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公开(公告)号：US20110166080A1
公开(公告)日：2011-07-07
申请号：US13048258
申请日：2011-03-15
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 cyclosporin 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它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。
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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％。
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3.发明申请公开(公告)号：US20100311944A1
公开(公告)日：2010-12-09
申请号：US12796616
申请日：2010-06-08
IPC分类号： 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 stereoselectivity. 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异构体的混合物显示与天然存在的和目前已知的环孢菌素相比，其效力和毒性降低的组合。 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。 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％。
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公开(公告)号：US20090318336A1
公开(公告)日：2009-12-24
申请号：US12427692
申请日：2009-04-21
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。
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公开(公告)号：US07429562B2
公开(公告)日：2008-09-30
申请号：US11375532
申请日：2006-03-13
IPC分类号： A61K38/13
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。
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公开(公告)号：US07160867B2
公开(公告)日：2007-01-09
申请号：US10845747
申请日：2004-05-13
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。
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7.发明授权13C glucose breath test for the diagnosis of diabetic indications and monitoring glycemic control 失效13C葡萄糖呼吸试验用于诊断糖尿病适应症并监测血糖控制公开(公告)号：US07118919B2
公开(公告)日：2006-10-10
申请号：US11069169
申请日：2005-02-28
IPC分类号： G01N37/00
CPC分类号： A61K51/1206 , A61B5/0813 , A61B5/0836 , A61B5/14532 , G01N33/497 , Y10T436/104998 , Y10T436/13 , Y10T436/24 , Y10T436/25875
摘要： Use of 13C glucose in an analytical assay to monitor glucose metabolism by measurement of labeled exhaled CO2 is provided. A breath test and kit for performing the breath test are described for the diagnosis of diabetic indications and monitoring of glycemic control. The breath test utilizes the measurement of expired 13C-labeled CO2 following the ingestion of a 13C-enriched glucose source.
摘要翻译： 提供了在分析测定中使用13 C葡萄糖以通过测量标记的呼出的CO 2 2监测葡萄糖代谢。 描述了用于进行呼吸试验的呼吸试验和试剂盒，用于诊断糖尿病适应症和监测血糖控制。 呼吸试验利用了摄入富含13 C的葡萄糖源后测量过期的13 C-标记的CO 2。
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8.发明授权13C glucose breath test for the diagnosis of diabetic indications and monitoring glycemic control 有权13C葡萄糖呼吸试验用于诊断糖尿病适应症并监测血糖控制公开(公告)号：US06878550B2
公开(公告)日：2005-04-12
申请号：US10439290
申请日：2003-05-16
CPC分类号： A61B5/0813 , A61B5/0836 , A61B5/14532 , A61K51/1206 , G01N33/497 , Y10T436/104998 , Y10T436/13 , Y10T436/24 , Y10T436/25875
摘要： Use of 13C glucose in an analytical assay to monitor glucose metabolism by measurement of labeled exhaled CO2 is provided. A breath test and kit for performing the breath test are described for the diagnosis of diabetic indications and monitoring of glycemic control. The breath test utilizes the measurement of expired 13C-labeled CO2 following the ingestion of a 13C-enriched glucose source.
摘要翻译： 提供了在分析测定中使用13 C葡萄糖以通过测量标记的呼出CO2监测葡萄糖代谢。 描述了用于进行呼吸试验的呼吸试验和试剂盒，用于诊断糖尿病适应症和监测血糖控制。 呼吸试验利用摄入富含13 C的葡萄糖源后测量过期的13 C标记的CO2。
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公开(公告)号：US06818200B2
公开(公告)日：2004-11-16
申请号：US09987370
申请日：2001-11-14
IPC分类号： A61K5100
CPC分类号： C07B59/002
摘要： A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.
摘要翻译： 提高药物（例如二氢吡啶类和抗菌剂），特别是硝苯地平和青霉素的效力和作用持续时间的方法，其中一个或多个氢原子被氘化，并且其中氘代药物在使用较低的时候意外地改善了性能 浓度高于未经修饰的药物。 还公开了一种用于确定新药物的身份和生物等效性的方法，其中新药物的分子和同位素结构通过同位素比质谱法测定，并与已知人类药物的分子和同位素结构进行比较。
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公开(公告)号：US06613739B1
公开(公告)日：2003-09-02
申请号：US09634945
申请日：2000-08-07
IPC分类号： A61K3800
CPC分类号： C07K7/64 , A61K38/00 , C07B59/008 , C07K1/13 , C07K7/645 , 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.
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