N-piperidinomethane-1,1-diphosphonic acid | 32545-72-5

• 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: N-piperidinomethane-1,1-diphosphonic acid
• 英文别名: piperidine-N-methyldiphosphonic acid；1-piperidinylmethylene-1,1-bisphosphonate；piperidinomethylenebis(phosphonic acid)；piperid-1-ylmethane-1,1-diphosphonic acid；(piperidin-1-yl-methanediyl)-bis-phosphonic acid；N-(piperidyl)aminomethylenebisphosphonic acid；(piperid-1-yl)methylenebisphosphonic acid；Piperidino-methylen-diphosphorsaeure；piperidinomethane-diphosphonic acid；Pmdpa；hydroxy-[(R)-phosphono(piperidin-1-ium-1-yl)methyl]phosphinate
• CAS: 32545-72-5
• 化学式: C₆H₁₅NO₆P₂
• 分子量: 259.136
• InChiKey: JTLZXDRXWWHVHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.6
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  118
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-piperidinomethane-1,1-diphosphonic acid 、 europium(III) perchlorate 在 高氯酸 作用下， 以 水 为溶剂， 生成 、 、 、 、
  参考文献：
  名称：

  Jensen, Mark P.; Beitz, James V.; Rogers, Robin D., Journal of the Chemical Society, Dalton Transactions, 2000, p. 3058 - 3064

  摘要：

  DOI：
• 作为产物：
  描述：

  tetraethyl piperidinomethylenebis(phosphonate) 在 盐酸 作用下， 生成 N-piperidinomethane-1,1-diphosphonic acid
  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

• Interactions of N-heteroalkylaminomethylenebisphosphonic acids with Cd(II) ions: Electrochemical and spectroscopic investigations
  作者：Agnieszka Dobosz、Jan Spychała、Tomasz Ptak、Gabriela Maciejewska、Ewa Chmielewska、Paweł Kafarski、Piotr Młynarz

  DOI：10.1016/j.ica.2015.05.034

  日期：2015.8

  excellent chelators for many metal ions. In this work, the coordination properties of three different aminomethylenebisphosphonates with N-substituted heteroalkyl moieties (L1, L2 and L3) and their N-pyridyl derivative (L4) toward cadmium(II) ions are described. Due to their coordination abilities over a broad range of pH, the compounds of this group are good candidates for heavy metal detoxification. To determine

  已知氨基亚甲基双膦酸酯是许多金属离子的极佳螯合剂。在这项工作中，描述了三种不同的氨基亚甲基双膦酸酯与N-取代的杂烷基部分（L1，L2和L3）及其N-吡啶基衍生物（L4）对镉（II）离子的配位性能。由于它们在很宽的pH值范围内的配位能力，因此这类化合物是重金属排毒的良好候选者。为了确定形成的氨基亚甲基双膦酸酯-镉（II）配合物的稳定性常数和配位模式，采用了四种分析方法：电位法，脉冲极谱法（DPP），核磁共振波谱法（NMR）和电喷雾电离质谱法（ESI-MS） 。进行的研究表明，配体L1 L2和L3具有相似的配位性能，Cd（II）离子在pH 2以下结合形成等摩尔配合物，在pH 6以上则形成双配合物。配体L4的行为不同，形成了六种化学计量不同的复合物：CdH4L3，CdH3L3，CdHL2，CdL2，CdH2L和Cd3H4L3。普通配合物d-青霉胺和所研究的配体之间的假设竞争曲线表明，在2-6的p
• 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。
• Novel heterocycle-substituted diphosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate matabolism
  申请人：Norwich Eaton Pharmaceuticals, Inc.

  公开号：EP0274158A1

  公开（公告）日：1988-07-13

  The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring hetero­cycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from about 0 to about 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R¹, R², and R³ are substituent groups. The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally, this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.

  本发明涉及新型杂环取代的二膦酸及其药学上可接受的盐和酯，其中二膦酸取代的碳原子分子连接到含氮六元环杂环，最好是哌啶环中的碳原子上。杂环取代的二膦酸化合物具有一般结构： 其中 Z 是选自哌啶基、重氮基和三嗪基的含氮六员环杂环分子；m、n 和 m+n 是约 0 至约 10；Q 是共价键或选自氧、硫或氮的分子；R¹、R² 和 R³ 是取代基。 本发明还涉及含有这些新型化合物的药物组合物。最后，本发明涉及利用本发明的化合物或药物组合物治疗或预防以钙和磷酸盐代谢异常为特征的疾病的方法。
• Preservative system for acidic beverages based on sequestrants
  申请人：PepsiCo, Inc.

  公开号：US10631557B2

  公开（公告）日：2020-04-28

  The present invention provides beverage preservative systems for use in high acid beverage products, and beverage products comprising the beverage preservative systems. The beverage preservative system prevents spoilage by microorganisms in a beverage within a sealed container for a period of at least 16 weeks. The present invention reduces or eliminates the use of conventional preservatives that pose health and/or environmental concerns. The components that make up the beverage preservative system of invention work together in a synergistic manner to reduce the amount of preservative required and so improve the inventive beverage's sensory impact over beverages having conventional preservatives.

  本发明提供了用于高酸饮料产品的饮料防腐剂系统，以及包含该饮料防腐剂系统的饮料产品。饮料防腐剂系统可防止密封容器中的饮料在至少 16 周的时间内因微生物而变质。本发明减少或消除了对健康和/或环境造成影响的传统防腐剂的使用。构成本发明饮料防腐剂系统的各种成分以协同增效的方式共同发挥作用，减少了所需的防腐剂用量，因此与使用传统防腐剂的饮料相比，本发明饮料的感官效果更好。
• 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.