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1. 发明申请

WO0236075A3 SMALL MOLECULE COMPOSITIONS FOR BINDING TO HSP90 审中-公开
标题翻译：用于绑定到HSP90的小分子组合物
公开(公告)号：WO0236075A3
公开(公告)日：2003-06-05
申请号：PCT/US0146303
申请日：2001-11-01
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , ROSEN NEAL
发明人： CHIOSIS GABRIELA , ROSEN NEAL
IPC分类号： G01N33/53 , A61K31/52 , A61K45/00 , A61P35/00 , A61P43/00 , C07D209/36 , C07D473/00 , C07D473/34 , C07D473/40 , C07K14/47 , G01N33/15 , G01N33/566 , C07D487/04 , A61K31/404 , A61K31/4184 , A61K31/423 , A61K31/428 , A61K31/437 , A61K31/519 , A61K31/522 , C07D209/08 , C07D209/12 , C07D209/18 , C07D209/22 , C07D235/08 , C07D235/12 , C07D235/16 , C07D235/18 , C07D235/26 , C07D263/56 , C07D263/57 , C07D277/64 , C07D277/66 , C07D471/04 , C07D473/02 , C07D473/18 , C07D473/22 , C07D473/24 , C07D473/28 , C07D473/30 , C07D473/36 , C07D498/04 , C07D513/04 , G01N33/543
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 are exploited to achieve differential degradation of k nases and other signaling proteins by using small molecules which interact with the N-terminal binding pocket with an affinity greater than ADP and different from ansamycin antibiotics for at least one HSP90 family species (Figure 5). These small molecules are soluble in aqueous media, providing a further advantage over ansamycins. Pharmaceutical compositions contain a carrier and a molecule that includes a moiety which binds to the N-terminal pocket of at least one member of the HSP90 family. Such binding moieties have anti proliferative activity against tumor cells which depend on proteins requiring chaperones of the HSP90 family. Different chemical species have different activity, allowing the selection of Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess inherent targeting capacity. The small molecules can be linked to targeting moieties to target the activity to specific classes of cells. The invention includes treatment of diseases, including cancers. Dimeric forms of the binding moieties may be employed.
摘要翻译：利用HSP90家族成员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小分子，以比ADP更大的亲和力和不同于安莎霉素抗生素的小分子来实现k蛋白和其他信号蛋白的差异降解至少有一个HSP90家族（图5）。这些小分子可溶于含水介质，提供了比安莎霉素更优越的优点。药物组合物含有载体和分子，其包括结合HSP90家族的至少一个成员的N末端口袋的部分。这种结合部分具有抗肿瘤细胞的抗增殖活性，其依赖于需要HSP90家族伴侣蛋白质的蛋白质。不同的化学物种具有不同的活性，允许选择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。小分子可以连接到靶向部分以将活性靶向特定类别的细胞。本发明包括治疗疾病，包括癌症。可以使用结合部分的二聚体形式。

2. 发明申请

WO2005012482B1 ASSAY FOR IDENTIFICATION OF BIOACTIVE COMPOUNDS THAT INTERACT WITH HEAT SHOCK PROTEIN 90 审中-公开
标题翻译：用于识别与热冲击蛋白质相互作用的生物化合物的测定90
公开(公告)号：WO2005012482B1
公开(公告)日：2005-12-22
申请号：PCT/US2004021297
申请日：2004-06-30
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , ROSEN NEAL , HUEZO HENRI
发明人： CHIOSIS GABRIELA , ROSEN NEAL , HUEZO HENRI
IPC分类号： C12N20060101 , G01N21/21 , G01N33/52 , G01N33/53 , G01N33/566 , G01N33/567
CPC分类号： G01N33/542 , C07D405/12 , G01N33/5008 , G01N33/5011 , G01N33/582 , G01N33/68 , G01N33/6845 , G01N2500/00 , G01N2500/02
摘要： A method for evaluation of molecules to identify those that can act as therapeutic inhibitors of Hsp90 makes use of a fluorescence polarization (FP) assay and a cell based assay, either individually or in combination. The FP assay uses a fluorescently-labeled Hsp90 binding agent and measure the degree of fluorescence polarization relative to the standard. A decrease in the degree of polarization indicates that fluorescently-labeled Hsp90 binding agent has been wholly or partially displaced by a candidate molecule, and identifies the molecule as having activity as an inhibitor of Hsp90. The cell based assay tests for decrease is an Hsp90-dependent activity of normal or tumor cells.
摘要翻译：用于评估分子以鉴定可以作为Hsp90的治疗性抑制剂的分子的方法使用单独或组合的荧光偏振（FP）测定和基于细胞的测定。 FP测定使用荧光标记的Hsp90结合剂，并测量相对于标准品的荧光偏振度。极化程度的降低表明荧光标记的Hsp90结合剂已经被候选分子完全或部分置换，并且将该分子鉴定为具有作为Hsp90抑制剂的活性。基于细胞的测定减少的测定是正常或肿瘤细胞的Hsp90依赖性活性。

3. 发明申请

WO2005012482A3 ASSAY FOR IDENTIFICATION OF BIOACTIVE COMPOUNDS THAT INTERACT WITH HEAT SHOCK PROTEIN 90 审中-公开
标题翻译：测定与热休克蛋白相互作用的生物活性化合物90
公开(公告)号：WO2005012482A3
公开(公告)日：2005-09-15
申请号：PCT/US2004021297
申请日：2004-06-30
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , ROSEN NEAL , HUEZO HENRI
发明人： CHIOSIS GABRIELA , ROSEN NEAL , HUEZO HENRI
IPC分类号： C12N20060101 , G01N21/21 , G01N33/52 , G01N33/53 , G01N33/566 , G01N33/567
CPC分类号： G01N33/542 , C07D405/12 , G01N33/5008 , G01N33/5011 , G01N33/582 , G01N33/68 , G01N33/6845 , G01N2500/00 , G01N2500/02
摘要： A method for evaluation of molecules to identify those that can act as therapeutic inhibitors of Hsp90 makes use of a fluorescence polarization (FP) assay and a cell based assay, either individually or in combination. The FP assay uses a fluorescently-labeled Hsp90 binding agent and measure the degree of fluorescence polarization relative to the standard. A decrease in the degree of polarization indicates that fluorescently-labeled Hsp90 binding agent has been wholly or partially displaced by a candidate molecule, and identifies the molecule as having activity as an inhibitor of Hsp90. The cell based assay tests for decrease is an Hsp90-dependent activity of normal or tumor cells.
摘要翻译：评估分子以鉴定那些可以充当Hsp90的治疗性抑制剂的方法使用荧光偏振（FP）测定法和基于细胞的测定法，单独或组合使用。 FP测定使用荧光标记的Hsp90结合剂并测量相对于标准的荧光偏振度。极化程度的降低表明荧光标记的Hsp90结合剂已经被候选分子全部或部分置换，并将该分子鉴定为具有作为Hsp90抑制剂的活性。基于细胞的测定测试降低是正常或肿瘤细胞的Hsp90依赖性活性。

4. 发明申请

WO2012138894A4 HSP90 INHIBITORS 审中-公开
标题翻译： HSP90抑制剂
公开(公告)号：WO2012138894A4
公开(公告)日：2012-12-06
申请号：PCT/US2012032371
申请日：2012-04-05
申请人： SLOAN KETTERING INST CANCER , SUN WEILIN , TALDONE TONY , PATEL PALLAV , CHIOSIS GABRIELA
发明人： SUN WEILIN , TALDONE TONY , PATEL PALLAV , CHIOSIS GABRIELA
IPC分类号： 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：本公开涉及其中Z 1，Z 2，Z 3，X a，X b，X c，X d，Y，X 2，和X 4如本文所定义的式（IA）和（IB）化合物及其药学上可接受的盐，式（IA）和/或（IB）的化合物的量以及治疗或预防过度表达Her-激酶的病症（例如癌症）的方法，所述方法包括向需要其的患者施用治疗有效量的式（IA）或（IB）。本公开还涉及其中X 2是用于引入放射性标记的原子例如124 I或131 I的离去的式（IA）和（IB）的化合物，并且涉及使用这些化合物制备放射性标记的化合物的方法，特别是用于成像。

5. 发明申请

WO2006084030B1 SMALL-MOLECULE HSP90 INHIBITORS 审中-公开
标题翻译：小分子HSP90抑制剂
公开(公告)号：WO2006084030B1
公开(公告)日：2007-04-05
申请号：PCT/US2006003676
申请日：2006-02-01
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , HUAZHONG HE , LLAUGER-BUFI LAURA , KIM JOUNGNAM , LARSON STEVE M , SMITH-JONES PETER
发明人： CHIOSIS GABRIELA , HUAZHONG HE , LLAUGER-BUFI LAURA , KIM JOUNGNAM , LARSON STEVE M , SMITH-JONES PETER
IPC分类号： C07D473/40 , A61K31/52 , A61K51/00 , A61K101/00 , A61P35/00 , A61P35/02 , C07D473/34
CPC分类号： C07D473/34 , A61K51/0459 , C07D491/056 , G01N33/60
摘要： Hsp90 inhibitors havin are rovided havin the formula: (I) 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, SO 2- alkyl, COO-alkyl, KH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C=SR 2 NSO 2 X 5 , C=OR 2 , where X 5 is F, NH2, alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl, C 1 to C 6 alkyl or alkoxy; or wherein X 1 has the formula -0-(CH 2 ) 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： Hsp90抑制剂具有下式：（I）在右侧芳基部分具有2'，4'，5'-取代模式。 X 1代表两个取代基，它们可以相同或不同，位于芳基的4'和5'位置，其中X 1选自卤素，烷基，烷氧基，卤代烷氧基，羟烷基，吡咯基，任选取代的芳氧基，，二烷基氨基，氨基甲酰基，酰氨基，烷基酰氨基二烷基，酰氨基，烷基磺酰氨基，三卤代甲氧基，trihalocarbon，硫代烷基，SO _{2 - 烷基，COO-烷基，KH _{2 ，OH，CN， SO _{2 5 _{5 ，NO _{2 ，NO，C = SR _{2 NSO ₂}}}}}}

6. 发明申请

WO2013009655A2 USES OF LABELED HSP90 INHIBITORS 审中-公开
标题翻译：标签HSP90抑制剂的使用
公开(公告)号：WO2013009655A2
公开(公告)日：2013-01-17
申请号：PCT/US2012045861
申请日：2012-07-06
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , PILLARSETTY NAGAVARAKISHORE , LEWIS JASON S , LARSON STEVEN M , TALDONE TONY , ALPAUGH MARY L , GOMES-DAGAMA ERICA M
发明人： CHIOSIS GABRIELA , PILLARSETTY NAGAVARAKISHORE , LEWIS JASON S , LARSON STEVEN M , TALDONE TONY , ALPAUGH MARY L , GOMES-DAGAMA ERICA M
IPC分类号： A61K51/04
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： This 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.
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。

7. 发明申请

WO2011022440A3 HEAT SHOCK PROTEIN BINDING COMPOUNDS, COMPOSITIONS, AND METHODS FOR MAKING AND USING SAME 审中-公开
标题翻译：热激蛋白结合化合物，组合物和制备和使用相同的方法
公开(公告)号：WO2011022440A3
公开(公告)日：2011-08-11
申请号：PCT/US2010045817
申请日：2010-08-17
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , TALDONE TONY , RODINA ANNA , PATEL PALLAV , KANG YANLONG
发明人： CHIOSIS GABRIELA , TALDONE TONY , RODINA ANNA , PATEL PALLAV , KANG YANLONG
IPC分类号： A61K31/54
CPC分类号： A61K31/513 , A61K31/496 , A61K31/506 , A61K2121/00 , C07D239/38 , C07D239/47 , C07D239/56 , C07D239/60 , C07D403/12 , C07D495/04
摘要： The present subject matter relates to a compound represented by the general formula (I) or (I') or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).
摘要翻译：本发明涉及由通式（I）或（I'）表示的化合物或其药理学上可接受的盐; 含有至少一种这些化合物的药物组合物; 制造这些化合物中的至少一种的方法; 使用这些化合物中的至少一种用于治疗和/或预防各种癌症和/或增殖性疾病的方法; 使用这些化合物中的至少一种来监测针对各种癌症的抗癌疗法的有效性的方法。在一个实施方案中，主题涉及以对热休克蛋白70（Hsp70）的特异性水平结合的化合物。在另一个实施方案中，本主题涉及以特异性水平结合以抑制热休克蛋白70（Hsp70）和热休克同源蛋白70（Hsc70）两者的化合物。

8. 发明申请

WO2006084030A2 SMALL-MOLECULE HSP90 INHIBITORS 审中-公开
标题翻译：小分子HSP90抑制剂
公开(公告)号：WO2006084030A2
公开(公告)日：2006-08-10
申请号：PCT/US2006003676
申请日：2006-02-01
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA , HUAZHONG HE , LLAUGER-BUFI LAURA , KIM JOUNGNAM , LARSON STEVE M , SMITH-JONES PETER
发明人： CHIOSIS GABRIELA , HUAZHONG HE , LLAUGER-BUFI LAURA , KIM JOUNGNAM , LARSON STEVE M , SMITH-JONES PETER
IPC分类号： A61K31/70
CPC分类号： C07D473/34 , A61K51/0459 , C07D491/056 , G01N33/60
摘要： Hsp90 inhibitors havin are rovided havin the formula: (I) 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, SO 2- alkyl, COO-alkyl, KH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C=SR 2 NSO 2 X 5 , C=OR 2 , where X 5 is F, NH2, alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl, C 1 to C 6 alkyl or alkoxy; or wherein X 1 has the formula -0-(CH 2 ) 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： Hsp90抑制剂在右侧芳基部分被划分为具有2'，4'，5'-取代模式的式（I）。 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，酰胺基，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，三卤代烃，硫代烷基，SO 2 - 烷基，COO-烷基，KH 2，OH，CN， SO 2，N 2，NO 2，NO，C = SR 2 NSO 2

9. 发明申请

WO2012149493A3 HSP90 COMBINATION THERAPY 审中-公开
标题翻译： HSP90联合治疗
公开(公告)号：WO2012149493A3
公开(公告)日：2014-05-08
申请号：PCT/US2012035690
申请日：2012-04-27
申请人： SLOAN KETTERING INST CANCER , CHIOSIS GABRIELA
发明人： CHIOSIS GABRIELA
IPC分类号： G01N33/574 , C12Q1/68
CPC分类号： G01N33/5748 , A61K31/52 , A61K45/06 , G01N33/5011 , G01N33/5041 , A61K2300/00
摘要： This disclosure concerns a method for selecting an inhibitor of a cancer-implicated pathway or of a component thereof for coadministration with an inhibitor of HSP90 the method comprising: (a) contacting a sample containing cancer cells from a subject with an inhibitor of HSP90 under conditions such that one or more cancer pathway components present in the sample bind to the HSP90 inhibitor; (b) detecting pathway components bound to the HSP90 inhibitor; (c) analyzing the pathway components detected in step (b) so as to identify a pathway which includes the components detected in step (b) and additional components of such pathway; and (d) selecting an inhibitor of the pathway or of a pathway component identified in step (c). The disclosure further concerns a method of treating a cancer patient by co administering an inhibitor of HSP90 and an inhibitor of a cancer-implicated pathway or component thereof.
摘要翻译：本公开涉及选择与癌症相关途径的抑制剂或其组分与HSP90抑制剂共同施用的方法，所述方法包括：（a）在条件下使来自受试者的含有癌细胞的样品与HSP90的抑制剂接触使样品中存在的一种或多种癌症途径成分与HSP90抑制剂结合; （b）检测与HSP90抑制剂结合的途径成分; （c）分析在步骤（b）中检测的途径组分，以便鉴定包含步骤（b）中检测到的组分和该途径的其它组分的途径; 和（d）选择步骤（c）中鉴定的途径或途径成分的抑制剂。本公开还涉及通过共同施用HSP90的抑制剂和癌症相关途径的抑制剂或其组分来治疗癌症患者的方法。

10. 发明申请

WO2008005937A3 TREATMENT OF NEURODEGENERATIVE DISEASES THROUGH INHIBITON OF HSP90 审中-公开
标题翻译：通过抑制HSP90治疗神经退行性疾病
公开(公告)号：WO2008005937A3
公开(公告)日：2008-12-11
申请号：PCT/US2007072671
申请日：2007-07-02
申请人： SLOAN KETTERING INST CANCER , UNIV ROCKEFELLER , CHIOSIS GABRIELA , GREENGARD PAUL , DOU FEI , LUO WENJIE
发明人： CHIOSIS GABRIELA , GREENGARD PAUL , DOU FEI , LUO WENJIE
IPC分类号： A01N43/90 , A61K31/52
CPC分类号： C07D473/40 , A61K31/52
摘要： Treatment of neurodegenerativ e diseases is achiev ed using smal l molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-biain bairiei or are othei wise delivered to the brain.
摘要翻译：使用小分子嘌呤脚手架化合物来实现神经变性疾病的治疗，所述化合物抑制Hsp90并且具有穿越血液中白细胞介素的能力或其他方式递送至大脑。

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