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    COMPOSITIONS AND METHODS TO TREAT CARDIAC DISEASES
    4.
    发明申请
    COMPOSITIONS AND METHODS TO TREAT CARDIAC DISEASES 有权
    组合物和治疗心脏病的方法

    公开(公告)号：US20110212924A1

    公开(公告)日：2011-09-01

    申请号：US13031805

    申请日：2011-02-22

    申请人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

    发明人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

    IPC分类号： A61K31/675 ,  C07F9/6561 ,  A61P9/00

    CPC分类号： A61K31/675 ,  A61K31/683 ,  C07F9/65616

    摘要： Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.

    摘要翻译： 描述了膦酸盐和次膦酸盐，其包括其前体药物类似物的N-甲基碳酰胺衍生物。 含有（N） - 甲烷卡巴（双环[3.1.0]己烷）环体系的代替核糖的2-氯-AMP衍生物MRS2339激活P2X受体，配体门控离子通道。 基于由于C-P键的稳定性而增加的体内半衰期的期望，使用Michaelis-Arbuzov和Wittig反应合成MRS2339的膦酸酯类似物。 当通过小型渗透泵（Alzet）将氯雷斯特林过度表达的小鼠（心力衰竭的遗传模型）施用时，一些类似物显着增加体内完整的心脏收缩功能，如通过超声心动图来源的分数缩短（FS）评估的，与 车辆输注小鼠。 用于治疗心力衰竭的碳环核苷酸类似物的范围已经扩大。

    Compositions and methods to treat cardiac diseases
    5.
    发明授权
    Compositions and methods to treat cardiac diseases 有权
    治疗心脏病的组合物和方法

    公开(公告)号：US08822434B2

    公开(公告)日：2014-09-02

    申请号：US13031805

    申请日：2011-02-22

    申请人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

    发明人： Bruce Liang ,  Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Thatikonda Santhosh Kumar

    IPC分类号： A61K31/675 ,  C07F9/6561

    CPC分类号： A61K31/675 ,  A61K31/683 ,  C07F9/65616

    摘要： Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.

    摘要翻译： 描述了膦酸盐和次膦酸盐，其包括其前体药物类似物的N-甲基碳酰胺衍生物。 含有（N） - 甲烷卡巴（双环[3.1.0]己烷）环体系的代替核糖的2-氯-AMP衍生物MRS2339激活P2X受体，配体门控离子通道。 基于由于C-P键的稳定性增加的体内半衰期的期望，使用Michaelis-Arbuzov和Wittig反应合成MRS2339的膦酸酯类似物。 当通过小型渗透泵（Alzet）将其加入到氯海洛酮过表达的小鼠（心力衰竭的遗传模型）时，一些类似物在体内显着增加了完整的心脏收缩功能，如通过超声心动图衍生的分数缩短（FS）评估的，与 车辆输注小鼠。 用于治疗心力衰竭的碳环核苷酸类似物的范围已经扩大。

    Purine derivatives as A3 and A1 adenosine receptor agonists
    6.
    发明授权
    Purine derivatives as A3 and A1 adenosine receptor agonists 失效
    嘌呤衍生物作为A3和A1腺苷受体激动剂

    公开(公告)号：US07825126B2

    公开(公告)日：2010-11-02

    申请号：US11574779

    申请日：2005-09-02

    申请人： Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Susanna Tchilibon

    发明人： Kenneth A. Jacobson ,  Bhalchandra V. Joshi ,  Susanna Tchilibon

    IPC分类号： C07D473/40 ,  C07D473/34 ,  C07D473/18 ,  A61K31/52 ,  A61K31/522 ,  A61P9/02 ,  C07D473/36 ,  C07D317/70 ,  C07D317/28

    CPC分类号： C07D473/00

    摘要： Disclosed are (N)-methanocarba adenine nucleosides of the formula: as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A1 and A3 adenosine receptors for use in cardioprotection.

    摘要翻译： 公开了下式的（N） - 甲氰胺腺嘌呤核苷：作为高效的A3腺苷受体激动剂，包含这种核苷的药物组合物，以及这些核苷的使用方法，其中R1-R6如说明书中所定义。 这些核苷被考虑用于治疗许多疾病，例如炎症，心脏缺血，中风，哮喘，糖尿病和心律失常。 本发明还提供了作为用于心脏保护的A1和A3腺苷受体的激动剂的化合物。