[go: up one dir, main page]

WO2003061385A1 - Composes et banques de nucleosides tricycliques, synthese et utilisation comme agents antiviraux - Google Patents

Composes et banques de nucleosides tricycliques, synthese et utilisation comme agents antiviraux Download PDF

Info

Publication number
WO2003061385A1
WO2003061385A1 PCT/US2002/031369 US0231369W WO03061385A1 WO 2003061385 A1 WO2003061385 A1 WO 2003061385A1 US 0231369 W US0231369 W US 0231369W WO 03061385 A1 WO03061385 A1 WO 03061385A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
group
sugar
alkynyl
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.)
Ceased
Application number
PCT/US2002/031369
Other languages
English (en)
Inventor
Haoyun An
Zhi Hong
Kenneth Smith
Yili Ding
Jean-Luc Girardet
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.)
Valeant Research and Development
Original Assignee
Ribapharm Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ribapharm Inc filed Critical Ribapharm Inc
Publication of WO2003061385A1 publication Critical patent/WO2003061385A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the field of the invention is tricyclic nucleoside libraries, compounds of and derived from such libraries, and their use, particularly for treatment of viral infections with HCN, HRN, RSN, HIN, and HBV, as well as treatment of viral infections with viruses of the families Flaviviridae, Paramyxoviridae, Orthomyxoviridae, Picornaviridae, Bunyaviridae, Arenaviridae, and Herpesviridae.
  • nucleoside analogues frequently interact with many biological targets, and some nucleoside analogues have been used as antimetabolites for treatment of cancers and viral infections.
  • nucleoside analogues can be phosphorylated to monophosphates by nucleoside kinases, and then further phosphorylated by nucleoside monophosphate kinases and nucleoside diphosphate kinases to give nucleoside triphosphates.
  • nucleoside analogue Once a nucleoside analogue is converted to its triphosphate inside the cell, it can be incorporated into D ⁇ A or R ⁇ A.
  • nucleoside analogue triphosphates are very potent, competitive inhibitors of D ⁇ A or R ⁇ A polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
  • nucleoside analogues can also act in other ways, for example, causing apoptosis of cancer cells and or modulating immune systems.
  • nucleoside antimetabolites a number of nucleoside analogues that show very potent anticancer and antiviral activities act through still other mechanisms.
  • Some well-known nucleoside anticancer drugs are thymidylate synthase inhibitors such as 5-fluorouridine, and adenosine deaminase inhibitors such as 2-chloroadenosine.
  • a well-studied anticancer compound, neplanocin A is an inhibitor of S-adenosylhomocysteine hydrolase, which shows potent anticancer and antiviral activities.
  • nucleoside analogues that can inhibit tumor growth or viral infections are also toxic to normal mammalian cells, primarily because these nucleoside analogues lack adequate selectivity between the normal cells and the virus-infected host cells or cancer cells. For this reason many otherwise promising nucleoside analogues fail to become therapeutics in treatment of various diseases.
  • nucleosides, nucleotides, and their analogs could be made through a combinatorial chemistry approach, a large number of such compounds could be synthesized within months instead of decades, and large libraries could be developed.
  • nucleoside analogues were usually designed as potential inhibitors of DNA or RNA polymerases and several other enzymes and receptors, including inosine monophosphate dehydrogenase, protein kinases, and adenosine receptors. If a vast number of diversified nucleoside analogues could be created, their use may be far beyond these previously recognized biological targets, which would open a new era for the use of nucleoside analogues as human therapeutics.
  • nucleoside analogues contain a sugar moiety and a nucleoside base, which are linked together through a glycosidic bond.
  • the formation of the glycosidic bond can be achieved through a few types of condensation reactions.
  • most of the reactions do not give a good yield of desired products, which may not be suitable to generation of nucleoside libraries.
  • the glycosidic bonds in many nucleosides are in labile to acidic condition, and many useful reactions in combinatorial chemistry approaches cannot be used in the generation of nucleoside analogue libraries.
  • the present invention is directed to tricyclic nucleoside libraries and library compounds that are prepared using combinatorial and non-combinatorial chemistry approaches.
  • Generally contemplated compounds will have a structure according to Formula 1, and particularly preferred compoimds will have a structure according to Formula 1 A (with substituents as defined in the section entitled "Detailed Description")-
  • contemplated compounds also include those having a structure according to Formulae 2-7 (with substituents as defined in the section entitled “Detailed Description”).
  • contemplated compounds may be used in a method of inhibiting propagation of a virus, wherein the virus is presented with one or more of the contemplated compounds at a concentration effective to reduce the propagation of the viras.
  • Particularly preferred viruses include HCV, HRV, RSN, HIV, HBV, as well as viruses of the families Flaviviridae, Paramyxoviridae, Orthomyxoviridae, Picornaviridae, Bunyaviridae, Arenaviridae, and Herpesviridae. Consequently, it is contemplated that a pharmaceutical composition may comprise one or more of the compounds according to the inventive subject matter at a concentration effective to reduce propagation of a virus in a patient infected with the virus.
  • nucleoside library refers to a plurality of chemically distinct nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs wherein at least some of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs include, or have been synthesized from a common precursor.
  • nucleoside library a plurality of nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs that were prepared from a protected -chlororibofuranose as a building block/precursor is considered a nucleoside library under the scope of this definition. Therefore, the term "common precursor" may encompass a starting material in a first step in a synthesis as well as a synthesis intermediate (i.e., a compound derived from a starting material).
  • At least one step in the synthesis of one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs is concurrent with at least one step in the synthesis of another one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and synthesis is preferably at least partially automated.
  • nucleoside library a collection of individually synthesized nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and especially a collection of compounds not obtained from a nucleoside library, is not considered a nucleoside library because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs will not have a common precursor, and because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs are not concurrently produced.
  • the complexity of contemplated libraries is at least 20 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, more typically at least 100 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, and most typically at least 1000 distinct nucleosides, nucleotide, nucleoside analogs, and or nucleotide analogs. Consequently, a typical format of a nucleoside library will include multi-well plates, or a plurality of small volume (i.e., less than 1ml) vessels coupled to each other.
  • library compound refers to a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog within a nucleoside library.
  • heterocycle and “heterocychc base” are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom.
  • heterocychc bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces maybe fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.
  • fused heterocycles include a 5-membered ring fused to a 6- membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).
  • a 6-membered ring e.g., purine, pyrrolo[2,3-d]pyrimidine
  • a 6-membered ring fused to another 6-membered or higher ring e.g., pyrido[4,5-d]pyrimidine, benzodiazepine
  • heterocychc bases examples include these and further preferred heterocychc bases.
  • Still further contemplated heterocychc bases may be aromatic, or may include one or more double or triple bonds.
  • contemplated heterocychc bases may include one or more substituents other than hydrogen, and especially contemplated substituents include those referenced below.
  • suitable heterocychc bases may further contain at least one hetero atom, such as O, S, N, or P.
  • Contemplated heterocycles or substituted heterocycles are typically attached directly to nucleoside bases or sugars but coupling of the heterocychc base to the sugar may also include a linker moiety with at least 1-4 atoms between the heterocychc base and the sugar.
  • sugar refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group in the sugar.
  • particularly contemplated deletions include 2'-deoxy and/or 3'-deoxy sugars.
  • Especially contemplated substitutions include replacement of the ring-oxygen with sulfur or methylene, or replacement of a hydroxyl group with a halogen, an amino, sulfhydryl, or methyl group, and especially contemplated additions include methylene phosphonate groups.
  • Further contemplated sugars also include sugar analogs (i.e., not naturally occurring sugars), and particularly carbocyclic ring systems.
  • carbocyclic ring system refers to any molecule in which a plurality of carbon atoms form a ring, and in especially contemplated carbocyclic ring systems the ring is formed from 3, 4, 5, or 6 carbon atoms. Examples of these and further preferred sugars are given below.
  • nucleoside refers to all compounds in which a heterocychc base is covalently coupled to a sugar, and an especially preferred coupling of the nucleoside to the sugar includes a Cl'-(glycosidic) bond of a carbon atom in a sugar to a carbon or heteroatom (typically nitrogen) in the heterocychc base.
  • nucleoside analog refers to all nucleosides in which the sugar is not a ribofuranose and/or in which the heterocychc base is not a naturally occurring base (e.g., A, G, C, T, I, etc.), however, it also includes naturally occurring nucleosides.
  • nucleoside also includes all prodrug forms of a nucleoside, wherein the prodrug form may be activated/converted to the active drag/nucleoside in one or more than one step, and wherein the activation conversion of the prodrug into the active drag/nucleoside may occur intracellularly or extracellularly (in a single step or multiple steps).
  • prodrug forms include those that confer a particular specificity towards a diseased or infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs" by Kenneth B.
  • nucleotide refers to a nucleoside that is coupled to a 5 '-phosphate group (or modified phosphate group, including phosphonate, thiophosphate, phosphate ester, etc.).
  • nucleotide analog refers to a nucleoside analog that is coupled to a 5'-phosphate group (or modified phosphate group, including phosphonate, thiophosphate, phosphate ester, etc.).
  • alkyl and “unsubstituted alkyl” are used interchangeably herein and refer to any linear, branched, or cyclic hydrocarbon in which all carbon-carbon bonds are single bonds.
  • substituted alkyl refers to any alkyl that further comprises a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and elecfrophihc groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC, etc.
  • elecfrophihc groups e.g., C(O)OR, C(X)OH, etc.
  • alkenyl and “unsubstituted alkenyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond.
  • substituted alkenyl refers to any alkenyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkynyl and “unsubstituted alkynyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon-carbon triple bond.
  • substituted alkynyl refers to any alkynyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • aryl and “unsubstituted aryl” are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl.
  • substituted aryl refers to any aryl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkaryl is employed where the aryl is further covalently bound to an alkyl, alkenyl, or alkynyl.
  • substituted as used herein also refers to a replacement of a chemical group or substituent (typically H or OH) with a functional group
  • functional groups include nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), and halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e.g.
  • suitable sugars will have a general formula of C n H n O n , wherein n is between 2 and 8, and wherein (where applicable) the sugar is in the D- or L- configuration.
  • sugar analogs there are numerous equivalent modifications of such sugars known in the art (sugar analogs), and all of such modifications are specifically included herein.
  • some of the contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion of the sugar is an atom other than oxygen (e.g., sulfur, carbon, or nitrogen) analogs, while other alternative sugars may not be cyclic but in a linear (open-chain) form. Suitable sugars may also include one or more double bonds.
  • Still further specifically contemplated alternative sugars include those with one or more non-hydroxyl substituents, and particularly contemplated substituents include mono-, di-, and triphosphates (preferably as C 5 ' esters), alkyl groups, alkoxygroups, halogens, amino groups and amines, sulfur-containing substituents, etc. It is still further contemplated that all contemplated substituents (hydroxyl substituents and non-hydroxyl substituents) may be directed in the alpha or beta position.
  • contemplated sugars and sugar analogs are commercially available. However, where contemplated sugars are not commercially available, it should be recognized that there are various methods known in the art to synthesize such sugars. For example, suitable protocols can be found in "Modern Methods in Carbohydrate Synthesis” by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212), in U.S. Pat Nos. 4,880,782 and 3,817,982, in WO88/00050, or in EP199.451.
  • X , Y , Z ⁇ , S , Se, NH , NR, CH 2 , CHR, P( ⁇ ), P( ⁇ ) ⁇ R
  • R H, O H , NHR, halo, CH 2 OH, CO OH, N 3 , alkyl, aryl, alkynyl, heterocycles, OR, SR, P(0)(O R) 2
  • An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups are covalently bound to sugar at the C , C' 2 ,C' 3 ,C 4 , or C' 5 atom, hi such alkylated sugars, it is especially preferred that the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one of the alkyl groups is a methyl group.
  • the alkyl group may or may not be substituted with one or more substituents.
  • Two exemplary classes of particularly preferred sugars are depicted below:
  • R is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl (branched, linear, or cyclic), with alkyl including between one and twenty carbon atoms.
  • suitable heterocyclic bases include all compounds that comprise at least three cyclic structures (preferably with at least one atom other than a carbon atom), wherein each of the cyclic structures shares at least one atom with another of the at least three cyclic structures.
  • cyclic structure refers to a plurality of atoms that are covalently bound to form a ring.
  • shared at least one atom means that a particular atom is part of the chain of atoms that form a cyclic structure in at least two cyclic structures.
  • contemplated cyclic structures include annulated ring systems, spiro-ring systems, and any reasonable combination thereof.
  • Exemplary heterocyclic bases are depicted below, in which Formula A represents an annulated tricyclic compound, and Formula B represents a spiro-tricyclic compound
  • cyclic structures include 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered rings, all of which may be partially or entirely desaturated or aromatic.
  • a particular ring size is not limiting to the inventive subject matter.
  • contemplated nucleosides comprise a tricyclic heterocyclic base
  • alternative heterocyclic bases may include additional cyclic structures, which may or may not be annulated or otherwise coupled to the tricyclic heterocyclic base.
  • suitable cyclic structures may be formed from various atoms, and especially preferred atoms include carbon, nitrogen, sulfur, selenium, oxygen, and phosphorous, hi further contemplated aspects, however, it is also contemplated that appropriate atoms may also include atoms other than carbon, nitrogen, sulfur, selenium, oxygen, and phosphorous, and all atoms are contemplated so long as such atoms may be part of at least one cyclic structure. Still further contemplated exemplary tricyclic heterocyclic base are depicted below.
  • substituents A, X, Y, R- . , R 2 , R 3 , and j are defined as in the respective portions of the detailed description below (e.g., section entitled "Contemplated Libraries and Nucleosides").
  • nucleosides or sugar, or heterocyclic base
  • coupled nucleoside or sugar, or heterocyclic base
  • contemplated solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • contemplated solid supports may also include glass, as described in U. S. Pat. No. 5,143,854.
  • Another preferred solid support comprises a "soluble" polymer support, which may be fabricated by copolymerization of polyethylene glycol, polyvinylalcohol, or polyvinylalcohol with polyvinyl pyrrolidine or derivatives thereof (e.g., see Janda and Hyunsoo (1996) Methods Enzymol. 267:234-247; Gravert and Janda (1997) Chemical Reviews 97:489-509; and Janda and Hyunsoo, PCT publication No. WO 96/03418).
  • Contemplated Combinatorial Reactions It is generally contemplated that all known types of combinatorial reactions and/or reaction sequences may be used in conjunction with the teaching presented herein so long as such combinatorial reactions between a substrate and at least two distinct reagents will result in at least two distinct products. Contemplated combinatorial reactions and/or reaction sequences may therefore be performed sequentially, in parallel, or in any chemically reasonable combination thereof. It is still further contemplated that suitable combinatorial reactions and/or reaction sequences may be performed in a single compartment or multiple compartments.
  • Preferred combinatorial reactions and/or reaction sequences include at least one step in which a substrate or reaction intermediate is coupled to a solid phase (which may include the wall of the reaction compartment or a solid or soluble polymers), and that the solid phase is physically separated from another substrate on another solid phase. While not limiting to the inventive subject matter, it is generally preferred that contemplated solid phase synthesis is at least partially automated.
  • a substrate or reaction intermediate is coupled to a solid phase (which may include the wall of the reaction compartment or a solid or soluble polymers), and that the solid phase is physically separated from another substrate on another solid phase.
  • contemplated compounds are synthesized using a library approach, it should be recognized that all of the contemplated compounds may also be synthesized individually in a classical single or multi-step reaction.
  • a heterocyclic base may be prepared separately from a sugar, and the heterocyclic compound may then be covalently coupled to the sugar in a subsequent reaction.
  • the present invention is generally directed to tricyclic nucleoside libraries and library compounds within these libraries, each of which may be synthesized by medicinal and or combinatorial approaches using solution- and/or solid-phase strategies.
  • tricyclic nucleoside libraries will comprise library compounds according to Formula 1 below
  • R 7 is H, NH 2 , NHR, NHCOR, NRR ⁇ NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 8 is H, C ⁇ -C 8 -alkyl, hydroxyalkyl, Ci- -alkenyl, C- .
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C -C 8 alkenyl, or C 2 -C 8 alkynyl (all of wliich may be linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C 12 aromatic rings.
  • R is hydrogen or a lower alkyl, and most preferably methyl
  • X is hydrogen, alkyl (and especially lower alkyl), or alkaryl.
  • Particularly preferred lower alkyls include methyl, ethyl, and hydroxyalkyl
  • especially preferred alkaryls include CH 2 - Phenyl.
  • contemplated tricyclic libraries will comprise library compounds according to Formula 2 below
  • R 7 is H, NH 2 , NHR, NHCOR, NRR', NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which may be linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C 1 aromatic rings.
  • tricyclic libraries will comprise library compounds according to Formula 3 below
  • R 7 is H, NH 2 , NHR, NHCOR, NRR', NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which maybe linear, branched, or cyclic), C 5 -C- .2 heterocycles or C 5 -C 12 aromatic rings.
  • substituted tricyclic libraries will comprise library compounds according to Formula 4 below:
  • R 7 is H, NH 2 , NHR, NHCOR, NRR', NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which may be linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C 12 aromatic rings.
  • substituted tricyclic libraries will comprise library compoimds according to Formula 5 below:
  • R 7 is H, NH 2 , NHR, NHCOR, NRR', NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which may be linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C ⁇ 2 aromatic rings.
  • substituted tricyclic libraries will comprise library compounds according to Formula 6 below:
  • R 7 is H, NH 2 , NHR, NHCOR, NRR', NHSO 2 R, NHCONHR, NHCSNHR, CH 2 NHR, CHRNHR', NHNH 2 , CN, alkyl, amino alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocycle, halogen, OH, OR, SR, or SH.
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', of may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of wliich maybe linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C 12 aromatic rings.
  • substituted tricyclic libraries will comprise library compounds according to Formula 7 below
  • R 10 is H, OH, NH 2 , NHR, NHCOR, NHNH 2 , NHNHR, alkyl, alkenyl, alkynyl, aryl, alkyaryl, heterocycle, aryl, halogen, COOR, CONH 2 , CONHR, CONRR', or may be null where Y is N; X, Y, W are independently N, C, CH, CR, S, or P; wherein R and R' are independently hydrogen, 1 ' CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which may be linear, branched, or cyclic), C 5 -C 1 heterocycles or C 5 -C 1 aromatic rings; and wherein
  • HET represents any one of the contemplated tricyclic heterocyclic bases (which may also be in alpha orientation (not shown));
  • R ⁇ and R 2 are independently H, OH, CH 3 , CF 3 , CHF 2 , CCI 3 , CHCI2, CH 2 C1, CH 2 OH, CN, CH 2 CN, CH 2 NH 2 , CH 2 NHR, CH 2 OR, CHO, CH 2 COR, C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which maybe linear, branched, or cyclic), C 5 -C 12 heterocycle or C 5 -C 1 aromatic ring, halogen (i.e., F, Cl, Br, or I), N 3 , NH 2 , NRR';
  • R 3 and R t are independently H, OH, SH, NH 2 , NHR, OR, SR, CH 2 OH, COOH, halogen, P(O)
  • R 5 , R 5 >, and R 6 are independently H, NH 2 , hydrazino, CH 3 , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl (all of which may be linear, branched, or cyclic), C 5 -C 12 heterocycles or C 5 -C 12 aromatic rings;
  • R ⁇ is H, RC(O)-, H 2 NCH(R)-CO, phosphonate, triphosphate, diphosphate, monophosphate, or a 3 ',5 '-cyclic phosphate and/or phosphonate;
  • A may be a covalent bond between R ⁇ and the C 5 '-atom, O, CH 2 , CF 2 , CC1 2 , S, NH,
  • the tricyclic heterocyclic base is typically formed from an appropriately substituted 6,7-disubstituted heterocyclic base (wliich may or may not be a purine-type heterocyclic base). Many of such 6,7-disubstituted heterocyclic bases are commercially available or may be made from commercially available precursors using protocols well known in the art.
  • a tricyclic nucleoside library with library compounds according to Formula 1 may be prepared following an exemplary synthetic route as depicted in Scheme 1 below.
  • a 7-deaza-6,7-disubstituted purine heterocyclic base is coupled to an appropriately protected (and activated) sugar to yield the corresponding nucleoside.
  • the so formed nucleoside is then reacted with substituted hydrazine (or a plurality of chemically distinct substituted hydrazines) and aqueous ammonia to form the third ring.
  • substituted hydrazine or a plurality of chemically distinct substituted hydrazines
  • the products will be substituted in the third ring with distinct substituents.
  • a first set of chemically distinct molecules may be prepared.
  • the so prepared tricyclic nucleosides may then be coupled to a solid phase and further modified at one or more positions in the heterocyclic base and/or sugar.
  • the amino group in the third ring may be used as a nucleophilic group for a reaction to further diversify with a plurality of electrophilic (or otherwise reactive) reagents.
  • R 3 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • a substituent may be added to the 8-position (numbering relative to the purine skeleton) by starting from an appropriately substituted and protected 8-Br-purine nucleoside.
  • the 8-Br-purine nucleoside need not be limited to a purine base, but that the purine base may be modified (e.g., deaza purine).
  • Scheme 2 depicts an exemplary synthetic route in which the 8-bromo group of a 7-deaza-6,7- disubstituted purine nucleoside is replaced with a desired nucleophile (preferably in a C-C- bond formation, e.g., via Heck, Stille, or Suzuki reaction) to yield the corresponding 8- substituted-7-deaza-6,7-disubstituted purine nucleoside.
  • a desired nucleophile preferably in a C-C- bond formation, e.g., via Heck, Stille, or Suzuki reaction
  • the so formed 8-substituted nucleoside may then be reacted with substituted hydrazine (or a plurality of chemically distinct substituted hydrazines) and aqueous ammonia to form the third ring as already exemplified in Scheme 1 above.
  • substituted hydrazine or a plurality of chemically distinct substituted hydrazines
  • aqueous ammonia to form the third ring as already exemplified in Scheme 1 above.
  • the so prepared tricyclic nucleosides may then be coupled to a solid phase and further modified at one or more positions in the heterocyclic base and/or sugar.
  • the amino group in the third ring may be used as a nucleophilic group for a reaction to further diversify with a plurality of elecfrophihc (or otherwise reactive) reagents.
  • tricyclic nucleoside libraries may be prepared in which the heterocyclic base (as calculated from the purine skeleton) comprises an additional nitrogen atom in the 8-position.
  • the heterocyclic base as calculated from the purine skeleton
  • a 7- deaza-8-aza-2,6,7-trisubstituted purine is coupled to an appropriately protected (and activated) sugar.
  • the so formed nucleoside is then subjected to one or more reactions involving the 6- and 7-substituent to form the third ring in a manner substantially the same as described for Schemes 1 and 2 above.
  • Diversity may again be imparted by reacting the substituted nucleosides with a plurality of chemically distinct substituted hydrazines to form the third ring.
  • additional diversity may be created by coupling the so prepared tricyclic nucleosides to a solid phase and modification of the tricyclic nucleosides at one or more positions in the heterocyclic base and/or sugar.
  • the amino group in the third ring may be used as a nucleophilic group for a reaction to further diversify with a plurality of electrophilic (or otherwise reactive) reagents.
  • R 3 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • a nitrogen atom may be replaced with an oxygen atom as depicted in Scheme 4 below.
  • a 6-7-disubstituted heterocyclic base may be reacted with hydroxylamine and aqueous ammonia to form the third ring, which now includes an oxygen atom.
  • the so formed tricyclic nucleoside may then be coupled to a solid phase and further modified at one or more positions in the heterocyclic base and/or sugar.
  • the amino group in the third ring may be used as a nucleophilic group for a reaction to further diversify with a plurality of elecfrophihc (or otherwise reactive) reagents.
  • a nitrogen atom in the tricyclic base may also be replaced with a carbon atom as depicted in the exemplary synthetic route of Scheme 5 below.
  • a C2 '-substituted and suitable protected sugar is reacted with a 7-deaza-2,6,7-trisubstituted purine heterocyclic base to form the corresponding nucleoside to form the corresponding 7-deaza-2,6,7- trisubstituted purine nucleoside.
  • the iodine in the 7-position is then replaced with a substituted alkynyl in a C-C forming reaction (e.g., in a Heck, Stille, or Suzuki reaction).
  • the third ring is formed in a reaction involving the triple bond of the 7-substituent and the nucleophilic substituent of the 6- position; consequently, the atoms distal to the former triple bond will form the substituent that is vicinal to the nitrogen heteroatom in the third ring).
  • the so formed tricyclic heterocyclic nucleoside may be derivatized at the nitrogen atom in the third ring by replacing the hydrogen atom with an electrophile (or otherwise reactive compound). Deprotection of the sugar OH protecting groups will then yield the corresponding substituted tricyclic nucleosides.
  • the third ring may be also formed by five atoms (with at least one heteroatom) as depicted in Scheme 6 below.
  • a 7-deaza-6,7-disubstituted purine is coupled to an appropriately protected (and activated) sugar following a procedure similar to those shown in Schemes 1-3 above.
  • the 6-substituent of the 7-deaza-6,7-disubstituted purine includes a nucleophilic group, while the 7-substituent includes an elecfrophihc center.
  • the third ring is formed in a reaction involving the elecfrophihc center of the 7-substituent and the nucleophilic group of the 6-position. Consequently, the atoms distal to the former elecfrophihc center will form the substituent that is vicinal to the nitrogen heteroatom in the third ring.
  • the so formed protected tricyclic nucleoside may then be deprotected (e.g. using ammonia), or further be modified by reacting the nitrogen atom in the third ring via reduction (e.g., using NaBH ) with an electrophile or plurality of electrophiles to generate greater diversity.
  • tricyclic heterocyclic nucleosides may be prepared in which the third ring is trisubstituted as depicted in Formulae 2 or 7 (supra), or in which the third ring has a single non-nitrogen heteroatom as shown in Formula 5 (supra).
  • contemplated tricyclic nucleoside libraries may be synthesized as shown in Scheme 7 below, in which a suitably protected 2-oxo-sugar is reacted with an appropriately activated alkyl (or alkenyl, alkynyl, etc.) substrate to form the corresponding protected C 2 '-substituted sugar.
  • the so prepared C 2 '-substituted sugar is then coupled to a 7- deaza-6,7-disubstituted purine heterocyclic base to yield the corresponding C 2 '-substituted-7- deaza-6,7-disubstituted purine nucleoside, which is then further reacted to the tricyclic nucleoside in a procedure substantially identical to those shown in Schemes 1 and 2 above, hi still further reactions, the tricyclic nucleoside may then be coupled to a solid phase, and further be modified at one or more positions in the heterocyclic base and/or sugar following a protocol substantially identical to that shown in Schemes 1 and 2 above.
  • R 3 , R 4 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • a tricyclic nucleoside library may be prepared by coupling a 7-deaza-2,6,7-trisubstituted purine heterocyclic base to a C 2 '-azido sugar (which may or may not be appropriately protected and activated) following a procedure essentially as that described in Scheme 1.
  • the N 3 group in the sugar of the so formed tricyclic nucleosides is then reduced to the corresponding amino group, which may then serve as a nucleophilic group for a reaction with a yet further elecfrophihc reagent (or plurality of elecfrophihc reagents where additional diversity is desired).
  • R 3 , . alkyl > alkenyl, alkynyl, aryl, heterocycles
  • contemplated tricyclic nucleoside libraries may be synthesized as shown in Scheme 9 below.
  • an exemplary synthesis starts with coupling of a C3 '-modified and suitably protected C- . '-alpha-chloro sugar to a 7-deaza-6,7-disubstituted purine to form the corresponding 7-deaza-6,7-disubstituted nucleoside.
  • the third ring is formed by reaction of the 7-deaza-6,7-disubstituted nucleoside with a substituted hydrazine, and the so formed tricyclic nucleoside may then be further derivatized at the amino group of the third ring by employing the amino group as a nucleophile for reaction with an elecfrophihc reagent (or plurality of chemically distinct elecfrophihc reagents). It should be recognized that the synthetic procedure for the compounds of Scheme 9 will essentially follow the protocol as shown in Scheme 3 above.
  • R 3 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • ribofuranose sugar of Scheme 9 may be replaced with a C3' -substituted sugar (in which the C3'-OH group is in beta orientation) as shown in Scheme 10 below.
  • Scheme 10 the same considerations as for Scheme 1 (supra) apply.
  • R 3 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • synthesis may start from a C3 '-azido sugar that is coupled to a suitable substituted heterocyclic base. After fonnation of the third ring (and further optional derivatization of the amino group in the third ring), the azido group is reduced to an amino group that is then employed as a nucleophilic reagent to react with various electrophilic reagents.
  • the same considerations as for Scheme 8 (supra) apply.
  • R 3 , R 4 alkyl, alkenyl, alkynyl, aryl, heterocycles
  • a tricyclic nucleoside is prepared from a protected 4-chloro-5-cyano-ribofuranosylpyrrolo[2,3- djpyrimidine that is reacted with methylhydrazine (Scheme 12) or ethylhydrazine (Scheme 13) and ethanol to form the conesponding tricyclic heterocyclic bases.
  • the sugar portions are then deprotected to yield the conesponding nucleosides.
  • benzyUiydrazine may be employed as reagent, wherein the benzyl group is subsequently removed from the tricyclic heterocyclic base as depicted in Scheme 14 below.
  • contemplated tricyclic nucleoside libraries may be synthesized as shown in Schemes 15-16 below, in which a 4-chloro-5-cyano- ribofuranosyl-pynolo[2,3-d]pyrimidine nucleoside with a 2'-methylribofuranose is reacted in a sequence substantially identical to the reaction sequences of Schemes 12-14 above.
  • Compound 25 was also synthesized by an alternative approach as shown in Scheme 17.
  • nucleosides that have numerous biological activities, and especially contemplated biological activities include in vitro and in vivo inhibition of DNA and/or RNA polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agents, antineoplastic agents, or immunomodulatory agents. Further particularly contemplated uses include those in which the compounds according to the inventive subject matter are employed as antineoplastic agents (e.g. , in the treatment of solid of lymphatic tumors).
  • Particularly contemplated antiviral activities include at least partial reduction of viral titers of respiratory syncytial virus (RSN), hepatitis B virus (HBN), hepatitis C virus (HCN), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIN), influenza A virus, Hanta virus (hemonhagic fever), human papilloma virus (HPN), yellow fever virus, measles virus, as well as viruses in the families of Flaviviridae, Paramyxoviridae, Orthomyxoviridae, Picornaviridae, Bunyaviridae, Arenaviridae, and Herpesviridae.
  • RSN respiratory syncytial virus
  • HBN hepatitis B virus
  • HCN hepatitis C virus
  • herpes simplex type 1 and 2 herpes simplex
  • the anti-HCN activity of the nucleosides and libraries were tested by Replicon and BNDN cell-line based assays.
  • the HCN ⁇ S5B polymerase activity was tested for the mono-, di-, and triphosphates of the nucleosides or 5'- methylenephosphonate derivatives.
  • the compounds and libraries were tested for their replication of Hepatitis C virus RNA by cell-line based HCN Replicon assay as described in N. Lohmann, F. Korner, J.-O. Koch, U. Herian, L. Theilmann, R. Bartenschlager, "Replication of a Subgenomic Hepatitis C virus R ⁇ As in a Hepatoma Cell Line", Sciences, 1999, 255, 110.
  • Especially contemplated immunomodulatory activity includes at least partial reduction of clinical symptoms and signs in arthritis, psoriasis, inflammatory bowel disease, juvenile diabetes, lupus, multiple sclerosis, gout and gouty arthritis, rheumatoid arthritis, rejection of transplantation, giant cell arteritis, allergy and asthma, but also modulation of some portion of a mammal's immune system, and especially modulation of cytokine profiles of Type 1 and Type 2.
  • modulation of Type 1 and Type 2 cytokines may include suppression of both Type 1 and Type 2, suppression of Type 1 and stimulation of Type 2, or suppression of Type 2 and stimulation of Type 1.
  • nucleosides are administered in a pharmacological composition
  • suitable nucleosides can be formulated in admixture with a pharmaceutically acceptable carrier.
  • contemplated nucleosides can be administered orally as pharmacologically acceptable salts, or intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5).
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5.
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5
  • Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose.
  • one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous fonnulations for a particular route of administration.
  • contemplated nucleosides may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in a patient.
  • the compounds according to the inventive subject matter may be fonnulated to provide a pharmaceutical composition comprising such compounds at a concentration effective to provide a desired pharmacological effect (e.g., reduce propagation of a virus in a patient infected with the virus).
  • a desired pharmacological effect e.g., reduce propagation of a virus in a patient infected with the virus.
  • reduction of viral propagation may be achieved by a direct antiviral effect, including competitive, allosteric, non-competitive (or otherwise) inhibition of a viral polymerase (e.g., especially of NS5B of HCV), inhibition of virus entry into a host cell, reduction of proper virus particle assembly, inhibition of viral protein processing.
  • a viral polymerase e.g., especially of NS5B of HCV
  • reduction of viral propagation may also be achieved by an indirect antiviral effect, including stimulation of immune response (e.g., enhanced CTL-activation) or modulation of Thl/Th2 balance (e.g., promoting a Thl response and/or reducing Th2 response).
  • prodrug forms of the above compounds may include a moiety that is covalently coupled to at least one of the C2'- OH, C3'-OH, and C5 -OH (or phosphate or modified phosphate group in these positions), herein the moiety is preferentially cleaved from the compound in a target cell (e.g., Hepatocyte) or a target organ (e.g., liver).
  • a target cell e.g., Hepatocyte
  • target organ e.g., liver
  • the sugar will be covalently coupled to a group that comprises a phosphorus atom (e.g., phosphate or phosphonate group), wherein the phosphate or phosphonate group is further covalently coupled to a removable group that is selectively removed in a liver cell.
  • a cellular enzyme particularly receptor, transporter and cytochrome- associated enzyme systems (e.g., CYP-system).
  • the sugar will be covalently coupled to a group that comprises a phosphorus atom (e.g., phosphate or phosphonate group), wherein the phosphate or phosphonate group is further covalently coupled to a removable group that is selectively removed in a liver cell.
  • Especially contemplated prodrugs comprise a cyclic phosphate, cyclic phosphonate and/or a cyclic phosphoamidate, which are preferentially cleaved in a hepatocyte to produce the contemplated compounds (as nucleoside or nucleotide).
  • a cyclic phosphate, cyclic phosphonate and/or a cyclic phosphoamidate which are preferentially cleaved in a hepatocyte to produce the contemplated compounds (as nucleoside or nucleotide).
  • prodrug forms are disclosed in WO 01/47935 (Novel Bisamidate Phosphonate Prodrugs), WO 01/18013 (Prodrugs For Liver Specific Drug Delivery), WO 00/52015 (Novel Phosphorus-Containing Prodrugs), and WO 99/45016 (Novel Prodrugs For Phosphorus-Containing Compounds), all of which are incorporated by reference herein. Consequently, especially suitable prodrug forms include those targeting a hepatocyte or the liver.
  • Still further particularly prefened prodrugs include those described by Renze et al. in Nucleosides Nucleotides Nucleic Acids 2001 Apr-Jul;20(4-7):931-4, by Balzarini et al. in Mol Pharmacol 2000 Nov;58(5):928-35, or in U.S. Pat. No. 6,312,662 to Erion et al., U.S. Pat. No. 6,271,212 to Chu et al, U.S. Pat. No. 6,207,648 to Chen et al., U.S. Pat. No.
  • Alternative contemplated prodrugs include those comprising a phosphate and/or phosphonate non-cyclic ester, and an exemplary collection of suitable prodrugs is described in U.S. Pat. No. 6,339,154 to Shepard et al., U.S. Pat. No. 6,352,991 to Zemlicka et al., and U.S. Pat. No. 6,348,587 to Schinazi et al.
  • contemplated prodrug forms are described in FASEB J. 2000 Sep;14(12):1784-92, Pharm. Res. 1999, Aug 16:8 1179-1185, and Antimicrob Agents Chemother 2000, Mar 44:3 477-483, all of which are incorporated by reference herein.
  • contemplated compounds may be administered alone or in combination with other agents for the treatment of various diseases or conditions.
  • Combination therapies according to the present invention comprise the administration of at least one compound of the present invention or a functional derivative thereof and at least one other pharmaceutically active ingredient.
  • the active ingredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this may occur simultaneously or separately in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Scheme 1 depicts a general approach for synthesis of contemplated libraries, and it should be appreciated that alternative libraries, and especially the libraries according to Schemes 2-11 may be prepared following substantially identical reaction conditions as described below, and/or reaction conditions well known to a person of ordinary skill in the art (e.g., reaction conditions for Heck, Stille, or Suzuki reactions).
  • the reaction mixture was cooled and evaporated.
  • the crude residue was co-evaporated three times with 15 mL portions of chloroform to remove trace L0 amounts of the acidic solvent. It was then diluted with 15 mL of saturated NaHCO 3 , and the mixture was extracted three times with 20 mL portions of ethyl acetate. The combined organic phase was dried (NaSO 4 ), and the solvent was evaporated.
  • 6-Amino-8-( ⁇ -D-ribofuranosyI)pyrroIo-[4,3,2-rfe]pyrimido[4,5-c]pyridazine (12).
  • To 5 mg (0.013 mmol) of benzyl intermediate 11 was added 4 mL of dry toluene, followed by 8.4 mg (0.063 mmol) of A1C1 3 .
  • the mixture was heated to 65 °C for 1 h, and the cooled reaction mixture was concentrated.
  • the residue was neutralized by the addition of 5 mL of a saturated solution of NaHCO 3 , and the mixture was stined for 30 min.
  • the aqueous solvent was removed, followed by the addition of 2 mL of methanol.
  • 6-Amino-8-(2,3,5-tri-0-acetyl-2-C-methyl- ⁇ -D-ribofuranosyl)-4-methyl- pyrrolo[4,3,2-rfe]pyrimido[4,5-c]pyridazine 17.
  • To a stined solution of 0.012 mL (3.2 mmol) of methylhydrazine in 20 mL of methanol 100 mg (2.3 mmol) of compound 15. The mixture was stined for 5 h at 25 °C, under an atmosphere of argon. Then it was evaporated to afford 16 as a light yellow-colored foam, which was used without further purification.
  • benzyl intermediate 24 was added 4 mL of dry toluene, followed by 8.4 mg (0.063 mmol) of A1C1 3 .
  • the mixture was heated to 65 °C for 1 h, then cooled, and concentrated.
  • the residue was neutralized by the addition of 5 mL of a saturated solution of NaHCO 3 and stirring for 30 min.
  • the aqueous solvent was removed, followed by the addition of 2 mL of methanol.
  • mixture was filtered through celite, and the filtrate was concentrated.
  • the crude product was purified by reversed phase HPLC to afford 0.2 mg of the desired compound 25 in 5 % yield.
  • Furthennore all known (and preferably commercially available) aliphatic, aromatic and heterocyclic acyl chlorides, sulfonyl chlorides, isocyanates, thioisocyanates, carboxylic acids, amino acids, isocyanides, halogenated heterocycles and other electrophiles may be used for the library synthesis.
  • the replicon cells (Huh-7) contain replicating HCN replicon R ⁇ A, wliich was modified in the structural region (replacing the structural region with a neomycin resistance marker). Survival of the replicon cells under G418 selection relies on the replication of HCN R ⁇ A and subsequently expression of neomycin phosphoryltransferase.
  • the ability of modified nucleoside libraries and compounds to suppress HCN R ⁇ A replication was determined using the Quantigene Assay Kit from Bayer. The assay measures the reduction of HCN R ⁇ A molecules in the treated cells. Replicon cells were incubated at 37°C for 3 days in the presence of nucleoside libraries and compounds before being harvested for detection.
  • the HCN subgenomic replicon cell line was provided by Dr. Bartenschlager.
  • the assay protocol was modified based on literature procedure (N. Lohmann, F. Korner, J. O. Koch, U. Herian, L. Theilmann, R. Bartenschlager, Science, 1999, 285, 110-113).
  • the inventors contemplate a method of inhibiting propagation of a virus, wherein the virus is presented with a compound according to the inventive subject matter at a concentration effective to reduce the propagation of the virus.
  • viruses include the HCV virus, and it should be recognized that the propagation may be in vitro in hepatocytes as well as in vivo in a patient infected with the virus.
  • the compound may be administered directly or that the compound may be converted in the hepatocyte from a prodrug (in a nucleoside or nucleotide form).
  • a prodrug in a nucleoside or nucleotide form

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des banques et des composés de nucléosides obtenus par des méthodes de chimie combinaitoire ou non combinatoire. Les composés envisagés conviennent particulièrement bien comme inhibiteurs de propagation virale, singulièrement dans le cas de l'hépatite C.
PCT/US2002/031369 2002-01-17 2002-10-01 Composes et banques de nucleosides tricycliques, synthese et utilisation comme agents antiviraux Ceased WO2003061385A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US35024902P 2002-01-17 2002-01-17
US60/350,249 2002-01-17
US39524102P 2002-07-10 2002-07-10
US60/395,241 2002-07-10

Publications (1)

Publication Number Publication Date
WO2003061385A1 true WO2003061385A1 (fr) 2003-07-31

Family

ID=27616767

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/031369 Ceased WO2003061385A1 (fr) 2002-01-17 2002-10-01 Composes et banques de nucleosides tricycliques, synthese et utilisation comme agents antiviraux

Country Status (1)

Country Link
WO (1) WO2003061385A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046331A2 (fr) 2002-11-15 2004-06-03 Idenix (Cayman) Limited Nucleoside a ramification en 2’ et mutation de flaviviridae
US6812219B2 (en) 2000-05-26 2004-11-02 Idenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US6914054B2 (en) 2000-05-23 2005-07-05 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
WO2005080388A1 (fr) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
WO2006077424A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
US7094770B2 (en) 2000-04-13 2006-08-22 Pharmasset, Ltd. 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections
WO2006093987A1 (fr) * 2005-02-28 2006-09-08 Genelabs Technologies, Inc. Composes nucleosidiques tricycliques de traitement d'infections virales
US7138376B2 (en) 2001-09-28 2006-11-21 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
US7268119B2 (en) 2003-08-27 2007-09-11 Biota Scientific Management Pty Ltd Tricyclic nucleosides or nucleotides as therapeutic agents
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
US7414031B2 (en) 2004-11-22 2008-08-19 Genelabs Technologies, Inc. 5-nitro-nucleoside compounds for treating viral infections
WO2008005542A3 (fr) * 2006-07-07 2008-10-30 Gilead Sciences Inc Composés antiviraux à base de phosphinate
US7456155B2 (en) 2002-06-28 2008-11-25 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7582618B2 (en) 2002-06-28 2009-09-01 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7598373B2 (en) 2002-12-12 2009-10-06 Idenix Pharmaceuticals, Inc. Process for the production of 2-C-methyl-D-ribonolactone
US7772208B2 (en) 2002-08-01 2010-08-10 Pharmasset, Inc. 2′,3′-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections
EP1694642A4 (fr) * 2003-12-19 2010-10-06 Koronis Pharmaceuticals Inc Heterocycles mutagenes
US8093380B2 (en) 2002-08-01 2012-01-10 Pharmasset, Inc. Compounds with the bicyclo[4.2.1]nonane system for the treatment of Flaviviridae infections
US8343983B2 (en) 2009-03-31 2013-01-01 Arqule, Inc. Substituted pyrazolo-pyrimidine compounds
US8420816B2 (en) 2009-06-08 2013-04-16 Takeda Pharmaceutical Company Limited Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK
US8658616B2 (en) 2006-11-24 2014-02-25 University College Cardiff Consultants Limited Nucleoside aryl phosphoramidates and their use as anti-viral agents for the treatment of hepatitis C virus
US9186369B2 (en) 2003-07-25 2015-11-17 Idenix Pharmaceuticals, Llc Purine nucleoside analogues for treating flaviviridae including hepatitis C
WO2018031818A3 (fr) * 2016-08-12 2018-05-11 Alios Biopharma, Inc. Nucléosides substitués, nucléotides et analogues de ceux-ci

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4123524A (en) * 1977-06-08 1978-10-31 The United States Of America As Represented By The Department Of Health, Education And Welfare Synthesis of 6-amino-4-methyl-8-(β-D-ribofuranosyl)pyrrolo[4,3,2-de]pyrimido[4,5-C]pyridazine-5'-phosphate as a novel compound and its utility against L-1210 mouse leukemia
US5633235A (en) * 1991-04-19 1997-05-27 Regents Of The University Of Michigan Triciribine and analogs as antiviral drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4123524A (en) * 1977-06-08 1978-10-31 The United States Of America As Represented By The Department Of Health, Education And Welfare Synthesis of 6-amino-4-methyl-8-(β-D-ribofuranosyl)pyrrolo[4,3,2-de]pyrimido[4,5-C]pyridazine-5'-phosphate as a novel compound and its utility against L-1210 mouse leukemia
US5633235A (en) * 1991-04-19 1997-05-27 Regents Of The University Of Michigan Triciribine and analogs as antiviral drugs
US5827833A (en) * 1991-04-19 1998-10-27 Regents Of The University Of Michigan Triciribine and analogs as antiviral drugs

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7094770B2 (en) 2000-04-13 2006-08-22 Pharmasset, Ltd. 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections
US7608597B2 (en) 2000-05-23 2009-10-27 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US7157441B2 (en) 2000-05-23 2007-01-02 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US6914054B2 (en) 2000-05-23 2005-07-05 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US10758557B2 (en) 2000-05-23 2020-09-01 Idenix Pharmaceuticals Llc Methods and compositions for treating hepatitis C virus
US10363265B2 (en) 2000-05-23 2019-07-30 Idenix Pharmaceuticals Llc Methods and compositions for treating hepatitis C virus
US7169766B2 (en) 2000-05-23 2007-01-30 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US7101861B2 (en) 2000-05-26 2006-09-05 Indenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US7105493B2 (en) 2000-05-26 2006-09-12 Idenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US7148206B2 (en) 2000-05-26 2006-12-12 Idenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US6812219B2 (en) 2000-05-26 2004-11-02 Idenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US7163929B2 (en) 2000-05-26 2007-01-16 Idenix Pharmaceuticals, Inc. Methods and compositions for treating flaviviruses and pestiviruses
US7138376B2 (en) 2001-09-28 2006-11-21 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
US7456155B2 (en) 2002-06-28 2008-11-25 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7582618B2 (en) 2002-06-28 2009-09-01 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7772208B2 (en) 2002-08-01 2010-08-10 Pharmasset, Inc. 2′,3′-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections
US8093380B2 (en) 2002-08-01 2012-01-10 Pharmasset, Inc. Compounds with the bicyclo[4.2.1]nonane system for the treatment of Flaviviridae infections
US7824851B2 (en) 2002-11-15 2010-11-02 Idenix Pharmaceuticals, Inc. 2′-branched nucleosides and Flaviviridae mutation
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
WO2004046331A2 (fr) 2002-11-15 2004-06-03 Idenix (Cayman) Limited Nucleoside a ramification en 2’ et mutation de flaviviridae
US7598373B2 (en) 2002-12-12 2009-10-06 Idenix Pharmaceuticals, Inc. Process for the production of 2-C-methyl-D-ribonolactone
US9186369B2 (en) 2003-07-25 2015-11-17 Idenix Pharmaceuticals, Llc Purine nucleoside analogues for treating flaviviridae including hepatitis C
US7268119B2 (en) 2003-08-27 2007-09-11 Biota Scientific Management Pty Ltd Tricyclic nucleosides or nucleotides as therapeutic agents
US7713941B2 (en) 2003-08-27 2010-05-11 Biota Scientific Management Pty Ltd Tricyclic nucleosides or nucleotides as therapeutic agents
EP1694642A4 (fr) * 2003-12-19 2010-10-06 Koronis Pharmaceuticals Inc Heterocycles mutagenes
EP2626354A1 (fr) 2004-02-20 2013-08-14 Boehringer Ingelheim International GmbH Inhibiteurs de la polymérase virale
WO2005080388A1 (fr) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
US7414031B2 (en) 2004-11-22 2008-08-19 Genelabs Technologies, Inc. 5-nitro-nucleoside compounds for treating viral infections
WO2006077424A1 (fr) 2005-01-21 2006-07-27 Astex Therapeutics Limited Composes pharmaceutiques
US7534771B2 (en) 2005-02-28 2009-05-19 Smithkline Beecham Corporation Tricyclic-nucleoside prodrugs for treating viral infections
WO2006093986A1 (fr) * 2005-02-28 2006-09-08 Genelabs Technologies, Inc. Promedicaments nucleosidiques tricycliques destines au traitement d'infections virales
US7524825B2 (en) 2005-02-28 2009-04-28 Smithkline Beecham Corporation Tricyclic-nucleoside compounds for treating viral infections
WO2006093987A1 (fr) * 2005-02-28 2006-09-08 Genelabs Technologies, Inc. Composes nucleosidiques tricycliques de traitement d'infections virales
US7842672B2 (en) 2006-07-07 2010-11-30 Gilead Sciences, Inc. Phosphonate inhibitors of HCV
WO2008005542A3 (fr) * 2006-07-07 2008-10-30 Gilead Sciences Inc Composés antiviraux à base de phosphinate
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
US8658616B2 (en) 2006-11-24 2014-02-25 University College Cardiff Consultants Limited Nucleoside aryl phosphoramidates and their use as anti-viral agents for the treatment of hepatitis C virus
US8343983B2 (en) 2009-03-31 2013-01-01 Arqule, Inc. Substituted pyrazolo-pyrimidine compounds
US8420816B2 (en) 2009-06-08 2013-04-16 Takeda Pharmaceutical Company Limited Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK
US8785429B2 (en) 2009-06-08 2014-07-22 Takeda Pharmaceutical Company Limited Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK
WO2018031818A3 (fr) * 2016-08-12 2018-05-11 Alios Biopharma, Inc. Nucléosides substitués, nucléotides et analogues de ceux-ci

Similar Documents

Publication Publication Date Title
WO2003061385A1 (fr) Composes et banques de nucleosides tricycliques, synthese et utilisation comme agents antiviraux
WO2003061576A2 (fr) Analogues de nucleosides de deazapurine et utilisation de ceux-ci en tant qu'agents therapeutiques
WO2003051899A1 (fr) Banques de deazapurine nucleosides et composes
US6211158B1 (en) Desazapurine-nucleotide derivatives, processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof for nucleic acid sequencing and as antiviral agents
CA2537114C (fr) Nucleotides ou nucleosides tricycliques en tant qu'agents therapeutiques
JP5937073B2 (ja) ジアステレオマーとして純粋なホスホルアミデートプロドラッグの調製方法
US20040063658A1 (en) Nucleoside derivatives for treating hepatitis C virus infection
WO2003051881A1 (fr) Banques de nucleosides purine et composes substitues par methodes combinatoires en phase solide
EP1476169A1 (fr) Procede d'inhibition de la replication d'orthopoxvirus avec des composes de nucleoside
WO2002057425A2 (fr) Derives de nucleoside comme inhibiteurs de l'arn polymerase virale arn-dependante
AU2002243600A1 (en) Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US8575331B2 (en) Synthesis and use of 2′-substituted-N6-modified nucleosides
WO2004080466A1 (fr) Analogues de la cytidine et methodes d'utilisation
AU2002243791A1 (en) Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
CA2405798A1 (fr) Nucleosides de pyrido¬2,3-d|pyrimidine et de pyrimido¬4,5-d|pyrimidine
EP1572705A2 (fr) Nucleosides a sucre modifie utilises en tant qu'inhibiteurs de la replication virale
WO2003051896A1 (fr) Bibliotheques a cytidine et composes de ces bibliotheques dont la synthese repose sur des strategies combinatoires en phase solide
WO2003051898A1 (fr) Banques de nucleosides et composes rares, et utilisations preferees comme agents anticancereux et antiviraux
WO2003051897A1 (fr) Composes et bibliotheques d'analogues de nucleosides
Seela et al. Syntheses of Pyrrolo [2, 3‐d] pyrimidine 2′, 3′‐Dideoxyribonucleosides Related to 2′, 3′‐Dideoxyadenosine and 2′, 3′‐Dideoxyguanosine and Inhibitory Activity of 5′‐Triphosphates on HIV‐1 Reverse Transcriptase
WO1994006438A1 (fr) Analogues de l'adenosine et procede d'intensification de la liberation de l'adenosine
US7217815B2 (en) 2-beta -modified-6-substituted adenosine analogs and their use as antiviral agents
WO2003052053A2 (fr) Bibliotheques nucleosidiques et composes obtenus au moyen de strategies combinatoires mcc realisees sur support solide
JP3014000B2 (ja) 選択的なアデノシンレセプター化合物
Koszytkowska-Stawińska et al. Synthesis of aza-analogues of Ganciclovir

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP