公开(公告)号：US06841549B1

公开(公告)日：2005-01-11

申请号：US10018688

申请日：2000-06-30

申请人： Osamu Asano ,  Hitoshi Harada ,  Seiji Yoshikawa ,  Nobuhisa Watanabe ,  Takashi Inoue ,  Tatsuo Horizoe ,  Nobuyuki Yasuda ,  Kaya Ohashi ,  Hiroe Minami ,  Junsaku Nagaoka ,  Manabu Murakami ,  Seiichi Kobayashi ,  Isao Tanaka ,  Tsutomu Kawata ,  Naoyuki Shimomura ,  Hiroshi Akamatsu ,  Naoki Ozeki ,  Toshikazu Shimizu ,  Kenji Hayashi ,  Toyokazu Haga ,  Shigeto Negi ,  Toshihiko Naito

发明人： Osamu Asano ,  Hitoshi Harada ,  Seiji Yoshikawa ,  Nobuhisa Watanabe ,  Takashi Inoue ,  Tatsuo Horizoe ,  Nobuyuki Yasuda ,  Kaya Ohashi ,  Hiroe Minami ,  Junsaku Nagaoka ,  Manabu Murakami ,  Seiichi Kobayashi ,  Isao Tanaka ,  Tsutomu Kawata ,  Naoyuki Shimomura ,  Hiroshi Akamatsu ,  Naoki Ozeki ,  Toshikazu Shimizu ,  Kenji Hayashi ,  Toyokazu Haga ,  Shigeto Negi ,  Toshihiko Naito

IPC分类号： A61P3/10 ,  A61P43/00 ,  C07D471/04 ,  C07D473/00 ,  C07D473/34 ,  C07D473/40 ,  A16K31/33 ,  C07D239/70 ,  C07D471/00 ,  C07D487/00 ,  A16K31/52

CPC分类号： C07D471/04 ,  C07D473/00 ,  C07D473/34 ,  C07D473/40

摘要： The present invention provides a preventive or therapeutic agent for diabetes mellitus and diabetic complications, which is a new type based on an adenosine A2 receptor antagonist action.That is, it provides a novel condensed imidazole compound which has an adenosine A2 receptor antagonist action, is effective for preventing or treating diabetes mellitus and diabetic complications, and is represented by the formula (I); (wherein R1 represents e.g. an amino group which may be substituted with an alkyl group; R2 represents e.g. hydrogen atom, an alkyl group, a cycloalkyl group or an alkyl group, alkenyl group or alkynyl group which may be substituted with hydrox etc.; R3 represents e.g. an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, pyridinone group, pyrimidinone group or piperadinone group; Ar represents e.g. an optionally substituted aryl or heteroaryl group; and Q and W are the same as or different from each other and each represents N or CH), a pharmacologically acceptable salt or hydrates thereof.

摘要翻译： 本发明提供了一种基于腺苷A2受体拮抗剂作用的新型糖尿病和糖尿病并发症的预防或治疗剂。即提供了具有腺苷A2受体拮抗剂作用的新颖的缩合咪唑化合物，是 有效预防或治疗糖尿病和糖尿病并发症，并由式（I）表示;（其中R 1表示例如可被烷基取代的氨基; R 2表示例如氢原子， 可以被羟基取代的烷基，环烷基或烷基，烯基或炔基; R 3表示例如任选取代的烷基，烯基，炔基，芳基，杂芳基， 吡啶酮基，嘧啶酮基或哌嗪酮基; Ar表示例如任选取代的芳基或杂芳基; Q和W彼此相同或不同，每个代表 N或CH），其药理学上可接受的盐或其水合物。

公开(公告)号：US07858809B2

公开(公告)日：2010-12-28

申请号：US11578134

申请日：2005-04-08

申请人： Shigeto Negi ,  Toshikazu Shimizu ,  Hiroshi Kuroda ,  Naoyuki Shimomura ,  Manabu Sasho ,  Yorihisa Hoshino ,  Manabu Kuboto

发明人： Shigeto Negi ,  Toshikazu Shimizu ,  Hiroshi Kuroda ,  Naoyuki Shimomura ,  Manabu Sasho ,  Yorihisa Hoshino ,  Manabu Kuboto

IPC分类号： C07D231/54

CPC分类号： C07D471/04

摘要： Intermediates useful for the synthesis of pyrazole-fused ring derivatives, such as 7-phenylpyrazolo [1,5-a]pyridine derivatives, and method for producing the same. Method for producing compound represented by the general formula (II), wherein Z1 and Z2 each independently represents a methine group or a nitrogen atom; Rl represents an ethyl group or the like; R5 represents a hydrogen atom or the like; R2 and R3 each independently represents a C1-6 alkyl group or the like, salts thereof, or solvates of both, comprising the step of: reacting a compound represented by the general formula (I), wherein Z1, Z2, R5, R1, R2 and R3 each has the same definition as described above, with an organometallic reagent; and then reacting the resulting product with pentafluoroiodobenzene.

摘要翻译： 用于合成吡唑稠合环衍生物如7-苯基吡唑并[1,5-a]吡啶衍生物的中间体及其制备方法。 制备由通式（II）表示的化合物的方法，其中Z1和Z2各自独立地表示次甲基或氮原子; R1表示乙基等; R5表示氢原子等; R 2和R 3各自独立地表示C 1-6烷基等，其盐或两者的溶剂合物，包括以下步骤：使通式（I）表示的化合物与其反应，其中Z1，Z2，R5，R1， R2和R3各自具有与上述相同的定义，与有机金属试剂; 然后使所得产物与五氟碘苯反应。

公开(公告)号：US20070191613A1

公开(公告)日：2007-08-16

申请号：US11578134

申请日：2005-04-08

申请人： Shigeto Negi ,  Toshikazu Shimizu ,  Hiroshi Kuroda ,  Naoyuki Shimomura ,  Manabu Sasho ,  Yorihisa Hoshino ,  Manabu Kubota

发明人： Shigeto Negi ,  Toshikazu Shimizu ,  Hiroshi Kuroda ,  Naoyuki Shimomura ,  Manabu Sasho ,  Yorihisa Hoshino ,  Manabu Kubota

IPC分类号： C07D231/54

CPC分类号： C07D471/04

摘要： An object of the invention is to find out intermediates usful for the synthesis of pyrazol-fused ring derivatives (such as 7-phenylpyrazolo[1,5-a]pyridine derivatives) and a method for producing the same. A method for producing compound represented by the general formula (II), wherein Z1 and Z2 each independently represents a methine group or a nitrogen atom; R1 represents an ethyl group or the like; R5 represents a hydrogen atom or the like; R2 and R3 each independently represents a C1-6 alkyl group or the like, salts thereof, or solvates of both, comprising the step of: reacting a compound represented by the general formula (I), wherein Z1, Z2, R5, R1, R2 and R3 each has the same definition as described above, with an organometallic reagent; and then reacting the resulting product with pentafluoroiodobenzene.

摘要翻译： 本发明的目的是找出有用于合成吡唑稠合环衍生物（如7-苯基吡唑并[1,5-a]吡啶衍生物）的中间体及其制备方法。 由通式（II）表示的化合物，其中Z 1和Z 2各自独立地表示次甲基或氮原子的方法; R 1表示乙基等; R 5表示氢原子等; R 2和R 3各自独立地表示C 1-6烷基等，其盐或两者的溶剂合物，包括 步骤：使通式（I）表示的化合物，其中Z 1，Z 2，R 5，R 5， 1，R 2和R 3各自具有与上述相同的定义与有机金属试剂; 然后使所得产物与五氟碘苯反应。

公开(公告)号：US07816405B2

公开(公告)日：2010-10-19

申请号：US11405619

申请日：2006-04-18

申请人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

发明人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

IPC分类号： A61K31/277 ,  C07C255/55

CPC分类号： C07C255/54

摘要： The present invention relates to calcium bis[(2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy) -2-fluoropropoxy]phenyl]-2-isopropoxypropionate] represented by formula (I), a hydrate thereof, a crystal of the compound of formula (I), and a crystal of the hydrate of the compound of formula (I) which are useful as pharmaceuticals, and to processes for producing the same, and intermediates therefore, and processes for production thereof.There is need for (2S)-3-[3-[(2S)-3-(4 -chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, in the form of a drug substance, purified so as to minimize a residual solvent content and having a uniformized specification and a highly favorable workability, and a process for producing the same.Crystalline calcium bis[(2S)-3-[3-[(2S)-3-(4 -chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate], a calcium salt of (2S) -3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, solves the above problem.

摘要翻译： 本发明涉及由式（I）表示的双[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸钙] ），其水合物，式（I）化合物的结晶和可用作药物的式（I）化合物的水合物的结晶及其制备方法和中间体，以及 其生产方法。 需要药物形式的（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸， 纯化以使残留溶剂含量最小化并且具有均匀的规格和高度有利的可加工性，以及其制备方法。 结晶的[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸钠]，（2S） - 3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸解决了上述问题。

公开(公告)号：US20090069591A1

公开(公告)日：2009-03-12

申请号：US11886664

申请日：2006-04-18

申请人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

发明人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

IPC分类号： C07C69/734 ,  C07C59/68

CPC分类号： C07C255/54

摘要： The present invention relates to calcium bis[(2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate] represented by formula (I), a hydrate thereof, a crystal of the compound of formula (I), and a crystal of the hydrate of the compound of formula (I) which are useful as pharmaceuticals, and to processes for producing the same, and intermediates therefore, and processes for production thereof.[Problem] There is need for (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, in the form of a drug substance, purified so as to minimize a residual solvent content and having a uniformized specification and a highly favorable workability, and a process for producing the same. [Solution] Crystalline calcium bis[(2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate], a calcium salt of (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, solves the above problem. [Selected Drawing] None

摘要翻译： 本发明涉及由式（I）表示的双[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸钙] ），其水合物，式（I）化合物的结晶和可用作药物的式（I）化合物的水合物的结晶及其制备方法和中间体，以及 其生产方法。 [问题]需要（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸，其形式为 纯化，以使残留溶剂含量最小化并具有均匀的规格和高度有利的可加工性，及其制备方法。 [溶液]结晶的双[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸]钙， 2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸解决了上述问题。 [已选图]无

公开(公告)号：US20070117866A1

公开(公告)日：2007-05-24

申请号：US11405619

申请日：2006-04-18

申请人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

发明人： Masanobu Shinoda ,  Fumiyoshi Matsuura ,  Kaoru Murata ,  Masaharu Gotoda ,  Kenji Hayashi ,  Manabu Sasho ,  Naoki Ozeki ,  Susumu Inoue ,  Katsutoshi Nishiura ,  Yoshihiko Hisatake ,  Teiji Takigawa ,  Mamoru Miyazawa ,  Shigeto Negi ,  Keisuke Matsuyama

IPC分类号： A61K31/277 ,  C07C255/55

CPC分类号： C07C255/54

摘要： The present invention relates to calcium bis[(2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate] represented by formula (I), a hydrate thereof, a crystal of the compound of formula (I), and a crystal of the hydrate of the compound of formula (I) which are useful as pharmaceuticals, and to processes for producing the same, and intermediates therefore, and processes for production thereof. [Problem]There is need for (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, in the form of a drug substance, purified so as to minimize a residual solvent content and having a uniformized specification and a highly favorable workability, and a process for producing the same. [Solution]Crystalline calcium bis[(2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate], a calcium salt of (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid, solves the above problem. [Selected Drawing] None

摘要翻译： 本发明涉及由式（I）表示的双[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸钙] ），其水合物，式（I）化合物的结晶和可用作药物的式（I）化合物的水合物的结晶及其制备方法和中间体，以及 其生产方法。 [问题]需要（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸，其形式为 纯化，以使残留溶剂含量最小化并具有均匀的规格和高度有利的可加工性，及其制备方法。 [溶液]结晶的双[（2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸]钙， 2S）-3- [3 - [（2S）-3-（4-氯-2-氰基苯氧基）-2-氟丙氧基]苯基] -2-异丙氧基丙酸解决了上述问题。 [已选图]无

公开(公告)号：US06620945B2

公开(公告)日：2003-09-16

申请号：US10142339

申请日：2002-05-08

申请人： Toyokazu Haga ,  Akio Kayano ,  Manabu Sasyou ,  Shigeto Negi ,  Hiroyuki Naka ,  Hirofumi Noda ,  Ken-ichi Sakai

发明人： Toyokazu Haga ,  Akio Kayano ,  Manabu Sasyou ,  Shigeto Negi ,  Hiroyuki Naka ,  Hirofumi Noda ,  Ken-ichi Sakai

IPC分类号： C07D20100

CPC分类号： C07D401/04 ,  C07B2200/07 ,  C07D207/12 ,  C07D453/02 ,  C07D491/04

摘要： The present invention provides a process for producing optically active 3-hydroxy-4-methoxypyrrolidine, which is an intermediate for synthesizing a quinuclidine derivative useful as a squalene synthetase inhibitor, a salt thereof, or a hydrate thereof by subjecting a pyrrolidine derivative represented by the following formula (1-4): wherein R3a and R3b are different and each of R3a and R3b represents a hydrogen atom or a methyl group, to optical division purification by using an optically active dibenzoyltartaric acid derivative or the like.

摘要翻译： 本发明提供了一种光学活性3-羟基-4-甲氧基吡咯烷的制备方法，该方法是合成用作角鲨烯合成酶抑制剂的奎宁环衍生物，其盐或其水合物的中间体， 下式（1-4）：其中R3a和R3b不同，R3a和R3b各自表示氢原子或甲基，通过使用光学活性二苯甲酰基酒石酸衍生物等进行光学分裂纯化。

公开(公告)号：US5128465A

公开(公告)日：1992-07-07

申请号：US468319

申请日：1990-01-22

申请人： Takashi Kamiya ,  Toshihiko Naito ,  Yuuki Komatu ,  Yasunobu Kai ,  Takaharu Nakamura ,  Manabu Sasho ,  Shigeto Negi ,  Isao Sugiyama ,  Kanemasa Katsu ,  Hiroshi Yamauchi

发明人： Takashi Kamiya ,  Toshihiko Naito ,  Yuuki Komatu ,  Yasunobu Kai ,  Takaharu Nakamura ,  Manabu Sasho ,  Shigeto Negi ,  Isao Sugiyama ,  Kanemasa Katsu ,  Hiroshi Yamauchi

IPC分类号： C07D498/04 ,  C07C237/06 ,  C07D498/08 ,  C07D501/00 ,  C07D501/18 ,  C07D501/24 ,  C07D501/46 ,  C07D501/56 ,  C07D519/00

CPC分类号： C07D498/08 ,  C07C237/06 ,  C07D501/00 ,  Y02P20/55

摘要： A cephem derivative represented by the following formula: ##STR1## wherein R.sub.1 means a fluorine-substituted lower alkyl and A.sub.1 denotes a cyclic or acyclic ammonio group, or a non-toxic salt thereof, is prepared by reacting a compound represented by the following formula: ##STR2## wherein A.sub.1 has the same meaning as defined above, with another compound represented by the following formula: ##STR3## wherein R.sub.1 has the same meaning as defined above, and if necessary, removing the protecting groups.

摘要翻译： 由下式表示的头孢烯衍生物：其中R1表示氟取代的低级烷基，A1表示环状或无环氨基，或其无毒盐，通过使下式表示的化合物 其中A 1具有与上述定义相同的含义，另外由下式表示的化合物：其中R 1具有与上述相同的含义，如有必要，除去保护基。

公开(公告)号：US5006649A

公开(公告)日：1991-04-09

申请号：US463519

申请日：1990-01-11

申请人： Takashi Kamiya ,  Toshihiko Naito ,  Shigeto Negi ,  Yuuki Komatu ,  Yasunobu Kai ,  Takaharu Nakamura ,  Isao Sugiyama ,  Yoshimasa Machida ,  Seiichiro Nomoto ,  Kyosuke Kitoh ,  Kanemasa Katsu ,  Hiroshi Yamauchi

发明人： Takashi Kamiya ,  Toshihiko Naito ,  Shigeto Negi ,  Yuuki Komatu ,  Yasunobu Kai ,  Takaharu Nakamura ,  Isao Sugiyama ,  Yoshimasa Machida ,  Seiichiro Nomoto ,  Kyosuke Kitoh ,  Kanemasa Katsu ,  Hiroshi Yamauchi

IPC分类号： C07D501/46 ,  A61K31/545 ,  A61K31/546 ,  C07D20060101 ,  C07D285/08 ,  C07D501/00 ,  C07D501/04 ,  C07D501/24 ,  C07D501/56 ,  C07D519/00

CPC分类号： C07D501/24

摘要： A 3-propenylcephem derivative of the following formula: ##STR1## wherein R.sub.1 represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A represents a cyclic or an acylic ammonio group, or a pharmaceutically acceptable salt thereof, exhibiting excellent anti-bacterial activities against both Gram-positive bacteria and Gram-negative bacteria; Process for the preparation thereof; Anti-bacterial composition; Intermediate for the 3-propenylcephem derivative; and Process for the preparation of the intermediate.

公开(公告)号：US4929612A

公开(公告)日：1990-05-29

申请号：US181427

申请日：1988-04-14

申请人： Yoshimasa Machida ,  Shigeto Negi ,  Takashi Kamiya ,  Yuuki Komatu ,  Isao Sugiyama ,  Yasunobu Kai ,  Takaharu Nakamura ,  Toshihiko Naito ,  Kyosuke Kitoh ,  Kanemasa Katsu ,  Hiroshi Yamauchi

发明人： Yoshimasa Machida ,  Shigeto Negi ,  Takashi Kamiya ,  Yuuki Komatu ,  Isao Sugiyama ,  Yasunobu Kai ,  Takaharu Nakamura ,  Toshihiko Naito ,  Kyosuke Kitoh ,  Kanemasa Katsu ,  Hiroshi Yamauchi

IPC分类号： C07D501/46 ,  C07D519/00

CPC分类号： C07D501/46 ,  C07D519/00

摘要： Novel thiadiazolylacetamide cephem derivatives of the following formula are described. ##STR1## wherein A represents a quaternary ammonio group; or a pharmaceutically acceptable salt thereof. These novel compounds are useful as antibacterial agents, because they have a broad antibacterial spectrum ranging from gram-negative bacteria to gram-positive bacteria. Processes for the preparation of these novel compounds are also described.