tetraethyl (cyclohexylaminomethylene)bisphosphonate | 124351-93-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: tetraethyl (cyclohexylaminomethylene)bisphosphonate
• 英文别名: tetraethyl (cyclohexylamino)methyl-1,1-bisphosphonate；N-[bis(diethoxyphosphoryl)methyl]cyclohexanamine
• CAS: 124351-93-5
• 化学式: C₁₅H₃₃NO₆P₂
• 分子量: 385.378
• InChiKey: DNEHFYCUOVWICM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  24
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  83.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tetraethyl (cyclohexylaminomethylene)bisphosphonate 在 盐酸 作用下， 反应 2.5h， 以45%的产率得到N-cyclohexylaminomethanediphosphonate
  参考文献：
  名称：

  新型骨吸收抑制剂的研究。I.氨基亚甲基双膦酸酯衍生物的合成和药理活性。

  摘要：

  合成了一系列氨基亚甲基双膦酸酯衍生物，并使用甲状旁腺激素（PTH）诱导的大鼠高钙血症模型（PIH模型）评估了其抗吸收活性。在这些化合物中，最终选择了（环庚基氨基）亚甲基双（膦酸）（3j）进行进一步研究，在PIH模型和固定化大鼠骨萎缩模型（DA模型）中证明其效力是帕米膦酸盐的10倍。讨论了该系列双膦酸酯的结构-活性关系。

  DOI：

  10.1248/cpb.41.688
• 作为产物：
  描述：

  异氰环已烷 、 亚磷酸三乙酯 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 tetraethyl (cyclohexylaminomethylene)bisphosphonate
  参考文献：
  名称：

  通过异腈与亚磷酸三烷基酯和氯化氢的反应制备N-取代的氨基亚甲基双膦酸酯及其四烷基酯。第1部分

  摘要：

  在氯化氢存在下，异腈与亚磷酸三烷基酯的反应通过N-亚甲基亚铵盐（亚硝鎓）得到四烷基N-取代的氨基亚甲基双膦酸酯。这些四烷基酯的水解或脱烷基化以高收率得到N-取代的氨基亚甲基双膦酸。

  DOI：

  10.1016/j.tetlet.2012.07.085

文献信息

• Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation
  作者：Erika Bálint、Ádám Tajti、Anna Dzielak、Gerhard Hägele、György Keglevich

  DOI：10.3762/bjoc.12.146

  日期：——

  practical method was elaborated for the synthesis of (aminomethylene)bisphosphine oxides comprising the catalyst- and solvent-free microwave-assisted three-component condensation of primary amines, triethyl orthoformate and two equivalents of diphenylphosphine oxide. The method is also suitable for the preparation of (aminomethylene)bisphosphonates using (MeO)2P(O)H/(MeO)3CH or (EtO)2P(O)H/(EtO)3CH reactant

  阐述了一种实用的合成（氨基亚甲基）双膦氧化物的方法，该方法包括无催化剂和无溶剂的微波辅助的伯胺，原甲酸三乙酯和两当量的二苯基膦氧化物的三组分缩合反应。该方法还适用于使用（MeO）2P（O）H /（MeO）3CH或（EtO）2P（O）H /（EtO）3CH反应物对甚至仲胺制备（氨基亚甲基）双膦酸酯。还可以鉴定出涉及反应机理的几种中间体以及一些副产物。
• Studies on Novel Bone Resorption Inhibitors. I. Synthesis and Pharmacological Activites of Aminomethylenebisphosphonate Derivatives.
  作者：Makoto TAKEUCHI、Shuichi SAKAMOTO、Makoto YOSHIDA、Tetsushi ABE、Yasuo ISOMURA

  DOI：10.1248/cpb.41.688

  日期：——

  A series of aminomethylenebisphosphonate derivatives was synthesized and evaluated for their antiresorptive activities using a parathyroid hormone (PTH)-induced hypercalcemia model in rats (PIH model). Among these compounds, (cycloheptylamino)methylenebis(phosphonic acid) (3j) was finally selected for further investigation, proving 10-fold as potent as pamidronate in the PIH model and an immobilization

  合成了一系列氨基亚甲基双膦酸酯衍生物，并使用甲状旁腺激素（PTH）诱导的大鼠高钙血症模型（PIH模型）评估了其抗吸收活性。在这些化合物中，最终选择了（环庚基氨基）亚甲基双（膦酸）（3j）进行进一步研究，在PIH模型和固定化大鼠骨萎缩模型（DA模型）中证明其效力是帕米膦酸盐的10倍。讨论了该系列双膦酸酯的结构-活性关系。
• Facile and potent synthesis of carbon bridged fullerene dimers (HC60–CR2–C60H type)
  作者：Juan-Juan Yin、Yu-Guo Li、Bin Li、Wen-Xin Li、Li-Mei Jin、Jin-Ming Zhou、Qing-Yun Chen

  DOI：10.1039/b501390a

  日期：——

  Novel carbon bridged fullerene dimers (HC60–CR2–C60H type) are obtained in high yield by the reaction of aminomethylenebis(phosphonate) anions with [60]fullerene.

  新型碳桥富勒烯二聚体（HC60âCR2âC60H 型）是通过氨基亚甲基双（膦酸盐）阴离子与 [60] 富勒烯反应高产获得的。
• Reactions of Fullerenes with Reactive Methylene Organophosphorus Reagents:  Efficient Synthesis of Organophosphorus Group Substituted C₆₀ and C₇₀ Derivatives
  作者：Juan-Juan Yin、Li-Mei Jin、Rui-Li Liu、Qing-Nuan Li、Chun-Hai Fan、Yan Li、Wen-Xin Li、Qing-Yun Chen

  DOI：10.1021/jo052263n

  日期：2006.3.1

  gave corresponding C70 dimers 1 in good yield, while the methanofullerenes, C70>CH(PO3Et2) (3) and C70>C(PO3Et2)2 (4) or C60>CH(PO3Et2) (5) and C60>C(PO3Et2)2 (6), were obtained, respectively, by the reaction of C70 or C60 with tetraethyl methylenediphosphonate in the presence of NaH. Diethyl cyanomethylphosphonate reacted with C60 or C70 under similar conditions to afford C60>C(PO3Et2)CN (7) and C70>C(PO3Et2)CN

  在NaH存在下，用环烷基氨基亚甲基双膦酸酯处理C 70得到相应的C 70二聚体1，收率良好，而亚甲基富勒烯C 70 > CH（PO 3 Et 2）（3）和C 70 > C（PO 3 Et 2）2通过C的反应分别获得（4）或C 60 > CH（PO 3 Et 2）（5）和C 60 > C（PO 3 Et 2）2（6）。NaH存在下，用亚甲基二膦酸四乙酯与70或C 60混合。氰基甲基膦酸二乙酯与C 60或C 70在相似条件下反应，得到C 60 > C（PO 3 Et 2）CN（7）和C 70 > C（PO 3 Et 2）CN（8）。此外，通过循环伏安法证明了富勒烯二聚体的两个富勒烯笼之间弱的电子相互作用的存在。在ESR研究的基础上，提出了形成富勒烯衍生物的基本机理。
• 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.