(2R,1‘R,3’R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium | 937179-74-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2R,1‘R,3’R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium
• 英文别名: 1'(R),3'(R)-[2(S)-cyclopentyl-2-phenyl-2-hydroxyacetoxy]-1'-methyl-1'-carboxymethylpyrrolidinium inner salt；(2R,1'R,3'R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium inner salt；2-[(1R,3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl]oxy-1-methylpyrrolidin-1-ium-1-yl]acetate
• CAS: 937179-74-3
• 化学式: C₂₀H₂₇NO₅
• 分子量: 361.438
• InChiKey: KTCKPDPJTAUEPP-JRGCBEDISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  86.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (2R,3’R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium 生成 (2R,1‘R,3’R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium 、 (2R,1’S,3’R) 3-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1-(carboxymethyl)-1-methylpyrrolidinium
  参考文献：
  名称：

  Soft anticholinergic esters

  摘要：

  以下是化学式： 其中，R1和R2都是苯基或R1和R2中的一个是苯基，另一个是环戊基；R是C1-C8烷基，直链或支链；X-是带有单负电荷的阴离子；每个星号标记一个手性中心。该化合物在每个手性中心上具有R、S或RS立体异构体构型，除非另有规定，或者是它们的混合物。

  公开号：

  US20070123557A1

文献信息

• Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate – syntheses and pharmacological evaluations
  作者：Wu、Wu、Mori、Buchwald、Bodor, Nicholas

  DOI：10.1691/ph.2008.7775

  日期：——

  Purpose. In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3′-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1′-methyl-1′-alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3′-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1′-methyl-1′-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. Methods. The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans-esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3′S-SGM, 2R3′R-SGM, 2S3′S-SGM, 2S3′R-SGM or 2R3′S-SGE, 2R3′R-SGE, 2S3′S-SGE, 2S3′R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3′R1′R, 2R3′S1′R, 2R3′R1′S, 2R3′S1′S, 2S3′R1′R, 2S3′S1′R, 2S3′R1′S, and 2S3′S1′S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. Results. Receptor binding pKi values at cloned human muscarinic receptors (M1–M4 subtypes) were in the 6.0–9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0–8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1′ (N) chiral center, the 3′R isomers were more active than the corresponding 3′S isomers (1.5–12.9 times), whereas, among the SGa isomers, the 3′S isomers were not always more active than the corresponding 3′R isomers indicating that activity determined based on configuration at chiral center 3′ is significantly affected by the configuration of the other two chiral centers, 2 and 1′. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1′S isomers were always more active than the corresponding 1′R isomers (1.8–22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3–5 times), and 2R and 3′S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3′S1′S ≈ 2R3′R1′S ≈ 2R3′S1′R > 2R3′R1′R > 2S3′R1′S > 2S3′S1′S ≈ 2S3′R1′R > 2S3′S1′R (p < 0.05). Conclusions. The stereospecificity and M3/M2 muscarinic-receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed.

  研究目的在这项研究中，两种基于甘吡咯酸盐的 N-取代软抗胆碱药 SGM（PcPOAGP_NA.Me）和 SGE（PcPOAGP_NA.Et）[3′-（2-环戊基-2-苯基-2-羟基乙酰氧基）-1′-甲基-1′-烷氧羰基吡咯烷鎓溴化物]及其闪氮代谢物 SGa（PcPOAGP_NA.H）[3′-(2-环戊基-2-苯基-2-羟基乙酰氧基)-1′-甲基-1′-羧甲基吡咯烷鎓内盐]的合成及其体外和体内药理活性的评价。方法。用光学纯的环戊基扁桃酸甲酯和 3-羟基-N-甲基吡咯烷合成 SGM 和 SGE 的异构体。用溴乙酸烷基酯进行反酯化，然后进行四分化反应，可得到四种 SGM 或 SGE 的异构体，其中氮手性中心未解决（2R3′S-SGM、2R3′S-SGM、2R3′S-SGM、2R3′S-SGM、2R3′S-SGM）、2R3′R-SGM、2S3′S-SGM、2S3′R-SGM 或 2R3′S-SGE、2R3′R-SGE、2S3′S-SGE、2S3′R-SGE）。将这四种异构体水解后再进行 HPLC 分离，可得到八种完全解析的 SGa 异构体（2R3′R1′R、2R3′S1′R、2R3′R1′S、2R3′S1′S、2S3′R1′R、2S3′S1′R、2S3′R1′S 和 2S3′S1′S）。药理活性通过体外受体结合测定和豚鼠回肠 pA2-测定进行评估，并通过评估体内兔迷走神经作用进行评估。结果与传统的抗胆碱能药物（如甘草酸苷、N-甲基东莨菪碱和托吡卡胺）以及以前制备的外消旋混合物和 2R 异构体的结果进行了比较。研究结果新合成的 SGM 和 SGE 异构体与克隆人毒蕈碱受体（M1-M4 亚型）的受体结合 pKi 值在 6.0-9.5 之间，SGa 异构体在 5.0-8.6 之间。在所有情况下，2R 异构体的活性都明显高于 2S 异构体（SGM 异构体为 27-447 倍，SGa 异构体为 6-4467 倍）。在四种具有未解决的 1′（N）手性中心的 SGM 异构体中，3′R 异构体的活性比相应的 3′S 异构体高（1.5-12.9 倍）。9 倍），而在 SGa 异构体中，3′S 异构体的活性并不总是高于相应的 3′R 异构体，这表明根据手性中心 3′的构型确定的活性受到另外两个手性中心 2 和 1′的构型的显著影响。在完全解析的八种 SGa 异构体（三个手性中心均已解析）中，1′S 异构体的活性始终高于相应的 1′R 异构体（1.8-22.4 倍）。结果还表明，一些异构体具有良好的 M3/M2 毒蕈碱受体亚型选择性（约 3-5 倍），而 2R 和 3′S 是这种特性的决定性构型。对 SGa 异构体进行的豚鼠回肠试验和兔眼球震颤试验进一步证实了其立体特异性。在兔眼中，一些 2R-SGa 异构体显示出与甘珀酸相似的致瞳孔散大效力，并超过了托吡卡胺，但其致瞳孔散大作用持续的时间要短得多，而且不会引起对侧经水处理的眼睛瞳孔散大。这些结果表明，这些化合物具有局部活性，但安全性较高，引起全身副作用的可能性较低。八种 SGa 异构体的药理效力估计为 2R3′S1′S ≈ 2R3′R1′S ≈ 2R3′S1′R > 2R3′R1′R > 2S3′R1′S > 2S3′S1′S ≈ 2S3′R1′R > 2S3′S1′R (p < 0.05)。结论软抗胆碱能药 SGM、SGE 和 SGa 的立体特异性和 M3/M2 毒蕈碱受体亚型选择性已得到证实。与之前的研究结果一致，这些药物的有效和安全使用潜力已得到证实。
• Soft anticholinergic esters
  申请人：Bodor S. Nicholas

  公开号：US20070123557A1

  公开（公告）日：2007-05-31

  Soft anticholinergic esters of the formulas: wherein R 1 and R 2 are both phenyl or one of R 1 and R 2 is phenyl and the other is cyclopentyl; R is C 1 -C 8 alkyl, straight or branched chain; and X − is an anion with a single negative charge; and wherein each asterisk marks a chiral center; said compound having the R, S or RS stereoisomeric configuration at each chiral center unless specified otherwise, or being a mixture thereof.

  以下是化学式： 其中，R1和R2都是苯基或R1和R2中的一个是苯基，另一个是环戊基；R是C1-C8烷基，直链或支链；X-是带有单负电荷的阴离子；每个星号标记一个手性中心。该化合物在每个手性中心上具有R、S或RS立体异构体构型，除非另有规定，或者是它们的混合物。