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。

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％。

公开(公告)号：US20070099848A1

公开(公告)日：2007-05-03

申请号：US11595397

申请日：2006-11-09

申请人： Mark Abel ,  Roman Szewda ,  Daniel Trepanier ,  Randall Yatscoff ,  Robert Foster

发明人： Mark Abel ,  Roman Szewda ,  Daniel Trepanier ,  Randall Yatscoff ,  Robert Foster

IPC分类号： A61K31/7052 ,  A61K31/4745 ,  A61K38/13 ,  C07D281/18

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.

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。

公开(公告)号：US20110092669A1

公开(公告)日：2011-04-21

申请号：US12977602

申请日：2010-12-23

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

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

IPC分类号： C07K1/107

CPC分类号： C07K7/645 ,  A61K9/0095 ,  A61K9/1075 ,  A61K9/4858 ,  A61K38/13 ,  A61K47/10

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称为ISATX247的环孢菌素A类似物的顺式和反式异构体及其衍生物。 ISATX247异构体和烷基化，芳基化和氘代衍生物通过立体选择性途径合成，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％。

公开(公告)号：US07141648B2

公开(公告)日：2006-11-28

申请号：US10274437

申请日：2002-10-17

申请人： Selvaraj A. Naicker ,  Randall W. Yatscoff ,  Robert T. Foster ,  Mark Abel ,  Seetharaman Jayaraman ,  Hans-Jürgen Mair ,  Jean-Michel Adam ,  Bruno Lohri

发明人： Selvaraj A. Naicker ,  Randall W. Yatscoff ,  Robert T. Foster ,  Mark Abel ,  Seetharaman Jayaraman ,  Hans-Jürgen Mair ,  Jean-Michel Adam ,  Bruno Lohri

IPC分类号： C07K1/00 ,  C07K1/107 ,  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％。

公开(公告)号：US20100062976A1

公开(公告)日：2010-03-11

申请号：US12555787

申请日：2009-09-08

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

发明人： Selvaraj A. Naicker ,  Randall W. Yatscoff ,  Robert T. 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称为ISATX247的环孢菌素A类似物的顺式和反式异构体及其衍生物。 ISATX247异构体和烷基化，芳基化和氘代衍生物通过立体选择性途径合成，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％。

公开(公告)号：US07160867B2

公开(公告)日：2007-01-09

申请号：US10845747

申请日：2004-05-13

申请人： Mark Abel ,  Roman Szweda ,  Daniel Trepanier ,  Randall W Yatscoff ,  Robert T. Foster

发明人： Mark Abel ,  Roman Szweda ,  Daniel Trepanier ,  Randall W Yatscoff ,  Robert T. Foster

IPC分类号： A61K31/70 ,  A61K31/44 ,  C07H15/00 ,  C07D487/00 ,  A61F13/00

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。

公开(公告)号：US08148168B2

公开(公告)日：2012-04-03

申请号：US12837141

申请日：2010-07-15

申请人： Douglas T. Gjerde ,  Allen Burge ,  Ronald Jones ,  Mark Abel

发明人： Douglas T. Gjerde ,  Allen Burge ,  Ronald Jones ,  Mark Abel

IPC分类号： G01N1/18

CPC分类号： G01N1/40 ,  B01J20/285 ,  B01J20/286 ,  B01J20/291 ,  B01J20/3244 ,  B01J2220/54 ,  B01J2220/64 ,  B82Y30/00 ,  G01N30/02 ,  G01N30/603 ,  G01N30/6065 ,  G01N2035/1053 ,  Y10T436/25375 ,  Y10T436/255 ,  B01D15/3804

摘要： The invention provides extraction columns for the purification of an analyte (e.g., a biological macromolecule, such as a peptide, protein or nucleic acid) from a sample solution, as well as methods for making and using such columns. The columns typically include a bed of extraction media positioned in the column, often between two frits. In some embodiments, the extraction columns employ modified pipette tips as column bodies. In some embodiments, the extraction columns are comprised of frits having a low pore. In some embodiments, the frits of the extraction columns have a pore volume of less than one microliter or less than 10% of the interstitial volume of the bed of extraction media.

摘要翻译： 本发明提供了用于从样品溶液中纯化分析物（例如生物大分子，如肽，蛋白质或核酸）的提取柱，以及制备和使用这些色谱柱的方法。 柱通常包括定位在柱中的提取介质床，通常在两个玻璃料之间。 在一些实施方案中，提取柱使用改进的移液管尖作为柱体。 在一些实施方案中，萃取柱由具有低孔的玻璃料组成。 在一些实施方案中，提取塔的玻璃料的孔体积小于提取介质床的间隙体积的小于1微升或小于10％。

公开(公告)号：US20110195518A1

公开(公告)日：2011-08-11

申请号：US13023519

申请日：2011-02-08

申请人： Douglas T. Gjerde ,  Lee Hoang ,  Chris Suh ,  Mark Abel

发明人： Douglas T. Gjerde ,  Lee Hoang ,  Chris Suh ,  Mark Abel

IPC分类号： G01N1/18 ,  B01L3/02

CPC分类号： B01L3/02 ,  B01L3/0275 ,  B01L2200/0631 ,  B01L2300/0681 ,  B01L2400/0487 ,  Y10T436/255

摘要： An apparatus and method of using a pipette with pipette tip columns were developed in which a pipette is operated with the pipette tip columns inserted into the wells of a microplate. In this configuration the pipette is free standing and is essentially perpendicular to the microplate. The open lower ends of the pipette tip column are approximately centered within the plate well. The columns and plate are designed in such a way that the open lower ends of the pipette tip columns are in contact with liquid in the plate well however, the columns do not seal on the well bottom, preventing flow in and out of the column. The pipette contains the appropriate firmware and software to control flow for all steps of pipette tip column operation.

摘要翻译： 开发了一种使用带有移液管尖端柱的移液器的装置和方法，其中移液管在移液管尖端柱插入微量培养板的孔中进行操作。 在该配置中，移液管是自由站立的，并且基本上垂直于微孔板。 移液管尖端柱的开放的下端大致在板孔内部居中。 柱和板被设计成使得移液管尖端柱的开口下端与板孔中的液体接触，但是柱不会密封在井底，防止流入和流出柱。 移液器包含适当的固件和软件，用于控制移液管尖端柱操作的所有步骤的流量。