公开(公告)号：US08232292B2

公开(公告)日：2012-07-31

申请号：US12216257

申请日：2008-07-01

申请人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko ,  Yoshihito Kanzawa

发明人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko ,  Yoshihito Kanzawa

IPC分类号： A61K31/47 ,  C07D401/02

CPC分类号： C07D401/12

摘要： (S)-1-(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine monohydrochloride and a crystal thereof, and a crystal of the aforementioned monohydrochloride having a major peak or peaks at one or more positions selected from the group consisting of positions where 2θs are about 13.9°, 21.5°, 21.7°, 22.4°, 22.8°, 24.5° and 35.0° in a powder X-ray diffraction spectrum, which have excellent properties as active ingredient of a medicament for prophylactic and/or therapeutic treatment of glaucoma and the like.

摘要翻译： （S）-1-（4-氯-5-异喹啉磺酰基）-3-（甲基氨基）吡咯烷一盐酸盐及其结晶，以及上述一盐酸盐的结晶，在一个或多个位置上具有主峰或峰 由粉末X射线衍射光谱中的2和等级为13.9°，21.5°，21.7°，22.4°，22.8°，24.5°和35.0°的位置组成，其作为预防药物的活性成分具有优异的性质 和/或治疗性青光眼等。

公开(公告)号：US20090156823A1

公开(公告)日：2009-06-18

申请号：US12216257

申请日：2008-07-01

申请人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko ,  Yoshihito Kanzawa

发明人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko ,  Yoshihito Kanzawa

IPC分类号： C07D217/22

CPC分类号： C07D401/12

摘要： (S)-1-(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine monohydrochloride and a crystal thereof, and a crystal of the aforementioned monohydrochloride having a major peak or peaks at one or more positions selected from the group consisting of positions where 2θs are about 13.9°, 21.5°, 21.7°, 22.4°, 22.8°, 24.5° and 35.0° in a powder X-ray diffraction spectrum, which have excellent properties as active ingredient of a medicament for prophylactic and/or therapeutic treatment of glaucoma and the like.

摘要翻译： （S）-1-（4-氯-5-异喹啉磺酰基）-3-（甲基氨基）吡咯烷一盐酸盐及其结晶，以及上述一盐酸盐的结晶，在一个或多个位置上具有主峰或峰 包括在粉末X射线衍射光谱中2θ为13.9°，21.5°，21.7°，22.4°，22.8°，24.5°和35.0°的位置，其作为用于预防和/ 或治疗青光眼等。

公开(公告)号：US08664243B2

公开(公告)日：2014-03-04

申请号：US13535116

申请日：2012-06-27

申请人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko

发明人： Hitoshi Kida ,  Koki Matsubara ,  Shunsuke Kaneko

IPC分类号： C07D401/12 ,  A61K31/47

CPC分类号： C07D401/12

摘要： (S)-1-(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine monohydrochloride and a crystal thereof, and a crystal of the aforementioned monohydrochloride having a major peak or peaks at one or more positions selected from the group consisting of positions where 2θs are about 13.9°, 21.5°, 21.7°, 22.4°, 22.8°, 24.5° and 35.0° in a powder X-ray diffraction spectrum, which have excellent properties as active ingredient of a medicament for prophylactic and/or therapeutic treatment of glaucoma and the like.

摘要翻译： （S）-1-（4-氯-5-异喹啉磺酰基）-3-（甲基氨基）吡咯烷一盐酸盐及其结晶，以及上述一盐酸盐的结晶，在一个或多个位置上具有主峰或峰 包括在粉末X射线衍射光谱中2thetas为约13.9°，21.5°，21.7°，22.4°，22.8°，24.5°和35.0°的位置，其作为用于预防和/ 或治疗青光眼等。

公开(公告)号：US20120270898A1

公开(公告)日：2012-10-25

申请号：US13535116

申请日：2012-06-27

申请人： Hitoshi KIDA ,  Koki Matsubara ,  Shunsuke Kaneko

发明人： Hitoshi KIDA ,  Koki Matsubara ,  Shunsuke Kaneko

IPC分类号： C07D401/12 ,  A61P27/02 ,  A61P27/06 ,  A61K31/4725

CPC分类号： C07D401/12

摘要： (S)-1-(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine monohydrochloride and a crystal thereof, and a crystal of the aforementioned monohydrochloride having a major peak or peaks at one or more positions selected from the group consisting of positions where 2θs are about 13.9°, 21.5°, 21.7°, 22.4°, 22.8°, 24.5° and 35.0° in a powder X-ray diffraction spectrum, which have excellent properties as active ingredient of a medicament for prophylactic and/or therapeutic treatment of glaucoma and the like.

摘要翻译： （S）-1-（4-氯-5-异喹啉磺酰基）-3-（甲基氨基）吡咯烷一盐酸盐及其结晶，以及上述一盐酸盐的结晶，在一个或多个位置上具有主峰或峰 由粉末X射线衍射光谱中的2和等级为13.9°，21.5°，21.7°，22.4°，22.8°，24.5°和35.0°的位置组成，其作为预防药物的活性成分具有优异的性质 和/或治疗性青光眼等。

公开(公告)号：US06495701B1

公开(公告)日：2002-12-17

申请号：US09937488

申请日：2001-09-26

申请人： Koki Matsubara ,  Hitoshi Kida

发明人： Koki Matsubara ,  Hitoshi Kida

IPC分类号： C07D20982

CPC分类号： C07D209/88 ,  C07C311/08 ,  C07C311/13

摘要： The present invention is directed to processes for the preparation of a compound useful for treating diabetes, obesity, hyperlipidemia and the like, which compound is represented by the formula (1): wherein R1 represents a lower alkyl group or a benzyl group; *1 represents an asymmetric carbon atom; R2 hydrogen atom, a halogen atom or a hydroxyl group; and A represents one of the following groups: wherein X represents NH, O or S; R6 represents a hydrogen atom, a hydroxyl group, an amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R6 is not a hydrogen atom, and to intermediates useful for the said processes. The processes of the present invention are convenient, practical preparing processes with low cost which comprise a small number of steps with good industrial work efficiency.

摘要翻译： 本发明涉及制备用于治疗糖尿病，肥胖症，高脂血症等的化合物的方法，该化合物由式（1）表示：其中R1表示低级烷基或苄基; * 1表示不对称碳原子; R2氢原子，卤素原子或羟基; A表示下列基团之一：其中X表示NH，O或S; R6表示氢原子，羟基，氨基或乙酰氨基; 和* 2表示当R6不是氢原子时的不对称碳原子，并且可用于所述方法的中间体。 本发明的方法是方便，实用的低成本的制备方法，其包括具有良好工业工作效率的少量步骤。

公开(公告)号：US07964613B2

公开(公告)日：2011-06-21

申请号：US12071921

申请日：2008-02-27

申请人： Koki Matsubara ,  Atsushi Iesato ,  Akifumi Oomura ,  Koh Kawasaki ,  Rintaro Yamada ,  Minoru Seto

发明人： Koki Matsubara ,  Atsushi Iesato ,  Akifumi Oomura ,  Koh Kawasaki ,  Rintaro Yamada ,  Minoru Seto

IPC分类号： A01N43/42 ,  A01N43/00 ,  A61K31/47 ,  A61K31/00 ,  C07D217/00 ,  C07D217/22

CPC分类号： A61K31/55 ,  A61K31/47 ,  C07D401/12

摘要： A compound represented by the formula (1) [A represents a nitrogen-containing saturated ring; m represents an integer of 0 to 2; n represents an integer of 1 to 4; G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group, or amino group; G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an amino group, an alkylsulfinyl group, an alkylsulfonyl group, or an aryl group; G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an amino group, an alkoxycarbonyl group, an acyl group, an acyloxy group, an alkylsulfinyl group, an alkylsulfonyl group, or an aryl group; Y represents a single bond, or —C(R3)(R4)— (R3 and R4 represent hydrogen atom, or an alkyl group, or alkylene groups which combine together to form a saturated hydrocarbon ring group); G4 represents hydroxyl group (Y is a single group), or —N(R1)(R2) (R1 and R2 represent hydrogen atom, an alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, a saturated heterocyclic group, an alkylsulfonyl group, an acyl group, or an amidino group); G5 is a substituent on a ring-constituting carbon atom of A, and represents hydrogen atom, fluorine atom, or an alkyl group] or a salt thereof, or a derivative thereof that is a prodrug, which potently inhibits Rho kinase.

摘要翻译： 由式（1）表示的化合物[A表示含氮饱和环; m表示0〜2的整数。 n表示1〜4的整数， G1表示氢原子，氯原子，羟基，烷氧基或氨基; G 2表示卤素原子，羟基，氰基，羧基，烷基，烯基，炔基，烷氧基，烷硫基，氨基，烷基亚磺酰基，烷基磺酰基或芳基 组; G3表示氢原子，卤素原子，羟基，氰基，羧基，烷基，烯基，炔基，烷氧基，烷硫基，氨基，烷氧基羰基，酰基， 酰氧基，烷基亚磺酰基，烷基磺酰基或芳基; Y表示单键，或-C（R3）（R4） - （R3和R4表示氢原子，或烷基或结合在一起形成饱和烃环基的亚烷基）; G4表示羟基（Y为单一基团）或-N（R1）（R2）（R1和R2表示氢原子，烷基，芳烷基，烯基，炔基，饱和杂环基， 烷基磺酰基，酰基或脒基）; G5是A的环构成碳原子上的取代基，代表氢原子，氟原子或烷基，或其盐，或其作为前体药物的衍生物，其有效抑制Rho激酶。

公开(公告)号：US06696573B1

公开(公告)日：2004-02-24

申请号：US10070249

申请日：2002-03-04

申请人： Koki Matsubara ,  Naoyuki Ishii ,  Masami Ogawa

发明人： Koki Matsubara ,  Naoyuki Ishii ,  Masami Ogawa

IPC分类号： C07D20988

CPC分类号： C07D307/91 ,  C07C205/26 ,  C07C205/45 ,  C07D209/88 ,  C07D333/76

摘要： A process for the preparation of tricyclic amino alcohol derivatives including 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]]amino-1-[(3-methylsulfonylamino)phenyl]ethanol useful in the treatment of diabetes, obesity, hyperlipidemia and so on; and intermediates as represented by formula (5) or (6) or the like useful in the preparation, wherein R11 is hydrogen or the like; and *1 represents an asymmetric carbon atom. 2-Halo-1-(3-nitrophenyl)ethanone derivatives and 1-(3-nitrophenyl)oxirane derivatives, which are intermediates for the preparation of tricyclic amino alcohol derivatives, are easy of purification, and particularly optically active 1-(3-nitrophenyl)oxirane derivatives are effective in enhancing the optical purities of the final products.

摘要翻译： 一种制备三环氨基醇衍生物的方法，包括用于治疗糖尿病的2- [N- [2-（9H-咔唑-2-基氧基）乙基]]氨基-1 - [（3-甲基磺酰基氨基）苯基]乙醇 ，肥胖，高脂血症等; 和由式（5）或（6）表示的中间体，其中R 11为氢等; * 1表示不对称碳原子。 2-卤代-1-（3-硝基苯基）乙酮衍生物和作为制备三环氨基醇衍生物的中间体的1-（3-硝基苯基）环氧乙烷衍生物易于纯化，特别是光学活性的1-（3- 硝基苯基）环氧乙烷衍生物有效提高最终产品的光学纯度。

公开(公告)号：US20090048223A1

公开(公告)日：2009-02-19

申请号：US12071921

申请日：2008-02-27

申请人： Koki Matsubara ,  Atsushi Iesato ,  Akifumi Oomura ,  Koh Kawasaki ,  Rintaro Yamada ,  Minoru Seto

发明人： Koki Matsubara ,  Atsushi Iesato ,  Akifumi Oomura ,  Koh Kawasaki ,  Rintaro Yamada ,  Minoru Seto

IPC分类号： A61K31/397 ,  C07D401/14 ,  A61K31/4725 ,  C07D401/02 ,  A61K31/496 ,  A61K31/5377 ,  C07D413/14 ,  C07D487/02 ,  A61K31/5025

CPC分类号： A61K31/55 ,  A61K31/47 ,  C07D401/12

摘要： A compound represented by the formula (1) [A represents a nitrogen-containing saturated ring; m represents an integer of 0 to 2; n represents an integer of 1 to 4; G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group, or amino group; G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an amino group, an alkylsulfinyl group, an alkylsulfonyl group, or an aryl group; G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an amino group, an alkoxycarbonyl group, an acyl group, an acyloxy group, an alkylsulfinyl group, an alkylsulfonyl group, or an aryl group; Y represents a single bond, or —C(R3)(R4)— (R3 and R4 represent hydrogen atom, or an alkyl group, or alkylene groups which combine together to form a saturated hydrocarbon ring group); G4 represents hydroxyl group (Y is a single group), or —N(R1)(R2) (R1 and R2 represent hydrogen atom, an alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, a saturated heterocyclic group, an alkylsulfonyl group, an acyl group, or an amidino group); G5 is a substituent on a ring-constituting carbon atom of A, and represents hydrogen atom, fluorine atom, or an alkyl group] or a salt thereof, or a derivative thereof that is a prodrug, which potently inhibits Rho kinase.

摘要翻译： 由式（1）表示的化合物[A表示含氮饱和环; m表示0〜2的整数。 n表示1〜4的整数， G1表示氢原子，氯原子，羟基，烷氧基或氨基; G 2表示卤素原子，羟基，氰基，羧基，烷基，烯基，炔基，烷氧基，烷硫基，氨基，烷基亚磺酰基，烷基磺酰基或芳基 组; G3表示氢原子，卤素原子，羟基，氰基，羧基，烷基，烯基，炔基，烷氧基，烷硫基，氨基，烷氧基羰基，酰基， 酰氧基，烷基亚磺酰基，烷基磺酰基或芳基; Y表示单键，或-C（R3）（R4） - （R3和R4表示氢原子，或烷基或结合在一起形成饱和烃环基的亚烷基）; G4表示羟基（Y为单一基团）或-N（R1）（R2）（R1和R2表示氢原子，烷基，芳烷基，烯基，炔基，饱和杂环基， 烷基磺酰基，酰基或脒基）; G5是A的环构成碳原子上的取代基，代表氢原子，氟原子或烷基，或其盐，或其作为前体药物的衍生物，其有效抑制Rho激酶。