WO2003051898A1 - Banques de nucleosides et composes rares, et utilisations preferees comme agents anticancereux et antiviraux - Google Patents

Banques de nucleosides et composes rares, et utilisations preferees comme agents anticancereux et antiviraux Download PDF

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WO2003051898A1
WO2003051898A1 PCT/US2002/040415 US0240415W WO03051898A1 WO 2003051898 A1 WO2003051898 A1 WO 2003051898A1 US 0240415 W US0240415 W US 0240415W WO 03051898 A1 WO03051898 A1 WO 03051898A1
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substituted
unsubstituted
formula
alkyl
aryl
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PCT/US2002/040415
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Haoyun An
Varaprasad Chamakura
Huanming Chen
Zhi Hong
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Ribapharm Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • 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 ofthe invention is combinatorial nucleoside libraries and related compounds.
  • nucleosides and related compounds interact with many biological targets, and some nucleoside analogues have been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, many 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. Once a nucleoside analogue is converted to its triphosphate inside the cell, it can be incorporated into DNA or RNA.
  • nucleic acid replicates or transcripts can interrupt gene expression by early chain termination, or by interfering with function ofthe modified nucleic acids.
  • nucleoside analogue triphosphates are very potent, competitive inhibitors of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
  • anti-HIV nucleoside analogues fall into this category, including 3'-C-azido-3'-deoxythymidine, 2',3'- dideoxycytidine, 2',3'-dideoxyinosine, and 2 , ,3'-didehydro-2',3'-dideoxythymidine.
  • 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 the treatment of various diseases.
  • nucleosides could be made through a combinatorial chemistry approach, a large number of nucleoside analogues could be synthesized within months instead of decades, and large nucleoside 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 ofthe glycosidic bond can be achieved through a few types of condensation reactions.
  • most ofthe reactions do not give a very good yield of desired products, which may not be suitable to generations 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.
  • contemplated nucleoside libraries and compounds include nucleosides in which the heterocyclic base is coupled to a sugar portion via an intermediary atom other than carbon, and in some cases such nucleosides may further comprise at least one electrophilic center and at least one leaving group.
  • Contemplated sugars include ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose (all in D-configuration or L-configuration), while contemplated heterocyclic bases include five-membered rings, six-membered rings, and fused aromatic systems that comprise nitrogen, sulfur, oxygen, or phosphorus.
  • contemplated compounds and libraries will have a structure according to Formulae 1, 2, 2A-2I, and 3, wherein the substituents are as described in the respective portions ofthe detailed description below (Library compounds will have H, OH, a phosphate, or other functional group instead ofthe solid phase).
  • contemplated libraries and compounds include nucleosides in which the heterocyclic base comprises a tricyclic heterocyclic base that includes a benzimidazole portion.
  • Particularly contemplated sugars include ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose (in D-configuration or L- configuration), and especially contemplated compounds and libraries will have a structure according to Formulae 4B-H, Formulae 5A-B, Formulae 6A-F wherein the substituents are as described in the respective portions ofthe detailed description below (Libraries will include a solid phase, typically coupled to the C5'-atom).
  • contemplated libraries and compounds include nucleosides in which a C 2 '-substituent is covalently bound to the sugar via a carbon atom, and contemplated libraries and compounds will have a structure according to Formulae 11 A-l IB and 12A-12B, wherein the substituents are as described in the respective portions ofthe detailed description below.
  • 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 using l'-azido or 1 '-amino ribofuranose 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 ofthe nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs is concurrent with at least one step in the synthesis of another one ofthe 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 “heterocyclic 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.
  • heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle” or "fused heterocyclic base” 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). Examples of these and further preferred heterocyclic bases are given below.
  • Still further contemplated heterocyclic bases may be aromatic, or may include one or more double or triple bonds.
  • contemplated heterocyclic bases and fused heterocycles may further be substituted in one or more positions (see below).
  • sugar refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group or atom in the sugar.
  • particularly contemplated deletions include 2'-deoxy and/or 3'-deoxy sugars.
  • Especially contemplated substitutions include replacement ofthe 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 heterocyclic base is covalently coupled to a sugar, and an especially preferred coupling ofthe 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 heterocyclic base.
  • nucleoside analog refers to all nucleosides in which the sugar is not a ribofuranose and/or in which the heterocyclic base is not a naturally occurring base (e.g., A, G, C, T, I, etc.).
  • nucleotide refers to a nucleoside to which a phosphate group is coupled to the sugar.
  • nucleotide analog refers to a nucleoside analog to which a phosphate group is coupled to the sugar.
  • nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog also includes all prodrug forms of a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog, wherein the prodrug form may be activated/converted to the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog in one or more than one step, and wherein the activation/conversion ofthe prodrug into the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog may occur intracellularly or extracellularly (in a single step or multiple steps).
  • Especially contemplated 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. Sloan (Marcel Dekker; ISBN: 0824786297), "Design of Prodrugs” by Hans Bundgaard (ASIN: 044480675X), or in copending US application number 09/594410, filed 06/16/2000, all of which are incorporated by reference herein.
  • Particularly suitable prodrug forms ofthe above compounds may include a moiety that is covalently coupled to at least one of the C2'-OH, C3'-OH, and C5'-OH, wherein 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
  • a target organ e.g., liver
  • cleavage ofthe prodrug into the active form ofthe drug is mediated (at least in part) by a cellular enzyme, particularly receptor, transporter and cytochrome-associated enzyme systems (e.g., CYP-system).
  • prodrugs comprise a cyclic phosphate, cyclic phosphonate and/or a cyclic phosphoamidates, which are preferentially cleaved in a hepatocyte to produce the compound according to Formula 1 or 2.
  • prodrugs There are numerous such prodrugs known in the art, and all of those are considered suitable for use herein.
  • 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 preferred prodrugs include those described by Renze et al. in
  • 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. Still further particularly 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.
  • 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.
  • 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.
  • 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.
  • aryl and “unsubstituted aryl” are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl.
  • alkaryl is employed where an aryl is covalently bound to an alkyl, alkenyl, or alkynyl.
  • substituted refers to a replacement of an atom or chemical group (e.g., H, NH 2 , or OH) with a functional group
  • functional groups include nucleophilic groups (e.g., -NH 2 , -OH, -SH, -NC, etc.), 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, -CI), and all chemically reasonable combinations thereof.
  • nucleophilic groups e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e
  • the term "functional group” and the term “substituent” are used interchangeably herein and refer to nucleophilic groups (e.g., -NH 2 , -OH, -SH, -NC, - CN etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH ⁇ , and halogens.
  • nucleophilic groups e.g., -NH 2 , -OH, -SH, -NC, - CN etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.
  • polar groups e.g., -OH
  • non-polar groups e.
  • suitable sugars will have a general formula of C n H 2n 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 contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion ofthe 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 C5 1 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 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 EP 199,451.
  • An exemplary collection of further contemplated sugars and sugar analogs is depicted below, wherein all ofthe exemplary sugars may be in D- or L- configuration, and wherein at least one ofthe substituents may further be in either alpha or beta orientation.
  • X, Y,Z ⁇ , S, Se,NH,NR,CH 2 , CHR, P( ⁇ ), P(0)OR
  • R H, OH, NHR, halo, CH 2 OH. COOH, N 3 , alkyl, aryl, alkynyl, heterocycles, OR, SR, P(0)(OR) 2
  • An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other functional groups, including alkenyl, alkynyl, aryl, halogen, CF, CHF 2 , CC1 3 , CHC1 2 , N 3 , NH 2 , etc.) are covalently bound to sugar at the C' ⁇ , C , 2 ,C , 3,C , 4 , or C 5 atom.
  • the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one ofthe alkyl groups is a methyl group.
  • the alkyl group may or may not be substituted with one or more functional groups.
  • One exemplary class of preferred sugars is depicted below:
  • R is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl (branched, linear, or cyclic), with R including between one and twenty carbon atoms.
  • heterocyclic bases have between one and three rings, wherein especially preferred rings include 5- and 6- membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.
  • Especially contemplated fused heterocycles include a 5-membered ring fused to a 6- membered ring (e.g., purine, pyrrolo [2,3 -djpyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).
  • An exemplary collection of appropriate heterocyclic bases is depicted below, wherein all ofthe depicted heterocyclic bases may further include one or more functional groups, double and triple bonds, and any chemically reasonable combination thereof. It should further be appreciated that all of the contemplated heterocyclic bases may be coupled to contemplated sugars via a carbon atom or a non-carbon atom in the heterocyclic base.
  • 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 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 (with may include the wall ofthe 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.
  • nucleoside analog libraries can be prepared in various combinatorial library approaches, including libraries in which diverse heterocyclic bases and/or diverse nucleoside analogs are prepared from precursor nucleosides (or modified sugars) that are derivatized in subsequent/parallel modification reactions, and libraries in which a modified heterocyclic base is coupled to a sugar portion.
  • nucleosides with the general structure A-M-B can be synthesized, in which A comprises a sugar, M comprises an intermediary atom other than carbon (e.g., nitrogen, oxygen, or sulfur, which may be introduced via an amino group, a hydroxyl group, or a thiol group on the sugar), and B comprises a heterocyclic base, wherein M is covalently bound to a carbon atom ofthe sugar and further covalently bound to the heterocyclic base.
  • A comprises a sugar
  • M comprises an intermediary atom other than carbon (e.g., nitrogen, oxygen, or sulfur, which may be introduced via an amino group, a hydroxyl group, or a thiol group on the sugar)
  • B comprises a heterocyclic base, wherein M is covalently bound to a carbon atom ofthe sugar and further covalently bound to the heterocyclic base.
  • heterocyclic bases include natural (e.g., A, G, C, T, U, I, etc.) and non-natural heterocyclic bases (e.g., substituted or unsubstituted triazine, purine, or pyrimidine, etc.). Further contemplated heterocyclic bases include those contemplated above.
  • nucleosides may further include an electrophilic center and a leaving group in the heterocyclic base, and in a particularly preferred aspect, the heterocyclic base comprises a five- membered ring, a six-membered ring, or a fused aromatic system with a heteroatom (e.g. , N, S, O, or P). It is further generally contemplated that all known sugars may be employed in such contemplated nucleosides. However, in some preferred compounds, the sugar comprises a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, or an arabinose (wherein the sugar may be in D-configuration or L-configuration). Exemplary libraries, compounds, and their synthesis are given below.
  • Contemplated triazole libraries compounds may be synthesized by various synthetic routes, and an exemplary route for synthesis of contemplated compound is depicted in Schemes 1 through 4.
  • a l'-azidoribofuranose is formed from commercially available protected ribofuranose and coupled to a solid support (the remaining OH groups on the sugar are protected). Reduction ofthe azido group yields the corresponding l'-amino group (in alpha or beta orientation), which is then reacted with 2,4,6--richloro-l,3,5-triazine.
  • the remaining CI substituents on the heterocyclic base serve as leaving groups (which may be replaced by one or more alternative leaving groups) and are covalently bound to an electrophilic carbon atom in the triazine, respectively. These carbon atoms then serve as electrophilic centers for subsequent substitution reactions with various nucleophiles (e.g., primary and/or secondary amines), to which various moieties may be coupled. At least one moiety may then further be chemically modified.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • An exemplary diversification reaction is shown in more detail in Scheme 2 in which primary amines and secondary amines are employed as nucleophiles.
  • a Set A amine building blocks, diisopropylethylamine, 0 °C to rt; b, Set B amine building blocks, diisopropylethylamine, 75-80 °C; c, 1M tetrabutylammonium fluoride in THF; d, 2% trifluoroacetic acid in dichloromethane, 1 mine.
  • a suitably modified sugar may be employed as depicted in Scheme 4, wherein the C 2 '-modified sugar is first converted into the corresponding azido sugar that is then coupled to the heterocyclic base.
  • heterocyclic base it should be recognized that numerous heterocyclic bases other than a trichlorotriazine are also appropriate so long as such heterocyclic bases comprise at least one reactive group that can react with a reagent to derivatize/modify the heterocyclic base.
  • alternative heterocyclic bases include at least one electrophilic center and at least one leaving group.
  • a particularly contemplated alternative heterocyclic base is dichlorodiazine or chlorotriazine.
  • heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine), fused heterocycles (e.g., purine, pyrrolo [2,3 -d]pyrimidine, pyrido[4,5-d]pyrimidine, or benzodiazepine).
  • non-carbon atom e.g., imidazole, pyrrole, triazole, dihydropyrimidine
  • fused heterocycles e.g., purine, pyrrolo [2,3 -d]pyrimidine, pyrido[4,5-d]pyrimidine, or benzodiazepine.
  • Numerous of contemplated heterocyclic bases are commercially available, and all of these commercially available heterocyclic bases are contemplated suitable for use herein.
  • electrophilic center refers to all atoms in a molecule that may be subject to attack of a nucleophile, and especially contemplated reactions of such nucleophiles include nucleophilic (aromatic) substitution reactions.
  • leaving group refers to any group that has an appreciable electron-withdrawing ability, is a relatively weak base once it has left the molecule it was previously attached to, and is polarizable at least to some degree.
  • leaving groups There are numerous leaving groups known in the art, and all of them are considered suitable for use herein. However, especially preferred leaving groups include halogens, tosyl, mesyl, and triflate groups.
  • the terms “nucleophilic reagent” and “nucleophilic substrate” are used interchangeably herein.
  • electrowettic reagent and electrowetting substrate
  • sugars other than a ribofuranose are also suitable for use in conjunction with the teachings presented herein, and it is especially contemplated that alternative sugars include ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose (in D-configuration or L-configuration).
  • sugar derivatives of sugars with four, five, or six carbon atoms may be also employed, and especially contemplated derivatives include substituents other than OH groups (e.g., N 3 , halogen, OCH , etc.).
  • the azido group in the azido sugar, which is employed as starting material for coupling the heterocyclic base to the sugar may be in a position other than the Ci '-position, and especially preferred alternative positions include C 2 '- and C 3 '-position. Therefore, contemplated nucleosides will also include nucleosides in which the heterocyclic base is attached to a position other than the Ci'-atom. Moreover, while the compounds in the Schemes 1-4 above include C2' and C3' substituents in alpha orientation, one or more ofthe substituents may also be in beta orientation.
  • protecting groups for the sugar will vary considerably, and while it is particularly contemplated that suitable protection groups include benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable. Among other groups, a collection of appropriate alternative protection groups and their reactions is described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. •Greene, John Wiley & Sons; ISBN: 0471160199.
  • Preferred 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).
  • reagents that may react with one or more reactive groups in the heterocyclic base
  • suitable substrates will include various nucleophilic reagents (e.g., primary and secondary substituted and unsubstituted amines, thiols, alcohols) and Grignard-type compounds (e.g., alkyl - MgBr).
  • nucleophilic reagents and Grignard-type compounds there are numerous nucleophilic reagents and Grignard-type compounds commercially available, and where such reagents are not commercially available, it is contemplated that they may be prepared from commercially available precursors using protocols well known in the art (supra). Particularly suitable nucleophilic substrates are listed in the experimental section below. Moreover, it should be recognized that suitable reagents, once introduced in the heterocyclic base, may further be derivatized. For example, where a reagent has a nucleophilic group, such a group may be modified via a nucleophilic substitution reaction with an additional reagent (e.g. , electrophilic reagent).
  • additional reagent e.g. , electrophilic reagent
  • a nucleoside library may include a first library compound and a second library compound, wherein each of the first and second library compounds has a structure A-M-B, wherein A comprises a sugar, M comprises an intermediary atom other than carbon, and B comprises a heterocyclic base, wherein M is covalently bound to a carbon atom of the sugar and further covalently bound to the heterocyclic base, and wherein the first library compound and the second library compound are chemically distinct.
  • the term "chemically distinct” as used herein means not identical, wherein not identical includes non- identity in mass, elemental composition, and stereochemistry. For example, L-adenosine is considered not identical with D-adenosine, because the stereochemistry ofthe sugar portion in the nucleoside is distinct.
  • a nucleoside library with at least two library compounds is prepared in which one ofthe at least two library compounds has a structure according to Formula 1 with a first set of substituents A, X, and Y, and wherein another one of the at least two library compounds has a structure according to Formula 1 with a second set of substituents A, X, and Y:
  • A is a sugar that is coupled to a solid phase, wherein the sugar is optionally protected
  • X and Y are independently R, OR, NRR', NHNHR, ONHR, or SR, and wherein R and R' are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein not all ofthe substituents A, X, and Y in the first set are the same as the substituents A, X, and Y in the second set.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3 '-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • contemplated compounds may have a structure according to Formulae 2 or 3
  • A is a sugar, wherein the sugar is optionally protected and optionally coupled to a solid phase
  • X and Y are independently R, OR, NRR', NHNHR, ONHR, or SR, and wherein R and R' are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein L is a leaving group, preferably independently selected from the group consisting of CI, Br, Tosyl, and Mesyl.
  • a heterocyclic base may also be formed from a substituted nitropyrimidine, which is further modified to a substituted nitropyrimidine library (and library compounds) as shown in Scheme 5 below.
  • a suitably protected l'-azidosugar which may or may not be coupled to a solid phase is reacted with 5-nitro-4,6-dichloropyrimidine to generate the corresponding nucleoside in which the heterocyclic base is coupled to the sugar with a nitrogen atom.
  • the nitro group in the heterocyclic base serves as an electron-withdrawing group, while the vicinal chlorine atom is employed as a leaving group that is replaced by a nucleophilic substrate to generate the corresponding substituted Ci'-N-nucleoside or nucleoside library. Deprotection and cleavage of the nucleoside or nucleoside library will then yield the nitropyrimidine compound(s).
  • the azido sugar it should be recognized that numerous sugars other than the depicted C ⁇ '-ribofuranose are also appropriate, and it is contemplated that all known sugars are suitable, so long as such sugars include an azido group, or a group that can be converted to an azido group.
  • Especially alternative sugars include those contemplated above in the section entitled "Contemplated Sugars".
  • Further particularly contemplated sugars include arabinose and xylose sugars, all of which may or may not be further substituted by one or more substituents.
  • the azido group may be positioned in a position other than the Ci '-position, and especially contemplated alternative positions include the C 2 ', C ', and C 5 '-position.
  • nucleosides may advantageously be produced from 5-nitro-4,6-dichloropyrimidine.
  • all heterocyclic bases are suitable, so long as such heterocyclic bases include a ring atom as electrophilic center that forms a covalent bond with the nitrogen ofthe Ci '-azido sugar. Consequently, alternative heterocyclic bases will include 5-membered rings, 6-membered rings, and fused ring systems of 5-membered rings and 6-membered rings, wherein all ofthe contemplated heterocyclic bases may include one or more heteroatoms (particularly contemplated heteroatoms include nitrogen, sulfur, and oxygen).
  • suitable heterocyclic bases need not be limited to nitro group containing heterocyclic bases, and it is generally contemplated that all groups with an electron-withdrawing effect are appropriate.
  • alternative groups include carboxylic acid groups, -CF 3 , etc.
  • the leaving group need not be restricted to a chlorine atom.
  • nucleophilic substrates there are numerous known leaving groups known in the art, and all ofthe known leaving groups are considered suitable for use herein.
  • alternative leaving groups include halogens (e.g., Br), nitrophenyl, tosylate or mesylate groups.
  • suitable nucleophilic substrates it should be recognized that numerous reagents and compounds are suitable, and especially contemplated nucleophilic substrates include those having a nitrogen atom, and especially primary and/or secondary amines, and those having an oxygen or sulfur atom (e.g., various alcohols and/or thiols).
  • suitable nucleophilic substrates also include reagents that form a C-C bond (e.g., Grignard reagents, etc.).
  • nucleophilic substrates will have the general formula NR ⁇ R 2 , RiOH, or RiSH, wherein Ri and R 2 are independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, and a substituted or unsubstituted heterocycle.
  • nucleophilic substrate is a secondary amine (or set of secondary amines):
  • contemplated compounds and libraries may include a modified sugar portion, and especially contemplated modified sugar portions include amino sugars.
  • exemplary synthetic routes for 5'-amino sugars are depicted in Schemes 7 and 8 below, wherein in Scheme 7 primary amines are employed as nucleophilic substrates, and wherein in Scheme 8 secondary amines are employed as nucleophilic substrates.
  • nucleoside library with at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 4 with a first set of substituents A, X, and R, and wherein another one ofthe at least two library compounds has a structure according to Formula 4 with a second set of substituents A, X, and R
  • A is a sugar that is coupled to a solid phase, wherein the sugar is optionally protected, X is chemical bond, NR', O, or S; wherein R and R' are independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein not all ofthe substituents A, X, and R in the first set -ire the same as the substituents A, X, and R in the second set.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or exposition.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or a OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • contemplated compounds may have a structure according to Formula 5
  • A is a sugar
  • X is a chemical bond, NR', O, or S
  • R and R' are independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or a OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • a substituted piperazino-pyrimidine library may be synthesized using 5-nitro-4,6-dichloropyrimidine and an amino acid to generate a bicyclic heterocyclic base as depicted in Scheme 9 below.
  • the protected and solid phase bound compound 9 is synthesized as shown in Schemes 5 above and reacted (under conditions as indicated in Scheme 9 above) with an amino acid to form the corresponding substituted amino acid substituted nitropyrimidine Ci'-N- nucleoside (or nucleoside library where more than one amino acid or more than one sugar is employed).
  • the piperazino-pyrimidine heterocyclic base is formed via intramolecular cyclization (under conditions as indicated above), and the desired piperazino- pyrimidine nucleoside or nucleoside library is obtained via deprotection and cleavage ofthe sugar form the solid phase.
  • the solid phase and the protection groups (including deprotection and cleavage ofthe sugar form the solid phase) the same considerations as described above apply.
  • various methods other than intramolecular cyclization using dioctyl viologen as electron-transfer catalyst oxidation of are also suitable, and appropriate methods may include intramolecular cyclization using catalysts and/or activated acid groups.
  • suitable amino acids will generally have the formula (NH 2 )[CH(R)] n (COCH 3 ), wherein n is between 1 and 3, and R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • especially contemplated amino acids include naturally occurring amino acids (in D- and/or L-configuration).
  • n is greater than 1 , the corresponding bicyclic heterocyclic base will have a seven-membered, eight-membered or higher ring.
  • nucleoside library with at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 6 with a first set of substituents A and R, and wherein another one ofthe at least two library compounds has a structure according to Formula 6 with a second set of substituents A and R
  • A is a sugar that is coupled to a solid phase, wherein the sugar is optionally protected, R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein not all ofthe substituents A and R in the first set are the same as the substituents A and R in the second set.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or a OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • contemplated compounds may have a structure according to Formula 7
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle;
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or a OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • a substituted imidazol- idino-pyrimidine library may be synthesized using 5-nitro-4,6-dichloropyrimidine as a starting material, which is first reacted with a first set of reagents and reduced to generate the corresponding substituted diamino pyrimidine, which is in a further step cyclized to a substituted imidazolidino-pyrimidine library as depicted in Scheme 10 below.
  • the protected and solid phase bound compound 9 is synthesized as shown in Scheme 5 above and reacted with a primary amine to form the corresponding substituted nitropyrimidine Cj'-N-nucleoside (or nucleoside library where more than one amino acid is employed).
  • the so generated substituted nitropyrimidine Ci'-N-nucleoside (or nucleoside library) is then reduced in a hydrogenation reaction to form the corresponding substituted aminopyrimidine Ci'-N-nucleoside or nucleoside library, which is then in a further step cyclized to the desired piperazino-pyrimidine heterocyclic nucleoside or nucleoside library.
  • cyclization may be omitted to obtain a substituted aminopyrimidine Ci'-N-nucleoside or nucleoside library after deprotection and cleavage ofthe sugar form the solid phase.
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted ary
  • nucleoside library with at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 8 with a first set of substituents A and R, and wherein another one ofthe at least two library compounds has a structure according to Formula 8 with a second set of substituents A and R
  • A is a sugar that is coupled to a solid phase, wherein the sugar is optionally protected, R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein not all ofthe substituents A and R in the first set are the same as the substituents A and R in the second set.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • contemplated compounds may have a structure according to Formula 9
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3 '-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • nucleoside libraries prepared according to Scheme 10 above will include one ofthe at least two library compounds with a structure according to Formula 10 with a first set of substituents A and R, and another one ofthe at least two library compounds with a structure according to Formula 10 with a second set of substituents A and R
  • A is a sugar that is coupled to a solid phase, wherein the sugar is optionally protected;
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and wherein not all ofthe substituents A and R in the first set are the same as the substituents A and R in the second set.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • contemplated compounds may also have a structure according to Formula 11
  • A is a sugar
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position of the ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • cyclization may be performed as depicted in Scheme 11.
  • a substituted aminopyrimidine Ci'-N-nucleoside or nucleoside library (15) is prepared as described in Schemes 2A-2C above, and cyclization is performed as shown to obtain the desired disubstituted imidazole-pyrimidine Ci'-N-nucleoside or nucleoside library.
  • contemplated nucleoside libraries will include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 12 with a first set of substituents A, Ri, and R 2 , and another one of the at least two library compounds with a structure according to Formula 12 with a second set of substituents A,
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C 3 '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3'-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • Ri and R 2 are independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle.
  • the sugar comprises a ribofuranose, wherein the ribofuranose may further be modified at the C 5 '-, C 2 '- or C '-position.
  • the modification in the C 5 '-position ofthe ribofuranose comprises an amino group in place of a hydroxyl group, and/or OR and/or R group (as defined above) in place of or in addition to the 2'- and 3 '-hydroxyl group.
  • Further particularly preferred alternative sugars include substituted or unsubstituted arabinose, or a carbocyclic moiety, wherein all ofthe contemplated sugars may be in D- or L-configuration.
  • C 5 '-modified sugar portions are employed in contemplated libraries and compounds, and an exemplary synthetic route for a C 5 '-amino sugar is shown in Scheme 12 below.
  • X N, NR, S, NHNH, NHO
  • a suitably protected l'-azido-5'-iodo sugar is reacted with an amino trityl-modified solid phase, wherein the amino group ofthe solid phase replaces the leaving group on the sugar (i.e., the iodine).
  • Concurrent and/or subsequent reduction will then afford the corresponding 1'- amino sugar that is covalently bound to the solid phase via an NH group.
  • the so prepared amino sugar can be coupled to a wide variety of heterocyclic bases, which may further be derivatized and/or combinatorialized to the corresponding Ci'-N-heterocyclic base nucleoside or nucleoside library (after optional deprotection and cleavage from the solid support).
  • heterocyclic bases, derivatization and/or combinatorialization include those described in the preceding schemes, wherein the same considerations as described above apply. It is particularly contemplated that in alternative aspects suitable sugars are not limited to ribofuranose sugars, and especially contemplated alternative sugars include substituted and unsubstituted arabinose, substituted and unsubstituted xylose, and substituted ribofuranose. Moreover, contemplated alternative sugars further include those described in the section entitled "Contemplated Sugars" above.
  • nucleosides and/or nucleoside libraries (which may or may not include a solid phase on the C '-atom or other position in the sugar moiety) are considered with above contemplated amino-sugars as shown below.
  • nucleoside libraries may be produced, wherein the heterocyclic base is a tricyclic heterocyclic base that includes a benzimidazole moiety.
  • tricyclic refers to any compound that includes a first, a second and a third ring, wherein the first ring is covalently bound to the second ring via at least two atoms in the first ring, and wherein the third ring is covalently bound to the first and/or second ring via at least two atoms in the first and/or second ring.
  • tricyclic nucleosides may comprise various sugar portions, it is typically preferred that the sugar is selected from the group consisting of a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar may be in D- or L-configuration.
  • Alternative contemplated sugar portions are described above in the section entitled "Contemplated Sugars”.
  • Scheme 13 depicts an exemplary approach to generate various tricyclic nucleosides from the corresponding substituted benzimidazole nucleosides.
  • the carboxylic acid groups of benzimidazole-5,6-dicarboxylic acid are protected, and the resultant protected benzimidazole- 5,6-dicarboxylic acid is then coupled to a suitable protected sugar (here: protected ribofuranose) to yield a protected benzimidazole nucleoside.
  • the protected benzimidazole nucleoside may then be employed as starting material (27) for various tricyclic nucleoside libraries using various synthetic routes, and exemplary synthetic routes "A", "B", “C”, and “D" are shown below.
  • a l- ⁇ -D-Ribofuranosyl-(6,7-substituted)-6,7-dihydro-lH-imidazo[4,5- g]phthalazine-5,8-dione nucleoside library may be produced following a synthetic route as depicted in route "A" in Scheme 13.
  • the dicarboxylic compound is reacted with a substituted hydrazine to form a tricyclic nucleoside.
  • the starting material is partially deprotected and coupled to a solid phase, and aliquots ofthe resin are then reacted with a plurality of chemically distinct substituted hydrazines.
  • the starting material may be reacted with one or more primary or secondary amines (which may or may not be chemically distinct) to form a l- ⁇ -D-Ribofuranosyl-lH-benzoimidazole-5,6-dicarboxylic Acid bis-substituted-amide (library).
  • Libraries may advantageously be produced from intermediate 29 from route "A”.
  • the intermediate 29 may also be modified to produce a 'fat nucleoside' by reacting the intermediate with a substituted diamine to form a substituted 6- ⁇ -D-Ribofuranosyl-4,6, 11,14-tetraaza-tricyclo[7.6.0.0 3 ' 7 ]pentadeca-l (9),2,4,7- tetraene-10,15-dione library.
  • the starting material may be cyclized to a tricyclic dione nucleoside, which is subsequently protected at the sugar moiety.
  • the so produced tricyclic dione nucleoside is then converted to the corresponding dichloro tricyclic nucleoside (l-(2',3',5'-Tri-0-acetyl- ⁇ -D-ribofuranosyl)-5,8-dichloro-6,7-dihydro-lH- imidazo[4,5-g]phthalazine) that serves as a substrate for one or more reactions with one or more primary or secondary amines to form a 5,8-disubstituted tricyclic nucleoside or 5,8-disubstituted tricyclic nucleoside library.
  • the tricyclic heterocyclic base is contemplated that such bases are produced from appropriately substituted benzimidazole compounds, all or almost all of which are commercially available.
  • a particular substituted benzimidazole compound is not commercially available, it should be appreciated that such compounds can be synthesized from commercially available precursors (e.g., 5,6-dihalogenated benzimidazole) following procedures well known in the art without undue experimentation (see e.g., Advanced Organic Chemistry: Structure and Mechanisms (Part A) by Francis A. Carey, Richard J. Sundberg; Plenum Pub Corp; ISBN: 0306462435; or Advanced Organic Chemistry : Reactions and Synthesis (Part B) by Francis Carey, Richard J. Sundberg; Plenum Pub Corp; ISBN: 0306434571, or Compendium of Organic Synthetic Methods, Volume 9, by Michael B. Smith, John Wiley & Sons; ISBN: 0471145793).
  • the tricyclic heterocyclic base from appropriately substituted benzimidazole compounds may also follow exemplary protocols as described in the experimental section (infra).
  • substituents include a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle, halogens, nitriles, acroxylic acids, amines, amides, sulfhydryls, etc.
  • R and R' are independently selected from a hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, and a heterocycle.
  • R and R' are independently selected from a hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, and a heterocycle.
  • Exemplary compounds are listed in the experimental section below.
  • many such amines are commercially available, and it is contemplated that where a particular amine is not commercially available, such compounds can be synthesized from commercially available precursors following procedures well known in the art without undue experimentation (supra).
  • substituted diamines in route "C” it should be recognized that various substituted diamines are appropriate, and especially preferred substituted diamines have a general formula RHN-(CH 2 ) n -NHR', with n between 1 -4, and wherein R and R' are independently selected from a hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, and a heterocycle.
  • R and R' are independently selected from a hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstitute
  • contemplated tricyclic nucleoside libraries may include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 14 with a first set of substituents X, Y, Ri, and R 2 , and wherein another one ofthe at least two library compounds has a structure according to Formula 14 with a second set of substituents X, Y, Ri, and R 2
  • Rj and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; wherein • comprises a solid phase; and wherein not all ofthe substituents X, Y, Ri, and R 2 in the first set are the same as the substituents X, Y, Ri, and R 2 in the second set.
  • contemplated tricyclic nucleosides may have a structure according to Formula 15
  • Ri and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; and wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • tricyclic nucleoside libraries may include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 16 with a first set of substituents X, Y, Ri, and R 2 , and wherein another one ofthe at least two library compounds has a structure according to Formula 16 with a second set of substituents X, Y, Ri, and R 2
  • Ri and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; wherein Ri and R 2 together may form a ring; wherein • comprises a solid phase; and wherein not all ofthe substituents X, Y, R 1 ⁇ and R 2 in the first set are the same as the substituents X, Y, Ri, and R 2 in the second set.
  • contemplated tricyclic nucleosides may have a structure according to Formula 17
  • Ri and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; and wherein Rj and R 2 together may form a ring.
  • tricyclic nucleoside libraries may include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 18 with a first set of substituents X, Y, Ri, and R 2 , and wherein another one ofthe at least two library compounds has a structure according to Formula 18 with a second set of substituents X, Y, Ri, and R 2
  • R x and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; wherein • comprises a solid phase; and wherein not all ofthe substituents X, Y, Ri, and R 2 in the first set are the same as the substituents X, Y, Ri, and R 2 in the second set.
  • contemplated tricyclic nucleosides may have a structure according to Formula 19
  • Ri and R are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; and wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • tricyclic nucleoside libraries may include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 20 with a first set of substituents X, Y, Ri, and R 2 , and wherein another one ofthe at least two library compounds has a structure according to Formula 20 with a second set of substituents X, Y, Ri, and R 2
  • Ri and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; wherein • comprises a solid phase; and wherein not all ofthe substituents X, Y, Ri, and R 2 in the first set are the same as the substituents X, Y, Ri, and R 2 in the second set.
  • contemplated tricyclic nucleosides may have a structure according to Formula 21
  • Rj and R 2 are independently selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; and wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • contemplated tricyclic nucleosides and libraries may be synthesized following a strategy as shown in Scheme 14 below.
  • dimethyl l-(2',3',5'-tri-0-benzoyl- ⁇ - D-ribofuranosyl)benzimidazole-5,6-dicarboxylate is employed as the starting material (see compound 27 above), which is in a further step brominated in the 2-positon ofthe heterocyclic base.
  • a substituted (or a plurality of substituted) hydrazine(s) is reacted to form the corresponding 2-(substituted)hydrazine (substituted) tricyclic nucleoside 38.
  • the brominated intermediate may be reacted with a (plurality of) primary and/or secondary amine(s) to yield a trisubstituted benzimidazole nucleoside (in which two substituents may form a ring).
  • a (plurality of) primary and/or secondary amine(s) to yield a trisubstituted benzimidazole nucleoside (in which two substituents may form a ring).
  • the primary and/or secondary amines may be identical or chemically distinct.
  • nucleosides and nucleoside libraries include coupling of a sugar to a solid phase
  • suitable solid phases and coupling/decoupling are contemplated as described in the section entitled "Contemplated Solid Phases" above.
  • a preferred position of a solid phase on contemplated sugars is the C 5 '-position, however, other positions are also suitable.
  • protection groups the same considerations as described above apply.
  • the material is a nucleoside in which the heterocyclic base comprises a benzimidazole, and it is especially preferred that the starting material is dimethyl l-(2',3',5 , -tri-0-benzoyl- ⁇ -D-ribofuranosyl)- benzimidazole-5,6-dicarboxylate.
  • nucleosides with one or more substituents on a benzimidazole-containing heterocyclic base are also contemplated.
  • suitable reagents include hydrazine, which may include at least one substituent and will generally have a formula of R'R"N-NR'R", wherein R' is typically hydrogen, or R", and wherein R" is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl.
  • R' is typically hydrogen, or R
  • R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl.
  • Exemplary hydrazines are listed in the experimental section below.
  • suitable reagents include primary and/or secondary amines to yield the desired trisubstituted benzimidazole nucleoside, and in particularly contemplated aspects, at least two ofthe substituents may form a ring.
  • Contemplated primary and secondary amines will have the general formula R-NR'H, wherein R' may be hydrogen or R, wherein R may be is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl. Exemplary hydrazines are listed in the experimental section below.
  • Ri, R 2 , and R 3 are independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and alkaryl; and wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • R 2 and R in compounds of Formula 5B may form a ring (or may be a covalent bond between the nitrogen atoms).
  • tricyclic nucleoside libraries and compounds may be synthesized following a synthetic route as depicted in Scheme 15 below.
  • 5,6-dimethyl benzimidazole is oxidized to the corresponding dicarboxylic acid, which is then further converted to the anhydride. Further reactions ofthe anhydride will yield the imidazo[4,5- g]quinazolin-8-(7H)-one as a heterocyclic base, which is subsequently coupled to a suitable protected sugar moiety to yield two isomeric forms (42/43) of a protected tricyclic nucleoside.
  • X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • tricyclic nucleoside libraries and compounds may be produced as shown above.
  • reagent or reagents used in the Heck/Stille or Suzuki reaction it is contemplated that all reagents are suitable that will replace the halogen with concurrent formation of a carbon-carbon bond. Particularly contemplated reagents are listed in the experimental section below.
  • contemplated tricyclic nucleoside libraries may include at least two library compounds in which one ofthe at least two library compounds has a structure according to Formula 26 or 27 with a first set of substituents X, Y, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 26 or 27 with a second set of substituents X, Y, R t , R 2 , and R 3
  • Ri, R 2 and R 3 are independently selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl; wherein • comprises a solid phase; and wherein not all ofthe substituents X, Y, Ri, R 2 , and R 3 in the first set are the same as the substituents X, Y, Ri, R 2 , and R 3 in the second set.
  • contemplated tricyclic nucleosides may have a structure according to
  • R R 2 and R 3 are independently selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted aryl, an unsubstituted aryl, and a heterocycle; and wherein X and Y are independently selected from the group consisting of H, OH, Halogen, OR, SH, SR, HNR, and R, wherein R is an alkyl, a substituted alkyl, an alkenyl, a ' substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl. 2'-C-substituted Nucleosides
  • nucleosides can be prepared in which the sugar portion in the nucleoside is modified with a substituent such that the 2'-position ofthe sugar is coupled to a carbon atom ofthe substituent ofthe 2'-position.
  • substituted sugars include substituted ribofuranose and substituted arabinose in D- and L- configuration.
  • An exemplary selection of suitable sugars includes one or more alkyl groups (or other substituents, including alkenyl, alkynyl, aryl, halogen, CF 3 , CHF 2 , CC1 3 , CHC1 2 , N 3 , NH 2 , etc.), which are covalently bound to sugar at the C' ⁇ , C' 2 ,C' 3 ,C' 4 , or C 5 atom.
  • the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one ofthe alkyl groups is a methyl group.
  • furanose most preferably a D- or L-ribofuranose
  • at least one ofthe alkyl groups is a methyl group.
  • the alkyl group may or may not be substituted with one or more substituents.
  • One exemplary class of preferred sugars is depicted below:
  • R is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl (branched, linear, or cyclic), with R including between one and twenty carbon atoms.
  • contemplated 2'-C- substituted sugars may be oriented in the alpha or beta direction. Consequently, contemplated sugars and nucleosides may advantageously be coupled to a solid phase (preferably at the 5'-position).
  • heterocyclic base it should be appreciated that the exact chemical nature is not limiting to the inventive subject matter. Therefore, alternative heterocyclic bases may include various modifications in the uridine portion, and particularly contemplated modifications include various substituents on the 4- and/or 5 -position (Particularly preferred substituents include halogens, alkyl, CF 3 , NH 2 , and NO 2 ). Furthermore, all known heterocyclic bases that include at least one carbonyl (keto) oxygen are contemplated suitable for use in conjunction with the teachings presented herein. However, especially contemplated nucleosides include naturally occurring and synthetic bases, including purine bases, pyrimidine bases, and triazole bases, wherein all of such bases may further comprise one or more substituents. Exemplary suitable heterocyclic bases are depicted above in the section entitled "Contemplated Heterocyclic Bases".
  • nucleophilic reagents it should be recognized that numerous reagents and compounds are suitable, and especially contemplated nucleophilic substrates include those having a nitrogen atom, and especially primary and/or secondary amines, and those having an oxygen or sulfur atom (e.g. , various alcohols and/or thiols). Moreover, suitable nucleophilic substrates also include reagents that form a C-C bond (e.g., Grignard reagents, etc.). Exemplary suitable nucleophilic substrates will have the general formula NR . R 2 , R .
  • nucleoside library with at least two library compounds in which one of the at least two library compounds has a structure according to Formula 30 with a first set of substituents A, Y, and R, and wherein another one ofthe at least two library compounds has a structure according to Formula 30 with a second set of substituents A, Y, and R
  • A is a 2'-beta-C-substituted sugar (in D- or L-configuration) that is coupled to a solid phase, wherein the sugar is optionally protected, and wherein the substituent is selected from the group consisting of a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle;
  • R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle;
  • Y is R or halogen, CF 3 , NO 2 , NH 3
  • contemplated compounds may have a structure according to Formula 31
  • A is a 2'-beta-C-substituted sugar (in D- or L-configuration), wherein the substituent is selected from the group consisting of a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; R is selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle; and Y is R or halogen, CF 3 , NO 2 , NH 3 .
  • the libraries according to the inventive subject matter may be used to facilitate structure-activity analysis of nucleoside-type compounds.
  • an enzyme employs a nucleoside as a substrate/co-substrate
  • an inhibitor or alternative substrate for the enzyme is desired
  • contemplated libraries will provide a researcher with rapid information on the impact of a particular substituent in a particular position ofthe library compound.
  • libraries according to the inventive subject matter will exhibit a significant source of revenue for a seller since in most cases purchase of a library of nucleosides, nucleoside analogs, nucleotides, and/or nucleotide analogs will be less costly to a user than individual synthesis of these compounds.
  • the library compounds may serve as in vitro and/or in vivo substrates or inhibitors with particularly desirable physicochemical and/or biological properties.
  • the library compounds may act as inhibitors of DNA and/or RNA for various nucleoside-using enzymes, and especially polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as an in vitro and/or in vivo antiviral agent, antineoplastic agent, or immunomodulatory agent.
  • nucleosides according to the inventive subject matter may be incorporated into oligo- or polynucleotides, which will then exhibit altered hybridization characteristics with single or double stranded DNA in vitro and in vivo.
  • Particularly contemplated antiviral activities include at least partial reduction of viral titers of respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIN), influenza A virus, Hanta virus (hemorrhagic fever), human papilloma virus (HPV), and measles virus.
  • 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 ofthe specification to provide numerous formulations for a particular route of administration.
  • contemplated nucleosides may be modified to render them more soluble in water or another 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 ofthe art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics ofthe present compounds for maximum beneficial effect in a patient.
  • prodrug forms of contemplated nucleosides may be formed for various purposes, including reduction of toxicity, increasing the organ- or target -> cell specificity, etc.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient (see above).
  • One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters ofthe pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect ofthe compound.
  • 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 ofthe 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 ofthe 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.
  • contemplated agents for combination with contemplated compounds it is especially preferred that such agents include interferon, and particularly IFN-alpha or IFN-beta (or fragments thereof).
  • the reaction mixture was shaken well at room temperature for 48 h.
  • the resin was filtered and washed sequentially with CH 2 C1 2 (3 X 25 mL), a mixture of CH 2 Cl 2 -MeOH-N,N-diisopropylethylamine (8.5:1 :0.5, 2 X 20 mL).
  • the resultant resin was then dried under vacuum over KOH for 16 hours.
  • the loading efficiency was 85% (1.46 mmol/g), calculated based on the starting material 2 recovered and the specified loading capacity ofthe resin.
  • FT-IR (KBr) 2107.3 cm _1 (N 3 group).
  • the amino resin 4 (1.0 g) was suspended in a solution of N,N-diisopropylethylamine in CH 2 C1 2 (5 mL, 20% v/v) and cooled to 0-5 °C. A solution of cyanuric chloride in CH 2 C1 2 (5 mL, 1.0 M) was added.
  • the resultant suspension was shaken well at room temperature for 1 h and filtered using a sintered funnel.
  • the resin was washed with CH 2 C1 2 (3 X 25 mL) and dried over KOH under vacuum for 16 h.
  • a small portion (0.10 g) of resin 5 was treated with 1.5 mL of TFA solution in CH 2 C1 2 (1.5%) for 60 seconds, filtered, and washed with CH 2 C1 2 (2 X 2 mL).
  • the reaction mixture was shaken well at room temperature for 2 h.
  • the resin was then washed sequentially with NMP (3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 10 mL).
  • the reaction mixture was shaken well at 80 °C for 6 h.
  • the resin was then washed with NMP (3 X 10 mL) and CH 2 C1 2 (3 X 10 mL).
  • the fully protected and substituted resin was obtained after being dried over KOH under vacuum for 16 h.
  • Resin 6 (0.05 g) was suspended in a solution of tetrabutylammoium fluoride in THF (1.5 mL, 1 M) and shaken well at room temperature for 16 h. The resin was filtered and treated with a DMF-AcOH-H 2 O mixture (8:1 :1, 1.5 mL) for 10 minutes to remove the excess amount of tetrabutylammonium salt.
  • the resin was filtered and washed sequentially with DMF- H 2 O mixture (9:1, 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 20 mL). After being dried over KOH under vacuum for 16 h, the resultant resin (50 mg) was suspended in 1.5 mL of TFA solution in CH 2 C1 2 (1.5%) and shaken well at room temperature for 60 seconds. The resin was filtered and further washed with MeOH (2 X 1 mL). The combined filtrate was concentrated under high vacuum to provide compound 7 as the corresponding trifluoroacetate salt.
  • Second amine substitution To the resultant mono-chloro triazine resin was added a solution of N,N-diisipropylethylamine in NMP (20%, 0.75 mL), followed by the addition of 8 secondary amines (building block set B) in NMP (0.75 mL, 1.0 M) in the respective rows. The reaction block was covered and shaken at 80 °C for 5 h. The reaction mixtures were filtered, and the resins were washed sequentially with DMF (X 3), a mixture of MeOH and CH 2 C1 2 (X 3), and finally with CH 2 C1 2 (X 2), and then dried under nitrogen.
  • N 1 ' [(5- ⁇ itro-N-alkyI or N,JV-dialkyI or 7V-cycloalkyl)pyrimidin-4-yl]-l'-(R, S)- amino- ⁇ -D-ribofuranose 11.
  • the resin was filtered and washed sequentially with MeOH (3 X 10 mL), CH 2 C1 2 (3 X 10 mL), an NMP- H 2 O mixture (3: 1, 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 10 mL).
  • the resultant resin, 10 (50 mg) was suspended in a solution of tetrabutylammonium fluoride (1.5 mL, 1 M) in THF and shaken well at room temperature for 16 h.
  • the resin was filtered and washed sequentially with THF (3 X 10 mL), MeOH (3 X 10 mL), an NMP-H 2 O mixture (3:1, 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 10 mL).
  • the resin was treated with a mixture of DMF-H 2 O-AcOH (8:1 : 1, 2 mL) and shaken well for 15 minutes to remove the excess amount of tetrabutylammonium salt.
  • the resin was filtered and washed with MeOH (3 X 10 mL), an NMP- H 2 O mixture (3: 1 , 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 10 mL).
  • the resultant clean resin was treated with a solution of TFA in CH 2 C1 2 (1.5 mL, 1.5%) for 60 seconds.
  • the resin was filtered and washed with MeOH (2 X 2.5 mL).
  • the combined filtrate was concentrated to provide product 11 (15-20 mg) as the corresponding trifluoroacetate salt.
  • the resin was filtered and washed with CH 2 C1 2 (3 X 25 mL), and then a mixture of CH 2 Cl 2 -MeOH-N,N- diisopropylethylamine (8.5:1:0.5, 2 X 20 mL).
  • the product resin was obtained after being dried over KOH under vacuum for 16 h. Loading efficiency was 84%, calculated based on the recovered starting material (1.52 mmol alcohol loaded).
  • FT-IR (KBr) of resin 2111.9 cm _1 ( ⁇ 3 group).
  • a small portion (50 mg) ofthe resin was treated with 1.5 mL of TFA solution in CH 2 C1 2 (1.5%) for 60 seconds, filtered, and washed with CH 2 C1 2 .
  • the filtrate was concentrated to give the starting azido compound 15, which was confirmed by ⁇ NMR.
  • Resin 17 (1.0 g) was suspended in a solution of N.N-diisopropylethylamine in ⁇ MP (8 mL, 20%) v/v) and then treated with 4,6-dichloro-5-nitropyrimidine (1.0 g, 5.18 mmol).
  • Resin 18 (50 mg) was suspended in a solution of N,N- diisoproplyethylamine in NMP (0.75 mL, 20% v/v), and an NMP solution of an amine (0.75 mL, 1 M) was then added. The suspension was shaken well at room temperature for 16 h.
  • the resin was filtered and washed sequentially with MeOH (3 X 10 mL), CH 2 C1 2 (3 X 10 mL), an NMP- H 2 O mixture (3:1, 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 10 mL).
  • the resultant resin was then treated with a mixture of TFA-H 2 O (9:1, 2 mL) and kept at room temperature for 1 h.
  • the reaction mixture was filtered, and the resin washed with MeOH (2 X 5 mL).
  • the combined filtrate was concentrated, and the residue was co-evaporated with toluene (2 X 5 mL) to provide the title compound (15-20 mg) as the corresponding trifluoroacetate salt.
  • the reaction mixture was shaken well at room temperature for 48 h.
  • the resin was filtered and washed with CH 2 CI 2 (3 X 25 mL), a mixture of CH 2 C-2-MeOH-N,N-diisopropylethylamine (8.5:1 :0.5, 2 X 20 mL).
  • the product resin 21 was obtained after dried over KOH under vacuum for 16 h. Loading efficiency was 86%, calculated based on the recovery ofthe starting material (1.57 mmol amino 20 loaded).
  • a small portion (50 mg) of resin 21 was treated with 1.5 mL of TFA solution in CH 2 H 2 (1.5%) for 60 seconds.
  • the resultant resin was filtered and washed with CH 2 C1 2 (25 mL).
  • the filtrate was concentrated to provide the starting azido compound 20, which was confirmed by 1H NMR.
  • Resin 22 was obtained after being dried over KOH under vacuum for 16 h. A small portion (0.10 g) of resin 22 was treated with a solution of TFA in CH 2 CI 2 (1.5%) for 60 seconds, filtered, and washed with CH 2 CI 2 (2 X 5 mL).
  • the resin was then treated with a DMF-AcOH-H 2 O mixture (8:1 :1, 1.5 mL) for 10 minutes and filtered.
  • the resin was washed with a DMF-H2O mixture (9:1, 3 X 10 mL), MeOH (3 X 10 mL), and CH 2 C1 2 (3 X 20 mL).
  • a suspension ofthe resultant resin 50 mg in 1.5 mL of TFA solution in CH 2 CI 2 (1.5%) was shaken well at room temperature for 60 seconds and filtered.
  • the resin was further washed with MeOH (2 X 1 mL), and the combined filtrate was concentrated to give product 25 as the corresponding trifluoroacetate salt.
  • Library L14 was synthesized from resin 24 and 96 amines by similar procedures as described for the synthesis of libraries Ll- 12 and L13.
  • Dimethyl benzimidazole-5,6-dicarboxylate (26). To a solution of 0.55 g of benzimidazole-5,6-dicarboxylic acid (25) in 60 ml of anhydrous methanol was added 1 ml of concentrated sulfuric acid. The mixture was refluxed for 72 hours. The reaction was cooled to •room temperature and sodium bicarbonate was added to neutralize this solution to pH 7. The solid was filtered and washed with methanol. The filtrate was evaporated to dryness to give crude product as white a solid, which was purified by silica gel column (chloroform-methanol, 20: 1) to give pure product as a white solid product 26.
  • Dimethyl 1 -(5 '- ⁇ 9-(4-methoxytrityl resin)- ⁇ -D-ribofuranosyl)benzimidazole-5,6- dicarboxylate (29).
  • a mixture of dimethyl l- ⁇ -D-ribofuranosylbenzimidazole-5,6-dicarboxylate (28) (2 equiv) and 4-methoxytrityl chloride resin (1 equiv) in anhydrous pyridine (8-10 ml/g resin) was shaken at room temperature for 2 days, then this resin was filtered and washed with anhydrous pyridine and anhydrous diethyl ether several times. After drying in vacuo, yellow resin 29 was obtained.
  • Benzimidazole-5,6-dicarboxylic Acid (27). To a 1000 ml three-necked, round-bottomed flask equipped with a condenser and a thermometer was added 140 ml of a 1 :1 (v/v) mixture of water and tert-butyl alcohol followed by 8.0 g of 5,6-dimethylbenzimidazole. Stirring of this heterogeneous mixture at room temperature for 30 min gave a homogeneous, slightly brown solution, to which was added dropwise a hot solution (86.5 g dissolved in 600 ml of water) prepared separately at 68-70 °C, and the rate of addition ofthe KMnO solution and heating were regulated so as to keep the temperature at this level.
  • a hot solution 86.5 g dissolved in 600 ml of water
  • Bromo-S-methyl-tricyclic nucleoside (740 mg, 1 mmol) was dissolved in methanol 20 ml. Sodium cyanide (450 mg, 9 mmol) was added and the reaction mixture was stirred at room temperature for 36 h. The reaction mixture was directly adsorbed on silica gel and evaporated to dryness. Dried silica gel was loaded on the silica gel column and the pure compound 47 was obtained using 8% methanol in chloroform as an eluent. (356 mg, 83%).
  • the resultant uridine-substituted resin was swelled in 20 ml of pyridine, 10 ml of dichloromethane and 3.0 ml of triethylamine.
  • t-Butyldimethylsilychloride (5.27 g, 5 eq.) and imidazole (2.38 g, 5 eq) were added to the mixture followed by 5 ml of DMF to improve the solubility.
  • the mixture was shaken at room temperature for 24 hours and filtered.
  • the resin was washed 4 times with pyridine-DMF (1 :1) and 3 times with dichloromethane, and dried under vacuum to provide dried resin 66 loaded with protectedcytidine.
  • the resin was washed 5 times with pyridine-DMF (1 :1) and 3 times with dichloromethane, and dried under vacuum to provide 7.2 g of resin 67 which was confirmed by MAS NMR spectrometry and ready for the parallel array synthesis of nucleoside library 69.
  • 50 mg of resin 67 was added to each ofthe 96 wells on the ACT parallel synthesizer.
  • 1 ml of base 0.3 M DMAP in pyridine containing diisopropylethylamine
  • 0.65 ml of each of the 96 amines (1 M in DMF) were added to each ofthe 96 reaction vessels.
  • the sealed reaction vessels in the reaction block were shaken at room temperature 6 hours.
  • the solvent was filtered off by vacuum.
  • the resins were washed 3 times with DMF, 3 times with DCM-MeOH, and 3 times with dichloromethane to give a library of 96 resins 68.

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Abstract

L'invention concerne la préparation de banques d'analogues de nucléosides sur la base d'une méthode de banque combinatoire. Les composés et banques particulièrement préférés comportent des analogues de nucléosides dans lesquels la base hétérocyclique est couplée au sucre via un atome non carbonique, des analogues de nucléosides dotés d'une base hétérocyclique tricyclique qui contient du benzimidazole, ainsi que des analogues de nucléosides dans lesquels un substituant C2' est lié par covalence au sucre via un atome de carbone. Les nucléosides de l'invention peuvent servir à traiter divers états pathologiques, en particulier les infections virales et les maladies néoplasiques.
PCT/US2002/040415 2001-12-17 2002-12-17 Banques de nucleosides et composes rares, et utilisations preferees comme agents anticancereux et antiviraux WO2003051898A1 (fr)

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US6777395B2 (en) 2001-01-22 2004-08-17 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus
US7105499B2 (en) 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US20080090774A1 (en) * 2002-07-24 2008-04-17 Ptc Therapeutics, Inc. Nucleoside compounds and their use for treating cancer and diseases associated with somatic mutations
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9150603B2 (en) 2011-04-13 2015-10-06 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9408863B2 (en) 2011-07-13 2016-08-09 Merck Sharp & Dohme Corp. 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases
US9416154B2 (en) 2011-07-13 2016-08-16 Merck Sharp & Dohme Corp. 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
CN112812145A (zh) * 2021-01-28 2021-05-18 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi293及其制备方法和应用
CN112920241A (zh) * 2021-01-28 2021-06-08 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi308及其制备方法和应用
CN112920242A (zh) * 2021-01-28 2021-06-08 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi292及其制备方法和应用
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777395B2 (en) 2001-01-22 2004-08-17 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus
US7105499B2 (en) 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7125855B2 (en) 2001-01-22 2006-10-24 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7202224B2 (en) 2001-01-22 2007-04-10 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US20080090774A1 (en) * 2002-07-24 2008-04-17 Ptc Therapeutics, Inc. Nucleoside compounds and their use for treating cancer and diseases associated with somatic mutations
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9150603B2 (en) 2011-04-13 2015-10-06 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9408863B2 (en) 2011-07-13 2016-08-09 Merck Sharp & Dohme Corp. 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases
US9416154B2 (en) 2011-07-13 2016-08-16 Merck Sharp & Dohme Corp. 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof
CN112812145A (zh) * 2021-01-28 2021-05-18 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi293及其制备方法和应用
CN112920241A (zh) * 2021-01-28 2021-06-08 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi308及其制备方法和应用
CN112920242A (zh) * 2021-01-28 2021-06-08 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi292及其制备方法和应用
CN112920242B (zh) * 2021-01-28 2021-12-21 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi292及其制备方法和应用
CN112812145B (zh) * 2021-01-28 2021-12-21 中国人民解放军东部战区总医院 一种苯并咪唑衍生物bi293及其制备方法和应用

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