92077-78-6

• 常用中文名：西拉普利
• 常用英文名：Cilazapril Monohydrate
• CAS号：92077-78-6
• 分子式：C₂₂H₃₃N₃O₆
• 分子量：435.51400
• 相关类别： 原料药 循环系统用药 抗高血压病药
• 发布时间：2018-03-18 08:00:00
• 更新时间：2024-02-03 09:50:26
• Cilazapril一水合物是血管紧张素转化酶抑制剂,可作用于高血压和充血性心力衰竭。

名称

• 中文名: 西拉普利
• 英文名: cilazapril
• 英文别名: Cilazapril Monohydrate; Cilazapril (monohydrate)

物化性质

• 沸点: 598.1ºC at 760mmHg
• 熔点: 98° (dec)
• 分子式: C₂₂H₃₃N₃O₆
• 分子量: 435.51400
• 闪点: 315.5ºC
• 精确质量: 435.23700
• PSA: 108.41000
• LogP: 1.79790
• 外观性状: 粉末
• 储存条件: -20℃
• 分子结构:

  1、 摩尔折射率：111.73

  2、 摩尔体积（cm³/mol）：330.3

  3、 等张比容（90.2K）：913.4

  4、 表面张力（dyne/cm）：58.4

  5、 极化率（10-24cm3）：44.29

• 计算化学:

  1.疏水参数计算参考值（XlogP）:无

  2.氢键供体数量:3

  3.氢键受体数量:8

  4.可旋转化学键数量:9

  5.互变异构体数量:2

  6.拓扑分子极性表面积100

  7.重原子数量:31

  8.表面电荷:0

  9.复杂度:608

  10.同位素原子数量:0

  11.确定原子立构中心数量:3

  12.不确定原子立构中心数量:0

  13.确定化学键立构中心数量:0

  14.不确定化学键立构中心数量:0

  15.共价键单元数量:2

• 更多:

  1.性状：从乙醇结晶。

  2.熔点（℃）：95-97。

  3.比旋光度([α]_D²⁰C=1%，乙醇)：-62.51。

生物活性

• 描述: Cilazapril一水合物是血管紧张素转化酶抑制剂,可作用于高血压和充血性心力衰竭。
• 相关类别:
  信号通路 >> 代谢酶/蛋白酶 >> 血管紧张素转换酶(ACE)
  研究领域 >> 心血管疾病
• 参考文献:

  [1]. Szucs, T., Cilazapril. A review. Drugs, 1991. 41 Suppl 1: p. 18-24.

  [2]. Nussberger, J., et al., Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers. J Cardiovasc Pharmacol, 1987. 9(1): p. 39-44.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : UR6113250 CHEMICAL NAME : 6H-Pyridazino(1,2-a)(1,2)diazepine-1-carboxylic acid, octahydro-9-((1-(ethoxycarbonyl)-3- phenylpropyl)amino)-10-oxo-, hydrate, (1S-(1-alpha,9-alpha(R*)))- CAS REGISTRY NUMBER : 92077-78-6 LAST UPDATED : 199706 DATA ITEMS CITED : 12 MOLECULAR FORMULA : C22-H31-N3-O5.H2-O MOLECULAR WEIGHT : 435.58 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Human - woman DOSE/DURATION : 15 mg/kg/22W-I TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) REFERENCE : LANCAO Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- Volume(issue)/page/year: 345,398,1995 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >5 gm/kg TOXIC EFFECTS : Gastrointestinal - changes in structure or function of salivary glands Gastrointestinal - hypermotility, diarrhea REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 830 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CDREEA Cardiovascular Drug Reviews. (Raven Press, 1185 Avenue of the Americas, New York, NY 10036) V.6- 1988- Volume(issue)/page/year: 8,1,1990 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >1 gm/kg TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) Behavioral - rigidity (including catalepsy) REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : >30 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 5 gm/kg TOXIC EFFECTS : Behavioral - altered sleep time (including change in righting reflex) Behavioral - convulsions or effect on seizure threshold Nutritional and Gross Metabolic - body temperature decrease REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 1300 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CDREEA Cardiovascular Drug Reviews. (Raven Press, 1185 Avenue of the Americas, New York, NY 10036) V.6- 1988- Volume(issue)/page/year: 8,1,1990 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >1 gm/kg TOXIC EFFECTS : Skin and Appendages - dermatitis, other (after systemic exposure) Skin and Appendages - hair REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >30 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1281,1989 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Primate - monkey DOSE/DURATION : >4 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : CDREEA Cardiovascular Drug Reviews. (Raven Press, 1185 Avenue of the Americas, New York, NY 10036) V.6- 1988- Volume(issue)/page/year: 8,1,1990 ** OTHER MULTIPLE DOSE TOXICITY DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 22750 mg/kg/13W-I TOXIC EFFECTS : Cardiac - changes in heart weight Blood - normocytic anemia Nutritional and Gross Metabolic - weight loss or decreased weight gain REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1295,1989 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Primate - monkey DOSE/DURATION : 22500 mg/kg/90D-I TOXIC EFFECTS : Cardiac - changes in heart weight Kidney, Ureter, Bladder - changes in tubules (including acute renal failure, acute tubular necrosis) Blood - changes in erythrocyte (RBC) count REFERENCE : YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1333,1989

制备

化合物(Ⅱ)(24.6g，7.7mmo1)溶于135ml甲苯，在10℃和搅拌下，加入20.2g碳酸氢钠在200ml水的溶液，再加入酰氯(I)(从其酸(33．8g，90mmo1)和13.1rnl氯化亚砜在甲苯中反应制得)在150ml甲苯的溶液，然后在室温下搅拌17h，分层，有机层用Florisil柱层析。蒸去洗脱液，剩余物为化合物(Ⅲ)，将其溶于500ml二甲基甲酰胺，加入5%钯-炭，氢化18h。滤去催化剂，滤液浓缩。剩余物用．50ml乙醚处理后，过滤。在10℃和搅拌下，将得到的白色固体溶于590ml二氯甲烷。在1.5min中，加入氯化亚砜(5.5ml，0.08mo1)，再在室温下搅拌4h。加入15.5g碳酸氢钾在155ml水的溶液。分出有机层，浓缩，剩余物经层析得25.1g化合物(Ⅳ)，收率76%，熔点188～189℃(乙酸乙酯-己烷)，[α]_D²⁰-85.1°(C=0.5，甲醇)。
化合物(Ⅳ)(36.5g，85mmo1)溶于85ml干燥四氢呋喃中，在冷却、搅拌和缓慢氮气流下，加入1mol/L硼烷的四氢呋喃溶液(75.2ml，75mmo1)，控制内温在10～15℃，约1h加毕。在10～15℃下搅拌1h，再在室温下搅拌3h。加入170ml二氯甲烷，再在搅拌下加入170ml 2mol/L盐酸。搅拌1.5min后，加入无水碳酸钠碱化。分出有机层，用盐水洗，浓缩。得31.7g化合物(V)，收率90%，熔点140.5～141.5℃(含水乙醇)，[α]_D²⁰-68.5°(C=1，甲醇)。
化合物(V)(8.26g，20mmo1)悬浮于82.6ml乙醇，加入水合肼(2.2g，44mmo1)，在室温下搅拌1h。蒸出溶剂，剩余物加入甲苯，再蒸干。加入82.6ml 2mol/L乙酸水溶液，搅拌16h。过滤，滤液用无水碳酸钠碱化后，用二氯甲烷提取。提取液加入40ml。10%碳酸钠溶液，再在室温和搅拌下，加入(2R)-2-三氟甲磺酰氧基-4-苯基丁酸乙酯(Ⅵ)(7.48g，22mmo1)在20ml二氯甲烷的溶液，继续搅拌5h。分出有机层，和10g Florisil(商品名，即硅酸镁载体)一起搅拌30min,，过滤，滤液含化合物(Ⅶ)，将其冷至0～5℃在搅拌下，通2h干燥的氯化氢气体。然后在室温下搅拌16h。浓缩，剩余物在水和乙醚之间进行分配。分出乙醚层，用1mol/L盐酸提取。提取液和水层合并，用5mol/L氢氧化钠溶液调至Ph=4.4。滤集固体，得7.21g西拉普利，收率83%。用二氯甲烷提取滤液，可得0.72g第二份西拉普利产品，收率8%。用含水乙醇重结晶后，熔点95～97℃，[α]_D²⁰-62.5°(C=1，乙醇)。