尼普地洛

尼普地洛用途

尼普拉洛尔(KT-210；K-351)是一种强效的α-1-肾上腺素能受体阻断剂。尼泊洛尔抑制了苯肾上腺素(HY-B0769)诱导的白化兔模型中的眼内压(IOP)升高。尼普拉多抑制去甲肾上腺素(NA)诱导的肌肉收缩,同时对狗冠状动脉也表现出血管舒张作用[1][2]。

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尼普地洛名称

[ CAS 号 ]:
81486-22-8

[ 中文名 ]:
尼普地洛

[ 英文名 ]:
Nipradilol

[英文别名 ]:

nipradilol(jan)
Nipradolol
Nipradilol (JAN)
Nipradilol
Hypadil
K-351
Nipradilolum [Latin]

尼普地洛生物活性

[ 描述 ]:

尼普拉洛尔(KT-210；K-351)是一种强效的α-1-肾上腺素能受体阻断剂。尼泊洛尔抑制了苯肾上腺素(HY-B0769)诱导的白化兔模型中的眼内压(IOP)升高。尼普拉多抑制去甲肾上腺素(NA)诱导的肌肉收缩,同时对狗冠状动脉也表现出血管舒张作用[1][2]。

[ 相关类别 ]:

研究领域 >> 心血管疾病

信号通路 >> G 蛋白偶联受体/G 蛋白 >> 肾上腺素能受体

[ 靶点 ]

α1-adrenergic receptor

[体外研究]

尼普拉洛尔(1μM；10分钟) 抑制钾诱导的犬肌肉收缩,第50页值为 0.8μM[1]尼普拉洛尔(1μM；10分钟) 降低静息张力,抑制近端区钠诱导的收缩[1]。

[体内研究]

尼普拉洛尔(0.125%、0.25%、0.5%；静脉注射; 单剂量) 以浓度依赖的方式抑制兔眼眼压的增加[2]。

[参考文献]

[1]. 3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran (K-351) and its denitrated derivative on smooth muscle cells of the dog coronary artery. Br J Pharmacol. 1983 May;79(1):285-95.

[2]. Nishio K. Alpha-1-adrenoceptor blocking activity of KT-210 (nipradilol ophthalmic solution) on intraocular pressure in the rabbit eye[J]. Nihon Ganka Kiyo (Folia Ophthalmol Jpn), 1999, 50: 655-660.

尼普地洛物理化学性质

[ 密度 ]:
1.3±0.1 g/cm3

[ 沸点 ]:
500.0±45.0 °C at 760 mmHg

[ 熔点 ]:
110-122ºC

[ 分子式 ]:
C₁₅H₂₂N₂O₆

[ 分子量 ]:
326.345

[ 闪点 ]:
256.2±28.7 °C

[ 精确质量 ]:
326.147797

[ PSA ]:
105.77000

[ LogP ]:
1.97

[ 外观性状 ]:
无色针状晶体

[ 蒸汽压 ]:
0.0±1.3 mmHg at 25°C

[ 折射率 ]:
1.561

尼普地洛毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: DJ2887000

CHEMICAL NAME :: 2H-1-Benzopyran-3-ol, 3,4-dihydro-8-(2-hydroxy-3-((1-methylethyl)amino)prop oxy)-, 3-nitrate

CAS REGISTRY NUMBER :: 81486-22-8

LAST UPDATED :: 199612

DATA ITEMS CITED :: 20

MOLECULAR FORMULA :: C15-H22-N2-O6

MOLECULAR WEIGHT :: 326.39

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 1040 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 144 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 850 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 78 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 461 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 147 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 416 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 68 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >400 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Gastrointestinal - nausea or vomiting Lungs, Thorax, or Respiration - dyspnea

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 20 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rabbit

DOSE/DURATION :: 300 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,725,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rabbit

DOSE/DURATION :: 20 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 20,228,1989 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 5250 mg/kg/5W-C

TOXIC EFFECTS :: Liver - changes in liver weight Endocrine - changes in spleen weight Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,733,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 93600 mg/kg/52W-I

TOXIC EFFECTS :: Kidney, Ureter, Bladder - other changes in urine composition Blood - normocytic anemia Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 30,221,1985 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5400 mg/kg

SEX/DURATION :: female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4)

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 30,1,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 4400 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Newborn - live birth index (measured after birth)

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,747,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2200 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetal death

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,747,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 550 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,747,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2700 mg/kg

SEX/DURATION :: female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Effects on Newborn - physical

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 30,1,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 260 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Embryo or Fetus - fetal death

REFERENCE :: OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 29,747,1985

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尼普地洛合成路线

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尼普地洛上下游产品

尼普地洛上游产品

尼普地洛下游产品

尼普地洛制备

消旋体的制备。1.82g2-烯丙基-6-甲氧基苯基乙酸酯溶于20ml二氯甲烷，加入3.0ml40%(W/V)过氧乙酸溶液和0.18g乙酸钾，在室温下搅拌48h。将反应液加到100ml氯仿和50ml5%亚硫酸钠水溶液中。分出有机层，水洗，无水硫酸钠干燥。减压浓缩得1.74g淡黄色粘稠液体的化合物(Ⅰ)，收率88.7%。

1.74g化合物(Ⅰ)溶于10ml乙醚，在0℃加入5.0ml20%(W/V)氯化氢的乙醚溶液，在室温下搅拌12h。加入100ml乙醚，用饱和碳酸氢钠溶液中和。分出醚层，水洗，无水硫酸钠干燥。减压浓缩得1.83g淡黄色粘稠液体的化合物(Ⅱ)，收率90.4%。

1.82g化合物(Ⅱ)溶于10ml二甲基甲酰胺，加入1.26g碳酸钾，在室温下搅拌2h后，加入50ml水和100ml苯。分出有机层，水洗，无水硫酸钠干燥。减压浓缩得1.53g淡黄色粘稠液体的化合物(Ⅲ)。

1.53g化合物(Ⅲ)溶于30ml甲醇，加入10ml1mol/L氢氧化钠溶液。在室温下搅拌1h后，加入12ml1mol/L盐酸。减压浓缩，剩余物用30ml苯提取。提取液水洗，无水硫酸钠干燥。减压浓缩得到的棕色粘稠油用苯-己烷重结晶，得0.66g无色棱状结晶的化合物c，收率52.1%，熔点79～82℃。

1.50g化合物1mol/L加到8.60g47%氢溴酸中，在90℃下搅拌9h。冷至室温，用氢氧化钠水溶液调至弱酸性后，用30ml乙酸乙酯提取。提取液用饱和盐水洗，无水硫酸钠干燥。减压浓缩，丙酮结晶得棕色固体。再用乙酮和己烷重结晶，得1.23g无色针状结晶的化合物(Ⅴ)，收率88.9%，熔点126～129℃。

20mmol化合物(Ⅴ)和23mmol三乙胺溶于20ml四氢呋喃，在0～5℃加入23mmol氯甲酸乙酯(或三氯乙酰氯)溶于35ml四氢呋喃的溶液，再搅拌0.5h。过滤，滤液减压浓缩。剩余物(4.85g)溶于80ml乙腈，冷至-8～－10℃，加入乙酰硝酸酯(从2.22g乙酸酐和1.36g发烟硝酸制得)，在此温度再搅拌0.5h。再在-8℃加入另一份乙酰硝酸酯(从1.36g乙酸酐和0.85g发烟硝酸制得)，继续搅拌0.5h。加入碳酸氢钠以终止反应，用180ml乙酸乙酯提取。提取液用碳酸氢钠溶液和饱和盐水洗，干燥，浓缩至干。剩余物棕色油溶于10ml甲醇和0.93g氢氧化钠溶于5ml水的混合溶液，在室温下搅拌0.5h。用浓盐酸酸化后，减压蒸去甲醇，用60ml乙酸乙酯提取。提取液用饱和盐水洗，干燥，浓缩至干。剩余的深棕色油用硅胶柱层析，用苯洗脱。得到的固体再用苯和己烷结晶，得无色结晶的化合物(Ⅵ)，收率65%，熔点101～103℃。

4mmol化合物(Ⅵ)溶于15ml1mol/L氢氧化钠，加入16mmol环氧氯丙烷，在50℃下搅拌2h。加入30ml乙酸乙酯。分出有机层，用10ml1mol/L氢氧化钠溶液和10ml饱和盐水洗，干燥，浓缩至干。得到的油状物无需提纯，可直接用于下列反应。取4mmol该油溶于30ml甲醇，加入20mmol异丙胺，在70℃下加热1h。浓缩至干，剩余油状物用三氧化二铝柱层析，氯仿洗脱。得到的固体用乙酸乙酯和己烷结晶，得尼普地洛，收率61%，熔点110～122℃。

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