[1-Hydroxy-3-(3H-imidazol-4-yl)-1-phosphono-propyl]-phosphonic 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: [1-Hydroxy-3-(3H-imidazol-4-yl)-1-phosphono-propyl]-phosphonic acid
• 英文别名: [1-hydroxy-3-(1H-imidazol-5-yl)-1-phosphonopropyl]phosphonic acid
• 化学式: C₆H₁₂N₂O₇P₂
• 分子量: 286.118
• InChiKey: OCVITJZAQBIHLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.5
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  164
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-(咪唑-4-基)丙酸 在 磷酸 、 三氯化磷 作用下， 以 氯苯 为溶剂， 反应 3.0h， 以38%的产率得到[1-Hydroxy-3-(3H-imidazol-4-yl)-1-phosphono-propyl]-phosphonic acid
  参考文献：
  名称：

  Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)

  摘要：

  Bisphosphonates (BP) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure.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

  DOI：

  10.1021/jm020819i

文献信息

• Certain 1-hydroxyethane, 1,1-di-phosphonic acid derivatives useful in
  申请人：Boehringer Mannheim GmbH

  公开号：US04687767A1

  公开（公告）日：1987-08-18

  The present invention provides diphosphonates of the general formula: ##STR1## wherein Het is an imidazole, oxazole, isoxazole, thiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or benzimidazole radical, which is optionally substituted by alkyl, alkoxy, halogen, hydroxyl, carboxyl, an amino group optionally substituted by alkyl or alkanoyl radicals or a benzyl radical optionally substituted by alkyl, nitro, amino or aminoalkyl, A is a straight-chained or branched, saturated or unsaturated hydrocarbon chain containing 2 to 8 carbon atoms, X is a hydrogen atom, optionally substituted by alkanoyl, or an amino group optionally substituted by alkyl or alkanoyl radicals and R is a hydrogen atom or an alkyl radical; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these diphosphonates and pharmaceutical compositions containing them.

  本发明提供了一般式为：##STR1## 的二膦酸盐，其中Het是咪唑、噁唑、异噁唑、噻唑、吡啶、1,2,3-三唑、1,2,4-三唑或苯并咪唑基团，该基团可选地被烷基、烷氧基、卤素、羟基、羧基、氨基（该氨基可选地被烷基或烷酰基基团取代）或苄基（该苄基可选地被烷基、硝基、氨基或氨基烷基取代）取代；A是含有2至8个碳原子的直链或支链、饱和或不饱和的碳氢链，X是氢原子，可选地被烷酰基取代，或氨基（该氨基可选地被烷基或烷酰基基团取代），R是氢原子或烷基基团；以及其药学上可接受的盐。本发明还提供了制备这些二膦酸盐的方法和含有它们的制剂。
• Triazole containing diphosphonate compounds and the use thereof
  申请人：Boehringer Mannheim GmbH

  公开号：US04784993A1

  公开（公告）日：1988-11-15

  The present invention provides diphosphonates of the general formula: ##STR1## wherein Het is 1,2,3-triazole, or 1,2,4-triazole radical, which is optionally substituted by alkyl, alkoxy, halogen, hydroxyl, carboxyl, an amino group optionally substituted by alkyl or acyl radicals or is a benzyl radical optionally substituted by alkyl, nitro, amino or aminoalkyl, A is a straight-chained or branched, saturated or unsaturated hydrocarbon chain containing 2 to 8 carbon atoms, X is a hydrogen atom, optionally substituted by acyl, or an amino group optionally substituted by alkyl or acyl radicals and R is a hydrogen atom or an alkyl radical; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these diphosphonates and pharmaceutical compositions containing them.

  本发明提供了一般式为：##STR1## 的二膦酸盐，其中Het是1,2,3-三唑基或1,2,4-三唑基，可以被烷基，烷氧基，卤素，羟基，羧基，氨基（可以被烷基或酰基基团取代）或苄基（可以被烷基，硝基，氨基或氨基烷基取代），A是含有2至8个碳原子的直链或支链，饱和或不饱和的碳氢链，X是氢原子，可以被酰基取代，或氨基（可以被烷基或酰基基团取代），R是氢原子或烷基基团；以及其药学上可接受的盐。本发明还提供了制备这些二膦酸盐的过程和含有它们的制药组合物。
• REMEDIES FOR INTRAMEDULLARY DISEASES
  申请人：TORAY INDUSTRIES, INC.

  公开号：EP0998934A1

  公开（公告）日：2000-05-10

  Remedies fix intramedullary diseases which are efficacious in correcting intramedullary biological balance, in particular, preventing inflammatory cellular infiltration and preventing increase in cell proliferation factors. These remedies contain as the active ingredient methanebisphosphonic acid derivatives, esters thereof, pharmaceutically acceptable salts thereof or hydrates of the same. Because of showing excellent therapeutic effects on intramedullary diseases, the above derivatives are expected as useful in preventing and treating intramedullary diseases such as rheumatoid arthritis, multiple myeloma and osteomyelitis. These compounds are also expected as useful in preventing and treating diseases of the hematopoietic system such as aplastic anemia and myelocytic leukemia.

  治疗髓内疾病的药物，可有效纠正髓内生物平衡，特别是防止炎症细胞浸润和防止细胞增殖因子增加。这些疗法的活性成分包括甲烷二膦酸衍生物、其酯类、药学上可接受的盐类或其水合物。由于上述衍生物对髓内疾病有很好的治疗效果，因此有望用于预防和治疗类风湿性关节炎、多发性骨髓瘤和骨髓炎等髓内疾病。这些化合物还有望用于预防和治疗再生障碍性贫血和骨髓细胞白血病等造血系统疾病。
• INTERLEUKIN-6 PRODUCTION INHIBITORS
  申请人：TORAY INDUSTRIES, INC.

  公开号：EP1057488A1

  公开（公告）日：2000-12-06

  An interleukin-6 production inhibitor is provided containing a methanebisphosphonic acid derivative as an active component, which has inhibitory effects on interleukin-6 production and is useful in prevention and treatment of diseases due to abnormal production of the interleukin-6. This pharmaceutical is anticipated to have effects in prevention and treatment of diseases related to the interleukin-6, for example, thrombocytosis, inflammatory diseases, abnormal immune response diseases, osteoporosis, rheumatoid arthritis, hypercalcemia, multiple myeloma, cachexia, and nephritis.

  本发明提供了一种白细胞介素-6 生成抑制剂，其活性成分为甲烷双膦酸衍生物，对白细胞介素-6 生成具有抑制作用，可用于预防和治疗因白细胞介素-6 生成异常而导致的疾病。预计这种药物在预防和治疗与白细胞介素-6 有关的疾病方面具有效果，例如血小板减少症、炎症性疾病、免疫反应异常疾病、骨质疏松症、类风湿性关节炎、高钙血症、多发性骨髓瘤、恶病质和肾炎。
• Neue Diphosphonsäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
  申请人：BOEHRINGER MANNHEIM GMBH

  公开号：EP0170228B1

  公开（公告）日：1988-12-28