公开(公告)号：US09173949B2

公开(公告)日：2015-11-03

申请号：US13516607

申请日：2010-12-14

申请人： Tomas Etrych ,  Petr Chytil ,  Jiri Strohalm ,  Karel Ulbrich ,  Blanka Rihova

发明人： Tomas Etrych ,  Petr Chytil ,  Jiri Strohalm ,  Karel Ulbrich ,  Blanka Rihova

IPC分类号： C08F20/56 ,  A61K47/48 ,  C08G83/00

CPC分类号： A61K47/482 ,  A61K47/48176 ,  A61K47/48207 ,  A61K47/48338 ,  A61K47/58 ,  A61K47/593 ,  A61K47/595 ,  A61K47/65 ,  C08G83/003

摘要： The present invention relates to water-soluble high-molecular-weight polymer drug carriers and their conjugates with drugs, derived from dendrimers of the amidoamine and 2,2-bis(hydroxymethyl)propanoic types, the amino and hydroxy end groups of which are attached to semitelechelic copolymers of N-(2 hydroxypropyl)methacrylamide (HPMA) through biodegradable spacers. The polymer carriers and conjugates enable targeted transport notably of anticancer drugs into solid tumors in which biodegradation, the associated controlled drug release and subsequent elimination of polymer carrier from the organism are provided. The polymer carrier conjugated with a cancerostatic for use in targeted therapy of human tumors.

摘要翻译： 本发明涉及水溶性高分子量聚合物药物载体及其与药物的共轭物，其衍生自酰氨基胺的树枝状大分子和2,2-双（羟甲基）丙酸类型，其氨基和羟基端基连接 通过可生物降解的间隔物将N-（2羟丙基）甲基丙烯酰胺（HPMA）的半触变共聚物。 聚合物载体和共轭物使得能够将抗癌药物靶向运输到实体瘤中，其中提供生物降解，相关的受控药物释放和随后从生物体中消除聚合物载体。 与用于靶向治疗人类肿瘤的癌症药物结合的聚合物载体。

公开(公告)号：US20120296048A1

公开(公告)日：2012-11-22

申请号：US13516607

申请日：2010-12-14

申请人： Tomas Etrych ,  Petr Chytil ,  Jiri Strohalm ,  Karel Ulbrich ,  Blanka Rihova

发明人： Tomas Etrych ,  Petr Chytil ,  Jiri Strohalm ,  Karel Ulbrich ,  Blanka Rihova

IPC分类号： C08F20/56

CPC分类号： A61K47/482 ,  A61K47/48176 ,  A61K47/48207 ,  A61K47/48338 ,  A61K47/58 ,  A61K47/593 ,  A61K47/595 ,  A61K47/65 ,  C08G83/003

摘要： The present invention relates to water-soluble high-molecular-weight polymer drug carriers and their conjugates with drugs, derived from dendrimers of the amidoamine and 2,2-bis(hydroxymethyl)propanoic types, the amino and hydroxy end groups of which are attached to semitelechelic copolymers of N-(2 hydroxypropyl)methacrylamide (HPMA) through biodegradable spacers. The polymer carriers and conjugates enable targeted transport notably of anticancer drugs into solid tumors in which biodegradation, the associated controlled drug release and subsequent elimination of polymer carrier from the organism are provided. The polymer carrier conjugated with a cancerostatic for use in targeted therapy of human tumors.

摘要翻译： 本发明涉及水溶性高分子量聚合物药物载体及其与药物的共轭物，其衍生自酰氨基胺的树枝状大分子和2,2-双（羟甲基）丙酸类型，其氨基和羟基端基连接 通过可生物降解的间隔物将N-（2羟丙基）甲基丙烯酰胺（HPMA）的半触变共聚物。 聚合物载体和共轭物使得能够将抗癌药物靶向运输到实体瘤中，其中提供生物降解，相关的受控药物释放和随后从生物体中消除聚合物载体。 与用于靶向治疗人类肿瘤的癌症药物结合的聚合物载体。

公开(公告)号：US20080318879A1

公开(公告)日：2008-12-25

申请号：US12065745

申请日：2006-09-05

申请人： Tomas Etrych ,  Petr Chytil ,  Martin Studenovsky ,  Michal Pechar ,  Karel Ulbrich ,  Blanka Rihova

发明人： Tomas Etrych ,  Petr Chytil ,  Martin Studenovsky ,  Michal Pechar ,  Karel Ulbrich ,  Blanka Rihova

IPC分类号： A61K47/48 ,  A61P35/00

CPC分类号： A61K47/58

摘要： A method for the preparation of polymeric conjugates of N-(2-hydroxypropyl)methacrylamide and a methacryloylaminoacylhydrazone of doxorubicin with pH-controlled release of the drug, comprising the following three steps of synthesis: a. preparation of a monomeric methacryloylaminoacylhydrazine, wherein the aminoacyl is derived from an amino acid or oligopeptide, by reaction of a methacryloyl halide with the respective peptide, amino acid, or a derivative thereof, and subsequent hydrazinolysis, b. synthesis of a polymeric precursor by direct copolymerization of N-(2-hydroxypropyl)methacrylamide with the methacryloylaminoacylhydrazine, and c. binding of doxorubicin to the polymeric precursor by reaction thereof with doxorubicin hydrochloride.

摘要翻译： 一种制备N-（2-羟丙基）甲基丙烯酰胺和多柔比星的甲基丙烯酰氨基酰腙的聚合物共轭物的方法，其具有pH控制释放的药物，包括以下三个合成步骤：a。 b。通过甲基丙烯酰卤与相应的肽，氨基酸或其衍生物的反应以及随后的肼解，制备单体甲基丙烯酰氨基酰肼，其中氨酰基衍生自氨基酸或寡肽。 通过N-（2-羟丙基）甲基丙烯酰胺与甲基丙烯酰基氨基酰肼的直接共聚合成聚合物前体，和c。 通过与多柔比星盐酸盐的反应将多柔比星与聚合物前体结合。

公开(公告)号：US08603990B2

公开(公告)日：2013-12-10

申请号：US12441619

申请日：2007-09-18

申请人： Tomas Etrych ,  Petr Chytil ,  Karel Ulbrich ,  Tomas Mrkvan ,  Blanka Rihova

发明人： Tomas Etrych ,  Petr Chytil ,  Karel Ulbrich ,  Tomas Mrkvan ,  Blanka Rihova

IPC分类号： A61K31/704 ,  C07K1/113 ,  C07H15/252 ,  A61P35/00

CPC分类号： A61K47/58 ,  A61K47/65

摘要： A polymeric drug, in which a cancerostatic connected via spacers containing hydrolytically cleavable hydrazone bonds is bound to a water-soluble polymeric carrier prepared on the basis of a N-(2-hydroxypropyl)methacrylamide copolymer, wherein the structure of the polymeric drug consists of the main chain of N-(2-hydroxypropyl)methacrylamide carrying the cancerostatic and another chain of N-(2-hydroxypropyl)methacrylamide—a graft, which may also carry a cancerostatic, said grafts being bound to the main chain by a bond that is stable in the body and/or by a bond cleavable in the body, especially by an oligopeptide spacer selected from the series of GlyLeuGly (SEQ ID. NO. 1), GlyPheGly (SEQ ID. NO. 2), GlyPheLeuGly (SEQ ID. NO. 3) and GlyLeuPheGly (SEQ ID. NO. 4), and a method of its preparation.

摘要翻译： 一种聚合物药物，其中通过含有可水解可切割腙键的间隔物连接的癌基团与基于N-（2-羟丙基）甲基丙烯酰胺共聚物制备的水溶性聚合物载体结合，其中聚合物药物的结构由 携带癌抑制剂的N-（2-羟丙基）甲基丙烯酰胺的主链和另一个N-（2-羟丙基）甲基丙烯酰胺链 - 也可以携带癌抑制剂的移植物，所述移植物通过键连接到主链上， 特别是通过选自GlyLeuGly（SEQ ID NO：1），GlyPheGly（SEQ ID NO：2），GlyPheLeuGly（SEQ ID NO：1），GlyPheLeuGly（SEQ ID NO：1）， ，3号）和GlyLeuPheGly（SEQ ID NO.4）及其制备方法。

公开(公告)号：US20090306004A1

公开(公告)日：2009-12-10

申请号：US12441619

申请日：2007-09-18

申请人： Tomas Etrych ,  Petr Chytil ,  Karel Ulbrich ,  Thomas Mrkvan ,  Blanka Rihova

发明人： Tomas Etrych ,  Petr Chytil ,  Karel Ulbrich ,  Thomas Mrkvan ,  Blanka Rihova

IPC分类号： A61K31/704 ,  C07K1/113 ,  C07H15/252 ,  A61P35/00

CPC分类号： A61K47/58 ,  A61K47/65

摘要： A polymeric drug, in which a cancerostatic connected via spacers containing hydrolytically cleavable hydrazone bonds is bound to a water-soluble polymeric carrier prepared on the basis of a N-(2-hydroxypropyl)methacrylamide copolymer, wherein the structure of the polymeric drug consists of the main chain of N-(2-hydroxypropyl)methacrylamide carrying the cancerostatic and another chain of N-(2-hydroxypropyl)methacrylamide—a graft, which may also carry a cancerostatic, said grafts being bound to the main chain by a bond that is stable in the body and/or by a bond cleavable in the body, especially by an oligopeptide spacer selected from the series of GlyLeuGly, GlyPheGly, GlyPheLeuGly and GlyLeuPheGly, and a method of its preparation.

摘要翻译： 一种聚合物药物，其中通过含有可水解可切割腙键的间隔物连接的癌基团与基于N-（2-羟丙基）甲基丙烯酰胺共聚物制备的水溶性聚合物载体结合，其中聚合物药物的结构由 携带癌抑制剂的N-（2-羟丙基）甲基丙烯酰胺的主链和另一个N-（2-羟丙基）甲基丙烯酰胺链 - 也可以携带癌抑制剂的移植物，所述移植物通过键连接到主链上， 特别是通过选自GlyLeuGly，GlyPheGly，GlyPheLeuGly和GlyLeuPheGly的寡肽隔离物及其制备方法，在体内和/或可通过体内可切割的键稳定。

公开(公告)号：US07919076B2

公开(公告)日：2011-04-05

申请号：US10499422

申请日：2002-12-20

申请人： Karel Ulbrich ,  Tomas Etrych ,  Blanka Rihova ,  Marketa Jelinkova ,  Marek Kovar

发明人： Karel Ulbrich ,  Tomas Etrych ,  Blanka Rihova ,  Marketa Jelinkova ,  Marek Kovar

IPC分类号： A61K31/74

CPC分类号： A61K47/6883 ,  A61K47/65

摘要： Conjugates consisting of a polymeric carrier constituted by 30 to 3,000 monomer units linked to form a polymeric chain, composed of a) 60 to 99% of N-(2-hydroxypropyl)methacrylamide units, b) 1 to 25% of units of methacryloylated hydrazones of α-amino acids, ε-amino acids, aromatic amino acids or oligopeptides terminated with a molecule of an anthracycline cancerostatic, c) 0.5 to 15% of units of methacryloylated α-amino acids, ε-amino acids, aromatic amino acids or oligopeptides or their sodium salts.

摘要翻译： 由聚合物载体构成的共轭体由连接形成聚合物链的30至3,000个单体单元构成，由a）60至99％的N-（2-羟丙基）甲基丙烯酰胺单元组成，b）1至25％的甲基丙烯酰化腙单元 α-氨基酸，α-氨基酸，芳香族氨基酸或用蒽环类抗癌药物分子终止的寡肽，c）0.5〜15％的甲基丙烯酰化α-氨基酸单元，氨基酸，芳香族氨基酸 或寡肽或其钠盐。

公开(公告)号：US20100190928A1

公开(公告)日：2010-07-29

申请号：US12376915

申请日：2007-08-08

申请人： Tomas Etrych ,  Karel Ulbrich

发明人： Tomas Etrych ,  Karel Ulbrich

IPC分类号： A61K47/48

CPC分类号： A61K47/58

摘要： A polymeric drug in the form of a conjugate of a copolymer of N-(2-hydroxypropyl)-methacrylamide (HPMA) with doxorubicin bound to the polymer via spacers containing hydrolytically cleavable hydrazone bonds, of formula (I), wherein SP1 represents an aminoacyl spacer, x=40 to 335, y=1 to 25, consisting of from 90 to 99.5 mol. % of units of HPMA and 10 to 0.5 mol. % of doxorubicin-containing comonomeric units. The conjugate is prepared via direct copolymerization of the doxorubicin-containing monomer of formula (II) with HPMA.

摘要翻译： N-（2-羟丙基） - 甲基丙烯酰胺（HPMA）与多柔比星的共聚物与多柔比星的共轭物形式的聚合物形式，其通过式（I）的含有水解可切割的腙键的间隔基与聚合物结合，其中SP1表示氨基酰基 间隔基，x = 40至335，y = 1至25，由90至99.5mol组成。 HPMA的单位％和10至0.5mol。 ％的含多柔比星的共聚单体。 通过式（II）的含多柔比星的单体与HPMA的直接共聚来制备缀合物。