公开(公告)号：US08883473B2

公开(公告)日：2014-11-11

申请号：US13533131

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

IPC分类号： A61K31/4439 ,  A61K31/427 ,  A61P19/02 ,  A61K31/425

CPC分类号： A61K31/425 ,  A61K31/4439 ,  C07K2299/00 ,  G01N2333/96486

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US20130040994A1

公开(公告)日：2013-02-14

申请号：US13533131

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

IPC分类号： A61K31/427 ,  A61P35/00 ,  A61P19/02 ,  A61P9/00 ,  A61P1/04 ,  A61P9/12 ,  A61P11/00 ,  A61P1/02 ,  A61P17/02 ,  A61P1/16 ,  A61P9/10 ,  A61P25/00 ,  A61P11/06 ,  A61P13/12 ,  A61P25/06 ,  C12N9/99 ,  A61K31/4439

CPC分类号： A61K31/425 ,  A61K31/4439 ,  C07K2299/00 ,  G01N2333/96486

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US20120302573A1

公开(公告)日：2012-11-29

申请号：US13479421

申请日：2012-05-24

申请人： Paul Francis JACKSON ,  Carl Manthey ,  Kenneth Rhodes ,  Robert Scannevin ,  Kristi Anne Leonard ,  Joseph Kent Barbay ,  Matthew Todd ,  Barry A. Springer

发明人： Paul Francis JACKSON ,  Carl Manthey ,  Kenneth Rhodes ,  Robert Scannevin ,  Kristi Anne Leonard ,  Joseph Kent Barbay ,  Matthew Todd ,  Barry A. Springer

IPC分类号： C12N9/99 ,  A61K31/4439 ,  A61K31/497 ,  A61K31/437 ,  A61K31/519 ,  A61K31/444 ,  A61K31/4985 ,  A61P35/00 ,  A61P19/02 ,  A61P9/00 ,  A61P1/04 ,  A61P9/12 ,  A61P11/00 ,  A61P1/00 ,  A61P1/02 ,  A61P17/02 ,  A61P25/06 ,  A61K31/427

CPC分类号： A61K31/519 ,  A61K31/427 ,  A61K31/454 ,  A61K31/4985

摘要： This invention relates to methods for preventing, treating or ameliorating an MMP9 and/or MMP13 mediated syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound listed in the examples section of this specification, or a form, composition or medicament thereof. Disorders treated and/or prevented include rheumatoid arthritis.

摘要翻译： 本发明涉及用于预防，治疗或改善MMP9和/或MMP13介导的综合征，障碍或疾病的方法，包括向有需要的受试者施用有效量的本说明书实施例部分列出的化合物或形式， 组合物或药物。 治疗和/或预防的疾病包括类风湿性关节炎。

公开(公告)号：US20060148812A1

公开(公告)日：2006-07-06

申请号：US11254276

申请日：2005-10-20

申请人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolf ,  Mark Wall ,  Ken Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Flores ,  Chris Molloy

发明人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolf ,  Mark Wall ,  Ken Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Flores ,  Chris Molloy

IPC分类号： A61K31/496 ,  A61K31/4545 ,  C07D409/14 ,  A61K31/4178

CPC分类号： C07D307/71 ,  C07D401/12 ,  C07D401/14 ,  C07D407/12 ,  C07D409/12 ,  C07D409/14

摘要： The invention is directed to compounds of Formula I: wherein A, X, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

摘要翻译： 本发明涉及式I化合物：其中A，X，R 2和W在本说明书中列出，以及其抑制蛋白质的溶剂合物，水合物，互变异构体和药学上可接受的盐 酪氨酸激酶，特别是c-fms激酶。 治疗自身免疫性疾病的方法 和具有炎症成分的疾病; 治疗卵巢癌，子宫癌，乳腺癌，结肠癌，胃癌，毛细胞白血病和非小细胞肺癌的转移; 并治疗疼痛，包括由肿瘤转移或骨关节炎引起的骨骼疼痛，或内脏，炎症和神经源性疼痛; 还提供了骨质疏松症，佩吉特氏病和其它骨吸收介导包括关节炎，假体失败，溶骨性骨肉瘤，骨髓瘤以及与式I化合物对骨的肿瘤转移的其它疾病。

公开(公告)号：US20060100201A1

公开(公告)日：2006-05-11

申请号：US11255043

申请日：2005-10-20

申请人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Jonathan Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee DesJarlais ,  Carl Manthey ,  Christopher Flores ,  Christopher Molloy

发明人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Jonathan Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee DesJarlais ,  Carl Manthey ,  Christopher Flores ,  Christopher Molloy

IPC分类号： A61K31/541 ,  A61K31/5377 ,  A61K31/496 ,  C07D417/14 ,  C07D413/14 ,  C07D405/14

CPC分类号： C07D263/34 ,  C07D207/34 ,  C07D233/90 ,  C07D307/68 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D405/14 ,  C07D409/12

摘要： The invention relates to compounds of Formula I: wherein A, X, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

摘要翻译： 本发明涉及式I化合物：其中A，X，R 2和W在本说明书中列出，以及其抑制蛋白酪氨酸的溶剂合物，水合物，互变异构体和药学上可接受的盐 激酶，特别是c-fms激酶。 治疗自身免疫性疾病的方法 和具有炎症成分的疾病; 治疗卵巢癌，子宫癌，乳腺癌，结肠癌，胃癌，毛细胞白血病和非小细胞肺癌的转移; 并治疗疼痛，包括由肿瘤转移或骨关节炎引起的骨骼疼痛，或内脏，炎症和神经源性疼痛; 还提供了骨质疏松症，佩吉特氏病和其它骨吸收介导包括关节炎，假体失败，溶骨性骨肉瘤，骨髓瘤以及与式I化合物对骨的肿瘤转移的其它疾病。

公开(公告)号：US20080051402A1

公开(公告)日：2008-02-28

申请号：US11737517

申请日：2007-04-19

申请人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Molloy

发明人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Molloy

IPC分类号： A61K31/454 ,  A61K31/4545 ,  A61K31/496 ,  A61K31/5377 ,  A61P35/00

CPC分类号： A61K31/5377 ,  A61K31/4178 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/496 ,  A61K45/06 ,  A61N5/10 ,  A61N2005/1098 ,  C07D307/68 ,  C07D401/12 ,  C07D401/14 ,  C07D407/12 ,  C07D409/12 ,  C07D409/14 ,  C12N9/99

摘要： A method of reducing or inhibiting kinase activity of C-KIT in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to C-KIT using a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. The present invention is further directed to methods for treating conditions such as cancers and other cell proliferative disorders.

摘要翻译： 降低或抑制细胞或受试者中C-KIT的激酶活性的方法，以及使用这些化合物在受试者中预防或治疗细胞增殖性疾病和/或与C-KIT相关的病症的方法， 本发明：或其溶剂合物，水合物，互变异构体或其药学上可接受的盐。 本发明还涉及治疗诸如癌症和其它细胞增殖性疾病的病症的方法。

公开(公告)号：US20060189623A1

公开(公告)日：2006-08-24

申请号：US11408096

申请日：2006-04-20

申请人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Flores ,  Christopher Molloy

发明人： Carl Illig ,  Shelley Ballentine ,  Jinsheng Chen ,  Sanath Meegalla ,  M. Rudolph ,  Mark Wall ,  Kenneth Wilson ,  Renee Desjarlais ,  Carl Manthey ,  Christopher Flores ,  Christopher Molloy

IPC分类号： A61K31/496 ,  C07D409/02 ,  A61K31/4545 ,  A61K31/454

CPC分类号： C07D307/71 ,  A61K45/06 ,  C07D401/12 ,  C07D401/14 ,  C07D407/12 ,  C07D409/12 ,  C07D409/14

摘要： The invention is directed to compounds of Formula I: wherein A, X, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

公开(公告)号：US20060189511A1

公开(公告)日：2006-08-24

申请号：US10514338

申请日：2003-05-13

申请人： Holly Koblish ,  Carl Manthey ,  Christopher Molly ,  Tianbao Lu ,  Daniel Parks ,  Louis Lafrance ,  Karen Milkiewicz ,  Theodore Carver ,  Bruce Grasberger

发明人： Holly Koblish ,  Carl Manthey ,  Christopher Molly ,  Tianbao Lu ,  Daniel Parks ,  Louis Lafrance ,  Karen Milkiewicz ,  Theodore Carver ,  Bruce Grasberger

IPC分类号： A61K38/17 ,  A01N1/02

CPC分类号： A61K31/5513

摘要： The present invention is directed to a method of protecting one or more cells from programmed cytotoxic cell death by contacting the cells with a cytoprotective amount of an MDM2 and/or HDM2 inhibitor. The cytoprotective amount of inhibitor is typically used as a pulsed administration. Useful inhibitors include a class of 1,4-benzodiazepines, which act as inhibitors of MDM2-p53 interactions. The method of the invention can be employed as an adjunct to chemotherapy or radiation therapy. In addition, the methods of the invention can be employed to treat a disease or condition that involves excessive cell death.

摘要翻译： 本发明涉及通过使细胞与细胞保护剂量的MDM2和/或HDM2抑制剂接触来保护一种或多种细胞免受程序性细胞毒性细胞死亡的方法。 抑制剂的细胞保护量通常用作脉冲给药。 有用的抑制剂包括一类1,4-苯二氮卓类，其作为MDM2-p53相互作用的抑制剂。 本发明的方法可以用作化疗或放射治疗的辅助物质。 此外，本发明的方法可用于治疗涉及过度细胞死亡的疾病或病症。