公开(公告)号：US08227481B2

公开(公告)日：2012-07-24

申请号：US13151946

申请日：2011-06-02

申请人： Zhongli Gao ,  Daniel Hall ,  Ryan Hartung

发明人： Zhongli Gao ,  Daniel Hall ,  Ryan Hartung

IPC分类号： C07D401/04 ,  A61K31/438

CPC分类号： C07D471/10

摘要： The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). wherein R1, R2, R3, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor are disclosed.

摘要翻译： 本公开涉及一系列式（I）的取代的N-苯基 - 联吡咯烷甲酰胺。 其中R1，R2，R3，m，n和p如本文所述。 更具体地，本发明的化合物是H3受体的调节剂，因此可用作药剂，特别是用于治疗和/或预防由H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。 另外，公开了制备取代的N-苯基 - 联吡咯烷甲酰胺及其中间体的方法。

公开(公告)号：US08604046B2

公开(公告)日：2013-12-10

申请号：US13527147

申请日：2012-06-19

申请人： Zhongli Gao ,  Daniel Hall ,  Ryan Hartung

发明人： Zhongli Gao ,  Daniel Hall ,  Ryan Hartung

IPC分类号： C07D401/14 ,  A61K31/438

CPC分类号： C07D471/10

摘要： The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). wherein R1, R2, R3, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor are disclosed.

摘要翻译： 本公开涉及一系列式（I）的取代的N-苯基 - 联吡咯烷甲酰胺。 其中R1，R2，R3，m，n和p如本文所述。 更具体地，本发明的化合物是H3受体的调节剂，因此可用作药剂，特别是用于治疗和/或预防由H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。 另外，公开了制备取代的N-苯基 - 联吡咯烷甲酰胺及其中间体的方法。

公开(公告)号：US08383814B2

公开(公告)日：2013-02-26

申请号：US13483503

申请日：2012-05-30

申请人： Zhongli Gao ,  Ryan Hartung ,  David Stefany

发明人： Zhongli Gao ,  Ryan Hartung ,  David Stefany

IPC分类号： C07D491/107 ,  C07D401/04 ,  C07D401/14 ,  C07D401/02

CPC分类号： C07D491/107

摘要： The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I): wherein R1, R2, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefore are disclosed.

摘要翻译： 本公开涉及一系列式（I）的取代的N-苯基 - 联吡咯烷甲酰胺：其中R 1，R 2，m，n和p如本文所述。 更具体地，本发明的化合物是H3受体的调节剂，因此可用作药剂，特别是用于治疗和/或预防由H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。 另外，公开了制备取代的N-苯基 - 联吡咯烷甲酰胺和中间体的方法。

公开(公告)号：US08217052B2

公开(公告)日：2012-07-10

申请号：US13151925

申请日：2011-06-02

申请人： Zhongli Gao ,  Ryan Hartung ,  David Stefany

发明人： Zhongli Gao ,  Ryan Hartung ,  David Stefany

IPC分类号： A61K31/438 ,  A61K31/454 ,  A61K31/4545 ,  A61K31/407 ,  C07D491/107 ,  C07D401/04 ,  C07D401/14 ,  C07D401/02

CPC分类号： C07D491/107

摘要： The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I): wherein R1, R2, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefore are disclosed.

摘要翻译： 本公开涉及一系列式（I）的取代的N-苯基 - 联吡咯烷甲酰胺：其中R 1，R 2，m，n和p如本文所述。 更具体地，本发明的化合物是H3受体的调节剂，因此可用作药剂，特别是用于治疗和/或预防由H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。 另外，公开了制备取代的N-苯基 - 联吡咯烷甲酰胺和中间体的方法。

公开(公告)号：US08846676B2

公开(公告)日：2014-09-30

申请号：US13617678

申请日：2012-09-14

申请人： Antonio Almario Garcia ,  Mathieu Barrague ,  Philippe Burnier ,  Cecile Enguehard-Gueiffier ,  Zhongli Gao ,  Pascal George ,  Alain Gueiffier ,  Adrien Tak Li ,  Frederic Peuch ,  Roy Vaz ,  Qiuxia Zhao

发明人： Antonio Almario Garcia ,  Mathieu Barrague ,  Philippe Burnier ,  Cecile Enguehard-Gueiffier ,  Zhongli Gao ,  Pascal George ,  Alain Gueiffier ,  Adrien Tak Li ,  Frederic Peuch ,  Roy Vaz ,  Qiuxia Zhao

IPC分类号： A01N43/58 ,  A01N43/60 ,  A61K31/50 ,  A61K31/495 ,  C07D487/04

CPC分类号： C07D487/04

摘要： The invention relates to the 6-cycloamino-3-(pyridin-4-yl)imidazo[I,2-b]pyridazine derivatives corresponding to general formula (I): Wherein R2, R3, R7, R8, A, L and B are as defined herein. Also disclosed are the preparative methods and therapeutic use thereof.

摘要翻译： 本发明涉及对应于通式（I）的6-环氨基-3-（吡啶-4-基）咪唑并[ⅰ，2-b]哒嗪衍生物：其中R2，R3，R7，R8，A，L和B 如本文所定义。 还公开了其制备方法及其治疗用途。

公开(公告)号：US20070142435A1

公开(公告)日：2007-06-21

申请号：US11520998

申请日：2006-09-14

申请人： Zhongli Gao ,  Larry Davis ,  Julian Levell ,  Mark Czekaj ,  Adam Sledeski

发明人： Zhongli Gao ,  Larry Davis ,  Julian Levell ,  Mark Czekaj ,  Adam Sledeski

IPC分类号： A61K31/453 ,  C07D409/02

CPC分类号： C07D409/06

摘要： The present invention extends to the compound of formula I: or a prodrug, pharmaceutically acceptable salt, or solvate of said compound. Furthermore, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I, and a pharmaceutically acceptable carrier. Furthermore, the present invention is directed to the use of a compound of formula I as an inhibitor of tryptase, comprising introducing the compound into a composition comprising tryptase. In addition, the present invention is directed to the use of a compound of formula I for treating a patient suffering from, or subject to, a physiological condition in need of amelioration of an inhibitor of tryptase comprising administering to the patient a therapeutically effective amount of the compound of claim 1 The present invention is directed also to the preparation of a compound of formula I.

摘要翻译： 本发明延伸到式I化合物：或所述化合物的前药，药学上可接受的盐或溶剂合物。 此外，本发明涉及包含药学有效量的式I化合物和药学上可接受的载体的药物组合物。 此外，本发明涉及式I化合物作为类胰蛋白酶抑制剂的用途，其包括将化合物引入包含类胰蛋白酶的组合物中。 此外，本发明涉及式I化合物用于治疗患有或受制于需要改善类胰蛋白酶抑制剂的生理条件的患者，包括向患者施用治疗有效量的 权利要求1的化合物本发明还涉及式I化合物的制备。

公开(公告)号：US5734062A

公开(公告)日：1998-03-31

申请号：US858987

申请日：1997-05-20

申请人： Thomas B. K. Lee ,  Zhongli Gao

发明人： Thomas B. K. Lee ,  Zhongli Gao

IPC分类号： C07D487/04 ,  C07D471/02

CPC分类号： C07D487/04

摘要： This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl; R.sub.1 is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; Rs is loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR2## wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy; X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises(a) contacting a compound of formula (II) as defined herein with fortified hydrogen bromide to afford a compound of formula (III) as defined herein; contacting the reaction mixture containing a compound of formula (III) with either (1) an isocyanate of formula R.sub.1 NCO or (2) with a compound of formula (IV) as defined to afford a compound of formula (V) as defined herein and contacting the reaction mixture containing the compound of formula (V) with an amine of the formula R.sub.1 R.sub.2 NH herein in the presence of a carboxylic acid of the formula R.sub.5 COOH and forming and isolating the product of Formula (I).

摘要翻译： 本发明涉及一种制备式（I）的产物的方法，其中R是低级烷基; R 1是氢，低级烷基，低级环烷基，低级环烷基低级烷基，低级双环烷基，芳基或芳基低级烷基; 低级烷基，低级环烷基，低级环烷基低级烷基，低级二环烷基，芳基或芳基低级烷基; 或者R 1和R 2与它们所连接的氮原子一起形成式（Ia）的基团，其中Y是氢或低级烷基，Z是氢，低级烷基，卤素，低级烷氧基或羟基; X是低级烷基，低级烷氧基，卤素或三氟甲基; m为0,1或2; 或其药学上可接受的盐; 该方法包括（a）使本文定义的式（II）化合物与强化溴化氢接触，得到本文定义的式（III）化合物; 使含有式（III）化合物的反应混合物与（1）式R1NCO或（2）的异氰酸酯与式（IV）化合物的定义相接触，得到如本文所定义的式（V）化合物和接触 本文在式R 5 COOH的羧酸存在下将含有式（Ⅴ）化合物的反应混合物与式R 1 R 2 NH的胺反应，并形成并分离式（I）的产物。

公开(公告)号：US5665880A

公开(公告)日：1997-09-09

申请号：US739402

申请日：1996-10-31

申请人： Thomas B. K. Lee ,  Zhongli Gao

发明人： Thomas B. K. Lee ,  Zhongli Gao

IPC分类号： C07D487/04 ,  C07D471/02

CPC分类号： C07D487/04

摘要： This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl; R.sub.1, is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralyl; R.sub.2 is lower alkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR2## wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy; X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises(a) contacting a compound of formula (II) as defined herein with fortified hydrogen bromide to afford a compound of formula (III) as defined herein; contacting the reaction mixture containing a compound of formula (III) with either (1) an isocyanate of formula R.sub.1 NCO or (2) with a compound of formula (IV) as defined to afford a compound of formula (V) as defined herein and contacting the reaction mixture containing the compound of formula (V) with an amine of the formula R.sub.1 R.sub.2 NH herein in the presence of a carboxylic acid of the formula R.sub.5 COOH and forming and isolating the product of Formula (I).

摘要翻译： 本发明涉及一种制备式（I）的产物的方法，其中R是低级烷基; R1，是氢，低级烷基，低级环烷基，低级环烷基低级烷基，低级双环烷基，芳基或芳基甲酰基; R2是低级烷基，低级环烷基，低级环烷基低级烷基，低级二环烷基，芳基或芳基低级烷基; 或者R 1和R 2与它们所连接的氮原子一起形成式（Ia）的基团，其中Y是氢或低级烷基，Z是氢，低级烷基，卤素，低级烷氧基或羟基; X是低级烷基，低级烷氧基，卤素或三氟甲基; m为0,1或2; 或其药学上可接受的盐; 该方法包括（a）使本文定义的式（II）化合物与强化溴化氢接触，得到本文定义的式（III）化合物; 使含有式（III）化合物的反应混合物与（1）式R1NCO或（2）的异氰酸酯与式（IV）化合物的定义相接触，得到如本文所定义的式（V）化合物和接触 本文在式R 5 COOH的羧酸存在下将含有式（Ⅴ）化合物的反应混合物与式R 1 R 2 NH的胺反应，并形成并分离式（I）的产物。

公开(公告)号：US08227504B2

公开(公告)日：2012-07-24

申请号：US12724044

申请日：2010-03-15

申请人： Werngard Czechtizky ,  Zhongli Gao ,  William Joseph Hurst ,  Lothar Schwink ,  Siegfried Stengelin

发明人： Werngard Czechtizky ,  Zhongli Gao ,  William Joseph Hurst ,  Lothar Schwink ,  Siegfried Stengelin

IPC分类号： A61K31/5513 ,  A61K31/4725 ,  A61K31/4439 ,  A61K31/422 ,  A61K31/4184 ,  A61K31/4178 ,  A61K31/4155 ,  A61K31/404 ,  A61K31/4025 ,  C07D471/04 ,  C07D405/14 ,  C07D407/14 ,  C07D401/14 ,  C07D403/14 ,  C07D403/06

CPC分类号： C07D401/12 ,  C07D207/09 ,  C07D401/14 ,  C07D403/12 ,  C07D405/12 ,  C07D413/12 ,  C07D471/04

摘要： The present invention discloses and claims a series of substituted N-phenyl-pyrrolidinylmethylpyrrolidine amides of formula (I). Wherein R, R1, R2, R3 and R4 are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted pyrrolidinylmethylpyrrolidine amides and intermediates therefor.

摘要翻译： 本发明公开并要求一系列取代的式（I）的N-苯基 - 吡咯烷基甲基吡咯烷酰胺。 其中R，R 1，R 2，R 3和R 4如本文所述。 更具体地，本发明的化合物是H3受体的调节剂，因此可用作药剂，特别是用于治疗和/或预防由H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。 此外，本发明还公开了制备取代的吡咯烷基甲基吡咯烷酰胺及其中间体的方法。

公开(公告)号：US20110312934A1

公开(公告)日：2011-12-22

申请号：US13058665

申请日：2009-08-12

申请人： Antonio Almario Garcia ,  Philippe Burnier ,  Sylvain Cote-Des Combes ,  Jean-François Gibert ,  Christophe Pacaud ,  Frédéric Puech ,  Yulin Chiang ,  Larry Davis ,  Zhongli Gao ,  Qiuxia Zhao

发明人： Antonio Almario Garcia ,  Philippe Burnier ,  Sylvain Cote-Des Combes ,  Jean-François Gibert ,  Christophe Pacaud ,  Frédéric Puech ,  Yulin Chiang ,  Larry Davis ,  Zhongli Gao ,  Qiuxia Zhao

IPC分类号： A61K31/551 ,  C07D498/10 ,  C07D471/08 ,  A61P25/30 ,  A61K31/5386 ,  A61P35/00 ,  A61P25/00 ,  C07D487/04 ,  A61K31/5025

CPC分类号： C07D487/04 ,  C07D519/00

摘要： The invention relates to 2-alkyl-6-cycloamino-3-(pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives of the general formula (I) where: R2 is a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, C1-4-alkyloxy-C-M-alkyl, C3-7-cycloalkyloxy-C1-4-alkyl>C3-7-cycloalkyl-C1-4-alkyloxy-C1-4-alkyl, hydroxy-C1-6-alkyl, C1-4-fluoroalkyl group; R3 is a hydrogen atom or a substituent selected from halogen atoms and the C1-3 alkyl, —NR4R5, hydroxyl or C1-4 alkyloxy groups; A is a C1-7-alkylene group optionally substituted by one or two Ra groups; B is a C1-7-alkylene group optionally substituted by one or two Rb groups; L is either a nitrogen atom optionally substituted by an Rc or Rd group or a carbon atom substituted by an Re1 group and an Rd group or by two Re2 groups; Rd is a group selected from a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, hydroxy-C1-6-alkyl group; Rf is a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C3-7-cycloalkyloxy-C1-4-alkyl, C3-7-cycloalkyl-C1-4-alkyloxy-C1-4-alkyl, hydroxy-C1-6-allyl, C1-6-fluoroalkyl or benzyl group. The invention also relates to a method for preparing same and to the therapeutic application thereof.

摘要翻译： 本发明涉及通式（I）的2-烷基-6-环氨基-3-（吡啶-4-基）咪唑并[1,2-b]哒嗪衍生物，其中：R2是C1-6烷基，C3 7-环烷基，C 3-7 - 环烷基-C 1-4 - 烷基，C 1-4 - 烷氧基-C1-烷基，C 3-7 - 环烷氧基-C 1-4 - 烷基，C 3-7 - 环烷基-C 1-4 - 烷氧基 C 1-4烷基，羟基-C 1-6 - 烷基，C 1-4 - 氟代烷基; R3是氢原子或选自卤素原子和C1-3烷基，-NR4R5，羟基或C1-4烷氧基的取代基; A是任选被一个或两个R a基团取代的C 1-7 - 亚烷基; B是任选被一个或两个Rb基团取代的C 1-7 - 亚烷基; L是任选被Rc或Rd基团取代的氮原子或被Re 1基团和Rd基团取代的碳原子或两个Re 2基团; Rd是选自氢原子或C 1-6 - 烷基，C 3-7 - 环烷基，C 3-7 - 环烷基-C 1-6 - 烷基，C 1-6 - 烷硫基-C 1-6 - 烷基，C 1-6 - 烷氧基-C 1-6 - 烷基，C 1-6 - 氟代烷基，羟基-C 1-6 - 烷基; R f是C 1-6 - 烷基，C 3-7 - 环烷基，C 3-7 - 环烷基-C 1-6 - 烷基，C 1-6 - 烷氧基-C 1-6 - 烷基，C 3-7 - 环烷氧基-C 1-4 - 烷基 C 3-7 - 环烷基-C 1-4 - 烷氧基-C 1-4 - 烷基，羟基-C 1-6 - 烯丙基，C 1-6 - 氟烷基或苄基。 本发明还涉及其制备方法及其治疗应用。