公开(公告)号：US08163747B2

公开(公告)日：2012-04-24

申请号：US12529090

申请日：2008-02-28

申请人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

发明人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

IPC分类号： A61K31/535 ,  C07D413/10

CPC分类号： C07D295/155 ,  A61K31/5377 ,  C07D261/18

摘要： The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

摘要翻译： 本发明涉及5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的新盐形式，特别是 甲磺酸盐，盐酸盐，酒石酸盐，磷酸盐和半富马酸盐; 到这种盐的结晶形式; 5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的多晶型物; 到上述新盐形式的水合物和多晶型物; 使用上述新的盐形式来制备用于治疗由Hsp90介导的病症的药物; 涉及使用新的盐形式治疗由Hsp90介导的病症的方法; 包括这种盐形式的制剂，特别是适于静脉内施用的水溶液; 以及填充这种制剂的琥珀色玻璃容器。

公开(公告)号：US20100093732A1

公开(公告)日：2010-04-15

申请号：US12529090

申请日：2008-02-28

申请人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

发明人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

IPC分类号： A61K31/5377 ,  C07D413/02 ,  A61P43/00 ,  B65D23/00

CPC分类号： C07D295/155 ,  A61K31/5377 ,  C07D261/18

摘要： The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

摘要翻译： 本发明涉及5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的新盐形式，特别是 甲磺酸盐，盐酸盐，酒石酸盐，磷酸盐和半富马酸盐; 到这种盐的结晶形式; 5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的多晶型物; 到上述新盐形式的水合物和多晶型物; 使用上述新的盐形式来制备用于治疗由Hsp90介导的病症的药物; 涉及使用新的盐形式治疗由Hsp90介导的病症的方法; 包括这种盐形式的制剂，特别是适于静脉内施用的水溶液; 以及填充这种制剂的琥珀色玻璃容器。

公开(公告)号：US08487095B2

公开(公告)日：2013-07-16

申请号：US13415268

申请日：2012-03-08

申请人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

发明人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

IPC分类号： C07D413/10

CPC分类号： C07D295/155 ,  A61K31/5377 ,  C07D261/18

摘要： The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

摘要翻译： 本发明涉及5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的新盐形式，特别是 甲磺酸盐，盐酸盐，酒石酸盐，磷酸盐和半富马酸盐; 到这种盐的结晶形式; 5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的多晶型物; 到上述新盐形式的水合物和多晶型物; 使用上述新的盐形式来制备用于治疗由Hsp90介导的病症的药物; 涉及使用新的盐形式治疗由Hsp90介导的病症的方法; 包括这种盐形式的制剂，特别是适于静脉内施用的水溶液; 以及填充这种制剂的琥珀色玻璃容器。

公开(公告)号：US20120172592A1

公开(公告)日：2012-07-05

申请号：US13415268

申请日：2012-03-08

申请人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

发明人： Martin James Drysdale ,  Brian William Dymock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

IPC分类号： C07D413/10

CPC分类号： C07D295/155 ,  A61K31/5377 ,  C07D261/18

摘要： The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

摘要翻译： 本发明涉及5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的新盐形式，特别是 甲磺酸盐，盐酸盐，酒石酸盐，磷酸盐和半富马酸盐; 到这种盐的结晶形式; 5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的多晶型物; 到上述新盐形式的水合物和多晶型物; 使用上述新的盐形式来制备用于治疗由Hsp90介导的病症的药物; 涉及使用新的盐形式治疗由Hsp90介导的病症的方法; 包括这种盐形式的制剂，特别是适于静脉内施用的水溶液; 以及填充这种制剂的琥珀色玻璃容器。

公开(公告)号：US20130296556A1

公开(公告)日：2013-11-07

申请号：US13938659

申请日：2013-07-10

申请人： Martin James Drysdale ,  Brian William Dyrnock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

发明人： Martin James Drysdale ,  Brian William Dyrnock ,  Christoph Krell ,  Michael Mutz ,  Holger Petersen ,  Weijia Zheng

IPC分类号： C07D295/155

CPC分类号： C07D295/155 ,  A61K31/5377 ,  C07D261/18

摘要： The present invention relates to new salt forms of 5-(-2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, lartrate, phosphate and hemi fumarate slat thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-4-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

摘要翻译： 本发明涉及5-（ - 2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-3-甲酸乙酰胺的新盐形式，特别是 甲磺酸盐，盐酸盐，酒石酸盐，磷酸盐和半富马酸盐盐; 到这种盐的结晶形式; 5-（2,4-二羟基-5-异丙基 - 苯基）-4-（4-吗啉-4-基甲基 - 苯基） - 异恶唑-4-甲酸乙酰胺的多晶型物; 到上述新盐形式的水合物和多晶型物; 使用上述新的盐形式来制备用于治疗由Hsp90介导的病症的药物; 涉及使用新的盐形式治疗由Hsp90介导的病症的方法; 包括这种盐形式的制剂，特别是适于静脉内施用的水溶液; 以及填充这种制剂的琥珀色玻璃容器。

公开(公告)号：US08642594B2

公开(公告)日：2014-02-04

申请号：US12690983

申请日：2010-01-21

申请人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

发明人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

IPC分类号： A61K31/519 ,  A61K31/5377 ,  A61K31/497 ,  A61P25/28 ,  C07D487/04 ,  C07D295/04 ,  C07D295/104

CPC分类号： C07D495/04 ,  A61K31/519

摘要： Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, cancer: wherein R2 is a group of formula —(Ar1)m-(Alk1)P-(Z)r-(Alk2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

摘要翻译： 式（1）化合物是体外或体内HSP90活性的抑制剂，尤其用于治疗癌症：其中R2是式 - （Ar1）m-（Alk1）P-（Z） r-（Alk2）SQ其中Ar1是任选取代的芳基或杂芳基，Alk'和Alk 2是任选取代的二价C 1 -C 3亚烷基或C 2 -C 3亚烯基，m，p，r和s独立地为0或1， Z是-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO 2 - ， - C（= O） （= S）NRA，-SO2NRA-，-NRAC（= O） - ，-NRASO2-或-NRA-，其中RA是氢或C1-C6烷基，Q是氢或任选取代的碳环或杂环基; R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基。

公开(公告)号：US20120252797A1

公开(公告)日：2012-10-04

申请号：US13525409

申请日：2012-06-18

申请人： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

发明人： Martin James Drysdale ,  Brian William Dymock ,  Harry Finch ,  Paul Webb ,  Edward McDonald ,  Karen Elizabeth James ,  Kwai Ming Cheung ,  Thomas Peter Matthews

IPC分类号： A61K31/42 ,  C07D413/10 ,  A61K31/5377 ,  A61K31/422 ,  A61K31/4439 ,  A61P35/00 ,  A61K31/427 ,  C07D413/14 ,  A61K31/496 ,  A61K31/454 ,  A61K31/541 ,  C07D261/08 ,  C07D417/04

CPC分类号： A61K31/541 ,  A61K31/42 ,  A61K31/422 ,  A61K31/427 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/4709 ,  A61K31/496 ,  A61K31/5377 ,  C07D261/08 ,  C07D261/10 ,  C07D413/04 ,  C07D413/10 ,  C07D417/04 ,  C07D495/04

摘要： Isoxazoles of formula (A) or (B) wherein R1 is a group of formula (IB) The isoxazoles are inhibitors of HSP90 activity, and useful for the treatment of, for example, cancers.

摘要翻译： 式（A）或（B）的异恶唑其中R1是式（IB）的基团异恶唑是HSP90活性的抑制剂，可用于治疗例如癌症。

公开(公告)号：US07820658B2

公开(公告)日：2010-10-26

申请号：US10569287

申请日：2004-08-26

申请人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

发明人： Brian William Dymock ,  Martin James Drysdale ,  Christofe Fromont ,  Allan Jordan ,  Xavier Barril-Alonso

IPC分类号： C07D487/04 ,  A61K31/519 ,  C07D295/04 ,  C07D295/104 ,  A61K31/5377 ,  A61K31/497 ,  A61P25/28

CPC分类号： C07D495/04 ,  A61K31/519

摘要： Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, Cancer: wherein R2 is a group of formula —(Ar1)m-(Alk1)P-(Z)r-(Alk 2)S-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk′ and Alk 2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)_, —NRASO2- or —NRA—wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group.

摘要翻译： 式（1）的化合物是体外或体内的HSP90活性的抑制剂，并且用于治疗尤其是癌症：其中R2是式 - （Ar1）m-（Alk1）P-（Z） r-（Alk 2）SQ其中Ar1是任选取代的芳基或杂芳基，Alk'和Alk 2是任选取代的二价C 1 -C 3亚烷基或C 2 -C 3亚烯基，m，p，r和s独立地为0或1 ，Z为-O - ， - S - ， - （C = O） - ， - （C = S） - ， - SO 2 - ， - C（= O） 其中RA是氢或C 1 -C 6烷基，Q是氢或任选取代的碳环或杂环基; C（= O）NR A - ， - SO 2 NRA-，-NRAC（= O） R 3是氢，任选的取代基，或任选取代的（C 1 -C 6）烷基，芳基或杂芳基; 并且R 4是羧酸酯，羧酰胺或磺酰胺基。

公开(公告)号：US07803831B2

公开(公告)日：2010-09-28

申请号：US10536898

申请日：2003-12-04

申请人： Mandy Christine Beswick ,  Paul Andrew Brough ,  Martin James Drysdale ,  Brian William Dymock

发明人： Mandy Christine Beswick ,  Paul Andrew Brough ,  Martin James Drysdale ,  Brian William Dymock

IPC分类号： A61K31/415 ,  A61K31/4155 ,  C07D401/12 ,  C07D403/12

CPC分类号： C07D231/14 ,  C07D401/12 ,  C07D405/12 ,  C07D409/12

摘要： Compounds of formula (IA) or (IB) or salts, N-oxides, hydrates or solvates thereof are Inhibitors of HSP90, and useful in the treatment of, for example, cancer: formula (IA), formula (IB) wherein Ar is an aryl or heteroaryl radical which is linked via a ring carbon, and which is substituted by a hydroxy group on a carbon in the 2-position, and which is otherwise either unsubstituted or optionally substituted; R1 is hydrogen or optionally substituted C1-C6 alkyl; R2 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide or carboxyl ester group; and R3 is a carboxamide group.

摘要翻译： 式（IA）或（IB）化合物或其盐，N-氧化物，水合物或溶剂化物是HSP90的抑制剂，可用于治疗例如癌症：式（IA），式（IB）其中Ar为 通过环碳连接并被2-位上的碳上的羟基取代的芳基或杂芳基，其另外是未取代的或任选被取代的; R 1是氢或任选取代的C 1 -C 6烷基; R 2是氢，任选取代的环烷基，环烯基，C 1 -C 6烷基，C 1 -C 6链烯基或C 1 -C 6炔基; 或羧基，羧酰胺或羧基酯基团; 并且R 3是羧酰胺基。

公开(公告)号：US07728016B2

公开(公告)日：2010-06-01

申请号：US10561969

申请日：2004-06-24

申请人： Kwai Ming Cheung ,  Brian William Dymock ,  Edward McDonald ,  Martin James Drysdale

发明人： Kwai Ming Cheung ,  Brian William Dymock ,  Edward McDonald ,  Martin James Drysdale

IPC分类号： A61K31/4192 ,  C07D249/06

CPC分类号： A61K31/4196 ,  A61K31/4192 ,  A61K31/427 ,  A61K31/433

摘要： Compound of a compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity: wherein ring A is an aromatic or non-aromatic carbocyclic or heterocyclic ring having 5 ring atoms, for example 1,2,3-triazolyl or a 1,2,4-triazolyl or a tetrazolyl ring; and R1 R2 R3 are as defined in the specification are inhibitors of HSP90 and therefore of use in the treatment of, for example, cancers, viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor, or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapie/CJD, Huntingdon's and Alzheimer's disease.

摘要翻译： 式（I）化合物或其盐，N-氧化物，水合物或溶剂化物的化合物在制备抑制HSP90活性的组合物中的用途：其中环A是具有5个或更多个碳原子的芳族或非芳族碳环或杂环 环原子，例如1,2,3-三唑基或1,2,4-三唑基或四唑基环; 和R1 R2 R3如本说明书中所定义的是HSP90的抑制剂，因此用于治疗例如癌症，病毒性疾病，炎性疾病如类风湿性关节炎，哮喘，多发性硬化，I型糖尿病，狼疮，牛皮癣 和炎症性肠病; 囊性纤维化血管生成相关疾病如糖尿病性视网膜病变，血管瘤和子宫内膜异位症; 或用于保护正常细胞免受化疗诱导的毒性; 或未能进行细胞凋亡的疾病是潜在的因素，或由于心脏和脑中Hsp70的升高而保护缺氧缺血性损伤; 瘙痒病/ CJD，亨廷顿氏症和阿尔茨海默病。