公开(公告)号：US20130178521A1

公开(公告)日：2013-07-11

申请号：US13825875

申请日：2011-09-22

申请人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

发明人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

IPC分类号： C07D317/72

CPC分类号： C07D317/72 ,  A61K31/357

摘要： To provide potassium salts of substituted pyrrolidine derivatives, which suppress the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, and crystals thereof. The present invention provides potassium(2-chloro-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide and potassium(2-bromo-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide, each of which suppresses the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, crystals thereof, and a pharmaceutical containing any of the same, and a prophylactic and/or therapeutic agent for sepsis containing any of the same.

摘要翻译： 提供抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎性介质的产生的取代的吡咯烷衍生物的钾盐及其结晶。 本发明提供了（2-氯-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基）-1,4-二氧杂螺[4.5]十碳六 （2-溴-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基） 二氧杂螺[4.5]十碳-6-烯-8-基]磺酰基}吖庚因，其各自抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎性介质的产生，其晶体和含有 以及含有任何相同的败血症的预防和/或治疗剂。

公开(公告)号：US08933117B2

公开(公告)日：2015-01-13

申请号：US13825875

申请日：2011-09-22

申请人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

发明人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

IPC分类号： A01N43/26 ,  A61K31/355 ,  C07D317/72 ,  A61K31/357

CPC分类号： C07D317/72 ,  A61K31/357

摘要： To provide potassium salts of substituted cycloalkene derivatives, which suppress the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, and crystals thereof. The present invention provides potassium (2-chloro-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide and potassium (2-bromo-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide, each of which suppresses the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, crystals thereof, and a pharmaceutical containing any of the same, and a prophylactic and/or therapeutic agent for sepsis containing any of the same.

摘要翻译： 提供抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎症介质的产生的取代环烯烃衍生物的钾盐及其结晶。 本发明提供了（2-氯-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基）-1,4-二氧杂螺[4.5]十碳六 （2-溴-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基） 二氧杂螺[4.5]十碳-6-烯-8-基]磺酰基}吖庚因，其各自抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎性介质的产生，其晶体和含有任何 以及含有任何相同的败血症的预防和/或治疗剂。

公开(公告)号：US20140073689A9

公开(公告)日：2014-03-13

申请号：US13825875

申请日：2011-09-22

申请人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

发明人： Nobuyuki Ohkawa ,  Kouki Iida ,  Takayoshi Nagasaki

IPC分类号： C07D317/72

CPC分类号： C07D317/72 ,  A61K31/357

摘要： To provide potassium salts of substituted pyrrolidine derivatives, which suppress the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, and crystals thereof. The present invention provides potassium(2-chloro-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide and potassium(2-bromo-4-fluorophenyl){[(2R,3R,8R)-7-(ethoxycarbonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-en-8-yl]sulfonyl}azanide, each of which suppresses the production of an inflammatory mediator caused by intracellular signal transduction or cell activation induced by endotoxin, crystals thereof, and a pharmaceutical containing any of the same, and a prophylactic and/or therapeutic agent for sepsis containing any of the same.

摘要翻译： 提供抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎性介质的产生的取代的吡咯烷衍生物的钾盐及其结晶。 本发明提供了（2-氯-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基）-1,4-二氧杂螺[4.5]十碳六 （2-溴-4-氟苯基）{[（2R，3R，8R）-7-（乙氧基羰基）-2,3-双（羟甲基） 二氧杂螺[4.5]十碳-6-烯-8-基]磺酰基}吖庚因，其各自抑制由内毒素诱导的细胞内信号转导或细胞活化引起的炎性介质的产生，其晶体和含有 以及含有任何相同的败血症的预防和/或治疗剂。

公开(公告)号：USRE43858E1

公开(公告)日：2012-12-11

申请号：US13224745

申请日：2006-09-13

申请人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

发明人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

IPC分类号： A61K31/335 ,  C07D317/72

摘要： A compound of formula (I) Wherein X, Y, ring A, ring B, l, m, R1, R2, R4 and R5 are as defined herein, to supress intracellular signal transduction or cell activation induced by endotoxin and to suppress cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts therefor, a preparation method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient which is superior in prophylaxis and/or treatment of diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), that are associated with intracellular signal transduction or cell activation induced by endotoxin and to cell responses to the intracellular signal transduction and cell activation.

摘要翻译： 式（I）化合物其中X，Y，环A，环B，l，m，R 1，R 2，R 4和R 5如本文所定义，以抑制由内毒素诱导的细胞内信号转导或细胞活化并抑制细胞反应 由于细胞内信号转导和细胞活化，例如过量产生炎症介质如TNF-α，其药理学上可接受的盐，其制备方法，以及含有上述取代的环烯烃衍生物作为活性成分的药物，其优于 与细胞内信号转导或由内毒素诱导的细胞活化以及对细胞内信号转导和细胞的细胞反应相关的诸如败血症（败血症休克，弥散性血管内凝血，多器官功能衰竭等）的疾病的预防和/或治疗 激活。

公开(公告)号：US07122666B2

公开(公告)日：2006-10-17

申请号：US10354648

申请日：2003-01-30

申请人： Tomio Kimura ,  Akira Nakao ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Takanori Yamazaki

发明人： Tomio Kimura ,  Akira Nakao ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Takanori Yamazaki

IPC分类号： C07D207/00 ,  C07D209/00

CPC分类号： C07D451/02 ,  C07D401/04 ,  C07D401/14 ,  C07D453/02 ,  C07D455/02 ,  C07D471/04 ,  C07D487/04

摘要： Compounds having activity against production of an inflammatory cytokine of formula (I)′: A′ is pyrrole; R1′ is phenyl or naphthyl; R2′ is pyridyl or pyrimidinyl; R3′ is (IIa)′, (IIb)′ or (IIc)′: m′ is 1; E′ is nitrogen; D′ is >C(R5′)—, R5′ is hydrogen, Substituent α′ or Substituent β′; B′ is nitrogen-containing 5-membered heterocyclic; R4′ is 1 to 3 substituents from Substituent α′, Substituent β′ and Substituent γ′; R1′ and R3′ are bonded to two atoms of the pyrrole adjacent to the pyrrole atom bonded to R2′; Substituent α′ is hydroxyl, nitro, cyano, halogen, alkoxy, halogeno alkoxy, alkylthio, halogeno alkylthio or —NRa′Rb′; Ra′ and Rb′ are hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkylsulfonyl, or Ra′ and Rb′ with the nitrogen atom form a heterocyclyl; Substituent β′ is alkyl, alkenyl, alkynyl, aralkyl or cycloalkyl; Substituent γ′ is oxo, hydroxyimino, alkoxyimino, alkylene, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, aryl, aryloxy, alkylidenyl or aralkylidenyl.

摘要翻译： 具有抗式产生式（I）的炎性细胞因子的活性化合物的化合物：A'是吡咯; R 1是苯基或萘基; R 2是吡啶基或嘧啶基; （IIa）'，（IIb）'或（IIc）'：m'为1; E'是氮; D'是> C（R 5'） - ，R 5'是氢，取代基α'或取代基β'; B'是含氮5元杂环; R 4'是1至3个取代基α'，取代基β'和取代基γ'的取代基; R 1'和R 3'连接到与R 2'连接的吡咯原子相邻的吡咯的两个原子上; 取代基α'是羟基，硝基，氰基，卤素，烷氧基，卤代烷氧基，烷硫基，卤代烷硫基或-NR a R b B。 R a，O和R b'是氢，烷基，烯基，炔基，芳烷基或烷基磺酰基，或者R a'和R“ b'与氮原子形成杂环基; 取代基β'是烷基，烯基，炔基，芳烷基或环烷基; 取代基γ'是氧代，羟基亚氨基，烷氧基亚氨基，亚烷基，亚烷基二氧基，烷基亚磺酰基，烷基磺酰基，芳基，芳氧基，亚烷基或芳亚烷基。

公开(公告)号：US07935835B2

公开(公告)日：2011-05-03

申请号：US12066813

申请日：2006-09-13

申请人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

发明人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

IPC分类号： C07D319/00 ,  C07D315/00 ,  C07D327/00

CPC分类号： C07C311/14 ,  C07C2601/16 ,  C07C2602/50 ,  C07D303/38 ,  C07D307/94 ,  C07D317/72 ,  C07D319/08 ,  C07D321/10 ,  C07D327/04 ,  C07D339/06 ,  C07D339/08 ,  C07D493/04 ,  C07D493/10

摘要： A compound of formula (I) Wherein X, Y, ring A, ring B, l, m, R1, R2, R4 and R5 are as defined herein, to supress intracellular signal transduction or cell activation induced by endotoxin and to suppress cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts therefor, a preparation method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient which is superior in prophylaxis and/or treatment of diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), that are associated with intracellular signal transduction or cell activation induced by endotoxin and to cell responses to the intracellular signal transduction and cell activation.

摘要翻译： 式（I）化合物其中X，Y，环A，环B，l，m，R 1，R 2，R 4和R 5如本文所定义，以抑制由内毒素诱导的细胞内信号转导或细胞活化并抑制细胞反应 由于细胞内信号转导和细胞活化，例如过量产生炎症介质如TNF-α，其药理学上可接受的盐，其制备方法，以及含有上述取代的环烯烃衍生物作为活性成分的药物，其优于 与细胞内信号转导或由内毒素诱导的细胞活化以及对细胞内信号转导和细胞的细胞反应相关的诸如败血症（败血症休克，弥散性血管内凝血，多器官功能衰竭等）的疾病的预防和/或治疗 激活。

公开(公告)号：US20070049620A1

公开(公告)日：2007-03-01

申请号：US11301296

申请日：2005-12-12

申请人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Akira Nakao ,  Takayoshi Nagasaki ,  Takaichi Shimozato

发明人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Akira Nakao ,  Takayoshi Nagasaki ,  Takaichi Shimozato

IPC分类号： A61K31/444 ,  A61K31/4439 ,  C07D401/14 ,  C07D403/14

CPC分类号： C07D471/04 ,  A61K31/437 ,  A61K31/444

摘要： A cyclic tertiary amine compound which is capable of inhibiting the production of inflammatory cytoines. The compound having a structure represented by the following formula (I): wherein A represents an optionally substituted trivalent group which is benzene, pyrimidine, pyrrole, pyridine, pyridazine, furan, thiopene, pyrazole, imidazole, isoxazole or isothiazole; R1 represents an aryl or a heteroaryl group, which is unsubstituted or substituted; R2 represents a heteroaryl group which is unsubtituted or substituted; and R3 represents a cyclic tertiary amino group, or a pharmacologically acceptable salt of the compound.

摘要翻译： 能够抑制炎性细胞因子产生的环状叔胺化合物。 具有由下式（I）表示的结构的化合物：其中A表示任选取代的三价基团，其为苯，嘧啶，吡咯，吡啶，哒嗪，呋喃，噻吩，吡唑，咪唑，异恶唑或异噻唑; R 1表示未取代或取代的芳基或杂芳基; R 2表示未取代或取代的杂芳基; R 3表示化合物的环状叔氨基或药理学上可接受的盐。

公开(公告)号：US20090233952A1

公开(公告)日：2009-09-17

申请号：US12066813

申请日：2006-09-13

申请人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

发明人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Atsuhiro Sugidachi ,  Osamu Ando

IPC分类号： A61K31/443 ,  C07D317/72 ,  A61K31/357 ,  C07D405/08 ,  A61K31/4025 ,  C07D319/04 ,  C07D405/10

CPC分类号： C07C311/14 ,  C07C2601/16 ,  C07C2602/50 ,  C07D303/38 ,  C07D307/94 ,  C07D317/72 ,  C07D319/08 ,  C07D321/10 ,  C07D327/04 ,  C07D339/06 ,  C07D339/08 ,  C07D493/04 ,  C07D493/10

摘要： [Object] To provide a substituted cycloalkene derivative having an action to suppress intracellular signal transduction or cell activation induced by endotoxin and to suppress cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts therefor, a medicament containing them as an active ingredient, a preparation method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient which is superior in prophylaxis and/or treatment of diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), that are associated with intracellular signal transduction or cell activation induced by endotoxin and to cell responses to the intracellular signal transduction and cell activation.[Solution] A compound represented by the general formula (I): {whereinX and Y represent a group in which X and Y together with a carbon atom to which they are bound form ring A (the ring is 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring), each represents a hydrogen atom, or X and Y together represent a substituent of ring B. l and m, independently from each other, represent an integer of 0 to 3, and l+m is 1 to 3. R1 is an aliphatic hydrocarbon group and the like which may be substituted with a group selected from Substituent group β and Substituent group γ. n represents an integer of 0 to 3. R2 is a C1-C6 alkyl group and the like which may be substituted with a group selected from a hydrogen atom and Substituent group β. R3 is a phenyl group, 5- to 6-membered heteroaryl group and the like which may be substituted with a group selected from Substituent group ε. R5 is a C1-C6 alkyl group and the like which may be substituted with a group selected from a hydrogen atom and Substituent group β. Provided that in the case where R3 is a phenyl group which may be substituted with a group selected from Substituent group ε, X and Y represent a group in which X and Y together with a carbon atom to which they are bound form ring A, or X and Y together represent a substituent of ring B.

公开(公告)号：US20050283006A1

公开(公告)日：2005-12-22

申请号：US10411061

申请日：2003-04-10

申请人： Tomio Kimura ,  Kazumasa Aoki ,  Akira Nakao ,  Shigeru Ushiyama ,  Takaichi Shimozato ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Takanori Yamazaki

发明人： Tomio Kimura ,  Kazumasa Aoki ,  Akira Nakao ,  Shigeru Ushiyama ,  Takaichi Shimozato ,  Nobuyuki Ohkawa ,  Takayoshi Nagasaki ,  Takanori Yamazaki

IPC分类号： C07D401/04 ,  C07D401/14 ,  C07D451/02 ,  C07D453/02 ,  C07D455/02 ,  C07D471/04 ,  C07D487/04 ,  C07D491/20 ,  C07D41/14 ,  C07D43/02

CPC分类号： C07D451/02 ,  C07D401/04 ,  C07D401/14 ,  C07D453/02 ,  C07D455/02 ,  C07D471/04 ,  C07D487/04

摘要： Compounds having activity against production of inflammatory cytokines of formula (I)′: A′ is pyrrole; R1′ is aryl or heteroaryl; R2′ is heteroaryl having at least one nitrogen atom; R3′ is (IIa)′, (IIb)′ or (IIc)′: m′ is 1 or 2; one of D′ and E′ is nitrogen and the other is >C(R5′)—, R5′ is hydrogen, Substituent α′ or Substituent β′; B′ is nitrogen-containing 4- to 7-membered heterocyclic; R4′ is 1 to 3 substituents from Substituent α′, Substituent β′ and Substituent γ′; R1′ and R3′ are bonded to two atoms of the pyrrole adjacent to the pyrrole atom bonded to R2′; Substituent α′: hydroxyl, nitro, cyano, halogen, alkoxy, halogeno alkoxy, alkylthio, halogeno alkylthio or —NRa′Rb′; Ra′ and Rb′ are hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkylsulfonyl, or Ra′ and Rb′ with the nitrogen atom form a heterocyclyl; Substituent β′: alkyl, alkenyl, alkynyl, aralkyl or cycloalkyl; Substituent γ′: oxo, hydroxyimino, alkoxyimino, alkylene, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, aryl, aryloxy, alkylidenyl or aralkylidenyl.

摘要翻译： 具有抗式产生式（I）的炎性细胞因子的化合物的化合物：A'是吡咯; R 1是芳基或杂芳基; R 2是具有至少一个氮原子的杂芳基; （IIa）'，（IIb）'或（IIc）'：m'为1或2; D'和E'之一是氮，另一个是> C（R 5'） - ，R 5'是氢，取代基α'或取代基β'; B'是含氮的4-至7-元杂环; R 4'是1至3个取代基α'，取代基β'和取代基γ'的取代基; R 1'和R 3'连接到与R 2'连接的吡咯原子相邻的吡咯的两个原子上; 取代基α'：羟基，硝基，氰基，卤素，烷氧基，卤代烷氧基，烷硫基，卤代烷硫基或-NR a R b b。 R a，O和R b'是氢，烷基，烯基，炔基，芳烷基或烷基磺酰基，或者R a'和R“ b'与氮原子形成杂环基; 取代基β'：烷基，烯基，炔基，芳烷基或环烷基; 取代基γ'：氧代，羟基亚氨基，烷氧基亚氨基，亚烷基，亚烷基二氧基，烷基亚磺酰基，烷基磺酰基，芳基，芳氧基，亚烷基或芳烷基。

公开(公告)号：US20050159444A1

公开(公告)日：2005-07-21

申请号：US11039423

申请日：2005-01-19

申请人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Kazumasa Aoki ,  Akira Nakao ,  Takayoshi Nagasaki

发明人： Tomio Kimura ,  Nobuyuki Ohkawa ,  Kazumasa Aoki ,  Akira Nakao ,  Takayoshi Nagasaki

IPC分类号： A61K31/4745 ,  C07D455/02

CPC分类号： A61K31/4745 ,  C07D455/02

摘要： A bicyclic unsaturated tertiary amine compound capable of inhibiting the production of inflammatory cytokines. The compound has the following formula (I): wherein A represents pyrrole or pyrazole, R1 represents an aryl group or a heteroaryl group which may be substituted, R2 represents a heteroaryl group which may be substituted, and R3 represents an indolizine group, or a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or a pharmacologically acceptable derivative thereof.

摘要翻译： 能够抑制炎性细胞因子产生的双环不饱和叔胺化合物。 化合物具有下式（I）：其中A表示吡咯或吡唑，R 1表示可被取代的芳基或杂芳基，R 2表示 可以被取代的杂芳基，R 3表示中氮茚基，或其药理学上可接受的盐，其药理学上可接受的酯或其药理学上可接受的衍生物。