公开(公告)号：US20060142377A1

公开(公告)日：2006-06-29

申请号：US10529513

申请日：2003-09-26

申请人： Gary Posner ,  Theresa Shapiro ,  Surojit Sur ,  Tanzina Labonte ,  Kristina Borstnik ,  Ik-Hyeon Paik ,  Andrew McRiner

发明人： Gary Posner ,  Theresa Shapiro ,  Surojit Sur ,  Tanzina Labonte ,  Kristina Borstnik ,  Ik-Hyeon Paik ,  Andrew McRiner

IPC分类号： A61K31/353 ,  A61K31/335 ,  C07D493/14

CPC分类号： C07D493/18

摘要： In only two steps and in 65% overall yield, natural trioxane artemisinin (I) was converted on gram scale into C-10-carba trioxane dimer (3). This new, very stable dimer was then transformed easily in one additional step into four different dimers (4-7). Alcohol and diol dimers (4 and 5) and ketone dimer (7) are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers (4 and 5) are strongly inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives (8a-10c and 12) were easily prepared from dimers (4-6); they are thermally stable even at 60° C. for 24 hours, are more orally efficacious as antimalarials than either artelinic acid or sodium artesunate, and have potent and selective anticancer activities. Further derivitization of the alcohol dimers (4 and 17), diol dimer (5) and ketone (7) has produced a number of analogs also antimalarially active in vitro at sub-nanomolar concentrations (most notably: pyridine N-oxides (13, 15, 18, 23, 24 and 25), phosphoric acid triesters (26 and 27), sulfonamide (40) and cyclic carbonate (41)). In addition, dimers (13 and 19) are more efficacious (when administered both orally and i.v.) and less toxic (when administered intraperitoneally to mice as a single dose) than clinically-used sodium artesunate, thereby giving them a better antimalarial therapeutic index than sodium artesunate.

摘要翻译： 只有两个步骤，65％的总产率，将天然的三恶烷青蒿素（I）按克标度转化为C-10-碳三三烷二聚物（3）。 然后将这种新的非常稳定的二聚体在一个额外的步骤中容易地转化成四种不同的二聚体（4-7）。 醇和二醇二聚体（4和5）和酮二聚体（7）在体外比青蒿素（1）具有10倍的抗疟药效力，醇和二醇二聚体（4和5）对几种人类癌细胞具有强烈的抑制作用但不具有细胞毒性 线条。 水溶性羧酸衍生物（8a-10c和12）容易由二聚体（4-6）制备; 它们甚至在60℃下热稳定24小时，作为抗疟药物比阿特金酸或青蒿琥酯钠更具口服效力，并且具有有效和选择性的抗癌活性。 醇二聚体（4和17），二醇二聚物（5）和酮（7）的进一步衍生产生了许多在亚纳摩尔浓度下体外抗疟活性的类似物（最引人注目的是：吡啶N-氧化物（13,15 ，18,23,24和25），磷酸三酯（26和27），磺酰胺（40）和环状碳酸酯（41））。 此外，二聚体（13和19）比临床使用的青蒿琥酯钠更有效（当口服和静脉内施用）和毒性较小（当以单剂量腹膜内给予小鼠时），从而给予它们更好的抗疟治疗指数 青蒿琥酯钠。

公开(公告)号：US07417156B2

公开(公告)日：2008-08-26

申请号：US10529513

申请日：2003-09-26

申请人： Gary H. Posner ,  Theresa A. Shapiro ,  Surojit Sur ,  Tanzina Labonte ,  Kristina Borstnik ,  Ik-Hyeon Paik ,  Andrew J. McRiner

发明人： Gary H. Posner ,  Theresa A. Shapiro ,  Surojit Sur ,  Tanzina Labonte ,  Kristina Borstnik ,  Ik-Hyeon Paik ,  Andrew J. McRiner

IPC分类号： A61K31/357 ,  C07D321/10

CPC分类号： C07D493/18

摘要： In only two steps and in 65% overall yield, natural trioxane artemisinin (I) was converted on gram scale into C-10-carba trioxane dimer (3). This new, very stable dimer was then transformed easily in one additional step into four different dimers (4-7). Alcohol and diol dimers (4 and 5) and ketone dimer (7) are 10 times more antimalarially potent in vitro than artemisinin (I), and alcohol and diol dimers (4 and 5) are strongly inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives (8a-10c and 12) were easily prepared from dimers (4-6); they are thermally stable even at 60° C. for 24 hours, are more orally efficacious as antimalarials than either artelinic acid or sodium artesunate, and have potent and selective anticancer activities. Further derivitization of the alcohol dimers (4 and 17), diol dimer (5) and ketone (7) has produced a number of analogs also antimalarially active in vitro at sub-nanomolar concentrations (most notably: pyridine N-oxides (13, 15, 18, 23, 24 and 25), phosphoric acid triesters (26 and 27), sulfonamide (40) and cyclic carbonate (41)). In addition, dimers (13 and 19) are more efficacious (when administered both orally and i.v.) and less toxic (when administered intraperitoneally to mice as a single dose) than clinically-used sodium artesunate, thereby giving them a better antimalarial therapeutic index than sodium artesunate.

摘要翻译： 只有两个步骤，65％的总产率，将天然的三恶烷青蒿素（I）按克标度转化为C-10-碳三三烷二聚物（3）。 然后将这种新的非常稳定的二聚体在一个额外的步骤中容易地转化成四种不同的二聚体（4-7）。 醇和二醇二聚体（4和5）和酮二聚体（7）在体外比青蒿素（I）具有10倍的抗疟药效力，醇和二醇二聚体（4和5）是强烈抑制的，但对几种人类癌细胞没有细胞毒性 线条。 水溶性羧酸衍生物（8a-10c和12）容易由二聚体（4-6）制备; 它们甚至在60℃下热稳定24小时，作为抗疟药物比阿特金酸或青蒿琥酯钠更具口服效力，并且具有有效和选择性的抗癌活性。 醇二聚体（4和17），二醇二聚物（5）和酮（7）的进一步衍生产生了许多在亚纳摩尔浓度下体外抗疟活性的类似物（最引人注目的是：吡啶N-氧化物（13,15 ，18,23,24和25），磷酸三酯（26和27），磺酰胺（40）和环状碳酸酯（41））。 此外，二聚体（13和19）比临床使用的青蒿琥酯钠更有效（当口服和静脉内施用）和毒性较小（当以单剂量腹膜内给予小鼠时），从而给予它们更好的抗疟治疗指数 青蒿琥酯钠。