27, 2012. |
| Interference 105,871, Order Cross Examination of Witnesses dated Jul. 5, 2012. |
| Interference 105,871, Order Denying Requests for Oral Argument dated Nov. 16, 2012. |
| Interference 105,871, Order evidentiary matters dated Jul. 15, 2013. |
| Interference 105,871, Order miscellaneous dated Aug. 1, 2013. |
| Interference 105,871, Order miscellaneous dated Jul. 2, 2013. |
| Interference 105,871, Order miscellaneous dated Jul. 1, 2013. |
| Interference 105,871, Order miscellaneous dated Nov. 26, 2013. |
| Interference 105,871, Order miscellaneous dated Sep. 11, 2013. |
| Interference 105,871, Order miscellaneous dated Sep. 18, 2013. |
| Interference 105,871, Order regarding conference call of Apr. 2, 2013 dated Apr. 3, 2013. |
| Interference 105,871, Order regarding inappropriate communications dated Jan. 16, 2014. |
| Interference 105,871, Order Regarding Miscellaneous Motion and Notion Numbering dated Aug. 16, 2012. |
| Interference 105,871, Redeclaration dated Mar. 22, 2013. |
| Interference 105,871, Sommadossi Clean Copy of Claims dated Mar. 7, 2012. |
| Interference 105,871, Sommadossi Exhibit List dated Jun. 5, 2012. |
| Interference 105,871, Sommadossi File Copy Request dated Mar. 7, 2012. |
| Interference 105,871, Sommadossi filing of demonstrative exhibits dated Dec. 30, 2013. |
| Interference 105,871, Sommadossi Filing of the Record dated Nov. 28, 2012. |
| Interference 105,871, Sommadossi list of exhibits containing testimony of Edith Badel dated Jul. 18, 2013. |
| Interference 105,871, Sommadossi list of exhibits dated Nov. 8, 2013. |
| Interference 105,871, Sommadossi List of Issues dated Oct. 18, 2013. |
| Interference 105,871, Sommadossi miscellaneous motion 10 dated Oct. 18, 2013. |
| Interference 105,871, Sommadossi Miscellaneous Motion 19 dated Jul. 18, 2012. |
| Interference 105,871, Sommadossi Miscellaneous Motion 8 dated Oct. 23, 2012. |
| Interference 105,871, Sommadossi Motion 5 dated Jun. 5, 2012. |
| Interference 105,871, Sommadossi Motions List dated Apr. 11, 2012. |
| Interference 105,871, Sommadossi notice of judicial review dated Feb. 6, 2014. |
| Interference 105,871, Sommadossi Notice of Real Parties in Interest dated Mar. 7, 2012. |
| Interference 105,871, Sommadossi notice of related litigations dated Apr. 11, 2013. |
| Interference 105,871, Sommadossi Notice of Related Proceedings dated Mar. 7, 2012. |
| Interference 105,871, Sommadossi Notice of Service of Supplemental Evidence 4 dated Jun. 3, 2013. |
| Interference 105,871, Sommadossi Opposition 1 dated Aug. 17, 2012. |
| Interference 105,871, Sommadossi Opposition 2 dated Aug. 17, 2012. |
| Interference 105,871, Sommadossi Opposition 3 dated Aug. 17, 2012. |
| Interference 105,871, Sommadossi Opposition 6 dated Aug. 17, 2012. |
| Interference 105,871, Sommadossi Opposition 7 dated Nov. 13, 2012. |
| Interference 105,871, Sommadossi opposition 9 dated Jul. 26, 2013. |
| Interference 105,871, Sommadossi Priority Statement dated Jun. 5, 2012. |
| Interference 105,871, Sommadossi Reply 1 dated Oct. 11, 2012. |
| Interference 105,871, Sommadossi reply 10 dated Nov. 22, 2013. |
| Interference 105,871, Sommadossi Reply 19 dated Jul. 30, 2012. |
| Interference 105,871, Sommadossi Reply 6 dated Oct. 11, 2012. |
| Interference 105,871, Sommadossi Reply 8 dated Nov. 19, 2012. |
| Interference 105,871, Sommadossi reply 9 dated Sep. 6, 2013. |
| Interference 105,871, Sommadossi request for rehearing dated Apr. 5, 2013. |
| Interference 105,871, Sommadossi responses to Clark's MF of Clark reply 9 dated Sep. 17, 2013. |
| Interference 105,871, Sommadossi Responses to Material Facts of Clark Corrected Reply 1 dated Oct. 18, 2012. |
| Interference 105,871, Sommadossi Responses to Material Facts of Clark Reply 2 dated Oct. 18, 2012. |
| Interference 105,871, Sommadossi Responses to Material Facts of Clark Corrected Reply 6 dated Oct. 18, 2012. |
| Interference 105,871, Sommadossi Submission of Clark Declarations dated Jun. 28, 2012. |
| Interference 105,871, Sommadossi submission of priority phase exhibits dated Nov. 8, 2013. |
| Interference 105,871, Sommadossi Substantive Motion 1 dated Jun. 5, 2012. |
| Interference 105,871, Sommadossi Substantive Motion 18 dated Jun. 22, 2012. |
| Interference 105,871, Sommadossi Substantive Motion 8 dated May 10, 2013. |
| Interference 105,871, Sommadossi supplemental notice of related proceedings dated Sep. 17, 2013. |
| Interference 105,871, Sommadossi supplemental notice of service of exhibits dated Jul. 26, 2013. |
| Interference 105,871, Sommodossi opposition 10 dated Nov. 8, 2013. |
| Interference 105,871, substitute Clark substantive motion 9 dated Jul. 22, 2013. |
| Interference 105,871, Substitute Sommadossi substantive motion 8, dated Jul. 18, 2013. |
| Interference 105,871, Transcript of Oral hearing held Jan. 7, 2014 dated Jan. 29, 2014. |
| Ishii et al., Hepatology 29: 1227-35 (1999). |
| Jeong, Lak S. et al., Unanticipated Retention of Configuration in the DAST Fluorination of Deoxy-4′-thiopyrimidine Nucleosides with “Up” Hydroxyl Groups, Tetrahedron Letters, vol. 35, No. 41, pp. 7569-7572 (1994). |
| Jordan et al., J. Infect. Dis. 182: 1214-17 (2000). |
| Julander et al., Antiviral Res. 86: 261-7 (2010). |
| Kim et al., Biochem. Biophys. Res. Commun. 290: 105-12 (2002). |
| Kolykhalov et al., Science 277: 570-74 (1997). |
| Krieger et al., J. Virol. 75: 4614-24 (2001). |
| Kuroboshi et al., Synlett 987-988 (1995). |
| Lal, G. Sankar, et al., Electrophilic NF Fluorinating Agents, Chem. Rev., vol. 96, pp. 1737-1755 (1996). |
| Lalezari, J., et al., Potent Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor R7128 with PEG-IFN and Ribavirin: Interim Results of R7128 500mg BID for 28 Days, J. Hepatology, vol. 48, Supplement 2, p. S29 (2008). |
| Lalezari, J., et al., Potent Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor, R7128, in Combination with PEG-IFN α-2a and Ribavirin, 43rd Annual Meeting of EASL, Milan, Italy, Apr. 23-27, 2008. |
| Lam et al., Antimicrob. Agents Chemother. 54: 3187-3196 (2010). |
| Lam et al., Antimicrob. Agents Chemother. 55: 2566-2575 (2011). |
| Lanford and Bigger, Virology 293: 1-9 (2002). |
| Lawitz et al., Abstract 102, Global Antiviral J. 5: 96. |
| Lawitz et al., Abstract 7, J. Hepatol. 56: S4 (2012). |
| Lesburg et al., Curr. Opin. Investig. Drugs 1: 289-96 (2000). |
| Limbach, Patrick A., et al., Summary: The Modified Nucleosides of RNA, Nucleic Acids Research, vol. 22, No. 12, pp. 2183-2196 (1994). |
| Lindenbach, B.D. and Rice, C.M., Flaviviridae: The Viruses and Their Replication (Chapter 32) in Knipe, D.M. et al., eds., Fields Virology, 4th ed. Philadelphia, Lippincott Williams & Wilkins (2001). |
| Lohmann et al. 1999, J. Biol. Chem. 274: 10807-15. |
| Lohmann et al., J. Virol. 71: 8416-28 (1997). |
| Lohmann et al., J. Virol. 75: 1437-49 (2001). |
| Lohmann, V., et al., Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line, Science, vol. 285, pp. 110-113 (1999). |
| Markland et al., Antimicrob. Agents Chemother. 44: 859-66 (2000). |
| Marshall, Science 290: 1870-71 (2000). |
| Matsuda et al., Chem. Pharm. Bull. 36(3): 945-953 and 3967-3970 (1988). |
| McGuigan et al, Antiviral Chem. & Chemother. 12: 293-300 (2001). |
| McGuigan et al., Antiviral Chem. Chemother. 5: 271-277 (1994). |
| McKenzie, Robin, M.D., et al., Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B, The New England Journal of Medicine, vol. 333, No. 17, pp. 1099-1105 (1995). |
| McManus, Appl. Environ. Microbiol. 31: 35-38 (1976). |
| Milne, H. Bayard and Peng, Chi-Hsieh, The Use of Benzylsulfonyl Chloride in Peptide Syntheses, J. Am. Chem. Soc., vol. 79, pp. 639-644 (1956). |
| Moradpour et al., J. Biol. Chem. 277: 593-601 (2002). |
| Mottola et al., Virology 293:31-43 (2002). |
| Murakami et al., J. Biol. Chem. 285: 34337-34347 (2010). |
| Ness and Fletcher, J. Org. Chem. 22: 1470-1473 (1957). |
| News & Analysis, Nature Reviews 10: 891 (2011). |
| Oh et al., J. Virol. 73: 7694-702 (1999). |
| Oxtoby, David W. et al., Principles of Modern Chemistry, Fourth Edition, pp. A.41-A.49 (1999). |
| Pietschmann et al., J. Virol. 75: 1252-64 (2001). |
| Prusoff, Cancer Res. 23: 1246-59 (1963). |
| Randall and Rice, Curr. Opin. Infect. Dis. 14: 743-47 (2001). |
| Rosenberg, J. Mol. Biol. 313: 451-64 (2001). |
| Schmit, Synlett 238-240 (1994). |
| Shi and Lai, Cell. Mol. Life Sci. 58: 1276-95 (2001). |
| Shim, J. et al., Canonical 3′-deoxyribonucleotides as a chain terminator for HCV NS5B RNA-dependent RNA polymerase, Antiviral Research, vol. 58, pp. 243-251 (2003). |
| Shimakami et al., Proc. Nat'l. Acad. Sci U.S.A. 109:941-6 (2012). |
| Singh, Rajendra P. and Shreeve, Jean'ne M., Recent Advances in Nucleophilic Fluorination Reactions of Organic Compounds Using Deoxofluor and DAST, Synthesis, No. 17, pp. 2561-2678 (2002). |
| Sofia et al., J. Med. Chem. 53: 7202-7218 (2010). |
| Sofia et al., Abstracts of Papers, 238th ACS National Meeting, Washington, DC, United States, Aug. 16-20, 2009, MEDI-101. |
| Sofia, Michael J., et al., Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase, J. Med. Chem., vol. 55, pp. 2481-2531 (2012). |
| Song, Xueqin, et al., Amino Acid Ester Prodrugs of the Anticancer Agent Gemcitabine: Synthesis, Bioconversion, Metabolic Bioevasion, and hPEPT1-Mediated Transport, Molecular Pharmaceutics, vol. 2, No. 2, pp. 157-167 (2004). |
| Sowa et al., Bulletin of the Chemical Society of Japan 48(7): 2084-2090 (1975). |
| Stuvyer, L.J. et al., Inhibition of Hepatitis C Replicon RNA Synthesis by β-D-2′-Deoxy-2′-fluoro-2′-C-methylcytidine: A Specific Inhibitor of Hepatitis C Virus Replication, Antimicrobial Agents & Chemotherapy, vol. 17, pp. 79-87 (2006). |
| Stuyver, L.J., et al., Inhibition of the Subgenomic Hepatitis C Virus Replicon in Huh-7 Cells by 2′-deoxy-2′-fluorocytidine, Antimicrobial Agents and Chemotherapy, vol. 48, No. 2, pp. 651-654 (2004). |
| Substitute Declaration of Christoph Seeger, Ph.D. |
| Substitute Declaration of Victor E. Marquez, Ph.D. |
| Taguchi et al., J. of the American Chemical Society 96: 3010-3011 (1974). |
| Taktakishvili and Nair, Tetrahedron Letters 41: 7173-7176 (2000). |
| The Journal of the Americal Chemical Society, Table of Contents, vol. 79, No. 3 (1957). |
| The Merck Index, 2001, 13th ed., 4401. |
| Tisdale et al., Antivir. Chem. Chemother., 4(5): 281-7 (1993). |
| Transcript of Deposition of Christoph Seeger, Ph.D., taken Jul. 25, 2012. |
| Transcript of Deposition of Christoph Seeger, Ph.D., taken Sep. 28, 2012. |
| Transcript of Deposition of Victor E. Marquez, Ph.D., taken Jul. 27, 2012. |
| Transcript of Deposition of Victor E. Marquez, Ph.D., taken Sep. 26, 2012. |
| Trost, Barry M. and Kallander, Lara S., A Versatile Enantioselective Strategy Toward L-C-Nucleosides: A Total Synthesis of L-Showdomycin, J. Org. Chem., vol. 64, No. 15, pp. 5427-5435 (1999). |
| Trost, Barry M., et al., Asymmetric Synthesis of Oxygen Heterocycles via Pd-Catalyzed Dynamic Kinetic Asymmetric Transformations: Application to Nucleosides, Chem Eur. J., vol. 9, pp. 4442-4451 (2003). |
| U.S. Appl. No. 11/854,218 Preliminary Amendment dated Sep. 12, 2007. |
| U.S. Appl. No. 10/608,907 Amendment filed Jul. 24, 2008. |
| U.S. Appl. No. 10/608,907 Amendment filed Aug. 20, 2007. |
| U.S. Appl. No. 10/608,907 Amendment filed Feb. 15, 2007. |
| U.S. Appl. No. 10/608,907 Amendment filed Jan. 20, 2009. |
| U.S. Appl. No. 10/608,907 Amendment filed May 25, 2006. |
| U.S. Appl. No. 10/608,907 Declaration and Power of Attorney filed Jan. 12, 2004. |
| U.S. Appl. No. 10/608,907 Notice of Allowance dated Apr. 7, 2009. |
| U.S. Appl. No. 10/608,907 Supplemental Amendment filed Oct. 30, 2007. |
| U.S. Appl. No. 11/005,444 Amendment dated Apr. 4, 2008. |
| U.S. Appl. No. 11/005,444 Amendment dated Apr. 6, 2009. |
| U.S. Appl. No. 11/005,446 Amendment dated May 7, 2007. |
| U.S. Appl. No. 11/005,469 Amendment dated Dec. 14, 2007. |
| U.S. Appl. No. 11/005,469 Amendment dated Apr. 5, 2007. |
| U.S. Appl. No. 11/854,218 Amendment dated Jun. 20, 2011. |
| U.S. Appl. No. 11/854,218 Amendment dated Oct. 11, 2010. |
| U.S. Appl. No. 11/854,218 Office Action dated Dec. 23, 2010. |
| U.S. Appl. No. 11/854,218 Office Action dated Jul. 22, 2010. |
| U.S. Appl. No. 12/131,868 Amendment dated Jun. 21, 2012. |
| U.S. Appl. No. 12/131,868 Amendment dated May 27, 2011. |
| U.S. Appl. No. 12/131,868 Amendment dated Sep. 20, 2011. |
| U.S. Appl. No. 12/131,868 Declaration and Power of Attorney filed Jun. 2, 2008. |
| U.S. Appl. No. 12/131,868, filed Jun. 2, 2008. |
| U.S. Appl. No. 12/131,868 Office Action dated Aug. 16, 2011. |
| U.S. Appl. No. 12/131,868 Office Action dated Mar. 3, 2011. |
| U.S. Appl. No. 12/131,868 Preliminary Amendment filed Jun. 2, 2008. |
| U.S. Appl. No. 12/131,868 Reponse to Notice to File Corrected Application Papers dated Sep. 17, 2008. |
| U.S. Appl. No. 12/131,868 Response to Restriction Requirement dated Dec. 14, 2010. |
| U.S. Appl. No. 12/131,868 Substitute Specification (clean version). |
| U.S. Appl. No. 12/131,868 Substitute Specification (marked up version). |
| U.S. Appl. No. 12/150,327 Amendment dated Nov. 16, 2010. |
| U.S. Appl. No. 12/878,262 Office Action dated Jun. 8, 2011. |
| U.S. Appl. No. 12/878,262 Preliminary Amendment dated Sep. 9, 2010. |
| U.S. Appl. No. 60/392,350 Corrected Filing Receipt dated Jan. 17, 2008. |
| U.S. Appl. No. 60/392,350 Provisional Application filed Jun. 28, 2002. |
| U.S. Appl. No. 60/474,368 Provisional Appln. Cover Sheet dated May 30, 2003. |
| U.S. Appl. No. 60/474,368, Petition to Correct Inventorship dated Jul. 11, 2005. |
| U.S. Pat. No. 7,429,572 Restriction Requirement dated Sep. 5, 2006. |
| Van Boom et al., Tetrahedron Letters 27: 1211-1214 (1986). |
| Victor E. Marquez, Ph.D. curriculum vitae. |
| Visser v. Hofvander, Interference 103,579, Final Decision (BPAI). |
| Vithanomsat et al., Southeast Asian J. Trop. Med. Public Health 15: 27-31 (1984). |
| Vorbrüggen and Ruh-Pohlenz, Handbook of Nucleoside Synthesis (John Wiley & Sons., Inc., New York), pp. 140-141 and 403 (2001). |
| W.J. Middleton, J. Org. Chem. 40(5): 574-578 (1975). |
| Wachtmeister et al., Tetrahedron 55: 10761-10770 (1999). |
| Wakita, T., et al., Production of infectious hepatitis C virus in tissue culture from a cloned viral genome, Nature Medicine, vol. 11, pp. 791-796 (2005). |
| Wang, Peiyuan, et al., An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NSSB Polymerase, J. Org. Chem., vol. 74, No. 17, pp. 6819-6824 (2009). |
| Watts and Damha, Can. J. Chem., 86: 641-656 (2008). |
| Wilds and Damha, Nucleic Acids Res. 28(18): 3625-3635 (2000). |
| Wohlrab et al., Biochim. Biophys. Acta, 824: 233-42 (1985). |
| Wu, Hepatology 33: 1550-51 (2001). |
| Yamashita et al., J. Biol. Chem. 273: 15479-86 (1998). |
| Yanagi et al., Proc. Natl. Acad. Sci. USA 94: 8738-43 (1997). |
| Yanagi et al., Virology 244: 161-72 (1998). |
| Yang, Shu Shu, et al., Synthesis of DL-1-deoxy-fluoro-6-O-methyl-chiro-inositol: confirmation of a structural-DAST fluorination correlation, Carbohydrate Research, vol. 249, pp. 259-263 (1993). |
| Yi et al., Proc. Nat'l Acad. Sci. U.S.A. 103:2310-5 (2006). |
| Yi, MinKyung, et al., Subgenomic Hepatitis C Virus Replicons Inducing Expression of a Secreted Enzymatic Reporter Protein, Virology, vol. 304, pp. 197-210 (2002). |
| Yoo et al., J. Virol. 69: 32-38 (1995). |
| Zuck, Paul, et al., A Cell-based β-lactamase Reporter Gene Assay for the Identification of Inhibitors of Hepatitis C Virus Replication, Analytical Biochemistry, vol. 344, pp. 344-355 (2004). |
| Codington et al., “Synthesis of 2′-Fluorothymidine, 2′-Fluorodeoxyuridine, and Other 2′-Halogeno-2′-Halogeno-2′-Deoxy Nucleosides,” J. Org. Chem., 29:558 (1964). |
| De Francesco and Rice, “New therapies on the horizon for hepatitis C: are we close?,” Clin. Liver Dis., 7:211-242 (2003). |
| Interference 105,981, Clark Reply 8 dated Jul. 9, 2014. |
| Interference 105,981, Clark Substantive Motion 7 dated Mar. 10, 2014. |
| Interference 105,981, Clark Substantive Motion 8 dated Mar. 10, 2014. |
| Interference 105,981, Clark Substantive Motion 9 dated Mar. 10, 2014. |
| Interference 105,981, Judgment dated Mar. 23, 2015. |
| Interference 105,981, Storer Opposition 7 dated May 23, 2014. |
| Interference 105,981, Storer Opposition 8 dated May 23, 2014. |
| Kawana et al., “The Synthesis of C-Methyl Branched—Chain Deoxy Sugar Nucleosides by the Deoxygenative Methylation of O-Tosylated Adenosines with Grignard Reagents,” Bull. Chem. Soc. Jpn., 61:2437-2442 (1988). |
| King et al., “Inhibition of the replication of a hepatitis C virus-like RNA template by interferon and 3′-deoxycytidine,” Antiviral Chemistry and Chemotherapy, 13:363-370 (2002). |
| O'Boyle, “Development of a cell-based high-throughput specificity screen using a hepatitis C virus-bovine viral diarrhea virus dual replicon assay,” Antimicrob. Agents Chemother., 49(4):1346-1353 (2005). |
| Pankiewicz, “Fluorinated nucleosides,” Carbohydr. Res., 327(1-2):87-105 (2000). |
| Stein et al., “Phosphorylation of Nucleoside Analog Antiretrovirals: A Review for Clinicians,” Phamacotherapy, 21:11-34 (2001). |
| Stuyver et al., “Hepatitis C therapeutics: current status and emerging strategies,” Nat. Rev. Drug Dicov., 1(11):867-881 (2002). |
| Tan et al., “Hepatitis C therapeutics: current status and emerging strategies,” Nat. Rev. Drug Discov., 1(11):867-881 (2002). |
| Tong et al., “Nucleosides of thioguanine and other 2-amino-6-substituted purines from 2-acetamido-5-chloropurine,” J. Org. Chem., 32:859-862 (1967). |
| Walker and Hong, “HCV RNA-dependent RNA polymerase as a target for antiviral development,” Curr. Opin. Pharmacol., 2(5):534-540 (2002). |
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| 60206585 | May 2000 | US |
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