tetraethyl (((benzo[d]thiazol-2-yl)amino)methylene)bis(phosphonate) | 118054-26-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: tetraethyl (((benzo[d]thiazol-2-yl)amino)methylene)bis(phosphonate)
• 英文别名: tetraethyl [(benzo[d]thiazol-2-amino)methyl]-1,1-bisphosphonate；1-(benzothiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester；N-[bis(diethoxyphosphoryl)methyl]-1,3-benzothiazol-2-amine
• CAS: 118054-26-5
• 化学式: C₁₆H₂₆N₂O₆P₂S
• 分子量: 436.406
• InChiKey: IIEMMBCBGCOXFH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tetraethyl (((benzo[d]thiazol-2-yl)amino)methylene)bis(phosphonate) 在 盐酸 、 水 作用下， 以72%的产率得到N-(benzothiazol-2-yl)aminomethylenebisphosphonic acid
  参考文献：
  名称：

  （2-氨基苯并噻唑）-甲基-1,1-双膦酸：靶向基质金属蛋白酶13抑制骨。

  摘要：

  基质金属蛋白酶（MMP）是分泌型和膜结合型酶的一个家族，在人类中已知有24种同工型。这些酶降解细胞外基质的蛋白质，并在所有组织的生理重塑中发挥至关重要的作用。但是，某些MMP，例如MMP-2，-9和-13，可能在包括癌症和转移在内的病理状态下过表达。因此，作为预防和阻碍转移性生长的策略，MMP抑制剂（MMPIs）的开发已进行了很长时间的探索，但是与混杂抑制MMPs相关的重要副作用却阻止了MMPIs的临床应用。因此，提出了几种策略来改善此类药物的治疗效果，包括提高了对特定MMP亚型的选择性以及对特定器官和组织的靶向性。结合这两种方法，我们通过体外和计算机模拟研究对一系列可作为MMP-13选择性抑制剂起作用的（2-氨基苯并噻唑）-甲基-1,1-双膦酸进行了合成和初步生物学评估，这可能证明是有用的由于双膦酸基团具有的骨靶向能力，因此可用于治疗骨转移。

  DOI：

  10.3390/ph14020085
• 作为产物：
  描述：

  2-氨基苯并噻唑 、 二乙基亚磷酸氢酯 在 原甲酸三乙酯 作用下， 以64%的产率得到tetraethyl (((benzo[d]thiazol-2-yl)amino)methylene)bis(phosphonate)
  参考文献：
  名称：

  Substituted aminomethanediphosphonic acids and use in medicaments

  摘要：

  配方为##STR1##的杂芳基氨甲二膦酸，其中R.sub.1代表一个可选择地与苯环或环己烯融合的5-成员杂芳基团，该杂芳基团包含2到4个N原子或1到2个N原子以及1个O原子或S原子，并且未取代或被较低烷基，未取代或被较低烷基、较低烷氧基和/或卤素，较低烷氧基，羟基，二较低烷基氨基，较低烷硫基和/或卤素取代；R.sub.2代表氢或较低烷基，以及它们的盐，在钙代谢上具有调节作用，并可作为药物的活性成分用于治疗可归因于钙代谢紊乱的疾病。例如，它们可以如下制备：在化合物##STR2##中，其中X.sub.1代表功能修饰的膦基团X，X.sub.2代表膦基或类似地代表功能修饰的膦基团X，膦基团X被转化为游离膦基。

  公开号：

  US05057505A1

文献信息

• Facile Synthesis, Antioxidant and Antimicrobial Activity of Amino Methylene Bisphosphonates
  作者：Uma Maheswara Rao Kunda、Satheesh Krishna Balam、Bakthavatchala Reddy Nemallapudi、Syama Sundar Chereddy、Sandip Kumar Nayak、Suresh Reddy Cirandur

  DOI：10.1248/cpb.60.104

  日期：——

  A green and efficient preparation method for the amino bisphosphonates is accomplished by simple mixing and stirring of diethylphosphite, triethylorthoformate and various amines in the presence of amberlyst-15 as catalyst at room temperature under solvent free conditions. The title compounds are characterized by IR, 1H-, 13C-, 31P-NMR and mass spectra, also studied their antimicrobial and antioxidant activity.

  在室温无溶剂条件下，以琥珀酸酯-15 为催化剂，通过简单混合和搅拌亚磷酸二乙酯、正甲酸三乙酯和各种胺，实现了一种绿色高效的氨基双膦酸盐制备方法。通过红外光谱、1H-、13C-、31P-NMR 和质谱对标题化合物进行了表征，并对其抗菌和抗氧化活性进行了研究。
• Aminodiphosphonate apolipoprotein e modulators
  申请人：Phan Trung Hieu

  公开号：US20050075317A1

  公开（公告）日：2005-04-07

  The present invention relates to methods of use of aminodiphosphonate to modulate apolipoprotein E levels and the use of such compounds in therapy, including cardiovascular and neurological disease states.

  本发明涉及使用氨基二膦酸盐来调节载脂蛋白E水平的方法，并将这些化合物用于治疗心血管和神经系统疾病状态。
• 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.
• Efficient catalyst free green synthesis and <i>in vitro</i> antimicrobial, antioxidant and molecular docking studies of <i>α</i>-substituted aromatic/heteroaromatic aminomethylene bisphosphonates
  作者：Mahammad Sadik Shaik、Maheshwara Reddy Nadiveedhi、Mohan Gundluru、Umamahesh Katike、Vijaya Sarathi Reddy Obulam、Suresh Reddy Cirandur

  DOI：10.1080/00397911.2020.1853778

  日期：2021.3.4