公开(公告)号：US07964727B2

公开(公告)日：2011-06-21

申请号：US10595948

申请日：2004-11-10

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Mikio Morita ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Mikio Morita ,  Chikara Uchida

IPC分类号： C07D221/02 ,  C07D215/00 ,  C07D413/00 ,  A01N43/40 ,  A01N43/42 ,  A61K31/435 ,  A61K31/44

CPC分类号： C04B35/632 ,  C07D401/12 ,  C07D401/14 ,  C07D405/14

摘要： This invention provides a compound of the formula (I): wherein Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents α1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, a n-propyl group or a cyclopentyl group; R2 represents a methyl group, a fluorine atom or a chlorine atom; R3 independently represents (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents, or (iii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents, and n is 1, 2 or 3, or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中Het表示具有一个氮原子的杂环基团，B直接与该碳原子结合，并且具有4至7个碳原子，所述杂环基团未被取代或被1至4个取代基取代 独立地选自取代基α1; A表示具有1至4个碳原子的亚烷基; B表示共价键或具有1至5个碳原子的亚烷基; R1表示异丙基，正丙基或环戊基; R2表示甲基，氟原子或氯原子; R3独立地表示（i）氧代基，羟基，氨基，烷基氨基或羧基; （ii）具有3至8个碳原子的环烷基，所述环烷基被1至5个取代基取代，或（iii）具有3至8个原子的杂环基，所述杂环基未被取代或被1 至5个取代基，n为1,2或3，或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US20080255113A1

公开(公告)日：2008-10-16

申请号：US10595948

申请日：2004-11-10

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Mikio Morita ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Mikio Morita ,  Chikara Uchida

IPC分类号： A61K31/5377 ,  C07D405/14 ,  A61K31/4709 ,  C07D401/12 ,  C07D401/14 ,  C07D413/14

CPC分类号： C04B35/632 ,  C07D401/12 ,  C07D401/14 ,  C07D405/14

摘要： This invention provides a compound of the formula (I): wherein Het represents a heterocyclic group having one nitrogen atom, to which B binds directly, and from 4 to 7 carbon atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of substituents α1; A represents an alkylene group having from 1 to 4 carbon atoms; B represents a covalent bond or an alkylene group having from 1 to 5 carbon atoms; R1 represents an isopropyl group, a n-propyl group or a cyclopentyl group; R2 represents a methyl group, a fluorine atom or a chlorine atom; R3 independently represents (i) an oxo group, a hydroxy group, an amino group, an alkylamino group or a carboxyl group; (ii) a cycloalkyl group having from 3 to 8 carbon atoms, and said cycloalkyl group being substituted by 1 to 5 substituents, or (iii) a heterocyclic group having from 3 to 8 atoms, and said heterocyclic group being unsubstituted or substituted by 1 to 5 substituents, and n is 1, 2 or 3, or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中Het表示具有一个氮原子的杂环基团，B直接与该碳原子结合，并且具有4至7个碳原子，所述杂环基团未被取代或被1至4个取代基取代 独立地选自取代基α1， A表示具有1至4个碳原子的亚烷基; B表示共价键或具有1至5个碳原子的亚烷基; R 1表示异丙基，正丙基或环戊基; R 2表示甲基，氟原子或氯原子; R 3独立地表示（i）氧代基，羟基，氨基，烷基氨基或羧基; （ii）具有3至8个碳原子的环烷基，所述环烷基被1至5个取代基取代，或（iii）具有3至8个原子的杂环基，所述杂环基未被取代或被1 至5个取代基，n为1,2或3，或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物，特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US20080293767A1

公开(公告)日：2008-11-27

申请号：US10597480

申请日：2005-01-18

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

IPC分类号： A61K31/4545 ,  A61P3/00 ,  A61P25/00 ,  A61P1/00 ,  A61P9/00 ,  C07D405/14 ,  C07D401/12

CPC分类号： C07D401/12 ,  C07D405/14

摘要： This invention provides a compound of formula (I): wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula —C(R4)(R5)— (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中R 1表示具有1至4个碳原子的烷基或卤原子，R 2表示具有1至4个碳原子的烷基，R 3表示氢原子或羟基 基团，A表示氧原子或式-C（R4）（R5） - （其中R4表示氢原子或具有1至4个碳原子的烷基，R5表示羟基或式 具有1至4个碳原子的烷氧基）或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US08362038B2

公开(公告)日：2013-01-29

申请号：US12708012

申请日：2010-02-18

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

IPC分类号： A61K31/4545 ,  C07D401/12

CPC分类号： C07D401/12 ,  C07D405/14

摘要： This invention provides a compound of formula (I): wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula —C(R4)(R5)— (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中R 1表示具有1至4个碳原子的烷基或卤原子，R 2表示具有1至4个碳原子的烷基，R 3表示氢原子或羟基 基团，A表示氧原子或式-C（R4）（R5） - （其中R4表示氢原子或具有1至4个碳原子的烷基，R5表示羟基或式 具有1至4个碳原子的烷氧基）或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US06979690B2

公开(公告)日：2005-12-27

申请号：US10337497

申请日：2003-01-07

申请人： Geoffrey Gymer ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita ,  Alan Stobie ,  Chikara Uchida ,  Seiji Nukui

发明人： Geoffrey Gymer ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita ,  Alan Stobie ,  Chikara Uchida ,  Seiji Nukui

IPC分类号： A61K31/4545 ,  A61P1/00 ,  A61P1/04 ,  A61P1/08 ,  A61P1/10 ,  A61P1/14 ,  A61P9/00 ,  A61P9/10 ,  A61P25/00 ,  A61P25/04 ,  A61P25/06 ,  A61P25/22 ,  A61P25/28 ,  A61P43/00 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D405/14 ,  A61K31/445

CPC分类号： C07D401/06 ,  C07D401/12 ,  C07D401/14

摘要： This invention provides compounds of the formula (I) and (II): or the pharmaceutically acceptable esters thereof, and the pharmaceutically acceptable salts thereof: wherein R1 is hydrogen or halo; R2 and R3 are independently hydrogen or C1-6 alkyl; R4 and R5 are independently hydrogen or C1-6 alkyl; R6 is hydrogen, C1-12 alkyl, C1-6 alkoxy (C1-6)alkyl or C1-12 alkyl substituted by up to 3 substituents selected from the groups consisting of C3-8 cycloalkyl, aryl, heteroaryl and heterocyclic; R7 and R8 are hydrogen or taken together may form alkylene chain having one or two carbon atoms; R9 is C1-6 alkyl or C3-8 cycloalkyl; R10 is C1-6 alkyl or NR11R12; L is (CR11R12)n or NR11; M is NR11 or (CR11R12)n; R11 and R12 are independently hydrogen or C1-6 alkyl; n is an integer from 0 to 5; and m is an integer from 0 to 2; said heterocyclic, aryl and heteroaryl are unsubstituted or are substituted by at least one substituent selected from the group consisting of halo and C1-6 alkyl; with the proviso that when R9 is C1-6 alkyl, L is not NR11. These compounds have 5-HT4 receptor binding activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans. This invention also provides a pharmaceutical composition comprising the above compound.

公开(公告)号：US20100144789A1

公开(公告)日：2010-06-10

申请号：US12708012

申请日：2010-02-18

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

IPC分类号： A61K31/4545 ,  C07D401/12 ,  A61P1/00 ,  A61P1/08 ,  A61P1/04 ,  A61P25/00 ,  A61P25/28 ,  A61P9/00 ,  A61P9/06

CPC分类号： C07D401/12 ,  C07D405/14

摘要： This invention provides a compound of formula (I): wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula —C(R4)(R5)— (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中R 1表示具有1至4个碳原子的烷基或卤原子，R 2表示具有1至4个碳原子的烷基，R 3表示氢原子或羟基 基团，A表示氧原子或式-C（R4）（R5） - （其中R4表示氢原子或具有1至4个碳原子的烷基，R5表示羟基或式 具有1至4个碳原子的烷氧基）或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US07691881B2

公开(公告)日：2010-04-06

申请号：US10597480

申请日：2005-01-18

申请人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

发明人： Tomoki Kato ,  Kiyoshi Kawamura ,  Chikara Uchida

IPC分类号： A61K31/445 ,  C07D401/12

CPC分类号： C07D401/12 ,  C07D405/14

摘要： This invention provides a compound of formula (I): wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula —C(R4)(R5)— (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

摘要翻译： 本发明提供式（I）化合物：其中R 1表示具有1至4个碳原子的烷基或卤原子，R 2表示具有1至4个碳原子的烷基，R 3表示氢原子或羟基 基团，A表示氧原子或式-C（R4）（R5） - （其中R4表示氢原子或具有1至4个碳原子的烷基，R5表示羟基或式 具有1至4个碳原子的烷氧基）或其药学上可接受的盐。 这些化合物具有5-HT 4受体激动活性，因此可用于治疗哺乳动物特别是人类的胃食管反流病，非溃疡性消化不良，功能性消化不良，肠易激综合征等。

公开(公告)号：US20080269211A1

公开(公告)日：2008-10-30

申请号：US11995179

申请日：2006-07-14

申请人： Asako Ishibashi ,  Tomoki Kato ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita

发明人： Asako Ishibashi ,  Tomoki Kato ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita

IPC分类号： A61K31/416 ,  A61P1/00 ,  A61P25/00 ,  A61P9/00 ,  C07D401/12 ,  C07D405/14 ,  A61K31/5377 ,  C07D403/12 ,  C07D413/14 ,  C07D401/14 ,  A61K31/454

CPC分类号： C07D401/12 ,  C07D403/12 ,  C07D405/14

摘要： This invention relates to compounds of the formula (I): or pharmaceutically acceptable salts thereof, wherein: R1, R2, R3, A and m are each as described herein and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT4 agonistic activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome.

摘要翻译： 本发明涉及式（I）化合物或其药学上可接受的盐，其中：R 1，R 2，R 3， A和m各自如本文所述，含有这些化合物的组合物和这些化合物在治疗由5-HT 4激动剂活性介导的病症中的用途，例如但不限于胃食管反流 疾病，胃肠道疾病，胃动力障碍，非溃疡性消化不良，功能性消化不良，肠易激综合征（IBS），便秘，消化不良，食管炎，胃食管疾病，恶心，中枢神经系统疾病，阿尔茨海默氏病，认知障碍，呕吐，偏头痛， 神经疾病，疼痛，心血管疾病，心力衰竭，心律失常，糖尿病和呼吸暂停综合征。

公开(公告)号：US07906532B2

公开(公告)日：2011-03-15

申请号：US11995179

申请日：2006-07-14

申请人： Asako Ishibashi ,  Tomoki Kato ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita

发明人： Asako Ishibashi ,  Tomoki Kato ,  Kiyoshi Kawamura ,  Sachiko Mihara ,  Mikio Morita

IPC分类号： A61K31/454 ,  A61K31/416 ,  C07D211/56 ,  C07D231/56

CPC分类号： C07D401/12 ,  C07D403/12 ,  C07D405/14

摘要： This invention relates to compounds of the formula (I): or pharmaceutically acceptable salts thereof, wherein: R1, R2, R3, A and m are each as described herein and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT4 agonistic activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome.

摘要翻译： 本发明涉及式（I）化合物或其药学上可接受的盐，其中：R1，R2，R3，A和m各自如本文所述，含有这些化合物的组合物和这些化合物在治疗中的用途 由5-HT4激动活性介导的病症，例如但不限于胃食管反流病，胃肠道疾病，胃动力障碍，非溃疡性消化不良，功能性消化不良，肠易激综合征（IBS），便秘，消化不良，食管炎，胃肠疾病 恶心，中枢神经系统疾病，阿尔茨海默病，认知障碍，呕吐，偏头痛，神经疾病，疼痛，心血管疾病，心力衰竭，心律失常，糖尿病和呼吸暂停综合征。

公开(公告)号：US07589109B2

公开(公告)日：2009-09-15

申请号：US11360095

申请日：2006-02-22

申请人： Chikara Uchida ,  Hiroki Sone ,  Kiyoshi Kawamura

发明人： Chikara Uchida ,  Hiroki Sone ,  Kiyoshi Kawamura

IPC分类号： A61K31/454 ,  C07D403/14

CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D405/14

摘要： This invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: A, R1, R2, R3, R4 and R5 are each as described herein or a pharmaceutically acceptable salt, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT4 agonistic activity such as, but not limited to, as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes or apnea syndrome.

摘要翻译： 本发明涉及式（I）化合物或其药学上可接受的盐，其中：A，R 1，R 2，R 3，R 4和R 5各自如本文所述或其药学上可接受的盐，以及含有这些化合物的组合物和 使用这些化合物治疗由5-HT4激动活性介导的病症，例如但不限于胃食道反流病，胃肠道疾病，胃动力障碍，非溃疡性消化不良，功能性消化不良，肠易激综合征（IBS） ），便秘，消化不良，食道炎，胃食管疾病，恶心，中枢神经系统疾病，阿尔茨海默病，认知障碍，呕吐，偏头痛，神经系统疾病，疼痛，心血管疾病，心力衰竭，心律失常，糖尿病或呼吸暂停综合征。