公开(公告)号：US20050085484A1

公开(公告)日：2005-04-21

申请号：US10915696

申请日：2004-08-11

申请人： Scott Mitchell ,  Robert DeSimone ,  James Darrow ,  Douglas Pippin ,  M. Danca

发明人： Scott Mitchell ,  Robert DeSimone ,  James Darrow ,  Douglas Pippin ,  M. Danca

IPC分类号： A61K31/498 ,  A61P35/00 ,  C07D487/04

CPC分类号： C07D487/04

摘要： Certain substituted imidazo[1,2-a]pyrazines and the pharmaceutically-acceptable salts thereof, are provided herein. Pharmaceutical compositions containing one or more compound of Formula I, or a pharmaceutically acceptable salt of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to EphB4 kinase modulation, which comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Thus methods of treatment include administering a sufficient amount of a compound of the invention to decrease the symptoms or slow the progression of these diseases or disorders. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with a compound of Formula I under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.

摘要翻译： 本文提供了某些取代的咪唑并[1,2-a]吡嗪及其药学上可接受的盐。 本文还提供了含有一种或多种式I化合物或这些化合物的药学上可接受的盐以及一种或多种药学上可接受的载体，赋形剂或稀释剂的药物组合物。 公开了治疗患有某些对EphB4激酶调节作用的疾病和病症的患者的方法，其包括给予这样的患者一定量的有效降低疾病或病症体征或症状的式I化合物。 这些疾病包括癌症，包括乳腺肿瘤，子宫内膜癌，结肠癌和颈部鳞状细胞癌。 因此，治疗方法包括施用足量的本发明化合物以减少症状或减缓这些疾病或病症的进展。 治疗方法包括给予式I化合物作为单一活性剂或将一种式I化合物与一种或多种其它治疗剂联合给药。 一种用于确定样品中血管生成激酶存在或不存在的方法，包括在允许检测血管生成激酶活性，检测血管生成激酶活性水平的条件下将样品与式I化合物接触 确定样品中存在或不存在血管生成激酶。

公开(公告)号：US20050054649A1

公开(公告)日：2005-03-10

申请号：US10776631

申请日：2004-02-10

申请人： Kevin Currie ,  Robert DeSimone ,  Douglas Pippin ,  James Darrow ,  Scott Mitchell

发明人： Kevin Currie ,  Robert DeSimone ,  Douglas Pippin ,  James Darrow ,  Scott Mitchell

IPC分类号： A61P35/02 ,  A61P37/00 ,  C07D487/04 ,  A61K31/498

CPC分类号： C07D487/04

摘要： This invention pertains to compounds of Formula I: and the pharmaceutically-acceptable forms thereof. The variables R1, R2, R3, Z1, Z2, W, and X shown in Formula I are defined herein. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain diseases and disorders responsive to Hsp90 complex modulation, which comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These diseases include cancer, including chronic myeloid leukemia, melanoma, breast, ovarian, brain, thyroid, colorectal, prostate, and bladder cancer, heart disease, stroke, autoimmune/inflammatory diseases, and neurodegenerative diseases. Thus methods of treatment include administering a sufficient amount of a compound of Formula I or form thereof to decrease the symptoms or slow the progression of these diseases or disorders. The invention also encompasses methods of treating non-human patients, including livestock and domesticated companion animals, suffering from a disease or disorder responsive to Hsp90 complex modulation. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agent. The invention also includes a method for determining the presence of certain kinases or Hsp90 complex in a sample, comprising contacting the sample with a compound of Formula I or form thereof, and detecting Hsp9O complex activity in the sample.

摘要翻译： 本发明涉及式I化合物及其药学上可接受的形式。 本文定义了式I中所示的变量R1，R2，R3，Z1，Z2，W和X. 本发明还提供含有一种或多种式I化合物或这些化合物的药学上可接受的形式的药物组合物和一种或多种药学上可接受的载体，赋形剂或稀释剂。 本发明还包括治疗患有对Hsp90复合物调节有反应的某些疾病和病症的患者的方法，其包括向所述患者施用一定量的有助于减少疾病或病症的体征或症状的式I化合物。 这些疾病包括癌症，包括慢性骨髓性白血病，黑素瘤，乳腺癌，卵巢癌，脑，甲状腺，结肠直肠癌，前列腺癌和膀胱癌，心脏病，中风，自身免疫/炎性疾病和神经变性疾病。 因此，治疗方法包括施用足量的式I化合物或其形式以减少症状或减缓这些疾病或病症的进展。 本发明还包括治疗患有针对Hsp90复合调节的疾病或病症的非人类患者，包括家畜和驯养伴侣动物的方法。 治疗方法包括给予式I化合物作为单一活性剂或将一种式I化合物与一种或多种其它治疗剂组合施用。 本发明还包括用于测定样品中某些激酶或Hsp90复合物的存在的方法，包括使样品与式I化合物或其形式接触并检测样品中的Hsp9O复合物活性。

公开(公告)号：US20050090499A1

公开(公告)日：2005-04-28

申请号：US10861791

申请日：2004-06-04

申请人： Kevin Currie ,  Robert DeSimone ,  Scott Mitchell ,  Douglas Pippin ,  James Darrow ,  Xiaobing Qian ,  Mark Velleca ,  Dapeng Qian

发明人： Kevin Currie ,  Robert DeSimone ,  Scott Mitchell ,  Douglas Pippin ,  James Darrow ,  Xiaobing Qian ,  Mark Velleca ,  Dapeng Qian

IPC分类号： A61K31/498 ,  A61P37/02 ,  C07D487/04 ,  C07D519/00

CPC分类号： C07D487/04

摘要： Compounds of Formula I-a and all pharmaceutically-acceptable forms thereof, are described herein. The variables R1, R2, R3, Z1, Q, and A shown in Formula I-a are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I-a, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I-a effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I-a as a single active agent or administering a compound of Formula I-a in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I-a under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

摘要翻译： 本文描述式I-a化合物及其所有药学上可接受的形式。 式Ia中所示的变量R 1，R 2，R 3，Z 1，Q和A 在本文中定义。 本文提供了含有一种或多种式I-a化合物或这些化合物的药学上可接受的形式的药物组合物和一种或多种药学上可接受的载体，赋形剂或稀释剂。 还给出了治疗患有某些对抑制酪氨酸激酶活性有响应的疾病的患者的方法。 在某些实施方案中，疾病对Btk活性和/或B细胞增殖的抑制有反应。 这样的方法包括向这样的患者施用一定量的有效减少疾病体征或症状的式I-a化合物。 这些疾病包括癌症，自身免疫和/或炎性疾病或急性炎症反应。 因此，治疗方法包括施用足够量的本文提供的化合物或盐以减少症状或减缓这些疾病的进展。 其他实施方案包括治疗其它动物，包括患有对抑制激酶活性有响应的疾病的家畜和驯养的伴侣动物的方法。 治疗方法包括施用式I-a化合物作为单一活性剂或给予式I-a的化合物与一种或多种其它治疗剂的组合。 一种用于确定样品中Btk的存在的方法，包括在允许检测Btk活性，检测样品中Btk活性水平的条件下使样品与式Ia化合物或其形式接触的方法， 样品中没有Btk。

公开(公告)号：US20060183746A1

公开(公告)日：2006-08-17

申请号：US11292300

申请日：2005-12-02

申请人： Kevin Currie ,  Robert Desimone ,  Scott Mitchell ,  Douglas Pippin ,  James Darrow ,  Xiaobing Qian ,  Mark Velleca ,  Dapeng Qian

发明人： Kevin Currie ,  Robert Desimone ,  Scott Mitchell ,  Douglas Pippin ,  James Darrow ,  Xiaobing Qian ,  Mark Velleca ,  Dapeng Qian

IPC分类号： A61K31/498 ,  C07D487/04

CPC分类号： C07D487/04 ,  C07D519/00

摘要： Certain compounds, such as at least one chemical entity choen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, may in certain embodiments be used to treat patients suffering from one or more diseases responsive to inhibition of tyrosine kinase activity. The diseases may, for instance, be responsive to inhibition of Btk activity and/or B-cell proliferation. Example diseases include cancer, an autoimmune and/or inflammatory disease, and an acute inflammatory reaction.

摘要翻译： 在某些实施方案中，某些化合物，例如从式1的化合物和其药学上可接受的盐，溶剂合物，结晶形式，螯合物，非共价复合物，前药及其混合物中选择的至少一种化学实体可用于治疗患有 响应抑制酪氨酸激酶活性的一种或多种疾病。 疾病可以例如对Btk活性和/或B细胞增殖的抑制作出反应。 示例性疾病包括癌症，自身免疫和/或炎性疾病和急性炎症反应。

公开(公告)号：US20050288295A1

公开(公告)日：2005-12-29

申请号：US10985023

申请日：2004-11-10

申请人： Kevin Currie ,  Robert DeSimone ,  Douglas Pippin ,  James Darrow ,  Scott Mitchell

发明人： Kevin Currie ,  Robert DeSimone ,  Douglas Pippin ,  James Darrow ,  Scott Mitchell

IPC分类号： A61K31/498 ,  C07D487/04

CPC分类号： C07D487/04

摘要： At least one chemical entity chosen from compounds of Formula 1 and pharmaceutically acceptable pharmaceutically acceptable salts, hydrates, solvates, crystal forms, diastereomers, and prodrugs thereof. Methods of treating or preventing disorders in which aberrant kinase activity is implicated, pharmaceutically compositions, and methods for detecting the presence kinases in cells or biological preparations and for identifying kinases of therapeutic interest.

摘要翻译： 至少一种选自式1化合物的化学实体及其药学上可接受的药学上可接受的盐，水合物，溶剂化物，晶型，非对映异构体和前药。 治疗或预防涉及异常激酶活性的病症的方法，药物组合物和用于检测细胞或生物制剂中存在的激酶以及鉴定治疗感兴趣的激酶的方法。

公开(公告)号：US20050054648A1

公开(公告)日：2005-03-10

申请号：US10776002

申请日：2004-02-10

申请人： Scott Mitchell ,  Kevin Currie ,  Robert DeSimone ,  Douglas Pippin

发明人： Scott Mitchell ,  Kevin Currie ,  Robert DeSimone ,  Douglas Pippin

IPC分类号： A61P35/02 ,  A61P37/00 ,  C07D487/04 ,  A61K31/498

CPC分类号： C07D487/04

摘要： This invention pertains to compounds of Formula I: and all pharmaceutically-acceptable forms thereof. The variables R1, R2, R3, Z1, Z2, W, and X shown in Formula I are defined herein. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain diseases and disorders responsive to EphB4 kinase modulation, which comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These diseases include cancer, including of breast neoplasma, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Thus methods of treatment include administering a sufficient amount of a compound or salt of the invention to decrease the symptoms or slow the progression of these diseases or disorders. The invention also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an disease or disorder responsive to EphB4 modulation. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agent. The invention also includes a method for determining the presence of EphB4 kinase in a sample, comprising contacting the sample with a compound of Formula I, or form thereof, and the detecting the amount of compound or form bound to EphB4 kinase, and therefrom determining the presence or absence of EphB4 kinase in the sample.

摘要翻译： 本发明涉及式I化合物及其所有药学上可接受的形式。 本文定义了式I中所示的变量R1，R2，R3，Z1，Z2，W和X. 本发明还提供含有一种或多种式I化合物或这些化合物的药学上可接受的形式的药物组合物和一种或多种药学上可接受的载体，赋形剂或稀释剂。 本发明还包括治疗患有对EphB4激酶调节有反应的某些疾病和病症的患者的方法，其包括给予这样的患者一定数量的有助于减少疾病或病症的体征或症状的式I化合物。 这些疾病包括癌症，包括乳腺肿瘤，子宫内膜癌，结肠癌和颈鳞状细胞癌。 因此，治疗方法包括施用足量的本发明的化合物或盐，以减少症状或减缓这些疾病或病症的进展。 本发明还包括治疗其它动物，包括患有对EphB4调节作用的疾病或病症的家畜和驯养的伴侣动物的方法。 治疗方法包括给予式I化合物作为单一活性剂或将一种式I化合物与一种或多种其它治疗剂组合施用。 本发明还包括用于测定样品中EphB4激酶存在的方法，包括使样品与式I化合物或其形式接触，并检测与EphB4激酶结合的化合物或形式的量，并从中确定 样品中存在或不存在EphB4激酶。

公开(公告)号：US20060199846A1

公开(公告)日：2006-09-07

申请号：US11331346

申请日：2006-01-13

申请人： Scott Mitchell ,  Mihaela Danca ,  Peter Blomgren ,  Robert DeSimone ,  Douglas Pippin ,  David Brittelli

发明人： Scott Mitchell ,  Mihaela Danca ,  Peter Blomgren ,  Robert DeSimone ,  Douglas Pippin ,  David Brittelli

IPC分类号： A61K31/4439 ,  C07D403/02

CPC分类号： C07D401/14 ,  C07D401/06

摘要： Certain chemical entities chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Methods of treatment include administering at least one chemical entity as a single active agent or administering such at least one chemical entity in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one chemical entity under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.

摘要翻译： 本文提供了选自式1化合物的某些化学实体及其药学上可接受的盐，溶剂合物，结晶形式，螯合物，非共价复合物，前药及其混合物。 本文还提供了包含至少一种化学实体和一种或多种药学上可接受的载体的药物组合物，其选自载体，佐剂和赋形剂。 公开了治疗患有对血管生成激酶调节反应的某些疾病和病症的患者的方法，其包括向这些患者施用一定量的至少一种有效减少疾病或病症体征或症状的化学实​​体。 这些疾病包括癌症，包括乳腺肿瘤，子宫内膜癌，结肠癌和颈部鳞状细胞癌。 治疗方法包括给予至少一种化学实体作为单一活性剂或者与一种或多种其它治疗剂组合施用这样的至少一种化学实体。 一种用于确定样品中存在或不存在血管生成激酶的方法，包括在允许检测血管生成激酶活性，检测血管生成激酶活性水平的条件下将样品与至少一种化学实体接触 确定样品中存在或不存在血管生成激酶。

公开(公告)号：US20060211738A1

公开(公告)日：2006-09-21

申请号：US11331347

申请日：2006-01-13

申请人： Scott Mitchell ,  Mihaela Danca ,  Peter Blomgren ,  Robert DeSimone ,  Douglas Pippin

发明人： Scott Mitchell ,  Mihaela Danca ,  Peter Blomgren ,  Robert DeSimone ,  Douglas Pippin

IPC分类号： A61K31/4439 ,  C07D403/02

CPC分类号： C07D401/04 ,  C07D401/06

摘要： Certain chemical entities chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Methods of treatment include administering at least one chemical entity as a single active agent or administering such at least one chemical entity in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one chemical entity under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.

公开(公告)号：US20050101604A1

公开(公告)日：2005-05-12

申请号：US10883646

申请日：2004-06-30

申请人： Kevin Currie ,  Robert DeSimone ,  Scott Mitchell ,  Douglas Pippin

发明人： Kevin Currie ,  Robert DeSimone ,  Scott Mitchell ,  Douglas Pippin

IPC分类号： C07D487/04 ,  A61K31/498 ,  C07D487/02

CPC分类号： C07D487/04

摘要： Compounds of Formula I and all pharmaceutically acceptable forms thereof, are described herein. The variables R1, R2, R3, Z2, and Q, shown in Formula I are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

摘要翻译： 本文描述了式I化合物及其所有药学上可接受的形式。 式I中所示的R 1，R 2，R 3，R 3，Z 2和Q的变量是 本文定义。 本文提供了含有一种或多种式I化合物或这些化合物的药学上可接受的形式的药物组合物和一种或多种药学上可接受的载体，赋形剂或稀释剂。 还给出了治疗患有某些对抑制酪氨酸激酶活性有响应的疾病的患者的方法。 在某些实施方案中，疾病对Btk活性和/或B细胞增殖的抑制有反应。 这样的方法包括向这样的患者施用一定量的有效降低疾病体征或症状的式I化合物。 这些疾病包括癌症，自身免疫和/或炎性疾病或急性炎症反应。 因此，治疗方法包括施用足够量的本文提供的化合物或盐以减少症状或减缓这些疾病的进展。 其他实施方案包括治疗其它动物，包括患有对抑制激酶活性有响应的疾病的家畜和驯养的伴侣动物的方法。 治疗方法包括给予式I化合物作为单一活性剂或将一种式I化合物与一种或多种其它治疗剂组合施用。 一种用于确定样品中Btk的存在的方法，包括在允许检测Btk活性，检测样品中Btk活性水平的条件下使样品与式I化合物或其形式接触的方法， 样品中没有Btk。

公开(公告)号：US20060229337A1

公开(公告)日：2006-10-12

申请号：US11371180

申请日：2006-03-09

申请人： David Brittelli ,  Kevin Currie ,  James Darrow ,  Jeffrey Kropf ,  Seung Lee ,  Steven Gallion ,  Scott Mitchell ,  Douglas Pippin ,  Peter Blomgren

发明人： David Brittelli ,  Kevin Currie ,  James Darrow ,  Jeffrey Kropf ,  Seung Lee ,  Steven Gallion ,  Scott Mitchell ,  Douglas Pippin ,  Peter Blomgren

IPC分类号： A61K31/4545 ,  A61K31/455 ,  A61K31/381 ,  A61K31/165 ,  C07D401/02 ,  C07D333/02

CPC分类号： C07D213/74 ,  C07D241/20 ,  C07D241/24 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D409/14 ,  C07D413/12 ,  C07D413/14 ,  C07D417/12 ,  C07D417/14 ,  C07D487/04

摘要： At least one chemical entity chosen from compounds of Formula 2 and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof is described herein. Pharmaceutical compositions comprising at least one chemical entity of the invention, together with at least one pharmaceutically acceptable vehicle chosen from carriers adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/or B-cell activity are described. Methods for determining the presence of Btk in a sample are described.

摘要翻译： 本文描述了至少一种选自式2化合物的化学实体及其药学上可接受的盐，溶剂合物，螯合物，非共价复合物，前药及其混合物。 描述了包含本发明的至少一个化学实体的药物组合物以及选自载体佐剂和赋形剂的至少一种药学上可接受的载体。 描述了治疗患有某些对Btk活性和/或B细胞活性的抑制作出反应的某些疾病的患者的方法。 描述了确定样品中Btk的存在的方法。