N-(thiomorpholinyl)aminomethylenebisphosphonic acid | 111072-49-2

• 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-(thiomorpholinyl)aminomethylenebisphosphonic acid
• 英文别名: (thiomorpholin-4-yl)methane-1,1-diphosphonic acid；(thiomorpholin-1-yl)methylenebisphosphonic acid；4-thiomorpholinylmethylene-1,1-bisphosphonate；(4-thiomorpholinylmethylene)-bisphosphonic acid；thiomorpholinomethylenebisphosphonic acid；thiomorpholinomethylenediphosphonic acid；[Phosphono(thiomorpholin-4-yl)methyl]phosphonic acid
• CAS: 111072-49-2
• 化学式: C₅H₁₃NO₆P₂S
• 分子量: 277.175
• InChiKey: RZULBGMWKROXRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5
• 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：
  144
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  [(Diethoxy-phosphoryl)-thiomorpholin-4-yl-methyl]-phosphonic acid diethyl ester 在 盐酸 作用下， 生成 N-(thiomorpholinyl)aminomethylenebisphosphonic 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

• 3-D QSAR Investigations of the Inhibition of <i>Leishmania </i><i>m</i><i>ajor</i> Farnesyl Pyrophosphate Synthase by Bisphosphonates
  作者：John M. Sanders、Aurora Ortiz Gómez、Junhong Mao、Gary A. Meints、Erin M. Van Brussel、Agnieszka Burzynska、Pawel Kafarski、Dolores González-Pacanowska、Eric Oldfield

  DOI：10.1021/jm0302344

  日期：2003.11.1

  set results (N = 62 compounds) yielded good correlations with each technique (R(2) = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC(50) values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate

  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
• 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
• Bisphosphonic acid derivatives, their production and use
  申请人：Leo Pharmaceutical Products Ltd. A/S

  公开号：US04870063A1

  公开（公告）日：1989-09-26

  Novel compounds of the formula I ##STR1## in which R.sub.1 -R.sub.11 can be the same or different and stand for hydrogen, a straight or branced aliphatic or alicyclic C.sub.1 -C.sub.10 hydrocarbon radical, an aryl or an aryl-C.sub.1 -C.sub.4 -alkyl radical; n is zero or one, and m is zero, one or two; or R.sub.2 and R.sub.4 when taken together form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted with one or more C.sub.1 -C.sub.4 alkyl radicals; and pharmaceutically acceptable salts and easily hydroyzable esters thereof, methods for producing said new compounds, pharmaceutical compositions containing the new compounds, dosage units of the compositions, and methods of treating patients using said compositions and dosage units. The present compounds are valuable in the human and veterinary practice by reducing bone resorption and surprisingly also stimulating bone alkaline phosphatase. A substantial increase in bone mass is actually observed during treatment with the present compounds.

  化合物的新结构为I ##STR1## 其中R.sub.1 -R.sub.11 可以相同也可以不同，代表氢、直链或支链脂肪或脂环烃基C.sub.1 -C.sub.10，芳基或芳基-C.sub.1 -C.sub.4 -烷基基团；n 为零或一，m 为零、一或二；或者当R.sub.2 和R.sub.4 联合形成饱和脂肪5、6或7-成员环时，该环可能被一个或多个C.sub.1 -C.sub.4 烷基基团取代；以及其药学上可接受的盐和易水解酯，制备上述新化合物的方法，含有新化合物的药物组合物，组合物的剂量单位，以及使用这些组合物和剂量单位治疗患者的方法。这些化合物在人类和兽医实践中非常有价值，可以通过减少骨吸收并出人意料地刺激骨碱性磷酸酶来实现。实际上，在使用这些化合物进行治疗时观察到骨量显著增加。
• 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.