(+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine | 681291-92-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine
• 英文别名: (+)-(2R-trans)-1-[3,5-bis(tritluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine；[(2R,4S)-2-benzyl-4-piperazin-1-ylpiperidin-1-yl]-[3,5-bis(trifluoromethyl)phenyl]methanone
• CAS: 681291-92-9
• 化学式: C₂₅H₂₇F₆N₃O
• 分子量: 499.499
• InChiKey: NEOQCQIBCCRRPO-FCHUYYIVSA-N

物化性质

• 沸点：
  539.2±50.0 °C(Predicted)
• 密度：
  1.290±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine 在 palladium 10% on activated carbon 噻吩 、 氢氧化钾 、 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 异丙醇 为溶剂， 反应 19.5h， 生成 [4-[4-[2-Benzyl-1-(4-methylthiadiazole-5-carbonyl)piperidin-4-yl]piperazin-1-yl]piperidin-1-yl]-(4-methylthiadiazol-5-yl)methanone
  参考文献：
  名称：

  [EN] SUBSTITUTED 1,4-DI-PIPERIDIN-4-YL-PIPERAZINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS
  [FR] DERIVES 1,4-DI-PIPERIDIN-4-YL-PIPERAZINES SUBSTITUES EN 1,4 ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DES NEUROKININES

  摘要：

  该发明涉及具有神经激肽拮抗活性的替代1,4-二哌啶-4-基哌嗪衍生物，特别是NK1拮抗活性，它们的制备，包含它们的组合物以及它们作为药物的用途，特别是用于治疗呕吐、焦虑、抑郁、疼痛、胰腺炎和肠易激综合征。根据该发明的化合物可以用一般公式（I）表示，并且还包括其药用可接受的酸或碱盐，其立体化学异构体形式，其N-氧化物形式以及其前药，其中所有取代基的定义如权利要求书1所述。鉴于它们通过阻断神经激肽受体来拮抗神经激肽的作用，特别是通过阻断NK1受体来拮抗P物质的作用，根据该发明的化合物可用作药物，特别是在预防和治疗神经激肽介导的情况下，如中枢神经系统疾病，特别是抑郁症、焦虑症、与压力有关的疾病、睡眠障碍、认知障碍、人格障碍、分裂情感障碍、进食障碍、神经退行性疾病、成瘾障碍、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呕吐；胃肠道疾病，特别是肠易激综合征（IBS）；皮肤疾病；血管痉挛性疾病；纤维化和胶原疾病；与免疫增强或抑制以及风湿疾病和体重控制相关的疾病。

  公开号：

  WO2004033428A1
• 作为产物：
  描述：

  4,4-(乙烯二氧基)-1-叔丁氧羰基哌啶 在 titanium(IV) isopropylate 、 四甲基乙二胺 、 5%-palladium/activated carbon 、 potassium tert-butylate 、 氢气 、 仲丁基锂 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 乙醚 、 异丙醇 为溶剂， -70.0~60.0 ℃ 、100.0 kPa 条件下， 反应 46.83h， 生成 (+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine
  参考文献：
  名称：

  Process Development of the Synthetic Route to R116301

  摘要：

  We describe in this paper the synthesis of compound 1 (R116301), which was developed to prepare pilot scale quantities (20-50 kg) of drug substance. The synthesis involves the (BuLi)-Bu-s deprotonation of Boc-protected piperidone acetal 2, followed by benzaldehyde addition and ring closure to cyclic carbamate 4. Piperidine acetal 5 is resolved with Brown's acid and acylated. The ketone obtained after piperidine acetal deprotection undergoes reductive amination with N-benzyl piperazine, the most critical step in the synthesis. After debenzylation, final coupling and salt formation, compound 1 is obtained over 10 steps with 4% overall yield.

  DOI：

  10.1021/op700086d

文献信息

• [EN] SUBSTITUTED 1-PIPERIDIN-4-YL-4-AZETIDIN-3-YL-PIPERAZINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES SUBSTITUES DE 1-PIPERIDINE-4-YL-4-AZETIDINE-3-YL-PIPERAZINE ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DE LA NEUROKININE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2004056800A1

  公开（公告）日：2004-07-08

  The invention concerns substituted 1-piperidin-4-yl-4-azefdin-3-yl-piperazine having neurokinin antagonistic activity, in particular NK1 and NK1/NK3- antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, emesis, anxiety, depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P by blocking the NK receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykininmediated conditions, such as, for instance CNS disorders, in particular depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, schizoaffective disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNSrelated conditions ; inflammation ; allergic disorders ; emesis ; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders ; vasospastic diseases ; fibrosing and collagen diseases ; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

  本发明涉及具有神经激肽拮抗活性的取代1-哌啶-4-基-4-氮杂二氢-3-基-哌嗪，特别是NK1和NK1/NK3-拮抗活性，它们的制备，包含它们的组合物以及它们作为药物的用途，特别是用于治疗精神分裂症、呕吐、焦虑、抑郁、肠易激综合征（IBS）、昼夜节律紊乱、疼痛、神经源性炎症、哮喘、排尿障碍如尿失禁和疼痛感知。根据本发明，这些化合物可以用一般式（I）表示，并且还包括其药学上可接受的酸或碱盐、立体化异构体、N-氧化物形式和前药形式，其中所有取代基的定义如权利要求1所述。由于这些化合物具有通过阻断神经激肽受体拮抗激肽的作用，特别是通过阻断NK受体拮抗P物质的作用的能力，根据本发明的化合物可用作药物，特别是在预防和治疗神经激肽介导的疾病方面，例如中枢神经系统疾病，特别是抑郁症、焦虑症、与压力相关的疾病、睡眠障碍、认知障碍、人格障碍、分裂情感障碍、进食障碍、神经退行性疾病、成瘾障碍、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呕吐；胃肠道疾病，特别是肠易激综合征（IBS）；皮肤疾病；血管痉挛性疾病；纤维化和胶原疾病；与免疫增强或抑制和风湿性疾病以及体重控制相关的疾病。
• [EN] SUBSTITUTED 1-PIPERIDIN-3-YL-4-PIPERIDIN-4-YL-PIPERAZINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES 1-PIPERIDIN-3-YL-4-PIPERIDIN-4-YL-PIPERAZINE SUBSTITUEE ET UTILISATIONS DE CES DERNIERS EN TANT QU'ANTAGONISTES DE LA NEUROKININE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2004056364A1

  公开（公告）日：2004-07-08

  This invention concerns substituted 1-piperidin-3-yl-4-piperidin-4-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 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 of schizophrenia, emesis, anxiety and depression, irritable bowel syndrom (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P, Neurokinin A and Neurokinin B by blocking the NK1, NK2 and NK3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

  本发明涉及具有神经激肽拮抗活性的取代1-哌啶-3-基-4-哌啶-4-基-哌嗪衍生物，特别是NK1拮抗活性，具有联合NK1/NK3拮抗活性和联合NK1/NK2/NK3拮抗活性，其制备，包含它们的组合物和用途作为药物，特别用于治疗精神分裂症、呕吐、焦虑和抑郁症、肠易激综合征(IBS)、昼夜节律紊乱、内脏疼痛、神经源性炎症、哮喘、排尿障碍，如尿失禁和疼痛感知。根据本发明的化合物可用一般式(I)表示，并且还包括其药学上可接受的酸或碱盐，其立体化异构体形式，其N-氧化物形式和其前药，其中所有取代基的定义如权利要求1所述。鉴于它们通过阻断神经激肽受体来拮抗激肽的作用，特别是通过阻断NK1、NK2和NK3受体来拮抗P物质、神经激肽A和神经激肽B的作用，根据本发明的化合物可用作药物，特别是在预防和治疗激肽介导的疾病中，例如中枢神经系统疾病，特别是精神分裂情感性障碍、抑郁症、焦虑障碍、与压力相关的障碍、睡眠障碍、认知障碍、人格障碍、饮食障碍、神经退行性疾病、成瘾障碍、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呕吐；胃肠道疾病，特别是肠易激综合征(IBS)；皮肤疾病；血管痉挛性疾病；纤维化和胶原疾病；与免疫增强或抑制和风湿性疾病以及体重控制相关的障碍。
• [EN] SUBSTITUTED 4-(4-PIPERIDIN-4-YL-PIPERAZIN-1-YL)-AZEPANE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES DE 4-(4-PIPERIDIN-4-YL-PIPERAZIN-1-YL)-AZEPANE SUBSTITUES ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DES NEUROKININES
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2004056805A1

  公开（公告）日：2004-07-08

  The invention concerns substituted 4-(4-piperidin-4-yl-piperazin-1-yl)-azepane 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 of pain, emesis, anxiety, depression and IBS. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P and Neurokinin B by blocking the NK1, NK2 and NK3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions ; inflammation ; allergic disorders ; emesis ; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders ; vasospastic diseases ; fibrosing and collagen diseases ; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

  该发明涉及具有神经激肽拮抗活性的取代的4-(4-哌啶-4-基哌嗪-1-基)-环庚烷衍生物，特别是NK1拮抗活性，它们的制备，包含它们的组合物以及它们作为药物的用途，特别是用于治疗疼痛、呕吐、焦虑、抑郁和肠易激综合征。根据该发明的化合物可以用一般式(I)表示，还包括其药学上可接受的酸或碱盐，其立体化异构体形式，其N-氧化物形式和其前药形式，其中所有取代基的定义如权利要求1所述。鉴于它们能够通过阻断神经激肽受体来拮抗激肽的作用，特别是通过阻断NK1、NK2和NK3受体来拮抗P物质和神经激肽B的作用，根据该发明的化合物可用作药物，特别是在预防和治疗激肽介导的疾病，例如中枢神经系统疾病，特别是分裂情感障碍、抑郁症、焦虑症、与压力有关的疾病、睡眠障碍、认知障碍、人格障碍、进食障碍、神经退行性疾病、成瘾障碍、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呕吐；胃肠道疾病，特别是肠易激综合征（IBS）；皮肤疾病；血管痉挛性疾病；纤维化和胶原病；与免疫增强或抑制和风湿性疾病以及体重控制有关的疾病。
• Substituted 4-(4-piperidin-4-yl-piperazin-1-yl)-azepane derivatives and their use as neurokinin antagonists
  申请人：Janssens Eduard Frans

  公开号：US20060058285A1

  公开（公告）日：2006-03-16

  The invention concerns substituted 4-(4-piperidin-4-yl-piperazin-1-yl)-azepane derivatives having neurokinin antagonistic activity, in particular NK 1 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of pain, emesis, anxiety, depression and IBS. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P and Neurokinin B by blocking the NK 1 , NK 2 and NK 3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

  本发明涉及具有神经激肽拮抗活性的取代 4-(4-哌啶-4-基-哌嗪-1-基)氮杂环庚烷衍生物，特别是 NK 1 拮抗活性的取代的 4-(4-哌啶-4-基-哌嗪-1-基)-氮杂环庚烷衍生物、它们的制备方法、包含它们的组合物以及它们作为药物的用途，特别是用于治疗疼痛、呕吐、焦虑、抑郁和肠易激综合征。 根据本发明的化合物可以由通式 (I) 表示 还包括其药学上可接受的酸或碱加成盐、其立体化学异构体形式、其 N-氧化物形式和其原药，其中所有取代基的定义如权利要求 1. 鉴于它们能够通过阻断神经激肽受体来拮抗速激肽的作用，特别是通过阻断 NK 1 、NK 2 和 NK 3 受体，根据本发明的化合物可用作药物，特别是用于预防和治疗速激肽介导的疾病，例如中枢神经系统疾病，尤其是精神分裂症、抑郁症、焦虑症、应激相关疾病、睡眠障碍、认知障碍、人格障碍、进食障碍、神经退行性疾病、成瘾性疾病、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呃逆；胃肠道疾病，特别是肠易激综合征（IBS）；皮肤疾病；血管痉挛性疾病；纤维化和胶原疾病；与免疫增强或抑制有关的疾病以及风湿性疾病和体重控制。
• Substituted 1-piperidin-4-yl-4-azetidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
  申请人：Janssens Eduard Frans

  公开号：US20060074069A1

  公开（公告）日：2006-04-06

  The invention concerns substituted 1-piperidin-4-yl-4-azetidin-3-yl-piperazine having neurokinin antagonistic activity, in particular NK 1 and NK 1 /NK 3 -antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, emesis, anxiety, depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P by blocking the NK receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, schizoaffective disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

  本发明涉及具有神经激肽拮抗活性的取代的 1-哌啶-4-基-4-氮杂环丁-3-基哌嗪，特别是 NK 1 和 NK 1 /NK 3 -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，特别是用于治疗精神分裂症、呕吐、焦虑、抑郁、肠易激综合征（IBS）、昼夜节律紊乱、疼痛、神经源性炎症、哮喘、排尿障碍（如尿失禁）和痛觉。根据本发明的化合物可以由通式 (I) 表示 还包括其药学上可接受的酸或碱加成盐、其立体化学异构体形式、其 N-氧化物形式及其原药，其中所有取代基的定义如权利要求 1. 鉴于本发明的化合物能够通过阻断神经激肽受体来拮抗速激肽的作用，特别是通过阻断 NK 受体来拮抗 P 物质的作用，因此本发明的化合物可用作药物，特别是用于预防和治疗速激肽介导的疾病、例如，中枢神经系统疾病，尤其是抑郁症、焦虑症、压力相关疾病、睡眠障碍、认知障碍、人格障碍、精神分裂症、进食障碍、神经退行性疾病、成瘾症、情绪障碍、性功能障碍、疼痛和其他中枢神经系统相关疾病；炎症；过敏性疾病；呕吐；胃肠道疾病，特别是肠易激综合征（IBS）；皮肤疾病；血管痉挛性疾病；纤维化和胶原疾病；与免疫增强或抑制有关的疾病以及风湿性疾病和体重控制。