tetraethyl 1-(homopiperidino)methylenebis(phosphonate) | 155137-08-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: tetraethyl 1-(homopiperidino)methylenebis(phosphonate)
• 英文别名: 1-[bis(diethoxyphosphoryl)methyl]azepane
• CAS: 155137-08-9
• 化学式: C₁₅H₃₃NO₆P₂
• 分子量: 385.378
• InChiKey: NRZUGURACTYIPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.68
• 重原子数：
  24.0
• 可旋转键数：
  11.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  74.3
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  tetraethyl 1-(homopiperidino)methylenebis(phosphonate) 在 盐酸 作用下， 生成 [(hexahydro-1H-azepin-1-yl)methylene]-1,1-bisphosphonate
  参考文献：
  名称：

  3-D QSAR研究双膦酸盐对利什曼原虫主要法呢基焦磷酸合酶的抑制作用。

  摘要：

  我们报告了作为利什曼原虫主要甲羟戊酸/异戊二烯生物合成途径酶，法呢基焦磷酸合酶的抑制剂的62二膦酸盐的活性。所研究的化合物具有约100 nM至约80 microM（相当于K（i）值低至10 nM）的活性（IC（50）值）。发现活性最高的化合物是唑来膦酸盐（据报道其单晶X射线结构），吡啶基-乙烷-1-羟基-1,1-双膦酸酯或吡啶甲基氨基亚甲基双膦酸酯。但是，N-脂环族氨基亚甲基双膦酸酯（如茚满膦酸酯）（N-环庚基氨基亚甲基双膦酸酯）以及含有短（n = 4、5）烷基链的脂族氨基亚甲基双膦酸酯也具有活性，IC（50）值在200-1700 nM范围内（对应于大约20-170 nM的K（i）值）。含有更长或多个（N，N-）烷基取代基的双膦酸酯是无活性的，环上缺少邻或间氮原子或具有多个卤素取代基或对氨基的芳香族化合物也是如此。为了将这些观察结果放在更定量的结构基础上，我们使用了三维定量结构-活性关系技

  DOI：

  10.1021/jm0302344
• 作为产物：
  描述：

  环己亚胺 、 原甲酸三乙酯 、 亚磷酸二乙酯 生成 tetraethyl 1-(homopiperidino)methylenebis(phosphonate)
  参考文献：
  名称：

  3-D QSAR研究双膦酸盐对利什曼原虫主要法呢基焦磷酸合酶的抑制作用。

  摘要：

  我们报告了作为利什曼原虫主要甲羟戊酸/异戊二烯生物合成途径酶，法呢基焦磷酸合酶的抑制剂的62二膦酸盐的活性。所研究的化合物具有约100 nM至约80 microM（相当于K（i）值低至10 nM）的活性（IC（50）值）。发现活性最高的化合物是唑来膦酸盐（据报道其单晶X射线结构），吡啶基-乙烷-1-羟基-1,1-双膦酸酯或吡啶甲基氨基亚甲基双膦酸酯。但是，N-脂环族氨基亚甲基双膦酸酯（如茚满膦酸酯）（N-环庚基氨基亚甲基双膦酸酯）以及含有短（n = 4、5）烷基链的脂族氨基亚甲基双膦酸酯也具有活性，IC（50）值在200-1700 nM范围内（对应于大约20-170 nM的K（i）值）。含有更长或多个（N，N-）烷基取代基的双膦酸酯是无活性的，环上缺少邻或间氮原子或具有多个卤素取代基或对氨基的芳香族化合物也是如此。为了将这些观察结果放在更定量的结构基础上，我们使用了三维定量结构-活性关系技

  DOI：

  10.1021/jm0302344

文献信息

• Synthesis and Evaluation of (Piperidinomethylene)bis(phosphonic acid) Derivatives as Anti-osteoporosis Agents.
  作者：Mitsuo MIMURA、Mitsuo HAYASHIDA、Kiyoshi NOMIYAMA、Satoru IKEGAMI、Yasuhito IIDA、Makoto TAMURA、Yoshiyuki HIYAMA、Yoshitaka OHISHI

  DOI：10.1248/cpb.41.1971

  日期：——

  Some (piperidinomethylene)bis(phosphonic acid) derivatives were prepared and their activity to inhibit a rise in serum calcium induced by parathyroid hormone in thyroparathyroidectomised rats was evaluated. Several (4-alkylidene-, 4,4-dialkyl-, or 4-alkyl-4-halopiperidinomethylene)bis(phosphonic acid) derivatives showed considerable inhibitory activity. But compounds having aromatic and polar substituents

  制备了一些（哌啶子基亚甲基）双（膦酸）衍生物，并评估了它们抑制甲状旁腺切除的大鼠的甲状旁腺激素诱导的血清钙升高的活性。几种（4-亚烷基-，4,4-二烷基-或4-烷基-4-卤代哌啶亚基）双（膦酸）衍生物表现出相当大的抑制活性。但是在哌啶环上具有芳族和极性取代基如叠氮基，羟基，氨基和酰胺基的化合物通常是无活性的。在这项研究中，两种4-亚烷基化合物（8a和8b）和4,4-环二烷基化合物（61）在静脉内或经口给药时均显示出强大的活性。
• Effects of Bisphosphonates on the Growth of <i>Entamoeba histolytica</i> and <i>Plasmodium </i>Species in Vitro and in Vivo
  作者：Subhash Ghosh、Julian M. W. Chan、Christopher R. Lea、Gary A. Meints、Jared C. Lewis、Zev S. Tovian、Ryan M. Flessner、Timothy C. Loftus、Iris Bruchhaus、Howard Kendrick、Simon L. Croft、Robert G. Kemp、Seiki Kobayashi、Tomoyoshi Nozaki、Eric Oldfield

  DOI：10.1021/jm030084x

  日期：2004.1.1

  The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC50 < 200 muM) versus E. histolytica growth in vitro. The most active compounds (IC50 similar to 4-9 muM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC50 similar to 10-20 muM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pK(a) values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC50 values <200 muM in an in vitro assay. The most active compounds were also simple n-alkyl-1-hydroxy-1,1-bisphosphonates, having IC50 values around 1 muM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
• Tailoring the Structure of Aminobisphosphonates To Target Plant P5C Reductase
  作者：Giuseppe Forlani、Andrea Occhipinti、Łukasz Berlicki、Gabriela Dziedzioła、Anna Wieczorek、Paweł Kafarski

  DOI：10.1021/jf800029t

  日期：2008.5.1

  Using the structure of (3,5-dichlorophenyl)aminomethylenebisphosphonic acid as a lead compound, 25 new phosphonates were synthesized and evaluated as possible inhibitors of Arabidopsis thaliana delta(1)-pyrroline-5-carboxylate (P5C) reductase. Derivatives substituted in the phenyl ring retained the inhibitory potential, though to a different extent. On the contrary any variation in the scaffold, i.e., the replacement of the second phosphonate moiety with a hydroxyl or an amino residue, resulted in a significant loss of biological activity. The availability of several structures capable of interfering with the catalytic mechanism in the micromolar to millimolar range allowed a proper structure-activity relationship analysis, leading us to hypothesize about the steric and electronic requirements for maintenance or enhancement of the inhibitory properties. Reversal experiments with suspension cultured cells provided evidence for the occurrence of enzyme inhibition in vivo. Because in higher plants the step catalyzed by P5C reductase is shared by all pathways leading to proline synthesis, these compounds may be exploited for the design of new substances endowed with herbicidal activity.