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阿雷地平

阿雷地平用途

MPC1304 是一种钙离子 (Ca2+) 通道拮抗剂,具有强大而持久的抗高血压作用。

阿雷地平名称

[ CAS 号 ]:
86780-90-7

[ 中文名 ]:
阿雷地平

[ 英文名 ]:
MPC1304

[中文别名 ]:

[英文别名 ]:

Sapresta
aranidipine
Mpc-1304
MPC1304

阿雷地平生物活性

[ 描述 ]:

MPC1304 是一种钙离子 (Ca2+) 通道拮抗剂,具有强大而持久的抗高血压作用。

[ 相关类别 ]:

信号通路 >> 跨膜转运 >> 钙通道

研究领域 >> 心血管疾病

[ 靶点 ]

Ca2+ Channel [1]

[体内研究]

MPC1304(MPC-1304)是自发性高血压大鼠中新的Ca2 +通道拮抗剂。口服给予自发性高血压大鼠(SHR)剂量为3和10 mg/kg的MPC1304后,与对照组相比,特异性[3H](+)- PN 200-110与心肌膜结合的Bmax值显着降低。值。与对照值相比,1小时(3mg/kg),1小时和6小时(10mg/kg)的Bmax值显着降低(分别为47.7,48.9和25.8％)。效果在1小时时最大,并随时间降低。口服MPC1304后6小时(3mg/kg)和12或24小时(10mg/kg)的Bmax值与对照值没有显着差异,表明MPC1304的作用消失。心肌[3H](+)- PN 200-110结合的Kd值通过口服MPC1304未改变[1]。

[动物实验]

大鼠[1]使用雄性SHR（11-15周）。在给药前禁食16小时，并通过胃管口服MPC1304（3,10mg / kg）。对照动物给予载体。在给药后1-24小时，在用乙醚轻度麻醉下通过降主动脉的出血杀死SHR，并且用来自主动脉的0.9％盐水灌注心肌和脑。然后，移除两个组织，并修剪掉血管。通过离心分离来自大鼠血液的血浆，并储存在-80℃直至测定MPC1304的浓度。

[参考文献]

[1]. Nozawa Y, et al. Receptor occupation and pharmacokinetics of MPC-1304, a new Ca²⁺ channel antagonist, in spontaneously hypertensive rats. Eur J Pharmacol. 1995 Dec 12;287(2):191-6.

[相关活性小分子]

阿雷地平物理化学性质

[ 密度 ]:
1.284 g/cm3

[ 沸点 ]:
530ºC at 760 mmHg

[ 熔点 ]:
155°

[ 分子式 ]:
C₁₉H₂₀N₂O₇

[ 分子量 ]:
388.37100

[ 闪点 ]:
274.3ºC

[ 精确质量 ]:
388.12700

[ PSA ]:
127.52000

[ LogP ]:
2.98680

[ 折射率 ]:
1.555

[ 储存条件 ]:
-20°C，密闭，干燥

阿雷地平毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: US7975620

CHEMICAL NAME :: 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2- oxopropyl ester

CAS REGISTRY NUMBER :: 86780-90-7

LAST UPDATED :: 199612

DATA ITEMS CITED :: 12

MOLECULAR FORMULA :: C19-H22-N2-O7

MOLECULAR WEIGHT :: 390.43

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 :: 1459 mg/kg

TOXIC EFFECTS :: Behavioral - convulsions or effect on seizure threshold Blood - normocytic anemia 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: 21(Suppl 4),S931,1993

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 143 mg/kg

TOXIC EFFECTS :: Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - respiratory depression Blood - normocytic anemia

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: 21(Suppl 4),S931,1993

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 7300 ug/kg

TOXIC EFFECTS :: Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - respiratory depression Blood - normocytic anemia

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: 21(Suppl 4),S931,1993

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 3333 mg/kg

TOXIC EFFECTS :: Cardiac - change in rate Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis

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: 21(Suppl 4),S931,1993 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 1365 mg/kg/13W-I

TOXIC EFFECTS :: Cardiac - changes in heart weight Kidney, Ureter, Bladder - other changes in urine composition Blood - changes in spleen

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: 21(Suppl 4),S947,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 3650 mg/kg/1Y-I

TOXIC EFFECTS :: Cardiac - changes in heart weight Kidney, Ureter, Bladder - urine volume increased 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: 21(Suppl 4),S1013,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 6825 mg/kg/13W-I

TOXIC EFFECTS :: Blood - change in clotting factors Nutritional and Gross Metabolic - weight loss or decreased weight gain Related to Chronic Data - death

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: 21(Suppl 4),S977,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 18200 mg/kg/52W-I

TOXIC EFFECTS :: Cardiac - EKG changes not diagnostic of specified effects Cardiac - pulse rate Blood - pigmented or nucleated red blood cells

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: 21(Suppl 4),S1041,1993 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 165 mg/kg

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

TOXIC EFFECTS :: Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - fetal death

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: 21(Suppl 4),S1095,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 52 mg/kg

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

TOXIC EFFECTS :: Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

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: 21(Suppl 4),S1139,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 468 mg/kg

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

TOXIC EFFECTS :: Reproductive - Maternal Effects - parturition Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - behavioral

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: 21(Suppl 4),S1139,1993

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 500 mg/kg

SEX/DURATION :: female 6-15 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

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: 21(Suppl 4),S1115,1993

阿雷地平合成路线

详细合成路线

阿雷地平上下游产品

阿雷地平上游产品

阿雷地平下游产品

阿雷地平制备

化合物(I)和3-氨基丁烯酸[2，2-(亚乙基二氧基)丙基]酯在乙醇中回流，缩合环合得到化合物(Ⅱ)，再酸性水解得到产物。

1. 乙酰乙酸(2,2-亚乙基二氧基)丙基酯的制备

在反应瓶中加入纯苯100ml和2,2-亚乙基二氧基丙醇20g(0.169mol),搅拌混合,加入50%的氢化钠(NaH)100mg,在搅拌回流下再滴加乙酰基乙烯酮20g(0.238mol),滴毕,继续搅拌回流反应2h.将反应液蒸除溶剂后,再减压蒸馏,收集90ºC/800Pa(6mmHg)馏分,得乙酰乙酸(2,2-亚乙基二氧基)丙基酯21.5g,收率70%左

右,产物为无色油状物.

2. 氨基丁烯酸[2,2-(亚乙基二氧基)丙基]酯的制备

在反应瓶中加入甲醇100ml和上步制备的化合物19g(0.094mol),在冰浴冷却下搅拌通入氨气((鼓泡)反应2.5h. 反应毕,将反应液蒸除溶剂,剩余物再减压蒸馏,收集120ºC/667Pa(5mmHg)馏分,得氨基丁烯酸[2,2-(亚乙基二氧基)丙基]酯淡黄色油状物16g,收率84%左右.

2. 甲基-2,2-亚乙基二氧丙基-2,6-二甲基-4-(2-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸酯的制备

在反应瓶中加入乙醇120ml、上步制备的化合物氨基丁烯酸[2,2-(亚乙基二氧基)丙基]酯7.5g(0.04mol)和2-硝基亚秝基乙酰乙酸甲酯10g(0.40mol),搅拌加热至回流,搅拌回流反应10h.然后将反应液静置过夜.析出结晶沉淀,过滤,滤饼用异丙醇/己烷重结晶,得黄色棱状结晶甲基-2,2-亚乙基二氧丙基-2,6-二甲基-4-(2-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸酯11.0g左右#收率63%左右.mp156ºC.

3. 1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲基-2-氧丙基酯(!阿雷地平)的合成

在反应瓶中加入乙醇35ml(含10%盐酸5ml)和上步制备的化合物甲基-2,2-亚乙基二氧丙基-2,6-二甲基-4-(2-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸酯8.2g(18.98mol),搅拌加热至回流,搅拌回流反应6h.将反应液溶剂蒸除#

剩余物加乙醚析晶#过滤后#滤饼用乙酸乙酯/己烷重结晶#得黄色棱状结晶1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲基-2-氧丙基酯(!阿雷地平)约4.8g,收率65%左右,mp55ºC.