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    Phosphonic acid based prodrugs of PMEA and its analogues
    1.
    发明授权
    Phosphonic acid based prodrugs of PMEA and its analogues 有权
    基于磷酸的前药PMEA及其类似物

    公开(公告)号：US07214668B2

    公开(公告)日：2007-05-08

    申请号：US10436922

    申请日：2003-05-12

    申请人： K. Raja Reddy ,  Mark D. Erion ,  Michael C. Matelich ,  Joseph J. Kopcho

    发明人： K. Raja Reddy ,  Mark D. Erion ,  Michael C. Matelich ,  Joseph J. Kopcho

    IPC分类号： C07F9/6574 ,  A61K31/675 ,  A61P31/20 ,  A61P31/14 ,  A61P35/00

    CPC分类号： C07F9/65742 ,  C07F9/65616

    摘要： Prodrugs of Formula I, their uses, their intermediates, and their method of manufacture are described: wherein: M and V are cis to one another and MPO3H2 is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, (R)-9-(2-phosphonylmethoxy propyl)adenine, 9-(2-phosphonylmethoxyethyl)guanine, 9-(2-phosphonylmethoxy ethyloxy)adenine, 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, 9-(3-hydroxy-2-phosphonylmethoxypropyl)guanine, and (S)-9-(3-fluoro-2-phosphonyl methoxypropyl)adenine; V is selected from a group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, and 3-thienyl, all optionally substituted with 1-3 substituents selected from a group consisting of F, Cl, Br, C1-C3 alkyl, CF3 and OR6; R6 is selected from the group consisting of C1-C3 alkyl, and CF3; and pharmaceutically acceptable salts thereof.

    摘要翻译： 描述了式I的前药，其用途及其中间体及其制备方法：其中：M和V彼此是顺式的，MPO 3 H 2是 选自9-（2-膦酰基甲氧基乙基）腺嘌呤，（R）-9-（2-膦酰基甲氧基丙基）腺嘌呤，9-（2-膦酰基甲氧基乙基）鸟嘌呤，9-（2-膦酰基甲氧基乙氧基）腺嘌呤， 9-（3-膦酰基甲氧基乙基）-2,6-二氨基嘌呤，（S）-1-（3-羟基-2-膦酰基甲氧基丙基）胞嘧啶，（S）-9-（3-羟基-2-膦酰基甲氧基丙基）腺嘌呤， （3-羟基-2-膦酰基甲氧基丙基）鸟嘌呤和（S）-9-（3-氟-2-膦酰基甲氧基丙基）腺嘌呤; V选自苯基，2-吡啶基，3-吡啶基，4-吡啶基，2-呋喃基，3-呋喃基，2-噻吩基和3-噻吩基，全部任选被1-3个选自 由F，Cl，Br，C 1 -C 3烷基，CF 3 3和OR 6构成的基团。 R 6选自C 1 -C 3烷基和CF 3 N; 及其药学上可接受的盐。

    Prodrugs for liver specific drug delivery
    9.
    发明授权
    Prodrugs for liver specific drug delivery 有权
    用于肝脏特异性药物递送的前药

    公开(公告)号：US07303739B2

    公开(公告)日：2007-12-04

    申请号：US10844747

    申请日：2004-05-12

    申请人： Mark D. Erion ,  K. Raja Reddy

    发明人： Mark D. Erion ,  K. Raja Reddy

    IPC分类号： A61K49/00 ,  A61K38/16

    CPC分类号： C07F9/657118 ,  C07F9/657127 ,  C07F9/657154 ,  C07F9/65846 ,  C07H15/252 ,  C07H15/26

    摘要： The present invention is directed towards novel cyclic phosph(oramid)ate prodrugs of alcohol-, amine-, and thiol-containing drugs, their preparation, their synthetic intermediates, and their uses. Another aspect of the invention is the use of the prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells that express cytochrome P450, including hepatitis, cancer, liver fibrosis, malaria, other viral and parasitic infections, and metabolic diseases where the liver is responsible for the overproduction of the biochemical end product, e.g. glucose (diabetes); cholesterol, fatty acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In one aspect, the invention is directed towards the use of the prodrugs to enhance oral drug delivery. In another aspect, the prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the prodrug methodology of the current invention is used to achieve sustained delivery of the parent drug. In another aspect, the prodrugs are used to increase the therapeutic index of the drug. In another aspect of the invention, a method of making these prodrugs is described. In another aspect, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver.

    摘要翻译： 本发明涉及新型环状磷酸酯（oramid），其包含醇，胺和硫醇的药物，其制备方法，其合成中间体及其用途。 本发明的另一方面是使用前药治疗受益于增强的药物分布到肝脏和表达细胞色素P450的组织和细胞（包括肝炎，癌症，肝纤维化，疟疾，其他病毒和寄生虫感染）的细胞的疾病，以及 肝脏负责生化终产物过度生成的代谢性疾病，例如， 葡萄糖（糖尿病）; 胆固醇，脂肪酸和甘油三酯（高脂血症）（动脉粥样硬化）（肥胖）。 一方面，本发明涉及前药用于增强口服药物递送的用途。 另一方面，前药用于延长药物的药效半衰期。 此外，本发明的前药方法用于实现母体药物的持续递送。 在另一方面，前药用于增加药物的治疗指数。 在本发明的另一方面，描述了制备这些前药的方法。 在另一方面，前药还可用于将诊断成像剂递送至肝脏。

    Prodrugs for liver specific drug delivery
    10.
    发明授权
    Prodrugs for liver specific drug delivery 有权
    用于肝脏特异性药物递送的前药

    公开(公告)号：US06752981B1

    公开(公告)日：2004-06-22

    申请号：US09657919

    申请日：2000-09-08

    申请人： Mark D. Erion ,  K. Raja Reddy

    发明人： Mark D. Erion ,  K. Raja Reddy

    IPC分类号： A61K4900

    CPC分类号： C07F9/657118 ,  C07F9/657127 ,  C07F9/657154 ,  C07F9/65846 ,  C07H15/252 ,  C07H15/26

    摘要： The present invention is directed towards novel cyclic phosph(oramid)ate prodrugs of alcohol, amine-, and thiol-containing drugs, their preparation, their synthetic intermediates, and their uses. Another aspect of the invention is the use of the prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells that express cytochrome P450, including hepatitis, cancer, liver fibrosis, malaria, other viral and parasitic infections, and metabolic diseases where the liver responsible for the overproduction of the biochemical end product, e.g. glucose (diabetes); cholesterol, fatty acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In one apsect, the invention is directed towards the use of the prodrugs to enhance oral drug delivery. In another aspect, the prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the prodrug methodology of the current invention is used to achieve sustained delivery of the parent drug. In another aspect, the prodrugs are used to increase the therapeutic index of the drug. In another aspect of the invention, a method of making these prodrugs is described. In another aspect, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver.

    摘要翻译： 本发明涉及新的环状磷酸酯（oramid），其包含醇，胺和硫醇的药物，其制备方法，其合成中间体及其用途。 本发明的另一方面是使用前药治疗受益于增强的药物分布到肝脏和表达细胞色素P450的组织和细胞（包括肝炎，癌症，肝纤维化，疟疾，其他病毒和寄生虫感染）的细胞的疾病，以及 代谢疾病，其中肝脏负责生化最终产品的过度生产，例如， 葡萄糖（糖尿病）; 胆固醇，脂肪酸和甘油三酯（高脂血症）（动脉粥样硬化）（肥胖）。 在一个实施方案中，本发明涉及使用前药来增强口服药物递送。 另一方面，前药用于延长药物的药效半衰期。 此外，本发明的前药方法用于实现母体药物的持续递送。 在另一方面，前药用于增加药物的治疗指数。 在本发明的另一方面，描述了制备这些前药的方法。 在另一方面，前药还可用于将诊断成像剂递送至肝脏。