N-(benzothiazol-2-yl)aminomethylenebisphosphonic acid | 118054-16-3

• 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: N-(benzothiazol-2-yl)aminomethylenebisphosphonic acid
• 英文别名: (benzo[d]thiazol-2-amino)methyl-1,1-bisphosphonic acid；1-(benzothiazol-2-yl-amino)methane-1,1-diphosphonic acid；[(1,3-benzothiazol-2-ylamino)-phosphonomethyl]phosphonic acid
• CAS: 118054-16-3
• 化学式: C₈H₁₀N₂O₆P₂S
• 分子量: 324.191
• InChiKey: WDRFJYZCRXWXDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  168
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  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

文献信息

• Substituted aminomethanediphosphonic acids and use in medicaments
  申请人：Ciba-Geigy Corporation

  公开号：US05057505A1

  公开（公告）日：1991-10-15

  Heteroarylaminomethanediphosphonic acids of the formula ##STR1## in which R.sub.1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstituted or is substituted by lower alkyl; by phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen; by lower alkoxy; by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen; and R.sub.2 represents hydrogen or lower alkyl, and their salts, have a regulatory action on the calcium metabolism and can be used as active ingredients in medicaments for the treatment of illnesses that can be attributed to disorders of the calcium metabolism. They are manufactured, for example, as follows: in a compound of the formula ##STR2## in which X.sub.1 represents a functionally modified phosphono group X and X.sub.2 represents phosphono or similarly represents a functionally modified phosphono group X, the group(s) X is(are) converted into free phosphono.

  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。
• Neue Substituiertaminomethandiphosphonsäuren
  申请人：CIBA-GEIGY AG

  公开号：EP0274346A1

  公开（公告）日：1988-07-13

  Heteroarylaminomethandiphosphonsäuren der Formel worin R1 einen unsubstituierten oder durch Niederalkyl, unsubstituiertes oder durch Niederalkyl, Niederalkoxy und/oder Halogen substituiertes Phenyl, Niederalkoxy, Hydroxy, Diniederalkylamino, Niaderalkylthio und/oder Halogen substituierten ggf. benzo- oder cyctohexenokondensierten 5-gliedrigen, als Heteroatom(e) 2 bis 4 N-Atome oder 1 oder 2-N-Atome sowie 1 O- oder S-Atome aufweisenden Heteroarylrest darstellt und R2 Wasserstoff oder Niederalkyl bedeutet, und ihre Salze wirken regulierend auf den Calciumstoffwechsel und können als Arzneimittelwirkstoff für die Behandlung von auf Störungen derselben zurückzuführende Erkrankungen verwendet werden. Sie werden z.B. hergestellt, indem man in einer Verbindung der Formel worin Xi eine funktionell abgewandelte Phosphonogruppe X und X2 Phospono oder ebenfalls eine funktionell abgewandelte Phosphonogruppe X bedeutet, die Gruppe(n) X in freies Phosphono überführt.

  式中的杂芳基氨基甲叉二膦酸 其中 R1 代表未取代的或低级烷基、未取代的或低级烷基、低级烷氧基和/或卤素取代的苯基、低级烷氧基、羟基、二低级烷基氨基、新烷硫基和/或卤素取代的、任选具有 2 至 4 个 N 原子的苯并或辛二烯缩合 5 元杂原子或具有 2 至 4 个 N 原子的苯并或辛二烯缩合 5 元杂芳基的杂原子。具有 2 至 4 个 N 原子或 1 至 2 个 N 原子和 1 个 O 原子或 S 原子作为杂原子的苯并或辛 并缩合 5 元杂芳基，R2 表示氢或低级烷基。它们的制备方法如下 其中 Xi 是功能修饰的膦酰基 X，X2 是膦酰基或也是功能修饰的膦酰基 X，基团 X 被转化为游离膦酰基。
• Azole-aminomethylene bisphosphonic acid derivatives
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP0282309A2

  公开（公告）日：1988-09-14

  Azole-aminomethylene bisphosphonic acids and lower alkyl esters and salts thereof, of the following general formula (I), are useful as drugs, e.g. as antiinflammatory and antirheumatic agents.

  以下通式（I）的唑-氨甲基双膦酸及其低级烷基酯和盐可用作药物，例如抗炎药和抗风湿药。
• 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.