(cyclopropylamino)methylenebis(phosphonic acid) | 124351-91-3

• 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: (cyclopropylamino)methylenebis(phosphonic acid)
• 英文别名: N-(cyclopropyl)aminomethylenebisphosphonic acid；[(Cyclopropylamino)-phosphonomethyl]phosphonic acid
• CAS: 124351-91-3
• 化学式: C₄H₁₁NO₆P₂
• 分子量: 231.082
• InChiKey: UGPXWDIZFKGVEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.3
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  127
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  [Cyclopropylamino-(diethoxy-phosphoryl)-methyl]-phosphonic acid diethyl ester 在 氢溴酸 、 溶剂黄146 作用下， 反应 2.0h， 以48.8%的产率得到(cyclopropylamino)methylenebis(phosphonic acid)
  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

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
• Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins
  作者：Mateusz Pospiech、Siân E. Owens、David J. Miller、Karl Austin‐Muttitt、Jonathan G. L. Mullins、James G. Cronin、Rudolf K. Allemann、I. Martin Sheldon

  DOI：10.1096/fj.202100164r

  日期：2021.6

  the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibiting this enzyme protected cells against cholesterol‐dependent cytolysins. We first synthesized 22 different nitrogen‐containing bisphosphonate molecules that were designed to inhibit squalene synthase. Squalene synthase inhibition was quantified using a cell‐free enzyme assay, and validated

  某些种类的病原细菌会通过分泌胆固醇依赖性溶血素来破坏组织，溶血素会在动物细胞的质膜上形成孔。但是，降低胆固醇可以保护细胞免受这些溶细胞素的侵害。鲨烯合酶催化胆固醇生物合成的第一步，我们探讨了抑制这种酶是否能保护细胞免受胆固醇依赖性溶血素的侵害。我们首先合成了22种不同的含氮双膦酸酯分子，这些分子旨在抑制角鲨烯合酶。对角鲨烯合酶的抑制作用可通过无细胞酶分析定量，并通过计算机模拟双膦酸酯分子与角鲨烯合酶的结合进行验证。然后筛选双膦酸盐保护HeLa细胞免受胆固醇依赖性细胞溶血素-溶血素引起的损害的能力。最有效的双膦酸盐可将溶血素诱导的乳酸脱氢酶向细胞上清液的泄漏减少> 80％，并将溶血素诱导的细胞溶解度从> 75％降低至<25％。此外，这种双膦酸盐减少了溶血素诱导的钾从细胞中的漏出，限制了细胞骨架的变化，防止了促分裂原活化的蛋白激酶对细胞的应激反应，并降低了细胞胆固醇。双膦酸盐还可以保护细胞免受
• (Cycloalkylamino)methylenebis(phosphonic acid)
  申请人：Yamanouchi Pharmaceutical Co., Ltd.

  公开号：US04970335A1

  公开（公告）日：1990-11-13

  (Cycloalkylamino)methylenebis(phosphonic acid) represented by the general formula: ##STR1## in which, R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 represent a hydrogen atom or a lower alkyl group, and n represents an integer from 3 to 10, a lower alkyl ester thereof or a pharmaceutically acceptable salt thereof; and a bone-resorption inhibitor and an anti-arthritis containing the same.

  “(环烷基氨基)亚甲基双(膦酸)”由一般式表示：##STR1## 其中，R、R.sup.1、R.sup.2、R.sup.3和R.sup.4代表氢原子或低碳基，n代表3到10的整数，其低碳酸酯或药学上可接受的盐；以及含有该化合物的骨吸收抑制剂和抗关节炎药物。
• (Cycloalkylamino)methylenebis(phosphonic acid) and medicines contaiing
  申请人：Yamanouchi Pharmaceutical Co., Ltd.

  公开号：US05041428A1

  公开（公告）日：1991-08-20

  (Cycloalkylamino)methylenebis(phosphonic acid) represented by the general formula: ##STR1## in which, R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 represent a hydrogen atom or a lower alkyl group, and n represents an integer from 3 to 10, a lower alkyl ester thereof or a pharmaceutically acceptable salt thereof; and a bone-resorption inhibitor and an anti-arthritis containing the same.

  “(环烷基氨基)亚甲基双(膦酸)”由通式表示为：##STR1## 其中，R、R.sup.1、R.sup.2、R.sup.3和R.sup.4代表氢原子或低级烷基，n代表从3到10的整数，其低级烷基酯或药学上可接受的盐；以及含有该化合物的骨吸收抑制剂和抗关节炎药物。
• 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.