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WO2003052053A2 - Bibliotheques nucleosidiques et composes obtenus au moyen de strategies combinatoires mcc realisees sur support solide - Google Patents

Bibliotheques nucleosidiques et composes obtenus au moyen de strategies combinatoires mcc realisees sur support solide Download PDF

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WO2003052053A2
WO2003052053A2 PCT/US2002/034025 US0234025W WO03052053A2 WO 2003052053 A2 WO2003052053 A2 WO 2003052053A2 US 0234025 W US0234025 W US 0234025W WO 03052053 A2 WO03052053 A2 WO 03052053A2
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substituted
unsubstituted
alkenyl
alkynyl
alkyl
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WO2003052053A3 (fr
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Zhi Hong
Frank Rong
Haoyun An
Weijian Zhang
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Ribapharm Inc.
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Publication of WO2003052053A3 publication Critical patent/WO2003052053A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
    • 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
    • C07H19/052—Imidazole 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
    • C07H19/056—Triazole or tetrazole 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
    • C07H19/06—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
    • 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
    • C07H19/22—Pteridine 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
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • C—CHEMISTRY; METALLURGY
    • 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
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support

Definitions

  • the field of the 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.
  • nucleoside analogue triphosphates are a very potent, competitive inhibitor of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
  • anti-HIV nucleoside analogues fall into this category, including 3'-C-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'- didehydro-2',3'-dideoxythymidine.
  • nucleoside analogues can also act in other ways, for example, causing apoptosis of cancer cells and/or modulating immune systems.
  • nucleoside antimetabolites a number of nucleoside analogues that show very potent anticancer and antiviral activities act through still other mechanisms.
  • Some well-known nucleoside anticancer drugs are thymidylate synthase inhibitors such as 5-fluorouridine, and adenosine deaminase inhibitors such as 2-chloroadenosine.
  • a well-studied anticancer compound, neplanocin A is an inhibitor of S-adenosylhomocysteine hydrolase, which shows potent anticancer and antiviral activities.
  • nucleoside analogues that can inhibit tumor growth or viral infections are also toxic to normal mammalian cells, primarily because these nucleoside analogues lack adequate selectivity between the normal cells and the virus-infected host cells or cancer cells. For this reason many otherwise promising nucleoside analogues fail to become therapeutics in treatment of various diseases.
  • nucleosides, nucleotides, and their analogs could be made through a combinatorial chemistry approach, a large number of such compounds could be synthesized within months instead of decades, and large libraries could be developed.
  • nucleoside analogues were usually designed as potential inhibitors of DNA or RNA polymerases and several other enzymes and receptors, including inosine monophosphate dehydrogenase, protein kinases, and adenosine receptors. If a vast number of diversified nucleoside analogues could be created, their use may be far beyond these previously recognized biological targets, which would open a new era for the use of nucleoside analogues as human therapeutics.
  • nucleoside analogues contain a sugar moiety and a nucleoside base, which are linked together through a glycosidic bond.
  • the formation of the glycosidic bond can be achieved through a few types of condensation reactions.
  • most of the reactions do not give a good yield of desired products, which may not be suitable to a 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.
  • many researchers focused their attention to areas in pharmaceutical chemistry that appear to present an easier access to potential therapeutic molecules and there seems to be a lack of methods for generating libraries of nucleosides and nucleotides using solid phase synthesis.
  • nucleoside analogs known in the art, all or almost all of them suffer from various disadvantages.
  • nucleoside molecules may be prepared following known procedures, combinatorial approaches to nucleoside libraries have not been successful. Therefore, there is still a need to provide new nucleosides and nucleoside analogs and methods for generation of libraries for same.
  • the present invention is directed to libraries comprising nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and compounds within such libraries.
  • the libraries are prepared using solid phase combinatorial strategies, in which each of the library compounds comprises a heterocyclic base covalently bound to a sugar, and wherein the heterocyclic base is formed by a multiple component condensation.
  • contemplated libraries (and compounds within the libraries) are prepared using solid phase combinatorial strategies, in which a library has at least two library compounds with each of the library compounds having a substituent covalently bound to a sugar, wherein the substituent is formed by a multiple component condensation.
  • a library has at least two library compounds with each of the library compounds having a substituent covalently bound to a sugar, wherein the substituent is formed by a multiple component condensation.
  • individual, or a group of selected nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs may also be synthesized in a classical solution based synthesis (i. e. , without library generation).
  • preferred heterocyclic bases comprise an imidazole, an imidazoline, a thiazolidine, a benzodiazepine, or a dihydropyrimidine, which may be l'-N-glycosidically, l'-C-glycosidically, 3'-N-glycosidically, or 3'-C- glycosidically bound to the sugar portion, and in further preferred aspects of contemplated sugars especially include a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D-configuration or L-configuration.
  • contemplated libraries will comprise ribofuranosylimidazole nucleosides according to Formula 1 or Formula 1 A
  • A, Ri, R 2 , and R 3 are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 1 or 1 A wherein A Ri, R 2 , and R 3 are also defined as in the respective portions of the detailed description below.
  • the bond in the N-A covalent bond in particularly preferred compounds couples the nitrogen atom of the N-A bond to a Ci', a C 2 ', or a C 3 ' atom of the sugar, or a to carbon atom of R
  • contemplated libraries will comprise ribofuranosyl benzodiazepine nucleosides according to Formula 2: Formula 2
  • A, Ri, R 2 , and R are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 2 wherein A, Ri, R 2 , and R 3 are also defined as in the respective portions of the detailed description below. It is particularly preferred that in such compounds the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C 2 ' atom of the sugar, a C 3 ' atom of the sugar, and a carbon atom of R
  • contemplated libraries will comprise 3',2',5',r-imidazole substituted nucleosides according to Formula 3
  • contemplated libraries will comprise dihydropyrimidine nucleosides according to Formula 4 or Formula 4A
  • nucleosides derived from such libraries will have a corresponding structure according to Formula A, wherein A, E, X, Ri, R 2 , and R 3 are also defined as in the respective portions of the detailed description below. It is still further preferred that in such compounds the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C 2 ' atom of the sugar, a C 3 ' atom of the sugar, a C 5 ' atom of the sugar, and a carbon atom of R 4 .
  • contemplated libraries will comprise 3',2',5',1 '-heterocyclic nucleoside according to Formula 5 or 6
  • contemplated libraries will comprise thiadiazolinone nucleosides according for Formula 7
  • contemplated libraries will comprise 3',2',5'-substituted amino nucleosides according to Formulae 8 and 9
  • R 1 ⁇ R 2 , and R 3 are also defined as in the respective portions of the detailed description below.
  • contemplated libraries will comprise N-substituted benzodiazepine nucleosides according to Formula 10
  • contemplated nucleosides derived frbm such libraries will have a corresponding structure according to Formula 10.
  • contemplated libraries will comprise substituted C-pyrrole nucleosides according to Formula 11
  • contemplated libraries will comprise substituted C-dihydropyrimidine nucleosides according to Formula 12
  • contemplated libraries will comprise substituted tetrazole nucleosides according to Formula 13
  • nucleoside library refers to a plurality of chemically distinct nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs wherein at least some of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs include, or have been synthesized from a common precursor.
  • nucleoside library a plurality of nucleosides, nucleotides,' nucleoside analogs, and/or nucleotide analogs that were prepared using l'-azido or l'-amino ribofuranose as a building block/precursor is considered a nucleoside library under the scope of this definition. Therefore, the term "common precursor" may encompass a starting material in a first step in a synthesis as well as a synthesis intermediate (i.e., a compound derived from a starting material).
  • At least one step in the synthesis of one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs is concurrent with at least one step in the synthesis of another one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and synthesis is preferably at least partially automated.
  • nucleoside library a collection of individually synthesized nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and especially a collection of compounds not obtained from a nucleoside library, is not considered a nucleoside library because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs will not have a common precursor, and because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs are not concurrently produced.
  • the complexity of contemplated libraries is at least 20 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, more typically at least 100 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, and most typically at least 1000 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs. Consequently, a typical format of a nucleoside library will include multi-well plates, or a plurality of small volume (i.e. , less than 1ml) vessels coupled to each other.
  • library compound refers to a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog within a nucleoside library.
  • heterocycle and “heterocyclic base” are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom.
  • heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle” or "fused heterocyclic base” as used herein.
  • fused heterocycles include a 5-membered ring fused to a 6-membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5- djpyrimidine, benzodiazepine). Examples of these and further preferred heterocyclic bases are given below.
  • Still further contemplated heterocyclic bases may be aromatic, or may include one or more double or triple bonds.
  • contemplated heterocyclic bases and fused heterocycles may further be substituted in one or more positions (see below).
  • sugar refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group or atom in the sugar.
  • particularly contemplated deletions include 2'-deoxy and/or 3'-deoxy sugars.
  • Especially contemplated substitutions include replacement of the ring-oxygen with sulfur or methylene, or replacement of a hydroxyl group with a halogen, an amino-, sulfliydryl-, 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, A, 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 of the nucleoside to the sugar includes a CI '-(glycosidic) bond of a carbon atom in a sugar to a carbon- or heteroatom (typically nitrogen) in the heterocyclic base.
  • nucleoside analog refers to all nucleosides in which the sugar is not a ribofuranose and/or in which the heterocyclic base is not a naturally occurring base (e.g., A, G, C, T, I, etc.).
  • nucleotide refers to a nucleoside to which a phosphate group is coupled to the sugar.
  • nucleotide analog refers to a nucleoside analog to which a phosphate group is coupled to the sugar.
  • nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog also includes all prodrug forms of a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog, wherein the prodrug form may be activated/converted to the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog in one or more than one step, and wherein the activation/conversion of the prodrug into the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog may occur intracellularly or extracellularly (in a single step or multiple steps).
  • Especially contemplated prodrug forms include those that confer a particular specificity towards a diseased or infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs” by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), "Design of Prodrugs” by Hans Bundgaard (ASIN: 044480675X), or in copending US application number 09/594410, filed 06/16/2000, all of which are incorporated by reference herein.
  • Particularly suitable prodrug forms of the above compounds may include a moiety that is covalently coupled to at least one of the C2'-OH, C3'-OH, and C5'-OH, wherein the moiety is preferentially cleaved from the compound in a target cell (e.g., Hepatocyte) or a target organ (e.g., liver).
  • a target cell e.g., Hepatocyte
  • a target organ e.g., liver
  • cleavage of the prodrug into the active form of the drug is mediated (at least in part) by a cellular enzyme, particularly receptor, transporter and cytochrome-associated enzyme systems (e.g., CYP-system).
  • prodrugs comprise a cyclic phosphate, cyclic phosphonate and/or cyclic phosphoamidates, which are preferentially cleaved in a hepatocyte to produce the compound according to Formula 1 or 2.
  • prodrugs There are numerous such prodrugs known in the art, and all of those are considered suitable for use herein.
  • prodrug forms are disclosed in WO 01/47935 (Novel Bisamidate Phosphonate Prodrugs), WO 01/18013 (Prodrugs For Liver Specific Drug Delivery), WO 00/52015 (Novel Phosphorus-Containing Prodrugs ), and WO 99/45016 (Novel Prodrugs For Phosphorus-Containing Compounds), all of which are incorporated by reference herein. Consequently, especially suitable prodrug forms include those targeting a hepatocyte or the liver.
  • Still further particularly preferred prodrugs include those described by Renze et al. in Nucleosides Nucleotides Nucleic Acids 2001 Apr-Jul;20(4-7):931-4, by Balzarini et al. in Mol Pharmacol 2000 Nov;58(5):928-35, or in U.S. Pat. No. 6,312,662 to Erion et al., U.S. Pat. No. 6,271,212 to Chu et al., U.S. Pat. No. 6,207,648 to Chen et al, U.S. Pat. No. 6,166,089 and U.S. Pat. No. 6,077,837 to Kozak, U.S. Pat. No.
  • prodrugs include those comprising a phosphate and/or phosphonate non-cyclic ester, and an exemplary collection of suitable prodrugs is described in U.S. Pat. No. 6,339,154 to Shepard et al., U.S. Pat. No. 6,352,991 to Zemlicka et al., and U.S. Pat. No. 6,348,587 to Schinazi et al. Still further particularly contemplated prodrug forms are described in FASEB J. 2000 Sep;14(12):1784- 92, Pharm. Res. 1999, Aug 16:8 1179-1185, and Antimicrob Agents Chemother 2000, Mar 44:3 477-483, all of which are incorporated by reference herein.
  • multiple component condensation refers to reactions between at least two distinct molecules and a sugar or sugar portion of a molecule, in which at least one of the two molecules forms a covalent bond with the sugar portion, wherein the reactions 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.
  • alkenyl and “unsubstituted alkenyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond.
  • alkynyl and “unsubstituted alkynyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon-carbon triple bond.
  • aryl and “unsubstituted aryl” are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl.
  • alkaryl is employed where an aryl is covalently bound to an alkyl, alkenyl, or alkynyl.
  • substituted refers to a replacement of an atom or chemical group (e.g., H, NH 2 , or OH) with a functional group
  • functional groups include nucleophilic groups (e.g., -NH 2 , -OH, -SH, -NC, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH ⁇ , and halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof.
  • nucleophilic groups e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e.g
  • the term "functional group” as used herein refers to nucleophilic groups (e.g., -NH 2 , -OH, -SH, -NC, -CN etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NHs " ), and halogens.
  • nucleophilic groups e.g., -NH 2 , -OH, -SH, -NC, -CN etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.
  • polar groups e.g., -OH
  • non-polar groups e.g., aryl, alkyl, al
  • 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 of contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion of the sugar is an atom other than oxygen (e.g., sulfur, carbon, or nitrogen) analogs, while other alternative sugars may not be cyclic but in a linear (open-chain) form. Suitable sugars may also include one or more double bonds.
  • Still further specifically contemplated alternative sugars include those with one or more non-hydroxyl substituents, and particularly contemplated substituents include mono-, di-, and triphosphates (preferably as C 5 ' esters), alkyl groups, alkoxygroups, halogens, amino groups and amines, sulfur-containing substituents, etc. It is still further contemplated that all contemplated substituents (hydroxyl substituents and non-hydroxyl substituents) may be directed in the alpha or beta position. Numerous of the 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 "Mode 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 of the exemplary sugars may be in D- or L-configuration, and wherein at least one of the substituents (typically H or OH) on the C ⁇ '-C ' atom of the sugar may be in either alpha or beta orientation.
  • X , Y,, Z O , S , S e, NH, NR, CH 2) C HR, P( ⁇ ), P(0 )O
  • R H, O H , NHR, halo, CH -OH, C O OH, N 3 , alkyl, aryl, alkynyl, heterocycles, OR, SR,-P (0)(O R) 2
  • An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other groups, including alkenyl, alkynyl, aryl, halogen, CF 3 , CHF , CC1 3 , CHC1 2 , N 3 , NH 2 , etc.) are covalently bound to sugar at the C' ⁇ , C' 2 ,C' 3 ,C 4 , and/or C 5 atom, such alkylated sugars, it is especially preferred that the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one of the alkyl groups is a methyl group.
  • the alkyl group may or may not be substituted with one or more substituents.
  • One exemplary class of preferred sugars is
  • 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, and/or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocycles may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.
  • fused heterocycles include a 5-membered ring fused to a 6-membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6- membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).
  • heterocyclic bases may further include one or more substituents, double and triple bonds, and any chemically reasonable combination thereof. It should also be appreciated that all of the contemplated heterocyclic bases may be coupled to contemplated sugars via a carbon atom or a non-carbon atom in the heterocyclic base.
  • nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs can be coupled to such solid phases, and so long as the coupled nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog (or sugar, or heterocyclic base) will remain coupled to the solid phase during at least one chemical reaction on the nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog (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 Bache Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • contemplated solid supports may also include glass, as described in U. S. Pat. No. 5,143,854.
  • Another preferred solid support comprises a "soluble" polymer support, which may be fabricated by copolymerization of polyethylene glycol, polyvinylalcohol, or polyvinylalcohol with polyvinyl pyrrolidine or derivatives thereof (e.g., see Janda and Hyunsoo (1996) Methods Enzymol. 267:234-247; Gravert and Janda (1997) Chemical Reviews 97:489-509; and Janda and Hyunsoo, PCT publication No. WO 96/03418).
  • Contemplated Combinatorial Reactions It is generally contemplated that all known types of combinatorial reactions and/or reaction sequences may be used in conjunction with the teaching presented herein. 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.
  • 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 of the reaction compartment or a solid or soluble polymer), and that the solid phase is physically separated from another substrate on another solid phase. While not limiting to the inventive subject matter, it is generally preferred that contemplated solid phase synthesis- is at least partially automated.
  • a substrate or reaction intermediate is coupled to a solid phase (with may include the wall of the reaction compartment or a solid or soluble polymer), and that the solid phase is physically separated from another substrate on another solid phase.
  • nucleoside analog libraries can be prepared in various combinatorial library approaches, particularly approaches in which diverse heterocyclic bases and/or diverse nucleoside substituents are prepared in a multiple component condensation (MCC) reaction.
  • MCC multiple component condensation
  • a nucleoside library may have at least two library compounds, wherein each of the library compounds comprises a heterocyclic base covalently bound to a sugar, and wherein the heterocyclic base is formed by a multiple component condensation.
  • heterocyclic bases comprise various imidazoles, imidazolines, thiazolidines, benzodiazepines, and dihydropyrimidines, wherein all of the contemplated heterocyclic bases maybe l'-N- glycosidically, l'-C-glycosidically, 2'-N-glycosidically, 3'-N-glycosidically, or 3'-C- glycosidically bound to the sugar portion.
  • contemplated nucleoside libraries may have at least two library compounds, wherein each of the library compounds comprises a moiety covalently bound to a sugar, and wherein the moiety is formed by a multiple component condensation
  • contemplated libraries include those in which a heterocyclic base coupled to the C 1 '-atom of a sugar (e.g. , ribofuranosylimidazole libraries, ribofuranosyl benzodiazepine libraries, imidazole substituted libraries, and dihydropyrimidine libraries) is built via an MCC
  • a heterocyclic base is added as a sugar substituent to a nucleoside (e.g., 3',2',5',l'-heterocyclic libraries)
  • a linear sugar substituent is added to the sugar of a nucleoside via an MCC reaction
  • MCC reaction e.g., 3',2',5'-substituted amino acid nucleoside libraries.
  • Scheme 1 depicts a general synthetic approach for a ribofuranosylimidazole library, in which a protected sugar (here: protected ribofuranose) is converted to the corresponding CI'- ribofuranose azide and further coupled to a solid phase via the C5'-atom.
  • the azide is then reduced to the amine, which serves as a nucleophilic group that is used to react with at least one of three substrates in an MCC reaction to form a substituted imidazole.
  • a first set of various first substrates reacts with the amine group in a first set of separate reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and third set of separate reactions with various third substrates will use the products from the second set of reactions.
  • the product of the third set of reactions is then converted to the imidazole ring.
  • a series of protected and solid phase-bound amino sugars may also be reacted with a series of three distinct substrates, respectively, wherein each sugar and three substrates are in a separate reaction vessel.
  • the protecting groups may be removed and the sugar is cleaved from the solid phase.
  • the heterocyclic base can be constructed in an alternative fashion using a carboxylic acid group on the sugar portion. Consequently, contemplated nucleosides will include a heterocyclic base that is coupled via a C-C bond to the sugar portion.
  • a first set of various first substrates may react with the COOH group in a first set of separate reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of separate reactions with Various third substrates will use the products from the second set of reactions.
  • the product of the third set of reactions is then converted to the imidazole ring.
  • a series of protected and solid phase-bound carboxylic acid sugars may also be reacted with a series of three distinct substrates, respectively, wherein each sugar and three substrates are in a separate reaction vessel.
  • the protecting groups maybe removed and the sugar cleaved from the solid phase.
  • contemplated alternative sugars include sugar derivatives of sugars with four, five, or six carbon atoms. Exemplary contemplated sugars are described and depicted above. Furthermore, it should be appreciated that the azide group may be introduced into the sugar in a position other than the Cl'-position. Consequently, it should be recognized that the imidazole moiety may also be formed in the C2'-, C3'-, or C5'- position. There are numerous methods known in the art to introduce an N 3 group into the C2'-, C3'-, or C5'-position of a sugar, and all such methods are contemplated herein (see e.g., Nucleic Acids Res.
  • protection groups include benzyl-, acetyl-, and TBDMS groups
  • numerous alternative protection groups are also considered suitable.
  • 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.
  • Ri, R 2 , and R 3 in the three substrates may vary considerably, and it is especially contemplated that Ri, R 2 , and R 3 are independently selected from the group consisting of hydrogen, a functional group, 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.
  • at least one of Ri, R 2 , and R 3 may comprise a sugar.
  • second substrates R COOH are commercially available, and where such substrates are not commercially available, it is contemplated that they may be prepared from commercially available precursors (e.g., via oxidation of corresponding alcohols or aldehydes, hydrolysis of corresponding esters, etc.) using protocols well known in the art (supra).
  • third substrates R NC are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).
  • solid phase 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).
  • nucleoside libraries with at least two library compounds can be synthesized, wherein one of the at least two library compounds has a structure according to Formula 1 with a first set of substituents A, Ri, R 2 , and R 3 , wherein another one of the at least two library compounds has a structure according to Formula 1 with a second set of substituents A, Ri, R 2 , and R 3 :
  • A is selected from the group consisting of 4 , a protected sugar that is covalently bound to a solid phase, and an unprotected sugar that is covalently bound to a solid phase;
  • Ri, R 2 , R 3 , and R 4 are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R 2 , and R 3 is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently bound to a
  • contemplated compounds may have a structure according to Formula 1 (supra) wherein A is R 4 , a protected sugar, or an unprotected sugar; Ri, R 2 , R 3 , and R 4 are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R 2 , and R 3 is a protected sugar or an unprotected sugar.
  • the sugar is a ribofuranose, a substituted ribofuranose (e.g., 2'-beta methyl ribofuranose), a carbocyclic ring system, or an arabinose, wherein the sugar is in D-configuration or i L-configuration. It is still further preferred that in such compounds and libraries the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to the atom, the C 2 ' atom, or the C 3 ' atom of the sugar, or to a carbon atom of R 4 .
  • the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to the atom, the C 2 ' atom, or the C 3 ' atom of the sugar, or to a carbon atom of R 4 .
  • Scheme 2 depicts a general synthetic approach for a ribofuranosylimidazole library, in which a Cl'-azidosugar (here: Cl'-azidoribofuranose) is protected and coupled via the C5'-atom to a solid phase. The protected and coupled sugar is then converted to the corresponding amino sugar.
  • the amino group in the amine sugar serves as a nucleophilic group that is used to react with at least one of the three substrates in an MCC reaction to form a substituted benzodiazepine.
  • a first set of various first substrates reacts with the amine group in a first set of reactions
  • the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions
  • a third set of reactions with various third substrates will use the products from the second set of reactions.
  • the product of the third set of reactions is then converted to form the benzodiazepine ring.
  • all combinations of R ⁇ -R 3 in the substrates will potentially be represented in the so generated library.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • Ri, R 2 , and R in the substrates may vary considerably, and it is especially contemplated that Ri, R , and R 3 are independently hydrogen, a functional group, 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.
  • Preparation of various first substrates with RjCOCHO are well known in the art and all known protocols to generate 2-oxoaldehydes are considered suitable for use herein (supra).
  • numerous 2-oxoaldehydes are commercially available and may also be used for synthesis of contemplated libraries. Exemplary 2-oxoaldehydes are listed in the experimental section below.
  • numerous second substrates substituted and unsubstituted aminobenzoic acids
  • Exemplary substituted and unsubstituted aminobenzoic acids are listed in the experimental section below.
  • numerous third substrates R 3 NC are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).
  • nucleoside libraries with at least two library compounds can be synthesized, wherein one of the at least two library compounds has a structure according to Formula 2 with a first set of substituents A, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 2 with a second set of substituents A, Ri, R 2 , and R 3
  • A is R 4 , a protected sugar that is covalently bound to a solid phase, or an unprotected sugar that is covalently bound to a solid phase; and Ri, R 2 , R 3 , and are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R 2 , and R 3 is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently bound to a solid phase; and wherein not all
  • contemplated compounds may have a structure according to formula 2 (supra) wherein A is R 4 , a protected sugar, or an unprotected sugar, and Ri, R 2 , R 3 , and are independently hydrogen, a functional group, 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, with the proviso that when A is I , then one of R ls R 2 , and R 3 is a protected sugar or an unprotected sugar.
  • the sugar comprises a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, or an arabinose, wherein the sugar is in the D- or L-configuration.
  • the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to the Ci' atom, the C ' atom, or the C 3 ' atom of the sugar, or to a carbon atom of .
  • Scheme 3 depicts a general synthetic approach for an imidazole substituted nucleoside library, in which a protected nucleoside comprising an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of the three substrates in an MCC reaction to form a substituted imidazole.
  • a first set of distinct first substrates reacts with the amino group in a first set of reactions
  • the products from the first set of reactions will react with a second set of distinct second substrates in a second set of reactions
  • a third set of reactions with distinct third substrates will use the products from the second set of reactions.
  • the product of the third set of reactions is then converted to the substituted imidazole ring.
  • Ri in the sugar and R 2 , R 3 , and Ar in the substrates will potentially be represented in the so generated library.
  • heterocyclic bases may vary considerably, and it is generally contemplated that all known heterocyclic bases are appropriate for use herein. Exemplary heterocyclic bases are described in the section entitled "Contemplated Heterocyclic Bases" above. Depending on the particular nature of the heterocyclic base, it is contemplated that one or more substituents or reactive groups in the heterocyclic may be protected by a suitably selected protecting group.
  • Ar, R 2 , and R 3 in the substrates may vary considerably, and it is especially contemplated that R 2 , and R are independently hydrogen, a functional group, 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.
  • Ar may vary considerably and contemplated Ar include a substituted aryl, an unsubstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle, and especially phenyl.
  • R 2 COOH second substrates (substituted and unsubstituted carboxylic acids)
  • R 3 NC third substrates
  • substituted imidazole nucleoside libraries with at least two library compounds can be prepared wherein one of the at least two library compounds
  • Pf compounds has a structure according to Formula 3 with a first set of substituents B , Ar, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 3 with a second set of substituents B PG , Ar, Ri, R 2 , and R 3 : Formula 3
  • B PG is a protected or unprotected heterocyclic base
  • Ar is a substituted aryl, an unsubstituted aryl, a substituted heterocycle, or an unsubstituted heterocycle
  • Scheme 4 depicts a general synthetic approach for a substituted dihydropyrimidine library, in wliich a protected CI'- amino sugar (here: l'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react in an MCC reaction to form a substituted dihydropyrimidine.
  • a first set of various first substrates reacts with the amino group in a first set of reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of reactions with various third substrates will use the products from the second set of reactions.
  • the product of the third set of reactions is then converted to the substituted dihydropyrimidine ring.
  • R ⁇ -R 3 in the substrates will potentially be represented in the so generated library.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • R i, R 2, R 3 H; aIkyI aryl) heterocyc i es substituted nucleosides
  • E is any electron- withdrawing group (i.e., a group with a -I effect, including COOR, COR, CN, NO 2 , Halogen, etc.), while X is preferably O or S.
  • E is any electron- withdrawing group (i.e., a group with a -I effect, including COOR, COR, CN, NO 2 , Halogen, etc.)
  • X is preferably O or S.
  • the sugar may also be coupled to the dihydropyrimidine in a position of the substituents Ri and R 2 .
  • R 1 ⁇ R 2 , and R 3 are independently hydrogen, a functional group, 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.
  • third substrates are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).
  • dihydropyrimidine nucleoside libraries can be prepared with at least two library compounds wherein one of the at least two library compounds has a structure according to Formula 4 or 4A with a first set of substituents A, E, X, Ri, R 2 , and R 3 , wherein another one of the at least two library compounds has a structure according to Formula 4 or 4 A with a second set of substituents A, E, X, Ri, R 2 , and R 3 :
  • A is a protected sugar covalently bound to a solid phase, or an unprotected sugar covalently bound to a solid phase
  • E is an electron withdrawing group
  • X is O or S
  • R ls R 2 , and R 3 are independently hydrogen, a functional group, 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, and wherein not all of the substituents E, X, Ri, R 2 , and R 3 in the first set are the same as the substituents E, X, Ri, R 2 , and R 3 in the second set.
  • contemplated compounds may have a structure according to Formula 4 or 4A (supra) wherein A is a protected sugar or an unprotected sugar; E is an electron withdrawing group, X is O or S, and Ri, R 2 , and R 3 are independently hydrogen, a functional group, 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.
  • Further contemplated compounds may have the dihydropyrimidine moiety bound to the C 2 ' atom, C 3 ' atom or C 5 ' atom of the sugar (when the protected amino sugar is a C 2 ' amino sugar, a C 3 ' amino sugar, or a C 5 ' amino sugar).
  • Particularly preferred sugars include a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D- or L-configuration.
  • the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C 2 ' atom of the sugar, a C 3 ' atom of the sugar, and a C 5 ' atom of the sugar.
  • Scheme 5 depicts a general synthetic approach for a 3',2',5',l'-heterocyclic library, in which a protected nucleoside (here: with any naturally occurring heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of three substrates in an MCC reaction to form a substituted heterocycle. It should be particularly appreciated that all combinations of Ri in the amino sugar and R 2 -R 4 in the substrates of the MCC reaction will potentially be represented in the so generated library.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • RNH2, RCO, and RNC at 1', 2', 3' are used to make novel nucleoside libraries from different sugars.
  • a first set of various first substrates reacts with the amino group in a first set of reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of reactions with various third substrates will use the products from the second set of reactions.
  • R , R 3 , and R 4 in the substrates may vary considerably, and it is especially contemplated that R 2 , R 3 , and R 4 are independently hydrogen, a functional group, 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.
  • protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.
  • Preparation of various first substrates with R 2 C(O)R 3 are well known in the art and all known protocols to generate various ketones (in which R 2 and R 3 may or may not be different) are considered suitable for use herein (supra; e.g., via addition, oxidation, reduction, or substitution). Moreover, numerous substituted ketones are commercially available and maybe used for synthesis of contemplated libraries.
  • the second substrate SCN " is commercially available as the corresponding salt (potassium thiocyanate), and numerous third substrates (isonitriles, R 3 NC) are also commercially available.
  • Such substrates may also be prepared from commercially available precursors using protocols well known in the art (supra, ox A. W. Hofmann, Ann. 146, 107 (1868); Ber. 3, 767 (1870), or P. A. S. Smith, N. W. Kalenda, J. Org. Chem. 23, 1599 (1958); M. B. Frankel et al., Tetrahedron Letters 1959, 5; H. L. Jackson, B. C. McKusick, Org. Syn. coll. vol. IN, 438 (1963); W. P. Weber, G. W. Gokel, Tetrahedron Letters 1972, 1637).
  • the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'- and C2'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding CI'- and C2'-position).
  • nucleoside libraries can be prepared in which at least one of the at least two library compounds has a structure according to Formula 5 with a first set of substituents B , Ri, R 2 , R 3 , and R- t and wherein another one of the at least two library compounds has a structure according to Formula 5 with a second set of substituents B PG , R l5 R 2 , R 3 and R 4 : Formula 5
  • B is a protected or unprotected heterocyclic base
  • R 2 , R 3 , and 4 are independently hydrogen, a functional group, 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, and
  • contemplated compounds may have a structure according to formula
  • B is a heterocyclic base
  • R 2 , R 3 , and R are independently hydrogen, a functional group, 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.
  • Scheme 6 depicts a general synthetic approach for another 3',2',5',l'-heterocyclic library, in which a protected nucleoside (here: with any naturally occurring heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted heterocycle.
  • R 2 and R 3 in the substrates may vary considerably, and it is especially contemplated that R 2 and R 3 are independently hydrogen, a functional group, 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.
  • protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.
  • first substrates with R 2 CHO Numerous preparation methods for various first substrates with R 2 CHO are well known in the art and all known protocols to generate various aldehydes are considered suitable for use herein (supra). Moreover, numerous aldehydes are commercially available and maybe used for synthesis of contemplated libraries. Similarly, many second substrates (various alpha- or beta-thio carboxylic acids) are commercially available and where particular second substrates are not commercially available, it is contemplated that such substrates may be prepared from commercially available precursors using protocols well known in the art (supra).
  • the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'-, C2'-, and C5'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding CI'-, C2'-, and C5'-position).
  • heterocyclic nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 6 with a first set of substituents B PG , Ri, R 2 and R 3 , wherein another one of the at least two library compounds has a structure according to Formula 6 with a second set of substituents B PG , Ri, R and R 3 :
  • B PG is a protected or unprotected heterocyclic base
  • R 2 and R 3 are independently hydrogen, a functional group, 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, and wherein not all
  • contemplated compounds may have a structure according to formula 6 A
  • B is a heterocyclic base
  • Scheme 7 depicts a general synthetic approach for a 3',2',5',l'-thiadiazolinone library, in which a protected nucleoside (here: with a naturally occurring heterocyclic base) with an azido sugar (here: 3'-azidoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the azido group is reduced to an amino group which then serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (e.g., a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted thiadiazolinone.
  • R' OCH 3 , OTBDMS, '
  • R 2 and R 3 in the substrates may vary considerably, and it is especially contemplated that R 2 and R 3 are independently hydrogen, a functional group, 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.
  • protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.
  • first substrates R 2 NCS Numerous preparation methods for various first substrates R 2 NCS are well known in the art and all known protocols to generate various isothiocyanates are considered suitable for use herein (supra). Moreover, numerous isothiocyanates are commercially available and maybe used for synthesis of contemplated libraries. Similarly, numerous second substrates R 2 NCO are commercially available and where a particular isocyanate is not commercially available, it is contemplated that such substrates may be prepared from commercially available precursors using protocols well known in the art (supra).
  • the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'-, C2'-, and C5'-position (then, the amino group in the azido sugar of the nucleoside is in the corresponding CI'-, C2'-, and C5 '-position).
  • thiadiazolinone nucleoside libraries with at least two library compounds can be prepared in wliich one of the at least two library compounds has a structure according to Formula 7 with a first set of substituents B , Ri, R 2 and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 7 with a second set of substituents B PG , Ri, R and R 3 :
  • B PG is a protected or unprotected heterocyclic base
  • R 2 and R 3 are independently hydrogen, a functional group, 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, wherein not all of
  • contemplated compounds may have a structure according to formula 7A
  • B is a heterocyclic base
  • R 2 and R 3 are independently hydrogen, a functional group, 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.
  • Scheme 8 depicts a general synthetic approach for a 3',2',5'-substituted amino nucleoside library, in which a protected nucleoside (here: with a purine heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group is used to react with a set of substrates to form a substituted amino nucleoside.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • R 2 in the substrate may vary considerably, and it is especially contemplated that R 2 is hydrogen, a functional group, 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.
  • protected heterocyclic base it is contemplated that suitable heterocyclic bases need not be restricted to a purine base and that all known heterocyclic bases are appropriate.
  • Especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.
  • substituted amino nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 8 with a first set of substituents B , R ls R 2 and R 3 , wherein another one of the at least two library compounds has a structure according to Formula 8 with a second set of substituents B PG , Ri, R 2 and R :
  • B PG is a protected or unprotected heterocyclic base
  • contemplated compounds may have a structure according to formula 8A
  • B is a heterocyclic base
  • nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms an open-chain substituent on a nucleoside or nucleoside analog, and a particularly preferred aspect is described below.
  • Scheme 9 depicts a general synthetic approach for a 3', 2', 5'-amino nucleoside library, in which a protected nucleoside with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase.
  • the amino group then serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted linear substituent.
  • MCC reaction a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • R 2 and R 3 in the substrates may vary considerably, and it is especially contemplated that R 2 and R 3 are independently hydrogen, a functional group, 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.
  • protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.
  • first substrates R 2 NC Numerous preparation methods for various first substrates R 2 NC are well known in the art and all known protocols to generate such isocyano compounds are considered suitable for use herein (supra). Moreover, numerous isocyano compounds are commercially available and maybe used for synthesis of contemplated libraries. Similarly, numerous second substrates R 2 CHO (aldehydes) are commercially available and where particular second substrates are not commercially available, it is contemplated that such aldehydes may be prepared from commercially available precursors using protocols well known in the art (supra).
  • the MCC generated linear substituent may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions particularly include the C2'-, and C5'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding C2'-, and C5'-position).
  • nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 9 with a first set of substituents B PG , Ri, R 2 and R 3 , wherein another one of the at least two library compounds has a structure according to Fonnula 9 with a second set of substituents B , Ri, R 2 and R 3 :
  • B PG is a protected or unprotected heterocyclic base
  • contemplated compounds may have a structure according to formula 9A
  • B is a heterocyclic base
  • R 2 and R 3 are independently hydrogen, a functional group, 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.
  • nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms an N-substituted benzodiazepine heterocyclic base, and one particularly preferred aspect is described below.
  • Scheme 10 depicts a general synthetic approach for a N-substituted benzodiazepine nucleoside library, in which a protected sugar aldehyde (here: protected 1'- formylribofuranose) is coupled via the C5'-atom to a solid phase.
  • the Ci aldehyde group then serves as an electrophilic group that is used to react with cyclohexylene isocyanate and at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a derivatized sugar.
  • Each of the preferred sets of substrates for the MCC reaction includes at least one set of substituents i, R 2 , and R 3 .
  • the derivatized sugar is cyclized to the corresponding N-substituted benzodiazepine. It should be particularly appreciated that all combinations of Ri and R 2 in the first set of substrates and R 3 in second set of substrates will potentially be represented in the so generated library. After cyclization, the protecting groups are removed and the sugar is cleaved from the solid phase.
  • suitable sugars need not be limited to the Ci-formylribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted Ci-formylribofuranoses and substituted and unsubstituted Ci-formylarabinoses, and further contemplated suitable sugars include those listed under the section "Contemplated Sugars". Moreover, it should be appreciated that while it is preferred that the aldehyde group is located on the Ci-carbon atom of the appropriate sugar, various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C 2 , C 3 , and C 5 ).
  • R may be 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.
  • N-substituted aminobenzoic acids are suitable for use herein, and that such reagents will preferable have one substituent Ri and one protecting/leaving group on the amino group, while the benzene moiety may further comprise a substituent R 3 as indicated in Scheme 10 above.
  • Prefened substituents Ri and R 3 include independently hydrogen, a functional group, 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.
  • protecting groups may be suitable for coupling to the nitrogen atom, however, especially preferred protecting/leaving groups include Boc, and Fmoc. It is generally contemplated that numerous of such second reagents are commercially available. However, where a particular primary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures well known in the art (supra).
  • cyclohexylene isocyanate it is contemplated that numerous reagents other than cyclohexylene isocyanate are also appropriate, so long as such reagents include a isocyanate group that is bound to a moiety which can serve as (part of) a leaving group when the heterocyclic base is formed.
  • nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 10 with a first set of substituents A, R ls R 2 and R 3 , wherein another one of the at least two library compounds has a structure according to Formula 10 with a second set of substituents A, Ri, R 2 and R 3 :
  • Ri, R 2 , and R 3 are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, R ls R , and R 3 in the first set are the same as the substituents A, Ri, R 2 , and R 3 in the second set.
  • contemplated compounds may have a structure according to formula 10 (supra), wherein A is a protected or unprotected sugar, and Ri, R 2 , and R 3 are independently hydrogen, a functional group, 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.
  • nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted C-pyrrole heterocyclic base, and one particularly preferred aspect is described below.
  • Scheme 11 depicts a general synthetic approach for a substituted C-pyrrole nucleoside library, in which a protected sugar aldehyde (here: protected 1'- formyhibofuranose) is coupled via the C5'-atom to a solid phase.
  • a protected sugar aldehyde here: protected 1'- formyhibofuranose
  • the Ci aldehyde group then serves as an electrophilic group that is used to react with cyclohexylene isocyanate and at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, and a second set of reactions with various second substrates using products from the first set of reactions) to form a derivatized sugar, and in a subsequent reaction, the heterocyclic base is reacted with an alkynyl having two substituents Ei and E 2 to form a substituted C-pyrrole nucleoside.
  • the protecting groups are removed and the sugar is cleaved from the solid phase.
  • preferred sets of substrates for the MCC reaction include substituents Ei, E 2 , Ri and R 2 , respectively, and it should be particularly appreciated that all combinations of Ri and R 2 in the first and second set of substrates and Ei and E 2 in the substituted alkynyl will potentially be represented in the so generated library.
  • suitable sugars need not be limited to the Ci-formylribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted - formylribofuranoses and substituted and unsubstituted Ci-formylarabinoses, and further contemplated suitable sugars include those listed under the section "Contemplated Sugars”.
  • aldehyde group is located on the Ci-carbon atom of the appropriate sugar
  • various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C 2 , C 3 , and C 5 ).
  • R may be hydrogen, a functional group, 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.
  • R may be hydrogen, a functional group, 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.
  • carboxylic acids are commercially available, and where a particular carboxylic acid is not commercially available, it should be recognized that such carboxylic acid may readily be synthesized from commercially available precursors following procedures well known in the art (supra).
  • alkynyls are contemplated suitable for use herein and appropriate alkynyls will have the general formula R-C ⁇ C-R', wherein R and R' are independently hydrogen, a functional group, 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.
  • alkynyls are commercially available, and where a particular alkynyl is not commercially available, it should be recognized that such alkynyl may readily be synthesized from commercially available precursors following procedures well known in the art (supra). With respect to the cyclohexylene isocyanate, the same considerations as described above apply.
  • nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 11 with a first set of substituents A, Ri, R 2 , Ei, and E 2 , wherein another one of the at least two library compounds has a structure according to Formula 11 with a second set of substituents A, Ri, R 2 , Ei, and E 2 :
  • Ri, R 2 , Ei, and E 2 are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, R 1 ⁇ R 2 , Ei, and E 2 in the first set are the same as the substituents A, Ri, R 2 , Ei, and E 2 in the second set.
  • contemplated compounds may have a structure according to formula 11 (supra), wherein A is a protected or unprotected sugar, and Ri, R 2 , Ei, and E 2 are independently hydrogen, a functional group, 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.
  • nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted C-dihydropyrimidine heterocyclic base, and one particularly preferred aspect is described below.
  • Scheme 12 depicts a general synthetic approach for a substituted C- dihydropyrimidine nucleoside library, in which (an optionally protected) sugar aldehyde (here: l'-formylribofuranose) is coupled via the C5'-atom to a solid phase.
  • the Ci aldehyde group then serves as an electrophilic group that is used to react with urea and at least one mono- or disubstituted substrate (having R and Ri substituents) in an MCC reaction to form a C-dihydropyrimidine heterocyclic base.
  • aldehyde group is located on the Ci-carbon atom of the appropriate sugar
  • various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C 2 , C 3 , and C 5 ).
  • R and Ri may independently be hydrogen, a functional group, 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.
  • beta-oxo-carboxylic acid esters are commercially available, and where a particular beta-oxo- carboxylic acid ester is not commercially available, it should be recognized that such beta- oxo-carboxylic acid esters may readily be synthesized from commercially available precursors (e.g., beta-oxo-carboxylic acids) following procedures 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.
  • precursors e.g., beta-oxo-carboxylic acids
  • R may be hydrogen, a functional group, 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.
  • urea may be replaced with various diamines, in ' which the amino groups are terminal amino groups, and wherein at least one of the amino groups may further be substituted.
  • suitable alternative compounds include thiourea, and N-substituted urea.
  • nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 12 with a first set of substituents A, Ri, and R 2 wherein another one of the at least two library compounds has a structure according to Formula 12 with a second set of substituents A, R ls and R Formula 12
  • A is a protected or unprotected sugar that is covalently bound to a solid phase
  • Ri and R 2 are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, Ri, and R 2 in the first set are the same as the substituents A, Ri, and R 2 in the second set.
  • contemplated compounds may have a structure according to formula 12 (supra), wherein A is a protected or unprotected sugar, and Ri and R 2 are independently hydrogen, a functional group, 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.
  • substituted tetrazole nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted tetrazole heterocyclic base, and one particularly preferred aspect is described below.
  • Scheme 13 depicts a general synthetic approach for a substituted tetrazole nucleoside library, in which a protected Cl'-amino-N-formyl sugar (here: l'-amino-N- formylribofuranose) is converted into the corresponding (partially) protected 1 '-isocyano sugar, which is subsequently coupled to a solid phase via the C5' atom of the ribose.
  • a protected Cl'-amino-N-formyl sugar here: l'-amino-N- formylribofuranose
  • the isocyano group then serves as a reactive group that is (directly and/or indirectly) reacted with (sodium) azide, a disubstituted ketone (having substituents Ri and R 2 ), and a secondary amine (having substituents R 3 and R 4 ) in an MCC reaction to form a substituted tetrazole nucleoside.
  • the sugar is then cleaved from the solid phase. It should be particularly appreciated that all combinations of Ri, R 2 , R 3 , and R 4 in the disubstituted ketone and the secondary amine will potentially be represented in the so generated library.
  • the C -amino-N-formyl sugar can be prepared following procedures well known in the art. It should further be appreciated that suitable sugars need not be limited to Cl'- amino-N-formyl ribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted Cl'-amino-N-formyl ribofuranoses and substituted and unsubstituted C -amino-N-formylarabinoses, and still further contemplated suitable sugars include those listed under the section "Contemplated Sugars".
  • amino-N- formyl group is located on the Ci-carbon atom of the appropriate sugar
  • various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C 2 , C , and C 5 ).
  • R ⁇ -C(O)- R 2 disubstituted ketones of the general formula R ⁇ -C(O)- R 2 are suitable for use herein, wherein Ri and R 2 may be independently hydrogen, a functional group, 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.
  • disubstituted ketones are commercially available, and where a particular disubstituted ketone is not commercially available, it should be recognized that such disubstituted ketones may readily be synthesized from commercially available precursors following procedures 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;
  • R 3 and R-i may be independently hydrogen, a functional group, 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.
  • nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 13 with a first set of substituents A, Ri, R 2 , R , and wherein another one of the at least two library compounds has a structure according to Formula 13 with a second set of substituents A, Ri, R 2 , R 3 , and R 4
  • A is a protected or unprotected sugar that is covalently bound to a solid phase
  • Ri, R 2 , R 3 , and R 4 are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, Ri, R 2 , R 3 , and R in the first set are the same as the substituents A, Ri, R , R , and R 4 U1 the second set.
  • contemplated compounds may have a structure according to Formula 13 (supra), wherein A is a protected or unprotected sugar, and Ri, R 2 , R 3 , and R-i are independently hydrogen, a functional group, 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.
  • A is a protected or unprotected sugar
  • Ri, R 2 , R 3 , and R-i are independently hydrogen, a functional group, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstit
  • contemplated libraries and compounds may be used to facilitate structure-activity analysis of nucleoside- type compounds.
  • contemplated libraries will provide a researcher with rapid information on the impact of a particular substituent in a particular position of the library compound.
  • libraries according to the inventive subject matter will exhibit a significant source of revenue for a seller since in most cases purchase of a library of nucleosides, nucleoside analogs, nucleotides, and/or nucleotide analogs will be less costly to a user than individual synthesis of these compounds.
  • the library compounds may serve as in vitro and/or in vivo substrates or inhibitors with particularly desirable physicochemical and/or biological properties.
  • the library compounds may act as inhibitors of DNA and/or RNA for various nucleoside-using enzymes, and especially polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agent, antineoplastic agent, or immunomodulatory agent.
  • nucleosides according to the inventive subject matter may be incorporated into oligo- or polynucleotides, which will then exhibit altered hybridization characteristics with single or double stranded DNA in vitro and in vivo.
  • Particularly contemplated antiviral activities include at least partial reduction of viral titers of respiratory syncytial virus (RSN), hepatitis B virus (HBN), hepatitis C virus (HCN), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (H1N), influenza A virus, Hanta virus (hemorrhagic fever), human papilloma virus (HPN), and measles virus.
  • RSN respiratory syncytial virus
  • HBN hepatitis B virus
  • HCN hepatitis C virus
  • herpes simplex type 1 and 2 herpes simplex type 1 and 2
  • herpes genitalis herpes keratitis
  • herpes encephalitis herpes zoster
  • human immunodeficiency virus H1N
  • influenza A virus Hanta virus (hemor
  • 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 apH of about 7.2 to 7.5).
  • physiological saline solution e.g., buffered to apH of about 7.2 to 7.5.
  • physiological saline solution e.g., buffered to apH of about 7.2 to 7.5
  • physiological saline solution e.g., buffered to apH of about 7.2 to 7.5
  • physiological saline solution e.g., buffered to apH 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
  • nucleosides may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present 0 compounds for maximum beneficial effect in a patient.
  • prodrug forms of contemplated nucleosides may be formed to for various purposes, including reduction of toxicity, increasing the organ or target cell specificity, etc.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds 5 to a target site within the host organism or patient (see above).
  • One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of the 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 of the compound.
  • contemplated compounds may be administered alone or in combination 0 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 i ⁇ gredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this 5 may occur simultaneously or separately in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • contemplated agents for combination with contemplated compounds it is especially preferred that such agents include interferon, and particularly IFN-alpha or IFN-beta (or 0 fragments thereof). Examples
  • Carboxypolystyrene resin (1.0 g, 2.0 mmol/g substitution) was treated with thionyl chloride (0.6 ml, 8.0 mmol) in 8.0 ml of benzene at 80 °C for 6 hours under nitrogen. The resin was filtered and washed with dry benzene three times and dried on vacuum. To the resin in 10 ml of dichloromethane was added of 2 (0.65 g, 3.0 mmol), 0.41 ml of triethylamine (3.0 mmol) and 24.4 mg of dimethylaminopyridine (0.2 mmol). The mixture was stirred for 24 hours at room temperature.
  • the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum.
  • the intermediate 3 was given in 90 % yield.
  • To the resin 3 (0.91 g) was added 5 ml of THF, 0.5 ml of water and 8.64 ml of 1.0 M trimethylphosphine in THF. The mixture was shaken at room temperature overnight. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum.
  • the intermediate 4 was given in 95 % yield.
  • the mixture was shaken at 100 °C for fourteen hours.
  • the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum to give the intermediate 6.
  • the intermediate 6 was treated with 3.0 ml of 80 % acetic acid in water at 50 °C for four hours.
  • the resin was filtered and washed with dimethylformamide three time, methanol three times, dichloromethane three times and dried on vacuum.
  • To the dried resin was added 1.5 ml of a solution of triethylamine, diethylamine, tetra-butylamine and dichloromethane. The mixture was shaken at room temperature for eighteen hours. Then, the resin was filtered. The filtrate was evaporated to give 12 mg of product 7.
  • Carboxypolystyrene resin (1.0 g, 2.0 mmol/g substitution) was treated with thionyl chloride (0.6 ml, 8.0 mmol) in 8.0 ml of benzene at 80 °C for 6 hours under nitrogen. The resin was filtered and washed with dry benzene three times and dried on vacuum. To the resin in 10 ml of dichloromethane was added of 9 (0.65 g, 3.0 mmol), 0.41 ml of triethylamine (3.0 mmol) and 24.4 mg of dimethylaminopyridine (0.2 mmol). The mixture was stirred for 24 hours at room temperature. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 10 was given in 90 % yield.
  • the following 10 isocyanides were used as building blocks for generation of ribofuranosyl 1,4-benzodiazepine and ribofuranosyl imidazole nucleoside library: lH-benzotriazol-1-ylmethyl isocyanide, p-toluenesulfonyhnethyl isocyanide, 2,6- dimethylphenyl isocyanide, 1,1,3,3-tetramethylbutyl isocyanide, 2-morpholinoethyl isocyanide, tert-butyl isocyanide, cyclohexyl isocyanide, n-butyl isocyanide, benzyl isocyanide and iso-propyl isocyanide.
  • the following 16 carboxylic acids were used as building blocks for generation of ribofuranosyl imidazole nucleoside library: 4-methoxycyclohexanecarboxylic acid, cycloheptanecarboxylic acid, 1-cyclopentene-l -acetic acid, cyclopropanecarboxylic acid, 2-methylcyclopanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentylacetic acid, 3-cyclopentylpropionic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid, 3-cyclohexylpropionic acid, 4-methyl-l -cyclohexanecarboxylic acid, 4-methylcyclohexaneacetic acid and tetral ⁇ ydrofuran-2-carboxylic acid.
  • Boc-2-aminobenzoic acid derivatives were used as building blocks for generation of ribofuranosyl 1,4-benzodiazepine nucleoside library: Boc-2-aminobenzoic acid, 5-bromo-Boc-2-aminobenzoic acid, 4-bromo-Boc-2-aminobenzoic acid, 5-chloro- Boc2-aminobenzoic acid, 5-fluoro-Boc-2-aminobenzoic acid, 3,5-dimethyl-Boc-2- aminobenzoic acid, 3-methoxy-Boc-2-aminobenzoic acid and 5-methyl-Boc-2- aminobenzoic acid.
  • the mixture was shaken at 100 °C for fourteen hours.
  • the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum.
  • the dried resin was treated with 3.0 ml of 80 % acetic acid in water at 50 °C for four hours.
  • the resin was filtered and washed with dimethylformamide three time, methanol three times, dichloromethane three times and dried on vacuum.
  • To the dried resin was added 1.5 ml of a solution of triethylamine, diethylamine, tetra-butylamine and dichloromethane.
  • the mixture was shaken at room temperature for eighteen hours.
  • the resin was filtered.
  • the filtrate was evaporated to give 12 mg of product.
  • Solid-phase synthesis of benzodiazepine derivatives using Ugi reaction Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in MeOH/DCM (1 :2) served as the aldehyde input, and an appropriate isocyanide (10 equiv) as a single input. Twelve amines (10 equivalents) in column 1-12 and eight carboxylic acid (10 equiv) in rows A-H were used for the construction of the library as follows. The esterstyrene resin (1.2 g, 1.5 mmol g) was partitioned equally into a 96-well polyethylene microtiter plate.
  • the eight carboxylic acids (1 M in MeOH, 138 ⁇ l, 10 equiv) and twelve amines (1 M in MeOH, 138 ⁇ l, 10 equiv) were each added to the appropriate wells. After 30 min the isocyanide (1 M in DCM, 138 ⁇ l, 10 equivalents) was added to all the wells. The plate was capped and shaken at room temperature for 24 h and rinsed with DCM (200 ⁇ l), MeOH (200 ⁇ l) and toluene (200 ⁇ l).
  • the products were removed from the resin, washed into a second 96-well plate with methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 ⁇ l) and MeOH (200 ⁇ l ). The solvents were removed in a reduced-pressure centrifuge.
  • the ester-styrene resin (0.88 g, 1.5 mmol g) was partitioned equally into a 96- well polyethylene microtiter plate.
  • the eight substituted ureas (1 M in THF, 138 ⁇ l, 10 equiv) and twelve yS-keto ester (1 M in THF, 138 ⁇ l, 10 equiv) were each added to the appropriate wells.
  • a 15 % HC1 solution (10. ⁇ l) was added to all the wells.
  • the plate was capped and shaken at 50 °C for 3 days.
  • the resin was rinsed with DCM (200 ⁇ l) and MeOH (200 ⁇ l).
  • a solution of 80% acidic acid was added to all the wells (1.5 ml each).
  • the plate was heated at 90 °C for 16 h.
  • the resin was washed with MeOH and DCM (3x 0.5 ml) and twelve amines (20 equiv) were added to column 1-12.
  • the plate was capped and heated at 50 °C for 16 h.
  • the products were removed from the resin, washed into a second 96-well plate with methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 ⁇ l) and MeOH (200 ⁇ l ).
  • the solvents were removed in a reduced-pressure centrifuge.
  • 2,3-O-isopropylidene- ⁇ -E>-ribofuranosylisocyanide To a solution of 5-0- (t- Butyldimethylsilyl)-2, 3-O-isopropylidene- ⁇ -E)- ribofuranosylisocyanide (2.40 g, 8.1 mmol) in THF (50ml) was added 1.0 M solution of TBAF in THF (8.91 ml, 8.91 mmol). The mixture was stirred at room temperature for 1 h and evaporated to give an oil. The product was purified by chromatography on silica gel (EtOAc:MeOH, 18:1) to give a colorless oil (1.32g, 82%).
  • Attachment of the sugar to the carboxypolystyrene Suspend the polymer-bound benzoyl chloride resin in DCM (10 ml g resin). Add 1.5 equivalents (based on starting resin substitution) of 2, 3-O-isopropylidene- ⁇ --D-ribofuranosylisocyanide in Py (1 M) and 0.1 equivalent of DM AP. The mixture was shaken with a mechanical shaker at room temperature for 24 h. The resin was filtered and washed with DCM, then with 50% (v/v) DCM/methanol, finally with methanol. The resin was dried in vacuo to a constant weight.
  • Solid-phase synthesis of tetrazole derivatives Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in MeOH DCM (1 :2) served as the isocyanide input, and hydrazoic acid (10 equivalents) as a single input. Twelve amines (10 equiv) in column 1-12 and eight aldehydes (10 equiv) in rows A-H were used for the construction of the library as follows.
  • the ester-styrene resin bound isocyanide (0.88 g, 1.5 mmol/g) was partitioned equally into a 96-well polyethylene microtiter plate.
  • the eight aldehydes (1 M in MeOH, 138 ⁇ l, 10 equiv) and twelve amines (1 M in MeOH, 138 ⁇ l, 10 equiv) were each added to the appropriate wells.
  • Hydraozic acid 108 ⁇ l, 5.5 % in benzene, 10 equiv was each added to all wells.
  • the plate was capped and shaken at room temperature for 16 h.
  • the resin was rinsed with DCM (200 ⁇ l) and MeOH (200 ⁇ l).

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Abstract

L'invention concerne des bibliothèques d'analogues nucléosidiques et des composés contenus dans ces bibliothèques, qui sont préparés selon une approche mettant en oeuvre des bibliothèques combinatoires en phase solide. Dans quelques aspects préférés de l'invention, diverses bases hétérocycliques et/ou divers substituants nucléosidiques sont préparés par condensation à plusieurs constituants (MCC). Dans d'autres aspects préférés de l'invention, la diversité des bibliothèques est obtenue par l'utilisation de nucléosides couplés en phase solide, dans une série d'au moins deux réactions de modification. Des composés particulièrement préférés comprennent des analogues nucléosidiques obtenus par la mise en oeuvre de bibliothèques de l'invention, qui peuvent être utiles pour le traitement de diverses affections, en particulier des infections virales ou des maladies néoplatiques.
PCT/US2002/034025 2001-12-17 2002-10-23 Bibliotheques nucleosidiques et composes obtenus au moyen de strategies combinatoires mcc realisees sur support solide WO2003052053A2 (fr)

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AU2002349905A AU2002349905A1 (en) 2001-12-17 2002-10-23 Nucleoside libraries and compounds by mcc combinatorial strategies on solid support

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US60/342,337 2001-12-17

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5650489A (en) * 1990-07-02 1997-07-22 The Arizona Board Of Regents Random bio-oligomer library, a method of synthesis thereof, and a method of use thereof
WO1996030392A1 (fr) * 1995-03-28 1996-10-03 Novartis Ag Procede de production de bibliotheques combinatoires de composes
WO1999034378A1 (fr) * 1997-12-23 1999-07-08 Siemens Aktiengesellschaft Dispositif pour la commande d'un actionneur electromecanique
EP1412495A2 (fr) * 2001-05-10 2004-04-28 Novozymes A/S Methode de production de polynucleotides recombines
NZ529465A (en) * 2001-06-15 2005-05-27 Crucell Holland B Chimaeric phages

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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