公开(公告)号：US20140031363A1

公开(公告)日：2014-01-30

申请号：US13862647

申请日：2013-04-15

申请人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

发明人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

IPC分类号： C07D295/088 ,  C07D213/74 ,  C07D209/34 ,  C07D211/52 ,  C07D215/227 ,  C07D233/32 ,  C07C311/08 ,  C07D263/58

CPC分类号： C07D209/34 ,  C07C217/20 ,  C07C235/20 ,  C07C311/08 ,  C07D211/52 ,  C07D213/74 ,  C07D215/227 ,  C07D233/32 ,  C07D233/34 ,  C07D235/26 ,  C07D263/58 ,  C07D295/088

摘要： Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein: each (L)k-Ar1 is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR1 or O and each R1 and R2 is independently H, alkyl, alkenyl or aralkyl or R1 and R2 taken together form a 5-8 membered ring; R3-R6 are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO2, CH2, NH, N(alkyl), or NHC(═O); and Z is OH, NR6R7, NR8SO2(alkyl), NR8C(O)NR6R7, NR8C(O)O(alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole or wherein Z can fuse with Ar2 to form selected heterocycles.

摘要翻译： 提供了治疗或预防与NMDA受体活性相关的病症的化合物，药物组合物和方法，包括神经性疼痛，中风，创伤性脑损伤，癫痫以及相关的神经系统事件或神经变性。 化合物为通式I，或其药学上可接受的盐，酯，前药或衍生物：其中：（L）k-Ar1为取代或未取代的单或双环芳基或杂芳基; W是键，烷基或烯基; X是键，NR 1或O，并且每个R 1和R 2独立地是H，烷基，烯基或芳烷基，或者R 1和R 2一起形成5-8元环; R 3 -R 6选自某些具体取代基或羰基; Y是键，O，S，SO，SO 2，CH 2，NH，N（烷基）或NHC（= O）; 并且Z是OH，NR 6 R 7，NR 8 SO 2（烷基），NR 8 C（O）NR 6 R 7，NR 8 C（O）O（烷基），NR 8 - 二氢噻唑或NR 8 - 二氢咪唑，或其中Z可与Ar 2融合形成选定的杂环。

公开(公告)号：US09079852B2

公开(公告)日：2015-07-14

申请号：US13862647

申请日：2013-04-15

申请人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

发明人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

IPC分类号： A61K31/421 ,  A61K31/4166 ,  A61K31/495 ,  C07D241/04 ,  C07D263/18 ,  C07D233/08 ,  C07D209/34 ,  C07C217/20 ,  C07C235/20 ,  C07C311/08 ,  C07D215/227 ,  C07D233/34 ,  C07D235/26 ,  C07D263/58 ,  C07D295/088 ,  C07D211/52 ,  C07D213/74 ,  C07D233/32

CPC分类号： C07D209/34 ,  C07C217/20 ,  C07C235/20 ,  C07C311/08 ,  C07D211/52 ,  C07D213/74 ,  C07D215/227 ,  C07D233/32 ,  C07D233/34 ,  C07D235/26 ,  C07D263/58 ,  C07D295/088

摘要： Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein: each (L)k-Ar1 is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR1 or O and each R1 and R2 is independently H, alkyl, alkenyl or aralkyl or R1 and R2 taken together form a 5-8 membered ring; R3−-R6 are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO2, CH2, NH, N(alkyl), or NHC(═O); and Z is OH, NR6R7, NR8SO2(alkyl), NR8C(O)NR6R7, NR8C(O)O(alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole or wherein Z can fuse with Ar2 to form selected heterocycles.

摘要翻译： 提供了治疗或预防与NMDA受体活性相关的病症的化合物，药物组合物和方法，包括神经性疼痛，中风，创伤性脑损伤，癫痫以及相关的神经系统事件或神经变性。 化合物为通式I，或其药学上可接受的盐，酯，前药或衍生物：其中：（L）k-Ar1为取代或未取代的单或双环芳基或杂芳基; W是键，烷基或烯基; X是键，NR 1或O，并且每个R 1和R 2独立地是H，烷基，烯基或芳烷基，或者R 1和R 2一起形成5-8元环; R 3 -R 6选自某些具体取代基或羰基; Y是键，O，S，SO，SO 2，CH 2，NH，N（烷基）或NHC（= O）; 并且Z是OH，NR 6 R 7，NR 8 SO 2（烷基），NR 8 C（O）NR 6 R 7，NR 8 C（O）O（烷基），NR 8 - 二氢噻唑或NR 8 - 二氢咪唑，或其中Z可与Ar 2融合形成选定的杂环。

公开(公告)号：US08420680B2

公开(公告)日：2013-04-16

申请号：US12165308

申请日：2008-06-30

申请人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Yesim Altas Tahirovic ,  Scott J. Myers

发明人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Yesim Altas Tahirovic ,  Scott J. Myers

IPC分类号： A61K31/4166 ,  A61K31/421 ,  A61K31/495 ,  C07D241/04 ,  C07D263/18 ,  C07D233/08

CPC分类号： C07D209/34 ,  C07C217/20 ,  C07C235/20 ,  C07C311/08 ,  C07D211/52 ,  C07D213/74 ,  C07D215/227 ,  C07D233/32 ,  C07D233/34 ,  C07D235/26 ,  C07D263/58 ,  C07D295/088

摘要： Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein: each (L)k-Ar1 is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR1 or O and each R1 and R2 is independently H, alkyl, alkenyl or aralkyl or R1 and R2 taken together form a 5-8 membered ring; R3−R6 are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO2, CH2, NH, N(alkyl), or NHC(═O); and Z is OH, NR6R7, NR8SO2(alkyl), NR8C(O)NR6R7, NR8C(O)O(alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole or wherein Z can fuse with Ar2 to form selected heterocycles.

摘要翻译： 提供了治疗或预防与NMDA受体活性相关的病症的化合物，药物组合物和方法，包括神经性疼痛，中风，创伤性脑损伤，癫痫以及相关的神经系统事件或神经变性。 化合物为通式I，或其药学上可接受的盐，酯，前药或衍生物：其中：（L）k-Ar1为取代或未取代的单或双环芳基或杂芳基; W是键，烷基或烯基; X是键，NR 1或O，并且每个R 1和R 2独立地是H，烷基，烯基或芳烷基，或者R 1和R 2一起形成5-8元环; R 3 -R 6选自某些具体取代基或羰基; Y是键，O，S，SO，SO 2，CH 2，NH，N（烷基）或NHC（= O）; 并且Z是OH，NR 6 R 7，NR 8 SO 2（烷基），NR 8 C（O）NR 6 R 7，NR 8 C（O）O（烷基），NR 8 - 二氢噻唑或NR 8 - 二氢咪唑，或其中Z可与Ar 2融合形成选定的杂环。

公开(公告)号：US20110160223A1

公开(公告)日：2011-06-30

申请号：US12938138

申请日：2010-11-02

申请人： Raymond J. Dingledine ,  Stephen F. Traynelis

发明人： Raymond J. Dingledine ,  Stephen F. Traynelis

IPC分类号： A61K31/495 ,  A61K31/18 ,  A61K31/496 ,  A61K31/423 ,  A61K31/138 ,  A61K31/451 ,  A61K31/4166 ,  A61P25/00

CPC分类号： A61K31/4465 ,  A61K31/496

摘要： Provided are pharmaceutical compositions and methods of treatment or prophylaxis of certain neuropsychiatric conditions, in particular mood disorders. The compounds are of the general Formula I-V as described herein.

摘要翻译： 提供了治疗或预防某些神经精神病症，特别是情绪障碍的药物组合物和方法。 这些化合物是本文所述的通式I-V。

公开(公告)号：US20100272648A1

公开(公告)日：2010-10-28

申请号：US12772798

申请日：2010-05-03

申请人： Dennis C. Liotta ,  Raymond J. Dingledine ,  Stephen F. Traynelis

发明人： Dennis C. Liotta ,  Raymond J. Dingledine ,  Stephen F. Traynelis

IPC分类号： A61K49/00 ,  C12Q1/02

CPC分类号： G01N33/9406 ,  A61K49/0008 ,  G01N33/5058 ,  G01N33/5088 ,  G01N33/84 ,  G01N2800/2835 ,  G01N2800/2842 ,  G01N2800/2857 ,  G01N2800/2871

摘要： Processes are provided for the identification a compound that is useful to treat or prevent a disorder that lowers the pH in a region of affected tissue comprising assessing the difference in potency, or potency boost, of the compound at physiological pH versus disorder-induced pH in a cell that expresses a human NMDA receptor. The assessment of potency boost can include measuring an IC50 of a compound at physiological pH and at disorder-induced pH (the “potency boost”) until a 95% confidence interval for the potency boost does not change more than 15% with the addition of a new experiment, wherein the measurements are repeated at least 5 times. The processes can be used for the selection of safe NMDA receptor antagonists for the treatment or prevention of a human disorder that lowers the pH in a region affected tissue. Such disorders include, but are not limited to, neuropathic pain, ischemic, Parkinsons disease, epilepsy and traumatic brain injuries.

摘要翻译： 提供了用于鉴定化合物的方法，该化合物可用于治疗或预防降低受影响组织的区域中的pH的病症，包括评估化合物在生理pH下与药物诱导的pH下的效力或效力升高的差异 表达人NMDA受体的细胞。 效力增强的评估可以包括测量化合物在生理pH和无序诱导的pH（“效力促进”）下的IC 50，直到效力增强的95％置信区间随着添加 一个新的实验，其中测量重复至少5次。 该方法可用于选择安全NMDA受体拮抗剂，用于治疗或预防降低受影响组织区域pH的人类病症。 这些病症包括但不限于神经性疼痛，缺血性，帕金森病，癫痫和创伤性脑损伤。

公开(公告)号：US20090253710A1

公开(公告)日：2009-10-08

申请号：US12165308

申请日：2008-06-30

申请人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

发明人： Dennis C. Liotta ,  James P. Snyder ,  Stephen F. Traynelis ,  Lawrence Wilson ,  Cara Mosley ,  Raymond J. Dingledine ,  Scott Myers ,  Yesim Altas Tahirovic

IPC分类号： A61K31/496 ,  C07D241/04 ,  C07D401/04 ,  A61P25/00 ,  A61K31/495

CPC分类号： C07D209/34 ,  C07C217/20 ,  C07C235/20 ,  C07C311/08 ,  C07D211/52 ,  C07D213/74 ,  C07D215/227 ,  C07D233/32 ,  C07D233/34 ,  C07D235/26 ,  C07D263/58 ,  C07D295/088

摘要： Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of disorders associated with NMDA receptor activity, including neuropathic pain, stroke, traumatic brain injury, epilepsy, and related neurologic events or neurodegeneration. Compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein: each (L)k-Ar1 is a substituted or unsubstituted, mono or bicyclic aryl or heteroaryl; W is a bond, alkyl, or alkenyl; X is a bond, NR1 or O and each R1 and R2 is independently H, alkyl, alkenyl or aralkyl or R1 and R2 taken together form a 5-8 membered ring; R3−R6 are selected from certain specific substituents or a carbonyl; Y is a bond, O, S, SO, SO2, CH2, NH, N(alkyl), or NHC(═O); and Z is OH, NR6R7, NR8SO2(alkyl), NR8C(O)NR6R7, NR8C(O)O(alkyl), NR8-dihydrothiazole, or NR8-dihydroimidazole or wherein Z can fuse with Ar2 to form selected heterocycles.

摘要翻译： 提供了治疗或预防与NMDA受体活性相关的病症的化合物，药物组合物和方法，包括神经性疼痛，中风，创伤性脑损伤，癫痫以及相关的神经系统事件或神经变性。 化合物为通式I，或其药学上可接受的盐，酯，前药或衍生物：其中：（L）k-Ar1为取代或未取代的单或双环芳基或杂芳基; W是键，烷基或烯基; X是键，NR 1或O，并且每个R 1和R 2独立地是H，烷基，烯基或芳烷基，或者R 1和R 2一起形成5-8元环; R 3 -R 6选自某些具体取代基或羰基; Y是键，O，S，SO，SO 2，CH 2，NH，N（烷基）或NHC（-O）; 并且Z是OH，NR 6 R 7，NR 8 SO 2（烷基），NR 8 C（O）NR 6 R 7，NR 8 C（O）O（烷基），NR 8 - 二氢噻唑或NR 8 - 二氢咪唑，或其中Z可与Ar 2融合形成选定的杂环。

公开(公告)号：US20090023791A1

公开(公告)日：2009-01-22

申请号：US12151633

申请日：2008-05-08

申请人： Stephen F. Traynelis ,  Dennis C. Liotta ,  James P. Snyder ,  Yesim Altas ,  David D. Mott ,  James J. Doherty, JR. ,  Raymond J. Dingledine

发明人： Stephen F. Traynelis ,  Dennis C. Liotta ,  James P. Snyder ,  Yesim Altas ,  David D. Mott ,  James J. Doherty, JR. ,  Raymond J. Dingledine

IPC分类号： A61K31/421 ,  C07C311/01 ,  A61K31/18 ,  A61K31/13 ,  A61P25/00 ,  C07C211/01 ,  C07C311/15 ,  C07D263/30

CPC分类号： C07C217/34 ,  C07C311/08 ,  C07C311/21 ,  C07D263/24

摘要： NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neurprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chrounic pain, vascular dementia and glioma rumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Prefebably the compounds provided herein are allosteric NMDA inhibitors.

摘要翻译： NMDA受体阻滞剂，包括pH敏感的NMDA受体阻断剂，作为神经保护药物提供，其可用于中风，创伤性脑损伤，癫痫以及涉及脑或脊髓组织酸化的其他神经系统事件。 本发明的组合物和方法用于治疗由NMDA受体活化引起的神经变性。 本文所述的化合物由于病理状况如卒中引起的缺氧，创伤性脑损伤，心脏手术期间可能发生的全身缺血，呼吸停止后可能发生的缺氧等病理状况，具有低于正常pH值的脑组织中的活性增强， 子痫，脊髓创伤，癫痫，腮腺炎，血管性痴呆和神经胶质瘤。 本文所述的化合物也可用于预防帕金森氏老年痴呆症，亨廷顿氏舞蹈病，ALS患者和本领域已知的对NMDA受体阻断剂治疗有反应的其它神经变性病症患者的神经变性。 本文提供的化合物可能是变构NMDA抑制剂。

公开(公告)号：US07375136B2

公开(公告)日：2008-05-20

申请号：US10469824

申请日：2002-03-08

申请人： Stephen F. Traynelis ,  Dennis C. Liotta ,  James P. Snyder ,  Yesim Altas ,  David D. Mott ,  James J. Doherty, Jr. ,  Raymond J. Dingledine

发明人： Stephen F. Traynelis ,  Dennis C. Liotta ,  James P. Snyder ,  Yesim Altas ,  David D. Mott ,  James J. Doherty, Jr. ,  Raymond J. Dingledine

IPC分类号： A61K31/18 ,  C07C311/18

CPC分类号： C07C217/34 ,  C07C311/08 ,  C07C311/21 ,  C07D263/24

摘要： NMDA receptor blockers, including pH-sensitive NMDA receptor blockers, are provided as neuroprotective drugs that are useful in stroke, traumatic brain injury, epilepsy, and other neurologic events that involve acidification of brain or spinal cord tissue. Compositions and methods of this invention are used for treating neurodegeneration resulting from NMDA receptor activation. The compounds described herein have enhanced activity in brain tissue having lower-than normal pH due to pathological conditions such as hypoxia resulting from stroke, traumatic brain injury, global ischemia that may occur during cardiac surgery, hypoxia that may occur following cessation of breathing, pre-eclampsia, spinal cord trauma, epilepsy, chronic pain, vascular dementia and glioma tumors. Compounds described herein are also useful in preventing neurodegeneration in patients with Parkinson's Alzheimer's, Huntington's chorea, ALS, and other neurodegenerative conditions known to the art to be responsive to treatment using NMDA receptor blockers. Preferably the compounds provided herein are allosteric NMDA inhibitors.

摘要翻译： 提供NMDA受体阻滞剂，包括pH敏感的NMDA受体阻断剂，作为神经保护药物，其可用于中风，创伤性脑损伤，癫痫和涉及脑或脊髓组织酸化的其它神经系统事件。 本发明的组合物和方法用于治疗由NMDA受体活化引起的神经变性。 本文所述的化合物由于病理状况如中风，外伤性脑损伤，心脏手术期间可能发生的全身缺血，呼吸停止后可能发生的缺氧等病理状况，具有低于正常pH值的脑组织中的活性增强， 癫痫，脊髓创伤，癫痫，慢性疼痛，血管性痴呆和神经胶质瘤。 本文所述的化合物还可用于预防帕金森氏老年痴呆症，亨廷顿舞蹈症，ALS患者和本领域已知的对NMDA受体阻断剂治疗有反应的其它神经变性病症患者的神经变性。 优选地，本文提供的化合物是变构NMDA抑制剂。