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100 条记录 (耗时 0.08 秒)

    Modified iRNA agents
    81.
    发明授权
    Modified iRNA agents 有权
    修饰的iRNA试剂

    公开(公告)号：US08507661B2

    公开(公告)日：2013-08-13

    申请号：US12714298

    申请日：2010-02-26

    申请人： Muthiah Manoharan ,  Venkitasamy Kesavan ,  Kallanthottathil G. Rajeev

    发明人： Muthiah Manoharan ,  Venkitasamy Kesavan ,  Kallanthottathil G. Rajeev

    IPC分类号： C07H15/00 ,  C07H17/00 ,  C07H17/02

    CPC分类号： C12N15/111 ,  A61K47/554 ,  C12N2310/14 ,  C12N2310/323 ,  C12N2310/344 ,  C12N2310/3515 ,  C12N2320/51

    摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.

    摘要翻译： 本发明涉及iRNA试剂，其优选包括其中核糖部分被除核糖以外的部分替代的单体。 包含这样的单体可以允许调节掺入其中的iRNA试剂的性质，例如通过使用非核糖部分作为配体或其它实体例如亲油部分的点。 例如胆固醇是直接或间接的系链。 本发明还涉及制备和使用这种修饰的iRNA试剂的方法。

    Carbohydrate conjugates as delivery agents for oligonucleotides
    82.
    发明授权
    Carbohydrate conjugates as delivery agents for oligonucleotides 有权
    碳水化合物缀合物作为寡核苷酸的递送剂

    公开(公告)号：US08450467B2

    公开(公告)日：2013-05-28

    申请号：US13326203

    申请日：2011-12-14

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Narayanannair K. Jayaprakash ,  Martin Maier

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Narayanannair K. Jayaprakash ,  Martin Maier

    IPC分类号： C07H5/04 ,  C07H5/06 ,  C08B37/00

    CPC分类号： A61K47/28 ,  A61K31/70 ,  A61K31/7004 ,  A61K31/7052 ,  A61K31/7088 ,  A61K31/713 ,  A61K47/16 ,  A61K47/22 ,  A61K47/543 ,  A61K47/549 ,  A61K47/60 ,  A61K48/00 ,  C07H21/02 ,  Y02A50/385 ,  Y02A50/411 ,  Y02A50/467 ,  Y02P20/55

    摘要： The present invention provides iRNA agents comprising at least one subunit of the formula (I): wherein: A and B are each independently for each occurrence O, N(RN) or S; X and Y are each independently for each occurrence H, OH, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-Linker-OP(Z′″)(Z″″)O-oligonucleotide, a nucleotide, an oligonucleotide, —P(Z′)(Z″)-formula (I), —P(Z′)(Z″)— or -Linker-R; R is LG, -Linker-LG, or has the structure shown below: LG is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide; RN is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and Z′, Z″, Z′″ and Z″″ are each independently for each occurrence O or S.

    摘要翻译： 本发明提供包含至少一个式（I）亚基的iRNA试剂：其中：A和B各自独立地为O，N（RN）或S; X和Y各自独立地为H，OH，羟基保护基，磷酸基，磷酸二酯基，活化磷酸酯基，活化亚磷酸酯基，亚磷酰胺，固体载体，-P（Z'）（ Z'）（Z“）O - 寡核苷酸，脂质，PEG，类固醇，亲脂体，聚合物，-P（Z'）（Z”）O （Z'）（Z“） - （Z”）（Z“）（Z”）（Z“）（Z”） （Z“） - 或-Linker-R; R是LG，-Linker-LG，或具有如下结构：每次出现LG独立为碳水化合物，例如单糖，二糖，三糖，四糖，寡糖，多糖; 乙烯基，丙基，异丙基，丁基或苄基各自独立地为N， Z'，Z“，Z”“和Z”“各自独立地为O或S.

    Processes and reagents for desilylation of oligonucleotides
    88.
    发明授权
    Processes and reagents for desilylation of oligonucleotides 有权
    寡核苷酸脱乙酰化的方法和试剂

    公开(公告)号：US08063198B2

    公开(公告)日：2011-11-22

    申请号：US12050633

    申请日：2008-03-18

    申请人： Muthiah Manoharan ,  Michael E. Jung ,  Kallanthottathil G. Rajeev ,  Rajendra K. Pandey ,  Gang Wang

    发明人： Muthiah Manoharan ,  Michael E. Jung ,  Kallanthottathil G. Rajeev ,  Rajendra K. Pandey ,  Gang Wang

    IPC分类号： C07H21/00 ,  C07C17/07

    CPC分类号： C07H21/00 ,  C07H21/04 ,  Y02P20/55

    摘要： The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloroamine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.

    摘要翻译： 本发明涉及用于寡核苷酸合成和纯化的方法和试剂。 本发明的一个方面涉及可用于在寡核苷酸合成中活化亚磷酰胺的化合物。 本发明的另一方面涉及使用本发明的活化剂通过亚磷酰胺方法制备寡核苷酸的方法。 本发明的另一方面涉及硫转移剂。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及通过用本发明的硫转移试剂处理亚磷酸酯制备硫代磷酸酯的方法。 在优选的实施方案中，硫转移剂是3-氨基-1,2,4-二噻唑烷-5-酮。 本发明的另一方面涉及清除在带有乙腈基保护基团的磷酸酯基团去保护过程中产生的丙烯腈的化合物。 在优选的实施方案中，丙烯腈清除剂是聚合物结合的硫醇。 本发明的另一方面涉及用于将亚磷酸盐氧化成磷酸盐的试剂。 在优选的实施方案中，氧化剂是亚氯酸钠，氯胺或吡啶-N-氧化物。 本发明的另一方面涉及通过退火第一单链寡核苷酸和第二单链寡核苷酸来纯化寡核苷酸以形成双链寡核苷酸的方法; 并对双链寡核苷酸进行色谱纯化。 在优选的实施方案中，色谱纯化是高效液相色谱法。

    Modified iRNA agents
    90.
    发明授权
    Modified iRNA agents 有权
    修饰的iRNA试剂

    公开(公告)号：US08017762B2

    公开(公告)日：2011-09-13

    申请号：US12510050

    申请日：2009-07-27

    申请人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Meena

    发明人： Muthiah Manoharan ,  Kallanthottathil G. Rajeev ,  Meena

    IPC分类号： C07H21/04 ,  A61K31/70

    CPC分类号： C07H21/02

    摘要： The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose that further includes a tether having one or more linking groups, in which at least one of the linking groups is a cleavable linking group. The tether in turn can be connected to a selected moiety, e.g., a ligand, e.g., a targeting or delivery moiety, or a moiety which alters a physical property. The cleavable linking group is one which is sufficiently stable outside the cell such that it allows targeting of a therapeutically beneficial amount of an iRNA agent (e.g., a single stranded or double stranded iRNA agent), coupled by way of the cleavable linking group to a targeting agent—to targets cells, but which upon entry into a target cell is cleaved to release the iRNA agent from the targeting agent.The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.

    摘要翻译： 本发明涉及iRNA试剂，其优选包括其中核糖部分已被核糖替代的单体，其进一步包括具有一个或多个连接基团的系链，其中至少一个连接基团是可切割的 连接组。 系链又可以连接到所选择的部分，例如配体，例如靶向或递送部分，或改变物理性质的部分。 可切割连接基团是在细胞外部足够稳定的连接基团，使得其允许靶向治疗有益量的iRNA试剂（例如，单链或双链iRNA试剂），其通过可切割连接基团连接至 靶向细胞靶向细胞，但是在进入靶细胞时被切割以从靶向剂释放iRNA试剂。 包含这样的单体可以允许调节掺入其中的iRNA试剂的性质，例如通过使用非核糖部分作为配体或其它实体例如亲油部分的点。 例如胆固醇是直接或间接的系链。 本发明还涉及制备和使用这种修饰的iRNA试剂的方法。