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1.发明授权Terminally-branched polymeric linkers and polymeric conjugates containing the same 失效末端支化的聚合物接头和含有它们的聚合物共轭物公开(公告)号：US06638499B2
公开(公告)日：2003-10-28
申请号：US10067930
申请日：2002-02-06
IPC分类号： A61K31785
CPC分类号： C07D491/22 , A61K47/60 , C07H15/252 , C08F283/00
摘要： The present invention is directed to polymeric-prodrug transport forms of the formula: wherein: E1-4 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, C1-6 heteroalkoxy, and at least one of E1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or wherein J1 is the same as J, or another member of the group defining J and E5 is the same as E1-4, or another member of the group defining E1-4, Y1-2 are independently O, S or NR9; M is a heteroatom 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(═Y2); R2-5 and R7-9 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 heteroakoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R1 is a polymeric residue. which is optionally capped with a moiety of the formula:
摘要翻译： 本发明涉及下式的聚合物 - 前药转运形式：其中：E1-4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，C 1-6烷氧基，苯氧基，C 1-6杂烷氧基，E1-4中的至少一个包括B部分 其中B是离去基团，OH，含羟基或氨基的部分的残基或其中J 1与J相同，或者定义J和E5的基团的另一个成员与E1-4相同或另一个成员 定义E1-4的基团，Y1-2独立地为O，S或NR9; M为选自X或Q的杂原子; 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和R7-9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杂烷基，取代的C1-6杂烷基，C1-6烷氧基，苯氧基和C1 -6杂芳氧基;（m1）和（m2）分别为零或一;（n1），（n2），（p1），（p2）和（q）分别为零或正整数，Z为吸电子基团 ; 并且R 1是聚合物残基，其任选地被下式的部分封端：
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2.发明授权Terminally-branched polymeric linkers and polymeric conjugates containing the same 失效末端支化的聚合物接头和含有它们的聚合物共轭物公开(公告)号：US06395266B1
公开(公告)日：2002-05-28
申请号：US09293624
申请日：1999-04-16
IPC分类号： A61K31785
CPC分类号： C07D491/22 , A61K47/60 , C07H15/252 , C08F283/00
摘要： The present invention is directed to polymeric-prodrug transport forms of the formula: wherein: E1-4 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, C1-6 heteroalkoxy, and at least one of E1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or wherein J1 is the same as J, or another member of the group defining J and E5 is the same as E1-4, or another member of the group defining E1-4; Y1-2 are independently O, S or NR9; M is a heteroatom 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(=Y2); R2-5 and R7-9 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, C1-16 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R1 is a polymeric residue. which is optionally capped with a moiety of the formula:
摘要翻译： 本发明涉及下式的聚合物 - 前药转运形式：其中：E1-4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，C 1-6烷氧基，苯氧基，C 1-6杂烷氧基，E1-4中的至少一个包括B部分 其中B是离去基团，OH，含羟基或氨基的部分的残基或其中J 1与J相同，或者定义J和E5的基团的另一个成员与E1-4相同或另一个成员 定义E1-4的基团; Y1-2独立地为O，S或NR9; M为选自X或Q的杂原子; 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和R7-9独立地选自氢，C1-6烷基 ，C3-12支链烷基，C3-8环烷基，C1-6取代烷基，C3-8取代环烷基，芳基，取代芳基，芳烷基，C1-16杂烷基，取代C1-6杂烷基，C1-6烷氧基，苯氧基和C1 -6杂烷氧基;（m1）和（m2）独立为零或一;（n1），（n2），（p1），（p2）和（q）独立为零或正整数，Z为吸电子基团 ; 并且R 1是聚合物残基，其任选地被下式的部分封端：
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3.发明授权公开(公告)号：US06251382B1
公开(公告)日：2001-06-26
申请号：US09293557
申请日：1999-04-15
IPC分类号： A61K4748
CPC分类号： A61K47/60
摘要： Polymeric compounds of the formula: (D)n—M—(R1)m (I) wherein (m) and (n) independently selected positive integers, preferably from about 1 to about 6 each; D is a residue of a biologically active moiety; M is a multifunctional linker/spacer moiety; and R1 is a polymer residue are disclosed. Methods of preparing the same and methods of treatment using the same are also included as part of the present invention.
摘要翻译： 下式的聚合化合物：其中（m）和（n）独立选择的正整数，优选约1至约6; D是生物活性部分的残基; M是多官能连接体/间隔子部分; 并且R 1是聚合物残基。 制备方法和使用该方法的方法也包括在本发明的一部分中。
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4.发明授权Terminally-branched polymeric linkers and polymeric conjugates containing the same 失效末端支化的聚合物接头和含有它们的聚合物共轭物
公开(公告)号：US6153655A
公开(公告)日：2000-11-28
申请号：US62305
申请日：1998-04-17
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，
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公开(公告)号：US6011042A
公开(公告)日：2000-01-04
申请号：US948872
申请日：1997-10-10
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。
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公开(公告)号：US06180095B2
公开(公告)日：2001-01-30
申请号：US09183557
申请日：1998-10-30
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。
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7.发明授权Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents 失效含氨基的生物活性剂的三烷基锁定促进的聚合物前药公开(公告)号：US06303569B1
公开(公告)日：2001-10-16
申请号：US09137430
申请日：1998-08-21
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。
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公开(公告)号：US5965566A
公开(公告)日：1999-10-12
申请号：US914927
申请日：1997-08-20
IPC分类号： A61K31/335 , A61K47/48 , C07D305/14 , C07D491/22 , C08G65/329 , A61K31/44
CPC分类号： A61K47/48215 , A61K31/335 , C07D305/14 , C08G65/329
摘要： The present invention is directed compositions of the formula: ##STR1## wherein: D is a residue of biologically active moiety;X is an electron withdrawing group;Y and Y' are independently O or S;(n) is zero (0) or a positive integer, preferably from 1 to about 12;wherein: R.sub.1 and R.sub.2 are independently selected from the group consisting of H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C.sub.1-6 alkyls;wherein: R.sub.3 is a substantially non-antigenic polymer, C.sub.1-12 straight or branched alkyl or substituted allyl, C.sub.5-8 cycloalkyl or substituted cycloalkyl, carboxyalkyl, carboalkoxy alkyl, dialkylaminoalkyl, phenylalkyl, phenylaryl or ##STR2## wherein: R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls, and substituted C.sub.1-6 alkyls or jointly form a cyclic C.sub.5 -C.sub.7 ring. In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.
摘要翻译： 本发明涉及下式的组合物：其中：D是生物活性部分的残基; X是吸电子基团; Y和Y'独立地为O或S; （n）为零（0）或正整数，优选1至约12; 其中：R 1和R 2独立地选自H，C 1-6烷基，芳基，取代的芳基，芳烷基，杂烷基，取代的杂烷基和取代的C 1-6烷基; 其中：R3是基本上非抗原性的聚合物，C1-12直链或支链烷基或取代的烯丙基，C5-8环烷基或取代的环烷基，羧基烷基，烷氧基烷基，二烷基氨基烷基，苯基烷基，苯基芳基或其中：R4和R5独立地选自 由H，C 1-6烷基，芳基，取代的芳基，芳烷基，杂烷基，取代的杂烷基和取代的C 1-6烷基组成的基团或共同形成环状C 5 -C 7环。 在优选的实施方案中，前药包含分子量为至少约20,000的聚乙二醇。
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9.发明授权公开(公告)号：US07897647B2
公开(公告)日：2011-03-01
申请号：US11502108
申请日：2006-08-09
IPC分类号： A01N33/08
CPC分类号： C07D333/34 , A61K38/00 , A61K47/60 , C07C271/16 , C07C271/20 , C07C271/22 , C07C317/28 , C07D207/452 , C07D277/16 , C07K14/43595
摘要： Activated polymeric bicine derivatives such as as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.
摘要翻译： 公开了活性聚合物双金属衍生物，以及由其制备的缀合物。 还公开了制备和使用双金属衍生物的方法。
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公开(公告)号：US06177087B1
公开(公告)日：2001-01-23
申请号：US09184910
申请日：1998-11-03
IPC分类号： A61K4500
CPC分类号： C08G65/3331 , A61K47/60 , C07K14/805 , C08G65/329 , C08G65/33303 , Y10S526/936 , Y10S530/815
摘要： Substantially non-antigenic polymers containing pI and/or pH optimum modulating moieties are disclosed. The polymers are useful as intermediates for synthesis of amine-based polymers and in the formation of activated polymers for conjugation with nucleophiles. Conjugates and methods of preparation and treatment with the conjugates are also disclosed.
摘要翻译： 公开了含有pI和/或pH最佳调节部分的基本非抗原性聚合物。 聚合物可用作合成基于胺的聚合物的中间体和用于与亲核试剂缀合的活化聚合物的形成。 还公开了共轭物的共轭物和制备和处理方法。
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