tert-butyl N-[(3S)-1-(9-bicyclo[3.3.1]nonanyl)pyrrolidin-3-yl]carbamate | 169451-74-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: tert-butyl N-[(3S)-1-(9-bicyclo[3.3.1]nonanyl)pyrrolidin-3-yl]carbamate
• CAS: 169451-74-5
• 化学式: C₁₈H₃₂N₂O₂
• 分子量: 308.464
• InChiKey: XWHYJOJVYWVNEY-UFFJXHMVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(3S)-1-(9-bicyclo[3.3.1]nonanyl)pyrrolidin-3-yl]carbamate 在 盐酸 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 2.0h， 生成 N-((S)-1-Bicyclo[3.3.1]non-9-yl-pyrrolidin-3-yl)-5-chloro-4-(cyclopropanecarbonyl-amino)-2-methoxy-benzamide
  参考文献：
  名称：

  多巴胺D3和D4受体拮抗剂：（S）-（+）-N-（1-苄基-3-吡咯烷基）-5-氯-4-[（环丙基羰基）氨基] -2-的合成与结构-活性关系甲氧基苯甲酰胺（YM-43611）和相关化合物。

  摘要：

  在这项研究中，我们合成了一系列（S）-N-（3-吡咯烷基）苯甲酰胺衍生物1、2a-d，5a-1和7及其对映体（R）-1和（R）- 5c-e，并评估了它们对克隆的多巴胺D2，D3和D4受体的结合亲和力以及它们对阿扑吗啡诱导的小鼠爬山行为的抑制活性。结果表明，D2，D3和D4受体对苯甲酰胺核上4-氨基（R1）的取代基具有不同的体积容忍度（D4> D3> D2），并且可能的是环丙基，环丁基和环戊基羰基在这个系列中，相对于D2受体，D3和D4的亲和力和选择性具有足够的体积。结果还表明，吡咯烷-3-基上的N-取代基（R2）在表达对D2，D3，D4受体和各亚型之间的选择性。化合物之一，（S）-（+）-N-（1-苄基-3-吡咯烷基）-5-氯-4-[（环丙基羰基+ ++）氨基] -2-甲氧基苯甲酰胺（5c）（YM-43611 ）对D3和D4受体表现出高亲和力（Ki值分别为21和2.1 nM），D4选择性比

  DOI：

  10.1021/jm9601720
• 作为产物：
  描述：

  双环(3.3.1)壬基-9-酮 、 (S)-(-)-1-苄基-3-(叔丁氧羰基氨基)吡咯烷 在 5percent Pd/C 氢气 作用下， 以 甲醇 为溶剂， 反应 12.0h， 生成 tert-butyl N-[(3S)-1-(9-bicyclo[3.3.1]nonanyl)pyrrolidin-3-yl]carbamate
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Naphthamides as Dopamine D₃ Receptor Ligands

  摘要：

  A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D-2 and D-3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19 -25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo-[3.3.1]nonan-3 beta -yl)-4- bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D-2 and D-3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D-3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D-2 and D-3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at Ds receptors, or (c) decrease the affinity at D-2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K-i) values of 1.8 and 0.2 nM for D-2 and D-3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K-i values of 62.8 and 2.4 nM for D-2 and D-3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(l-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma (1) and sigma (2) sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3 beta -yl central ring were found to be selective for sigma (2) receptors.

  DOI：

  10.1021/jm0100077

文献信息

• N-(3-PYRROLIDINYL)BENZAMIDE DERIVATIVE
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP0757985A1

  公开（公告）日：1997-02-12

  N-(3-Pyrrodinyl)benzamide derivatives represented by the following general formula (I) which have potent and selective antagonism against dopamine D3 and/or D4 receptor and are useful as a psychotropic, a schizophrenia-treating agent and the like, or a pharmaceutically acceptable salt thereof or a pharmaceutical preparation thereof. (wherein each symbol in the formula has the following meaning, R1: hydrogen, lower alkyl, aralkyl, or cycloalkyl or cycloalkyl-lower alkyl having 3 to 8 ring atoms, R2: bicyclic or tricyclic bridged hydrocarbon ring of 4 to 16 ring atoms which may have lower alkyl, R3: lower alkoxy, amino or mono- or di-lower alkylamino, R4: hydrogen, halogen, lower alkyl which may have hydroxyl, lower alkoxy, cyano, nitro, amino, mono- or di-lower alkylamino, acyl or a group represented by -S(O)m-R5, R5: lower alkyl, amino or mono- or di-lower alkylamino, m: 0, 1 or 2, X: a bond or a group represented by -O-, -S(O)n-, -NH- or -CONH-, and n: 0, 1 or 2, with the proviso that, when R1 is cycloalky, the cases wherein X is -CONH-, R3 is lower alkoxy and R4 is halogen are excluded.)

  N-(3-吡咯烷基)苯甲酰胺衍生物，由以下通式(I)代表，对多巴胺 D3 和/或 D4 受体具有强效和选择性拮抗作用，可用作精神药物、精神分裂症治疗剂等，或其药学上可接受的盐或其药物制剂。 (式中各符号含义如下、 R1：氢、低级烷基、芳烷基、环烷基或具有 3 至 8 个环原子的环烷基-低级烷基、 R2：具有 4 至 16 个环原子的双环或三环桥式烃环，其中可能有低级烷基、 R3：低级烷氧基、氨基或单或双低级烷基氨基、 R4：氢、卤素、可能具有羟基的低级烷基、低级烷氧基、氰基、硝基、氨基、单或双低级烷基氨基、酰基或由 -S(O)m-R5 所代表的基团、 R5：低级烷基、氨基或单或双低级烷基氨基、 m：0、1 或 2、 X：键或由-O-、-S(O)n-、-NH-或-CONH-代表的基团，以及 n:0、1 或 2、 但当 R1 为环烷基时，不包括 X 为-CONH-、R3 为低级烷氧基和 R4 为卤素的情况）。
• Synthesis and Structure−Activity Relationships of Naphthamides as Dopamine D₃ Receptor Ligands
  作者：Yunsheng Huang、Robert R. Luedtke、Rebekah A. Freeman、Li Wu、Robert H. Mach

  DOI：10.1021/jm0100077

  日期：2001.5.1

  A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D-2 and D-3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19 -25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo-[3.3.1]nonan-3 beta -yl)-4- bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D-2 and D-3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D-3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D-2 and D-3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at Ds receptors, or (c) decrease the affinity at D-2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K-i) values of 1.8 and 0.2 nM for D-2 and D-3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K-i values of 62.8 and 2.4 nM for D-2 and D-3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(l-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma (1) and sigma (2) sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3 beta -yl central ring were found to be selective for sigma (2) receptors.
• Dopamine D₃ and D₄ Receptor Antagonists:  Synthesis and Structure−Activity Relationships of (<i>S</i>)-(+)-<i>N</i>-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl)amino]-2-methoxybenzamide (YM-43611) and Related Compounds
  作者：Junya Ohmori、Kyoichi Maeno、Kazuyuki Hidaka、Kazuhiro Nakato、Mitsuyuki Matsumoto、Shoko Tada、Hanae Hattori、Shuichi Sakamoto、Shin-ichi Tsukamoto、Shinji Usuda、Toshiyasu Mase

  DOI：10.1021/jm9601720

  日期：1996.1.1

  (R1) on the benzamide nuclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl groups likely possess adequate bulkiness with respect to D3 and D4 affinity and selectivity over D2 receptors in this series. The results also suggested that the N-substituent (R2) on the pyrrolidin-3-yl group performs an important role in expressing affinity for D2, D3, and D4 receptors and selectivity among the

  在这项研究中，我们合成了一系列（S）-N-（3-吡咯烷基）苯甲酰胺衍生物1、2a-d，5a-1和7及其对映体（R）-1和（R）- 5c-e，并评估了它们对克隆的多巴胺D2，D3和D4受体的结合亲和力以及它们对阿扑吗啡诱导的小鼠爬山行为的抑制活性。结果表明，D2，D3和D4受体对苯甲酰胺核上4-氨基（R1）的取代基具有不同的体积容忍度（D4> D3> D2），并且可能的是环丙基，环丁基和环戊基羰基在这个系列中，相对于D2受体，D3和D4的亲和力和选择性具有足够的体积。结果还表明，吡咯烷-3-基上的N-取代基（R2）在表达对D2，D3，D4受体和各亚型之间的选择性。化合物之一，（S）-（+）-N-（1-苄基-3-吡咯烷基）-5-氯-4-[（环丙基羰基+ ++）氨基] -2-甲氧基苯甲酰胺（5c）（YM-43611 ）对D3和D4受体表现出高亲和力（Ki值分别为21和2.1 nM），D4选择性比