公开(公告)号：US20030212249A1

公开(公告)日：2003-11-13

申请号：US10274437

申请日：2002-10-17

申请人： Isotechnika, Inc.

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： C07K007/64

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. 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％。