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：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：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：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％。