1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine

• 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: 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine
• 英文别名: (2R-cis)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine；(+/-)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine；[(2R,4R)-2-benzyl-4-(4-benzylpiperazin-1-yl)piperidin-1-yl]-[3,5-bis(trifluoromethyl)phenyl]methanone
• 化学式: C₃₂H₃₃F₆N₃O
• 分子量: 589.624
• InChiKey: WPQYIUBQOZPAHV-FQLXRVMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  42
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  26.8
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 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 、 potassium tert-butylate 、 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 41.83h， 生成 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-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。
• Novel Formulations For Opioid-Based Treatments Of Pain Comprising 1-(1,2-Disubstituted Piperidinyl)-4-Substituted Piperazine Derivatives
  申请人：Janssens Frans Eduard

  公开号：US20080070924A1

  公开（公告）日：2008-03-20

  This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives having neurokinin antagonistic activity, in particular NK 1 antagonistic activity the use of said formulation for the manufacture of a medicament for the prevention and/or treatment of emesis, pain and/or nociception, in particular in acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments and the use of an NK 1 -receptor antagonist for the manufacture of a medicament for the prevention and/or treatment of respiratory depression and tolerance in opioid-based treatments of pain. The pharmaceutical formulations according to the invention comprise NK 1 -antagonists according to the general Formula (I) 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. The pharmaceutical composition according to the invention reduces to a large extent a number of unwanted side-effects associated with opioid analgesics, in particular respiratory depression and tolerance, thereby increasing the total tolerability of said opioids in pain treatment.

  本发明涉及一种新型的阿片类止痛和/或止痛药物治疗的配方，包括阿片类镇痛剂和1-(1,2-二取代哌啶基)-4-取代哌嗪衍生物，具有神经激肽拮抗活性，特别是NK1拮抗活性。所述配方的用途是制造用于预防和/或治疗呕吐、疼痛和/或痛觉的药物，特别是在急性和慢性疼痛治疗中，更特别是在炎症、术后、急诊室、突破性、神经病理性和癌症疼痛治疗中；以及使用NK1受体拮抗剂制造用于预防和/或治疗阿片类止痛药物治疗中的呼吸抑制和耐受性的药物。本发明的制药配方包括一般式(I)的NK1拮抗剂、其药学上可接受的酸或碱盐、其立体化学异构体形式、其N-氧化物形式和其前药，其中所有取代基均如权利要求1所定义。本发明的制药组合物大大减少了与阿片类镇痛剂相关的许多不良副作用，特别是呼吸抑制和耐受性，从而增加了在疼痛治疗中阿片类药物的总耐受性。
• [EN] (2-BENZYL-4-{4-[1-(TETRAHYDROFURAN-3-CARBONYL)-PYRROLIDIN-3-YL]-PIPERAZIN-1-YL}-PIPERIDIN-1-YL)-(3,5-TRIFLUOROMETHYL-PHENYL))-METHANONE FOR THE TREATMENT OF SCHIZOPHRENIA<br/>[FR] (2-BENZYLE-4-{4-[1-(TETRAHYDROFURANE-3-CARBONYLE)-PYRROLIDINE-3-YLE]-PIPERAZINE-1-YLE}-PIPERIDINE-1-YLE)-(3,5-TRIFLUOROMETHYLE-PHENYLE))-METHANONE UTILISEE DANS LE TRAITEMENT DE LA SCHIZOPHRENIE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005123081A3

  公开（公告）日：2006-03-16
• 1-(1,2-DISUBSTITUTED PIPERIDINYL)-4-SUBSTITUTED PIPERAZINE DERIVATIVES
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP0862566B1

  公开（公告）日：2000-01-12