公开(公告)号：WO2011072627A2

公开(公告)日：2011-06-23

申请号：PCT/CZ2010/000131

申请日：2010-12-14

Applicant: USTAV MAKROMOLEKULARNI CHEMIE AV CR, V.V.I. ,  MIKROBIOLOGICKY USTAV AV CR, V.V.I. ,  ETRYCH, Tomas ,  CHYTIL, Petr ,  STROHALM, Jiri ,  ULBRICH, Karel ,  RIHOVA, Blanka

Inventor： ETRYCH, Tomas ,  CHYTIL, Petr ,  STROHALM, Jiri ,  ULBRICH, Karel ,  RIHOVA, Blanka

IPC: A61K47/48

CPC classification number: A61K47/482 ,  A61K47/48176 ,  A61K47/48207 ,  A61K47/48338 ,  A61K47/58 ,  A61K47/593 ,  A61K47/595 ,  A61K47/65 ,  C08G83/003

Abstract: 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.

Abstract translation: 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转运到实体瘤中，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：WO2007110003A3

公开(公告)日：2008-05-15

申请号：PCT/CZ2007000020

申请日：2007-03-28

Applicant: ZENTIVA AS ,  CHYTIL PETR ,  ETRYCH TOMAS ,  HRUBY MARTIN ,  ULBRICH KAREL ,  RIHOVA BLANKA

Inventor： CHYTIL PETR ,  ETRYCH TOMAS ,  HRUBY MARTIN ,  ULBRICH KAREL ,  RIHOVA BLANKA

IPC: A61K47/48

CPC classification number: A61K47/6907 ,  A61K47/543 ,  A61K47/58 ,  A61K47/60

Abstract: A micellar system destined for controlled release of medical drug is formed by a micellar structure, constituted by a hydrophilic or amphiphilic polymer, to which the drug is bound by a covalent linkage, the molecules of which are arranged on the hydrophilic surface of the micelle, while the nucleus of the micelle is constituted by hydrophobic components of the system, which are linked with the polymer on the surface by a chemical bond.

Abstract translation: 注射用于药物控制释放的胶束系统由胶束结构形成，胶束结构由亲水或两亲性聚合物构成，药物通过共价键结合，其分子布置在胶束的亲水表面上， 而胶束的核由系统的疏水组分构成，其通过化学键与表面上的聚合物连接。

公开(公告)号：WO03053473A2

公开(公告)日：2003-07-03

申请号：PCT/CZ0200070

申请日：2002-12-20

Applicant: LECIVA A S ,  ULBRICH KAREL ,  ETRYCH TOMAS ,  RIHOVA BLANKA ,  JELINKOVA MARKETA ,  KOVAR MAREK

Inventor： ULBRICH KAREL ,  ETRYCH TOMAS ,  RIHOVA BLANKA ,  JELINKOVA MARKETA ,  KOVAR MAREK

IPC: A61K31/78 ,  A61K39/395 ,  A61K47/48 ,  A61P35/00 ,  C07K5/083 ,  C07K5/103 ,  C07K7/06 ,  C07K16/00

CPC classification number: A61K47/6883 ,  A61K47/65

Abstract: 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 alpha -amino acids, epsilon -amino acids, aromatic amino acids or oligopeptides terminated with a molecule of an anthracycline cancerostatic, c) 0.5 to 15 % of units of methacryloylated alpha -amino acids, epsilon -amino acids, aromatic amino acids or oligopeptides or their sodium salts.

Abstract translation: 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个单体单元组成，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，ε-氨基酸，芳族氨基酸或用蒽环类抗癌药物分子终止的寡肽，c）0.5至15％的甲基丙烯酰化α-氨基酸，ε-氨基酸，芳族氨基酸或寡肽的单位 或其钠盐。

公开(公告)号：WO2011072627A3

公开(公告)日：2011-08-11

申请号：PCT/CZ2010000131

申请日：2010-12-14

Applicant: USTAV MAKROMOLEKULARNI CHEMIE ,  MIKROBIOLOGICKY USTAV AV CR V V I ,  ETRYCH TOMAS ,  CHYTIL PETR ,  STROHALM JIRI ,  ULBRICH KAREL ,  RIHOVA BLANKA

Inventor： ETRYCH TOMAS ,  CHYTIL PETR ,  STROHALM JIRI ,  ULBRICH KAREL ,  RIHOVA BLANKA

IPC: A61K47/48 ,  A61P35/00 ,  C08G83/00

CPC classification number: A61K47/482 ,  A61K47/48176 ,  A61K47/48207 ,  A61K47/48338 ,  A61K47/58 ,  A61K47/593 ,  A61K47/595 ,  A61K47/65 ,  C08G83/003

Abstract: 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.

Abstract translation: 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缀合物，所述药物衍生自酰氨基胺和2,2-双（羟甲基）丙酸类型的树枝状聚合物，其氨基和羟基端基连接 （N-羟丙基）甲基丙烯酰胺（HPMA）通过可生物降解间隔物的半共聚物。 聚合物载体和缀合物使得能够特别将抗癌药靶向转运成实体瘤，其中提供了生物降解，相关的受控药物释放和随后从生物体中消除聚合物载体。 聚合物载体与癌症抑制剂缀合用于人肿瘤的靶向治疗。

公开(公告)号：WO2008034391A1

公开(公告)日：2008-03-27

申请号：PCT/CZ2007/000087

申请日：2007-09-18

Applicant: ZENTIVA, A.S. ,  ETRYCH, Tomas ,  CHYTIL, Petr ,  ULBRICH, Karel ,  MRKVAN, Tomas ,  RIHOVA, Blanka

Inventor： ETRYCH, Tomas ,  CHYTIL, Petr ,  ULBRICH, Karel ,  MRKVAN, Tomas ,  RIHOVA, Blanka

IPC: A61K47/48

CPC classification number: A61K47/58 ,  A61K47/65

Abstract: 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.

Abstract translation: 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 - 也可携带癌抑制剂的移植物，所述移植物通过以下结合键与主链结合： 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：WO2007028347A3

公开(公告)日：2007-05-10

申请号：PCT/CZ2006000056

申请日：2006-09-05

Applicant: ZENTIVA AS ,  ETRYCH TOMAS ,  CHYTIL PETR ,  STUDENOVSKY MARTIN ,  PECHAR MICHAL ,  ULBRICH KAREL ,  RIHOVA BLANKA

Inventor： ETRYCH TOMAS ,  CHYTIL PETR ,  STUDENOVSKY MARTIN ,  PECHAR MICHAL ,  ULBRICH KAREL ,  RIHOVA BLANKA

IPC: A61K47/48 ,  A61P35/00 ,  C08F8/34 ,  C08F220/58

CPC classification number: A61K47/58

Abstract: 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.

Abstract translation: 一种制备N-（2-羟基丙基）甲基丙烯酰胺和多柔比星的甲基丙烯酰氨基酰腙与pH控制释放药物的聚合物共轭物的方法，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：WO2003053473A3

公开(公告)日：2003-07-03

申请号：PCT/CZ2002/000070

申请日：2002-12-20

Applicant: LECIVA, A.S. ,  ULBRICH, Karel ,  ETRYCH, Tomás ,  RIHOVA, Blanka ,  JELINKOVA, Markéta ,  KOVAR, Marek

Inventor： ULBRICH, Karel ,  ETRYCH, Tomás ,  RIHOVA, Blanka ,  JELINKOVA, Markéta ,  KOVAR, Marek

IPC: A61K47/48

Abstract: 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.

公开(公告)号：WO2010045896A3

公开(公告)日：2010-08-12

申请号：PCT/CZ2009000115

申请日：2009-09-30

Applicant: ZENTIVA K S ,  ETRYCH TOMAS ,  ULBRICH KAREL ,  HOVORKA ONDREJ ,  RIHOVA BLANKA

Inventor： ETRYCH TOMAS ,  ULBRICH KAREL ,  HOVORKA ONDREJ ,  RIHOVA BLANKA

IPC: A61K47/48 ,  A61P35/00

CPC classification number: A61K47/6883 ,  A61K47/58 ,  A61K47/65

Abstract: By mixing two polymeric conjugates of doxorubicin which differ in the mode of causing death of tumour cells in an appropriate ratio, synergy in an anti-tumour effect can be achieved, and such a composition is a particularly effective agent for treatment of tumour diseases.

Abstract translation: 通过混合两种适当比例引起肿瘤细胞死亡方式不同的多柔比星聚合物缀合物，可以实现抗肿瘤作用的协同作用，并且这种组合物是治疗肿瘤疾病的特别有效的药剂。

公开(公告)号：WO2007110003A2

公开(公告)日：2007-10-04

申请号：PCT/CZ2007/000020

申请日：2007-03-28

Applicant: ZENTIVA, A.S. ,  CHYTIL, Petr ,  ETRYCH, Tomas ,  HRUBY, Martin ,  ULBRICH, Karel ,  RIHOVA, Blanka

Inventor： CHYTIL, Petr ,  ETRYCH, Tomas ,  HRUBY, Martin ,  ULBRICH, Karel ,  RIHOVA, Blanka

IPC: A61K47/48 ,  A61P35/00

CPC classification number: A61K47/6907 ,  A61K47/543 ,  A61K47/58 ,  A61K47/60

Abstract: A micellar system destined for controlled release of medical drug is formed by a micellar structure, constituted by a hydrophilic or amphiphilic polymer, to which the drug is bound by a covalent linkage, the molecules of which are arranged on the hydrophilic surface of the micelle, while the nucleus of the micelle is constituted by hydrophobic components of the system, which are linked with the polymer on the surface by a chemical bond.

Abstract translation: 用于药物控制释放的胶束系统由胶束结构形成，胶束结构由亲水或两亲性聚合物构成，药物通过共价键结合，其分子布置在胶束的亲水表面上， 而胶束的核由系统的疏水组分构成，其通过化学键与表面上的聚合物连接。

公开(公告)号：WO2005007798A3

公开(公告)日：2006-04-06

申请号：PCT/IB2004052127

申请日：2004-07-15

Applicant: USTAV MAKROMOLEKULARNI CHEMIE ,  MIKROBIOLOGICK USTAV AVCR ,  SUBR VLADIMIR ,  ULBRICH KAREL ,  RIHOVA BLANKA

Inventor： SUBR VLADIMIR ,  ULBRICH KAREL ,  RIHOVA BLANKA

IPC: A61K47/30 ,  A61K47/48 ,  C07D277/04 ,  C08F8/34 ,  C08F120/56 ,  C08F128/02 ,  C08F220/56 ,  C08F220/58 ,  C08F228/02 ,  C12N20060101 ,  A61P35/00

CPC classification number: C08F220/58 ,  A61K47/58 ,  A61K47/6883 ,  C08F8/34 ,  C08F2810/40 ,  C08F20/58

Abstract: The solution concerns reactive polymers and copolymers based on N-(2­hydroxypropyl)methacrylamide, which contain reactive thiazolidine-2-thione groups in side chains of the polymers or at the ends of polymer chains. The solution also includes a method of their preparation and their use for synthesis of polymer drugs and conjugates with proteins and preparation of gene delivery systems.

Abstract translation: 该溶液涉及基于N-（2-羟丙基）甲基丙烯酰胺的反应性聚合物和共聚物，其在聚合物的侧链或聚合物链的末端含有活性噻唑烷-2-硫酮基团。 该溶液还包括其制备方法及其用于合成聚合物药物和与蛋白质偶联物以及基因递送系统的制备的用途。