公开(公告)号：US6011042A

公开(公告)日：2000-01-04

申请号：US948872

申请日：1997-10-10

申请人： Richard B. Greenwald ,  Annapurna Pendri ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Annapurna Pendri ,  Yun H. Choe

IPC分类号： C07D519/00 ,  A61K31/33 ,  C07D491/22

CPC分类号： C07D519/00

摘要： The present invention is directed to conjugates such as polymeric prodrugs of aromatic, hydroxyl-containing compounds and methods of making and using the same. These polymeric prodrugs are preferably esters of hydroxyl-containing aromatic compounds and are formed by reacting a desired aromatic, hydroxyl-containing compound with a substantially non-antigenic polymer so as to produce a transport form having an ester linkage between the aromatic compound and the polymer. Preferred aromatic hydroxyl-containing compositions include 10- and 11-hydroxycamptothecin derivatives. Methods of treatment are also disclosed.

摘要翻译： 本发明涉及诸如芳香族，含羟基化合物的聚合前体药物的共轭物，以及制备和使用它们的方法。 这些聚合前药优选为含羟基的芳族化合物的酯，并且通过使所需的含芳族羟基的化合物与基本上非抗原性的聚合物反应形成，以产生在芳族化合物和聚合物之间具有酯键的转运体 。 优选的含芳族羟基的组合物包括10-和11-羟基喜树碱衍生物。 还公开了治疗方法。

公开(公告)号：US06777387B2

公开(公告)日：2004-08-17

申请号：US09823296

申请日：2001-03-29

申请人： Richard B. Greenwald ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Yun H. Choe

IPC分类号： A61K3816

CPC分类号： C08G73/02

摘要： The present invention is directed to polymeric prodrug transport forms and methods of making and using the same. In one preferred aspect, the prodrugs are of the formula: wherein G is a polymeric residue; Z is one of: and B is a residue of a biologically active amine-containing moiety or a hydroxyl-containing moiety.

摘要翻译： 本发明涉及聚合物前药运输形式及其制备和使用方法。 在一个优选的方面，前药具有下式：其中G是聚合物残基; Z是以下之一：B是含生物活性胺的部分或含羟基部分的残基。

公开(公告)号：US06180095B2

公开(公告)日：2001-01-30

申请号：US09183557

申请日：1998-10-30

申请人： Richard B. Greenwald ,  Annapurna Pendri ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Annapurna Pendri ,  Yun H. Choe

IPC分类号： A61K3121

CPC分类号： A61K47/60

摘要： The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula: wherein: L1 is a bifunctional linking moiety; G is H or where B is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety; Y1-4 are independently, O, S, or NR12; R1, R4, R9, R10, and R12, are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls; R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls; Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group; (m), (r), (s), (t), (u) and (v) are independently zero or one; (p) is zero or a positive integer; and R11 is a substantially non-antigenic polymer. The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, preferably as a result of 1,6 or 1,4 benzyl elimination-reaction. Methods of preparing the compounds and methods of treatment are also disclosed.

摘要翻译： 本发明涉及含有基于聚合物的输送形式的双重前药。 这些聚合前药优选具有下式：其中：L1是双官能连接部分; G是H或其中B是H，离去基团，含胺部分的残基或含羟基部分的残基; Y1- 4独立地是O，S或NR 12; R 1，R 4，R 9，R 10和R 12独立地选自氢，C 1-6烷基，C 3-12支链烷基，C 3-8环烷基， 6个取代的烷基，C 3-8取代的环烷基，芳基，取代的芳基，芳烷基，C 1-6杂烷基，取代的C 1-6杂烷基; R 2，R 3，R 5和R 6独立地选自氢，C 1-6烷基， C 1-6烷氧基，苯氧基，C 1-8杂烷基，C 1-8杂烷氧基，取代的C 1-6烷基，C 3-8环烷基，C 3-8取代的环烷基，芳基，取代的芳基，芳烷基，卤代，硝基 - ，氰基 - 羧基 - ，C 1-6羧基烷基和C 1-6烷基羰基; Ar是当式（I）中包括时形成多取代芳族烃或多元醇的部分 取代杂环基;（m），（r），（s），（t），（u）和（v）分别为0或1;（p）为零或正整数; 并且R11是基本上非抗原性的聚合物。当双前体药物的聚合物部分被切割并且之后在体内快速产生母体分子时，优选由1,6或1,4苄基消除 - 反应。 还公开了制备化合物的方法和治疗方法。

公开(公告)号：US6153655A

公开(公告)日：2000-11-28

申请号：US62305

申请日：1998-04-17

申请人： Anthony J. Martinez ,  Annapurna Pendri ,  Richard B. Greenwald ,  Yun H. Choe

发明人： Anthony J. Martinez ,  Annapurna Pendri ,  Richard B. Greenwald ,  Yun H. Choe

IPC分类号： A61K47/34 ,  A61K47/48 ,  A61P1/00 ,  A61P9/08 ,  A61P15/08 ,  A61P15/18 ,  A61P25/04 ,  A61P25/22 ,  A61P25/28 ,  A61P29/00 ,  C07D491/22 ,  C07H15/252 ,  C08F283/00 ,  C08G65/329 ,  C08G85/00 ,  A61K47/30

CPC分类号： C07D491/22 ,  A61K47/48215 ,  C07H15/252 ,  C08F283/00

摘要： The present invention is directed to polymeric- prodrug transport forms of the formula: ##STR1## wherein: B is a leaving group, OH, a residue of a hydroxyl-containing moiety or ##STR2## wherein B.sub.1 is a leaving group, OH or a residue of a hydroxyl-containing moiety;Y.sub.1-2 are independently O or S;M is selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(.dbd.Y.sub.2); R.sub.2-5 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.3-12 branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted alkyls, C.sub.3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.sub.1-6 heteroalkyls and substituted C.sub.1-6 heteroalkyls;(m) is zero or one;(n) is a positive integer;(p) is zero or a positive integer;Z is an electron withdrawing group; andR.sub.1 is a polymeric residue which is optionally capped with a moiety of the Formula (v) ##STR3##

摘要翻译： 本发明涉及下式的聚合物 - 前药转运形式：其中：B是离去基团，OH，含羟基部分的残基或其中B1是离去基团，OH或含羟基的残基 部分; Y1-2独立地为O或S; M选自X或Q; 其中X是吸电子基团，Q是含有从C（= Y2）定位为三至六个原子的自由电子对的部分; R2-5独立地选自氢，C1-6烷基，C3-12支链烷基，C3-8环烷基，C1-6取代的烷基，C3-8取代的环烷基，芳基，取代的芳基，芳烷基，C1- 6个杂烷基和取代的C 1-6杂烷基; （m）为零或一; （n）是正整数; （p）为零或正整数; Z是吸电子基团; 并且R 1是聚合物残基，其任选地用式（v）的部分封端，

公开(公告)号：US07262164B2

公开(公告)日：2007-08-28

申请号：US10290694

申请日：2002-11-08

申请人： Yun H. Choe ,  Richard B. Greenwald

发明人： Yun H. Choe ,  Richard B. Greenwald

IPC分类号： A61K38/16

CPC分类号： A61K47/60

摘要： Thiol-linked polymeric prodrugs, methods of making and using the same are disclosed. The use of a sulfhydryl bond in combination with a benzyl elimination system results in the formation of prodrugs which can take advantage of plasma enzymes in vivo for regeneration of the parent molecule. A preferred prodrug in accordance with the invention is: where S-MP is 6-mercaptopurine.

摘要翻译： 公开了硫醇连接的聚合物前药，其制备和使用方法。 使用巯基键与苄基消除系统结合导致前体药物的形成，其可以在体内利用血浆酶来再生母体分子。 根据本发明优选的前药是：其中S-MP是6-巯基嘌呤。

公开(公告)号：US06936597B2

公开(公告)日：2005-08-30

申请号：US10103323

申请日：2002-03-21

申请人： Richard B. Greenwald ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Yun H. Choe

IPC分类号： A61K31/74 ,  A61K31/77 ,  A61K47/48 ,  A61P1/04 ,  A61P5/38 ,  A61P9/00 ,  A61P9/08 ,  A61P15/18 ,  A61P19/06 ,  A61P25/00 ,  A61P25/02 ,  A61P25/22 ,  A61P29/00 ,  A61P31/10 ,  A61P35/00 ,  A61P43/00 ,  C07C235/16 ,  C08G65/329 ,  A61K31/70 ,  A61K31/7068 ,  C07C63/00 ,  C07H19/06

CPC分类号： C07C235/16 ,  A61K31/74 ,  A61K47/60

摘要： Polymeric prodrugs of the formula: wherein B is selected from the group consisting of OH, leaving groups, residues of amine-containing moieties and a residues of hydroxyl-containing moieties; Y1 is selected from the group consisting of O, S, and NR5; M is NR3, O or S; Ar is a moiety which when included in Formula I forms a multi-substituted aromatic or heteroaromatic hydrocarbon or a multi-substituted heterocyclic group; (m) is zero or a positive integer; R1-3 and R5 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy; and R4 is a polymeric residue; as well as methods of making and using the same are disclosed.

摘要翻译： 下式的聚合物前体药物：其中B选自OH，离去基团，含胺部分的残基和含羟基部分的残基; Y 1选自O，S和NR 5; M是NR 3，O或S; Ar是当式I中包含时形成多取代的芳族或杂芳族烃或多取代杂环基的部分; （m）为零或正整数; R 1-3和R 5各自独立地选自氢，C 1-6烷基，C 3-8环烷基， 12个支链烷基，C 3〜8个环烷基，C 1-6 - 取代的烷基，C 3-8 - 取代的环烷基，芳基 取代的芳基，芳烷基，C 1-6 - 杂烷基，取代的C 1-6 - 杂烷基，C 1-6烷氧基，苯氧基和C 1-6烷基， 杂烷基; R 4是聚合物残基; 以及制造和使用该方法的方法。

公开(公告)号：US06303569B1

公开(公告)日：2001-10-16

申请号：US09137430

申请日：1998-08-21

申请人： Richard B. Greenwald ,  Yun H. Choe ,  Annapurna Pendri

发明人： Richard B. Greenwald ,  Yun H. Choe ,  Annapurna Pendri

IPC分类号： A61K31215

CPC分类号： C07C237/22 ,  A61K47/60 ,  C07B2200/11 ,  C07C271/16 ,  C07C271/22

摘要： The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric compounds comprise the formula: wherein: B is H, OH, OSiR13, a residue of an amine-containing target moiety or a residue of a hydroxyl-containing moiety; L1 and L2 are bifunctional linking moieties; Y2is O or S; R2 is selected from the group consisting of C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy, and C1-6 heteroalkoxy; R9, R10, R13 are independently one of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3 S substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy, and C1-6 heteroalkoxy; Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group; (m) is zero or one; and R11 is a polymer residue. The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, as a result of a trialkyl lock type lactonization-type reaction.

摘要翻译： 本发明涉及含有基于聚合物的输送形式的双重前药。 这些聚合化合物包括下式：其中：B是H，OH，OSiR13，含胺目标部分的残基或含羟基部分的残基; L1和L2是双官能连接部分; Y 2是O或S; R 2 选自C1-6烷基，C3-12支链烷基，C3-8环烷基，C1-6取代烷基，C3-8取代环烷基，芳基，取代芳基，芳烷基，C1-6杂烷基，取代C1- 6个杂烷基，C 1-6烷氧基，苯氧基和C 1-6杂烷氧基; R 9，R 10，R 13独立地为氢，C 1-6烷基，C 3-12支链烷基，C 3-8环烷基，C 1-6取代的烷基，C 3 S取代的环烷基，芳基，取代的芳基，芳烷基，C 1-6杂烷基，取代的C 1-6杂烷基，C 1-6烷氧基，苯氧基和C 1-6杂烷氧基; Ar是当式（I）中包括时， 取代的芳族烃或多取代的杂环基;（m）为0或1; 并且R11是聚合物残基。当双前体药物的聚合部分被切割并且其后在体内快速产生母体分子时，由于三烷基锁定型内酯化反应的结果产生第一种前体药物。

公开(公告)号：US5965119A

公开(公告)日：1999-10-12

申请号：US676

申请日：1997-12-30

申请人： Richard B. Greenwald ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Yun H. Choe

IPC分类号： A61K31/135 ,  A61K31/136 ,  A61K31/65 ,  A61K31/704 ,  A61K31/7068 ,  A61K38/00 ,  A61K45/00 ,  A61K47/48 ,  A61P43/00 ,  C07C237/22 ,  C07C271/16 ,  C07C271/22 ,  C08G65/329 ,  A61K31/765

CPC分类号： A61K47/48215 ,  C07C237/22 ,  C07C271/16 ,  C07C271/22 ,  C07B2200/11

摘要： The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula: ##STR1## wherein: B is a leaving group or a residue of an amine-containing target moiety;G is ##STR2## or CH.sub.2 ; Y.sub.1-2 are independently O or S;M is X or Q; where X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(.dbd.Y.sub.2);R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and R.sub.13 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.3-12 branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted alkyls, C.sub.3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.sub.1-6 heteroalkyls, substituted C.sub.1-6 heteroalkyls;R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.1-6 alkoxy, phenoxy, C.sub.1-8 heteroalkyls, C.sub.1-8 heteroalkoxy, substituted C.sub.1-6 alkyls, C.sub.3-8 cycloalkyls, C.sub.3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-; carboxy-, C.sub.1-6 carboxyalkyls and C.sub.1-6 alkyl carbonyls;(m) is zero or one;(n) is zero or a positive integer;(p) is zero, one or two; andR.sub.11 is a substantially non-antigenic polymer.The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, as a result of a trialkyl lock type lactonization-type reaction.

摘要翻译： 本发明涉及含有基于聚合物的输送形式的双重前药。 这些聚合前药优选具有下式：其中：B是离去基团或含胺目标部分的残基; G是或CH2; Y1-2独立地为O或S; M为X或Q; 其中X是吸电子基团，Q是含有从C（= Y2）定位3至6个原子的自由电子对的部分; R 1，R 4，R 7，R 8，R 9，R 10和R 13独立地选自氢，C 1-6烷基，C 3-12支链烷基，C 3-8环烷基，C 1-6取代的烷基，C 3-8取代的环烷基 芳基，取代的芳基，芳烷基，C 1-6杂烷基，取代的C 1-6杂烷基; R 2，R 3，R 5和R 6独立地选自氢，C 1-6烷基，C 1-6烷氧基，苯氧基，C 1-8杂烷基，C 1-8杂烷氧基，取代的C 1-6烷基，C 3-8环烷基， C 3-8取代的环烷基，芳烷基，芳基，取代的芳基，例如被卤素，硝基和氰基取代的芳基; 羧基，C 1-6羧基烷基和C 1-6烷基羰基; （m）为零或一; （n）为零或正整数; （p）为零，一或二; R11是基本上非抗原性的聚合物。 当双前体药物的聚合物部分被切割并且其后在体内快速产生母体分子时，由于三烷基锁定型内酯化反应的结果，产生第一种前体药物。

公开(公告)号：US07033583B2

公开(公告)日：2006-04-25

申请号：US10290695

申请日：2002-11-08

申请人： Yun H. Choe ,  Richard B. Greenwald

发明人： Yun H. Choe ,  Richard B. Greenwald

IPC分类号： A61K31/74 ,  A61K31/75

CPC分类号： C08G63/688 ,  A61K47/60 ,  C08G63/46 ,  C08G63/685

摘要： Thiol-linked polymeric prodrugs and methods of making and using the same are disclosed. The use of a sulfhydryl bond as the basic link for linking the polymer to the drug allows a prodrug to be formed which takes advantage of plasma enzymes in vivo. A preferred conjugate is Methods of preparing and treatment are also disclosed.

公开(公告)号：US06756037B2

公开(公告)日：2004-06-29

申请号：US09823283

申请日：2001-03-29

申请人： Richard B. Greenwald ,  Yun H. Choe

发明人： Richard B. Greenwald ,  Yun H. Choe

IPC分类号： A61K39395

CPC分类号： A61K47/60

摘要： The present invention is directed to polymer conjugates of biologically active agents and methods of preparing the same. In preferred aspects of the invention, the conjugates are of the formula wherein G is a linear or branched polymer residue such as a polyethylene glycol and B is a residue of an amine-containing or a hydroxyl-containing biologically active moiety such as Ara-C.

摘要翻译： 本发明涉及生物活性剂的聚合物共轭物及其制备方法。 在本发明的优选方面，缀合物是式（3），其中G是直链或支链聚合物残基例如聚乙二醇，B是含胺或含羟基的生物活性部分例如Ara-C的残基。