公开(公告)号：US07115630B2

公开(公告)日：2006-10-03

申请号：US10381987

申请日：2001-09-25

申请人： Dominique Jean-Pierre Mabire ,  Marc Gaston Venet ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Anne Simone Josephine Lesage

发明人： Dominique Jean-Pierre Mabire ,  Marc Gaston Venet ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Anne Simone Josephine Lesage

IPC分类号： C07D215/17 ,  C07D215/20 ,  A61K31/47

CPC分类号： C07D215/04 ,  C07D215/12 ,  C07D215/14 ,  C07D215/18 ,  C07D215/227 ,  C07D215/36 ,  C07D215/38 ,  C07D215/48 ,  C07D215/50 ,  C07D215/54 ,  C07D221/10 ,  C07D221/12 ,  C07D221/16 ,  C07D401/04 ,  C07D401/06 ,  C07D401/12 ,  C07D405/04 ,  C07D405/06 ,  C07D405/12 ,  C07D409/04 ,  C07D409/06 ,  C07D409/12 ,  C07D417/04 ,  C07D453/06 ,  C07D471/04 ,  C07D491/04 ,  C07D495/04 ,  C07F7/0812

摘要： The present invention concerns compounds of formula. In a preferable embodiment, X represents O; R1 represents C1-6alkyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyloxy, aryl, halo or thienyl; R2 represents hydrogen; halo; C1-6alkyl or amino; R3 and R4 each independently represent hydrogen or C1-6alkyl; or R2 and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula —Z4—CH2—CH2—CH2— or —Z4—CH2—CH2— with Z4 being O or NR11 wherein R11 is C1-6alkyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl; or R3 and R4 may be taken together to form a bivalent radical of formula —CH2—CH2—CH2—CH2—; R5 represents hydrogen; Y represents O; and aryl represents phenyl optionally substituted with halo. The invention also relates to the use of a compound according to the invention as a medicament and in the manufacture of a medicament for treating or preventing glutamate-induced diseases of the central nervous system, as well as formulations comprising such a compound and processes for preparing such a compound.

公开(公告)号：US20100292228A1

公开(公告)日：2010-11-18

申请号：US11913890

申请日：2006-03-03

申请人： Frans Eduard Jenssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Bruno Schoentjes

发明人： Frans Eduard Jenssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Bruno Schoentjes

IPC分类号： A61K31/537 ,  C07D498/10 ,  A61P25/18 ,  A61P25/24

CPC分类号： C07D498/10 ,  B82Y5/00

摘要： This invention concerns substituted oxa-diaza-spiro-[5.5]-undecanone derivatives having neurokinin antagonistic activity, in particular an NK1 antagonistic activity, an NK3 antagonistic activity, a combined NK1/NK2 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性的取代的氧杂 - 二氮杂螺 - [5.5] - 十一烷酮衍生物，特别是NK1拮抗活性，NK3拮抗活性，组合NK1 / NK2拮抗活性和组合NK1 / NK2 / NK3拮抗活性 ，它们的制剂，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛 ，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US08138334B2

公开(公告)日：2012-03-20

申请号：US11913890

申请日：2006-03-03

申请人： Frans Eduard Jenssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Bruno Schoentjes

发明人： Frans Eduard Jenssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Bruno Schoentjes

IPC分类号： C07D285/16 ,  C07D407/00 ,  C07D493/00 ,  A01N43/42 ,  A61K31/44

CPC分类号： C07D498/10 ,  B82Y5/00

摘要： This invention concerns substituted oxa-diaza-spiro-[5.5]-undecanone derivatives having neurokinin antagonistic activity, in particular an NK1 antagonistic activity, an NK3 antagonistic activity, a combined NK1/NK2 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性的取代的氧杂 - 二氮杂螺 - [5.5] - 十一烷酮衍生物，特别是NK1拮抗活性，NK3拮抗活性，组合NK1 / NK2拮抗活性和组合NK1 / NK2 / NK3拮抗活性 ，它们的制剂，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛 ，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US07544694B2

公开(公告)日：2009-06-09

申请号：US11547889

申请日：2005-04-04

申请人： Frans Eduard Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan René Ferdinand Simonnet

发明人： Frans Eduard Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan René Ferdinand Simonnet

IPC分类号： A61K31/438 ,  C07D471/10

CPC分类号： C07D471/10 ,  C07D519/00

摘要： This invention concerns substituted diaza-spiro-[5.5]-undecane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, COPD and micturition disorders such as urinary incontinence.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性，特别是NK1拮抗活性，组合NK1 / NK2拮抗活性，组合NK1 / NK3拮抗活性和组合NK1 / NK2 / NK3拮抗活性的取代二氮 - 螺 - [5.5] - 十一烷衍生物 ，它们的制剂，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛 ，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，COPD和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US08604200B2

公开(公告)日：2013-12-10

申请号：US11886175

申请日：2006-03-03

申请人： Frans Eduard Janssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan Rene Ferdinand Simonnet ,  Bruno Schoentjes

发明人： Frans Eduard Janssens ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan Rene Ferdinand Simonnet ,  Bruno Schoentjes

IPC分类号： C07D215/00 ,  C07D217/00 ,  C07D219/00 ,  C07D221/00 ,  A01N43/42 ,  A61K31/44

CPC分类号： C07D487/08

摘要： This invention concerns substituted diaza-spiro-[4.4]-nonane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性的具有神经激肽拮抗活性的取代的二氮杂螺 - [4.4] - 壬烷衍生物，特别是NK1拮抗活性，其制备方法，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症， 呕吐，焦虑和抑郁，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿障碍 作为尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US07612056B2

公开(公告)日：2009-11-03

申请号：US11547705

申请日：2005-04-04

申请人： Frans Eduard Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan René Ferdinand Simonnet

发明人： Frans Eduard Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Philippe Poncelet ,  Yvan René Ferdinand Simonnet

IPC分类号： A61K31/44

CPC分类号： C07D471/10

摘要： This invention concerns substituted diaza-spiro-[4.5]-decane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性，特别是NK1拮抗活性，组合NK1 / NK2拮抗活性，组合NK1 / NK3拮抗活性和组合NK1 / NK2 / NK3拮抗活性的取代的二氮 - 螺 - [4.5] - 癸烷衍生物 ，它们的制剂，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛 ，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US20070232636A1

公开(公告)日：2007-10-04

申请号：US11547889

申请日：2005-04-04

申请人： Frans Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Poncelet ,  Yvan Simonnet

发明人： Frans Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Poncelet ,  Yvan Simonnet

IPC分类号： A61K31/438 ,  C07D215/00

CPC分类号： C07D471/10 ,  C07D519/00

摘要： This invention concerns substituted diaza-spiro-[5.5]-undecane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, COPD and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性，特别是NK 1拮抗活性的组合NK 1 / NK 2的取代的二氮 - 螺 - [5.5] - 十一烷衍生物 组合的NK 1 / NK 3拮抗活性和组合的NK 1 / NK 2拮抗活性， 拮抗活性，它们的制备，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁症，肠易激综合征（肠易激综合征 IBS），昼夜节律紊乱，先兆子痫，伤害感受，疼痛，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，COPD和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US09573933B2

公开(公告)日：2017-02-21

申请号：US12678961

申请日：2008-09-18

申请人： Virginie Sophie Poncelet ,  Sophie Coupa ,  Pierre-Henri Storck ,  Bruno Schoentjes

发明人： Virginie Sophie Poncelet ,  Sophie Coupa ,  Pierre-Henri Storck ,  Bruno Schoentjes

IPC分类号： C07C59/13 ,  C07D311/04 ,  A61K31/352 ,  C07D491/052 ,  A61K31/4741 ,  C07D405/10 ,  A61K31/4184 ,  A61K31/192 ,  C07D405/04 ,  A61K31/4709 ,  C07D409/10 ,  A61K31/381 ,  A61K45/06 ,  C07D401/12 ,  C07D487/04

CPC分类号： A61K31/4439 ,  A61K9/28 ,  A61K31/438 ,  A61K31/4709 ,  A61K31/5377 ,  A61K31/55 ,  A61K45/06 ,  C07D401/12 ,  C07D487/04

摘要： The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds: wherein n, m, p, s, t, R1, R2, R3, R4, R5, R6, R7, R20, X, Y, Q and Z have defined meanings.

摘要翻译： 本发明提供式（I）化合物，其作为p53-MDM2相互作用抑制剂的用途以及包含所述化合物的药物组合物：其中n，m，p，s，t，R1，R2，R3，R4， R5，R6，R7，R20，X，Y，Q和Z具有定义的含义。

公开(公告)号：US20090221641A1

公开(公告)日：2009-09-03

申请号：US11886175

申请日：2006-03-03

申请人： Frans Eduard Janssens ,  Sophie Coupa ,  Alain Phillippe Poncelet ,  Yvan Rene Ferdinand Simonnet ,  Bruno Schoentjes

发明人： Frans Eduard Janssens ,  Sophie Coupa ,  Alain Phillippe Poncelet ,  Yvan Rene Ferdinand Simonnet ,  Bruno Schoentjes

IPC分类号： A61K31/454 ,  C07D401/14 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P29/00 ,  A61P11/00 ,  A61P11/06

CPC分类号： C07D487/08

摘要： This invention concerns substituted diaza-spiro-[4.4]-nonane derivatives having neurokinin antagonistic activity, in particular NK1 antagonist ic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nocicept ion, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性的具有神经激肽拮抗活性的取代的二氮杂螺 - [4.4] - 壬烷衍生物，特别是NK1拮抗剂活性，其制备方法，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症 呕吐，焦虑和抑郁症，肠易激综合征（IBS），昼夜节律紊乱，先兆子痫，伤痛感染，疼痛，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿 疾病如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US20070254904A1

公开(公告)日：2007-11-01

申请号：US11547705

申请日：2005-04-04

申请人： Frans Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Poncelet ,  Yvan Simonnet

发明人： Frans Janssens ,  Bruno Schoentjes ,  Sophie Coupa ,  Alain Poncelet ,  Yvan Simonnet

IPC分类号： A61K31/438 ,  A61P1/12 ,  A61P13/00 ,  A61P25/18 ,  A61P25/24 ,  C07D401/02

CPC分类号： C07D471/10

摘要： This invention concerns substituted diaza-spiro-[4.5]-decane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and micturition disorders such as urinary incontinence. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及具有神经激肽拮抗活性，特别是NK 1拮抗活性的组合NK 1 / NK 2的取代的二氮 - 螺 - [4.5] - 癸烷衍生物 组合的NK 1 / NK 3拮抗活性和组合的NK 1 / NK 2拮抗活性， 拮抗活性，它们的制备，包含它们的组合物及其作为药物的用途，特别是用于治疗和/或预防精神分裂症，呕吐，焦虑和抑郁症，肠易激综合征（肠易激综合征 IBS），昼夜节律障碍，先兆子痫，伤害感受，疼痛，特别是内脏和神经性疼痛，胰腺炎，神经源性炎症，哮喘，慢性阻塞性肺病（COPD）和排尿障碍如尿失禁。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。