(+/-)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone | 190964-86-4

• 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-piperidinone
• 英文别名: (35)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone；((+/-)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmetlryl)-4-piperidinone)；(+/-)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone；2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperidin-4-one
• CAS: 190964-86-4
• 化学式: C₂₁H₁₇F₆NO₂
• 分子量: 429.362
• InChiKey: IUCFHIJVTHFYJE-UHFFFAOYSA-N

物化性质

• 沸点：
  479.3±45.0 °C(Predicted)
• 密度：
  1.357±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (+/-)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone 在 palladium 10% on activated carbon 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 (+)-(2R-trans)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine
  参考文献：
  名称：

  [EN] SUBSTITUTED 1-PIPERIDIN-4-YL-4-AZETIDIN-3-YL-PIPERAZINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS
  [FR] DERIVES SUBSTITUES DE 1-PIPERIDINE-4-YL-4-AZETIDINE-3-YL-PIPERAZINE ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DE LA NEUROKININE

  摘要：

  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。

  公开号：

  WO2004056800A1
• 作为产物：
  描述：

  4,4-(乙烯二氧基)-1-叔丁氧羰基哌啶 在 四甲基乙二胺 、 5%-palladium/activated carbon 、 potassium tert-butylate 、 氢气 、 仲丁基锂 、 sodium methylate 、 三乙胺 作用下， 以 甲醇 、 乙醚 、 异丙醇 、 甲苯 为溶剂， 反应 18.0h， 生成 (+/-)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone
  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 4-ALKYL- AND 4-ALKANOYL-PIPERIDINE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES DE 4-ALKYL- ET 4-ALKANOYL-PIPERIDINE SUBSTITUES ET UTILISATION DE CEUX-CI COMME ANTAGONISTES DES NEUROKININES
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005097774A1

  公开（公告）日：2005-10-20

  The invention concerns substituted 4-alkyl- and 4-alkanoyl-piperidine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity and a combined NK1/NK3 antagonistic activity, 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.

  该发明涉及具有神经激肽拮抗活性的取代的4-烷基和4-烷酰基哌啶衍生物，特别是NK1拮抗活性和联合NK1/NK3拮抗活性，包含它们的组合物以及它们作为药物的用途，特别是用于治疗和/或预防精神分裂症、恶心、焦虑和抑郁症、肠易激综合征（IBS）、昼夜节律紊乱、子痫前期、疼痛感知、疼痛，特别是内脏和神经病理性疼痛、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。根据该发明的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性或碱性加盐物，其立体化学异构体形式，其N-氧化物形式和其前药，其中所有取代基的定义如权利要求1中所述。
• 1-(1,2-disubstituted pipeidinyl)-4-substituted piperidine derivatives
  申请人：Janssen Pharmaceutica N.V.

  公开号：US06346540B1

  公开（公告）日：2002-02-12

  The present invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 0, 1 or 2; ═Q is ═O or ═NR3; X is a covalent bond or a bivalent radical of formula —O—, —S—, —NR3—; R1 is Ar1; Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent of formula —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—; R2 is Ar2; Ar2C1-6alkyl; Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; R4 is hydrogen; C1-4alkyl; C1-4alkyloxyC1-4alkyl; hydroxyC1-4alkyl; carboxyl; C1-4alkyloxycarbonyl or Ar3; R5 is hydrogen; hydroxy; Ar3; Ar3C1-6alkyloxy; di(Ar3)C1-6alkyloxy; Ar3C1-6alkylthio; di(Ar3)C1-6alkylthio; Ar3C1-6alkylsulfoxy; di(Ar3)C1-6alkylsulfoxy; Ar3C1-6alkylsulfonyl; di(Ar3)C1-6alkylsulfonyl; —NR7R8; C1-6alkyl substituted with —NR7R8; or a radical of formula (a-1) or (a-2); R4 and R5 may also be taken together; R6 is hydroxy; C1-6alkyloxy; C1-6alkyl or Ar3C1-6alkyl; Ar1, Ar2 and Ar3 are phenyl or substituted phenyl; Ar2 is also naphtalenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; as substance P antagonists; their preparation, compositions containing them and their use as a medicine.

  本发明涉及以下式的化合物 其中n为0、1或2；m为1或2，但如果m为2，则n为1；p为0、1或2；═Q为═O或═NR3；X为配位键或式的二价基团—O—、—S—、—NR3—；R1为Ar1；Ar1C1-6烷基或二(Ar1)C1-6烷基，其中每个C1-6烷基基团可选择地用羟基、C1-4烷氧基、氧代基或式的缩醛基团取代—O—CH2—CH2—O—或—O—CH2—CH2—CH2—O—；R2为Ar2；Ar2C1-6烷基；Het或HetC1-6烷基；R3为氢或C1-6烷基；R4为氢；C1-4烷基；C1-4烷氧基C1-4烷基；羟基C1-4烷基；羧基；C1-4烷氧羰基或Ar3；R5为氢；羟基；Ar3；Ar3C1-6烷氧基；二(Ar3)C1-6烷氧基；Ar3C1-6烷硫基；二(Ar3)C1-6烷硫基；Ar3C1-6烷磺氧基；二(Ar3)C1-6烷磺氧基；Ar3C1-6烷磺基；二(Ar3)C1-6烷磺基；—NR7R8；用—NR7R8取代的C1-6烷基；或式的基团(a-1)或(a-2)；R4和R5也可结合在一起；R6为羟基；C1-6烷氧基；C1-6烷基或Ar3C1-6烷基；Ar1、Ar2和Ar3为苯基或取代苯基；Ar2也为萘基；Het为可选择地取代的单环或双环杂环；作为P物质拮抗剂；它们的制备、含有它们的组合物以及它们作为药物的用途。
• [EN] SUBSTITUTED DIAZA-SPIRO-[4.5]-DECANE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES DE DIAZA-SPIRO-[4.5]-DECANE SUBSTITUES, LEUR UTILISATION COMME ANTAGONISTES VIS-A-VIS DE LA NEUROKININE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005097794A1

  公开（公告）日：2005-10-20

  This invention concerns substituted diaza-spiro-[4.5]-decane derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK2 antagonist ic activity, a combined NK1/NK3 antagonist ic 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.

  这项发明涉及具有神经激肽拮抗活性的替代二氮杂螺[4.5]癸烷衍生物，特别是NK1拮抗活性，具有联合NK1/NK2拮抗活性、联合NK1/NK3拮抗活性和联合NK1/NK2/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，特别是用于治疗和/或预防精神分裂症、恶心、焦虑和抑郁症、肠易激综合征（IBS）、昼夜节律紊乱、子痫前期、疼痛感知、疼痛，特别是内脏和神经痛、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用一般式（I）表示，并包括其药学上可接受的酸盐或碱盐加合物、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中所述。
• [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 DIAZA-SPIRO-[5.5]-UNDECANE DERIVATIVES AND THEIR USE AS NEUROKININ ANTAGONISTS<br/>[FR] DERIVES DE DIAZA-SPIRO-[5.5]-UNDECANE SUBSTITUES ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DE LA NEUROKININE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005097795A1

  公开（公告）日：2005-10-20

  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) (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.

  本发明涉及替代的二氮杂螺[5.5]十一烷衍生物，具有神经激肽拮抗活性，特别是NK1拮抗活性、NK1/NK2联合拮抗活性、NK1/NK3联合拮抗活性和NK1/NK2/NK3联合拮抗活性，它们的制备、包含它们的组合物和它们作为药物的用途，特别是用于治疗和/或预防精神分裂症、恶心、焦虑和抑郁症、肠易激综合征（IBS）、昼夜节律紊乱、妊娠高血压、疼痛感知、疼痛，特别是内脏和神经病性疼痛、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用一般式（I）（I）表示，并且还包括其药用可接受的酸盐或碱盐加合物、立体化异构体形式、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中所定义。