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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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2.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：US6127355A
公开(公告)日：2000-10-03
申请号：US277230
申请日：1999-03-26
IPC分类号： A61K31/335 , A61K47/48 , C07D305/14 , C07D491/22 , C08G65/329 , A61K31/395 , A61K31/41 , A61K31/415 , A61K31/43 , A61K31/505
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 a 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;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;R.sub.3 is a substantially non-antigenic polymer, C.sub.1-12 straight or branched alkyl or substituted alkyl, C.sub.5-8 cycloalkyl or substituted cycloalkyl, carboxyalkyl, carboalkoxy alkyl, dialkylaminoalkyl, phenylalkyl, phenylaryl or ##STR2## 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; 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; 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烷基，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R4和R5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，或共同形成环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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公开(公告)号：US6111107A
公开(公告)日：2000-08-29
申请号：US974909
申请日：1997-11-20
IPC分类号： C07D498/22 , C07D305/14
CPC分类号： C07D498/22
摘要： The present invention is directed to methods of forming esters of tertiary alcohols. The methods include reacting a compound containing a tertiary alcohol with an acyl heteroaromatic ion-based compound of the formula: ##STR1## wherein R.sub.1 is an aromatic or aliphatic acid residue;Y is O or S;Z is R.sub.2 N;X is selected from the group consisting of ##STR2## wherein R.sub.2 and R.sub.3 are independently selected from the group consisting ofH, C.sub.1-6 alkyls, C.sub.1-6 substituted alkyls, C.sub.1-6 heteroalkyls, C.sub.3-8, branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted heteroalkyls, aryls, substituted aryls, except that R.sub.2 is not H when X is ##STR3## C.sub.1-6 alkyl aralkyls, C.sub.1-6 heteroalkyl aralkyls, C.sub.3-8, branched alkyl aralkyls and C.sub.3-8 cycloalkyl aralkyls; and R.sub.2 ' is the same as R.sub.2 except that R.sub.2 ' is not H;in the presence of a lanthanide.sup.III metal-based catalyst and a base. In preferred embodiments, a substantially pure optical isomer of a compound containing a tertiary alcohol is used and the resultant esters are of sufficient purity so that expensive and time consuming recrystallization or purification steps are avoided.
摘要翻译： 本发明涉及形成叔醇酯的方法。 所述方法包括使含有叔醇的化合物与下式的酰基杂芳族离子基化合物反应：其中R1是芳族或脂族酸残基; Y为O或S; Z为R2 N; X选自其中R 2和R 3独立地选自H，C 1-6烷基，C 1-6取代的烷基，C 1-6杂烷基，C 3-8，支链烷基，C 3-8环烷基， C 1-6取代的杂烷基，芳基，取代的芳基，但当X为C 1-6烷基芳烷基时，R 2不为H，C 1-6杂烷基芳烷基，C 3-8，支链烷基芳烷基和C 3-8环烷基芳烷基; R2'与R2相同，不同之处在于R2'不为H; 在镧系金属III金属基催化剂和碱的存在下。 在优选的实施方案中，使用含有叔醇的化合物的基本上纯的光学异构体，所得到的酯具有足够的纯度，从而避免了昂贵且耗时的重结晶或纯化步骤。
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5.发明授权公开(公告)号：US07122189B2
公开(公告)日：2006-10-17
申请号：US10218167
申请日：2002-08-13
IPC分类号： A61K39/395 , A01N33/08 , A01N31/06 , A61K39/44
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：US06194580B1
公开(公告)日：2001-02-27
申请号：US09495581
申请日：2000-02-04
IPC分类号： C07D49114
CPC分类号： C07D498/22
摘要： The present invention is directed to methods of forming esters of tertiary alcohols. The methods include reacting a compound containing a tertiary alcohol with an acyl heteroaromatic ion-based compound of the formula: wherein R1 is an aromatic or aliphatic acid residue; Y is O or S; Z is CR2 or N; X is selected from the group consisting of wherein R2 and R3 are independently selected from the group consisting of H, C1-6 alkyls, C1-6 substituted alkyls, C1-6 heteroalkyls, C3-8 branched alkyls, C3-8 cycloalkyls, C1-6 substituted heteroalkyls, aryls, substituted aryls, C1-6 alkyl aralkyls, C1-6 heteroalkyl aralkyls, C3-8 branched alkyl aralkyls and C3-8 cycloalkyl aralkyls; and R2′ is the same as R2 except that R2′ is not H; in the presence of a lanthanideIII metal-based catalyst and a base. In preferred embodiments, a substantially pure optical isomer of a compound containing a tertiary alcohol is used and the resultant esters are of sufficient purity so that expensive and time consuming recrystallization or purification steps are avoided.
摘要翻译： 本发明涉及形成叔醇酯的方法。 所述方法包括使含有叔醇的化合物与下式的酰基杂芳族离子基化合物反应：其中R 1是芳族或脂族酸残基; Y是O或S; Z是CR 2或N; X选自 其中R 2和R 3独立地选自H，C 1-6烷基，C 1-6取代的烷基，C 1-6杂烷基，C 3-8支链烷基，C 3-8环烷基，C 1-6取代的杂烷基，芳基，取代的 芳基，C 1-6烷基芳烷基，C 1-6杂烷基芳烷基，C 3-8支链烷基芳烷基和C 3-8环烷基芳烷基; 并且R 2'与R 2相同，除了R 2'不是H;在镧系元素III金属基催化剂和碱的存在下。 在优选的实施方案中，使用含有叔醇的化合物的基本上纯的光学异构体，所得到的酯具有足够的纯度，从而避免了昂贵且耗时的重结晶或纯化步骤。
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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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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：US5880131A
公开(公告)日：1999-03-09
申请号：US537207
申请日：1995-09-29
IPC分类号： A61K31/335 , A61K47/48 , C07D305/14 , C07D491/22 , A61K31/44
CPC分类号： A61K31/335 , C07D305/14
摘要： High molecular weight, water-soluble prodrugs of the formula: ##STR1## wherein: D is a biologically active moiety;M is X or Q;X is an electron withdrawing group;Q is a moiety containing a free electron pair positioned five or six atoms from Y';Y and Y' are oxygen or sulfur;R is a polyalkylene oxide; andZ is OH, C.sub.1-4 all moieties or ##STR2## are disclosed. In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.
摘要翻译： 具有下式的高分子量的水溶性前药：其中：D是生物活性部分; M为X或Q; X是吸电子基团; Q是含有自由电子对的部分，其位于Y'的5或6个原子上; Y和Y'是氧或硫; R是聚环氧烷; 并且Z是OH，C1-4所有部分或
。 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。 -
10.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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