WO2001027114A1 - ANALOGUES NUCLEOSIDIQUES DE PYRROLO[2,3-d]PYRIMIDINE - Google Patents

ANALOGUES NUCLEOSIDIQUES DE PYRROLO[2,3-d]PYRIMIDINE Download PDF

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Publication number
WO2001027114A1
WO2001027114A1 PCT/US2000/022674 US0022674W WO0127114A1 WO 2001027114 A1 WO2001027114 A1 WO 2001027114A1 US 0022674 W US0022674 W US 0022674W WO 0127114 A1 WO0127114 A1 WO 0127114A1
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Prior art keywords
group
pyrrolo
cell
aralkyl
alkynyl
Prior art date
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PCT/US2000/022674
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English (en)
Inventor
Guangyi Wang
Robert Tam
Zbigniew Pietrzkowski
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Icn Pharmaceuticals, Inc.
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Filing date
Publication date
Priority to EP00959267A priority Critical patent/EP1212326A4/fr
Priority to CA002381297A priority patent/CA2381297A1/fr
Priority to IL14790800A priority patent/IL147908A0/xx
Priority to SK177-2002A priority patent/SK1772002A3/sk
Application filed by Icn Pharmaceuticals, Inc. filed Critical Icn Pharmaceuticals, Inc.
Priority to SI200020035A priority patent/SI20819A/sl
Priority to HU0301875A priority patent/HUP0301875A2/hu
Priority to BR0013642-5A priority patent/BR0013642A/pt
Priority to AU70618/00A priority patent/AU769578B2/en
Priority to JP2001530332A priority patent/JP2003511454A/ja
Priority to MXPA02001753A priority patent/MXPA02001753A/es
Priority to KR1020027002570A priority patent/KR20020092904A/ko
Priority to US09/797,549 priority patent/US6831069B2/en
Publication of WO2001027114A1 publication Critical patent/WO2001027114A1/fr
Priority to HR20020163A priority patent/HRP20020163A2/hr
Priority to NO20020931A priority patent/NO20020931D0/no

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    • 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
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the field of the invention is nucleoside analogs.
  • Nucleoside analogs have long been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, nucleoside analogs are frequently phosphorylated by nucleoside salvage pathways, in which the analogs are typically phosphorylated to the corresponding mono-, di-, and triphosphates. Among other intracellular destinations, triphosphorylated nucleoside analogs often are used as substrate for DNA or RNA polymerases and consequently incorporated into DNA or RNA. Where triphosphorylated nucleoside analogs are strong polymerase inhibitors, they may induce premature termination of a nascent nucleic acid molecule. Where triphosphorylated nucleoside analogs are incorporated into nucleic acid replicates or transcripts, gene expression or disruption of function may result.
  • nucleoside analogs can also interfere with the cell cycle, and especially desirable effects of nucleoside analogs include induction of apoptosis of cancer cells. Furthermore, nucleoside analogs are also known to modulate certain immune responses.
  • nucleoside analogs with relatively potent anti-cancer activity are known in the art.
  • known drugs include thymidylate synthase inhibitors such as 5-f uorouridine, adenosine deaminase inhibitors, including 2-chloroadenosine, and neplanocin A, which is an inhibitor of S-adenosylhomocysteine hydrolase.
  • thymidylate synthase inhibitors such as 5-f uorouridine
  • adenosine deaminase inhibitors including 2-chloroadenosine
  • neplanocin A which is an inhibitor of S-adenosylhomocysteine hydrolase.
  • all or almost all of the known nucleoside analogs also imply a threat to normal mammalian cells, primarily because these nucleoside analog's lack adequate selectivity between normal cells and tumor cells. Unfortunately, lack of adequate selectivity is frequently associated with severe side effects, and therefore often
  • the present invention is directed to nucleoside analogs with modifications on the sugar moieties of the pyrrolo[2,3-d]pyrimidine nucleoside analogs, which can significantly reduce the toxicity of the nucleoside analogs to the mammalian cells while they also provide significant cytotoxicity to cancer cells. These modifications include but are not limited to substitutions at the C4' and C5' positions of ribofuranose moieties.
  • the present invention also demonstrates that certain pyrrolo[2,3-d]pyrimidine nucleoside analogs have desired immunomodulation effects, including enhancement of Type 1 cytokines such as IL-2 and suppression of Type 2 cytokines such as IL-4. These immunomodulation properties can be useful in anticancer, antiviral and autoimmune diseases, treating inflammation and preventing graft rejection.
  • the nucleoside analog is a pyrrolo[2,3]pyrimidine nucleoside having a structure according to the formula (I):
  • A is O, S, or CH2;
  • X is H, NH 2 or OH;
  • Y is H, halogen or NH 2 ;
  • R 2 and R are independently selected from the group consisting of H, F, and OH;
  • R is selected from the group consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R 4 optionally has at least one of a heteroatom and a functional group;
  • R 5 is H, OH, OP(O)(OH)
  • the nucleoside analog is a pyrrolo[2,3d]pyrimidine nucleoside having a structure according to the formula (II):
  • contemplated compounds are utilized to inhibit tumor growth or to modulate Type 1 and Type 2 cytokine. and chemokine production.
  • Fig. 1 is a first exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig. 2 is a second exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig.3 is a third exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig. 4 is a fourth exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig. 5 is a fifth exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig. 6 is a sixth exemplary synthetic scheme of reactions included in the production of compounds according to the inventive subject matter.
  • Fig. 7 depicts exemplary compounds according to the inventive subject matter.
  • Fig. 8 A and 8B are graphs representing the effect of compounds according to the inventive subject matter on the expression of Type 1 and Type 2 cytokines, respectively.
  • Fig. 9 is a table indicating cytotoxicity of various compounds according to the inventive subject matter.
  • Fig. 10 is a table indicating rates of DNA synthesis in cells treated with of various compounds according to the inventive subject matter.
  • Fig. 1 1 is a graph depicting the inhibition of VEGF release from human prostate cancer cells upon treatment with compounds according to the inventive subject matter.
  • Fig. 12 is a graph depicting the inhibition of IL-8 release from human prostate cancer cells upon treatment with compounds according to the inventive subject matter.
  • A is O, S. or CH 2 ;
  • X is H, NH 2 or OH;
  • Y is H. halogen or NH 2 ;
  • R is selected from the group consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R optionally has at least one of a heteroatom and a functional group
  • R 5 is H, OH, OP(O)(OH) 2 , P(O)(OH) 2 , OP(O)(OR') 2 , or P(O)(OR') 2 , wherein R' is a masking group
  • R 5 ' is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R_y has at least two carbon atoms, and optionally has at least one of a heteroatom and a functional group.
  • alkyl alkenyl
  • alkynyl alkynyl
  • aralkyl refers to both linear and branched species. With respect to the substituents R 2 and R 3 , it should be appreciated that both R 2 and R 3 may be independently directed to the ⁇ - or ⁇ -face. Furthermore, where the substituents on C_y are non-identical, substitution on Cs may result in an R- or S-chiral center.
  • heteroatom refers to non-carbon atoms in an organic molecule, and particularly contemplated heteroatoms include halogens, nitrogen, oxygen, and sulfur.
  • the term "functional group” as used herein refers to a reactive bond (e.g., double or triple bond) or reactive group (e.g., -OH, -SH, -NH , -N 3 , -CN, COOH, -CHO, -CONH 2 , etc.).
  • the pyrrolo[2,3-d]pyrimidine nucleoside analog according to formula (II) has the following structure:
  • contemplated forms include prodrug forms or otherwise modified forms in which contemplated molecules are chemically and/or enzymatically modified to improve pharmacological and/or pharmacodynamical properties, including higher specificity towards target organs, cells or subcellular compartments and increased half-life time in the organism.
  • cholesterol adducts may be formed to increase target specificity towards the liver, or apolipoprotein adducts may be formed to enhance penetration of the modified drug across the blood brain barrier to the brain.
  • receptor ligand complexes may be synthesized to target the modified drug to a particular cell expressing a receptor specific for the ligand.
  • antibody or antibody fragment complexes may be formed to increase selective delivery of the modified drug to a subcellular location.
  • charged or uncharged groups, lipophilic or polar groups may be added to contemplated molecules to increase the half-life time in serum or other target organs and/or cells.
  • contemplated compounds, where phosphorylated at the C 5 atom may also be di-, or tri-phosphorylated, or incorporate a thiophosphate.
  • contemplated compounds have a sugar moiety in the
  • contemplated compounds may have a sugar moiety in the L-configuration.
  • Further stereochemical aspects especially include R and S configurations at the C 5 atom where appropriate, and it should be appreciated that the substituents in contemplated compounds may be directed to ⁇ or ⁇ phase.
  • contemplated compounds can be formulated in various formulations, including liquid, syrup or gel forms (e.g., for injection, ingestion, or topical administration) and solid forms (e.g., for ingestion, injection, or deposition in a body cavity).
  • liquid, syrup or gel forms e.g., for injection, ingestion, or topical administration
  • solid forms e.g., for ingestion, injection, or deposition in a body cavity.
  • injection of a preferably isotonic solution is particularly contemplated.
  • contemplated forms may be administered in form of a syrup or tablet.
  • contemplated compounds may also be formulated for topical or transdermal applications.
  • formulations known in the art all of which are also contemplated suitable in conjunction with the inventive subject matter presented herein, and particularly contemplated formulations are described in "Drug Products for Clinical Trials: An Intl. Guide to Formulation, Production, Quality Control" by Donald C. Monkhouse and Christopher T. Rhodes (Editors); ISBN:082479852X.
  • contemplated compounds and formulations may include functional and non-functional additives.
  • skin penetration enhancers may be added.
  • pharmaceuticals including cytostatic, antiviral, or immunomodulatory agents may be added to synergistically or additively improve the function of contemplated compounds.
  • non- functional additives include fillers, antioxidants, flavor, or color agents to enhance a particular quality of contemplated compounds.
  • the concentration of contemplated compounds is in a range of approximately 1 ⁇ M to about 1 OO ⁇ M when measured at the site of action.
  • appropriate concentrations may also be in the range of 999nM to lOnfvl, and less.
  • contemplated concentrations may be 0.1 mM and lOOmM, and more. Consequently, the dosage of contemplated compounds may vary significantly, but appropriate dosages can readily be determined in in vitro or animal experiments.
  • a contemplated method of changing secretion of a cytokine from a cell may comprise a step in which a compound according to formula (I) is provided and has a further step in which the cell is presented with the compound according to formula (I) at a concentration effective to change the secretion of the cytokine.
  • substituents in formula (I) are generally contemplated, particularly contemplated compounds are compounds according to formula (I) wherein R 4 and Ry are independently selected from the group consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl.
  • the compound employed to change the secretion of a cytokine from a cell may also be a compound according to the following structure:
  • R 5 is H, OH, OP(O)(OH) 2 , P(O)(OH) 2 , OP(O)(OR') 2 , or P(O)(OR') 2 , with R being a masking group.
  • Contemplated cytokines particularly include Type 1 (e.g., IFN ⁇ ) and Type 2 (e.g., IL-4) cytokines.
  • Type 1 e.g., IFN ⁇
  • Type 2 e.g., IL-4
  • cytokines include lymphocytes and cancer cells (e.g., prostate cancer cells, infra).
  • a method of reducing growth of a hyperproliferative cell may comprise a step in which a compound according to formula (I) is provided, and another step in which the hyperproliferative cell is presented with the compound at a concentration effective to reduce the growth of the hyperproliferative cell.
  • Particularly preferred compounds include compounds according to formula (I) wherein R is selected from the group consisting of a hydrogen, an alkyl. an alkenyl, an alkynyl, and an aralkyl. wherein R optionally contains at least one of a heteroatom and a functional group, and wherein R 5' is selected from the group consisting of a hydrogen, an alkyl. an alkenyl. an alkynyl. and an aralkyl. wherein R 5' has at least two carbon atoms, and optionally contains at least one of a heteroatom and a functional group, with the proviso that R and Ry are not together hydrogen, and with the remaining substituents as defined above in formula (I).
  • hyperproliferative cells include cancer cells, and an especially contemplated cancer cell is a prostate cancer cell. While not whishing to be bound to a particular theory, it is contemplated that the reduction of growth comprises reduction of DNA synthesis.
  • a method of reducing a release of a growth factor from a cell has a step in which a compound according to formula (I) is provided, and another step in which the cell is presented with the compound at a concentration effective to reduce the release of the growth factor. It is contemplated that the release of various growth factors may be reduced by the method presented herein, however reduction of VEGF release is especially contemplated. Similarly, while all cells known to secrete growth factors are contemplated in conjunction with the method presented herein, particularly contemplated cells include cancer cells, and especially prostate cancer cells.
  • pyrrolo[2,3-d]pyrimidine nucleoside analogs can be synthesized via various synthetic routes, and the following procedures are provided by way of example only. Synthesis of C5 '-modified pyrrolo [2, 3-d] pyrimidine nucleoside analogs
  • the 5 '-substituted nucleoside analogs are prepared from the condensation of the pyrrolo[2.3-d]pyrimidine bases and the properly protected, 5 '-substituted ribofuranoses.
  • Compound 1 prepared according to a published procedure (Jones et al. Methods in carbohydrate Chemistry (edited by Whistler and Moffat), vol. VI, pp315-322,
  • the pyrrolo[2,3-d]pyrimidine nucleoside analogs of the present invention are bioactive since they indicate some level of cytotoxicity in vitro.
  • the compounds tested were applied to cell culture of normal human fibroblasts, human Prostate cancer cells 81 , human Melanoma cancer cells 140, Human Lung Cancer cells 177, and human Ovarian Cancer cells R and NR (all available from ATCC). In these experiments cells were plated at density of 2000 cells per 200 ⁇ l of medium per well (96-well plate). The compounds tested were applied to the wells once, at concentration range 0.78-100 ⁇ M, just after plating of cells. The colorimetric cytotoxicity assay MTS was performed after 72 hrs of treatment.
  • 4-Amino-5-cyano-7-(2,3-dideoxy- ⁇ -D- glicero-pentofuranosyl)pyrrolo[2,3- ⁇ /]pyrimidine was prepared from 4-amino-5-cyano-7-(2,3- dideoxy- ⁇ -D-pent-2-enofuranosyl)pyrrolo[2.3- ⁇ Jpyrimidine.
  • toyocamicin 43 To a stirred solution of toyocamicin 43 (5.83 g, 20.0 mmol) in anhydrous pyridine (100 mL) at 0°C was added tert-butylchlorodiphenylsilane (6.2 mL, 24.0 mmol). The resulting mixture was stirred at room temperature for 18 h and then cooled to 0°C, and methanesulfonyl chloride (3.4 mL, 44.0 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, cooled with ice, quenched by adding water (2 mL), and stirred at room temperature for 30 min. The solvent was evaporated.

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Abstract

La présente invention concerne des compositions et des techniques destinées à des analogues nucléosidiques de pyrrolo[2,3-d]pyrimidine possédant des substituants en C4' et C5' de la fraction de ribofuranose. Ces compositions présentent, entre autres effets, des effets anticancéreux et immunorégulateurs pour une cytotoxicité réduite.
PCT/US2000/022674 1999-08-27 2000-08-17 ANALOGUES NUCLEOSIDIQUES DE PYRROLO[2,3-d]PYRIMIDINE WO2001027114A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
HU0301875A HUP0301875A2 (hu) 1999-08-27 2000-08-17 Pirrolo[2,3-d]pirimidinnukleozid-származékok
IL14790800A IL147908A0 (en) 1999-08-27 2000-08-17 PYRROLO[2,3-d] PYRIMIDINE NUCLEOSIDE ANALOGS
SK177-2002A SK1772002A3 (en) 1999-08-27 2000-08-17 Nucleoside analog, method of change of cytokine secreting from a cell and method for inhibiting the growth of hyperproliferative cells
AU70618/00A AU769578B2 (en) 1999-08-27 2000-08-17 Pyrrolo(2,3-d)pyrimidine nucleoside analogs
SI200020035A SI20819A (sl) 1999-08-27 2000-08-17 Analogi pirolo/2,3-d/pirimidinskih nukleozidov
CA002381297A CA2381297A1 (fr) 1999-08-27 2000-08-17 Analogues nucleosidiques de pyrrolo¬2,3-d|pyrimidine
BR0013642-5A BR0013642A (pt) 1999-08-27 2000-08-17 Análogos de nucleosìdeo de pirrolo[2,3-d]pirimidina
EP00959267A EP1212326A4 (fr) 1999-08-27 2000-08-17 ANALOGUES NUCLEOSIDIQUES DE PYRROLO 2,3-d]PYRIMIDINE
JP2001530332A JP2003511454A (ja) 1999-08-27 2000-08-17 ピロロ［２，３−ｄ］ピリミジンヌクレオシド類似化合物
MXPA02001753A MXPA02001753A (es) 1999-08-27 2000-08-17 Analogos de nucleosido de pirrolo [2,3-d]pirimidina.
KR1020027002570A KR20020092904A (ko) 1999-08-27 2000-08-17 피롤로[2,3-ｄ]피리미딘 누클레오사이드 유사체
US09/797,549 US6831069B2 (en) 1999-08-27 2001-02-28 Pyrrolo[2,3-d]pyrimidine nucleoside analogs
HR20020163A HRP20020163A2 (en) 1999-08-27 2002-02-22 PYRROLO[2,3-d]PYRIMIDINE NUCLEOSIDE ANALOGS
NO20020931A NO20020931D0 (no) 1999-08-27 2002-02-26 Pyrrolo[2,3-d]pyrimidin-nukleosid-analoger

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US15123399P 1999-08-27 1999-08-27
US60/151,233 1999-08-27

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EP (1) EP1212326A4 (fr)
JP (1) JP2003511454A (fr)
KR (1) KR20020092904A (fr)
CN (1) CN1384834A (fr)
AU (1) AU769578B2 (fr)
BR (1) BR0013642A (fr)
CA (1) CA2381297A1 (fr)
HR (1) HRP20020163A2 (fr)
HU (1) HUP0301875A2 (fr)
IL (1) IL147908A0 (fr)
MX (1) MXPA02001753A (fr)
NO (1) NO20020931D0 (fr)
PL (1) PL354094A1 (fr)
RU (1) RU2002103501A (fr)
SI (1) SI20819A (fr)
SK (1) SK1772002A3 (fr)
WO (1) WO2001027114A1 (fr)
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EP1278528A1 (fr) * 2000-02-15 2003-01-29 ICN Pharmaceuticals, Inc. Analogues de nucleoside a base bicyclique modifiee par carboxamidine
WO2003051884A1 (fr) * 2001-12-18 2003-06-26 Takeda Chemical Industries, Ltd. Compose indolique condense, son procede de production et son utilisation
US7638496B2 (en) 2000-02-15 2009-12-29 Valeant Pharmaceuticals North America Nucleoside analogs with carboxamidine modified monocyclic base
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9073960B2 (en) 2011-12-22 2015-07-07 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
WO2016178870A1 (fr) 2015-05-04 2016-11-10 Eli Lilly And Company Analogues nucléosidiques 5'-substitués
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
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
JP2022130644A (ja) * 2018-05-15 2022-09-06 イルミナ インコーポレイテッド 表面結合オリゴヌクレオチドを化学開裂および脱保護するための組成物および方法
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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AU769578B2 (en) 2004-01-29
NO20020931L (no) 2002-02-26
IL147908A0 (en) 2002-08-14
CN1384834A (zh) 2002-12-11
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PL354094A1 (en) 2003-12-29
MXPA02001753A (es) 2002-10-23
HRP20020163A2 (en) 2004-02-29
HUP0301875A2 (hu) 2003-09-29
SI20819A (sl) 2002-08-31
BR0013642A (pt) 2002-05-07
ZA200201567B (en) 2003-07-30
EP1212326A1 (fr) 2002-06-12

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