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    Metabolites of cyclosporin analogs
    1.
    发明申请
    Metabolites of cyclosporin analogs 审中-公开
    环孢菌素类似物的代谢物

    公开(公告)号：US20060223743A1

    公开(公告)日：2006-10-05

    申请号：US11313239

    申请日：2005-12-19

    申请人： Mark Abel ,  Robert Foster ,  Derrick Freitag ,  Daniel Trepanier ,  Shin Sugiyama ,  Seetharaman Jayaraman ,  Randall Yatscoff

    发明人： Mark Abel ,  Robert Foster ,  Derrick Freitag ,  Daniel Trepanier ,  Shin Sugiyama ,  Seetharaman Jayaraman ,  Randall Yatscoff

    IPC分类号： A61K38/13 ,  C07K7/64

    CPC分类号： A61K38/13 ,  C07K7/64 ,  C07K7/645

    摘要： Isolated metabolites of the cyclosporine analog ISA247 are disclosed, including in vitro methods for their preparation. The metabolites comprise a chemical modification of ISA247, wherein the modification is at least one reaction selected from the group consisting of hydroxylation, N-demethylation, diol formation, epoxide formation, and intramolecular cyclization phosphorylation, sulfation, glucuronide formation and glycosylation. Methods of preparation include semi-synthetic methods, wherein metabolites of ISA247 are produced from the microsomal extracts of animal liver cells, or from cultures using microorganisms, and completely synthetic methods, such as chemically modifying the parent compound or isolated metabolites using organic synthetic methods.

    摘要翻译： 公开了环孢菌素类似物ISA247的分离的代谢物，包括其制备方法。 代谢物包括ISA247的化学修饰，其中所述修饰是选自羟基化，N-去甲基化，二醇形成，环氧化物形成和分子内环化磷酸化，硫酸化，葡糖苷酸形成和糖基化中的至少一种反应。 制备方法包括半合成方法，其中ISA247的代谢物由动物肝细胞的微粒体提取物或使用微生物的培养物产生，以及完全合成的方法，例如使用有机合成方法化学改性母体化合物或分离的代谢物。

    Synthesis of cyclosporin analogs
    2.
    发明申请
    Synthesis of cyclosporin analogs 审中-公开
    环孢菌素类似物的合成

    公开(公告)号：US20070087963A1

    公开(公告)日：2007-04-19

    申请号：US11549575

    申请日：2006-10-13

    申请人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster ,  Mark Abel ,  Seetharaman Jayaraman ,  Hans-Jurgen Mair ,  Jean-Michel Adam ,  Bruno Lohri

    发明人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster ,  Mark Abel ,  Seetharaman Jayaraman ,  Hans-Jurgen Mair ,  Jean-Michel Adam ,  Bruno Lohri

    IPC分类号： A61K38/13

    CPC分类号： C07K7/645 ,  A61K9/0095 ,  A61K9/1075 ,  A61K9/4858 ,  A61K38/00 ,  A61K38/13 ,  B82Y5/00 ,  C07K7/64 ,  Y10S530/806

    摘要： The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. Stereoselective pathways may utilize a Wittig reaction, or an organometallic reagent comprising inorganic elements such as boron, silicon, titanium, and lithium. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.

    摘要翻译： 本发明涉及结构类似于环孢霉素A的环孢菌素类似物的异构体混合物。该混合物具有比单个异构体和天然存在的和其它目前已知的环孢菌素和环孢菌素衍生物更强的功效和降低的毒性。 本发明的实施方案涉及被称为ISA 247的环孢菌素A类似物及其衍生物的顺式和反式异构体。 通过立体选择性途径合成烷基化，芳基化和氘代衍生物，其中反应的特定条件决定了立体选择性的程度。 立体选择性途径可以利用维蒂希反应或包含无机元素如硼，硅，钛和锂的有机金属试剂。 基于混合物的总重量，混合物中异构体的比例可以为（E） - 异构体的约10至90重量％至（Z） - 异构体的约90至10重量％。

    Rapamycin carbohydrate derivatives
    4.
    发明申请
    Rapamycin carbohydrate derivatives 审中-公开
    雷帕霉素碳水化合物衍生物

    公开(公告)号：US20060079466A1

    公开(公告)日：2006-04-13

    申请号：US11229007

    申请日：2005-09-15

    申请人： Mark Abel ,  Roman Szweda ,  Daniel Trepaier ,  Randall Yatscoff ,  Robert Foster

    发明人： Mark Abel ,  Roman Szweda ,  Daniel Trepaier ,  Randall Yatscoff ,  Robert Foster

    IPC分类号： A61K31/7052 ,  C07H17/02

    CPC分类号： A61K31/7052 ,  A61K31/436 ,  C07D498/18 ,  C07H15/04 ,  C07H19/01

    摘要： This invention provides modified rapamycins that have specific monosaccharide(s), oligosaccharide(s), pseudosugar(s) or derivatives thereof attached through a linker to create rapamycin carbohydrate derivatives having enhanced pharmacokinetic and/or pharmacodynamic profiles. For example, administration of the rapamycin carbohydrate derivative results in altered pharmacokinetic profiles and reduced toxicities. Thus, the present invention provides compounds with characteristics that are distinct from other drugs in its class such as rapamycin.

    摘要翻译： 本发明提供了具有通过连接体连接的具有增强的药代动力学和/或药效学特征的雷帕霉素碳水化合物衍生物的特异性单糖，寡糖，假糖或其衍生物的修饰的雷帕霉素。 例如，雷帕霉素碳水化合物衍生物的施用导致药代动力学特征改变和毒性降低。 因此，本发明提供具有与其同类其他药物不同的特征的化合物，例如雷帕霉素。

    Novel cyclosporine analog formulations
    6.
    发明申请
    Novel cyclosporine analog formulations 有权
    新型环孢菌素类似物制剂

    公开(公告)号：US20060217309A1

    公开(公告)日：2006-09-28

    申请号：US11375532

    申请日：2006-03-13

    申请人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    发明人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    IPC分类号： A61K38/17 ,  A61K31/355 ,  A61K47/00

    CPC分类号： A61K9/1075 ,  A61K9/0095 ,  A61K9/4858 ,  A61K38/13 ,  A61K47/10

    摘要： The present invention relates to formulations containing cyclosporin analogs that are structurally similar to cyclosporin A, in particular isomeric mixtures of cyclosporin analogs that are structurally similar to cyclosporin A. The formulations form stable microemulsion preconcentrates and may provide superior drug bioavailability and/or may reduce one or more adverse effects associated with the administration of cyclosporin. Also disclosed are methods for using and preparing the formulations.

    摘要翻译： 本发明涉及结构上类似于环孢菌素A的环孢菌素类似物的制剂，特别是在结构上类似于环孢菌素A的环孢菌素类似物的异构体混合物中。制剂形成稳定的微乳液预浓缩物，并可提供优异的药物生物利用度和/或减少一种 或更多与施用环孢菌素相关的不良反应。 还公开了使用和制备制剂的方法。

    Deuterated cyclosporin analogs and their use as immunomodulating agents
    7.
    发明申请
    Deuterated cyclosporin analogs and their use as immunomodulating agents 有权
    氘代环孢菌素类似物及其作为免疫调节剂的用途

    公开(公告)号：US20060052290A1

    公开(公告)日：2006-03-09

    申请号：US11245775

    申请日：2005-10-06

    申请人： Salvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    发明人： Salvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    IPC分类号： A61K38/13 ,  C07K7/64

    CPC分类号： C07K7/645 ,  A61K38/00 ,  C07B59/008 ,  C07K1/13 ,  C07K7/64 ,  Y10S530/806 ,  Y10S530/807

    摘要： Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives.

    摘要翻译： 公开了与天然存在的和其他目前已知的环孢菌素和环孢菌素衍生物相比具有增强的功效和降低的毒性的环孢菌素衍生物。 本发明的环孢菌素衍生物通过以下方式通过环孢菌素A（CsA）分子的化学和同位素取代产生：（1）氨基酸1的化学取代和任选的氘取代; 和（2）在环孢菌素A分子的代谢关键位置的氘代替，例如氨基酸1,4,9。还公开了产生环孢菌素衍生物的方法和与所公开的环孢菌素衍生物一起产生具有降低的毒性的免疫抑制的方法。

    Cyclosporine analogue mixtures and their use as immunomodulating agents
    8.
    发明申请
    Cyclosporine analogue mixtures and their use as immunomodulating agents 有权
    环孢霉素类似物混合物及其作为免疫调节剂的用途

    公开(公告)号：US20050192214A1

    公开(公告)日：2005-09-01

    申请号：US11118830

    申请日：2005-04-28

    申请人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    发明人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    IPC分类号： A61K38/00 ,  A61K9/00 ,  A61K9/107 ,  A61K9/48 ,  A61K38/13 ,  A61P19/02 ,  A61P37/06 ,  C07K7/00 ,  C07K7/52 ,  C07K7/64

    CPC分类号： C07K7/645 ,  A61K9/0095 ,  A61K9/1075 ,  A61K9/4858 ,  A61K38/00 ,  A61K38/13 ,  B82Y5/00 ,  C07K7/64 ,  Y10S530/806

    摘要： The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. Mixtures of ISATX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of siereoselectivity. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.

    摘要翻译： 本发明涉及结构类似于环孢霉素A的环孢菌素类似物的异构体混合物。该混合物具有比单个异构体和天然存在的和其它目前已知的环孢菌素和环孢菌素衍生物更强的功效和降低的毒性。 本发明的实施方案涉及被称为ISA 247的环孢菌素A类似物及其衍生物的顺式和反式异构体。 ISA 247异构体的混合物显示了与天然存在的和目前已知的环孢菌素相比增强的效力和降低的毒性的组合。 通过立体选择性途径合成烷基化，芳基化和氘代衍生物，其中反应的特定条件决定了Silectoslectivity的程度。 基于混合物的总重量，混合物中异构体的比例可以为（E） - 异构体的约10至90重量％至（Z） - 异构体的约90至10重量％。

    Deuterated cyclosporin analogs and their use as immunomodulating agents
    9.
    发明申请
    Deuterated cyclosporin analogs and their use as immunomodulating agents 有权
    氘代环孢菌素类似物及其作为免疫调节剂的用途

    公开(公告)号：US20050176628A1

    公开(公告)日：2005-08-11

    申请号：US11105897

    申请日：2005-04-13

    申请人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    发明人： Selvaraj Naicker ,  Randall Yatscoff ,  Robert Foster

    IPC分类号： A61K38/00 ,  C07B59/00 ,  C07K1/13 ,  C07K7/64 ,  A61K38/13

    CPC分类号： C07K7/645 ,  A61K38/00 ,  C07B59/008 ,  C07K1/13 ,  C07K7/64 ,  Y10S530/806 ,  Y10S530/807

    摘要： Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives.

    摘要翻译： 公开了与天然存在的和其他目前已知的环孢菌素和环孢菌素衍生物相比具有增强的功效和降低的毒性的环孢菌素衍生物。 本发明的环孢菌素衍生物通过以下方式通过环孢菌素A（CsA）分子的化学和同位素取代产生：（1）氨基酸1的化学取代和任选的氘取代; 和（2）在环孢菌素A分子的代谢关键位置的氘代替，例如氨基酸1,4,9。还公开了产生环孢菌素衍生物的方法和与所公开的环孢菌素衍生物一起产生具有降低的毒性的免疫抑制的方法。