N-(thiazol-2-yl)aminomethylenebisphosphonic acid

• 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: N-(thiazol-2-yl)aminomethylenebisphosphonic acid
• 英文别名: 1-[(2-thiazolyl)amino]-methane-1,1-diphosphonic acid；1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid；Hydrogen phosphono(1,3-thiazol-3-ium-2-ylamino)methylphosphonate；hydroxy-[(S)-phosphono-(1,3-thiazol-3-ium-2-ylamino)methyl]phosphinate
• 化学式: C₄H₈N₂O₆P₂S
• 分子量: 274.131
• InChiKey: KCMZCJPKBVPPJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  168
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(thiazol-2-yl)aminomethylenebisphosphonic acid 在 silver nitrate 作用下， 以 水 为溶剂， 生成 disilver 1-(thiazol-2-ylamino)-methane-1,1-diphosphonate
  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
• 作为产物：
  描述：

  tetraethyl ((1,3-thiazol-2-ylamino)methylene)bisphosphonate 在 C.I.颜料红53：1 、 甲醇 作用下， 以 盐酸 为溶剂， 反应 6.0h， 以4.33 g (93% of the theoretical yield) of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275° (decomposition)的产率得到N-(thiazol-2-yl)aminomethylenebisphosphonic acid
  参考文献：
  名称：

  Substituted aminomethanediphosphonic acids and use in medicaments

  摘要：

  式子为##STR1##的杂环氨甲基二膦酸，其中R.sub.1代表一个可选的苯并或环己烯并的5元杂环芳基基团，该基团包含2到4个N原子或1或2个N原子以及1个O原子或S原子作为杂原子，未被取代或被低烷基取代；被苯基取代，该苯基未被取代或被低烷基，低烷氧基和/或卤素取代；被低烷氧基取代；被羟基取代；被二低烷基氨基取代；被低烷基硫基和/或卤素取代；R.sub.2代表氢或低烷基，以及它们的盐，具有对钙代谢的调节作用，并可以用作治疗可以归因于钙代谢紊乱的疾病的药物的活性成分。例如，它们可以制造如下：在公式##STR2##的化合物中，其中X.sub.1代表功能修饰的膦酸基团X，X.sub.2代表膦酸基团或类似地代表功能修饰的膦酸基团X，基团X被转化为自由膦酸。

  公开号：

  US05057505A1

文献信息

• 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  Bisphosphonates (BP) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure.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.