公开(公告)号：US20090298857A1

公开(公告)日：2009-12-03

申请号：US12307063

申请日：2007-07-02

申请人： Gabriela Chiosis ,  Paul Greengard ,  Fei Dou ,  Wenjie Luo

发明人： Gabriela Chiosis ,  Paul Greengard ,  Fei Dou ,  Wenjie Luo

IPC分类号： A61K31/52

CPC分类号： C07D473/40 ,  A61K31/52

摘要： Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.

摘要翻译： 使用抑制Hsp90的小分子嘌呤支架化合物实现神经退行性疾病的治疗，并具有穿过血脑屏障的能力，或者被其他方式递送到脑中。

公开(公告)号：US10336757B2

公开(公告)日：2019-07-02

申请号：US12307063

申请日：2007-07-02

申请人： Gabriela Chiosis ,  Paul Greengard ,  Fei Dou ,  Wenjie Luo ,  Huazhong He ,  Danuta Zatorska

发明人： Gabriela Chiosis ,  Paul Greengard ,  Fei Dou ,  Wenjie Luo ,  Huazhong He ,  Danuta Zatorska

IPC分类号： A01N43/90 ,  A61K31/52 ,  A01N43/54 ,  C07D239/42 ,  C07D401/04 ,  A01N43/50 ,  A61K31/415 ,  A01N43/30 ,  A61K31/36 ,  C07D473/40

摘要： Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.

公开(公告)号：US09546170B2

公开(公告)日：2017-01-17

申请号：US14110095

申请日：2012-04-05

申请人： Tony Taldone ,  Gabriela Chiosis

发明人： Tony Taldone ,  Gabriela Chiosis

IPC分类号： C07D473/34 ,  C07D473/40

CPC分类号： A61K31/52 ,  C07D473/34 ,  C07D473/40

摘要： The disclosure relates to Compounds of Formula (1) : and pharmaceutically acceptable salts thereof wherein Z1, Z2, Z3, Xa, Xb, Xc, Y, X2, and X4 are as defined herein, compositions comprising an effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof, and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof.

摘要翻译： 本公开涉及式（1）的化合物及其药学上可接受的盐，其中Z1，Z2，Z3，Xa，Xb，Xc，Y，X2和X4如本文所定义，组合物包含有效量的式 （1）或其药学上可接受的盐，以及治疗或预防诸如过表达Her-激酶的癌症的病症的方法，包括向有需要的患者施用治疗有效量的式（1）的化合物或 其药学上可接受的盐。

公开(公告)号：US20110104054A1

公开(公告)日：2011-05-05

申请号：US12939807

申请日：2010-11-04

申请人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-bufi ,  Joungnam Kim ,  Steven M. Larson ,  Peter Smith-Jones

发明人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-bufi ,  Joungnam Kim ,  Steven M. Larson ,  Peter Smith-Jones

IPC分类号： A61K31/52 ,  C07D473/34 ,  A61P35/00 ,  A61K51/00 ,  A61P43/00 ,  C12N5/02

CPC分类号： C07D473/34 ,  A61K51/0459 ,  C07D491/056 ,  G01N33/60

摘要： Hsp90 inhibitors having are provided having the formula: with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2-alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula -0-(CH2)n-0-, wherein n is an integer from O to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

摘要翻译： 提供具有下式的Hsp90抑制剂：右侧芳基部分具有2'，4'，5'-取代模式。 X1表示在芳基的4'和5'位置上可以相同或不同的两个取代基，其中X 1选自卤素，烷基，烷氧基，卤代烷氧基，羟基烷基，吡咯基，任选取代的芳氧基，烷基氨基 ，二烷基氨基，氨基甲酰基，酰氨基，烷基酰氨基二烷基酰氨基，酰基氨基，烷基磺酰氨基，三卤甲氧基，三卤代烷基，硫代烷基，SO2-烷基，COO-烷基，KH 2，OH，CN，SO 2 X 5，NO 2，NO，C≡SR2 NSO 2 X 5，C = OR 2，其中 X5是F，NH2，烷基或H，R2是烷基，NH2，NH-烷基或O-烷基，C1-C6烷基或烷氧基; 或其中X 1具有式-O-（CH 2）n -O-，其中n是0至2的整数，优选1或2，并且其中一个氧键在5'-位上而另一个在 芳基环的4'-位。 该化合物可用于癌症治疗和放射成像配体。

公开(公告)号：US09403828B2

公开(公告)日：2016-08-02

申请号：US13176903

申请日：2011-07-06

申请人： Gabriela Chiosis

发明人： Gabriela Chiosis

IPC分类号： C07D473/34

CPC分类号： C07D473/34 ,  C07D519/00

摘要： Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

摘要翻译： 嘌呤支架Hsp90抑制剂可用于治疗应用和放射成像配体。

公开(公告)号：US07834181B2

公开(公告)日：2010-11-16

申请号：US11814506

申请日：2006-02-01

申请人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-Bufi ,  Joungnam Kim ,  Steve M. Larson ,  Peter Smith-Jones

发明人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-Bufi ,  Joungnam Kim ,  Steve M. Larson ,  Peter Smith-Jones

IPC分类号： C07D473/34 ,  C07D473/40 ,  A61K31/52 ,  A61P35/00

CPC分类号： C07D473/34 ,  A61K51/0459 ,  C07D491/056 ,  G01N33/60

摘要： Hsp90 inhibitors are provided having the formula: with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2−alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula —O—(CH2)n—O—, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygen is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

摘要翻译： 提供具有下式的Hsp90抑制剂：右侧芳基部分具有2'，4'，5'-取代模式。 X1表示在芳基的4'和5'位置上可以相同或不同的两个取代基，其中X 1选自卤素，烷基，烷氧基，卤代烷氧基，羟基烷基，吡咯基，任选取代的芳氧基，烷基氨基 ，二烷基氨基，氨基甲酰基，酰氨基，烷基酰氨基二烷基酰氨基，酰基氨基，烷基磺酰氨基，三卤甲氧基，三卤代烷基，硫代烷基，SO2-烷基，COO-烷基，KH 2，OH，CN，SO 2 X 5，NO 2，NO，C≡SR2 NSO 2 X 5，C = OR 2，其中 X5是F，NH2，烷基或H，R2是烷基，NH2，NH-烷基或O-烷基，C1-C6烷基或烷氧基; 或其中X 1具有式-O-（CH 2）n -O-的化合物，其中n为0至2的整数，优选1或2，并且一个氧键在5'位置而另一个在 芳基环的4'-位。 该化合物可用于癌症治疗和放射成像配体。

公开(公告)号：US07439359B2

公开(公告)日：2008-10-21

申请号：US10415868

申请日：2001-11-01

申请人： Gabriela Chiosis ,  Neal Rosen

发明人： Gabriela Chiosis ,  Neal Rosen

IPC分类号： C07D473/40 ,  C07D473/30 ,  C07D473/34 ,  A61K31/52 ,  A61K31/522 ,  A61P35/00

CPC分类号： C07D473/00 ,  A61K31/52 ,  C07D209/36 ,  C07D473/34 ,  C07D473/40

摘要： Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

摘要翻译： 可以利用HSP90家族成员的结合口袋的结构差异，通过使用与N末端结合口袋相互作用的设计的小分子来实现激酶和其他信号传导蛋白质的差异降解，其亲和力大于ADP和不同 对于至少一种HSP90家族的安莎霉素抗生素。 此外，这些小分子可以被设计成可溶于含水介质，因此比使用安莎霉素抗生素提供了进一步的优点。 药物组合物可以配制成含有药学上可接受的载体和分子，该分子包括与蛋白质的HSP90家族的至少一个成员的N-末端口袋结合的结合部分。 发现这样的结合部分具有抗肿瘤细胞的抗增殖活性，其依赖于需要HSP90家族伴侣的功能的蛋白质。 不同的化学物质具有不同的活性，然而，允许选择例如Her2降解而不降解Raf激酶。 因此，结合部分具有固有的靶向能力。 此外，小分子可以连接到靶向部分，以提供对特定细胞类别的活性的靶向。 因此，本发明还提供了通过施用这些组合物来治疗疾病，包括癌症的方法。 还可以使用结合部分的二聚体形式。

公开(公告)号：US09346808B2

公开(公告)日：2016-05-24

申请号：US14009976

申请日：2012-04-05

申请人： Weilin Sun ,  Tony Taldone ,  Pallav Patel ,  Gabriela Chiosis

发明人： Weilin Sun ,  Tony Taldone ,  Pallav Patel ,  Gabriela Chiosis

IPC分类号： A61K31/52 ,  C07D473/34 ,  C07D473/40

CPC分类号： C07D473/34 ,  A61K31/52 ,  C07D473/40

摘要： The disclosure relates to Compounds of Formulae (IA) and (IB): and pharmaceutically acceptable salts thereof wherein Z1, Z2, Z3, Xa, Xb, Xc, Xd, Y, X2, and X4 are as defined herein, compositions comprising an effective amount of a Compound of Formula (IA) and/or (IB), and methods to treat or prevent a condition, such cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (IA) or (IB). The disclosure further relates to compounds of Formulae (IA) and IB) in which X2 is a leaving for introducing a radiolabeled atom, such as 124I or 131I and to methods of using such compounds in the preparation of radiolabeled compounds, particularly for use in imaging.

摘要翻译： 本公开涉及式（IA）和（IB）的化合物及其药学上可接受的盐，其中Z1，Z2，Z3，Xa，Xb，Xc，Xd，Y，X2和X4如本文所定义， 式（IA）和/或（IB）的化合物的量，以及治疗或预防这种过度表达Her-激酶的这种癌症的方法，包括向有需要的患者施用治疗有效量的式 （IA）或（IB）。 本公开还涉及式（IA）和IB）的化合物，其中X 2是用于引入放射性标记的原子（例如124I或131I）的离去，以及在制备放射性标记化合物中使用这些化合物的方法，特别是用于成像 。

公开(公告)号：US20140294725A1

公开(公告)日：2014-10-02

申请号：US14131420

申请日：2012-07-06

申请人： Gabriela Chiosis ,  Nagavarakishore Pillarsetty ,  Jason S. Lewis ,  Steven M. Larson ,  Tony Taldone ,  Mary L. Alpaugh ,  Erica M. Gomes

发明人： Gabriela Chiosis ,  Nagavarakishore Pillarsetty ,  Jason S. Lewis ,  Steven M. Larson ,  Tony Taldone ,  Mary L. Alpaugh ,  Erica M. Gomes

IPC分类号： A61K51/04 ,  G01N33/574

CPC分类号： A61K51/0459 ,  A61K31/52 ,  G01N33/5011 ,  G01N33/5017 ,  G01N33/5044 ,  G01N33/574 ,  G01N33/57407 ,  G01N33/57426 ,  G01N2500/04 ,  G01N2800/52

摘要： The invention concerns various methods of using labeled HSP90 inhibitors to improve treatment of cancer patients with HSP90 inhibitors, including ex vivo and in vivo methods for determining whether a tumor will likely respond to therapy with an HSP90 inhibitor. The disclosure provides a method for determining whether a tumor will likely respond to therapy with an HSP90 inhibitor which comprises the following steps: (a) contacting the tumor or a sample containing cells from the tumor with a detectably labeled HSP90 inhibitor which binds preferentially to a tumor-specific form of HSP90; (b) measuring the amount of labeled HSP90 inhibitor bound to the tumor or the tumor cells in the sample; and (c) comparing the amount of labeled HSP90 inhibitor bound to the tumor or the tumor cells in the sample measured in step (b) to the amount of labeled-HSP90 inhibitor bound to a reference.

摘要翻译： 本发明涉及使用标记的HSP90抑制剂改善用HSP90抑制剂治疗癌症患者的各种方法，包括用于确定肿瘤是否可能对HSP90抑制剂治疗有反应的离体和体内方法。 本公开提供了一种用于确定肿瘤是否可能响应于HSP90抑制剂治疗的方法，该方法包括以下步骤：（a）使来自肿瘤的肿瘤或含有细胞的样品与优先结合于肿瘤的可检测标记的HSP90抑制剂接触 肿瘤特异性形式的HSP90; （b）测量与样品中的肿瘤或肿瘤细胞结合的标记的HSP90抑制剂的量; 和（c）将在步骤（b）中测量的样品中与肿瘤或肿瘤细胞结合的标记HSP90抑制剂的量与结合参考物的标记的HSP90抑制剂的量进行比较。

公开(公告)号：US20140242602A1

公开(公告)日：2014-08-28

申请号：US14131423

申请日：2012-07-06

申请人： Gabriela Chiosis ,  Tony Taldone ,  Mary L. Alpaugh ,  Erica M. Gomes-Dagama ,  Monica L. Guzman ,  Hongliang Zong

发明人： Gabriela Chiosis ,  Tony Taldone ,  Mary L. Alpaugh ,  Erica M. Gomes-Dagama ,  Monica L. Guzman ,  Hongliang Zong

IPC分类号： G01N33/574

CPC分类号： A61K51/0459 ,  A61K31/52 ,  G01N33/5011 ,  G01N33/5017 ,  G01N33/5044 ,  G01N33/574 ,  G01N33/57407 ,  G01N33/57426 ,  G01N2500/04 ,  G01N2800/52

摘要： The disclosure provides evidence that the abundance of this particular “oncogenic HSP90” species, which is not dictated by HSP90 expression alone, predicts for sensitivity to HSP90 inhibition therapy, and thus is a biomarker for HSP90 therapy. The disclosure also provides evidence that identifying and measuring the abundance of this oncogenic HSP90 species in tumors predicts of response to HSP90 therapy. “Oncogenic HSP90” is defined herein as the HSP90 fraction that represents a cell stress specific form of chaperone complex, that is expanded and constitutively maintained in the tumor cell context, and that may execute functions necessary to maintain the malignant phenotype. Such roles are not only to regulate the folding of overexpressed (i.e. HER2), mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl), but also to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes (i.e. STATS, BCL6).

摘要翻译： 该公开提供了证据表明，单独HSP90表达不规定的特定“致癌HSP90”物种的丰度预测对HSP90抑制疗法的敏感性，因此是HSP90治疗的生物标志物。 本公开还提供了证据，确定和测量肿瘤中这种致癌HSP90物种的丰度预测了对HSP90治疗的反应。 “致癌HSP90”在本文中被定义为代表分子伴侣复合物的细胞应激特异性形式的HSP90级分，其在肿瘤细胞环境中被扩增和组成型维持，并且可以执行维持恶性表型所需的功能。 这样的作用不仅是调节过表达（即HER2），突变（即mB-Raf）或嵌合蛋白（即Bcr-Abl）的折叠，而且还促进涉及异常激活的信号传导复合体的分子的支架和复合物形成 即STATS，BCL6）。