[(3-pyridinylamino)methylene]-1,1-bisphosphonate

• 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: [(3-pyridinylamino)methylene]-1,1-bisphosphonate
• 英文别名: (pyridin-3-ylamino)methylenebisphosphonic acid；hydrogen {phosphono[(pyridin-1-ium-3-yl)amino]methyl}phosphonate；Hydrogen {phosphono[(pyridin-1-ium-3-yl)amino]methyl}phosphonate；hydroxy-[(R)-phosphono-(pyridin-1-ium-3-ylamino)methyl]phosphinate
• 化学式: C₆H₁₀N₂O₆P₂
• 分子量: 268.103
• InChiKey: IFOAJHQSAXHBDS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.6
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  140
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-(pyridin-3-yl)formamide 在 甲醇 、 三氟甲磺酸三甲基硅酯 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 20.0 ℃ 、66.66 Pa 条件下， 生成 [(3-pyridinylamino)methylene]-1,1-bisphosphonate
  参考文献：
  名称：

  的新合成的官能化的芳基和吡啶基酸氨基亚甲基和它们的衍生物通过硅辅助方法

  摘要：

  通过硅辅助方法已经开发了新的方便的合成官能化的芳基和吡啶基氨基亚甲基双膦酸及其衍生物的方法。利用亚磷酸三（三甲基甲硅烷基）酯与N的独特反应，获得了含有吡啶部分的新功能化氨基亚甲基双膦酸-甲酰基氨基吡啶和三氟甲磺酸三甲基甲硅烷基酯在温和条件下作为催化剂。中间体–形成的四（三甲基甲硅烷基）氨基亚甲基双膦酸酯通过用过量甲醇进一步处理而转化为目标酸。相反，在氯化锌催化剂的存在下，在加热（130℃）下，将四种组分的混合物（亚磷酸二乙基三甲基甲硅烷基酯，原甲酸三乙基酯，芳基或吡啶基胺和亚磷酸二乙基酯）合成相应的四乙基氨基亚甲基双膦酸酯。提出并详细讨论了目标物质形成的催化方案。

  DOI：

  10.1016/j.jorganchem.2020.121177

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
• Insight into the mechanism of three component condensation leading to aminomethylenebisphosphonates
  作者：Ewa Dąbrowska、Agnieszka Burzyńska、Artur Mucha、Ewa Matczak-Jon、Wanda Sawka-Dobrowolska、Łukasz Berlicki、Paweł Kafarski

  DOI：10.1016/j.jorganchem.2009.07.025

  日期：2009.11

  mechanism of the reaction remains unknown. p-Nitroaniline has been found an interesting tool to shed light on this matter. Its use allowed to separate and identify four intermediates, both non-phosphorus and phosphorus containing, and subsequently suggest the mechanism of the whole process. The acquired knowledge was helpful in explanation the route and the final product structure obtained for more

  伯胺，亚磷酸二乙酯和原甲酸三乙酯的三组分反应，然后加合物的酸水解，以良好的收率提供了N-取代的氨基亚甲基双膦酸。它用途广泛，通常用于制备具有潜在抗骨质疏松，抗菌，抗癌，抗寄生虫或除草活性的化合物。但是，反应机理仍然未知。p-硝基苯胺已被发现是阐明这一问题的有趣工具。它的使用可以分离和鉴定出四种不含磷和含磷的中间体，随后提示了整个过程的机理。获得的知识有助于解释使用4-氨基吡啶进行更复杂反应的路线和最终产物结构。毫无疑问地证明了吡啶氮原子的另外的烷基化，导致意外的N-（1-烷基吡啶-4-氨基）亚甲基双膦酸。
• [EN] NOVEL METHYLENEBISPHOSPHONIC ACID DERIVATIVES
  申请人：LEIRAS OY

  公开号：WO1992011269A1

  公开（公告）日：1992-07-09

  (EN) Novel pharmacologically active methylenebisphosphonates having formula (I) wherein R1-R4 independently are C1-C10-alkyl, C3-C10-cycloalkyl, aryl, aralkyl, silyl SiR3 or hydrogen, whereby in formula (I) at least one of the groups R1-R4 is hydrogen and at least one of the groups R1-R4 is different from hydrogen, Q1 is hydrogen, hydroxyl, halogen, amino NH2, or OR'1, wherein R'1 is C1-C4-alkyl or acyl, Q2 is the group ($g(a)) wherein Y is a six-membered heterocyclic group, or a carbocyclic aromatic group, X is a bond, O, S or NR''', wherein R''' is hydrogen, lower alkyl, or acyl, n is the integer 0 to 6, and R' and R' are hydrogen or lower alkyl provided that as a ring atom of the ring Y and/or a chain atom of the group X, there is always at least one heteroatom from the group of O, N and S, including the stereoisomers and the salts of the compounds.(FR) L'invention se rapporte à de nouveaux méthylènebiphosphonates pharmacologiquement actifs, qui sont représentés par la formule (I), où: R1 à R4 représentent séparément alkyle C1-C10, cycloalkyle C3-C10, aryle, aralkyle, SiR3 silyle ou hydrogène, de sorte que, dans la formule (I), au moins l'un des groupes R1 à R4 représentent hydrogène et au moins l'un des groupes R1-R4 représente un élément différent de l'hydrogène; Q1 représente hydrogène, hydroxyle, halogène, NH2 amino, ou OR'1, où R'1 représente alkyle C1-C4 ou acyle; Q2 représente le groupe ($g(a)), où Y représente un groupe hétérocyclique à six éléments ou un groupe aromatique carbocyclique, X représente une liaison, O, S ou NR''', où R''' représente hydrogène, alkyle inférieure ou acyle, n est égal à un nombre entier compris entre 0 et 6, et R' et R' représentent hydrogène ou alkyle inférieur, à condition que, comme atome cyclique de la chaîne fermée Y et/ou comme atome de chaîne du groupe X, il y ait toujours au moins un hétéroatome provenant du groupe O, N et S; ainsi qu'aux stéréoisomères et aux sels de ces composés.

  新的药理活性亚甲基双膦酸酯具有公式（I），其中R1-R4独立地为C1-C10烷基，C3-C10环烷基，芳基，芳基烷基，硅基SiR3或氢，其中在公式（I）中至少有一个基团R1-R4为氢，至少有一个基团R1-R4不同于氢，Q1为氢，羟基，卤素，氨基NH2或OR'1，其中R'1为C1-C4烷基或酰基，Q2为($g(a))基团，其中Y为六元杂环基或碳环芳基，X为键，O，S或NR'''，其中R'''为氢，低烷基或酰基，n是整数0到6，R'和R'为氢或低烷基，只要作为环Y的环原子和/或基团X的链原子，始终至少有一个来自O，N和S的杂原子，包括化合物的立体异构体和盐。
• Mevalonate pathway inhibitor as highly-efficient vaccine adjuvant
  申请人：Tsinghua University

  公开号：US11382971B2

  公开（公告）日：2022-07-12

  Disclosed are inhibitors of mevalonate pathway as an efficient vaccine adjuvant and use thereof. In particular, the inhibitor is an acetoacetyl-CoA transferase inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase inhibitor, a mevalonate kinase inhibitor, a phosphomevalonate kinase inhibitor, a mevalonate-5-pyrophosphate decarboxylase inhibitor, an isopentenyl pyrophosphate isomerase inhibitor, a farnesyl pyrophosphate synthase inhibitor, a geranylgeranyl pyrophosphate synthase inhibitor or a geranylgeranyl transferase (I, II) inhibitor. Also disclosed is an immunogenic composition comprising inhibitors of mevalonate pathway as an adjuvant.

  所公开的是作为高效疫苗佐剂的甲羟戊酸途径抑制剂及其用途。特别是，抑制剂是乙酰乙酰-CoA 转移酶抑制剂、HMG-CoA 合成酶抑制剂、HMG-CoA 还原酶抑制剂、甲羟戊酸激酶抑制剂、磷酸甲羟戊酸激酶抑制剂、甲羟戊酸-5-焦磷酸脱羧酶抑制剂、焦磷酸异戊烯酯异构酶抑制剂、焦磷酸法呢酯合成酶抑制剂、焦磷酸香叶酯合成酶抑制剂或香叶基香叶基转移酶 (I, II) 抑制剂。还公开了一种免疫原组合物，该组合物包含作为佐剂的甲羟戊酸途径抑制剂。
• 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.