sodium dichloromethylene bisphosphonate | 10595-91-2

• 物质功能分类: 有机原料 - 有机膦化合物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物
• 英文名称: sodium dichloromethylene bisphosphonate
• 英文别名: tetrasodium clodronate；(dichloromethylene)bisphosphonic acid tetrasodium salt；sodium salt of dichloromethane diphosphonic acid
• CAS: 10595-91-2；10596-24-4；22560-50-5；29329-69-9
• 化学式: CCl₂O₆P₂*4Na
• 分子量: 332.82
• InChiKey: FJXQZKHJWBPUJG-UHFFFAOYSA-J

物化性质

• 熔点：
  >330°C
• 溶解度：
  易溶于水，几乎不溶于乙醇（96%），微溶于甲醇。

计算性质

• 辛醇/水分配系数(LogP)：
  -5.09
• 重原子数：
  12.0
• 可旋转键数：
  2.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  126.38
• 氢给体数：
  0.0
• 氢受体数：
  6.0

安全信息

• WGK Germany：
  3
• 海关编码：
  2931900090
• RTECS号：
  SZ7640700
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P501,P273,P260,P270,P264,P280,P391,P314,P337+P313,P305+P351+P338,P301+P312+P330
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410

制备方法与用途

双膦酸盐类药物

氯屈膦酸二钠是第一代双膦酸盐类治疗骨质疏松药物，双膦酸盐（bisphosphonates，BPs）是用于各类骨疾患及钙代谢性疾病的一类新药物。能特异的与骨质中的羟膦灰石结合，抑制破骨细胞活性，从而抑制骨质吸收。用于治疗骨质疏松症，变形性骨炎，恶性肿瘤骨转移引起的高钙血症和骨痛症等。

生物活性

Clodronate Disodium，一种二膦酸盐，是一种有效的抗溶骨剂，能够抑制骨吸收。

体外研究

Clodronate显著降低J774细胞培养物的总存活率， EC50为300 μM，同时脂质体包裹的Clodronate降低J774细胞培养物的总存活率，EC50为 1 μM。Clodronate 和脂质体包裹的Clodronate代谢为一个不可水解的三磷酸腺苷（ATP）的类似物，腺苷5'-（β，γ-二氯亚甲基）三磷酸，它可以在J774细胞提取物中通过蛋白液相色谱进行快速检测。 Clodronate诱导离体的破骨细胞凋亡。Clodronate，当在脂质体中给药时，也可诱导小鼠体外腹膜巨噬细胞和小鼠体内肝巨噬细胞的凋亡，但对鼠巨噬细胞样的RAW-264细胞没有作用。 Clodronate被脂质体输送到巨噬细胞会杀死这些细胞作为细胞内累积和不可逆代谢损伤的结果。依据治疗方案，Clodronate包裹于脂质体（clodrolip）作用于F9畸胎癌小鼠和携带人类A673横纹肌肉瘤的小鼠模型，可有效地减少吞噬细胞从而显著抑制75至> 92％的肿瘤的生长。 Clodronate，缺乏氮的二膦酸盐，对蛋白质异戊二烯化无抑制作用，但可以在细胞内代谢为一种ATP类似物beta-gamma-methylene（AppCp型），这是对体外巨噬细胞的细胞毒作用。Clodronate代谢成AppCCl（2）p，然后AppCCl（2）P通过参与竞争性地抑制ADP / ATP移位酶的机制，从而抑制线粒体的氧消耗。

体内研究

Clodronic acid (Clodronate) disodium salt (6.25-25 mg/kg; p.o.; daily for 28 days) slightly decreases the hindpaw swelling at doses of 12.5 and 25 mg/kg.

Animal Model:	Male Lewis rats, aged 7 weeks
Dosage:	6.25, 12.5, and 25 mg/kg
Administration:	P.o.; daily for 28 days
Result:	Hindpaw swelling was significantly smaller than in adjuvant-arthritis (AA)-control at 25 mg/kg on days 21 and 28 (87 and 88% of AA-control, respectively) and at 12.5 mg/kg on day 28.

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 sodium dichloromethylene bisphosphonate 反应 24.0h， 以74%的产率得到O,O''-diacetyl (dichloromethylene)bisphosphonate disodium salt
  参考文献：
  名称：

  Bisphosphonate Prodrugs:  Synthesis and in Vitro Evaluation of Novel Clodronic Acid Dianhydrides as Bioreversible Prodrugs of Clodronate

  摘要：

  P,P'-Diacetyl, P,P'-dibutyroyl, P,P'-dipivaloyl, and P,P'-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a-d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a-d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between l-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 degrees C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 degrees C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.

  DOI：

  10.1021/jm9810809

文献信息

• Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products
  作者：Susan Kunnas-Hiltunen、Matti Haukka、Jouko Vepsäläinen、Markku Ahlgrén

  DOI：10.1039/c002403a

  日期：——

  and Na2L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na3Cl2C(PO3)2}(H2O)4]n (1). The other metal complexes prepared comprised the polymeric Ba2+ complex of L12− ligand [BaCl2C(PO2O(C(O)Me))2}(H2O)3]n (2); the new Sr2+ complex of clodronic acid [Sr2(Cl2C(PO3)2)(H2O)4}·H2O]n (3), and the K+ complex of the L32− ligand [K2Cl2C(PO2O(C(O)C6H5))2}O]n

  的碱金属和碱土金属配合物 P，P '二乙酰基-（L1 2−）; 新的P，P '-dipropanoyl- （L2 2-）和P，P '二苯甲酰（二氯亚甲基）双膦酸盐（L3 2-）和制备和使用该单晶X射线衍射技术和光谱特征，与研究水解的意图它们的水解产物和这些潜在的氯膦酸盐前药的协调特性。Na 2 L1和Na 2 L2形成了这些二酐的第一个晶体水解产物，3D聚合三钠氯膦酸盐，[Na 3 Cl 2 C（PO 3）2 }（H 2 O）4 ] n（1）。制备的其他金属配合物包括聚合物钡2+复杂的L1 2-配体[巴CL 2 C（PO 2 O（C（O）Me）中）2 }（H 2 O）3 ] Ñ（2）; 新的Sr 2+氯膦酸[Sr 2（Cl 2 C（PO 3）2）（H 2 O）4 }·H 2 O] n（3）的络合物和L3 2-配体的K +络合物[K 2 Cl 2 C（PO 2 O（C（O）C 6 H