YM-58790 (free base)

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: YM-58790 (free base)
• 英文别名: [1-[[4-(methylamino)phenyl]methyl]piperidin-4-yl] N-benzhydrylcarbamate
• 化学式: C₂₇H₃₁N₃O₂
• 分子量: 429.562
• InChiKey: YLHJUSKJLHTVJY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  53.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  tert-butyl N-p-tolyl-N-methylcarbamate 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 四氯化碳 、 乙醇 、 乙腈 为溶剂， 反应 37.0h， 生成 YM-58790 (free base)
  参考文献：
  名称：

  Selective Muscarinic Antagonists. I. Synthesis and Antimuscarinic Properties of 4-Piperidyl Benzhydrylcarbamate Derivatives.

  摘要：

  合成了一系列1-取代-4-哌啶基苯二氢基氨基甲酸酯衍生物，并评估了其对M1、M2和M3受体的结合亲和力及抗毒蕈碱活性。受体结合实验表明，1-苄基-4-哌啶基苯二氢基氨基甲酸酯衍生物对M1和M3受体表现出更高的亲和力，且在选择性上对M3优于M2受体，相较于相应的酯类类似物更为显著。这些结果表明，氨基甲酸酯键是毒蕈碱拮抗剂的一种新型连接基团，能够锁定分子构象，使分子的疏水部分和阳离子位点与M1和M3毒蕈碱受体结合。在所制备的化合物中，1-(4-甲基氨基苄基)-4-哌啶基苯二氢基氨基甲酸酯单盐酸盐（18b, YM-58790）在反射引发的节律性收缩中对膀胱压力表现出强抑制活性，与氧布氟对应，并且在大鼠对氧酸震颤素引起的唾液分泌抑制作用上大约比氧布氟低十倍。进一步对大鼠的心动过缓和升压反应以及小鼠震颤的抗毒蕈碱效应评估表明，YM-58790作为膀胱选择性M3拮抗剂，可以用于尿迫性失禁的治疗，且副作用较少。

  DOI：

  10.1248/cpb.46.1274

文献信息

• [EN] 3,4,6,7-TETRAHYDRO-1 H-PYRROLO[3,4-D]PYRIMIDINE-2,5-DIONES AND THEIR THERAPEUTIC USE<br/>[FR] 3,4,6,7-TÉTRAHYDRO-1H-PYRROLO[3,4-D]PYRIMIDINE-2,5-DIONES ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：ARGENTA DISCOVERY LTD

  公开号：WO2009060203A1

  公开（公告）日：2009-05-14

  A compound of formula (IA) or (IB): wherein A is aryl or heteroaryl; D is oxygen or sulphur; R1, R2, R3 and R5 are independently each hydrogen, halogen, nitro, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, hydroxy or C1-C6-alkoxy or C2-C6- alkenyloxy,, wherein C1-C6-alkyl and C1-C6-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4-alkoxy; R4 is hydrogen CrC6-alkyl, formyl, aminocarbonyl, mono- or di-C1-C4- alkylaminocarbonyl, C3-C8-cycloalkylcarbonyl, C1-C6-alkylcarbonyl, C1-C6- alkoxycarbonyl, N-(C1-C4-alkylsulfonyl)-aminocarbonyl, N-(C1-C4-alkylsulfonyl)-N-(C1-C4-alkyl)-aminocarbonyl, heteroaryl, heterocycloalkyl, heteroarylcarbonyl or heterocycloalkylcarbonyl; wherein C1-C6-alkyl, mono- and di-C1-C4- alkylaminocarbonyl, C1-C6-alkylcarbonyl, C1-C2-alkoxycarbonyl, heteroaryl and heterocycloalkyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxyl, C1-C4-alkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, aminocarbonyl, mono and di-C1-C4- alkylaminocarbonyl, amino, mono- and di-C1-C4-alkylamino, C1-C4- alkylcarbonylamino, cyano, N-(mono- and di-Ci-C4-alkylamino-d-C4-alkyl)- aminocarbonyl, N-(C1-C4-alkoxy-C1-C4-alkyl)-aminocarbonyl or halogen; -[Linker]- is a divalent linker radical; and M is a moiety having M3 receptor antagonist activity.

  式（IA）或（IB）的化合物：其中A是芳基或杂环芳基；D是氧或硫；R1、R2、R3和R5分别独立地是氢、卤素、硝基、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、羟基或C1-C6-烷氧基或C2-C6-烯氧基，其中C1-C6-烷基和C1-C6-烷氧基可以进一步被选择自卤素、羟基和C1-C4-烷氧基的相同或不同基团取代；R4是氢、CrC6-烷基、甲酰基、氨基甲酰基、单或双C1-C4-烷基氨基甲酰基、C3-C8-环烷基甲酰基、C1-C6-烷基甲酰基、C1-C6-烷氧基甲酰基、N-(C1-C4-烷基磺酰基)-氨基甲酰基、N-(C1-C4-烷基磺酰基)-N-(C1-C4-烷基)-氨基甲酰基、杂环芳基、杂环烷基、杂环芳基甲酰基或杂环烷基甲酰基；其中C1-C6-烷基、单和双C1-C4-烷基氨基甲酰基、C1-C6-烷基甲酰基、C1-C2-烷氧基甲酰基、杂环芳基和杂环烷基可以被选择自芳基、杂环芳基、羟基、C1-C4-烷氧基、羟基甲酰基、C1-C6-烷氧基甲酰基、氨基甲酰基、单和双C1-C4-烷基氨基甲酰基、氨基、单和双C1-C4-烷基胺基、C1-C4-烷基甲酰胺基、氰基、N-(单和双C1-C4-烷基胺基-d-C4-烷基)-氨基甲酰基、N-(C1-C4-烷氧基-C1-C4-烷基)-氨基甲酰基或卤素的相同或不同基团取代；-[连接物]-是二价连接物基团；M是具有M3受体拮抗活性的基团。
• Pharmaceutical composition comprising beta-3-adrenoceptor-agonists and antimuscarinic agents
  申请人：Wienrich Marion

  公开号：US20050261328A1

  公开（公告）日：2005-11-24

  A pharmaceutical composition useful in the treatment of functional bladder disorders comprising an antimuscarinic agent and a beta-3-adrenoceptor agonist is described.
• Use of a beta-3-agonist for the treatment of patients with spinal cord injury and suffering from renal and bladder complaints
  申请人：Michel C. Martin

  公开号：US20070078181A1

  公开（公告）日：2007-04-05

  This invention relates to the use of beta-3-adrenoceptor agonists for the prevention and treatment of kidney damage and/or functional bladder complaints, particularly bladder complaints of neurogenic origin as the result of spinal cord injury.
• Selective Muscarinic Antagonists. I. Synthesis and Antimuscarinic Properties of 4-Piperidyl Benzhydrylcarbamate Derivatives.
  作者：Ryo NAITO、Makoto TAKEUCHI、Koichiro MORIHIRA、Masahiko HAYAKAWA、Ken IKEDA、Tadao SHIBANUMA、Yasuo ISOMURA

  DOI：10.1248/cpb.46.1274

  日期：——

  A series of 1-substituetd-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M1, M2 and M3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M1 and M3 receptors, and good selectivities for M3 over M2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M1 and M3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrate that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M3 antagonist with fewer side effects.

  合成了一系列1-取代-4-哌啶基苯二氢基氨基甲酸酯衍生物，并评估了其对M1、M2和M3受体的结合亲和力及抗毒蕈碱活性。受体结合实验表明，1-苄基-4-哌啶基苯二氢基氨基甲酸酯衍生物对M1和M3受体表现出更高的亲和力，且在选择性上对M3优于M2受体，相较于相应的酯类类似物更为显著。这些结果表明，氨基甲酸酯键是毒蕈碱拮抗剂的一种新型连接基团，能够锁定分子构象，使分子的疏水部分和阳离子位点与M1和M3毒蕈碱受体结合。在所制备的化合物中，1-(4-甲基氨基苄基)-4-哌啶基苯二氢基氨基甲酸酯单盐酸盐（18b, YM-58790）在反射引发的节律性收缩中对膀胱压力表现出强抑制活性，与氧布氟对应，并且在大鼠对氧酸震颤素引起的唾液分泌抑制作用上大约比氧布氟低十倍。进一步对大鼠的心动过缓和升压反应以及小鼠震颤的抗毒蕈碱效应评估表明，YM-58790作为膀胱选择性M3拮抗剂，可以用于尿迫性失禁的治疗，且副作用较少。