3-[N-(4-Phenylbutyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid | 129951-00-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-[N-(4-Phenylbutyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid
• 英文别名: 3-[N-(2-phenethylethyl)-N-methyl-amino]-1-hydroxy-propane-1,1-diphosphonic acid；{1-Hydroxy-3-[methyl(4-phenylbutyl)amino]propane-1,1-diyl}bis(phosphonic acid)；[1-hydroxy-3-[methyl(4-phenylbutyl)amino]-1-phosphonopropyl]phosphonic acid
• CAS: 129951-00-4
• 化学式: C₁₄H₂₅NO₇P₂
• 分子量: 381.303
• InChiKey: VFLFYDXGZMGUAF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.2
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  139
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-(4-phenylbutylamino)-1-hydroxy-propane-1,1-diphosphonic acid 在 聚合甲醛 、 甲酸 作用下， 生成 3-[N-(4-Phenylbutyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid
  参考文献：
  名称：

  Phenylaliphatylaminoalkanediphosphonic acids

  摘要：

  Phenylaliphatylaminoalkanediphosphonic acids的中文翻译为：苯基脂肪基氨基烷二膦酸。其中R.sub.1是一个具有4个至7个碳原子的脂肪烃基，被苯基取代，R.sub.2是一个具有1个至4个碳原子的一价脂肪烃基，alk是一个具有2个至4个碳原子的二价脂肪烃基，它们的盐对钙代谢具有特别显著的调节作用，并可用作治疗与其紊乱有关的疾病的药物。例如，它们可通过将具有以下结构的化合物与磷酸化剂反应并水解初级产物来制备：其中X.sub.3表示羧基。

  公开号：

  US05162310A1

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 COMPOUNDS AND METHODS
  申请人：Oldfield Eric

  公开号：US20070275931A1

  公开（公告）日：2007-11-29

  The invention provides, inter alia, novel bisphosphonate compounds and methods of making and using. In embodiments, the invention provides compounds and methods in connection with research and therapeutic applications, e.g., for tumor cell growth inhibition, activation of gammadelta T cells, inhibition of farnesyldiphosphate (FPPS) and/or undecaprenyldiphosphate synthase enzymes, bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases. In regards to certain embodiments, a surprising advance has been the recognition that certain structural features can significantly enhance the activity of the compounds. For example, the presence of particular cationic species e.g., phosphonium, sulfonium, and arsonium moieties can contribute to desirable functional activity when positioned near a bisphosphonate moiety. In other embodiments of non-nitrogen containing bisphosphonates, terphenyl and benzyl bisphosphonate compounds and methods are provided. Further variations are also provided.

  本发明提供了新型双膦酸盐化合物及其制备和使用方法。在实施例中，本发明提供了与研究和治疗应用相关的化合物和方法，例如用于抑制肿瘤细胞生长、激活γδT细胞、抑制法尼酰二磷酸合酶（FPPS）和/或十一烷基二磷酸合酶酶、骨吸收疾病、癌症、免疫失调、免疫疗法和传染病。关于某些实施例，一个令人惊讶的进展是认识到某些结构特征可以显著增强化合物的活性。例如，特定阳离子物种的存在，例如磷酸铵、磺酸盐和砷酸盐基团，当位于双膦酸盐基团附近时，可以促进理想的功能活性。在另一些非氮双膦酸盐的实施例中，提供了苯并双膦酸盐化合物和方法。还提供了进一步的变化。
• Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)
  作者：Leo Widler、Knut A. Jaeggi、Markus Glatt、Klaus Müller、Rolf Bachmann、Michael Bisping、Anne-Ruth Born、Reto Cortesi、Gabriela Guiglia、Heidi Jeker、Rémy Klein、Ueli Ramseier、Johann Schmid、Gerard Schreiber、Yves Seltenmeyer、Jonathan R. Green

  DOI：10.1021/jm020819i

  日期：2002.8.1

  Bisphosphonates (BP) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED50 of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
• 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.
• Phenylaliphatylaminoalkandi-phosphonsäuren
  申请人：CIBA-GEIGY AG

  公开号：EP0371921B1

  公开（公告）日：1994-06-08