EP1656093A2 - Nucleosides for treatment of infection by corona viruses, toga viruses and picorna viruses - Google Patents

Nucleosides for treatment of infection by corona viruses, toga viruses and picorna viruses

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Publication number
EP1656093A2
EP1656093A2 EP04776022A EP04776022A EP1656093A2 EP 1656093 A2 EP1656093 A2 EP 1656093A2 EP 04776022 A EP04776022 A EP 04776022A EP 04776022 A EP04776022 A EP 04776022A EP 1656093 A2 EP1656093 A2 EP 1656093A2
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EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
pharmaceutically acceptable
compound
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04776022A
Other languages
German (de)
French (fr)
Inventor
Jean-Pierre Sommadossi
Gilles Gosselin
Paolo La Colla
Richard Storer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universita degli Studi di Cagliari
Idenix Cayman Ltd
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universita degli Studi di Cagliari
Idenix Cayman Ltd
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Application filed by Centre National de la Recherche Scientifique CNRS, Universita degli Studi di Cagliari, Idenix Cayman Ltd filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1656093A2 publication Critical patent/EP1656093A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • This invention is in the area of methods and pharmaceutical compositions for the treatment of viral infections, including the viral causative agent of severe acute respiratory syndrome.
  • Coronaviruses are a diverse group of positively (+)-stranded RNA viruses that have been implicated in causing a variety of pathological conditions in both humans and other animals (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10).
  • the coronavirus is composed of an envelope5 and helical nucleocapsid with club-shaped surface projections that provide "attachment to cells, hemagglutination, and membrane fusion.” (Biichen-Osmond, C. (Ed), (2003). 00.026.0.01. Coronaviridae. In: ICTVdB - The Universal Virus Database, version 3.
  • ICTVdB Management The Earth Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA).
  • the complete genome is 25,000 to 33,000 nucleotides long and0 consists of a "single molecule of linear positive-sense single-stranded RNA (Biichen- Osmond, C. (Ed), (2003). 00.026.0.01. Coronaviridae.
  • ICTVdB The Universal Virus Database, version 3.
  • ICTVdB Management The Earth Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA).
  • the Coronaviruses are broken up into three distinct categories based upon antigenic relationships whereby groups I and II are mammalian viruses and group III is an avian virus (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10). Within each antigenic category (I, II, or III), the Coronaviruses are further classified based upon their narrow host range and genome organization (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10).
  • group III is an avian virus
  • HCV-229E human respiratory coronavirus
  • TGEV porcine transmissible gastroenteritis virus
  • CCV canine coronavirus
  • FECV feline enteric coronavirus
  • FIPV feline infectious peritonitis virus
  • RbCV rabbit coronavirus
  • the mammalian viruses for Antigenic group II include human respiratory coronavirus (HCV-OC43) (causes human respiratory infection and may be implicated in enteric infections), mouse hepatitis virus (MHV) (causes mouse respiratory infection, enteric infection, hepatitis, and neurologic infection), sialodacryoadnavirus (SDAV) (causes rat neurologic infection), porcine hemagglutinating encephalomyelitis virus (HEV) (causes pig respiratory infection, enteric infection, and neurologic infection), bovine coronavirus (BCV) (causes cow enteric infection), rabbit enitis coronavirus (RbEVC) (causes rabbit enteric infection), and turkey coronavirus (TCV) (causes turkey respiratory infection, enteric infection, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis) (KN.
  • the avian virus for Antigenic group III include avian infectious bronchitis virus (IBV) (causes chicken respiratory infection, hepatitis, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis) (KN. Holmes and M.M.C.
  • IBV infectious bronchitis virus
  • the complete genome of this family of viruses is composed of 9,700 to 11,800 nucleotides and contains "one molecule of linear positive-sense single stranded R ⁇ A.” This family of viruses infects both vertebrates and plants.
  • the complete genome of the alphavirus genus of the Togaviridae family is 11,000 to 12,000 nucleotides and is composed of "one molecule of linear positive-sense single stranded R ⁇ A (B ⁇ chen-Osmond, C. (Ed), (2003). 00.026.0.01. Alphavirus.
  • ICTVdB The Universal Virus Database, version 3.
  • ICTVdB Management The Earth
  • the alphaviruses unlike the coronaviruses discussed above, have a broad host range and have the ability to replicate in a variety of cell types (S. Schlesinger and M.J. Schlesinger, "Togaviridae: The viruses and their replication," Fields Virology, B. ⁇ . Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers,
  • viruses classified within this genus are the Sindbis virus,
  • the genus Rubivirus of the Togaviridae family are distinguished from alphaviruses on the basis of a limited host range. This genus consists of only the Rubella virus, which is found exclusively in humans.
  • the Picornaviridae family of viruses are categorized as small, naked, icosahedral, R ⁇ A-containing animal viruses that are separated into six genera: the rhinoviruses, enteroviruses, aphthoviruses, cardioviruses, hepatoviruses, and unassigned (R.R. Rueckert, "Picornaviridae: The viruses and their replication," Fields Virology, B.N.
  • the genus rhinovirus includes the human rhinoviruses lA-100, IB, "Hanks," and bovine rhinoviruses 1, 2, and 3.
  • the human rhinoviruses consist of at least 105 serotypes (a classification scheme based on the variation of surface epitopes) and represent the most common etiological agent for the common cold.
  • this particular genus is highly labile and the complete genome consists of 100-170 nucleotides (retrieved from All the Virology on the World Wide Web, Internet URL: http://www.mlane.edu/dmsanderAVWW/335/Picornaviruses.html). While seven serotypes have been identified to date (A; C; O; SAT1,2,3; Asia-1), at least fifty-three subtypes have also been characterized. The cardioviruses consist of two serotypes.
  • Encephalomyocarditis (EMC) virus a mouse virus that can infect humans, elephants, and squirrels; includes mengovirus, Maus-Elberfield virus, and the Columbia virus
  • EMC Encephalomyocarditis
  • TEE Theiler's murine encephalocyelitis virus
  • TO, GDVII Theiler's murine encephalocyelitis virus
  • R.R. Rueckert "Picornaviridae: The viruses and their replication," Fields Virology, B.N. Fields, D.M. Knipe and P.M.
  • SARS severe acute respiratory syndrome
  • SARS is characterized by a non-specific onset and an incubation period of 2-10 days, both of which favor transmission among individuals. Transmission appears to occur by close contacts with infected individuals, thus suggesting that spread is via body secretions and fluids, but may also occur by droplets via aerosol routes.
  • the disease begins with a prodrome of fever greater than 38 °C, sometimes accompanied by chills, headaches, malaise and/or myalgias.
  • Respiratory symptoms generally are mild at this early stage. However, at about day 3 to day 4, a dry cough or dyspnea, sore throat, and erythema on the trunk of the patient appear. These symptoms are accompanied by hypoxemia that may require mechanical intervention and bilateral chest opacifications. While the chests of some patients remain clear, most patients exhibit foci of interstitial infiltrates that eventually become generalized, opaque patches or "crackles". Chest radiographs from some late stage SARS patients show areas of foci consolidation (Canada Communicable Disease Report, PREVIEW, 21 March 2003).
  • results of laboratory tests indicate elevated levels of aspartate aminotransferase, lactate dehydrogenase, and maximal levels of C-reactive protein at about day 7 or day 8, together with lymphopenia, leukopenia, and thrombocytopenia.
  • a period of convalescence generally begins on about day 10 following infection except in about 4- 15% of the infected population in which the disease is fatal (Drosten et al., The New England Journal of Medicine Online, April 10, 2003, pp. 1-10).
  • the etiologic agent responsible for SARS is a new coronavirus, SARS Co-V, first suggested by J. Peiris, C. Drosten, and T.G. Ksiazek working at three different research facilities. M.
  • SARS Co-V genome Peiris and his research group in Canada were first to successfully sequence the SARS Co-V genome, which was later confirmed by the Centers for Disease Control. They identified 11 open reading frames (ORFs) that correspond to regions predicted to encode a variety of polypeptides including polymerase proteins (polymerase la and lb), spike protein (S), small membrane protein (E), membrane protein (M), and nucleocapsid protein (N).
  • ORFs open reading frames
  • S spike protein
  • E small membrane protein
  • M membrane protein
  • N nucleocapsid protein
  • the complete SARS Co-V genome comprises 29,727 nucleotides and has a structural organization that is similar to other coronaviruses. (Retrieved from the Center for Disease Control; Internet URL: http://www.cdc.gov/ncidod/sars/sequence.html).
  • antiviral agents that have been identified as active against (+)-RNA viruses include interferon and ribavirin (Battaglia, A.M. et al., Ann. Pharmacother, 2000,. 34, 487-494); Berenguer, M. et al. Antivir. Ther., 1998, 3 (Suppl. 3), 125-136).
  • Interferon Interferons are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, and are known to suppress serum viral RNA to undetectable levels. Additionally, IFN normalizes serum amino transf erase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8%-9% of patients with chronic viral infection (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Interferons (IFNs) have been commercially available for the treatment of chronic hepatitis for nearly a decade. In addition, a number of patents disclose anti-viral treatments using interferon-based therapies. For example, U.S. Patent No. 5,928,636 to
  • Alber et al. discloses the combination therapy of interleukin-12 and interferon alpha for the treatment of infectious diseases.
  • U.S. Patent No. 5,908,621 to Glue et al. discloses the use of polyethylene glycol modified interferon for the treatment of viral infections.
  • U.S. Patent No. 5,849,696 to Chretien et al. discloses the use of thymosins, alone or in combination with interferon, for treating viral infections.
  • Valtuena et al. discloses a combination anti-viral therapy employing interferon and a free radical scavenger.
  • U.S. Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins for treating viral infections.
  • Other interferon-based treatments are disclosed in U.S. Patent No. 5,676,942 to Testa et al, U.S. Patent No. 5,372,808 to Blatt et al, and U.S. Patent No. 5,849,696.
  • Ribavirin (l- ⁇ -D-ribofuranosyl-l-l,2,4-triazole-3-carboxarnide) is a synthetic, non-interferon-inducing, broad spectrum antiviral nucleoside analog. It is sold under the trade names VirazoleTM (The Merck Index, 11th edition, Editor: Budavari, S., Merck & Co., Inc., Rahway, NJ, pl304, 1989); Rebetol (Schering Plough) and Co-Pegasus
  • Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses (Gary L. Davis. Gastroenterology 2000, 118:S104-S114).
  • U.S. Patent No 4,211,771 discloses the use of ribavirin as an antiviral agent. Ribavirin (Battaglia, A.M. et al., Ann.
  • Ribavirin reduces serum amino transferase levels to normal in 40% of patients, but it does not lower viral serum levels (Gary L. Davis. Gastroenterology 2000, 118:S104-S114). Thus, ribavirin alone is not effective in reducing viral RNA levels.
  • ribavirin has significant toxicity and is known to induce anemia.
  • antiviral agents that have been identified as active against certain (+)-RNA viruses are: (1) Substrate-based NS3 protease inhibitors (for example, Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al.
  • Substrate-based NS3 protease inhibitors for example, Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al
  • Inhibitors of serine proteases including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate (for example, Llinas-Brunet et al, PCT WO 99/07734); (2) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (for example, Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and
  • a method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active 1', 2', 3' or 4' -branched ⁇ -D or ⁇ -L nucleosides or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. See also U.S. Patent
  • WO 03/051899, WO 03/061576, WO 03/062255 WO 03/062256, WO 03/062257, and WO 03/061385, filed by Ribapharm, also are directed to the use of certain nucleoside analogs to treat viral infections.
  • RNA vimses infected with any one of these (+)-stranded RNA vimses. It is yet another object of the present invention to provide a compound, composition, and method of use for the treatment of a host, especially a human, infected with the SARS coronavirus in an attempt to halt the spread of SARS.
  • compositions for the treatment of infections caused by a coronavirus, togavims or picomavims include administering an effective amount of a ⁇ -D or ⁇ -L-nucleoside of the formula below or a pharmaceutically acceptable salt or prodrug thereof.
  • a compound for the treatment of a coronavirus, togavirus or picomavims is provided wherein the compound is of the formula (AA), or a pharmaceutically acceptable salt or prodmg thereof:
  • R 1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodmg); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group that when administered in
  • X is O, S, SO 2 , CH 2 , or CHOH; m is 0, 1 or 2;
  • R 13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
  • A is H, OH, C alkyl, halo (F, CI, Br, or I), azido, cyano, C 2-6 alkenyl, C 2-6 alkynyl, Br-vinyl, 2-Br-ethyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(alkenyl), CF 3 , NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , or -N(acyl) 2 ; and
  • Base is as defined in the specification, including a purine or pyrimidine or a compound including but not limited to:
  • each R 8 , R , 10 , R , R , 1 I 2 and R .13 i •ndependently is H, NH 2 , SH, CF 3 , halo, NO 2 , N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl (preferably optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH-heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O-heterocycle, -O- heteroaryl, C 1-4 alkylamino, di(C ⁇ -4 alkyl)amino, C 3-6 cycloalkylamino, Ci.
  • the compound for use in the present invention is in the form of its 2', 3', and/or 5 '-prodmg.
  • the compound is a prodmg that includes biologically cleavable moieties at the 2', 3' and or
  • the compound is an acyl prodrug with biologically cleavable acyl moieties at the 2', 3' and/or 5' positions.
  • the compound is an amino acid ester prodmg with biologically cleavable amino acid moieties at the 2', 3' and/or 5' positions.
  • Preferred moieties are amino acid esters including valyl, and alkyl esters including acetyl.
  • this invention specifically includes the 2'-L-amino acid ester, 3'-L-amino acid ester, 2',5'-L-diamino acid ester, and 3',5'-L-diamino acid ester of the nucleosides of the present invention; and the 2'- ester, 3'-ester, 2',5'-diester and 3',5'-diester of the nucleosides wherein (i) the 2' and/or 3' ester is an amino acid ester and the 5 '-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2' and/or 3' ester is independently an alkyl or aryl ester and the 5 '-ester is an amino acid ester.
  • the active compounds of the present invention can be administered in combination, alternation or sequential steps with another antiviral agent, including an anti-(+)-stranded RNA vims agent.
  • an anti-(+)- stranded RNA vims compound is used that exhibits an EC50 of less than 10 ⁇ M, and preferably less than 1-5 ⁇ M.
  • the active compounds of the present invention include both ⁇ -D and ⁇ -L nucleoside compounds of the general formula (AA) or a pharmaceutically acceptable salt or prodmg thereof; a pharmaceutical composition comprising one or more of these compounds; a medicament comprising one or more of these compounds; and a process for preparing such a composition and/or medicament.
  • Figure 1 shows exemplified compounds of the invention.
  • Figure 2 shows a phylogenetic tree of the SARS-associated coronavims.
  • the present invention provides a compound, method and composition for the treatment of a host, and in particular a human or an animal, infected with a (+)-stranded RNA vims that is a coronavims, such as SARS-CoV, a togavims, such as a rubiviras (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), or a picomavirus, such as an enterovims (particularly Coxsackieviruses, poliovimses, hepatitis A, echovirases and the four human enterovims species), a rhinovirus, a cardiovims and an aphthoviras.
  • a coronavims such as SARS-CoV
  • a togavims such as a rubiviras (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis)
  • a picomavirus such
  • This treatment includes administering an effective amount of an anti-coronavims, anti-togavirus, or anti-picornavirus ⁇ -D- or ⁇ -L- nucleoside as described herein, or a pharmaceutically acceptable salt or prodmg thereof, optionally in a pharmaceutically acceptable carrier.
  • the compounds of this invention either possess antiviral activity, or are metabolized to a compound that exhibits such activity. All coronavimses, togavimses and picornaviruses are intended for inclusion within the scope of this invention. In particular, the invention is directed to:
  • Togavimses such as, for example, mbivimses that cause rubella and alphaviruses that cause encephalitis;
  • Picornaviruses including all four (4) major genera of enteroviruses (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enterovims species), rhinoviruses, cardiovimses and aphthovimses.
  • coronaviruses that can be treated according to this invention includes, but are not limited to, human respiratory coronavirus (HCV-229E), porcine transmissible gastroenteritis vims (TGEV), canine coronavims (CCV), feline enteric coronavims (FECV), feline infectious peritonitis vims (FIPV), rabbit coronavims (RbCV), human respiratory coronavirus (HCV-OC43), mouse hepatitis vims (MHV), sialodacryoadnavirus (SDAV), porcine hemagglutinating encephalomyelitis vims (HEV), bovine coronavims (BCV), rabbit enitis coronavims (RbEVC), turkey coronavirus (TCV), and avian infectious bronchitis vims (IBV).
  • HCV-229E human respiratory coronavirus
  • TGEV porcine transmissible gastroenteritis vims
  • Togavimses that can be treated according to the present invention includes, but are not limited, alphavimses (such as for example Sindbis virus, EasternAVestern encephalitis vimses, Semliki Forest vims, and Ross River vims) and mbivimses (such as for example Rubella vims).
  • alphavimses such as for example Sindbis virus, EasternAVestern encephalitis vimses, Semliki Forest vims, and Ross River vims
  • mbivimses such as for example Rubella vims.
  • the present invention provides the following: a) a pharmaceutical composition comprising a ⁇ -D- or ⁇ -L-nucleoside compound of the general Formula (AA), (I-XXVHI), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, optionally with a pharmaceutically acceptable carrier, excipient or diluent; b) a pharmaceutical composition comprising a ⁇ -D- or ⁇ -L-nucleoside compound of the general Formula (AA), (I-XXVHT), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodmg, thereof, with one or more other effective antiviral agents (for example other effective anti-coronavims, such as anti-SARS- CoV, anti-togavims, such as anti-rubivirus (the causative agent for rubella) and anti- alphavims (the causative agent for
  • a coronavirus such as SARS- CoV
  • a togavirus such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis)
  • a picomavirus such as an enteroviras (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enteroviras species), a rhinovirus, a cardiovirus and an aphthoviras infection in a host, such as a mammal, for example a human; m) use of a coronavirus, such as SARS- CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavirus, such as an enteroviras (particularly Coxsackieviruses, poliovimses, hepatitis A, echo
  • a coronavirus such as SARS- CoV
  • a togavirus such as a rubivirus (the causative agent for rubella)
  • an alphavirus such as SARS- CoV
  • a picomavims such as an enterovims (particularly Coxsackievirases, polioviruses, hepatitis A, echovirases and the four human enteroviras species), a rhinovirus, a cardiovims and an aphthoviras, infection are described that include administering an effective amount of a ⁇ -D or ⁇ -L-nucleoside of the general formula below, or a pharmaceutically acceptable salt or prodmg thereof.
  • a compound for the treatment of a coronavirus, togavims or picomavirus is provided wherein the compound is of the formula (AA):
  • R 1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo
  • X is O, S, SO 2 , CH 2 , or CHOH; m is 0, 1 or 2; R 13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl; A is H, OH, C 1-4 alkyl, halo (F, CI, Br, or I), azido, cyano, C 2-6 alkenyl, C 2-6 alkynyl, Br-vinyl, 2-Br-ethyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(alkenyl), CF 3 , NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , or -N(acyl) 2 ; and
  • each R 8 , R 10 , R 11 , R 12 and R 13 independently is H, NH 2 , SH, CF 3 , halo, NO 2 , N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl (preferably optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH-heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O-heterocycle, -O- heteroaryl, C M alkylamino, di(CM alkyl)amino, C 3-6 cycloalkylamino, .
  • compositions for the treatment of SARS- CoV, coronavims, togavirases, and/or picornaviruses infection, or more generally any (+)-RNA viral infection include administering an effective amount of a ⁇ -D or ⁇ -L-nucleoside of the Formulae (I) - (XXVHI), or a pharmaceutically acceptable salt or prodmg thereof.
  • use of a compound for the treatment of a coronavirus, togaviras or picomavims is provided wherein the compound is of the formula (I):
  • R 1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo
  • cycloalkylamino an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), a C 3-7 cycloalkylamino, CF 3 , mercapto, optionally substituted C 1-4 alkyl, . ⁇ 2 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 2-6 alkenyloxy, C alkylthio, C ⁇ -8 alkylcarbonyloxy, aryloxycarbonyl, C 1-4 alkylamino, di(C alkyl)amino, Br-vinyl, -C(O)O(alkyl), O-phosphate or O- phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); O-acyl (including lower acyl);
  • X is O, S, SO 2, CH 2 , CHOH, CH-halogen, C-(halogen) 2 ;
  • m is 0, 1 or 2;
  • R 4 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
  • A is H, OH, C ⁇ -4 alkyl, halo, azido, cyano, C 2-6 alkenyl, C 2-6 alkynyl, Br-vinyl, 2-Br- ethyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(alkenyl), CF 3 , NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , or -N(acyl) 2 ; and Base is defined in the specification, including but not limited to:
  • Y is O or S; Y' is H, OH, SH, NH 2 , halo, CF 3 , C alkyl, C M alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, or C 1-4 alkoxy; Z is H, NH 2 , CF 3 , C 1- alkyl, C M alkylamino, di(CM alkyl)amino, or C 3-6 cycloalkylamino, and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • R 1 , R 3 , and R 5 are defined as above;
  • R' is H, OH, SH, halo (F, CI, Br, or I), optionally substituted C 1- alkyl, optionally substituted C 2-4 alkenyl or C 2-4 alkynyl, N 3 , CN, CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, alkoxy, CF 3 , C(A) 3 , 2-Br- ethyl, CH 2 F, CH 2 C1, CH 2 CF 3 , CF 2 CF 3 , CH 2 (A), C(A) 2 (A) 3 , haloalkenyl, Br- vinyl, haloalkynyl;
  • a compound for the treatment of a coronavirus, togavirus or picomavims wherein the compound is of the formula (HI):
  • R , R , R , R' and A are all as defined above; or R' and R , together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or unsaturated ring that optionally may have one or more heteroatoms selected from the group consisting of O, S, N, or P;
  • X is defined as above; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • R 1 , R 3 , R 5 , and R' are all as defined above;
  • X is as defined above; and
  • Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • R 1 , R 3 , R 5 and R' are all as defined above;
  • X * is CH, C-OH, or C-halogen (wherein halogen includes F, CI, Br, and I); and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • the use of a compound for the treatment of a coronavirus, togaviras or picomavirus is provided wherein the compound is of the formulas (V ⁇ ), (Vi ⁇ ), (IX), or (X):
  • R 1 , R 3 , R 5 , R' are all as defined above;
  • X is defined as above; is an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S, and/or N);
  • Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • a compound for the treatment of a coronavirus, togavirus or picomavims wherein the compound is of the formulae (XI), (Xn), (Xffl), or (XIV):
  • R 1 , R 3 , R 5 , and R' are all as defined above, except that R' in Formula (XI) is -OH, -NH 2 or -SH only when X is C; X is as defined above;
  • Each R 2' and R 4' independently, is H, -OH, -SH, -NH 2 , -CF 3 , CI, F, Br, I, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, -CH 2 OH, alkoxy, CH 2 F, CH 2 N 3 , CH 2 CN, -(CH 2 ) m C(O)OR 4 , -(CH 2 ) m C(O)NHR 4 , -(CH 2 ) m C(O)N(R 4 ) 2 , -NH(alkyl), -
  • R l , R 2' , R 3 , R 5 , R 6 , and R' are all as defined above, except that R 6 is -OH, -NH 2 or - SH only when X is C;
  • X and X* are as defined above; each R 7 is independently H, -OR 1 , -OH, -NO 2 , -CF 3 , -NH 2 , CI, F, Br, I, N 3 , CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br-vinyl, -CH 2 OH, -O(R), alkoxy, -(CH 2 ) m C(O)O(R), -OC(O)O-aryl, -OC(O)O-aralkyl, -SR, -(CH 2 ) m NHR,
  • R 1 , R 3 , R 5 , R 6 , R 7 , and R' are all as defined above, except that R 6 is -OH, -NH 2 or - SH only when X is C; X is defined as above; m is 0, 1 or 2; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • a compound for the treatment of a coronavirus, togaviras or picomavirus wherein the compound is of the formulas Al-Nl :
  • the compound of the present invention is in the form of its 2', 3', and/or 5 '-prodmg.
  • the compound is a prodrug that includes biologically cleavable moieties at the 2', 3' and or
  • the compound is an acyl prodrug with biologically cleavable acyl moieties at the 2', 3' and or 5' positions.
  • the compound is an amino acid ester prodrug with biologically cleavable amino acid moieties at the 2', 3' and/or 5' positions.
  • Preferred moieties are amino acid esters including valyl, and alkyl esters including acetyl.
  • this invention specifically includes the 2'-L-amino acid ester, 3'-L-amino acid ester, 2',5'-L-diamino acid ester, and 3',5'-L-diamino acid ester of the nucleosides of the present invention; and the 2'- ester, 3 '-ester, 2',5'-diester and 3',5'-diester of the nucleosides wherein (i) the 2' and/or 3' ester is an amino acid ester and the 5 '-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2' and/or 3' ester is independently an alkyl or aryl ester and the 5 '-ester is an amino acid ester.
  • the active compounds of the present invention can be administered alone or in combination, alternation or sequential steps with another anti-coronavims, such as anti- SARS-CoV, anti-togavirus, such as anti-mbiviras (the causative agent for rabella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picornavirus, such as anti-enterovims (particularly Coxsackievirases, poliovirases, hepatitis A, echovirases and the four human enteroviras species), anti-rhinovirus, anti-cardioviras and anti- aphthovirus, or more generally any (+)-RNA active agent.
  • anti-coronavims such as anti- SARS-CoV, anti-togavirus, such as anti-mbiviras (the causative agent for rabella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picornavirus, such as anti-
  • an anti-SARS-CoV, anti-coronaviras, anti- togavirus, and/or anti-picornavirus compound that exhibits an EC 50 of 10-15 ⁇ M or less, or preferably less than 1-5 ⁇ M is desirable.
  • the active compound can be administered as any salt or prodrag 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, which are alternatively referred to as "physiologically acceptable salts", and a compound that has been alkylated or acylated at the 3'- or 5'- position or on the purine or pyrimidine base, thereby forming a type of "pharmaceutically acceptable prodrag".
  • 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 prodrag and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art.
  • alkyl as used herein, unless otherwise specified, includes a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically to Cio, and specifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethybutyl, and 2,3- dimethylbutyl.
  • the term includes both substituted and unsubstituted alkyl groups.
  • Moieties with which the alkyl group can be substitoted with one or more substitoents include but are not limited to halo, including CI, F, Br and I so as to form, for eg., CF 3 , 2- Br-ethyl, CH 2 F, CH 2 C1, CH 2 CF 3 , or CF 2 CF 3 ; hydroxyl, for eg.
  • CH 2 OH amino, for eg., CH 2 NH 2 , CH 2 NHCH 3 , or CH 2 N(CH 3 ) 2 ; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido, for eg., CH 2 N 3 ; cyano, for eg., CH 2 CN; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, either unprotected or protected as necessary, known to those skilled in the art, for eg., as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition (1991), incorporated herein by reference.
  • lower alkyl as used herein, and unless otherwise specified, includes a Ci to C 6 saturated straight, branched, or if appropriate, cyclic as in cyclopropyl, for eg., alkyl group, including both substituted and unsubstitoted 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.
  • alkylamino and “arylamino” refer to an amino group that has one or two alkyl or aryl substituents, respectively.
  • aryl as used herein and, unless otherwise specified, includes phenyl, biphenyl or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties.
  • the aryl group can be substitoted with one or more moieties including but not limited to alkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, alkylthio, carboxamido, carboxylate, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected as necessary, as known to those skilled in the art, for eg., as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition (1991), incorporated herein by reference.
  • moieties including but not limited to alkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, alkylthio, carboxamido, carboxylate, sulfonic acid, sulfate,
  • alkaryl and akylaryl refer to an alkyl group with an aryl sustitoent.
  • aralkyl and “arylalkyl” refer to an aryl group with an alkyl substituent.
  • halo as used herein includes bromo, chloro, iodo and fluoro.
  • base refers to any purine or pyrimidine base including, but not limited to, adenine, N 6 -alkylpurines, (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 - acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -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, C 5 -alkylpyrimidines, C 5 -benzyl
  • each Q 8 is independently H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylamino, di(C ]-4 alkyl)amino, hydroxy, C ⁇ -6 alkoxy, C ⁇ -6 alkylthio, C 1-6 alkylsulfonyl, (C 1- alkyl)0-2 aminomethyl, N, CN, NO 2 , .
  • each Ti and T 2 is independently selected from N, CH, or each Q 16 , U, and Y is independently selected from is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 , Br-vinyl, -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, NH 2 , NH- alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl,
  • each T 3 and T 4 is independently selected from N or CQ ,22.
  • each Q 22 is independently selected from H, OH, substituted or unsubstitoted alkyl, substitoted or unsubstituted alkenyl, substitoted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 , Br-vinyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, NH 2 , NH-alkyl, N-dialkyl, NH- acyl, N-aryl, N-aralkyl,
  • 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.
  • acyl includes 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 halogen, C ⁇ -C 6 alkyl or C ⁇ -C 6 alkoxy; sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl; the mono-, di- or triphosphate ester; trityl or monomethoxytrityl; substituted benzyl; trialkylsilyl as, for eg., dimethyl-t-butylsilyl or diphenylmethylsilyl.
  • Aryl groups in the esters optimally comprise a phenyl group.
  • the term "acyl" or O-linked ester refers to a group of the formula C(O)R', wherein R' is an straight, branched, or cyclic alkyl (including lower alkyl), carboxylate residue of an amino acid, aryl including phenyl, heteroaryl, alkaryl, aralkyl including benzy 1, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substitoted with chloro, bromo, fluoro, iodo, to C 4 alkyl or Q to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-
  • Aryl groups in the esters optimally comprise a phenyl group.
  • acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl- carboxy, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyloctanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, ⁇ -methoxy- ⁇ -trifluoromethyl- phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2- diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroace
  • lower acyl includes an acyl group in which the non-carbonyl moiety is lower alkyl.
  • amino acid includes naturally occurring and synthetic ⁇ , ⁇ , ⁇ , or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine arid histidine.
  • the amino acid is in the L- configuration, but can also be used in the D-configuration.
  • the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ - leucinyl, ⁇ -isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ - glycin
  • the terms “substantially free of and “substantially in the absence of refer to a nucleoside composition that includes at least 85 or 90% by weight, preferably at least 95% or 98% by weight, and even more preferably at least 99% or 100% by weight, of the designated enantiomer of that nucleoside.
  • the compounds listed in the methods and compounds of this invention are substantially free of enantiomers other than for the one designated.
  • isolated refers to a nucleoside composition that includes at least 85% or 90% by weight, preferably 95% or98% y weight, and even more preferably 99% or 100% by weight, of the nucleoside.
  • the term "host”, as used herein, refers to a 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 coronavims, togavims and/or picomavims 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 coronavims, togaviras and/or picomavims 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 in chimpanzees.
  • pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (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.
  • 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 coronavirus, togaviras and/or picomavims or are metabolized to a compound that exhibits such activity.
  • nucleotide Prodrug Formulations Any of the nucleosides described herein can be administered as a nucleotide prodmg to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
  • a number of nucleotide prodmg ligands are known.
  • alkylation, acylation or other lipophilic modification of the mono-, di- or triphosphate of the nucleoside reduces polarity and allows passage into cells.
  • 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.
  • Bischoferger Antiviral Research, 1995, 27:1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.
  • administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • 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, ascorate; ⁇ -ketoglutarate, and ⁇ -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.
  • 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. Raen, Modest E.K., D.L.W., and C.
  • lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, W090/00555, W091/16920, W091/18914, W093/00910, W094/26273, W0 96/15132, EP 0 350287, EP 93917054.4, and WO 91/19721.
  • Combination and Alternation Therapy Drug-resistant variants of coronavirus, togaviras and/or picomavims may emerge after prolonged treatment with an antiviral agent. Drag resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against the viral 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 drag 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 vims. Any of the viral treatments described in the Background of the Invention can be used in combination or alternation with the compounds described in this specification. Nonlimiting examples include:
  • Interferon A number of patents disclose anti-viral treatments, using interferon-based therapies.
  • U.S. Patent No. 5,928,636 to Alber et al. discloses the combination therapy of interleukin-12 and interferon alpha for the treatment of infectious diseases.
  • U.S. Patent No. 5,849,696 to Chretien et al. discloses the use of thymosins, alone or in combination with interferon.
  • U.S. Patent No. 5,830,455 to Valtoena et al. discloses a combination therapy employing interferon and a free radical scavenger.
  • U.S. Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins.
  • Interferon alpha-2a and interferon alpha-2b are currently approved as monotherapy.
  • ROFERON ® -A (Roche) is the recombinant form of interferon alpha-2a.
  • Pegasys ® (Roche) is the pegylated (i.e. polyethylene glycol modified) form of interferon alpha-2a.
  • Interferon alpha-2b is the recombinant form of Interferon alpha-2b
  • PEG-INTRON ® is the pegylated form of interferon alpha-2b.
  • Other forms of interferon alpha, as well as interferon beta, gamma, tau and omega are currently in clinical development.
  • INFERGEN interferon alphacon-1 by InterMune
  • OMNIFERON natural interferon
  • ALBUFERON Human Genome Sciences
  • REBIF interferon beta- la
  • Ares-Serono Omega Interferon by BioMedicine
  • Oral Interferon Alpha by Amarillo Biosciences
  • interferon gamma interferon tau
  • interferon gamma- lb by InterMune
  • Combination therapy with an alpha interferon and ribavirin is a common antiviral therapy.
  • the combination of interferon and ribavirin has been reported to be effective in the treatment of interferon na ⁇ ve patients (for example, Battaglia, A.M. et al.,
  • REBETOL ® (Ribavirin, USP) capsules is available from Schering Corporation. REBETOL ® (Schering Corporation) has also been approved in combination with
  • Substrate-based NS3 protease inhibitors for example, Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral
  • Non-substrate-based inhibitors for example, 2,4,6-trihydroxy-3-nitro- benzamide derivatives (for example, Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), 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; (5) Thiazolidine derivatives which show relevant inhibition in a reverse- phase HPLC assay (for example Sudo K.
  • NS3 inhibitors for example, those based on the macromolecule elgin c, isolated from leech (for example, Qasim M.A. et al., Biochemistry, 1997, 36, 1598-1607);
  • Helicase inhibitors for example Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D.
  • Inhibitors of IRES-dependent translation for example, Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP- 08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Pub.
  • Nuclease-resistant ribozymes for example Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995).
  • Nucleoside analogs have also been developed for the treatment of viral infections. Examples include the following. Idenix Pharmaceuticals, Ltd. discloses branched nucleosides, and their use in the treatment of HCV and flaviviruses and pestiviruses in US Patent Publication No. 2003/0050229 Al and US Patent Publication No. 2003/0060400 Al, which correspond to International Publication Nos. WO 01/90121 and WO 01/92282.
  • a method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active 1', 2 ', 3' or 4' -branched ⁇ -D or ⁇ -L nucleosides or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. See also U.S . Patent Publication Nos. 2004/0006002 and 2004/0006007 as well as WO 03/026589 and WO 03/026675. Idenix Pharmaceuticals, Ltd. also discloses in US Patent Publication No.
  • WO 02/18404 (PCT/EP01/09633; published August 21, 2001); WO 02/100415 and WO 02/094289, filed by F. Hoffmann- La Roche AG discloses various nucleoside analogs for the inhibition of viral RNA replication.
  • Pharmasset Limited discloses various nucleosides and antimetabolites for the treatment of a variety of viruses, in WO 02/32920, WO 01/79246, WO 02/48165, WO 03/068162, WO 03/068164 and 2004/013298.
  • Merck & Co., Inc. and Isis Pharmaceuticals disclose in US Patent Publication No. 2002/0147160 and the corresponding International Patent Publication Nos.
  • WO 02/057425 (PCT/US02/01531; filed January 18, 2002) and WO 02/057287 (PCT/US02/03086; filed January 18, 2002) various nucleosides, and in particular several pyrrolopyrimidine nucleosides, for the treatment of vimses whose replication is dependent upon RNA-dependent RNA polymerase. See also WO 03/068244, WO 2004/003138, WO 2004/007512, and WO 2004/009020. US Patent Publication No. 2003/028013 Al as well as International Patent Publication Nos.
  • WO 03/051899, WO 03/061576, WO 03/062255 WO 03/062256, WO 03/062257, and WO 03/061385, filed by Ribapharm, also are directed to the use of certain nucleoside analogs to treat viral infections.
  • Miscellaneous compounds including, for example, 1-amino- alkylcyclohexanes (for example, U.S. Patent No. 6,034,134 to Gold et al.), alkyl lipids (for example, U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (for example, U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (for example, U.S. Pat. No. 5,846,964 to Ozeki et al.), N- (phosphonoacetyl)-L-aspartic acid (for example, U.S. Pat. No.
  • IDN-6556 by Idun Pharma. XTL-002 by XTL., HCV/MF59 by Chiron, CINACIR by NABI, LEVOVIRIN by ICN, VIRAMIDINE by ICN, ZADAXIN (thymosin alfa-1) by Sci Clone, CEPLENE (histamine dihydrochloride) by Maxim, VX 950 / LY 570310 by Vertex/Eli Lilly, /ISIS 14803 by Isis Pharmaceutical/Elan, IDN-6556 by Idun Pharmaceuticals, Inc. and JTK 003 by AKROS Pharma.
  • Hosts including humans, infected with a coronavims, togaviras and/or picomavirus or another organism replicating through a RNA-dependent RNA viral polymerase, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrag 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, sucutaneously, or topically, in liquid or solid form.
  • a preferred dose of the compound for a coronavims, togavims and/or picomavims 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 prodmgs 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.
  • An oral dosage of 50-1000 mg is usually convenient.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 ⁇ M, preferably about 1.0 to 10 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
  • concentration of active compound in the drag 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.
  • 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.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Pharmaceutically compatible inding agents, and/or adjuvant materials can e included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating
  • dosage unit form 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.
  • 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; antiacterial 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.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antiacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • the parental preparation can be enclosed in ampoules, disposale syringes or multiple dose vials made of glass or plastic.
  • preferred carriers are physiological saline or phosphate buffered saline (PS).
  • 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, biodegradale, 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.
  • Liposomal suspensions including liposomes targeted to infected cells with monoclonal antiodies 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. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety).
  • 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.
  • 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, though preferably alkylating the appropriately modified sugar, followed by glycosylation.
  • the following non-limiting embodiments illustrate some general methodology to obtain the nucleosides of the present invention.
  • R 1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substitoted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substitoted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substitoents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group
  • X is O, S, SO 2 , CH 2 , or CHOH; m is 0, 1 or 2;
  • R 13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
  • A is H, OH, C M alkyl, halo, azido, cyano, C 2-6 alkenyl, C 2-6 alkynyl, Br-vinyl, 2-Br- ethyl, -C(O)O(alkyl), -C(O)O(lower alkyl), -O(acyl), -O(lower acyl), -O(alkyl), -O(alkenyl), CF 3 , NO 2 , NH 2 , -NH(lower alkyl), -NH(acyl), -N(lower alkyl) 2 , or -N(acyl) 2 ; and
  • the key starting material for this process is an appropriately substituted lactone.
  • the lactone may be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques.
  • the lactone optionally can be 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 like a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TAF with the appropriate non-protic solvent at a suitable temperature, to give the l'-alkylated sugar.
  • a suitable coupling agent such as an organometallic carbon nucleophile like a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TAF with the appropriate non-protic solvent at a suitable temperature
  • 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.
  • a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltriflate
  • 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.
  • the l'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively, dexoyribonucleoside is desired.
  • the formed ribonucleoside an 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.
  • the 2'- OH can be activated to facilitate reduction as, for example, via the Barton reduction.
  • the key starting material for this process is an appropriately substitoted hexose.
  • the hexose can be purchased or can be prepared by any known means including standard epimerization (as, for example, via alkaline treatment), substitution and coupling techniques.
  • the hexose can be protected selectively to give the appropriate hexa- furanose, as taught by Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.
  • the l'-OH optionally can be activated to a suitable leaving group such as an acyl group or a halogen 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.
  • an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltriflate in an appropriate solvent at a suitable temperature.
  • a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate.
  • the l'-CH 2 -OH if protected, selectively can be deprotected by methods well known in the art.
  • the resultant primary hydroxyl can be reduced to give the methyl, using a suitable reducing agent.
  • the hydroxyl can be activated prior to reduction to facilitate the reaction, i.e., via the Barton reduction.
  • 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 R 6 -SiMe 3 in TAF with an appropriate non-protic solvent at a suitable temperature.
  • a carbon nucleophile such as a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TAF with an appropriate non-protic solvent at a suitable temperature.
  • the l'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 2.
  • deoxyribonucleoside is desired.
  • the formed ribonucleoside optionally can 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.
  • the 2'- OH can be activated to facilitate reduction as, for example, via the Barton reduction.
  • 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 the starting material.
  • R 1 , R 3 , R 5 , and R' are all as defined above; X is as defined above; Base is as defined in the specification; or a pharmaceutically acceptable salt or prodrag thereof; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • the key starting material for this process is an appropriately substitoted sugar with a 2' -OH and 2'-H, with an appropriate leaving group (LG), such as an acyl or halogen group, for example.
  • LG leaving group
  • the sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and/or reduction techniques.
  • the substituted sugar can then be oxidized with an 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 and sulfuric acids), Collins' reagent (dipyridine Cr(VI)oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl 2 -pyridine, H 2 O 2 -ammonium molydate, NarO 2 -CAN, NaOCl in HOAc, copper chromate, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf- Verley reagent (aluminum t-utoxide with another ketone) and N-bromosuccinimide.
  • Jones' reagent a mixture of chromic and sulfuric acids
  • Collins' reagent dipyridine Cr(VI)oxide
  • Corey's reagent
  • an organometallic carbon nucleophile such as a Grignard reagent, an organolithium, lithium dialkylcopper or R -SiMe 3 in TAF with the ketone and an appropriate non-protic solvent at a suitable temperature, yields the 2'-alkylated sugar.
  • the alkylated sugar optionally can be 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,
  • an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium, tetrachloride, or trimethylsilyltriflate in an appropriate solvent at a suitable temperature.
  • a halo-sugar can e coupled to a silylated base in the presence of trimethylsilyltriflate.
  • the nucleoside can be deprotected by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
  • the 2' -C-branched ribonucleoside is desired, the synthesis of which is shown in Scheme 3.
  • a deoxyribonucleoside is desired.
  • the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2' -OH can e reduced with a suitable reducing agent.
  • the 2' -OH can be activated to facilitate reduction, such as, for example, by the Barton reduction.
  • the key starting material for this process is an appropriately substitoted 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 optionally can be protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
  • the appropriately protected nucleoside then can be oxidized with an appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2' -modified sugar.
  • Possible oxidizing agents include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' reagent (dipyridine Cr(VI)oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl 2 -pyridine, H 2 O 2 -ammonium molydate, NarO 2 - CAN, NaOCl in HO Ac, copper chromate, copper oxide, Raney nickel, palladium acetate,
  • nucleoside can e deprotected y methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
  • a 2' -C-branched ribonucleoside is desired, the synthesis of which is shown in Scheme 4.
  • the deoxyribonucleoside may be desired.
  • the formed ribonucleoside optionally may be protected by methods well known to those skilled in the art, as 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.
  • the 2'- OH can be activated to facilitate reduction such as, for example, by the Barton reduction.
  • the L-enantiomers are desired.
  • These L- enantiomers corresponding to the compounds of the invention may be prepared following the same general methods given above, but beginning with the corresponding L-sugar or nucleoside L-enantiomer as the starting material.
  • R 1 , R 3 , R 5 , and R' are all as defined above; X is as defined above; Base is as defined in the specification; or a pharmaceutically acceptable salt or prodrag thereof; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
  • the key starting material for this process is an appropriately substitoted sugar with a 3' -OH and a 3'-H, with an appropriate leaving group (LG) such as, for example, an acyl group or a halogen.
  • LG leaving group
  • the sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and/or reduction techniques.
  • the substitoted sugar then can be oxidized by an appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 3 '-modified sugar.
  • Possible oxidizing agents include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' reagent (dipyridine Cr(VI)oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate,
  • phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl 2 -pyridine, H 2 O 2 -ammonium molydate, NarO - CAN, NaOCl in HOAc, copper chromate, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-utoxide with another ketone) and N- bromosuccinimide.
  • an organometallic carbon nucleophile such as a Grignard reagent, an organolithium, lithium dialkylcopper or R 6 -SiMe 3 in TAF with the ketone and an appropriate non-protic solvent at a suitable temperature, yields the 3'-C-branched sugar.
  • the 3 '-C-branched sugar optionally can e 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 y Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.
  • an acylated sugar can e coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltriflate in an appropriate solvent at a suitable temperature.
  • a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate.
  • the nucleoside can be deprotected by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
  • the 3 '-C-branched ribonucleoside is desired, the synthesis of which is shown in Scheme 5.
  • a deoxyribonucleoside is desired.
  • the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as 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.
  • the 2'- OH can be activated to facilitate reduction, such as, for example, by the Barton reduction.
  • the key starting material for this process is an appropriately substitoted 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 include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' reagent (dipyridine Cr(VI)oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO 2 , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl 2 -pyridine, H2 ⁇ 2 -ammonium molybdate,
  • nucleoside can be deprotected by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
  • the 3 '-C-branched ribonucleoside is desired, the synthesis of which is shown in Scheme 6.
  • a deoxyribonucleoside is desired.
  • the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as by Greene et al.,
  • the 2' -OH can be reduced with a suitable reducing agent.
  • the 2'- OH can be activated to facilitate reduction, such as, for example, by the Barton reduction.
  • the L-enantiomers are desired.
  • These L- enantiomers corresponding to the compounds of the invention may e prepared following the same general methods given above, but beginning with the corresponding L-sugar or nucleoside L-enantiomer as the starting material.
  • Example 1 CC 50 and EC 50 Test Results for ⁇ -D-2' -C-methyl-adenosine (Compound A) and ⁇ -D-2' -C-methyl-2-amino adenosine (Compound B)
  • Cell lines utilized include MT-4 for HIV; Vero 76, African green monkey kidney cells for SARS-CoV; BHK for Bovine Viral Diarrhea Viras; Sb-1 for poliovims Sabin type-1; CVB-2, CVB-3, CVB-4, and CVA-9 for Coxsackievimses B-2, B-3, B-4 and A- 9; and REO-1 for double-stranded RNA viruses.
  • Example 9 CC 50 Test Results for ⁇ -D-2' -C-methyl-adenosine (Compound A), ⁇ -D-2' - C-methyl-2-amino adenosine (Compound B), and ⁇ -D-2' -C-methyl-2-amino-6- cyclopropyl adenosine(Compound K)
  • BVDV bovine viral diarrhea viras
  • YFV yellow fever viras
  • WNV West Nile virus
  • CVB-2 Coxsackie B-2 virus
  • Sb-1 Sabin type 1 poliomyelitis viras
  • REO double-stranded RNA Reoviras.
  • Example 10 CC 50 Test Results for ⁇ -D-2' -C-methyl-guanosine (Compound C), ⁇ -D- 2'-C-methyl-l-(methyl-2-oxo-2-phenyl ethyl)guanosine (Compound L), and ⁇ -D-2'-C- methyl-6-chloro guanosine (Compound D)
  • Example 14 CC50 Test Results for ⁇ -D-2' -C-methyl-cytidine (Compound G), 3'-0- valinyl ester of ⁇ -D-2' -C-methyl-cytidine dihydrochloride salt (Compound M), and ⁇ -D- 2'-C-methyl-uracil (Compound N)

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Abstract

This invention is in the area of methods and pharmaceutical compositions for treating a host, especially a human, infected with a coronavirus, togavirus or picornavirus, comprising administering to that host an effective amount of a compound described herein or its salt, ester or prodrug. The compound can be administered alone or in combination with another optionally substituted pentofuranonucleoside or in combination with another anti-coronavirus, anti-togavirus and/or anti-picornavirus agent.

Description

NUCLEOSIDES FOR TREATMENT OF INFECTION BY CORONAVIRUSES, TOGAVIRUSES AND PICORNA VIRUSES
CROSS-REFERENCE FOR THE INVENTION
This application claims priority to U.S. Provisional No. 60/470,949, filed May 5 14, 2003.
FIELD OF THE INVENTION
This invention is in the area of methods and pharmaceutical compositions for the treatment of viral infections, including the viral causative agent of severe acute respiratory syndrome.
o BACKGROUND OF THE INVENTION
Coronaviruses (order Nidovirales, family Coronaviridae, genus Coronavirus) are a diverse group of positively (+)-stranded RNA viruses that have been implicated in causing a variety of pathological conditions in both humans and other animals (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10). The coronavirus is composed of an envelope5 and helical nucleocapsid with club-shaped surface projections that provide "attachment to cells, hemagglutination, and membrane fusion." (Biichen-Osmond, C. (Ed), (2003). 00.026.0.01. Coronaviridae. In: ICTVdB - The Universal Virus Database, version 3. ICTVdB Management, The Earth Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA). The complete genome is 25,000 to 33,000 nucleotides long and0 consists of a "single molecule of linear positive-sense single-stranded RNA (Biichen- Osmond, C. (Ed), (2003). 00.026.0.01. Coronaviridae. In: ICTVdB - The Universal Virus Database, version 3. ICTVdB Management, The Earth Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA). The Coronaviruses are broken up into three distinct categories based upon antigenic relationships whereby groups I and II are mammalian viruses and group III is an avian virus (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10). Within each antigenic category (I, II, or III), the Coronaviruses are further classified based upon their narrow host range and genome organization (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10). The mammalian viruses for Antigenic group
I include human respiratory coronavirus (HCV-229E) (causes human respiratory infection), porcine transmissible gastroenteritis virus (TGEV) (causes pig respiratory infection, enteric infection, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis), canine coronavirus (CCV) (causes dog enteric infection), feline enteric coronavirus (FECV) (causes cat enteric infection), feline infectious peritonitis virus (FIPV) (causes cat respiratory infection, enteric infection, hepatitis, neurologic infection, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis), and rabbit coronavirus (RbCV) (causes rabbit , infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis) (KN. Holmes and M.M.C. Lai, "Coronaviridae: The viruses and their replication," Fields Virology, B.Ν. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 34, pp. 1075-93). The mammalian viruses for Antigenic group II include human respiratory coronavirus (HCV-OC43) (causes human respiratory infection and may be implicated in enteric infections), mouse hepatitis virus (MHV) (causes mouse respiratory infection, enteric infection, hepatitis, and neurologic infection), sialodacryoadnavirus (SDAV) (causes rat neurologic infection), porcine hemagglutinating encephalomyelitis virus (HEV) (causes pig respiratory infection, enteric infection, and neurologic infection), bovine coronavirus (BCV) (causes cow enteric infection), rabbit enitis coronavirus (RbEVC) (causes rabbit enteric infection), and turkey coronavirus (TCV) (causes turkey respiratory infection, enteric infection, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis) (KN. Holmes and M.M.C. Lai, "Coronaviridae: The viruses and their replication," Fields Virology, B.Ν. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 34, pp. 1075-93). The avian virus for Antigenic group III include avian infectious bronchitis virus (IBV) (causes chicken respiratory infection, hepatitis, infectious peritonitis, immunological disorders, runting, nephritis, pancreatitis, parotitis, and adenitis) (KN. Holmes and M.M.C. Lai, "Coronaviridae: The viruses and their replication," Fields Virology, B.Ν. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 34, pp. 1075-93). The Togaviridae family of viruses are separated into two genera: the alphaviruses and the rubiviruses (Biichen-Osmond, C. (Ed), (2003). 00.026.0.01. Togaviridae. In: ICTVdB - The Universal Virus Database, version 3. ICTVdB Management, The Earth Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA). The complete genome of this family of viruses is composed of 9,700 to 11,800 nucleotides and contains "one molecule of linear positive-sense single stranded RΝA." This family of viruses infects both vertebrates and plants. The complete genome of the alphavirus genus of the Togaviridae family is 11,000 to 12,000 nucleotides and is composed of "one molecule of linear positive-sense single stranded RΝA (Bϋchen-Osmond, C. (Ed), (2003). 00.026.0.01. Alphavirus. In: ICTVdB - The Universal Virus Database, version 3. ICTVdB Management, The Earth
Institute, Biosphere 2 Center, Columbia University, Oracle, AZ, USA). The alphaviruses, unlike the coronaviruses discussed above, have a broad host range and have the ability to replicate in a variety of cell types (S. Schlesinger and M.J. Schlesinger, "Togaviridae: The viruses and their replication," Fields Virology, B.Ν. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers,
Philadelphia, PA; Chpt. 27, pp. 825-41). Among the viruses classified within this genus are the Sindbis virus,
Eastern/Western encephalitis viruses, Semliki Forest virus, and Ross River virus. The genus Rubivirus of the Togaviridae family are distinguished from alphaviruses on the basis of a limited host range. This genus consists of only the Rubella virus, which is found exclusively in humans. The Picornaviridae family of viruses are categorized as small, naked, icosahedral, RΝA-containing animal viruses that are separated into six genera: the rhinoviruses, enteroviruses, aphthoviruses, cardioviruses, hepatoviruses, and unassigned (R.R. Rueckert, "Picornaviridae: The viruses and their replication," Fields Virology, B.N. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 21, pp. 609-54). The genus rhinovirus includes the human rhinoviruses lA-100, IB, "Hanks," and bovine rhinoviruses 1, 2, and 3. The human rhinoviruses consist of at least 105 serotypes (a classification scheme based on the variation of surface epitopes) and represent the most common etiological agent for the common cold. This is a major point of economic concern as it results in lost work days for everyone and "predisposes [the young and elderly] to secondary bacterial infections - a major problem in infants and elderly, (retrieved from All the Virology on the World Wide Web, Internet URL: http://www.talane.edu/dmsanderAVWW/335/Picornaviruses.html)." The genus enterovirus, which inhabits the enteric track, is composed of a total of 95 serotypes. These serotypes include the Human polioviruses 1, 2, and 3 (A23- echo virus; echo = Enteric Cytopathic Human Orphan viruses ) (3 serotypes), Human coxsackieviruses Al-22, 24 (23 serotypes), Human coxsackieviruses Bl-6 (swine vesicular disease virus is very similar to coxsackie B5 virus) (6 serotypes), Human echoviruses 1-7, 9, 11-27, 29-34 (30 serotypes; these viruses show a seasonal, epidemic pattern of infection primarily associated with meningitis, paralysis (usually less severe than acute poliomyelitis), and myocarditis), Human enteroviruses 68-71 (4 serotypes), Vilyuisk virus (1 serotype), Simian enteroviruses 1-18 (18 serotypes), Bovine enteroviruses 1, 2 (2 serotypes), and Porcine enteroviruses 1-8 (8 serotypes) (R.R.
Rueckert, "Picornaviridae: The viruses and their replication," Fields Virology, B.N. Fields, D.M. Knipe and P.M. Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 21, pp. 609-54). The genus apthovirus "infect[s] cloven-footed animals [with foot-and-mouth disease virus (FMDV)], especially cattle, goats, pigs, and sheep," while rarely infecting humans. The apthoviruses, therefore, have the potential to impose significant worldwide economic burdens when substantial numbers of cattle become infected. Further, this particular genus is highly labile and the complete genome consists of 100-170 nucleotides (retrieved from All the Virology on the World Wide Web, Internet URL: http://www.mlane.edu/dmsanderAVWW/335/Picornaviruses.html). While seven serotypes have been identified to date (A; C; O; SAT1,2,3; Asia-1), at least fifty-three subtypes have also been characterized. The cardioviruses consist of two serotypes. Namely, Encephalomyocarditis (EMC) virus (a mouse virus that can infect humans, elephants, and squirrels; includes mengovirus, Maus-Elberfield virus, and the Columbia virus) and Theiler's murine encephalocyelitis (TME) virus (TO, GDVII) (R.R. Rueckert, "Picornaviridae: The viruses and their replication," Fields Virology, B.N. Fields, D.M. Knipe and P.M.
Howley, Editiors; 1996, Lippincott-Raven Publishers, Philadelphia, PA; Chpt. 21, pp. 609-54). of EMCV (really a mouse virus, but can infect man, elephants, and squirrels). The last two genera of the Picornaviridae family are the Hepatovirus and the Unassigned. The Hepatovirus (1 serotype) has Human hepatitis virus A' as its sole member and the Unassigned genus (3 serotypes) includes the Equine rhinoviruses 1,2, cricket paralysis virus, and the Drosophila C virus. New to the mammalian coronavirus groups is the coronavirus causative agent of severe acute respiratory syndrome (SARS), a disease that threatens to become a global epidemic. Easily transmissible and capable of killing 4-15% of the people who contract it, SARS has spread rapidly from its place of origin in Guangdong Province, China, to most of the rest of the world; only Europe and South America are relatively unaffected by this disease, which is spread by travelers. It is believed to have begun in mid- November, 2002, although it was not recognized until late February, 2003 (Jane Parry, British Medical I., April 19, 2003, 326:839; Editorial Comment, British Medical J., April 19, 2003, 326:831-2). As of May 5, 2003, more than 6,000 patients from 29 countries have been diagnosed with the disease (C. Drosten and W. Preiser, Kamps- Hoffmann SARS Reference - 05/2003, May 12, 2003, retrieved from Bernd Sebastian Kamp, Internet URL: http://www.amedeo.com/sars/sars.htm). SARS is characterized by a non-specific onset and an incubation period of 2-10 days, both of which favor transmission among individuals. Transmission appears to occur by close contacts with infected individuals, thus suggesting that spread is via body secretions and fluids, but may also occur by droplets via aerosol routes. Usually the disease begins with a prodrome of fever greater than 38 °C, sometimes accompanied by chills, headaches, malaise and/or myalgias. Respiratory symptoms generally are mild at this early stage. However, at about day 3 to day 4, a dry cough or dyspnea, sore throat, and erythema on the trunk of the patient appear. These symptoms are accompanied by hypoxemia that may require mechanical intervention and bilateral chest opacifications. While the chests of some patients remain clear, most patients exhibit foci of interstitial infiltrates that eventually become generalized, opaque patches or "crackles". Chest radiographs from some late stage SARS patients show areas of foci consolidation (Canada Communicable Disease Report, PREVIEW, 21 March 2003). Results of laboratory tests indicate elevated levels of aspartate aminotransferase, lactate dehydrogenase, and maximal levels of C-reactive protein at about day 7 or day 8, together with lymphopenia, leukopenia, and thrombocytopenia. A period of convalescence generally begins on about day 10 following infection except in about 4- 15% of the infected population in which the disease is fatal (Drosten et al., The New England Journal of Medicine Online, April 10, 2003, pp. 1-10). The etiologic agent responsible for SARS is a new coronavirus, SARS Co-V, first suggested by J. Peiris, C. Drosten, and T.G. Ksiazek working at three different research facilities. M. Peiris and his research group in Canada were first to successfully sequence the SARS Co-V genome, which was later confirmed by the Centers for Disease Control. They identified 11 open reading frames (ORFs) that correspond to regions predicted to encode a variety of polypeptides including polymerase proteins (polymerase la and lb), spike protein (S), small membrane protein (E), membrane protein (M), and nucleocapsid protein (N). The complete SARS Co-V genome comprises 29,727 nucleotides and has a structural organization that is similar to other coronaviruses. (Retrieved from the Center for Disease Control; Internet URL: http://www.cdc.gov/ncidod/sars/sequence.html).
Moreover, a recent article by Rota, et al., however, lends further support that the SARS Co-V is phylogenetically distinct from any previously classified coronavirus and suggested that these unique genomic features may give rise to its infectious role in SARS (Rota, et al., Sciencexpress, May 1, 2003, pp. 1-10). Preliminary studies show that SARS Co-V is stable in feces and urine at room temperature for 1-2 days, and appears to have greater stability in higher pH stools from patients with diarrhea. Supematants of infected cells cultures show a minimal reduction in SARS Co-V concentration after 21 days at 4 °C. and -80 °C. A viral reduction of one log is observed after 48 hours at room temperature, indicating that this coronavirus is more stable than other known human coronaviruses. Inactivation of SARS Co-V is accomplished by heating to 56 °C, and infectivity is lost with exposure to certain fixatives and disinfectants (C. Drosten and W. Preiser, Kamps-Hojfmann SARS Reference - 05/2003, May 12, 2003, retrieved from Bernd Sebastian Kamp, Internet URL: http://www.amedeo.com/sars/sars.htm'). To date, treatment of patients infected with SARS Co-V consists of administering Ribavirin, a broad spectrum anti-RNA-viral agent, however it is not very efficacious. Efforts also are underway to produce an anti-SARS vaccine, but this is expected to take
1-2 years to develop. Thus, there is an urgent need to find ways to treat patients with
SARS before a vaccine is available that can result in prevention of the disease. Examples of antiviral agents that have been identified as active against (+)-RNA viruses include interferon and ribavirin (Battaglia, A.M. et al., Ann. Pharmacother, 2000,. 34, 487-494); Berenguer, M. et al. Antivir. Ther., 1998, 3 (Suppl. 3), 125-136).
Interferon Interferons (IFNs) are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, and are known to suppress serum viral RNA to undetectable levels. Additionally, IFN normalizes serum amino transf erase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8%-9% of patients with chronic viral infection (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Interferons (IFNs) have been commercially available for the treatment of chronic hepatitis for nearly a decade. In addition, a number of patents disclose anti-viral treatments using interferon-based therapies. For example, U.S. Patent No. 5,928,636 to
Alber et al. discloses the combination therapy of interleukin-12 and interferon alpha for the treatment of infectious diseases. U.S. Patent No. 5,908,621 to Glue et al. discloses the use of polyethylene glycol modified interferon for the treatment of viral infections. U.S. Patent No. 5,849,696 to Chretien et al. discloses the use of thymosins, alone or in combination with interferon, for treating viral infections. U.S. Patent No. 5,830,455 to
Valtuena et al. discloses a combination anti-viral therapy employing interferon and a free radical scavenger. U.S. Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins for treating viral infections. Other interferon-based treatments are disclosed in U.S. Patent No. 5,676,942 to Testa et al, U.S. Patent No. 5,372,808 to Blatt et al, and U.S. Patent No. 5,849,696. Ribavirin (l-β-D-ribofuranosyl-l-l,2,4-triazole-3-carboxarnide) is a synthetic, non-interferon-inducing, broad spectrum antiviral nucleoside analog. It is sold under the trade names Virazole™ (The Merck Index, 11th edition, Editor: Budavari, S., Merck & Co., Inc., Rahway, NJ, pl304, 1989); Rebetol (Schering Plough) and Co-Pegasus
(Roche). United States Patent No. 3,798,209 and RE29,835 (ICN Pharmaceuticals) disclose and claim ribavirin. Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses (Gary L. Davis. Gastroenterology 2000, 118:S104-S114). U.S. Patent No 4,211,771 (to ICN Pharmaceuticals) discloses the use of ribavirin as an antiviral agent. Ribavirin (Battaglia, A.M. et al., Ann.
Pharmacother, 2000,. 34, 487-494; Berenguer, M. et al. Antivir. Ther., 1998, 3 (Suppl. 3), 125-136). Ribavirin reduces serum amino transferase levels to normal in 40% of patients, but it does not lower viral serum levels (Gary L. Davis. Gastroenterology 2000, 118:S104-S114). Thus, ribavirin alone is not effective in reducing viral RNA levels.
Additionally, ribavirin has significant toxicity and is known to induce anemia.
Combination of Interferon and Ribavirin Schering-Plough sells ribavirin as Rebetol® capsules (200 mg). The U.S. FDA has approved Rebetol capsules to treat chronic viral infection in combination with
Schering' s alpha interferon-2b products Intron® A and PEG-Intron™. Rebetol capsules are not approved for monotherapy (i.e., administration independent of Intron® A or PEG- Intron™), although Intron® A and PEG-Intron™ are approved for monotherapy (i.e., administration without ribavirin). Hoffman La Roche is selling ribavirin under the name CoPegus in Europe and the United States, also for use in combination with interferon for the treatment of viral infection. Other alpha interferon products include Roferon-A (Hoffmann-La Roche), Infergen® (Intermune, formerly Amgen' s product), and Wellferon® (Wellcome Foundation). The combination of IFN and ribavirin for the treatment of viral infection has been reported to be effective in the treatment of IFN naϊ've patients (Battaglia, A.M. et al,
Ann. Pharmacother. 34:487-494, 2000). However, the side effects of combination therapy can be significant and include hemolysis, flu-like symptoms, anemia, and fatigue (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).
Other examples of antiviral agents that have been identified as active against certain (+)-RNA viruses are: (1) Substrate-based NS3 protease inhibitors (for example, Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al. Inhibitors of serine proteases, PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate (for example, Llinas-Brunet et al, PCT WO 99/07734); (2) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (for example, Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and
Chemotherapy, 1998, 9, 186), 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; (3) Thiazolidine derivatives that show relevant inhibition in a reverse-phase HPLC assay (for example, Sudo K. et al, Antiviral Research, 1996, 32, 9-18), especially compound RD- 1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193; (4) Thiazolidines and benzanilides for example, identified in Kakiuchi N. et al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical Biochemistry, 1997, 247, 242- 246; (5) A phenanthrenequinone possessing activity against protease in a SDS-PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., for example, Sch 68631 (for example, Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and Sch 351633, isolated from the fungus Penicϊllium griscofuluum, which demonstrates activity in a scintillation proximity assay (for example, Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952); (6) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (for example, Qasim M.A. et al, Biochemistry, 1997, 36, 1598-1607); (7) Polymerase inhibitors such as nucleotide analogues, gliotoxin (for example,
Ferrari R. et al. Journal of Virology, 1999, 73, 1649-1654), and the natural product cerulenin (for example, Lohmann V. et al, Virology, 1998, 249, 108-118); (8) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the vims (for example, Alt M. et al, Hepatology, 1995, 22, 707-717); (9) Inhibitors of IRES-dependent translation (for example, Ikeda N et al, Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Pub. JP-10101591); (10) Nuclease-resistant ribozymes (for example, Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995); (11) Nucleoside analogs have also been developed for the treatment of viral infections; (12) Other miscellaneous compounds including 1-amino-alkylcyclohexanes (for example, U.S. Patent No. 6,034,134 to Gold et al), alkyl lipids (for example, U.S. Pat. No. 5,922,757 to Chojkier et al), vitamin E and other antioxidants (for example, U.S.
Pat. No. 5,922,757 to Chojkier et al), squalene, amantadine, bile acids (for example, U.S. Pat. No. 5,846,964 to Ozeki et al), N-(phosphonoacetyl)-L-aspartic acid (for example, U.S. Pat. No. 5,830,905 to Diana et al), benzenedicarboxamides (for example, U.S. Pat. No. 5,633,388 to Diana et al), polyadenylic acid derivatives (for example, U.S. Pat. No. 5,496,546 to Wang et al), 2',3'-dideoxyinosine (for example, U.S. Pat. No.
5,026,687 to Yarchoan et al), and benzimidazoles (for example, U.S. Pat. No. 5,891,874 to Colacino et al); and (13) Other compounds currently in clinical development for treatment of a coronavirus, togavirus, and/or picomavirus infection, or more generally any (+)-RNA active agent. Idenix Pharmaceuticals, Ltd. discloses branched nucleosides, and their use in the treatment of HCV and flaviviruses and pestiviruses in US Patent Publication No. 2003/0050229 Al and US Patent Publication No. 2003/0060400 Al, which correspond to International Publication Nos. WO 01/90121 and WO 01/92282. A method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active 1', 2', 3' or 4' -branched β-D or β-L nucleosides or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. See also U.S. Patent
Publication Nos. 2004/0006002 and 2004/0006007 as well as WO 03/026589 and WO 03/026675. Idenix Pharmaceuticals, Ltd. also discloses in US Patent Publication No. 2004/0077587 pharmaceutically acceptable branched nucleoside prodrugs, and their use in the treatment of HCV and flavi vimses and pestiviruses in prodmgs. See also PCT Publication Nos. WO 04/002422, WO 04/002999, and WO 04/003000. ICN Pharmaceuticals, Inc. discloses various nucleoside analogs that are useful in modulating immune response in US Patent Nos. 6,495,677 and 6,573,248. See also WO 98/16184, WO 01/68663, and WO 02/03997. US Patent Publication Nos. 2003/083307 Al and US 2003/008841 Al, and the corresponding International Patent Publication Nos. WO 02/18404 (PCT/EPOl/09633; published August 21, 2001); WO 02/100415 and WO 02/094289, filed by F. Hoffmann- La Roche AG discloses various nucleoside analogs for the treatment of HCV RNA replication. Pharmasset Limited discloses various nucleosides and antimetabolites for the treatment of a variety of vimses, in WO 02/32920, WO 01/79246, WO 02/48165, WO
03/068162, WO 03/068164 and 2004/013298. Merck & Co., Inc. and Isis Pharmaceuticals disclose in US Patent Publication No.
2002/0147160 and the corresponding International Patent Publication Nos. WO
02/057425 (PCT US02/01531; filed January 18, 2002) and WO 02/057287 (PCT/US02/03086; filed January 18, 2002) various nucleosides, and in particular several pyrrolopyrimidine nucleosides, for the treatment of vimses whose replication is dependent upon RNA-dependent RNA polymerase. See also WO 03/068244, WO 04/003138, WO 04/007512, and WO 04/009020. US Patent Publication No. 2003/028013 Al as well as International Patent Publication Nos. WO 03/051899, WO 03/061576, WO 03/062255 WO 03/062256, WO 03/062257, and WO 03/061385, filed by Ribapharm, also are directed to the use of certain nucleoside analogs to treat viral infections.
In view of the severity of diseases associated with coronaviruses, toga vimses, and picomavimses and their pervasiveness in animals and humans, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with any one of these (+)-stranded RNA vimses. It is yet another object of the present invention to provide a compound, composition, and method of use for the treatment of a host, especially a human, infected with the SARS coronavirus in an attempt to halt the spread of SARS. It is another object of the present invention to provide a method and pharmaceutically-acceptable composition for the prophylaxis and treatment of a host, and particularly a human, infected with a togavirus, picomavims and/or a coronavims, and SARS-CoV in particular. It is still another object of the invention to provide compounds and physiologically acceptable salts, esters or prodrugs thereof, for the manufacture of a medicament to be used in the prophylaxis or treatment of a host infected with a togavims, picomavims and/or a coronavims, and especially SARS-CoV.
SUMMARY OF THE INVENTION
Methods and compositions for the treatment of infections caused by a coronavirus, togavims or picomavims are described that include administering an effective amount of a β-D or β-L-nucleoside of the formula below or a pharmaceutically acceptable salt or prodrug thereof. In a first principal embodiment, the use of a compound for the treatment of a coronavirus, togavirus or picomavims is provided wherein the compound is of the formula (AA), or a pharmaceutically acceptable salt or prodmg thereof:
AA or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, wherein: R1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodmg); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), or C3-7 cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring such as, for example, a C3-7 cycloalkylamino), an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, -12 alkoxy, C2-4alkenyl, C2-4 alkynyl, C -6 alkenyloxy, C1-4 alkylthio, Cι-8 alkylcarbonyloxy, aryloxycarbonyl, Cι-4 alkylamino, di(Cι- alkyl)amino, Br- vinyl, -C(O)O(alkyl), O-phosphate or O-phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); O-acyl (including lower acyl); O-alkyl (including lower alkyl); O-sulfonate ester including O-alkyl or O- arylalkyl sulfonyl including O-methanesulfonyl; O-aryl; O-benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); -S(alkenyl); optionally substituted O-arylsulfonyl; an O- linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O-linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br-vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O-aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2, CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, C alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is as defined in the specification, including a purine or pyrimidine or a compound including but not limited to:
wherein: each R8, R , 10 , R , R , 1I2 and R .13 i •ndependently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl (preferably optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH-heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O-heterocycle, -O- heteroaryl, C1-4 alkylamino, di(Cι-4 alkyl)amino, C3-6 cycloalkylamino, Ci. 4 alkyl-C(=O)OH, CM alkyl-C(=O)O-aryl (preferably C1-4 alkyl-C(=O)O- phenyl), Cμ alkyl-C(=O)O-heterocycle, C alkyl-C(=O)O-heteroaryl, or C1-4 alkoxy; and R9 is O or S; and all tautomeric, enantiomeric and stereoisomeric forms thereof. In a particular embodiment of the invention, the compound for use in the present invention is in the form of its 2', 3', and/or 5 '-prodmg. In one embodiment, the compound is a prodmg that includes biologically cleavable moieties at the 2', 3' and or
5' positions. In one embodiment, the compound is an acyl prodrug with biologically cleavable acyl moieties at the 2', 3' and/or 5' positions. In a particular embodiment, the compound is an amino acid ester prodmg with biologically cleavable amino acid moieties at the 2', 3' and/or 5' positions. Preferred moieties are amino acid esters including valyl, and alkyl esters including acetyl. Therefore, this invention specifically includes the 2'-L-amino acid ester, 3'-L-amino acid ester, 2',5'-L-diamino acid ester, and 3',5'-L-diamino acid ester of the nucleosides of the present invention; and the 2'- ester, 3'-ester, 2',5'-diester and 3',5'-diester of the nucleosides wherein (i) the 2' and/or 3' ester is an amino acid ester and the 5 '-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2' and/or 3' ester is independently an alkyl or aryl ester and the 5 '-ester is an amino acid ester. In one embodiment, the active compounds of the present invention can be administered in combination, alternation or sequential steps with another antiviral agent, including an anti-(+)-stranded RNA vims agent. In preferred embodiments, an anti-(+)- stranded RNA vims compound is used that exhibits an EC50 of less than 10 μM, and preferably less than 1-5 μM. It is intended that the active compounds of the present invention include both β-D and β-L nucleoside compounds of the general formula (AA) or a pharmaceutically acceptable salt or prodmg thereof; a pharmaceutical composition comprising one or more of these compounds; a medicament comprising one or more of these compounds; and a process for preparing such a composition and/or medicament. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows exemplified compounds of the invention. Figure 2 shows a phylogenetic tree of the SARS-associated coronavims.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound, method and composition for the treatment of a host, and in particular a human or an animal, infected with a (+)-stranded RNA vims that is a coronavims, such as SARS-CoV, a togavims, such as a rubiviras (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), or a picomavirus, such as an enterovims (particularly Coxsackieviruses, poliovimses, hepatitis A, echovirases and the four human enterovims species), a rhinovirus, a cardiovims and an aphthoviras. This treatment includes administering an effective amount of an anti-coronavims, anti-togavirus, or anti-picornavirus β-D- or β-L- nucleoside as described herein, or a pharmaceutically acceptable salt or prodmg thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral activity, or are metabolized to a compound that exhibits such activity. All coronavimses, togavimses and picornaviruses are intended for inclusion within the scope of this invention. In particular, the invention is directed to:
• the SARS-CoV coronavims; • human and avian coronaviruses;
• Togavimses such as, for example, mbivimses that cause rubella and alphaviruses that cause encephalitis; and
• Picornaviruses, including all four (4) major genera of enteroviruses (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enterovims species), rhinoviruses, cardiovimses and aphthovimses. The coronaviruses that can be treated according to this invention includes, but are not limited to, human respiratory coronavirus (HCV-229E), porcine transmissible gastroenteritis vims (TGEV), canine coronavims (CCV), feline enteric coronavims (FECV), feline infectious peritonitis vims (FIPV), rabbit coronavims (RbCV), human respiratory coronavirus (HCV-OC43), mouse hepatitis vims (MHV), sialodacryoadnavirus (SDAV), porcine hemagglutinating encephalomyelitis vims (HEV), bovine coronavims (BCV), rabbit enitis coronavims (RbEVC), turkey coronavirus (TCV), and avian infectious bronchitis vims (IBV). Togavimses that can be treated according to the present invention includes, but are not limited, alphavimses (such as for example Sindbis virus, EasternAVestern encephalitis vimses, Semliki Forest vims, and Ross River vims) and mbivimses (such as for example Rubella vims). Picomavimses that can be treated according to the present invention includes, but are not limited to, the rhinovimses (such as for example human rhinoviruses lA-100, IB, "Hanks," and bovine rhinovimses 1, 2, and 3), enteroviruses (such as for example human poliovimses 1, 2, and 3 (A23-echovirus; echo = Enteric Cytopathic Human Orphan vimses ) (3 serotypes), human coxsackievimses Al-22, 24 (23 serotypes), human coxsackieviruses Bl-6, human echovirases 1-7, 9, 11-27, 29, human enterovimses 68-71 (4 serotypes), vilyuisk vims (1 serotype), simian enterovimses 1-18 (18 serotypes), bovine enteroviruses 1, 2 (2 serotypes), and porcine enteroviruses 1-8 (8 serotypes)), aphthoviruses (such as for example foot-and-mouth disease vims (FMDV)), cardioviruses(such as for example encephalomyocarditis (EMC) vims, mengovirus, Maus-Elberfield virus, Columbia virus, and Theiler's murine encephalocyelitis (TME) vims (TO, GDVII)), hepatovimses (such as for example human hepatitis virus A), and unassigned (such as for example equine rhinovimses 1,2, cricket paralysis virus, and the drosophila C vims).
In particular, the present invention provides the following: a) a pharmaceutical composition comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVHI), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, optionally with a pharmaceutically acceptable carrier, excipient or diluent; b) a pharmaceutical composition comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVHT), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodmg, thereof, with one or more other effective antiviral agents (for example other effective anti-coronavims, such as anti-SARS- CoV, anti-togavims, such as anti-rubivirus (the causative agent for rubella) and anti- alphavims (the causative agent for encephalitis), and/or anti-picornavirus, such as anti-enterovirus (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enterovims species), anti-rhinovims, anti-cardiovims and anti- aphthovims, or more generally any (+)-RNA active agent), optionally with a pharmaceutically acceptable carrier or diluent; c) a pharmaceutical composition for the treatment or prophylaxis of a coronavims, such as SARS-CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavims, such as an enterovims (particularly Coxsackievimses, poliovimses, hepatitis A, echovirases and the four human enterovims species), a rhinovirus, a cardiovims and an aphthoviras infection, in a host, such as a mammal, for example a human, especially a host diagnosed as having or being at risk for such infection, comprising a β-D- or β-L- nucleoside compound of the general Formula (AA), (I-XXVUI), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, optionally with a pharmaceutically acceptable carrier or diluent; d) a pharmaceutical composition for the treatment or prophylaxis of a coronavims, such as SARS-CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavims, such as an enterovims (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enterovims species), a rhinovims, a cardiovims and an aphthoviras infection, in a host, such as a mammal, for example a human, especially a host diagnosed as having or being at risk for such infection, comprising a β-D- or β-L- nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, with one or more other effective antiviral agents (for example other effective anti-coronavims, such as anti-SARS-CoV, anti-togavims, such as anti-rubivims (the causative agent for rubella) and anti-alphavirus (the causative agent for encephalitis), and/or anti- picornavirus, such as anti-enteroviras (particularly Coxsackieviruses, poliovirases, hepatitis A, echovirases and the four human enterovims species), anti-rhinovirus, anti-cardiovirus and anti-aphthovirus, or more generally any (+)-RNA active agent), optionally with a pharmaceutically acceptable carrier or diluent; e) a pharmaceutical formulation comprising the β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIJI), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, together with a pharmaceutically acceptable carrier, excipient or diluent; f) a method for the treatment of a coronavims, such as SARS-CoV, a togavirus, such as a mbivims (the causative agent for rubella) and an alphavims (the causative agent for encephalitis), and/or a picomavirus, such as an enterovims (particularly Coxsackievimses, poliovirases, hepatitis A, echovirases and the four human enteroviras species), a rhinovirus, a cardio virus and an aphthoviras, infection in a host, such as a mammal, for example a human, comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIU), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, optionally with a pharmaceutically acceptable carrier, excipient or diluent; g) a method for the treatment of a coronavims, such as SARS-CoV, a togavirus, such as a rubivims (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavirus, such as an enterovims (particularly Coxsackievimses, poliovirases, hepatitis A, echovirases and the four human enteroviras species), a rhinovims, a cardiovims and an aphthoviras, infection in a host, such as a mammal, for example a human, comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIIJ.), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, with one or more other effective antiviral agents, such as one or more other anti-coronavims, such as anti-SARS-CoV, anti-togavims, such as anti-rubivirus (the causative agent for rubella) and anti-alphavirus (the causative agent for encephalitis), and/or anti- picornavirus, such as anti-enteroviras (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enteroviras species), anti-rhinovirus, anti-cardiovirus and anti-aphthovims, or more generally any (+)-RNA active agent, optionally with a, pharmaceutically acceptable carrier, excipient or diluent; h) a method for the treatment of a SARS-CoV infection in a host, such as a mammal, for example a human, comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIH), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodrug, thereof, optionally with a pharmaceutically acceptable carrier, excipient or diluent; i) a method for the treatment of a SARS-CoV infection in a host, such as a mammal, for example a human, comprising a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodmg, thereof, with one or more other effective antiviral agents, such as one or more other anti-coronavims, such as anti-SARS-CoV, anti- togavirus, such as anti-rabiviras (the causative agent for rubella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picornavirus, such as anti- enteroviras (particularly Coxsackieviruses, poliovirases, hepatitis A, echovirases and the four human enteroviras species), anti-rhinovirus, anti-cardiovims and anti- aphthovirus, or more generally any (+)-RNA active agent, optionally with a pharmaceutically acceptable carrier, excipient or diluent; j) use of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, optionally with a pharmaceutically acceptable carrier or diluent, for the treatment of a coronavirus, such as SARS-CoV, a togavirus, such as a mbivims (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavirus, such as an enteroviras (particularly Coxsackieviruses, poliovirases, hepatitis A, echovirases and the four human enteroviras species), a rhinovirus, a cardiovirus and an aphthoviras infection in a host, such as a mammal, for example a human; k) use of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, with one or more other effective antiviral agents, such as an anti- coronavims, such as anti-SARS-CoV, anti-togavims, such as anti-rubivirus (the causative agent for rubella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picomavims, such as anti-enterovirus (particularly Coxsackievimses, poliovimses, hepatitis A, echovimses and the four human enteroviras species), anti- rhinovirus, anti-cardiovims and anti-aphthovirus, or more generally any (+)-RNA active agent, optionally with a pharmaceutically acceptable carrier or diluent, for the treatment of a coronavirus, such as SARS-CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavirus, such as an enteroviras (particularly Coxsackievimses, poliovirases, hepatitis A, echovimses and the four human enteroviras species), a rhinovirus, a cardiovims and an aphthoviras infection in a host, such as a mammal, for example a human;
1) use of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, optionally with a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment of a coronavirus, such as SARS- CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavirus, such as an enteroviras (particularly Coxsackieviruses, poliovimses, hepatitis A, echovimses and the four human enteroviras species), a rhinovirus, a cardiovirus and an aphthoviras infection in a host, such as a mammal, for example a human; m) use of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodrug, thereof, with one or more other effective antiviral agents, such as an anti- coronavirus, such as anti-SARS-CoV, anti-togavims, such as anti-rabivirus (the causative agent for rubella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picomavims, such as anti-enterovirus (particularly Coxsackieviruses, poliovirases, hepatitis A, echoviruses and the four human enteroviras species), anti- rhinovirus, anti-cardioviras and anti-aphthovirus, or more generally any (+)-RNA active agent, optionally with a pharmaceutically acceptable carrier or diluent, the manufacture of a medicament for the treatment of a coronavims, such as SARS-CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus (the causative agent for encephalitis), and/or a picomavims, such as an enterovims (particularly Coxsackievirases, poliovimses, hepatitis A, echovimses and the four human enteroviras species), a rhinovirus, a cardiovims and an aphthoviras infection in a host, such as a mammal, for example a human; n) a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, substantially in the absence of enantiomers of the described nucleoside, or substantially isolated from other chemical entities; o) a process for the preparation of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, as provided in more detail below; p) a process for the preparation of a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIII), a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodrug, thereof, substantially in the absence of enantiomers of the described nucleoside or substantially isolated from other chemical entities; and q) a β-D- or β-L-nucleoside compound of the general Formula (AA), (I-XXVIH), or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof;
I. Active Compounds, Physiologically Acceptable Salts and Prodrugs Thereof
Methods, uses and compositions for the treatment of a coronavirus, such as SARS- CoV, a togavirus, such as a rubivirus (the causative agent for rubella) and an alphavirus
(the causative agent for encephalitis), and/or a picomavims, such as an enterovims (particularly Coxsackievirases, polioviruses, hepatitis A, echovirases and the four human enteroviras species), a rhinovirus, a cardiovims and an aphthoviras, infection are described that include administering an effective amount of a β-D or β-L-nucleoside of the general formula below, or a pharmaceutically acceptable salt or prodmg thereof. In a principal embodiment, use of a compound for the treatment of a coronavirus, togavims or picomavirus is provided wherein the compound is of the formula (AA):
AA or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodrug, thereof, wherein: R1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), or C3- cycloalkylamino; each R , R and R independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)raN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring such as, for example, a C3- cycloalkylamino), an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, Cι_ι alkoxy, C2-4alkenyl, C2-4 alkynyl, C2-6 alkenyloxy, CM alkylthio, C1-8 alkylcarbonyloxy, aryloxycarbonyl, Cι-4 alkylamino, di(CM alkyl)amino, Br- vinyl, -C(O)O(alkyl), O-phosphate or O-phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); O-acyl (including lower acyl); O-alkyl (including lower alkyl); O-sulfonate ester including O-alkyl or O- arylalkyl sulfonyl including O-methanesulfonyl; O-aryl; O-benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); -S(alkenyl); optionally substituted O-arylsulfonyl; an O- linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O-linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br-vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O-aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2, CH2, or CHOH; m is 0, 1 or 2; R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl; A is H, OH, C1-4 alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and Base is as defined in the specification, including a purine or pyurimidine base or a compound including but not limited to:
wherein: each R8, R10, R11, R12 and R13 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl (preferably optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH-heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O-heterocycle, -O- heteroaryl, CM alkylamino, di(CM alkyl)amino, C3-6 cycloalkylamino, . 4 alkyl-C(=O)OH, CM alkyl-C(=O)O-aryl (preferably C1-4 alkyl-C(=O)O- phenyl), C alkyl-C(=O)O-heterocycle, C1-4 alkyl-C(=O)O-heteroaryl, or CM alkoxy; and R9 is O or S; and all tautomeric, enantiomeric and stereoisomeric forms thereof. In another embodiment, methods and compositions for the treatment of SARS- CoV, coronavims, togavirases, and/or picornaviruses infection, or more generally any (+)-RNA viral infection, are described that include administering an effective amount of a β-D or β-L-nucleoside of the Formulae (I) - (XXVHI), or a pharmaceutically acceptable salt or prodmg thereof. In a yet another embodiment, use of a compound for the treatment of a coronavirus, togaviras or picomavims is provided wherein the compound is of the formula (I):
(I) or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, wherein: R1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substituted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substituted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R3 and R5 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO , NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring such as, for example, a C3. cycloalkylamino), an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, .ι2 alkoxy, C2-4alkenyl, C2-4 alkynyl, C2-6 alkenyloxy, C alkylthio, Cι-8 alkylcarbonyloxy, aryloxycarbonyl, C1-4 alkylamino, di(C alkyl)amino, Br-vinyl, -C(O)O(alkyl), O-phosphate or O- phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); O-acyl (including lower acyl); O-alkyl (including lower alkyl); O- sulfonate ester including O-alkyl or O-arylalkyl sulfonyl including O- methanesulfonyl; O-aryl; O-benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); -S(alkenyl); optionally substituted O-arylsulfonyl; an O-linked lipid, including an O- phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O-linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O- phosphate;
X is O, S, SO2, CH2, CHOH, CH-halogen, C-(halogen)2; m is 0, 1 or 2; R4 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, Cι-4 alkyl, halo, azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and Base is defined in the specification, including but not limited to:
(i) (i') wherein: Y is O or S; Y' is H, OH, SH, NH2, halo, CF3, C alkyl, CM alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, or C1-4 alkoxy; Z is H, NH2, CF3, C1- alkyl, CM alkylamino, di(CM alkyl)amino, or C3-6 cycloalkylamino, and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, use of a compound for the treatment of a coronavirus, togavims or picomavims is provided wherein the compound is of the formula (H):
(II) or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodrug, thereof, wherein: R1, R3, and R5 are defined as above; R' is H, OH, SH, halo (F, CI, Br, or I), optionally substituted C1- alkyl, optionally substituted C2-4 alkenyl or C2-4 alkynyl, N3, CN, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br- ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)mC(O)OR4, -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -NO* -NH2, -(CH2)mNHR4, -(CH2)mN(R4)2, -(CH2)mC(O)NHR4, -(CH2)mC(O)N(R4)2, or C3-7 cycloalkylamino, and where the optional substitutions on alkyl, alkenyl and/or alkynyl may be one or more halogen, hydroxy, amino, alkoxy, or alkylthio groups or atoms taken in any combination; or alternatively R' and R5, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or unsaturated ring that optionally may have one or more heteroatoms selected from the group consisting of O, S, N, or P; A is H, OH, C1- alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; m is 0, 1 or 2; R4 is H, alkyl, alkenyl, alkynyl, or acyl; X is defined as above; and Base is as in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, the use of a compound for the treatment of a coronavirus, togavirus or picomavims is provided wherein the compound is of the formula (HI):
(IH)
or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, wherein: R , R , R , R' and A are all as defined above; or R' and R , together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered saturated or unsaturated ring that optionally may have one or more heteroatoms selected from the group consisting of O, S, N, or P; X is defined as above; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, the use of a compound for the treatment of a coronavims, togavirus or picomavims is provided wherein the compound is of the formula (IV):
(IV) or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrag, thereof, wherein: R1, R3, R5, and R' are all as defined above, except that R' is -OH, -SH or -NH2 only when X is C; X is as defined above; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof. In another embodiment, the use of a compound for the treatment of a coronavirus, togavirus or picomavirus is provided wherein the compound is of the formula (V):
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrag, or salt of a prodrag, thereof, wherein: R1, R3, R5, and R' are all as defined above; X is as defined above; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, the use of a compound for the treatment of a coronavirus, togavims or picomavims is provided wherein the compound is of the formula (VI):
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodmg, thereof, wherein: R1, R3, R5 and R' are all as defined above; X* is CH, C-OH, or C-halogen (wherein halogen includes F, CI, Br, and I); and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof. In another embodiment, the use of a compound for the treatment of a coronavirus, togaviras or picomavirus is provided wherein the compound is of the formulas (Vπ), (Viπ), (IX), or (X):
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodrug, thereof, wherein: R1, R3, R5, R' are all as defined above; X is defined as above; is an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S, and/or N); and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, the use of a compound for the treatment of a coronavirus, togavirus or picomavims is provided wherein the compound is of the formulae (XI), (Xn), (Xffl), or (XIV):
or (XIV)
or a pharmaceutically acceptable salt, ester, salt of an ester, prodmg, or salt of a prodmg, thereof, wherein: R1, R3, R5, and R' are all as defined above, except that R' in Formula (XI) is -OH, -NH2 or -SH only when X is C; X is as defined above; Each R2' and R4', independently, is H, -OH, -SH, -NH2, -CF3, CI, F, Br, I, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, -CH2OH, alkoxy, CH2F, CH2N3, CH2CN, -(CH2)mC(O)OR4, -(CH2)mC(O)NHR4, -(CH2)mC(O)N(R4)2, -NH(alkyl), -N(alkyl)2, -NH(acyl), -N(acyl)2, or C3-7 cycloalkylamino; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof. In another embodiment, the use of a compound for the treatment of a coronavirus, togavims or picomavirus is provided wherein the compound is of the formulae (XV) or (XVI):
(XV) or (XVI)
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrag, or salt of a prodrag, thereof, wherein: Rl, R2', R3, R5, R6, and R' are all as defined above, except that R6 is -OH, -NH2 or - SH only when X is C; X and X* are as defined above; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br-vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O-aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl; m is 0, 1 or 2; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another embodiment, the use of a compound for the treatment of a coronavirus, togavirus or picomavirus is provided wherein the compound is of the formula (XVII),
(xvπi), (xix), (xx), (xxi), (xxii), (xxm), (xxrv), (xxv), (xxvi), (xxvπ), or
(XXVIII):
(XVII) (xvm) (XIX)
(XXHT)
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrag, or salt of a prodrag, thereof, wherein: R1, R3, R5, R6, R7, and R' are all as defined above, except that R6 is -OH, -NH2 or - SH only when X is C; X is defined as above; m is 0, 1 or 2; and Base is as defined in the specification; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
In another particular embodiment of the present invention, the use of a compound for the treatment of a coronavirus, togaviras or picomavirus is provided wherein the compound is of the formulas Al-Nl :
(El) (Fl)
In a particular embodiment of the invention, the compound of the present invention is in the form of its 2', 3', and/or 5 '-prodmg. In one embodiment, the compound is a prodrug that includes biologically cleavable moieties at the 2', 3' and or
5' positions. In one embodiment, the compound is an acyl prodrug with biologically cleavable acyl moieties at the 2', 3' and or 5' positions. In a particular embodiment, the compound is an amino acid ester prodrug with biologically cleavable amino acid moieties at the 2', 3' and/or 5' positions. Preferred moieties are amino acid esters including valyl, and alkyl esters including acetyl. Therefore, this invention specifically includes the 2'-L-amino acid ester, 3'-L-amino acid ester, 2',5'-L-diamino acid ester, and 3',5'-L-diamino acid ester of the nucleosides of the present invention; and the 2'- ester, 3 '-ester, 2',5'-diester and 3',5'-diester of the nucleosides wherein (i) the 2' and/or 3' ester is an amino acid ester and the 5 '-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2' and/or 3' ester is independently an alkyl or aryl ester and the 5 '-ester is an amino acid ester. The active compounds of the present invention can be administered alone or in combination, alternation or sequential steps with another anti-coronavims, such as anti- SARS-CoV, anti-togavirus, such as anti-mbiviras (the causative agent for rabella) and anti-alphavirus (the causative agent for encephalitis), and/or anti-picornavirus, such as anti-enterovims (particularly Coxsackievirases, poliovirases, hepatitis A, echovirases and the four human enteroviras species), anti-rhinovirus, anti-cardioviras and anti- aphthovirus, or more generally any (+)-RNA active agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The' dosages given will depend on absorption, inactivation and excretion rates of the drag ;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. In preferred embodiments, an anti-SARS-CoV, anti-coronaviras, anti- togavirus, and/or anti-picornavirus compound that exhibits an EC50 of 10-15 μM or less, or preferably less than 1-5 μM, is desirable. The active compound can be administered as any salt or prodrag 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, which are alternatively referred to as "physiologically acceptable salts", and a compound that has been alkylated or acylated at the 3'- or 5'- position or on the purine or pyrimidine base, thereby forming a type of "pharmaceutically acceptable prodrag". 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 prodrag and testing its antiviral activity according to the methods described herein, or other methods known to those skilled in the art.
II. Definitions
The term "alkyl" as used herein, unless otherwise specified, includes a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically to Cio, and specifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethybutyl, and 2,3- dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. Moieties with which the alkyl group can be substitoted with one or more substitoents include but are not limited to halo, including CI, F, Br and I so as to form, for eg., CF3, 2- Br-ethyl, CH2F, CH2C1, CH2CF3, or CF2CF3; hydroxyl, for eg. CH2OH; amino, for eg., CH2NH2, CH2NHCH3, or CH2N(CH3)2; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido, for eg., CH2N3; cyano, for eg., CH2CN; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, either unprotected or protected as necessary, known to those skilled in the art, for eg., as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition (1991), incorporated herein by reference. The term "lower alkyl" as used herein, and unless otherwise specified, includes a Ci to C6 saturated straight, branched, or if appropriate, cyclic as in cyclopropyl, for eg., alkyl group, including both substituted and unsubstitoted 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 terms "alkylamino" and "arylamino" refer to an amino group that has one or two alkyl or aryl substituents, respectively. The term "protected" as used herein and, unless otherwise defined, includes a group that is added to an oxygen, nitrogen or phosphoms atom to prevent its further reaction or for other purposes. Numerous 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, includes phenyl, biphenyl or naphthyl, and preferably phenyl. The term includes both substituted and unsubstituted moieties. The aryl group can be substitoted with one or more moieties including but not limited to alkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, alkylthio, carboxamido, carboxylate, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected as necessary, as known to those skilled in the art, for eg., as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition (1991), incorporated herein by reference. The terms "alkaryl" and "akylaryl" refer to an alkyl group with an aryl sustitoent. The terms "aralkyl" and "arylalkyl" refer to an aryl group with an alkyl substituent. The term "halo" as used herein includes bromo, chloro, iodo and fluoro. The term base refers to any purine or pyrimidine base including, but not limited to, adenine, N6-alkylpurines, (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, C -cyanopyrimidine, C5-nitropyrimidine, C5-amino- pyrimidine, N -alkylpurines, N -alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,
0) («) (iii)
(iv) (v) (vi)
wherein: each G and L is independently CH or N; each D is independently N, CH, C-CN, C-NO2, C-Q-3 alkyl, C-NHCONH2, C- CONQuQn, C-CSNQV, CCOOQ11, C-C(=NH)NH2, C-hydroxy, C-Q. 3alkoxy,C-amino, C-Q^ alkylamino, C-di(CM alkyl)amino, C-halogen, C- (l,3-oxazol-2-yl), C-(l,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and Q-3 alkoxy; each E is independently N or CQ5; each W is independently O, S, or NR; each R is independently H, OH, alkyl; each Q6 is independently H, OH, SH, NH2, C alkylamino, di(Cι-4 alkyl)amino, C3-6 cycloalkylamino, halogen, CM alkyl, C alkoxy, or CF3; each Q5 is independently H, Ci^ alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, halogen, N, CN, NO2, NHCONH2, CONQuQn, CSNQUQU, COOQ11, C(=NH)NH2, hydroxy, Cι-3alkoxy,amino, CM alkylamino, di(C1-4 alkyl)amino, halogen, l,3-oxazol-2-yl, l,3-thiazol-2-yl, or imidazol-2-yl; wherein alkyl is unsubstitoted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and -3 alkoxy; each Q7 and Q14 is independently selected from the group consisting of H, CF3, OH, SH, OR, SR C1- alkyl, amino, CM alkylamino, C3-6 cycloalkylamino, and di(CM alkylamino; each Q11 is independently H or C i .6 alkyl; each Q8 is independently H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C]-4 alkyl)amino, hydroxy, Cι-6 alkoxy, Cι-6 alkylthio, C1-6 alkylsulfonyl, (C1- alkyl)0-2 aminomethyl, N, CN, NO2, .3 alkyl, NHCONH2, CONQnQn, CSNC Q11, COOQ11, C(=NH)NH2, 1,3- oxazol-2-yl, l,3-thiazol-2-yl, or imidazol-2-yl, wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and Q-3 alkoxy; (D) CE)
wherein: each Ti and T2 is independently selected from N, CH, or each Q16, U, and Y is independently selected from is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4R5 or SR5, Br-vinyl, -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, NH2, NH- alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S- acyl, S-aryl, S-cycloalkyl, S-aralkyl, CN, N3, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, OH, CF3, CH2OH, (CH2)mOH, (CH2)raNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2, (CH2)mCONH2, CM alkylamino, di(C]-4 alkyl)amino, C3-6 cycloalkylamino, CM alkoxy, C1-4 alkoxycarbonyl, Cι-6 alkylthio, Cι-6 alkylsulfonyl, (CM alkyl)0-2 aminomethyl, or- NHC(=NH)NH2; each R4 and R5 is independently selected from hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl); each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each Z is independently S, SO, SO2, C=O, or NQ20; each Q is independently H or alkyl; and each Vi and V2 is independently selected from CH or N;
or
(F) (G) (H) (I) wherein: each T3 and T4 is independently selected from N or CQ ,22. ; each Q22 is independently selected from H, OH, substituted or unsubstitoted alkyl, substitoted or unsubstituted alkenyl, substitoted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4R5 or SR5, Br-vinyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-acyl, -O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH- acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S- cycloalkyl, S-aralkyl, CN, N3, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, OH, CF3, CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2, (CH2)raCONH2, CM alkylamino, di(C alkyl)amino, C3-6 cycloalkylamino, Cμ4 alkoxy, CM alkoxycarbonyl, Cι-6 alkylthio, Cι-6 alkylsulfonyl, (C alkyl)0-2 aminomethyl, or -NHC(=NH)NH2; T5 is NH; each R4 and R5 is independently selected from hydrogen, acyl (including lower acyl), or alkyl (including but not limited to methyl, ethyl, propyl and cyclopropyl); each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each T6, T7, T8, T9, Tι0, Tπ, and Tι2 is independently selected from N or CH; each U2 is independently H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4R5 or SR5; each Y2 is independently O, S, NH, NR or CQ24Q26 where R is H, OH, or alkyl; each Q24 and Q2 is independently selected from H, alkyl, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR4, NR4R5 or SR5.
Further examples of 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" includes 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 halogen, Cι-C6 alkyl or Cι-C6 alkoxy; sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl; the mono-, di- or triphosphate ester; trityl or monomethoxytrityl; substituted benzyl; trialkylsilyl as, for eg., dimethyl-t-butylsilyl or diphenylmethylsilyl.
Aryl groups in the esters optimally comprise a phenyl group. The term "acyl" or O-linked ester refers to a group of the formula C(O)R', wherein R' is an straight, branched, or cyclic alkyl (including lower alkyl), carboxylate residue of an amino acid, aryl including phenyl, heteroaryl, alkaryl, aralkyl including benzy 1, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substitoted with chloro, bromo, fluoro, iodo, to C4 alkyl or Q to C4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimally comprise a phenyl group. In nonlimiting embodiments, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl- carboxy, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyloctanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl- phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2- diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl, 7- chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2- methoxy-benzoyl, 4-(l,l,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega- aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzene- carboxyl, O-acetylmandelyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane- carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, l-methyl-lH-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl. The term "lower acyl" includes an acyl group in which the non-carbonyl moiety is lower alkyl. The term amino acid includes naturally occurring and synthetic α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine arid histidine. In a preferred embodiment, the amino acid is in the L- configuration, but can also be used in the D-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β- leucinyl, β-isoleuccinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β- glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β- aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. As used herein, the terms "substantially free of and "substantially in the absence of refer to a nucleoside composition that includes at least 85 or 90% by weight, preferably at least 95% or 98% by weight, and even more preferably at least 99% or 100% by weight, of the designated enantiomer of that nucleoside. In a preferred embodiment, the compounds listed in the methods and compounds of this invention are substantially free of enantiomers other than for the one designated. Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85% or 90% by weight, preferably 95% or98% y weight, and even more preferably 99% or 100% by weight, of the nucleoside. The term "host", as used herein, refers to a 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 coronavims, togavims and/or picomavims 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 coronavims, togaviras and/or picomavims 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 in chimpanzees. The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (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 coronavirus, togaviras and/or picomavims or are metabolized to a compound that exhibits such activity.
III. Nucleotide Prodrug Formulations Any of the nucleosides described herein can be administered as a nucleotide prodmg to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside. A number of nucleotide prodmg ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono-, di- or triphosphate of the nucleoside reduces polarity and allows passage into cells. 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. Bischoferger, Antiviral Research, 1995, 27:1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect. 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, ascorate; 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. 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. Raen, 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, CA. Wallen, S. Piantadosi, and EJ. 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 inhiition of human immunodeficiency vims type 1 replication in CEM and HT4-6C cells by 3 '-deoxy thymidine diphosphate dimyristoylglycerol, a lipid prodrag of 3-deoxythymidine." Antimicro. Agents
Chemother. 36:2025.2029; Hosetler, K.Y., L.M. Stuhmiller, H.. 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. Patent Nos. 5,149,794 (Sep. 22,
1992, Yatvin et al); 5,194,654 (Mar. 16, 1993, Hostetler et al, 5,223,263 (June 29,
1993, Hostetler et al); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2, 1995, Hostetler et al); 5,463,092 (Oct. 31, 1995, Hostetler et al); 5,543,389 (Aug. 6, 1996, Yatvin et al); 5,543,390 (Aug. 6, 1996, Yatvin et al); 5,543,391 (Aug. 6, 1996, Yatvin et al); and 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, W090/00555, W091/16920, W091/18914, W093/00910, W094/26273, W0 96/15132, EP 0 350287, EP 93917054.4, and WO 91/19721.
IV. Combination and Alternation Therapy Drug-resistant variants of coronavirus, togaviras and/or picomavims may emerge after prolonged treatment with an antiviral agent. Drag resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against the viral 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 drag 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 vims. Any of the viral treatments described in the Background of the Invention can be used in combination or alternation with the compounds described in this specification. Nonlimiting examples include:
(1) Interferon A number of patents disclose anti-viral treatments, using interferon-based therapies. For example, U.S. Patent No. 5,928,636 to Alber et al. discloses the combination therapy of interleukin-12 and interferon alpha for the treatment of infectious diseases. U.S. Patent No. 5,849,696 to Chretien et al. discloses the use of thymosins, alone or in combination with interferon. U.S. Patent No. 5,830,455 to Valtoena et al. discloses a combination therapy employing interferon and a free radical scavenger. U.S. Patent No. 5,738,845 to Imakawa discloses the use of human interferon tau proteins.
Other interferon-based treatments are disclosed, for example, in U.S. Patent No.
5,676,942 to Testa et al., U.S. Patent No. 5,372,808 to Blatt et al., and U.S. Patent No.
5,849,696. A number of patents also disclose pegylated forms of interferon, such as U.S.
Patent Nos. 5,747,646, 5,792,834 and 5,834,594 to Hoffmann-La Roche Inc; PCT Publication No. WO 99/32139 and WO 99/32140 to Enzon; WO 95/13090 and US
Patent Nos. 5,738,846 and 5,711,944 to Schering; and U.S. Patent No. 5,908,621 to Glue i et al.. Interferon alpha-2a and interferon alpha-2b are currently approved as monotherapy. For example, ROFERON®-A (Roche) is the recombinant form of interferon alpha-2a. Pegasys® (Roche) is the pegylated (i.e. polyethylene glycol modified) form of interferon alpha-2a. INTRON®A (Schering Corporation) is the recombinant form of Interferon alpha-2b, and PEG-INTRON® (Schering Corporation) is the pegylated form of interferon alpha-2b. Other forms of interferon alpha, as well as interferon beta, gamma, tau and omega are currently in clinical development. For example, INFERGEN (interferon alphacon-1) by InterMune, OMNIFERON (natural interferon) by Viragen, ALBUFERON by Human Genome Sciences, REBIF (interferon beta- la) by Ares-Serono, Omega Interferon by BioMedicine, Oral Interferon Alpha by Amarillo Biosciences, and interferon gamma, interferon tau, and interferon gamma- lb by InterMune are in development.
Combination of Interferon and Ribavirin Combination therapy with an alpha interferon and ribavirin is a common antiviral therapy. The combination of interferon and ribavirin has been reported to be effective in the treatment of interferon naϊve patients (for example, Battaglia, A.M. et al.,
Ann. Pharmacother. 34:487-494, 2000), as well as for treatment of patients when histological disease is present (Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3): 125-136, 1998). Studies have show that more patients respond to pegylated interferon- alpha/ribavirin combination therapy than to combination therapy with unpegylated interferon alpha. However, as with monotherapy, significant side effects develop during combination therapy, including hemolysis, flu-like symptoms, anemia, and fatigue, (for example, Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Combination therapy with PEG-INTRON® (peginterferon alpha-2b) and
REBETOL® (Ribavirin, USP) capsules is available from Schering Corporation. REBETOL® (Schering Corporation) has also been approved in combination with
INTRON® A (Interferon alpha-2b, recombinant, Schering Corporation). Roche's Pegasys® (pegylated interferon alpha-2a) and COPEGUS® (ribavirin) are also approved for the treatment of HCV. I PCT Publication Nos. WO 99/59621, WO 00/37110, WO 01/81359, WO 02/32414 and WO 03/024461 by Schering Corporation disclose the use of pegylated interferon alpha and ribavirin combination therapy. PCT Publication Nos. WO 99/15194, WO 99/64016, and WO 00/24355 by Hoffmann-La Roche Inc also disclose the use of pegylated interferon alpha and ribavirin combination.
(3) Substrate-based NS3 protease inhibitors (for example, Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral
Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C vims 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-Branet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734). (4) Non-substrate-based inhibitors, for example, 2,4,6-trihydroxy-3-nitro- benzamide derivatives (for example, Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), 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; (5) Thiazolidine derivatives which show relevant inhibition in a reverse- phase HPLC assay (for example Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially compound RD- 1-6250, possessing a fused cinnamoyl moiety substitoted with a long alkyl chain, RD4 6205 and RD4 6193; (6) Thiazolidines and benzanilides (for example Kakiuchi N. et al. J. EBS Letters 421, 217-220; and Takeshita N. et al. Analytical Biochemistry, 1997, 247, 242- 246); (7) A phenanthrenequinone possessing activity against protease in a SDS- PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., for example, Sch 68631 (for example, Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (for example, Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952); (8) Selective NS3 inhibitors, for example, those based on the macromolecule elgin c, isolated from leech (for example, Qasim M.A. et al., Biochemistry, 1997, 36, 1598-1607); (9) Helicase inhibitors (for example 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); (10) Polymerase inhibitors for example nucleotide analogues, gliotoxin (for example, Ferrari R. et al. Journal of Virology, 1999, 73, 1649-1654), and the natural product cemlenin (for example, Lohmann V. et al., Virology, 1998, 249, 108-118); (11) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the viras (for example, Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides comprising the 3' end of the NCR and/or nucleotides located in the core coding region of the viral RNA
(for example, Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257). (12) Inhibitors of IRES-dependent translation (for example, Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP- 08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Pub.
JP-10101591). (13) Nuclease-resistant ribozymes (for example Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995). (14) Nucleoside analogs have also been developed for the treatment of viral infections. Examples include the following. Idenix Pharmaceuticals, Ltd. discloses branched nucleosides, and their use in the treatment of HCV and flaviviruses and pestiviruses in US Patent Publication No. 2003/0050229 Al and US Patent Publication No. 2003/0060400 Al, which correspond to International Publication Nos. WO 01/90121 and WO 01/92282. A method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active 1', 2 ', 3' or 4' -branched β-D or β-L nucleosides or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. See also U.S . Patent Publication Nos. 2004/0006002 and 2004/0006007 as well as WO 03/026589 and WO 03/026675. Idenix Pharmaceuticals, Ltd. also discloses in US Patent Publication No. 2004/0077587 pharmaceutically acceptable branched nucleoside prodrugs, and their use in the treatment of HCV and flavivimses and pestivirases in prodrugs. See also PCT Publication Nos. WO 04/002422, WO 04/002999, and WO 04/003000. Emory University and the University of Georgia Research Foundation, Inc. (UGARF) discloses the use of 2'-fluoronucleosides in US Patent No. 6,348,587. See also International Patent Publication WO 99/43691. BioChem Pharma Inc. (now Shire Biochem, Inc.) discloses the use of various 1,3-dioxolane nucleosides in International Publication No. WO 01/32153
(PCT/CA00/01316; filed November 3, 2000). BioChem Pharma Inc. (now Shire Biochem, Inc.) also disclose s various other 2'- halo, 2' -hydroxy and 2' -alkoxy nucleosides in International Publication No. WO 01/60315 (PCT/CA01/00197; filed February 19, 2001). ICN Pharmaceuticals, Inc. discloses various nucleoside analogs that are useful in modulating immune response in US Patent Nos. 6,495,677 and 6,573,248. See also WO 98/16184, WO 01/68663, and WO 02/03997. US Patent Publication Nos. 2003/083307 Al and US 2003/008841 Al, and the corresponding International Patent Publication Nos. WO 02/18404 (PCT/EP01/09633; published August 21, 2001); WO 02/100415 and WO 02/094289, filed by F. Hoffmann- La Roche AG discloses various nucleoside analogs for the inhibition of viral RNA replication. Pharmasset Limited discloses various nucleosides and antimetabolites for the treatment of a variety of viruses, in WO 02/32920, WO 01/79246, WO 02/48165, WO 03/068162, WO 03/068164 and 2004/013298. Merck & Co., Inc. and Isis Pharmaceuticals disclose in US Patent Publication No. 2002/0147160 and the corresponding International Patent Publication Nos. WO 02/057425 (PCT/US02/01531; filed January 18, 2002) and WO 02/057287 (PCT/US02/03086; filed January 18, 2002) various nucleosides, and in particular several pyrrolopyrimidine nucleosides, for the treatment of vimses whose replication is dependent upon RNA-dependent RNA polymerase. See also WO 03/068244, WO 2004/003138, WO 2004/007512, and WO 2004/009020. US Patent Publication No. 2003/028013 Al as well as International Patent Publication Nos. WO 03/051899, WO 03/061576, WO 03/062255 WO 03/062256, WO 03/062257, and WO 03/061385, filed by Ribapharm, also are directed to the use of certain nucleoside analogs to treat viral infections.
(15) Miscellaneous compounds including, for example, 1-amino- alkylcyclohexanes (for example, U.S. Patent No. 6,034,134 to Gold et al.), alkyl lipids (for example, U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (for example, U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (for example, U.S. Pat. No. 5,846,964 to Ozeki et al.), N- (phosphonoacetyl)-L-aspartic acid (for example, U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (for example, U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (for example, U.S. Pat. No. 5,496,546 to Wang et al.), 2',3'- dideoxyinosine (for example, U.S. Pat. No. 5,026,687 to Yarchoan et al.), and benzimidazoles for example, (U.S. Pat. No. 5,891,874 to Colacino et al.). (16) Other compounds currently in clinical development include, for example: Interleukin-10 by Schering-Plough, IP-501 by Intemeuron, Merimebodib VX-497 by Vertex, AMANTADINE (Symmetrel) by Endo Labs Solvay, HEPTAZYME by RPI,
IDN-6556 by Idun Pharma., XTL-002 by XTL., HCV/MF59 by Chiron, CINACIR by NABI, LEVOVIRIN by ICN, VIRAMIDINE by ICN, ZADAXIN (thymosin alfa-1) by Sci Clone, CEPLENE (histamine dihydrochloride) by Maxim, VX 950 / LY 570310 by Vertex/Eli Lilly, /ISIS 14803 by Isis Pharmaceutical/Elan, IDN-6556 by Idun Pharmaceuticals, Inc. and JTK 003 by AKROS Pharma.
V. Pharmaceutical Compositions
Hosts, including humans, infected with a coronavims, togaviras and/or picomavirus or another organism replicating through a RNA-dependent RNA viral polymerase, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrag 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, sucutaneously, or topically, in liquid or solid form. A preferred dose of the compound for a coronavims, togavims and/or picomavims 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 prodmgs 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. An oral dosage of 50-1000 mg is usually convenient. Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 μM, preferably about 1.0 to 10 μM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient. The concentration of active compound in the drag 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 inding agents, and/or adjuvant materials can e included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, 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; antiacterial 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, disposale syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PS). 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, biodegradale, 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 antiodies 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. Patent 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.
VI. Processes for the Preparation of Active Compounds
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, though preferably alkylating the appropriately modified sugar, followed by glycosylation. The following non-limiting embodiments illustrate some general methodology to obtain the nucleosides of the present invention.
A. General Synthesis ofl '-C-branched Nucleosides A l'-C branched ribonucleoside of the following structure, for example:
(I) or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, or salt of a prodmg, thereof, wherein: R1 is H, phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); optionally substituted acyl (including lower acyl); optionally substituted alkyl (including lower alkyl); optionally substitoted sulfonate ester including alkyl or arylalkyl sulfonyl such as methanesulfonyl; optionally substitoted aryl; optionally substituted benzyl, wherein the phenyl group is optionally substituted with one or more substitoents as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R is independently H or phosphate; each R2 and R4 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substitoted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substitoted carbocycle, an optionally substitoted heterocycle, an optionally substituted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), or C3-7 cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2C(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring such as, for example, a C3- cycloalkylamino), an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), an optionally substitoted heteroaryl (preferably a heteroaromatic ring having one or more O, S and/or N atoms), a C3- cycloalkylamino, CF3, mercapto, optionally substituted Q-4 alkyl, Cι-i2 alkoxy, Qz^alkenyl, C2-4 alkynyl, C2.6 alkenyloxy, Cι-4 alkylthio, Cι-8 alkylcarbonyloxy, aryloxycarbonyl, Cι-4 alkylamino, di(Q-4 alkyl)amino, Br- vinyl, -C(O)O(alkyl), O-phosphate or O-phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); O-acyl (including lower acyl); O-alkyl (including lower alkyl); O-sulfonate ester including O-alkyl or O- arylalkyl sulfonyl including O-methanesulfonyl; O-aryl; O-benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of an aryl given herein; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); -S(alkenyl); optionally substituted O-arylsulfonyl; an O- linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O-linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein the requisite R , R or R is independently OH or O-phosphate;
X is O, S, SO2, CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, CM alkyl, halo, azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, -NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is as defined in the specification, including but not limited to:
wherein: Each R7, R8, R10, Rπ and R12 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl (preferably optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH-heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O-heterocycle, -O- heteroaryl, CM alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, CM alkyl-C(=O)OH, Q-4 alkyl-C(=O)O-aryl (preferably C1-4 alkyl- C(=O)O-phenyl), CM alkyl-C(=O)O-heterocycle, CM alkyl-C(=O)O- heteroaryl, or C1- alkoxy; R9 is O or S; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
Modification from the Lactone The key starting material for this process is an appropriately substituted lactone. The lactone may be purchased or can be prepared by any known means including standard epimerization, substitution and cyclization techniques. The lactone optionally can be 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 like a Grignard reagent, an organolithium, lithium dialkylcopper or R6-SiMe3 in TAF with the appropriate non-protic solvent at a suitable temperature, to give the l'-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 Nuceleotides,
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 l'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively, dexoyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside an 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'- OH can be activated to facilitate reduction as, for example, via the Barton reduction.
Alternative Method for the Preparation of 1 '-C-branched Nucleosides The key starting material for this process is an appropriately substitoted hexose. The hexose can be purchased or can be prepared by any known means including standard epimerization (as, for example, via alkaline treatment), substitution and coupling techniques. The hexose can be protected selectively to give the appropriate hexa- furanose, as taught by Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. The l'-OH optionally can be activated to a suitable leaving group such as an acyl group or a halogen 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 an appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate. The l'-CH2-OH, if protected, selectively can be deprotected by methods well known in the art. The resultant 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 TAF with an appropriate non-protic solvent at a suitable temperature. In a particular embodiment, the l'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively, deoxyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside optionally can 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'- OH can be activated to facilitate reduction as, for example, via the Barton reduction.
Scheme 2 Alkaline D-fructose ■ Treatment
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 the starting material.
General Synthesis of 2' -C-branched Nucleosides A 2' -C-branched ribonucleoside of the following structure as an example:
(H)
wherein R1, R3, R5, and R' are all as defined above; X is as defined above; Base is as defined in the specification; or a pharmaceutically acceptable salt or prodrag thereof; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
1. Glycosylation of the nucleoase with an appropriately modified sugar The key starting material for this process is an appropriately substitoted sugar with a 2' -OH and 2'-H, with an appropriate leaving group (LG), such as an acyl or halogen group, for example. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and/or reduction techniques. The substituted sugar can then be oxidized with an 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 and sulfuric acids), Collins' 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 molydate, NarO2-CAN, NaOCl in HOAc, copper chromate, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf- Verley reagent (aluminum t-utoxide with another ketone) and N-bromosuccinimide. Then coupling of an organometallic carbon nucleophile such as a Grignard reagent, an organolithium, lithium dialkylcopper or R -SiMe3 in TAF with the ketone and an appropriate non-protic solvent at a suitable temperature, yields the 2'-alkylated sugar. The alkylated sugar optionally can be 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 an appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can e coupled to a silylated base in the presence of trimethylsilyltriflate. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as 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 which is shown in Scheme 3. Alternatively, a deoxyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2' -OH can e reduced with a suitable reducing agent. Optionally, the 2' -OH can be activated to facilitate reduction, such as, for example, by the Barton reduction.
Scheme 3
2. Modification of a pre-formed nucleoside The key starting material for this process is an appropriately substitoted 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 optionally can be protected with suitable protecting groups, preferably with acyl or silyl groups, by methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The appropriately protected nucleoside then can be oxidized with an appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2' -modified sugar. Possible oxidizing agents include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' 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 molydate, NarO2- CAN, NaOCl in HO Ac, copper chromate, copper oxide, Raney nickel, palladium acetate,
Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N- bromosuccinimide. Subsequently, the nucleoside can e deprotected y methods well known to those skilled in the art, as by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In a particular embodiment, a 2' -C-branched ribonucleoside is desired, the synthesis of which is shown in Scheme 4. Alternatively, the deoxyribonucleoside may be desired. To obtain these nucleosides, the formed ribonucleoside optionally may be protected by methods well known to those skilled in the art, as 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'- OH can be activated to facilitate reduction such as, for example, by the Barton reduction.
Scheme 4
1) Optional Protection 2) Optional Reduction t
Optional Deprotection In another embodiment of the invention, the L-enantiomers are desired. These L- enantiomers corresponding to the compounds of the invention may be prepared following the same general methods given above, but beginning with the corresponding L-sugar or nucleoside L-enantiomer as the starting material.
C. General Synthesis of 3 '-C-branched Nucleosides A 3'-C-branched ribonucleoside of the following structure as an example:
(III)
wherein R1, R3, R5, and R' are all as defined above; X is as defined above; Base is as defined in the specification; or a pharmaceutically acceptable salt or prodrag thereof; and all tautomeric, enantiomeric and stereoisomeric forms thereof.
Glycosylation of the nucleoase with an appropriately modified sugar. The key starting material for this process is an appropriately substitoted sugar with a 3' -OH and a 3'-H, with an appropriate leaving group (LG) such as, for example, an acyl group or a halogen. The sugar can be purchased or can be prepared by any known means including standard epimerization, substitution, oxidation and/or reduction techniques. The substitoted sugar then can be oxidized by an appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 3 '-modified sugar. Possible oxidizing agents include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' reagent (dipyridine Cr(VI)oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate,
MnO , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, Cl2-pyridine, H2O2-ammonium molydate, NarO - CAN, NaOCl in HOAc, copper chromate, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-utoxide 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 TAF with the ketone and an appropriate non-protic solvent at a suitable temperature, yields the 3'-C-branched sugar. The 3 '-C-branched sugar optionally can e 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 y Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can e coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride, or trimethylsilyltriflate in an appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base in the presence of trimethylsilyltriflate. Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as 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 which is shown in Scheme 5. Alternatively, a deoxyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as 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'- OH can be activated to facilitate reduction, such as, for example, by the Barton reduction. Scheme 5
1) Optional Protection 2) Optional Reduction
. ptional, DejKptectipn..
Modification of a pre-formed nucleoside. The key starting material for this process is an appropriately substitoted 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 include Jones' reagent (a mixture of chromic and sulfuric acids), Collins' 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, H2θ2-ammonium molybdate,
NarO2-CAN, NaOCl in HOAc, copper chromate, 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 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 which is shown in Scheme 6. Alternatively, a deoxyribonucleoside is desired. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as 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'- OH can be activated to facilitate reduction, such as, for example, by the Barton reduction.
Scheme 6
1) Optional Protection 2) Optional Reduction 1
In another embodiment of the invention, the L-enantiomers are desired. These L- enantiomers corresponding to the compounds of the invention may e prepared following the same general methods given above, but beginning with the corresponding L-sugar or nucleoside L-enantiomer as the starting material.
The present invention is described by way of illustration in the following examples. It will be understood by one of ordinary skill in the art that these examples are in no way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention.
EXAMPLES
Example 1. CC50 and EC50 Test Results for β-D-2' -C-methyl-adenosine (Compound A) and β-D-2' -C-methyl-2-amino adenosine (Compound B)
Note: Cell lines utilized include MT-4 for HIV; Vero 76, African green monkey kidney cells for SARS-CoV; BHK for Bovine Viral Diarrhea Viras; Sb-1 for poliovims Sabin type-1; CVB-2, CVB-3, CVB-4, and CVA-9 for Coxsackievimses B-2, B-3, B-4 and A- 9; and REO-1 for double-stranded RNA viruses.
Example 2. CC50 and EC50 Test Results for β-D-2' -C-methyl-guanosine (Compound C) and β-D-2' -C-methyl-6-chloro-guanosine (Compound D)
Example 3. CC50 and EC50 Test Results for 3',5'-di-0-valinyl ester of β-D-2' -C- methyl -guanosine dihydrochloride salt (Compound E)
Example 4. CC50 and EC50 Test Results for β-D-2' -C-methyl-7-methyl-6-phenyl- 3,3a,5,8a-tetrahydro-l,3,4,5,7a-penta-aza-s-indacen-8-one (Compound F)
Example 5. CC50 and EC50 Test Results for β-D-2' -C-methyl-cytidine (Compound G)
Example 6. CC50 and EC50 Test Results for β-D-2' -C-ethynyl-adenosine (Compound H)
Example 7. CC50 and EC50 Test Results for β-D-2' -C-ethynyl-cytidine (Compound I)
Example 8. CC50 and EC50 Test Results for β-D-2-amino-adenosine (Compound J)
Example 9. CC50 Test Results for β-D-2' -C-methyl-adenosine (Compound A), β-D-2' - C-methyl-2-amino adenosine (Compound B), and β-D-2' -C-methyl-2-amino-6- cyclopropyl adenosine(Compound K)
Note: BVDV = bovine viral diarrhea viras; YFV = yellow fever viras; WNV = West Nile virus; CVB-2 = Coxsackie B-2 virus; Sb-1 = Sabin type 1 poliomyelitis viras; and REO = double-stranded RNA Reoviras.
Example 10. CC50 Test Results for β-D-2' -C-methyl-guanosine (Compound C), β-D- 2'-C-methyl-l-(methyl-2-oxo-2-phenyl ethyl)guanosine (Compound L), and β-D-2'-C- methyl-6-chloro guanosine (Compound D)
Example 11. CC50 Test Results for 3',5'-di-0-valinyl ester of β-D-2' -C-methyl- guanosine dihydrochloride salt (Compound E)
Example 12. CC50 Test Results for β-D-2' -C-methyl-7-methyl-6-phenyl-3,3a,5,8a- tetrahydro-l,3,4,5,7a-penta-aza-J-indacen-8-one (Compound F)
Example 13. CC50 Test Results for β-D-2' -C-ethynyl-adenosine (Compound H)
Example 14. CC50 Test Results for β-D-2' -C-methyl-cytidine (Compound G), 3'-0- valinyl ester of β-D-2' -C-methyl-cytidine dihydrochloride salt (Compound M), and β-D- 2'-C-methyl-uracil (Compound N)

Claims

WE CLAIM:
A method of treating a host infected with a coronavims, togavims or picomavims, comprising administering an effective amount of a biologically active nucleoside analogue, wherein the nucleoside analogue has the structure of Formula (AA):
AA or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R1 is H; phosphate; mono-, di-, or triphosphate; stabilized phosphate prodrag; optionally substituted acyl; optionally substituted lower acyl; optionally substituted alkyl; optionally substituted lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo (F, CI, Br, I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substitoted carbocycle, an optionally substituted heterocycle, an optionally substitoted heteroaryl, or C3-7 cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted 3-7 membered carbocyclic ring, a C3- cycloalkylamino, an optionally substitoted heterocycle, an optionally substituted heteroaryl, a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, Cι_i2 alkoxy, C2- alkynyl, C2-6 alkenyloxy, Cι-4 alkylthio, C1-8 alkylcarbonyloxy, aryloxycarbonyl, Cj-4 alkylamino, d .4 alkyl)amino, Br-vinyl, - C(O)O(alkyl), O-phosphate, O-mono-, di-, or triphosphate, O-stabilized phosphate prodrug; O-acyl; O-lower acyl; O-alkyl; O-lower alkyl; O- sulfonate ester, O-alkyl or O-arylalkyl sulfonyl; O-methanesulfonyl; O- benzyl, wherein the phenyl group is optionally substitoted with one or more substituents; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); -S(alkenyl); optionally substitoted O-arylsulfonyl; an O-linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O-linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br- vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O- aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2, CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, C alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is a purine, a pyrimidine or a base selected from the group consisting of:
wherein: each R8, R , 1i0U, T RJ I"I, D R112 and R 1113J i •ndependently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substitoted aryl, optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH- heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O- heterocycle, -O-heteroaryl, C alkylamino, di(Cι-4 alkyl)amino, C3-6 cycloalkylamino, CM alkyl-C(=O)OH, CM alkyl-C(=O)O-aryl, C1-4 alkyl-C(=O)O-phenyl, CM alkyl-C(=O)O-heterocycle, C1-4 alkyl- C(=O)O-heteroaryl, or Cι-4 alkoxy; and R9 is O or S; optionally in a pharmaceutically acceptable carrier or diluent.
2. The method of claim 1, wherein the coronavirus is a SARS-CoV viras.
3. The method of claim 1, wherein the togavirus is a rabiviras (the causative agent for rabella) or an alphavims (the causative agent for encephalitis)
4. The method of claim 1, wherein the a picomavims is an enterovims, a rhinovims, a cardiovims or an aphthoviras.
5. The method of claim 4, wherein the enteroviras is a Coxsackievirus, poliovirus, hepatitis A viras, echoviras, or a human enteroviras species.
6. The method of claim 1 wherein the host is a mammal.
7. The method of claim 6 wherein the mammal is a human.
8. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Al):
(Al) or a pharmaceutically acceptable salt or prodrag thereof.
9. The method of claim 1 wherein the compound of Formula (AA) has the structure of (Bl):
or a pharmaceutically acceptable salt or prodrug thereof.
10. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (CI):
or a pharmaceutically acceptable salt or prodrag thereof.
11. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Dl):
(Dl) or a pharmaceutically acceptable salt or prodmg thereof.
12. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (El):
(El) or a pharmaceutically acceptable salt or prodrug thereof.
13. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Fl):
(FI) or a pharmaceutically acceptable salt or prodrug thereof.
14. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Gl):
or a pharmaceutically acceptable salt or prodrag thereof.
15. The method of claim 1 wherein the compound of Formula (AA) has the structure of (HI):
(HI) or a pharmaceutically acceptable salt or prodmg thereof.
16. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (II):
or a pharmaceutically acceptable salt or prodrag thereof.
17. The method of claim 1 wherein the compound of Formula (AA) has the structure of (Jl):
(Jl) or a pharmaceutically acceptable salt or prodrag thereof.
18. The method of claim 1 wherein the compound of Formula (AA) has the structure of (KI):
or a pharmaceutically acceptable salt or prodmg thereof.
19. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Ll):
or a pharmaceutically acceptable salt or prodrug thereof.
20. The method of claim 1 wherein the compound of Formula (AA) has the stractore of (Ml):
or a pharmaceutically acceptable salt or prodrag thereof.
21. The method of claim 1 wherein the compound of Formula (AA) has the structure of (Nl):
or a pharmaceutically acceptable salt or prodrag thereof.
22. The method of claim 1 wherein the compound of Formula (AA) is administered in combination and/or alternation with one or more other anti- viral agent.
23. The method of claim 22, wherein the other anti-viral agent is an anti-coronavims, anti-togavims, and/or anti-picomavims agent.
24. The method of claim 23, wherein the anti-coronaviras agent is an anti-SARS- CoV agent.
25. The method of claim 23, wherein the anti-togavirus agent is an anti-rubivirus or an anti-alphavirus agent.
26. The method of claim 23, wherein the anti-picomavims is an anti-enterovims, anti-rhinovirus, anti-cardioviras and/or anti-aphthovirus agent.
27. The method of claim 26, wherein the anti-enterovirus agent is an anti- Coxsackievirus, anti-polioviras, anti-hepatitis A virus, and/or an anti-echoviras agent.
28. A pharmaceutical composition for the treatment of a coronavirus, togavirus or picomavims comprising a treatment effective amount of a nucleoside analogue of the stractore of Formula (AA):
AA or a pharmaceutically acceptable salt, ester or prodmg thereof, wherein: R1 is H; phosphate; mono-, di-, or triphosphate; stabilized phosphate prodmg; optionally substituted acyl; optionally substituted lower acyl; optionally substituted alkyl; optionally substitoted lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo (F, CI, Br, I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substituted heteroaryl, or C3-7 cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted 3-7 membered carbocyclic ring, a C3- cycloalkylamino, an optionally substituted heterocycle, an optionally substituted heteroaryl, a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted CM alkyl, .π alkoxy, C2-4alkenyl, C2-4 alkynyl, C2-6 alkenyloxy, C1- alkylthio, C1-8 alkylcarbonyloxy, aryloxycarbonyl, C1-4 alkylamino, di(C1- alkyl)amino, Br-vinyl, -C(O)O(alkyl), O-phosphate, O-mono-, di-, or triphosphate, O-stabilized phosphate prodrug; O-acyl; O-lower acyl; O-alkyl; O-lower alkyl; O- sulfonate ester, O-alkyl or O-arylalkyl sulfonyl; O-methanesulfonyl; O- benzyl, wherein the phenyl group is optionally substituted with one or more substituents; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); - S(alkenyl); optionally substitoted O-arylsulfonyl; an O-linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O- linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br- vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O- aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2, CH2, or CHOH; m is 0, 1 or 2;
R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, CM alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is a purine, pyrimidine, or a base selected from the group consisting of:
wherein: each R8, R10, Ru, R12 and R13 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substitoted aryl, optionally substituted phenyl, -NH-cycloalkyl, -NH-cycloalkenyl, -NH- heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O- heterocycle, -O-heteroaryl, CM alkylamino, di(C1- alkyl)amino, C3-6 cycloalkylamino, Cι-4 alkyl-C(=O)OH, CJ-4 alkyl-C(=O)O-aryl, CM alkyl-C(=O)O-ρhenyl, CM alkyl-C(=O)O-heterocycle, CM alkyl- C(=O)O-heteroaryl, or CM alkoxy; and R9 is O or S; optionally in combination with one or more other effective anti-coronaviras, anti- picornavirus, and/or anti-togavirus agents, optionally in a pharmaceutically acceptable carrier or diluent.
29. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (Al):
or a pharmaceutically acceptable salt or prodrag thereof.
30. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the stractore of (Bl): or a pharmaceutically acceptable salt or prodrag thereof.
31. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (CI):
or a pharmaceutically acceptable salt or prodrag thereof.
32. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (Dl):
(Dl) or a pharmaceutically acceptable salt or prodrug thereof.
33. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the stractore of (El): (El) or a pharmaceutically acceptable salt or prodrug thereof.
34. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the stractore of (FI):
or a pharmaceutically acceptable salt or prodmg thereof.
35. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (Gl):
or a pharmaceutically acceptable salt or prodrag thereof.
36. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (HI):
or a pharmaceutically acceptable salt or prodrag thereof.
37. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (II):
(ID or a pharmaceutically acceptable salt or prodrug thereof.
38. The pharmaceutical composition of claim 28 wherein the compound of Formula (A A) has the stractore of (Jl):
(Jl) or a pharmaceutically acceptable salt or prodrag thereof.
39. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (KI):
or a pharmaceutically acceptable salt or prodrag thereof.
40. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (LI):
or a pharmaceutically acceptable salt or prodrag thereof.
41. The pharmaceutical composition of claim 28 wherein the compound of Formula (AA) has the structure of (Ml):
or a pharmaceutically acceptable salt or prodrug thereof.
42. The pharmaceutical composition of claim 28 wherein the compound of Formula (A A) has the structure of (Nl): O
HO ° ΛO cHg HO OH (Nl) or a pharmaceutically acceptable salt or prodrug thereof.
43. The pharmaceutical composition of claim 28, wherein the anti-coronavims agent is an anti-SARS-CoV agent.
44. The pharmaceutical composition of claim 28, wherein the anti-togavims agent is an anti-mbiviras or an anti-alphavirus agent.
45. The pharmaceutical composition of claim 28, wherein the anti-picomavims is an anti-enterovims, anti-rhinovirus, anti-cardioviras and/or anti-aphthovirus agent.
46. The pharmaceutical composition of claim 45, wherein the anti-enterovirus agent is an anti-Coxsackieviras, anti-polioviras, anti-hepatitis A viras, and/or an anti- echoviras agent.
47. Use of an effective amount of compound of the structure of Formula (AA):
AA or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R1 is H; phosphate; mono-, di-, or triphosphate; stabilized phosphate prodmg; optionally substituted acyl; optionally substitoted lower acyl; optionally substituted alkyl; optionally substituted lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, optionally substituted alkyl, optionally substituted alkenyl, optionally substitoted alkynyl, halo (F, CI, Br, I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substituted heteroaryl, or C3- cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)raC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted 3-7 membered carbocyclic ring, a C3-7 cycloalkylamino, an optionally substitoted heterocycle, an optionally substituted heteroaryl, a C3-7 cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, Cι-12 alkoxy, C^alkenyl, C2-4 alkynyl, C2-6 alkenyloxy, C1-4 alkylthio, Cι-8 alkylcarbonyloxy, aryloxycarbonyl, C1-4 alkylamino, di(CM alkyl)amino, Br-vinyl, -C(O)O(alkyl), O-phosphate, O-mono-, di-, or triphosphate, O-stabilized phosphate prodmg; O-acyl; O-lower acyl; O-alkyl; O-lower alkyl; O- sulfonate ester, O-alkyl or O-arylalkyl sulfonyl; O-methanesulfonyl; O- benzyl, wherein the phenyl group is optionally substituted with one or more substituents; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); - S(alkenyl); optionally substitoted O-arylsulfonyl; an O-linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O- linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br- vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O- aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2> CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, Cι-4 alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is a purine, a pyrimidine or a base selected from the group consisting of:
wherein: each R8, R10, R11, R12 and R13 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substitoted aryl, optionally substitoted phenyl, -NH-cycloalkyl, -NH-cycloalkenyl, -NH- heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O- heterocycle, -O-heteroaryl, CM alkylamino, di(C1- alkyl)amino, C3-6 cycloalkylamino, C1-4 alkyl-C(=O)OH, C1-4 alkyl-C(=O)O-aryl, C1-4 alkyl-C(=O)O-phenyl), CM alkyl-C(=O)O-heterocycle, C1- alkyl- C(=O)O-heteroaryl, or CM alkoxy; and R9 is O or S; optionally in a pharmaceutically acceptable carrier or diluent; for the treatment of a coronavirus, togavirus or picomavims infection in a host.
48. The use of claim 47 wherein the compound of Formula (AA) has the structure of (Al):
or a pharmaceutically acceptable salt or prodrag thereof.
49. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (Bl): or a pharmaceutically acceptable salt or prodrug thereof.
50. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (CI):
or a pharmaceutically acceptable salt or prodmg thereof.
51. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (Dl):
(Dl) or a pharmaceutically acceptable salt or prodmg thereof.
52. The use of claim 47 wherein the compound of Formula (AA) has the structure of (El): (El) or a pharmaceutically acceptable salt or prodmg thereof.
53. The use of claim 47 wherein the compound of Formula (AA) has the structure of (FI):
(FI) or a pharmaceutically acceptable salt or prodrag thereof.
54. The use of claim 47 wherein the compound of Formula (AA) has the stractore of (Gl):
or a pharmaceutically acceptable salt or prodmg thereof.
55. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (HI):
(Hi) or a pharmaceutically acceptable salt or prodrag thereof.
56. The use of claim 47 wherein the compound of Formula (AA) has the structure of (II):
or a pharmaceutically acceptable salt or prodrug thereof.
57. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (Jl):
(Jl) or a pharmaceutically acceptable salt or prodrag thereof.
58. The use of claim 47 wherein the compound of Formula (AA) has the stractore of (KI):
or a pharmaceutically acceptable salt or prodrug thereof.
59. The use of claim 47 wherein the compound of Formula (AA) has the stractore of (LI):
or a pharmaceutically acceptable salt or prodrag thereof.
60. The use of claim 47 wherein the compound of Formula (AA) has the structure of (Ml):
or a pharmaceutically acceptable salt or prodrug thereof.
61. The use of claim 47 wherein the compound of Formula (AA) has the stracture of (Nl):
or a pharmaceutically acceptable salt or prodrag thereof.
62. The use of claim any one of claims 47-61, further in combination and/or alternation with one or more other anti-viral agent.
63. The use of claim 62, wherein the other anti-viral agent is an anti-coronavims, anti-togavirus, and or anti-picomavims agent.
64. The use of claim 63, wherein the anti-coronavims agent is an anti-SARS-CoV agent.
65. The use of claim 63, wherein the anti-togavirus agent is an anti-rubivims or an anti-alphavirus agent.
66. The use of claim 63, wherein the anti-picomavims is an anti-enterovirus, anti- rhinovirus, anti-cardiovirus and/or anti-aphthovirus agent.
67. The use of claim 66, wherein the anti-enteroviras agent is an anti-Coxsackievirus, anti-poliovirus, anti-hepatitis A virus, and/or an anti-echovirus agent.
68. The use of any one of claims 47-67, wherein the coronavirus is a SARS-CoV virus.
69. The use of any one of claims 47-67, wherein the togavims is a rubivirus (the causative agent for rabella) or an alphavirus (the causative agent for encephalitis)
70. The use of any one of claims 47-67, wherein the a picomavirus is an enterovims, a rhinovirus, a cardiovims or an aphthoviras.
71. The use of claim 70, wherein the enteroviras is a Coxsackievirus, polioviras, hepatitis A viras, echoviras, or a human enteroviras species.
72. The use of any one of claims 47-71 wherein the host is a mammal.
73. The use of claim 72 wherein the mammal is a human.
74. Use of an effective amount of a compound of the structure of Formula (AA):
AA or a pharmaceutically acceptable salt, ester or prodrag thereof, wherein: R1 is H; phosphate; mono-, di-, or triphosphate; stabilized phosphate prodrag; optionally substituted acyl; optionally substituted lower acyl; optionally substituted alkyl; optionally substitoted lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, optionally substituted alkyl, optionally substitoted alkenyl, optionally substituted alkynyl, halo (F, CI, Br, I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)raC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR , -O(R ), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substitoted heteroaryl, or C3-7 cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted 3-7 membered carbocyclic ring, a C3- cycloalkylamino, an optionally substituted heterocycle, an optionally substituted heteroaryl, a C3-7 cycloalkylamino, CF3, mercapto, optionally substitoted CM alkyl, C n alkoxy, C^alkenyl, C2- alkynyl, C2-6 alkenyloxy, C alkylthio, C1-8 alkylcarbonyloxy, aryloxycarbonyl, CM alkylamino, di(Cι-4 alkyl)amino, Br-vinyl, - C(O)O(alkyl), O-phosphate, O-mono-, di-, or triphosphate, O-stabilized phosphate prodrag; O-acyl; O-lower acyl; O-alkyl; O-lower alkyl; O- sulfonate ester, O-alkyl or O-arylalkyl sulfonyl; O-methanesulfonyl; O- benzyl, wherein the phenyl group is optionally substituted with one or more substituents; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); - S(alkenyl); optionally substituted O-aryl sulfonyl; an O-linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O- linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br- vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O- aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2> CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, CM alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl) , or -N(acyl)2; and
Base is a purine, pyrimidine or a base selected from the group consisting of:
wherein: each R8, R10, R11, R12 and R13 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substitoted aryl, optionally substituted phenyl), -NH-cycloalkyl, -NH-cycloalkenyl, -NH- heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O- heterocycle, -O-heteroaryl, C alkylamino, di(CM alkyl)amino, C3-6 cycloalkylamino, C1-4 alkyl-C(=O)OH, CM alkyl-C(=O)O-aryl, C1- alkyl-C(=O)O-phenyl, C1-4 alkyl-C(=O)O-heterocycle, CM alkyl- C(=O)O-heteroaryl, or CM alkoxy; and R9 is O or S; optionally in a pharmaceutically acceptable carrier or diluent; in the manufacture of a medicament for the treatment of a coronavims, togaviras or picomavirus infection in a host.
75. The use of claim 74 wherein the compound of Formula (AA) has the structure of (Al):
(Al) or a pharmaceutically acceptable salt or prodrag thereof.
76. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (Bl):
or a pharmaceutically acceptable salt or prodrug thereof.
77. The use of claim 74 wherein the compound of Formula (AA) has the structure of (CI):
or a pharmaceutically acceptable salt or prodrag thereof.
78. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (Dl):
(Dl) or a pharmaceutically acceptable salt or prodrag thereof.
79. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (El):
(El) or a pharmaceutically acceptable salt or prodrag thereof.
80. The use of claim 74 wherein the compound of Formula (AA) has the structure of (FI):
(FI) or a pharmaceutically acceptable salt or prodrag thereof.
Ill
81. The use of claim 74 wherein the compound of Formula (AA) has the structure of (Gl):
(Gl) or a pharmaceutically acceptable salt or prodrag thereof.
82. The use of claim 74 wherein the compound of Formula (AA) has the stracture of (HI):
or a pharmaceutically acceptable salt or prodrag thereof.
83. The use of claim 74 wherein the compound of Formula (AA) has the stracture of (II):
(ID or a pharmaceutically acceptable salt or prodrug thereof.
84. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (Jl):
(Jl) or a pharmaceutically acceptable salt or prodmg thereof.
85. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (KI):
or a pharmaceutically acceptable salt or prodrug thereof.
86. The use of claim 74 wherein the compound of Formula (AA) has the structure of (LI):
or a pharmaceutically acceptable salt or prodrag thereof.
87. The use of claim 74 wherein the compound of Formula (AA) has the stractore of (Ml):
or a pharmaceutically acceptable salt or prodrug thereof.
88. The use of claim 74 wherein the compound of Formula (AA) has the stracture of (Nl):
(Nl) or a pharmaceutically acceptable salt or prodrag thereof.
89. The use of claim any one of claims 74-88, further in combination and/or alternation with one or more other anti-viral agent.
90. The use of claim 89, wherein the other anti-viral agent is an anti-coronaviras, anti-togavirus, and/or anti-picomavims agent.
91. The use of claim 90, wherein the anti-coronavims agent is an anti-SARS-CoV agent.
92. The use of claim 90, wherein the anti-togaviras agent is an anti-rabiviras or an anti-alphavirus agent.
93. The use of claim 90, wherein the anti-picomavims is an anti-enterovims, anti- rhinovirus, anti-cardioviras and or anti-aphthovirus agent.
94. The use of claim 93, wherein the anti-enteroviras agent is an anti-Coxsackievirus, anti-poliovirus, anti-hepatitis A virus, and/or an anti-echovirus agent.
95. The use of any one of claims 74-94, wherein the coronavirus is a SARS-CoV virus.
96. The use of any one of claims 74-94, wherein the togaviras is a rubivirus (the causative agent for rubella) or an alphavirus (the causative agent for encephalitis)
97. The use of any one of claims 74-94, wherein the a picomavirus is an enterovims, a rhinovirus, a cardiovims or an aphthoviras.
98. The use of claim 97, wherein the enteroviras is a Coxsackievirus, polioviras, hepatitis A vims, echoviras, or a human enterovirus species.
99. The use of any one of claims 74-98 wherein the host is a mammal.
100. The use of claim 99 wherein the mammal is a human.
101. A pharmaceutical composition for the treatment of a coronavirus, togaviras or picomavirus infection in a host, comprising an effective amount of a compound of the Formula (AA):
AA or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R1 is H; phosphate; mono-, di-, or triphosphate; stabilized phosphate prodrag; optionally substituted acyl; optionally substitoted lower acyl; optionally substitoted alkyl; optionally substitoted lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; aryl; benzyl, wherein the phenyl group is optionally substitoted with one or more substituents; optionally substituted arylsulfpnyl; a lipid; a phospholipid; an amino acid derivative; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving /group that when administered in vivo, provides a compound wherein R1 is independently H or phosphate; each R2 and R4 independently is H, OH, optionally substituted alkyl, optionally substitoted alkenyl, optionally substituted alkynyl, halo (F, CI, Br, I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br- vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)raC(O)SR13; -O(alkenyl), -(CH2)raNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted carbocycle, an optionally substituted heterocycle, an optionally substitoted heteroaryl, or C3- cycloalkylamino; each R3, R5 and R6 independently is H, OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, halo (F, CI, Br, or I), NO2, NH2, N3, CH2N3, CH2NH2, CN, CH2CN, CH2N3, CH2NHCH3, CH2N(CH3)2, CH2OH, halogenated alkyl, alkoxy, CF3, C(A)3, 2-Br-ethyl, CH2F, CH2C1, CH2CF3, CF2CF3, CH2(A), C(A)2(A)3, SCN, OCN, NCO, haloalkenyl, Br-vinyl, haloalkynyl; -(CH2)mC(O)OR13, -(CH2)mC(O)SR13; -O(alkenyl), -(CH2)mNHR13, -(CH2)mN(R13)2, -(CH2)mC(O)NHR13, -(CH2)mC(O)N(R13)2, -C(O)OR13, -O(R13), an optionally substituted 3-7 membered carbocyclic ring, a C3- cycloalkylamino, an optionally substitoted heterocycle, an optionally substitoted heteroaryl, a C3- cycloalkylamino, CF3, mercapto, optionally substituted C1-4 alkyl, Cι.12 alkoxy, C2-4alkenyl, C2-4 alkynyl, C2-6 alkenyloxy, CM alkylthio, Cι-8 alkylcarbonyloxy, aryloxycarbonyl, C1-4 alkylamino, di(C1-4 alkyl)amino, Br-vinyl, -C(O)O(alkyl), O-phosphate, O-mono-, di-, or triphosphate, O-stabilized phosphate prodrag; O-acyl; O-lower acyl; O-alkyl; O-lower alkyl; O- sulfonate ester, O-alkyl or O-arylalkyl sulfonyl; O-methanesulfonyl; O- benzyl, wherein the phenyl group is optionally substituted with one or more substitoents; -OC(O)O-aryl; -OC(O)O-aralkyl; -S(acyl); -S(alkyl); - S(alkenyl); optionally substituted O-arylsulfonyl; an O-linked lipid, including an O-phospholipid; an O-linked amino acid; an O-linked carbohydrate; an O- linked peptide; O-linked cholesterol; or other O-linked pharmaceutically acceptable leaving group that when administered in vivo, provides independently OH or O-phosphate; each R7 is independently H, -OR1, -OH, -NO2, -CF3, -NH2, CI, F, Br, I, N3, CN, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, Br- vinyl, -CH2OH, -O(R), alkoxy, -(CH2)mC(O)O(R), -OC(O)O-aryl, -OC(O)O- aralkyl, -SR, -(CH2)mNHR, -(CH2)mN(R)2, or C3-7 cycloalkylamino; each R is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
X is O, S, SO2) CH2, or CHOH; m is 0, 1 or 2;
R13 is H, alkyl, alkenyl, alkynyl, acyl, aryl or aralkyl;
A is H, OH, CM alkyl, halo (F, CI, Br, or I), azido, cyano, C2-6 alkenyl, C2-6 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, NO2, NH2, - NH(lower alkyl), -NH(acyl), -N(lower alkyl)2, or -N(acyl)2; and
Base is a purine, a pyrimidine or a base selected from the group consisting of:
wherein: each R8, R10, R11, R12 and R13 independently is H, NH2, SH, CF3, halo, NO2, N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substitoted aryl, optionally substituted phenyl, -NH-cycloalkyl, -NH-cycloalkenyl, -NH- heterocycle, -NH-heteroaryl, -O-cycloalkyl, -O-cycloalkenyl, -O- heterocycle, -O-heteroaryl, CM alkylamino, di(CM alkyl)amino, C3-6 cycloalkylamino, CM alkyl-C(=O)OH, C1-4 alkyl-C(=O)O-aryl, C1-4 alkyl-C(=O)O-phenyl), CM alkyl-C(=O)O-heterocycle, C alkyl- C(=O)O-heteroaryl, or CM alkoxy; and R9 is O or S; optionally in a pharmaceutically acceptable carrier or diluent.
102. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the stracture of (Al):
or a pharmaceutically acceptable salt or prodrag thereof.
103. The pharmaceutical composition of claim 101 wherein the compound of Formula (A A) has the structure of (Bl):
or a pharmaceutically acceptable salt or prodrag thereof.
104. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the stracture of (CI):
or a pharmaceutically acceptable salt or prodrug thereof.
105. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (Dl):
(Dl) or a pharmaceutically acceptable salt or prodrug thereof.
106. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the stractore of (El):
(El) or a pharmaceutically acceptable salt or prodrag thereof.
107. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the stracture of (FI):
(FI) or a pharmaceutically acceptable salt or prodrag thereof.
108. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (Gl):
or a pharmaceutically acceptable salt or prodrag thereof.
109. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (HI):
or a pharmaceutically acceptable salt or prodrag thereof.
110. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (II):
(II) or a pharmaceutically acceptable salt or prodmg thereof.
111. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the stractore of (Jl):
(Jl) or a pharmaceutically acceptable salt or prodrag thereof.
112. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (KI):
or a pharmaceutically acceptable salt or prodrag thereof.
113. The pharmaceutical composition of claim 101 wherein the compound of Formula (A A) has the stracture of (LI):
or a pharmaceutically acceptable salt or prodrag thereof.
114. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (Ml):
or a pharmaceutically acceptable salt or prodrag thereof.
115. The pharmaceutical composition of claim 101 wherein the compound of Formula (AA) has the structure of (Nl):
(Nl) or a pharmaceutically acceptable salt or prodrug thereof.
116. The pharmaceutical composition of any one of claims claim 101-115, further in combination and/or alternation with one or more other anti- viral agent.
117. The pharmaceutical composition of claim 116, wherein the other anti-viral agent is an anti-coronavims, anti-togavirus, and or anti-picomavirus agent.
118. The pharmaceutical composition of claim 117, wherein the anti-coronaviras agent is an anti-SARS-CoV agent.
119. The pharmaceutical composition of claim 117, wherein the anti-togavims agent is an anti-rubivirus or an anti-alphavirus agent.
120. The pharmaceutical composition of claim 117, wherein the anti-picomavirus is an anti-enterovirus, anti-rhinovirus, anti-cardioviras and/or anti-aphthovirus agent.
121. The pharmaceutical composition of claim 120, wherein the anti-enteroviras agent is an anti-Coxsackievirus, anti-polioviras, anti-hepatitis A virus, and/or an anti- echoviras agent.
122. The pharmaceutical composition of any one of claims 101-121, wherein the coronavims infection is a SARS-CoV infection.
123. The pharmaceutical composition of any one of claims 101-121, wherein the togaviras infection is a rubivirus infection (the causative agent for rubella) or an alphavirus infection (the causative agent for encephalitis).
124. The pharmaceutical composition of any one of claims 101-121, wherein the a picomavirus infection is an enteroviras, a rhinovirus, a cardiovims or an aphthoviras infection.
125. The pharmaceutical composition of claim 124, wherein the enteroviras is a Coxsackievirus, poliovirus, hepatitis A virus, echovirus, or a human enteroviras species.
126. The pharmaceutical composition of any one of claims 101-125, wherein the host is a mammal.
127. The pharmaceutical composition of claim 126 wherein the mammal is a human.
EP04776022A 2003-05-14 2004-05-14 Nucleosides for treatment of infection by corona viruses, toga viruses and picorna viruses Withdrawn EP1656093A2 (en)

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