[[(3-Methyl-2-pyridinyl)amino]methylidene]bisphosphonic Acid Tetraethyl Ester | 70010-74-1

• 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-Methyl-2-pyridinyl)amino]methylidene]bisphosphonic Acid Tetraethyl Ester
• 英文别名: 3-methylpyridyl-2-aminomethylene-bis(phosphonic acid diethyl ester)；N-[bis(diethoxyphosphoryl)methyl]-3-methylpyridin-2-amine
• CAS: 70010-74-1
• 化学式: C₁₅H₂₈N₂O₆P₂
• 分子量: 394.345
• InChiKey: BHPWCKXAIGRABY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  25
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  96
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  [[(3-Methyl-2-pyridinyl)amino]methylidene]bisphosphonic Acid Tetraethyl Ester 在 盐酸 作用下， 生成 (3-methyl-2-pyridylamino)methylene bis(phosphonic acid)
  参考文献：
  名称：

  Effects of Bisphosphonates on the Growth of Entamoeba histolytica and Plasmodium Species in Vitro and in Vivo

  摘要：

  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.

  DOI：

  10.1021/jm030084x
• 作为产物：
  描述：

  2-氨基-3-甲基吡啶 在 copper(I) oxide potassium tert-butylate 、 三氯氧磷 作用下， 以 四氢呋喃 、 叔丁醇 为溶剂， 反应 30.5h， 生成 [[(3-Methyl-2-pyridinyl)amino]methylidene]bisphosphonic Acid Tetraethyl Ester
  参考文献：
  名称：

  A stereoselective process for the preparation of novel phosphonoalkylphosphinates

  摘要：

  We have devised both a contiguous and a stepwise strategy for the synthesis of the pyridylaminomethane-based class of phosphonoalkylphosphinates (PAPs) that form via the intermediacy of the phosphonoethoxyaminomethane XIa. The PAPs result from condensation of picolines and phosphonoacetals in high chemoselective yield. Following reduction of aminopyridine IIIb, the unprecedented Pt(0)-catalyzed epimerization of the chelated amidine [(hydroxy)methylphosphinyl]-[(3-methyl-2 -piperidinyl-idene)amino]methylphosphonic acid (IIIa) yielded a single racemic pair of PAPs (IIIc). The epimerization was found to occur more slowly than amidine formation itself.

  DOI：

  10.1016/s0022-328x(96)06846-5

文献信息

• Sulfonic acid functionalized hyper-cross-linked polymer: An efficient heterogeneous acid catalyst for the synthesis of N-containing bisphosphonates
  作者：Sirigireddy Sudharsan Reddy、Reddi Mohan Naidu Kalla、Anuraj Varyambath、Il Kim

  DOI：10.1016/j.catcom.2019.04.009

  日期：2019.6

  then functionalized by chlorosulfonic acid to obtain sulfonated HCBP (HCBP-SO3H) having surface area of 452 m2/g. The synthesized HCBP and HCBP-SO3H were characterized systematically by spectroscopic techniques. Further, the catalytic potential was evaluated towards the one-pot synthesis of N-containing bisphosphonates (N-BPs). To the delight, catalyst showed excellent activity in the synthesis of various

  一种新的微多孔超交联2,2'-联苯酚聚合物（氯代联苯）与770微米的良好的比表面积2 / g的合成，然后通过氯磺酸官能化以获得磺化氯代联苯（氯代联苯-SO 3 1H）具有表面积为452m 2 / g。用光谱技术对合成的HCBP和HCBP-SO 3 H进行了系统表征。此外，催化电位朝向一锅合成的评价Ñ含双膦酸盐（Ñ -bps）。令人高兴的是，催化剂在合成各种具有生物活性的芳族和杂芳族N时表现出出色的活性。-血压。值得注意的是，它可以循环使用七个周期，而其酸官能度没有任何重大损失。
• Methylenebisphosphonic acid derivatives
  申请人：Leiras Oy

  公开号：US05393748A1

  公开（公告）日：1995-02-28

  Novel pharmacologically active methylenebisphosphonates having formula (I) wherein R.sup.1 -R.sup.4 independently are C.sub.1 -C.sub.10 -alkyl, C.sub.3 -C.sub.10 -cycloalkyl, aryl, aralkyl, silyl SiR.sub.3 or hydrogen, whereby in formula (I) at least one of the groups R.sup.1 -R.sup.4 is hydrogen and at least one of the groups R.sup.1 -R.sup.4 is different from hydrogen, Q.sup.1 is hydrogen, hydroxyl, halogen, amino NH.sub.2, or OR'.sub.1, wherein R'.sub.1 is C.sub.1 -C.sub.4 -alkyl or acyl, Q.sup.2 is the group (.alpha.) 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 O, N and S, including the steroisomers and the salts of the compounds.

  具有公式(I)的新型药理活性亚甲基双膦酸酯，其中R.sup.1-R.sup.4独立地为C.sub.1-C.sub.10-烷基，C.sub.3-C.sub.10-环烷基，芳基，芳基烷基，硅基SiR.sub.3或氢，其中在公式(I)中至少有一个基团R.sup.1-R.sup.4为氢，至少有一个基团R.sup.1-R.sup.4不同于氢，Q.sup.1为氢，羟基，卤素，氨基NH.sub.2或OR'.sub.1，其中R'.sub.1为C.sub.1-C.sub.4-烷基或酰基，Q.sup.2为组(.alpha.)，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为整数0到6，且R'和R"为氢或低烷基，前提是在环Y的环原子和/或组X的链原子中，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。
• [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。
• Bisphosphonates Inhibit the Growth of <i>Trypanosoma </i><i>b</i><i>rucei</i>, <i>Trypanosoma </i><i>c</i><i>ruzi</i>, <i>Leishmania </i><i>d</i><i>onovani</i>, <i>Toxoplasma </i><i>g</i><i>ondii</i>, and <i>Plasmodium </i><i>f</i><i>alciparum</i>:  A Potential Route to Chemotherapy
  作者：Michael B. Martin、Joshua S. Grimley、Jared C. Lewis、Huel T. Heath、Brian N. Bailey、Howard Kendrick、Vanessa Yardley、Aura Caldera、Renee Lira、Julio A. Urbina、Silvia N. J. Moreno、Roberto Docampo、Simon L. Croft、Eric Oldfield

  DOI：10.1021/jm0002578

  日期：2001.3.1

  We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC50 activity values against parasite replication (e.g. o-risedronate, IC50 = 220 nM for T. brucei rhodesiense; risedronate, IC50 = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
• SUZUKI FUMIO;FUJAKAWA YOSHIDEMI;OHYA TUNEHIKO;IKAI TAKASHI;OGUCHI TOSHIHI+
  作者：SUZUKI FUMIO、FUJAKAWA YOSHIDEMI、OHYA TUNEHIKO、IKAI TAKASHI、OGUCHI TOSHIHI+

  DOI：——

  日期：——