methyl (RS)-4-amino-3-(4-chlorophenyl)butanoate hydrochloride

• 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: methyl (RS)-4-amino-3-(4-chlorophenyl)butanoate hydrochloride
• 英文别名: 2-(4-clorophenyl)-3-methoxycarbonylpropylammonium chloride；baclofen methyl ester hydrochloride；[2-(4-Chlorophenyl)-4-methoxy-4-oxobutyl]azanium;chloride
• 化学式: C₁₁H₁₄ClNO₂*ClH
• mdl: MFCD05260655
• 分子量: 264.152
• InChiKey: XLJRVNXVBJCANH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.63
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  52.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl (RS)-4-amino-3-(4-chlorophenyl)butanoate hydrochloride 在 三乙基硼氢化锂 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 6.5h， 生成 (RS)-4--3-(4-chlorophenyl)butanol
  参考文献：
  名称：

  Synthesis and Pharmacology of the Baclofen Homologues 5-Amino-4-(4-chlorophenyl)pentanoic Acid and the R- and S-Enantiomers of 5-Amino-3-(4-chlorophenyl)pentanoic Acid

  摘要：

  (RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acid(B) (GABA(B)) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R,5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12.HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABA(A) or GABA(B) receptor sites and was inactive as an agonist or an antagonist at GABA(B) receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABA(A) receptor sites, and in agreement with the findings far (S)-baclofen, 12 did not interact significantly with GABA(B) receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 mu M), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 mu M) as an inhibitor of GABA(B) binding. Accordingly, 11 (EC50 = 150 +/- 23 mu M) was shown to be weaker than 2 (EC50 = 11 +/- 1 mu M) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABA(B) antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 mu M) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.

  DOI：

  10.1021/jm990076+
• 作为产物：
  描述：

  二甲基[1-(4-氯苯基)-2-硝基乙基]丙二酸酯 生成 methyl (RS)-4-amino-3-(4-chlorophenyl)butanoate hydrochloride
  参考文献：
  名称：

  GRINEVA, V. S.;NOVIKOV, B. M.;TITOVA, E. V.;KOPYLOVA, G. B., METODY SINTEZA, STROENIE I XIM. PREVRASHCHENIYA NITRO-SOED. I AMINOKISLOT+

  摘要：

  DOI：

文献信息

• Synthesis of new 6-(4-chlorophenyl)perhydro-1,3-diazepine-2,4-diones<i>via</i>ureidobutyric acids
  作者：Jean Guillon、Pascal Sonnet、Patrick Dallemagne、Hugues Miel、Sylvain Rault、Martine Daoust、Michel Boulouard

  DOI：10.1002/jhet.5570350308

  日期：1998.5

  Synthesis of new 6-(4-chlorophenyl)perhydro-1,3-diazepine-2,4-diones was accomplished starting from 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen). The chemical pathway involved the cyclisation of various 3-(4-chlorophenyl)-4-ureidobutyric acids. However, none of the new derivatives retained the anticonvulsant activity of their six-membered ring homologues, belonging to the phenylpyrimidinedione

  从4-氨基-3-（4-氯苯基）丁酸（巴氯芬）开始完成新的6-（4-氯苯基）过氢-1,3-二氮杂-2,4-二酮的合成。化学途径涉及各种3-（4-氯苯基）-4-脲基丁酸的环化。然而，没有一种新的衍生物保留其六元环同系物的抗惊厥活性，该六族环同系物属于我们最近描述的苯基嘧啶二酮系列。
• Perhydro-1,3-diazepine-2,4-diones by cyclization of 4-ureidobutyric acids with thionyl chloride: A reinvestigation
  作者：Roland Heckendorn、Tammo Winkler

  DOI：10.1002/jhet.5570370118

  日期：2000.1

  The structures of the previously reported aryl-perhydro-1,3-diazepine-2,4-diones are shown to be pyrro-lidinone carboxamide derivatives by nmr spectroscopy.

  先前报道的芳基-过氢-1,3-二氮杂-2,4-二酮的结构通过核磁共振光谱法显示为吡咯烷酮酮酰胺衍生物。
• Pharmacological Evaluation of New Baclofen Derivatives
  作者：J. Guillon、V. Levasseur、P. Sonnet、S. Stiebing、M. Boulouard、P. Dallemagne、M-A. Quermonne、S. Rault

  DOI：10.1211/146080899128734686

  日期：1999.3.1
• ——
  作者：Christiane Leisen

  DOI：10.1023/a:1023437603555

  日期：——

  Purpose. Distribution to the effect site is a prerequisite for the therapeutic effect and determined by physicochemical properties and affinities to inside- and outside-directed membrane transporters. Based on the hypothesis that lipophilic esters of the GABA-derivative baclofen have a higher affinity to brain tissue, baclofen esters ( methyl, ethyl, 1-propyl, 2-propyl, butyl) were studied regarding their penetration through the blood-brain barrier and their affinities to P-glycoprotein (P-gp).Methods. Octanol-water distribution coefficients ( D) served as lipophilicity parameters. Blood and brain concentrations of baclofen and its methyl ester were determined in vivo in rats following intraperitoneal administration. Affinities to P-gp were evaluated using a radioligand binding assay based on P-gp-overexpressing cells and [H-3]talinolol as radioligand.Results. Log D values for baclofen and ester derivatives were -0.96 (baclofen), 0.48 (methyl), 0.77 (ethyl), 1.31 (1- propyl), 1.27 (2-propyl), and 1.42 (butyl). In-vitro studies yielded negligible affinity of baclofen to P-gp, whereas IC50-values for the esters ranged between 1300 muM (methyl) and 290 muM (2-propyl). Affinity parameters correlated well with the lipophilicity parameters.Conclusions. Despite the P-gp affinity, brain concentrations of methyl ester were significantly higher than those of baclofen, however, baclofen levels following administration of the ester were smaller than with baclofen administration indicating only partial hydrolysis.