WO2003051881A1 - Banques de nucleosides purine et composes substitues par methodes combinatoires en phase solide - Google Patents

Banques de nucleosides purine et composes substitues par methodes combinatoires en phase solide Download PDF

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WO2003051881A1
WO2003051881A1 PCT/US2002/040414 US0240414W WO03051881A1 WO 2003051881 A1 WO2003051881 A1 WO 2003051881A1 US 0240414 W US0240414 W US 0240414W WO 03051881 A1 WO03051881 A1 WO 03051881A1
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substituted
alkynyl
alkenyl
aryl
alkyl
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PCT/US2002/040414
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WO2003051881B1 (fr
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Haoyun An
Esmir Gunic
Yung-Hyo Koh
Huanming Chen
Dinesh Barawkar
Weijian Zhang
Jean-Luc Girardet
Frank Rong
Zhi Hong
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Ribapharm Inc.
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Publication of WO2003051881B1 publication Critical patent/WO2003051881B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • 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
    • 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 nucleosides 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-fiuo ouridine, and adenosine deaminase inhibitors such as 2-chloroadenosine.
  • neplanocin A is an inhibitor of S-adenosylhomocysteine hydrolase, which shows potent anticancer and antiviral activities.
  • Many of these 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 generation of nucleoside libraries.
  • the glycosidic bonds in many nucleosides are in labile to acidic condition, and many useful reactions in combinatorial chemistry approaches cannot be used in the generation of nucleoside analogue libraries.
  • the present invention is directed to nucleoside analog libraries and compounds represented in and derived from these libraries.
  • Contemplated nucleoside analog libraries and their compounds especially include various 2-C-substituted purines, 3-deoxy/aza-6- substituted purines, substituted 2-thioadenosines, 2-amino-6,8-disubstituted purines, 2,8- disubstituted guanosines, 6-substituted purines, 2,6-disubstituted adenosines, and 6,8- disubstituted adenosines.
  • 2'-C-substituted nucleoside libraries and compounds include nucleosides in which a sugar is covalently bound to a purine having a substituent in a 2-position, wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine (with the proviso that the 2-C-substituent is not -C ⁇ C-R, with R being alkyl or substituted alkyl).
  • the carbon atom in the substituent is a chiral center
  • the 2-C-substituted purine is formed by reacting an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, or a heterocyclic carboxylic acid with 5- amino-4-imidazolylcarboxamide that is covalently bound to the sugar.
  • Exemplary libraries and compounds will include compounds according to Formulae 1 A and IB wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formulae 2A and 2B, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formulae 2C and 2D, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formula 3, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formulae 4 and 4A, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formula 5, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formula 6, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • contemplated libraries and compounds include nucleosides according to Formulae 7 or 8, wherein the substituents are described as in the respective portion ofthe detailed description below.
  • nucleoside library refers to a plurality of chemically distinct nucleosides, wherein at least some ofthe nucleosides have been synthesized from a common synthesis intermediate.
  • synthesis intermediate explicitly excludes starting materials ofthe synthesis. It is generally contemplated that the complexity of contemplated libraries is at least 20 distinct nucleosides, more typically at least 100 distinct nucleosides, and most typically at least 1,000 distinct nucleosides.
  • library compound refers to a nucleoside within the 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" as used herein.
  • Especially contemplated 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).
  • 6-membered ring e.g., purine, pyrrolo[2,3-d]pyrimidine
  • a 6-membered ring fused to another 6-membered or higher ring e.g., pyrido[4,5-d]pyrimidine, benzodiazepine
  • 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.
  • sugar refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group in the sugar.
  • particularly contemplated deletions include 2'-deoxy and/or 3 '-deoxy sugars.
  • Especially contemplated substitutions include replacement 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.), however, also includes nucleosides.
  • nucleoside also includes all prodrug forms of a nucleoside, wherein the prodrug form may be activated/converted to the active drug/nucleoside in one or more than one step, and wherein the activation/conversion ofthe prodrug into the active drug/nucleoside may occur intracellularly or extracellularly (in a single step or multiple steps).
  • prodrug forms include those that confer a particular specificity towards a diseased or infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs" by Kenneth B.
  • multiple component condensation refers to a reaction between at least two distinct molecules and a sugar or sugar portion of a molecule, in which at least one ofthe two molecules forms a covalent bond with the sugar portion, wherein the reaction may be carried out simultaneously or sequentially (which may further involve an optional purification step).
  • alkyl and “unsubstituted alkyl” are used interchangeably herein and refer to any linear, branched, or cyclic hydrocarbon in which all carbon-carbon bonds are single bonds.
  • substituted alkyl refers to any alkyl that further comprises a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and 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 + ), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC,
  • alkenyl and “unsubstituted alkenyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond.
  • substituted alkenyl refers to any alkenyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkynyl and “unsubstituted alkynyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon- carbon triple bond.
  • substituted alkynyl refers to any alkynyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • aryl and “unsubstituted aryl” are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl.
  • substituted aryl refers to any aryl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.
  • alkaryl is employed where the aryl is further covalently bound to an alkyl, alkenyl, or alkynyl.
  • substituted as used herein also refers to a replacement of a chemical group or substituent (typically H or OH) with a functional group
  • functional groups include nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NHs ), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e.g.,
  • substituted includes nucleophilic (e.g., -NH 2 , -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.
  • nucleophilic e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e.g., -OH
  • non-polar groups e.g., aryl, alkyl, alkenyl, alkynyl, etc.
  • 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 C 5 ' esters), alkyl groups, alkoxygroups, halogens, amino groups and amines, sulfur-containing substituents, etc. It is still further contemplated that all contemplated substituents (hydroxyl substituents and non-hydroxyl substituents) may be directed in the alpha or beta position. Numerous ofthe contemplated sugars and sugar analogs are commercially available. However, where contemplated sugars are not commercially available, it should be recognized that there are various methods known in the art to synthesize such sugars.
  • suitable protocols can be found in "Modern Methods in Carbohydrate Synthesis” by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212), in U.S. Pat Nos.4,880,782 and 3,817,982, in WO88/00050, or in EP199,451.
  • 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.
  • R H, OH, NHR, halo, CH 2 OH, COOH, N 3 , alkyl, aryl, alkynyl, heterocycles, OR, S , P(0)(OR) 2
  • An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other substituents, including alkenyl, alkynyl, aryl, halogen, CF 3 , CHF 2 ,
  • CCI3, 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 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.
  • 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-d]pyrimidine), 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 substituents, double and triple bonds, and any chemically reasonable combination thereof. It should further be appreciated that all ofthe 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 substituents are prepared from precursor nucleosides (or modified sugars) that are derivatized in subsequent/parallel modification reactions.
  • 2-C-substituted purine nucleoside libraries and library compounds may be synthesized, wherein the nucleoside comprises a sugar that is covalently bound to a purine (or purine analog) having a substituent in the 2-position, wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine.
  • the 2-C- substituent is -C ⁇ C-R, that R is not alkyl or substituted alkyl.
  • the carbon atom (that forms the covalent bond to the purine in 2-position) in the substituent forms a chiral center
  • the 2-C-substituted purine is formed by reacting a ' carboxylic acid (e.g., an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, or a heterocyclic carboxylic acid) with a substituted or unsubstituted 5-amino-4-imidazolylcarboxamide that is covalently bound to the sugar.
  • a ' carboxylic acid e.g., an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, or a heterocyclic carboxylic acid
  • Scheme 1 depicts an exemplary synthetic approach for a 2-C-substituted ribofuranosylpurine library, in which l-ribofuranosyl-5-amino-4-imidazolylcarboxamide is reacted with a protected amino acid to form the corresponding protected 2-C-substituted ribofuranosylpurine, which is either deprotected to form a 2-C-substituted ribofuranosylpurine, or which may further be reacted (after coupling the sugar to a solid phase and protecting the OH groups ofthe sugar) in a combinatorial approach with a nucleophile (preferably a primary or secondary amine) that replaces a previously introduced leaving group. Deprotection and cleavage ofthe (library) nucleoside will then yield me (collection oij desired nucleoside(s).
  • a nucleophile preferably a primary or secondary amine
  • sugar it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration. Further suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C 2 ' and/or C 3 ' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • the coupling ofthe heterocyclic base to the sugar may be in a position other than the Ci'-position, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C 2 ' and C 3 '-position.
  • protecting groups for the sugar may 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.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • 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).
  • a solid phase is employed in the combinatorial approach, it should also be recognized that the solid phase may also be omitted where appropriate.
  • heterocyclic bases While 5- amino-4-imidazolylcarboxamide is a preferred commercially available heterocyclic base, numerous alternative heterocyclic bases are also appropriate so long as such heterocyclic bases provide at least 2 amino groups that are positioned such that the at least two amino groups can react with a carboxylic acid to form a ring.
  • suitable heterocyclic bases may include aromatic or (at least partially saturated) ring systems that comprise at least one ring of at least 3 atoms (triazine, diazole, etc.). While it is generally contemplated that alternative heterocyclic bases include nitrogen as the heteroatom, alternative heteroatoms (e.g., O, S, P, Se, etc.) are also contemplated.
  • heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above (so long as such heterocyclic bases include at least 2 amino groups that are positioned such that the at least two amino groups can react with a carboxylic acid to form a ring). It is further contemplated that many ofthe preferred and/or alternative heterocyclic bases are commercially available. However, it should be recognized that where a particular heterocyclic base is not commercially available, suitable bases can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (see e.g., Advanced Organic Chemistry: Structure and Mechanisms (Part A) by Francis A. Carey, Richard J.
  • Particularly contemplated protected amino acids for reaction with the heterocyclic base include all naturally occurring proteinogenic amino acids in L-configuration, however, it should be recognized that the particular chemical nature and/or the stereochemical configuration is not limiting to the inventive subject matter. Consequently, suitable amino acids may also include D-amino acids, non-natural amino acids, and various non-amino acids, so long as such acids will react with the amino groups ofthe heterocyclic base to form a ring.
  • suitable acids include alkyl carboxylic acids, arylcarboxylic acids, alkenylcarboxylic acids, alkynylcarboxylic acids, and heterocyclic carboxylic acids, all of which may further include one or more substituents (e.g., OH, SH, NH 2 , COOH, CONH, CNHNH 2 , etc.). It is generally contemplated that many ofthe contemplated carboxylic acids are commercially available, however, it should be recognized that where a particular carboxylic acid is not commercially available, such carboxylic acids can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (supra). Cyclization ofthe two amino groups with contemplated carboxylic acids may be performed using various procedures well known in the art, and all ofthe known protocols are deemed suitable for use herein.
  • 2-C-substituted purine nucleosides formed using contemplated reactions may further be modified by reaction of such compounds with a nucleophilic reagent that replaces a previously introduced leaving group.
  • a nucleophilic reagent that replaces a previously introduced leaving group.
  • nucleophilic reagents include various nitrogen-containing reagents (e.g., various primary and secondary amines, RNH 2 , RRNH), thiols (RSH), alcohols (ROH), and Grignard reagents (RMgX).
  • nitrogen-containing reagents e.g., various primary and secondary amines, RNH 2 , RRNH), thiols (RSH), alcohols (ROH), and Grignard reagents (RMgX).
  • nitrogen-containing reagents e.g., various primary and secondary amines, RNH 2 , RRNH
  • RSH thiols
  • RH thiols
  • ROH alcohols
  • RMgX Grignard reagents
  • the so formed purine may further be reacted on the 8-position with various substituents in a substitution reaction in which hydrogen is replaced with an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N 3 , CF 3 , COOH, NHR, or NHNHR, wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.
  • these substituents in the 8-position may also be incorporated by use of appropriately substituted contemplated heterocyclic bases prior to the cyclization reaction.
  • Particularly contemplated alternative heterocyclic bases include those in which the 8- position is covalently bound to a hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N 3s CF 3 , COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.
  • nucleoside libraries will have at least two library compounds according to Formula 1, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Y, R ls R 2 , R 3 , and R 4 wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Y, R ls R 2 , R 3 , and R 4
  • A is a protected or unprotected sugar covalently bound to a solid phase
  • X is O , S, NH, NHNH, NHO, or CH 2
  • Y is CH 2 or NH
  • R h R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N , CF 3 , COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, and wherein not all ofthe substituents A, X, Y, R ls R 2 , R
  • contemplated compounds may have a structure according to Formula 1
  • A is a sugar (preferably ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose, all of which may be in D-configuration or L-configuration)
  • X is O, S, NH, NHO, NHNH, or CH 2
  • Y is CH 2 or NH
  • R h R 2 , R 3 , and j are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N 3 , CF 3 , COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted
  • contemplated compounds may also have a structure according to Formula IB
  • A is a sugar (preferably ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose, all of which may be in D-configuration or L-configuration)
  • X is O, S
  • NH alkyl, aryl, alkenyl, alkynyl, or alkaryl
  • R R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N 3 , CF 3 , COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl
  • 3- deoxy-6-substituted purine libraries may be produced following a synthetic scheme as depicted in Scheme 2.
  • the amino group in the heterocyclic base is protected and the 2'- and 3'- hydroxyl groups are converted into the corresponding 2',3'-epoxy group to form a protected 2',3'-epoxyguanosine, which is subsequently reduced to the corresponding 3'- deoxynucleoside.
  • the so generated 3'-deoxynucleoside is then coupled to a solid phase (preferably via the C 5 '-atom) and the keto-oxygen ofthe heterocyclic base is replaced with a leaving group (preferably TPSC1), which is replaced with a set of nucleophilic reagents (preferably primary amines) to generate molecular diversity.
  • a leaving group preferably TPSC1
  • nucleophilic reagents preferably primary amines
  • sugars include a vicinal diol, which is preferably a C 2 ' and C 3 ' hydroxyl group. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.
  • protecting groups for the sugar may vary considerably, and while it is particularly contemplated that suitable protection groups include trityl-, benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable.
  • suitable alternative protection groups and their reactions are described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all l ⁇ iown solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • 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).
  • contemplated sugars are coupled to the solid phase via the C 5 '-atom, however, in alternative aspects coupling to an atom other than the C 5 '-atom is also considered suitable.
  • heterocyclic base While guanosine is generally preferred as a heterocyclic base, it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one keto-oxygen and at least one amino group (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.
  • heterocyclic bases and especially guanine are commercially available, and where a particular alternative heterocyclic base is not commercially available, it is contemplated that such heterocyclic bases may be synthesized from a commercially available precursor without undue experimentation following procedures well known in the art (see e.g., "Modern Methods in Carbohydrate Synthesis” by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN:
  • heterocyclic bases may also be coupled to a sugar moiety to form a nucleoside, and that all known nucleosides are suitable for use in conjunction with the teachings presented herein.
  • especially preferred nucleosides include those in which the heterocyclic base has at least one keto-oxygen and at least one amino group (supra).
  • Epoxidation ofthe 2'- and 3'-hydroxyls to a 2',3'-epoxy group is preferably performed as described below (see experimental section), however, it should be recognized that numerous alternative reactions are also suitable, and all ofthe known epoxidation reactions for sugars are considered suitable for use herein.
  • reduction ofthe epoxy group to the corresponding alcohol and hydrogen at the C 2 ' and C 3 '-atom, respectively is preferably performed as described below.
  • alternative methods to convert the epoxy group to the corresponding alcohol and hydrogen at the C 2 ' and C 3 '-atom, respectively are also considered appropriate and may include catalytic reduction and/or electrochemical reduction.
  • nucleophilic reagents include all reagents that can replace a leaving group (and preferably OTPS) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.).
  • nucleophiles e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.
  • nucleophilic reagents include RNH , RR'NH, RSH, ROH, etc, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • a 3 '-deoxy sugar is coupled to heterocyclic base in a condensation reaction to form the corresponding 3'-deoxynucleoside 5 which is then subjected to one or more derivatization reactions.
  • the 3'- deoxynucleoside is a 3'-deoxyguanosine that is converted to the corresponding 3'-deoxy-6- chloroguanosine and coupled to a solid phase (preferably via the C 5 '-atom).
  • the chlorine atom in the heterocyclic base is replaced with a set of nucleophilic reagents (preferably primary and/or secondary amines) to generate molecular diversity.
  • the nucleosides are cleaved from the solid support and deprotected to the corresponding (library) nucleoside.
  • the sugar, the protecting groups, and the solid phase the same considerations as described for Scheme 2 above apply.
  • Coupling ofthe appropriate sugar to a particular heterocyclic base will generally follow protocols well known in the art. While it is generally preferred that in a synthetic route as depicted in Scheme 3 the leaving group is a halogen, and most preferably chloride, alternative leaving groups are also considered suitable.
  • suitable leaving groups may include Tosyl groups, Mesyl groups, etc.
  • nucleophilic reagents include all reagents that can replace a leaving group (and preferably Cl) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.). Exemplary nucleophilic reagents include RNH 2 , RR'NH, RSH, ROH, etc, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • RNH 2 , RR'NH, RSH, ROH, etc wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substitute
  • nucleophilic reagents there are numerous nucleophilic reagents commercially available, and it is contemplated that where a particular reagent is not commercially available, such contemplated reagents may be synthesized from commercially available precursors following protocols well known in the art. Further contemplated reagents are listed below in the experimental section.
  • a 3'-deoxy-6-substituted purine library (and the corresponding library compounds) may be prepared starting from 3'- deoxyguanosine (synthesis see above), wherein the keto-oxygen ofthe heterocyclic base is converted into a leaving group that is subsequently replaced in an aromatic substitution reaction to yield the corresponding 3'-deoxy-6-C-substituted purine. Further reaction ofthe 3'- deoxy-6-C-substituted purine with a set of electrophilic reagents (in which the nucleoside may or may not be coupled to a solid phase) results in the corresponding library of corresponding 3'-deoxy-6-C-substituted purines.
  • substituents include substituted alkyls, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyl, and/or substituted and unsubstituted aryls.
  • the substituent may further be modified in various manners.
  • a further reactant to modify the substituent includes dienophiles.
  • a reactant to modify the substituent particularly includes nucleophiles (e.g., RXH with X being NH, NR, S, O, or C), and where the reactive group comprises an electrophilic group, a reactant to modify the substituent particularly includes nucleophiles.
  • particularly preferred 6-substituents may have the general structure R-Y-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' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH 2 .
  • a nucleoside library may comprise a plurality of library compounds according to Formula 2 A, wherein a first compound ofthe plurality of compounds has a first set of substituents X and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X and R
  • X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;
  • R is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; or where XR together are R-Y-R', wherein
  • R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl
  • R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl
  • Y is NH, NR, S, O, or CH 2 ;
  • NH PG is a protected amino group, O PG is a protected hydroxyl group, • is a solid phase, and wherein not all ofthe substituents X and R in the first set are the same as the substituents X and R in the second set.
  • contemplated compounds may have a structure according to Formula 2B
  • R is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; or where XR together are R-Y-R', wherein R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH 2 .
  • 3'-azido-6-substituted purine nucleoside libraries and their corresponding library compounds may be synthesized as shown in Scheme 4.
  • a suitably protected 2',3'-epoxyguanosine is reacted with aN 3 " donor to the corresponding 3'-azidoguanosine, which is subsequently coupled to a solid phase (preferably via the C 5 '-atom), and in a further reaction, the amino group ofthe heterocyclic base is protected with a protecting group.
  • the keto-oxygen ofthe heterocyclic base is converted into a leaving group that is subsequently replaced by a set of nucleophiles to generate molecular diversity.
  • Deprotection and cleavage ofthe nucleosides from the solid support will then yield the 3'-azido-6-substituted purine nucleoside library compounds.
  • heterocyclic base With respect to the heterocyclic base, the sugar, the protecting groups, the solid phase, the introduction and nature ofthe substituent in the 6-position ofthe heterocyclic base the same considerations as described for Scheme 2 above apply. Furthermore, it is contemplated that while NaN 3 is the preferred N 3 " donor, numerous alternative methods of introduction of the azide group in the sugar are also contemplated and include KN 3 as the N 3 " donor.
  • contemplated libraries and library compounds also include compounds in which the 2-amino position is derivatized with a suitable reactive reagent.
  • suitable reactive reagents include electrophilic reagents, most preferably activated acids.
  • a nucleoside library may comprise a plurality of library compounds according to Formula 2C, wherein a first compound ofthe plurality of compounds has a first set of substituents X, Y, and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X, Y, and R
  • X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl
  • Y is hydrogen, C(O)R', C(NH)R', or C(S)R'
  • R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl
  • O PG is a protected OH, • is a solid phase, and wherein not all ofthe substituents X, Y, and Rin the first set are the same as the substituents X, Y, and R in the second set.
  • contemplated compounds may have a structure according to Formula 2D
  • X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;
  • Y is hydrogen, C(O)R', C(NH)R', or C(S)R';
  • R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.
  • substituted 2-thioadenosine libraries can be prepared by reacting a protected and solid phase-bound 2-amino-6-chloropurine riboside with a disulfide compound to generate the corresponding substituted 2-thio-6-chloropurine riboside.
  • the chloro group serves as a leaving group in a substitution reaction through which a second set of substituents can be introduced as depicted in Scheme 6.
  • protecting groups for the sugar may 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.
  • suitable alternative protection groups and their reactions are described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • 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). Still further, it should be appreciated that while coupling ofthe nucleoside to the solid phase is preferably via the C 5 '-atom ofthe sugar, alternative coupling are also contemplated and especially include coupling to the C 2 '- or C 3 '-atom ofthe sugar.
  • heterocyclic bases include those with at least one halogen (preferably Cl) and at least one amino group (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.
  • nucleosides e.g., 2-amino-6- chloropurine riboside
  • nucleosides may be synthesized from a commercially available precursor without undue experimentation following procedures well l ⁇ iown in the art (see e.g., "Modern Methods in Carbohydrate Synthesis” by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212)).
  • disulfide reagents are suitable for use in conjunction with the teachings presented herein.
  • contemplated disulfide reagents include R1-S-S-R1', in which Ri and Ri' may or may not be identical (and wherein R 1 and Ri' are independently 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, a 5-membered heterocycle, a 6-membered heterocycle, or a fused heterocycle).
  • disulfide reagents may be produced from oxidation ofthe corresponding thiols, and all methods of forming a disulfide from thiols are contemplated suitable herein.
  • a vast number of thiols are commercially available. However, where a particular thiol is not commercially available, it should be recognized that such thiols may be produced from commercially available precursors without undue experimentation following protocols well l ⁇ iown in the art.
  • the second set of substituents may be introduced into the heterocyclic ring at the 6-position using a wide variety of reagents.
  • particularly contemplated reagents include nucleophilic reagents, and especially suitable nucleophilic reagents include all reagents that can replace a leaving group (and preferably Cl) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.).
  • nucleophilic reagents include RNH 2 , RR*NH, RSH, ROH, R-CH 2 CH 2 NH 2 , RNH-NH 2 , etc, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • nucleoside library will include a plurality of compounds according to Formula 3, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R 2 and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R 2
  • Ri is selected from the group consisting of 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, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle;
  • X is NH, S, O, CH, CH 2 CH 2 NH, or NHNH
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted ary
  • contemplated compounds will include a compound according to Formula 3
  • A is a sugar
  • X is NH, S, O, CH, CH 2 CH 2 NH, or NHNH
  • R x is selected from the group consisting of 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, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.
  • 2-amino-6,8-disubstituted purine libraries can be prepared by partially protecting an 8-bromo- purine nucleoside, and then reacting the heterocyclic base with a tributyl-tin reagent in a C-C bond forming reaction (e.g., Heck, Stille, Suzuki reaction) to form the corresponding 8- substituted partially protected nucleoside.
  • a C-C bond forming reaction e.g., Heck, Stille, Suzuki reaction
  • the so formed 8-substituted partially protected nucleoside is then coupled to a solid phase, and the keto-oxygen in the heterocyclic base is converted to a leaving group (preferably to OTPS using TPSCl), which is in a further step replaced by a nucleophilic reagent (preferably a primary or secondary amine). Cleavage ofthe nucleoside from the solid phase and deprotection will then yield the corresponding library nucleosides.
  • a nucleophilic reagent preferably a primary or secondary amine
  • Scheme 7 Alternatively, and especially where it is desired to form an ether bond with a substituent ofthe heterocyclic base in the 6-position, a synthetic strategy as depicted in Scheme 8 may be employed.
  • a partially protected 8-bromo-purine nucleoside is reacted at the heterocyclic base with a tributyl-tin reagent in a C-C bond forming reaction (e.g., Heck, Stille, Suzuki reaction) to form the corresponding 8-substituted partially protected nucleoside.
  • a C-C bond forming reaction e.g., Heck, Stille, Suzuki reaction
  • the so formed 8-substituted partially protected nucleoside is then coupled to a solid phase, and the keto-oxygen in the heterocyclic base is replaced by an alcohol under conditions as described below in the experimental section to form the corresponding ether-bound substituent. Cleavage ofthe nucleoside from the solid phase and deprotection will then yield the corresponding library nucleosides.
  • protecting groups for the sugar may 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.
  • suitable alternative protection groups and their reactions are described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • 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).
  • coupling ofthe nucleoside to the solid phase is preferably via the 2-amino group in the heterocyclic base
  • coupling may also be performed via the sugar (e.g., via the C 2 '-, C '-, or C 5 '-atom ofthe sugar).
  • heterocyclic bases include those with at least one halogen (preferably Br) in the 8-position, a keto group in the 6-position, and at least one amino group, preferably in the 2-position (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.
  • tributyl-tin reagent is not limited to a particular tributyl-tin reagent, and in further contemplated aspects, various reagents suitable for a C-C bind formation are also contemplated, including reagents for a Heck, Stille, and/or Suzuki reaction. Further suitable reagents include Grignard reagents. Consequently, suitable 8-substituents will include an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and/or a substituted aryl. Numerous such reagents are commercially available. However, where a particular reagent is not commercially available, it is contemplated that such reagents may be produced from a precursor without undue experimentation following procedures well known in the art.
  • nucleophilic reagents include all reagents that can replace a leaving group (and preferably OTPS) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.).
  • nucleophilic reagents include RNH 2 , RR'NH, RSH, ROH, etc, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • Preferred alcohols include all primary alcohols with the general formula ROH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a • substituted alkynyl, an aryl and a substituted aryl.
  • ROH general formula
  • a nucleoside library will include a plurality of compounds according to Formula 4, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R 2 Formula 4
  • A is a protected or unprotected sugar
  • X is NH, S, O, CH, CH 2 CH 2 NH, or NHNH
  • R t is selected from the group consisting of 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, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; and wherein not
  • contemplated compounds will include a compound according to Formula 4A
  • A is a sugar
  • X is NH, S, O, CH, CH 2 CH 2 NH, or NHNH
  • Ri is selected from the group consisting of 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, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.
  • 2,8-disubstituted guanosine libraries can be prepared from a commercially available purine nucleoside analog (here: 8-bromoguanosine), which is reacted to the corresponding 8- substituted nucleoside as described above in Schemes 7, and/or 8.
  • the so formed 8-substituted nucleoside is then reacted with a suitable keto-oxygen protecting group at the heterocyclic base, and in a further step, the 2-amino group ofthe heterocyclic base is replaced with a fluorine atom via fiuorination with HF.
  • the so modified and protected 8-substituted-2- fluoronucleoside is then coupled to a solid phase (preferably via the C 5 '-atom ofthe sugar), and in a still further reaction, the fiuoro-group is replaced with a nucleophilic reagent (preferably a primary or secondary amine).
  • a nucleophilic reagent preferably a primary or secondary amine
  • sugar portion of such nucleosides is a ribofuranose
  • numerous alternative sugar portions are also contemplated, and all known sugars and sugar analogs are contemplated suitable for use herein.
  • particularly contemplated sugars and sugar analogs include substituted and unsubstituted ribofuranose, and arabinose.
  • Further suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C 2 ' and/or C 3 ' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, O-alkyl, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • the coupling ofthe purine heterocyclic base to the sugar may be in a position other than the exposition, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C 2 ' and C 3 '-position.
  • protecting groups for the sugar may 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.
  • Suitable protecting groups for the amino group in the heterocyclic base are also well known in the art and all of such known groups are contemplated suitable herein.
  • a collection of appropriate 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.
  • nucleosides may be coupled to the solid phase at any position (i.e., in the heterocyclic base as well as in the sugar), however, it is especially preferred that the coupling ofthe solid phase to the nucleoside is via the C 5 ' position in the sugar.
  • Appropriate solid phases and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling.
  • 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).
  • heterocyclic base While 8-bromoguanine is generally preferred (among other advantages: commercially available) as a heterocyclic base, it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one halogen (preferably Br) in 8-position, a keto group in 6-position, and at least one amino group, preferably in 2-position (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.
  • reagents include all reagents that can form a covalent bond with carbon atom in a Heck reaction (e.g., R-C ⁇ CH).
  • alternative reagents also include reagents suitable for a Suzuki (e.g., arylB(OH) 2 ) or Stille (e.g., arylSnBu 3 ) reaction. Reaction conditions for all of such reactions are well l ⁇ iown in the art (see e.g., Can. J. Chem. (2000), Vol.
  • reagents include R-C ⁇ CH, wherein R is alkyl, alkenyl, alkynyl, aryl, and alkaryl, all of which may further be substituted, and ArSnBu , wherein R is aryl and aralkyl, both of which may further be substituted. It is generally contemplated that almost all such reagents are commercially available.
  • nucleophilic reagents may vary considerably, and it should be recognized that all nucleophilic reagents are suitable so long as such reagents can replace the fluorine atom in the heterocyclic base.
  • especially preferred nucleophilic reagents include primary and secondary amines with the general formula RNH 2 or RR"NH, wherein R and R are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.
  • nucleophilic reagents include various thiols (e.g., RSH), alcohols (e.g., R-OH), and Grignard compounds, wherein R is defined as above for the amines. Consequently, it is contemplated that a nucleoside library may comprise a plurality of compounds according to Formula 5, wherein a first compound ofthe plurality of compounds has a first set of substituents A, Ri, R 2 , and R' 2 and wherein a second compound ofthe plurality of compounds has a second set of substituents A, R ls R 2 , and R' 2
  • Ri , R 2 , and R' 2 are independently selected from the group consisting of 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, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and wherein not all ofthe substituents A, R 1; R 2 , and R' 2 in the first set are the same as the substituents A, Ri, R 2 , and R' 2 in the second set.
  • contemplated compounds include compounds according to Formula 5
  • Ri , R 2 , and R' 2 are independently selected from the group consisting of 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, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle.
  • sugars include ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar may be in D-configuration or in L-configuration. 6-substituted Purine Libraries
  • a 6-substituted purine library can be synthesized from commercially available 6-chloropurine riboside by protecting the OH groups in the sugar and subsequent derivatization ofthe protected 6-chloropurine riboside to the corresponding protected 6-substituted purine using a nucleophilic reagent to replace the halogen (here: Cl) with a desired substituent as depicted in exemplary Scheme 10.
  • reagents include primary and secondary amines (RNH , RR"NH), alcohols (ROH), or thiols (RSH), wherein R or R" is independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid.
  • RNH , RR"NH primary and secondary amines
  • R alcohols
  • RSH thiols
  • nucleophilic reagents include CN “ , N 3 " , Grignard reagents and reagents with similar reactivity.
  • a 6-substituted purine library will comprise a plurality of compounds according to Formula 6, wherein a first compound ofthe plurality of compounds has a first set of substituents Rand X wherein a second compound ofthe plurality of compounds has a second set of substituents R and X
  • A is a protected or unprotected sugar bound to a solid phase
  • R is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid
  • X is NHNH, NHOH, S, O, NH, C(O), or a covalent bond; and wherein not all ofthe substituents Rand X in the first set are the same as the substituents Ri and R 2 in the second set.
  • a compound may have a structure according to Formula 6 (supra), wherein A is a sugar, R is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid, and X is NHNH, NHOH, S, O, NH, C(O), or a covalent bond.
  • a first nucleophilic reagent replaces the chlorine atom on the heterocyclic base to form a first product, which is then converted into a second product via a reaction with a second nucleophilic reagent. Cleavage ofthe second product from the solid phase yields the corresponding library nucleosides.
  • the first product l from Scheme 11 may be reacted in a C-C bond formation reaction (e.g., Heck, Stille, or Suzuki reaction) to form a second product, which may then be cleaved from the solid phase to yield the corresponding library nucleosides.
  • a C-C bond formation reaction e.g., Heck, Stille, or Suzuki reaction
  • a protected guanosine is reacted with an electrophile at the amino group ofthe heterocyclic base prior to coupling the protected nucleoside (preferably via C 5 '-atom ofthe sugar) to a solid phase.
  • the keto-oxygen ofthe heterocyclic base is converted into a leaving group (preferably OTIPS).
  • the so prepared compound is then derivatized in a first reaction with an alcohol to form the corresponding N-derivatized nucleoside, which is in a second reaction with a nucleophilic reagent (that replaces the leaving group) further converted to the desired solid phase-bound library nucleoside. Cleavage ofthe so formed nucleoside from the solid phase yields the corresponding library nucleosides.
  • sugar it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration. Further suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C 2 ' and/or C ' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • the coupling ofthe heterocyclic base to the sugar may be in a position other than the C ⁇ '-position, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C 2 ' and C 3 '-position.
  • protecting groups for the sugar may vary considerably, and while it is particularly contemplated that suitable protection groups include acetyl-, benzyl-, 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.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • 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).
  • a solid phase is employed in the combinatorial approach, it should also be recognized that the solid phase may also be omitted where appropriate.
  • heterocyclic bases there respect to contemplated heterocyclic bases, it should be appreciated that numerous alternative heterocyclic bases are also appropriate and suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above. It is further contemplated that many ofthe preferred and/or alternative heterocyclic bases are commercially available. However, it should be recognized that where a particular heterocyclic base is not commercially available, suitable bases can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (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).
  • Suitable substituents for the 8-position may vary considerably and may include halogens, various saturated and unsaturated hydrocarbons (which may or may not be substituted, and may include an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid), CN, esters, ethers, etc.
  • 8-substituted purine nucleosides commercially available, and all of these are considered suitable for use herein.
  • nucleosides may be prepared following protocols well known in the art (e.g., bromination with NBS and subsequent substitution ofthe bromine with desired substituent, or other strategies as described above).
  • nucleophilic reagents of Schemes 11 and 13 it is generally contemplated that all nucleophilic reagents with sufficient reactivity to replace a leaving group in the heterocyclic base are suitable for use herein.
  • particularly contemplated reagents include primary and secondary amines (RNH 2 , RR"NH), alcohols (ROH), or thiols (RSH), wherein R or R" is independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid.
  • nucleophilic reagents include CN “ , N " , Grignard reagents and reagents with similar reactivity.
  • all C-C bond forming reagents are generally considered appropriate as reagents for a synthesis according to Scheme 12.
  • especially preferred reagents include reagents suitable for a Heck reaction (e.g., R- CH ⁇ CH), a Stille reaction (e.g., R-Sn), and a Suzuki reaction (e.g., R-B(OH) 2 ).
  • contemplated alcohols of Scheme 13 particularly include primary alcohols with a formula ROH.
  • secondary and even tertiary alcohols are also contemplated and have the formulae RR'CHOH and RR'R"COH, respectively, wherein R, R', and R" are independently alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, or a heterocycle.
  • a 2,6-disubstituted adenine library will comprise a plurality of compounds according to Formula 7, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Y and Z, and wherein a second compound of the plurality of compounds has a second set of substituents A, X, Y and Z
  • A is a protected or unprotected sugar bound to a solid phase
  • X is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid
  • Y is NRR', SR, 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, or OR;
  • Z is NRR', SR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl
  • a compound may have a structure according to Formula 7 (supra), wherein A is a sugar; X is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid; Y is NRR', SR, OR, 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, or an unsubstituted alkaryl; Z is NRR', SR, OR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted
  • 6,8-disubstituted adenosine libraries can be synthesized, and exemplary synthetic schemes are depicted in Schemes 14-17 below.
  • the introduction ofthe substituent in the 8-position is preferably performed via the corresponding 8-bromoadenosine as shown in Scheme 14.
  • the sugar portion of commercially available 8-bromoadenosine is first protected with suitable protecting groups, and the so protected 8-bromoadenosine is then subjected to a Suzuki reaction to yield the corresponding protected 8-substituted adenosine.
  • 8- bromoadenosine may be subjected to a Stille-type reaction to yield the corresponding 8- substituted adenosine.
  • the so prepared 8-substituted adenosine may then be coupled to a solid phase, preferably via the C5'-atom ofthe sugar, as depicted in Scheme 15 below. Further derivatization may then be achieved by reacting the 6-amino group ofthe heterocyclic base with an alcohol to form the corresponding 6,8-disubstituted adenosine, which may then be cleaved from the solid support thereby yielding the desired library nucleoside.
  • the 8-substituent may be introduced as shown in Scheme 16 below.
  • 8-bromoadenosine is reacted with an aromatic thiol (preferably toluene thiol) to form the corresponding 8-S-toluene nucleoside.
  • the so prepared 8-S-toluene nucleoside is then protected on the sugar moiety and the toluene group is replaced with a cyano group that is transformed in several steps to the corresponding 8-methylcarboxylic acid ester.
  • the 8- methylcarboxylic acid ester nucleoside is then coupled to a solid phase and derivatized at the 6-amino group with an alcohol.
  • the derivatized nucleoside is then reacted with amines to form the desired 6,8-substituted adenosine library nucleosides.
  • the 8-substituent in the heterocyclic base is not bound to the heterocyclic base via a carbon atom
  • an exemplary synthetic route as depicted in Scheme 17 below may be employed.
  • the bromine atom of 8-bromoadenosine is replaced by reacting the nucleoside with a nucleophilic reagent (preferably an alcohol or a thiol) to form the corresponding 8-substituted adenosine, which is then suitably protected at the sugar moiety and the 6-amino group before coupling the protected nucleoside to a solid phase.
  • a nucleophilic reagent preferably an alcohol or a thiol
  • the nucleoside is then further derivatized by reacting the 6-amino group with an alcohol to the corresponding 6,8-disubstituted library nucleoside. Deprotection and cleavage from the solid phase will then yield the desired library nucleoside.
  • R aliphatic or aromatic
  • RI aliphatic or aromatic
  • contemplated reagents include R-C ⁇ C-R', R-C ⁇ CH, R-SnBu 3 , and R-B(OH) 2 , wherein R and R' are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or a substituted aryl.
  • preferred alcohols for derivatization ofthe 6- amino group as depicted in Schemes 15, 16, and 17 include all primary alcohols with the general formula ROH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • ROH general formula
  • R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • RR'CHOH secondary alcohol
  • nucleophilic reagents for derivatization ofthe 8 -methyl carboxylic acid ester substituent may vary considerably, and it should be recognized that all nucleophilic reagents are suitable so long as such reagents can form a covalent bond with the 8-methyl carboxylic acid ester substituent.
  • nucleophilic reagents include primary and secondary amines with the general formula RNH 2 or RR"NH, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.
  • R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.
  • RSH thiols
  • alcohols e.g., R-OH
  • Grignard compounds wherein R is defined as above for the amines.
  • a 6,8-disubstituted adenosine library will comprise a plurality of compounds according to Formula 8, wherein a first compound ofthe plurality of compounds has a first set of substituents A, R ls R 2 , and R 3 , wherein a second compound ofthe plurality of compounds has a second set of substituents A, Ri, R 2 , and R 3
  • A is a protected or unprotected sugar covalently bound to a solid phase
  • R t is R, OR, SR, or C(O)NR 2 R 3
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; and wherein not all ofthe substituents R l5 R 2 , and R 3 in the first set are the same as the substituents R 1; R 2 , and R 3 in the second set.
  • contemplated compounds may include compounds having a structure according to Formula 8 (supra) wherein A is a sugar; Ri is R, OR, SR, or C(O)NR R 3 ; R 2 and R 3 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; and wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • A is a sugar
  • Ri is R, OR, SR, or C(O)NR R 3
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkeny
  • Preferred libraries and library compounds include those in which the sugar is selected from the group consisting of a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in a D-configuration or in an L- configuration.
  • nucleosides that have numerous biological activities, and especially contemplated biological activities include in vitro and in vivo inhibition of DNA and/or RNA polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agents, antineoplastic agents, or immunomodulatory agents. Still further, it is contemplated that 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 (HIV), 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 other vehicle, which for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill 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 puposes, including reduction of toxicity, increasing the organ- or target cell specificity, etc.
  • acylated (acetylated or other) derivatives, pyridine esters and various salt forms ofthe present compounds are preferred.
  • 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.
  • 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 of the present invention or a functional derivative thereof and at least one other pharmaceutically active ingredient.
  • the active ingredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this may occur simultaneously or separately in any order.
  • the amounts 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.
  • sequence of derivatization or derivatizations may be altered where appropriate.
  • additional reagents not indicated in the exemplary schemes may be included to obtain a particular nucleoside or nucleoside library.
  • one or more reactions may be performed on solid support where no solid support is indicated in the schemes described below (or vice versa).
  • synthesis of contemplated compounds and libraries preferably employs solid phase combinatorial strategies, it should be appreciated that numerous alternative synthetic strategies, including solution phase and general/medicinal chemistry strategies are also suitable for synthesis of contemplated compounds and libraries.
  • Compound 2 Compound 1 (2.58 g, 10 mmol) was taken into anhydrous methanol (100 ml) and to this was added sodium methoxide (32 ml). This reaction mixture was heated at 60 °C till it gave a clear solution and then BOC protected amino acid ester (amino acid can have side chain protecting groups cleavable by acid) or any other ester was added and kept stirring for 24 hrs at 60 °C. The reaction was brought to neutral pH by adding Amberlite CG50 resin, filtered and then concentrated to dryness. This was further purified by silica gel column chromatography.
  • Resin 5 A mixture of resin 4 (0.1 mmol), anhydrous DMF (2 ml), t-butyldimthylsilyl chloride (5 mmol) and imidazole (10 mmol) was shaken at room temperature for 60 hrs. The resin was filtered and successively washed with DMF, MeOH and CH 2 C1 2 .
  • Resin 6 To a mixture of resin 5 (0.1 mmol) and anhydrous CH 2 C1 2 (2 ml) were added Triisopropylbenzenesulfonyl chloride (0.3 g 1 mmol), DMAP (0.012 gm, 0.1 mmol) and TEA (0.55 ml, 4 mmol). The reaction mixture was shaken at room temperature for 24 hrs. The resin was filtered and washed with DMF, methanol and CH 2 C1 2 successively.
  • guanosine (8) 100 g was suspended in 1000 ml of anhydrous methanol, and 168 ml of N,N-dimethylformamide dimethyl acetal was added under argon. The suspension was stirred for 4 days at room temperature. The resulting white precipitates were filtered and washed with cold methanol, and dried under reduced pressure to afford pure product 9.
  • the water phase was extracted with chloroform.
  • the combined chloroform solution was dried over anhydrous sodium sulfate, filtered, and concentrated to a small volume.
  • the concentrated solution was added dropwise to 2000 ml of hexanes with vigorous stirring. The solid was filtered, washed with hexanes and dried in vacuo to provide pure product 11.
  • 3'-Deoxy-5'-O-tritylguanosine (12) A solution of 2',3'-anhydro-5'-O-trityl-N2- (dimethylamino)methyleneguanosine (11) (5.6 g) in 100 ml of dry THF was degassed under argon for 30 min and 100 ml of super-hydride (IM in THF) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature under argon atmosphere. 5% Acetic acid aqueous solution (200 ml) was added dropwise (at the beginning of addition, it must be very slow, drop by drop). The argon or air was passed through the reaction mixture for 1-2 hours. The mixture was concentrated in vacuo to half volume and cooled at 0 °C. The white precipitate was filtered, washed with water and dried over phosphorus pentaoxide in vacuo at 70-80 °C to give product 12.
  • IM in THF super-hydride
  • 2 ⁇ N 2 -Diacetyl-3'-deoxyguanosine (15): 2',N 2 ⁇ O-Diacetyl-3'-deoxy-5'-O- tritylguanosine (14) (10 g) was dissolved in 150 ml of hexafluoroisopropanol in a high- pressure reaction vessel. The reaction mixture was stirred at 80 °C for 3 days and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using chloroform-methanol (15:1) as an eluent to give pure product 15 as a foam.
  • 6-Substituted Alcohols and phenols Benzyl alcohol, 4-Chlorophenol: A mixture of 2' ,N 2 -diacetyl-3 ' -deoxy-5 ' -O-(4-methoxytritylresin)-O 6 -(2,4,6- triisopropylbenzenesulfonyl)guanosine (17) (50 mg), 0.75 ml of IM alcohol or phenol in dichloroethane, and 0.4 ml of IM DABCO in dichloroethane was shaken overnight at room temperature. After 0.3 ml of IM DBU in dichloroethane was added, the resulting mixture was shaken at 70 °C for 2 days. The resin was filtered and washed three times with methanol and dichloromethane. Then, the resin was treated with 1.5% TFA in dichloromethane to give the corresponding compound.
  • 6-Substituted tbio-alcohols and thio-phenols Cyclohexyl mercaptan, 4- chlorothiophenol: A mixture of 2',N 2 -diacetyl-3'-dDeoxy-5'-O-(4-methoxytritylresin)-O 6 - (2,4,6-triisopropylbenzenesulfonyl)guanosine (17), (50 mg) 0.75 ml of IM thio-alcohols and thio-phenols in dichloroethane, and 0.75 ml of IM N-methyl-2-pyrrolidine in dichloroethane was shaken at 70 °C for 2 days. The resin was filtered and washed tliree times with methanol and dichloromethane. Then, the resin was treated with 1.5% TFA in dichloromethane to give the corresponding compounds.
  • DIPEA IM diisopropylethylamine
  • the resin was filtered, washed three times with methanol and dichloromethane. After 1.5 ml of 2M dimethylamine in methanol was added, the mixture was shaken at 70 °C for 24 hours. The resin was filtered and washed three times with methanol and dichloromethane. The resin was treated with 1.5% TFA in dichloromethane to give the corresponding compound.
  • 9,N 2 -Diacetylguanine (26) To a suspension of guanine (25) (15.1 g, 0.1 mole) in 150 ml of anhydrous DMF was added acetic anhydride (30.6 g, 0.3 mole) at room temperature. The mixture was heated at 160 °C for 2 hours to yield a clear solution. The reaction mixture was cooled to 0 °C, and the resulting crystalline was filtered and washed with ethanol to give 20.8 g of product 26 as a white solid.
  • Toluene-4-sulfonyl chloride (3.8 g, 20 mmol) was added to a suspension of 2'-O- acetyl-3' -deoxy-5 '-O-tritylguanosine (13) (5.5 g, 10 mmol), triethylamine (2.87 ml, 20 mmol), and DMAP (244 mg, 2 mmol) in 150 ml of anhydrous dichloromethane at 0 °C under argon. The reaction mixture was stirred at room temperature overnight. A clear brown solution was obtained. The reaction mixture was diluted with dichloromethane and washed successively with water and brine.
  • Tributyl(vinyl)tin (1.46 ml, 5 mmol) was added and the mixture was heated under reflux for 4 hours. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on a silica gel column using chloroform-methanol (50:1) as an eluent to give pure product 43 as a yellow foam.
  • 2-Amino-6-substituted-ethyl-9-(2-O-acetyl-5-O-trityl-3-deoxy- ⁇ -D- ribofuranosyl)purine (49) (solution phase approach): 6-(2-(amino acid ester)ethyl): L-Cystein ethyl ester, DL-Homocystein, H-Ser-Ome: To a solution of 2-amino-6-vinyl-9-(2-O-acetyl-3- deoxy-5-O-trityl- ⁇ -D-ribofuranosyl)purine (43) (1 equiv) in chloroform-methanol (50:1) or ethanol was added amino acid ester (1 equiv) at room temperature.
  • 2-Amino-6-vinyl-9-(2-O-ace1 l-3-deoxy- ⁇ -D-ribofuranosyl)purine (44) A solution of 2-amino-6-vinyl-9-(2-O-ace1yl-3-deoxy-5-O-tri1yl- ⁇ -D-ribofuranosyl)purine (43) in a 1 :1 mixture of formic acid and diethyl ether was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo at room temperature and the residue was chromatographed on a silica gel column using chloroform-methanol (30:l)as an eluent to give the corresponding pure product 44.
  • the resin was then filtered, and washed with DMF (3 x 15 mL), MeOH (3 x 15 mL), and CH 2 C1 2 (3 x 15 mL). The washed resin was dried in vacuo at 45°C overnight to yield 0.17 g (63%) of product 57.
  • 2-Amino-6-(N-alkyl)-8-phenylpurine riboside 60: To each reaction vessel containing resin nucleoside 57 (70 mg) was added a solution of triethylamine (0.10 mL) and 4-dimethylaminopyridine (9 mg) in anhydrous CH 2 C1 2 (1.0 mL). To the mixture was added a solution of triisopropylbenzenesulfonyl chloride (0.10 g) in anhydrous CH 2 C1 2 (0.5 mL). After being shaken at room temperature for 24 h, the mixture was filtered.
  • 2-Amino-6-alkoxy-8-phenylpurine riboside 64.
  • nucleoside resin 62 70 mg
  • a 1.5 M solution of appropriate alcohols in anhydrous THF 0.4 mL
  • the reaction vessel was cooled to 0 °C.
  • a solution of triphenylphosphme and diethyl azodicarboxylate 1.5 mL, freshly prepared from 75 mL of 1.0 M Ph 3 P in anhydrous THF and 30 mL of 2.0 M DEAD in anhydrous THF was added.
  • the mixture was shaken at room temperature for 36 h.
  • the resin was filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH 2 C1 2 (3 x 1 mL) to yield resin nucleoside 63.
  • DMF 3 x 1 mL
  • MeOH 3 x 1 mL
  • CH 2 C1 2 3 x 1 mL
  • the residue was purified by flash chromatography on a silica gel column using CH 2 Cl 2 :EtOAc (75:25) as an eluent to give 2',3',5'-tri-O-acetyl-2-amino-6-[2-(4- nitrophenyl)ethoxy]-8-phenylpurine riboside as a yellow solid.
  • the product was dissolved in methanolic ammonia (50 mL, saturated) at 0 °C and the solution was stirred at room temperature in a sealed bomb for 15 h. The bomb was cooled to 0°C before opening to the air and the mixture was concentrated.
  • the residue was purified by flash chromatography on a silica gel column using CH 2 Cl 2 :MeOH (90:10) as an eluent providing 3.1 g (66% for 2 steps) of 65 as a pale foam.
  • 2-(N-Alkyl)-8-phenylguanosine library (68): To each reaction vessel containing 70 mg of resin nucleoside 67 was added a 0.5 M solution of appropriate amines in anhydrous 1- methyl-2-pyrrolidinone (1.6 mL). The vessels were shaken at 60 °C for 4 hrs and then shaken at 80 °C for 20 h to make animation complete. The vessels were cooled down, filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH 2 C1 2 (3 x 1 mL).
  • the vessels were shaken at 50 °C for 24 h and the solution was pushed down into the receiving vessels while keeping the temperature at 50 °C.
  • the reaction vessels were washed with a 1 : 1 mixture of MeOH:CH 2 Cl 2 (1.5 mL).
  • the combined solution (3 mL) was concentrated to yield product 68.
  • 6-Chloro-2-iodoadenosine (75) To a suspension of 74 (20 g, 66.2 mmol), Cul (13.4 g, 87 mmol), CH 2 I 2 (53.4 mL, 66.4 mmol) and Iodine (17 g, 66.6 mmol) in THF (500 mL) was added isoamylnitrite (30 mL, 216 mmol) at room temperature. The reaction mixture was heated to reflux for 3 h, cooled to room temperature and filtered. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column to yield 14.0 g (39%) of product 75.
  • 5'-Resin 76 A solution of 75 (20.0 g, 48.5 mmol) and 2,6-lutidine (7.5 mL) in anhydrous THF (145 mL) was added to a reaction vessel containing MMTCl-resin (17.95 g, 32.3 mmol). The reaction mixture was shaken at room temperature for 64 h. The reaction mixture was quenched by the addition of methanol (10 mL), followed by shaking for 30 min. The suspension was then filtered, and washed with DMF (3x30 mL), MeOH (3x30 mL), and CH 2 C1 2 (3x30 mL). The washed resin was dried in vacuo at 45 °C overnight to yield 27.7 g (80%) of product 76.
  • 82b and 82c were prepared in the same fashion as described for 82a from 81b and 81c, respectively.
  • Guanosine (8) (25 g, 88.33 mmol, dried at 110 °C, 24 h, high vacuum, with P 2 O 5 ) was suspended in DMF (500 ml) and treated with imidazole (48.2 g, 706.5 mmol) and TBDMSCl (53.2 g, 353.35 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. MeOH was added and the mixture was stirred at room temperature for 20 min. The mixture was concentrated and the resulting syrup was partitioned between EtOAc and aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water, dried, and concentrated to give a syrup, which crystallized (quantitative) upon overnight drying in vacuo.
  • 2-N-Dichloroacetyl-2',3'-O-di-TBDMS-guanosine (85) To a solution of 2',3',5'-O- tri-TBDMS-guanosine (84) (5.0 g, 7.95 mmol) in 1,4-dioxane (30 ml) was added dichloroacetic anhydride (5 ml), and the resulting mixture was stirred at 150 °C for 15 min. The yellow solution was cooled down to room temperature and poured into cold water. The aqueous solution was extracted with DCM (3x50 ml).
  • Attachment 85 on solid support To a mixture of 2-N-dichloroacetyl-2', 3'-O-di- TBDMS-guanosine (85) (900 mg, 1.45 mmol) and DMAP (9 mg) in pyridine (4.3 ml) was added mono-methoxytrityl chloride styrene resin (Nova, 0.537 g, 1.80 mmol/g, 0.967 mmol). The mixture was shaken at room temperature for 48 h.
  • the resin was filtered, washed with pyridine (4x5 ml) and ethyl ether (4x5 ml), and dried in Vacuo in the presence of KOH at room temperature for 4 h to give a brown-yellow resin 86 (1.0 g, 82%).
  • Solid-phase synthesis of 2, 6-disubstituted purine nucleoside library 90 Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.05 mmol ofthe MMT-styrene resin 87 bound nucleoside per well served as the scaffold. Twelve amines (10 equiv) in column 1-12 and eight alcohols (10 equiv) in rows A-H were used for the construction ofthe library as follows. The MMT- styrene resin bound nucleoside (3.2 g, 1.5 mmol/g) was partitioned equally into a 96-well polyethylene microtiter plate.
  • the plate was shalcen at 50 °C for 16 h.
  • the resin was washed with DMF (10 ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml).
  • a solution of methylamine and TBAF in THF (both 1 M) was added to all the wells (10 equiv each).
  • the plate was shalcen at 50 °C for 4 h.
  • the resin was washed liberally with DMF, DCM, MeOH and DCM.
  • the products were cleaved from the resin by 1% TFA in DCM (2 x 600 ⁇ l) and washed into a second 96-well plate.
  • the resins were rinsed with DCM (200 ⁇ l) and MeOH (200 ⁇ l).
  • the combined solution was concentrated under reduced pressure to provide library 90.
  • 8-(Hex-l-ynyl)adenosine (92a) General Procedure (Heck). A solution of 8-bromo adenosine (91) (8.00 g, 23.1 mmol), triphenylphosphme (303 mg, 1.16 mmol), Cul (220 mg, 1.16 mmol) in dry DMF (200 mL) was purged with argon for 30 min.
  • 8-(4-Phenyl-butyn)-l-yladenosine (92 ) This compound was prepared in the same fashion as described for 92a, except that phenyl but-3-yne was used instead of 1-hexyne.
  • Tins compound was prepared in the same fashion as described for 92n, except that 2-(tributylstannyl)thiophene was used instead of 2- (tributylstannyl)furan.
  • the resin was washed with DMF (4x3.0 mL), CH 2 C1 2 (3x3.0 mL), MeOH (3x3.0 mL) and CH 2 C1 2 (1x3.0 mL). The resin was then dried yielding 100a.
  • N 6 -Rr8-(Hexyn-l-yl)adenosine (102a).
  • TFA 3.5 mL, 1.5% in DCE
  • the reaction mixture was shalcen at room temperature for 5 min and filtered.
  • the resin was rinsed with CH 2 Cl 2 :MeOH (1:1, 0.5 mL).
  • the filtrate was concentrated, dissolved in methanolic ammonia:CH 2 Cl 2 :MeOH (1 :6:6, 5 mL) and concentrated again to dryness to yield 102a.
  • 8-(4-Methylphenyl)thioadenosine (103).
  • 8-Bromoadenosine (91) 70 g, 202 mmol
  • p-thiocresol 9.3 g, 240 mmol
  • triethylamine 60 ml, 400 mmol
  • the reaction mixture was refluxed overnight. After cooling the resulted yellow crystalline material was filtered, washed thoroughly with methanol and dried to provide 73 g (93%) of product 103.
  • 8-Carbonylimidomethoxyadenosine (106). 8-(4-Methylphenyl) sulphonyl -2',3',5'-tri- O-acetyladenosine (105) (73 g, 133 mmol) and sodium cyanide (10 g, 200 mmol) were dissolved in DMF and stirred at room temperature for 4.5 h. The reaction mixture was neutralized with IN HCl and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO 4 and concentrated. The residue (31.5 g crude) was dissolved in anhydrous methanol (200 ml) and 2.5 g of sodium methoxide was added. After stirring at room temperature overnight, the precipitate was filtered and washed thoroughly with methanol to give 31.5 g of product 106.
  • 8-Carbonylmethoxyadenosine (107).
  • a stirred mixture of 8- carbonylimidomethoxyadenosine (106) (30g, 92mmol) in methanol (400ml) and water (IL) was cooled to 0 °C. 1 N HCl was added into the reaction mixture. After stirring at 0 °C for 2 hours, the reaction mixture was neutralized with sodium bicarbonate solution. The precipitate thus obtained was filtered and washed thoroughly with ice cold water and dried to give 21 g (70%) of product 107.
  • Tetrabutylammoniumflouride (IM solution, 100 ml) was added slowly into the reaction mixture. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was purified by flash chromatography on a silica gel column to 18.5 g (95%) of pure product 108.
  • Resin 109 A mixture of 2',3'-O-acetyl-6-N-acetyl-8-carbonylmethoxyadenosine (108) (24 g, 53.2 mmol), anhydrous pyridine (120 ml) and MMTrCl resin (23.5 g, 41.63 mmol) was shaken at room temperature for 36 hours. The mixture was treated with 30 ml of methanol and left for 30 minutes. The resin was filtered off and washed thoroughly with 3X100ml MeOH, 3X100 ml CH 2 C1 2 , 3X100 ml DMF, 3XmeOH to provide 35.5 g of resin 109 after being dried for two days at 50 °C in the oven.
  • Resin 110 (Mitsunobu reaction). To each sealed reaction vessel containing ⁇ 50 mg ( ⁇ 0.045-0.05 mmol) ofthe loaded resin 109 was added 0.4 mL of 1.5 M alcohols in anhydrous THF. The reaction vessel were cooled to 0 °C (for ACT synthesizer, -10 °C was recommended since heat transfer between the reaction block and the cooling block is not very efficient). After keeping at -10 °C for 15 min, 1.5 mL of Ph 3 P/DEAD solution (freshly prepared from 75 mL of 1.0 M Ph 3 P in anhydrous THF and 30 mL of 2.0 M DEAD in anhydrous THF) was added. The reaction vessels were shalcen at room temperature for 30-36 h and washed with DMF (3x), with MeOH (3X), and with DCM (3x).
  • Resin 111 1.7 mL of 2.0 M amines in DMF was added to each reaction vessel and the reaction vessels were shalcen at room temperature for 16 h for small or reactive primary amines, or at 65 °C for 24 h for large primary or reactive secondary amines. The resins were washed as described above.
  • the vessels were shalcen at room temperature for 5 min and 0.5 mL of MeOH was added. The vessels were shaken for 5 min again. 150 mg basic resin (Amberlite IRA-93, supplied by ICN, washed with MeOH) was added to each vessel, which was then shaken for 5 min. The solutions were pushed into the receiving vials. The reaction vessels were washed with 0.5 mL of MeOH/DCM (1:1). Evaporation ofthe solvent provided library 112.
  • Resin 118 2',3'-O-Diacetyl-6-N-acetyl-8-S/O-allcyl/aryl-adenosine (117) (6 mmol) was dissolved in dry pyridine (20 ml) and MMTrCl resin (5mmol) was added. The mixture was shalcen well at room temperature for 36 hours. The mixture was treated with 10 ml methanol and left for 30 minutes. Resin was filtered off and washed thoroughly with 3X100ml MeOH, 3X100ml CH 2 C1 2 , 3X100ml DMF, 3XMeOH. The resin 118 was dried for two days at 50 °C in the oven.
  • General Procedure for the Synthesis of Library 119 2',3'-O-Diacetyl-6-N-acetyl-8-S/O-allcyl/aryl-adenosine (117) (6 mmol) was dissolved in dry pyridine (20 ml) and MMTrCl

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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. Dans des modes préférés de réalisation, l'utilisation de nucléosides couplés en phase solide au cours d'une série de deux réactions de modification au moins permet d'assurer la diversité des banques. Les banques et composés étudiés comprennent diverses purines 2-C-substituées, purines 3-désoxy/aza-6-substituées, 2-thioadénosines substituées, purines 2-amino-6,8- disubstituées, guanosines 2,8-disubstituées, purines 6-substituées, adénosines 2,6- disubstituées, et adénosines 6,8- disubstituées. Les composés particulièrement préférés comprennent des analogues de nucléoside obtenus à l'aide des banques étudiées ; ceux-ci pouvant servir à traiter divers états pathologiques, en particulier les infections virales et les maladies néoplasiques.
PCT/US2002/040414 2001-12-17 2002-12-17 Banques de nucleosides purine et composes substitues par methodes combinatoires en phase solide WO2003051881A1 (fr)

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US7105499B2 (en) 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
WO2011150512A1 (fr) * 2010-05-31 2011-12-08 Alphora Research Inc. Procédé de synthèse de carbonucléoside et des intermédiaires y participant
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
US10138507B2 (en) 2013-03-15 2018-11-27 Modernatx, Inc. Manufacturing methods for production of RNA transcripts
US10286086B2 (en) 2014-06-19 2019-05-14 Modernatx, Inc. Alternative nucleic acid molecules and uses thereof
US10385088B2 (en) 2013-10-02 2019-08-20 Modernatx, Inc. Polynucleotide molecules and uses thereof
US10407683B2 (en) 2014-07-16 2019-09-10 Modernatx, Inc. Circular polynucleotides
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
WO2019221024A1 (fr) * 2018-05-14 2019-11-21 国立大学法人 宮崎大学 Dérivé de guanosine et son procédé de production
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US10858647B2 (en) 2013-03-15 2020-12-08 Modernatx, Inc. Removal of DNA fragments in mRNA production process
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US11027025B2 (en) 2013-07-11 2021-06-08 Modernatx, Inc. Compositions comprising synthetic polynucleotides encoding CRISPR related proteins and synthetic sgRNAs and methods of use
US11377470B2 (en) 2013-03-15 2022-07-05 Modernatx, Inc. Ribonucleic acid purification
US11434486B2 (en) 2015-09-17 2022-09-06 Modernatx, Inc. Polynucleotides containing a morpholino linker
WO2022232810A1 (fr) * 2021-04-28 2022-11-03 Astrocyte Pharmaceuticals, Inc. Nucléosides de purine, leurs intermédiaires et leurs procédés de préparation
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof
US12109274B2 (en) 2015-09-17 2024-10-08 Modernatx, Inc. Polynucleotides containing a stabilizing tail region

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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
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
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
CN102958931A (zh) * 2010-05-31 2013-03-06 阿方拉研究股份有限公司 碳环核苷和其中使用的中间体的合成方法
CN102958931B (zh) * 2010-05-31 2016-04-06 阿方拉研究股份有限公司 碳环核苷和其中使用的中间体的合成方法
WO2011150512A1 (fr) * 2010-05-31 2011-12-08 Alphora Research Inc. Procédé de synthèse de carbonucléoside et des intermédiaires y participant
US9403864B2 (en) 2010-05-31 2016-08-02 Alphora Research Inc. Process for the synthesis of carbonucleoside and intermediates for use therein
US11911474B2 (en) 2011-03-31 2024-02-27 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US10898574B2 (en) 2011-03-31 2021-01-26 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
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
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
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
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
US11845772B2 (en) 2013-03-15 2023-12-19 Modernatx, Inc. Ribonucleic acid purification
US10138507B2 (en) 2013-03-15 2018-11-27 Modernatx, Inc. Manufacturing methods for production of RNA transcripts
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US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
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US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10407683B2 (en) 2014-07-16 2019-09-10 Modernatx, Inc. Circular polynucleotides
US11434486B2 (en) 2015-09-17 2022-09-06 Modernatx, Inc. Polynucleotides containing a morpholino linker
US12071620B2 (en) 2015-09-17 2024-08-27 Modernatx, Inc. Polynucleotides containing a morpholino linker
US12109274B2 (en) 2015-09-17 2024-10-08 Modernatx, Inc. Polynucleotides containing a stabilizing tail region
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof
JPWO2019221024A1 (ja) * 2018-05-14 2021-07-29 国立大学法人 宮崎大学 グアノシン誘導体及びその製造法
WO2019221024A1 (fr) * 2018-05-14 2019-11-21 国立大学法人 宮崎大学 Dérivé de guanosine et son procédé de production
WO2022232810A1 (fr) * 2021-04-28 2022-11-03 Astrocyte Pharmaceuticals, Inc. Nucléosides de purine, leurs intermédiaires et leurs procédés de préparation

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