公开(公告)号：US07687617B2

公开(公告)日：2010-03-30

申请号：US10717434

申请日：2003-11-18

申请人： Charlotte Albaek Thrue ,  Christoph Rosenbohm ,  Henrik Frydenlund Hansen ,  Majken Westergaard ,  Nikolaj Dam Mikkelsen ,  Signe M. Christensen ,  Troels Koch ,  Daniel Sejer Pedersen ,  Miriam Frieden

发明人： Charlotte Albaek Thrue ,  Christoph Rosenbohm ,  Henrik Frydenlund Hansen ,  Majken Westergaard ,  Nikolaj Dam Mikkelsen ,  Signe M. Christensen ,  Troels Koch ,  Daniel Sejer Pedersen ,  Miriam Frieden

IPC分类号： C07H21/04 ,  A61K31/70

CPC分类号： C12N15/113 ,  A61K31/7088 ,  C07H19/04 ,  C07H19/06 ,  C07H19/16 ,  C07H21/00 ,  C07H21/02 ,  C07H21/04 ,  C12N15/111 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2310/315 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/344 ,  C12N2320/30 ,  C12N2320/51

摘要： The present invention is directed to novel oligonucleotides with improved antisense properties. The novel oligonucleotides comprise at least one Locked Nucleic Acid (LNA) selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides. The present invention also provides a new class of pharmaceuticals which comprise antisense oligonucleotides and are useful in antisense therapy.

摘要翻译： 本发明涉及具有改进的反义性质的新型寡核苷酸。 所述新型寡核苷酸包含至少一种选自β-D-thio / amino-LNA或α-L-氧基/硫代/氨基-LNA的锁定核酸（LNA）。 包含LNA的寡核苷酸还可以包括DNA和/或RNA核苷酸。 本发明还提供了一类新的药物，其包含反义寡核苷酸并且可用于反义治疗。

公开(公告)号：US07569575B2

公开(公告)日：2009-08-04

申请号：US10435607

申请日：2003-05-08

申请人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

发明人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

IPC分类号： C07D473/06 ,  C07D473/16 ,  C07D473/18 ,  C07D473/34 ,  C07D473/32 ,  C07D473/40 ,  C07D239/10 ,  C07D239/22 ,  A61K31/52 ,  A61K31/522 ,  A61K31/506 ,  A61P31/22

CPC分类号： C07H19/20 ,  C07H19/00 ,  C07H19/04 ,  C07H19/048

摘要： The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as α-L-oxy-LNA, amino-LNA, α-L-amino-LNA, thio-LNA, α-L-thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilizing intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues.

摘要翻译： 本发明涉及一种用于合成锁定核酸衍生物的新策略，例如α-小鼠，L

公开(公告)号：US09045518B2

公开(公告)日：2015-06-02

申请号：US10535472

申请日：2003-11-18

申请人： Signe M. Christensen ,  Nikolaj Dam Mikkelsen ,  Miriam Frieden ,  Henrik Frydenlund Hansen ,  Troels Koch ,  Daniel Sejer Pedersen ,  Christoph Rosenbohm ,  Charlotte Albaek Thrue ,  Majken Westergaard

发明人： Signe M. Christensen ,  Nikolaj Dam Mikkelsen ,  Miriam Frieden ,  Henrik Frydenlund Hansen ,  Troels Koch ,  Daniel Sejer Pedersen ,  Christoph Rosenbohm ,  Charlotte Albaek Thrue ,  Majken Westergaard

IPC分类号： C07H21/04 ,  C07H19/16 ,  A61K31/7088 ,  C07H21/00 ,  C12N15/11 ,  C07H19/04 ,  C12N15/113 ,  C07H19/06 ,  C07H21/02

CPC分类号： C12N15/113 ,  A61K31/7088 ,  C07H19/04 ,  C07H19/06 ,  C07H19/16 ,  C07H21/00 ,  C07H21/02 ,  C07H21/04 ,  C12N15/111 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2310/315 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2310/344 ,  C12N2320/30 ,  C12N2320/51

摘要： A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

摘要翻译： 一种新型的药物，其包含可用于反义治疗的锁定核酸（LNA）。 这些新型寡核苷酸具有改善的反义性质。 所述新型寡核苷酸由至少一种选自β-D-thio / amino-LNA或α-L-氧基/硫代/氨基-LNA的LNA组成。 包含LNA的寡核苷酸还可以包括DNA和/或RNA核苷酸。

公开(公告)号：US20140288299A1

公开(公告)日：2014-09-25

申请号：US13811771

申请日：2011-07-25

申请人： Michael Meldgaard ,  Marianne Mogensen ,  Christian Frauendorf ,  Christoph Rosenbohm

发明人： Michael Meldgaard ,  Marianne Mogensen ,  Christian Frauendorf ,  Christoph Rosenbohm

IPC分类号： C12N15/10

CPC分类号： C12N15/1017 ,  C07H21/04 ,  C12N15/111 ,  C12N2310/322 ,  C12N2310/3231 ,  C12N2310/341 ,  C12N2330/30 ,  C12N2310/3531

摘要： The present invention relates to a process for preparing a short oligonucleotide comprising the steps of: (i) preparing a crude mixture comprising the oligonucleotide (ii) subjecting the mixture formed in step (i) to a desalting step; wherein the process does not comprise a chromatographic purification step.

摘要翻译： 本发明涉及一种制备短寡核苷酸的方法，包括以下步骤：（i）制备包含寡核苷酸的粗混合物（ii）使步骤（i）中形成的混合物经历脱盐步骤; 其中该方法不包括色谱纯化步骤。

公开(公告)号：US20100062994A1

公开(公告)日：2010-03-11

申请号：US12373640

申请日：2007-07-06

申请人： Jacob Ravn ,  Christoph Rosenbohm ,  Katrine Qvortrup ,  Troels Koch

发明人： Jacob Ravn ,  Christoph Rosenbohm ,  Katrine Qvortrup ,  Troels Koch

IPC分类号： A61K31/52 ,  C07H19/167 ,  A61P43/00

CPC分类号： C07D473/00 ,  C07H19/16

摘要： The present application discloses locked nucleoside compounds of the Formula I which act as antagonists of adenosine receptors, in particular the adenosine A3 receptor, and the use of such adenosine A3 receptor compounds in medicine, e.g. for the treatment or alleviation or prophylaxis of selected from the group consisting of pain; inflammatory diseases, arthritis, multiple sclerosis, inflammation, asthma and psoriasis; gastro-intestinal disorders; allergy; disorders associated with mast cell or eosinophil activation and degranulation; cardio-vascular disorders; cutaneous diseases; wound healing; opthalmological disorders; respiratory disorders; kidney diseases; central nervous system disorders; Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease and Parkinson's disease; trauma and seizure; diabetes; osteoporosis; diseases of the immune system; cancers, infections; high blood pressure, locomotor hyperactivity, hypertension and depression; acute hypoxia; neonatal hypoxia, hypoxia and chronic hypoxia; and infertility.

摘要翻译： 本申请公开了作为腺苷受体，特别是腺苷A3受体的拮抗剂的式I的锁定核苷化合物，以及这些腺苷A3受体化合物在医学中的应用。 用于治疗或减轻或预防选自疼痛的组; 炎性疾病，关节炎，多发性硬化，炎症，哮喘和银屑病; 胃肠道疾病; 过敏; 与肥大细胞或嗜酸性粒细胞活化和脱颗粒相关的疾病; 心血管疾病; 皮肤病; 伤口愈合; 眼科疾病; 呼吸系统疾病; 肾脏疾病; 中枢神经系统疾病; 阿尔茨海默病，克雅氏病，亨廷顿氏病和帕金森病; 创伤和癫痫发作; 糖尿病; 骨质疏松症 免疫系统疾病; 癌症，感染; 高血压，运动过度活动，高血压和抑郁; 急性缺氧 新生儿缺氧，缺氧和慢性缺氧; 和不育症。

公开(公告)号：US20120322848A1

公开(公告)日：2012-12-20

申请号：US13443557

申请日：2012-04-10

申请人： Christoph Rosenbohm ,  Lene S. Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens B. Hansen ,  Marlene Asklund

发明人： Christoph Rosenbohm ,  Lene S. Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens B. Hansen ,  Marlene Asklund

IPC分类号： A61K31/712 ,  A61P35/02 ,  A61P35/00

CPC分类号： C12N15/1135 ,  A61K38/00 ,  C12N2310/11 ,  C12N2310/315 ,  C12N2310/319 ,  C12N2310/3341

摘要： The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5′-(MeCx)(Tx)MeCxAsAstsCsCsastsgsgsMeCxAx(Gx)(c)-3′, and preferably of the general formula 5′-MeCxTxMeCxAsastscscsastsgsgsMeCxAxGxc-3′, wherein capital letters designate an LNA nucleotide analogue selected from β-D-oxy-LNA, β-D-thio-LNA, β-D-amino-LNA and α-L-oxy-LNA, small letters designate a deoxynucleotide, and underline designates either an LNA nucleotide analogue as defined above or a deoxynucleotide. Such LNA oligonucleotides exhibit surprisingly good properties with respect to inhibition of the expression of Survivin by means of an anti-sense mechanism, and thereby lead to reduction or inhibition of tumour development in vivo. The LNA oligonucleotides are superior to other LNA oligonucletides targeting Surviving mRNA measured by functional read outs such as apoptosis induction and proliferation inhibition, and is potent in down-regulating Survivin mRNA and protein in transfected cancer cell lines, and induce apoptosis in combination with Taxol superior compared to other LNA oligonucleotides.

摘要翻译： 本公开内容涉及具有通式5'（（MeCx）（Tx）MeCxAsAstsCsCsastsgsgsMeCxAx（Gx）（c）-3'，优选通式为5'-MeCxTxMeCxAsastscscsastsgsgsMeCxAxGxc-3'的（亚）序列的LNA寡核苷酸， 其中大写字母表示选自以下的LNA核苷酸类似物：-D-oxy-LNA，＆bgr; -D-thio-LNA，＆bgr; -D-氨基-LNA和α-L-氧-LNA，小字母表示脱氧核苷酸 ，下划线表示如上定义的LNA核苷酸类似物或脱氧核苷酸。 这样的LNA寡核苷酸在通过反义机制抑制存活蛋白的表现方面表现出惊人的良好性质，从而导致体内肿瘤发展的减少或抑制。 LNA寡核苷酸优于靶向通过功能读数（如凋亡诱导和增殖抑制）测量的存活mRNA的其他LNA寡核苷酸，并且在转染的癌细胞系中下调Survivin mRNA和蛋白质，并且与Taxol优异结合诱导凋亡有效 与其他LNA寡核苷酸相比。

公开(公告)号：US20060154888A1

公开(公告)日：2006-07-13

申请号：US11272124

申请日：2005-11-09

申请人： Christoph Rosenbohm ,  Lene Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens Hansen ,  Marlene Asklund

发明人： Christoph Rosenbohm ,  Lene Kjaerulff ,  Majken Westergaard ,  Margit Wissenbach ,  Jens Hansen ,  Marlene Asklund

IPC分类号： A61K48/00

CPC分类号： C12N15/1135 ,  A61K38/00 ,  C12N2310/11 ,  C12N2310/315 ,  C12N2310/319 ,  C12N2310/3341

摘要： The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5′-(MeCx)(Tx)MeCxAsAstscscsastsgsgsMeCxAx(Gx)(c)-3′, and preferably of the general formula 5′-MeCxTxMeCxAsastscscsastsgsgsMeCxAxGxc-3′, wherein capital letters designate an LNA nucleotide analogue selected from β-D-oxy-LNA, β-D-thio-LNA, β-D-amino-LNA and α-L-oxy-LNA, small letters designate a deoxynucleotide, and underline designates either an LNA nucleotide analogue as defined above or a deoxynucleotide. Such LNA oligonucleotides exhibit surprisingly good properties with respect to inhibition of the expression of Survivin by means of an anti-sense mechanism, and thereby lead to reduction or inhibition of tumour development in vivo. The LNA oligonucleotides are superior to other LNA oligonucletides targeting Surviving mRNA measured by functional read outs such as apoptosis induction and proliferation inhibition, and is potent in down-regulating Survivin mRNA and protein in transfected cancer cell lines, and induce apoptosis in combination with Taxol superior compared to other LNA oligonucleotides.

公开(公告)号：US20120165514A1

公开(公告)日：2012-06-28

申请号：US13336303

申请日：2011-12-23

申请人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

发明人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

IPC分类号： C07H19/02

CPC分类号： C07H19/20 ,  C07H19/00 ,  C07H19/04 ,  C07H19/048

摘要： The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as α-L-oxy-LNA, amino-LNA, α-L-amino-LNA, thio-LNA, α-L-thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilising intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues.

摘要翻译： 本发明涉及一种合成锁定核酸衍生物的新策略，如α-L-氧-LNA，氨基-LNA，α-L-氨基-LNA，硫代-LNA，α-L-硫代-LNA， 硒代-LNA和亚甲基LNA，其利用也可以产生其他LNA类似物如oxy-LNA的中间体提供可伸缩的高产反应。 此外，式X的化合物是可能与各种亲核试剂反应的重要中间体，导致各种各样的LNA类似物。

公开(公告)号：US08084458B2

公开(公告)日：2011-12-27

申请号：US12534711

申请日：2009-08-03

申请人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

发明人： Mads Detlef Sørensen ,  Jesper Wengel ,  Troels Koch ,  Signe M. Christensen ,  Christoph Rosenbohm ,  Daniel Sejer Pedersen

IPC分类号： C07D473/06 ,  C07D473/16 ,  C07D473/18 ,  C07D473/34 ,  C07D473/40 ,  C07D239/10 ,  C07D239/52 ,  A61P31/22

CPC分类号： C07H19/20 ,  C07H19/00 ,  C07H19/04 ,  C07H19/048

摘要： Methods are described for the synthesis of Locked Nucleic Acid (LNA) derivatives using certain nitrogen-containing nucleophiles.

摘要翻译： 描述了使用某些含氮亲核试剂合成锁定核酸（LNA）衍生物的方法。

公开(公告)号：US20090118213A1

公开(公告)日：2009-05-07

申请号：US12066852

申请日：2006-09-01

申请人： Henrik Frydenlund Hansen ,  Bo Hansen ,  Majken Westergaard ,  Ellen Marie Straarup ,  Christoph Rosenbohm

发明人： Henrik Frydenlund Hansen ,  Bo Hansen ,  Majken Westergaard ,  Ellen Marie Straarup ,  Christoph Rosenbohm

IPC分类号： A61K31/7088 ,  C07H21/04

CPC分类号： C12N15/113 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/315 ,  C12N2310/3231 ,  C12N2310/3341 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2310/3515

摘要： Oligonucleotides directed against the Apo-B100 gene are provided for modulating the expression of Apo-B100. The compositions comprise oligonucleotides, particularly antisense oligonucleotides, targeted to nucleic acids encoding the Apo-B100. Methods of using these compounds for modulation of Apo-B100 expression and for the treatment of diseases associated with either overexpression of Apo-B100, expression of mutated Apo-B100 or both are provided. Examples of diseases are cancer such as lung, breast, colon, prostate, pancreas, lung, liver, thyroid, kidney, brain, testes, stomach, intestine, bowel, spinal cord, sinuses, bladder, urinary tract or ovaries cancers. The oligonucleotides may be composed of deoxyribonucleosides or a nucleic acid analogue such as for example locked nucleic acid or a combination thereof.

摘要翻译： 提供针对Apo-B100基因的寡核苷酸用于调节Apo-B100的表达。 组合物包含针对编码Apo-B100的核酸的寡核苷酸，特别是反义寡核苷酸。 提供了使用这些化合物调节Apo-B100表达和治疗与Apo-B100的过度表达相关的疾病，突变的Apo-B100或两者的表达的方法。 疾病的例子包括肺，乳腺，结肠，前列腺，胰腺，肺，肝，甲状腺，肾，脑，睾丸，胃，肠，肠，脊髓，鼻窦，膀胱，尿道或卵巢癌等癌症。 寡核苷酸可以由脱氧核糖核苷或核酸类似物例如锁定的核酸或其组合构成。