甲磺酸溴隐亭

中文名称:

甲磺酸溴隐亭

中文同义词:

甲磺酸溴隐亭;2-溴-alpha-麦角环肽甲磺酸盐;2-溴-Α-麦角隐亭甲磺酸盐;甲黄酸溴麦角环肽;甲磺酸溴隐亭/甲黄酸溴麦角环肽;(6AR,9R)-5-溴-N-((2R,5S,10AS,10BS)-10B-羟基-5-异丁基-2-异丙基-3,6-二氧八氢-2H-恶唑[3,2-A]吡咯并[2,1-C]吡嗪-2-基)-7-甲基-4,6,6A,7,8,9-六氢吲哚并[4,3-FG]喹啉-9-甲酰胺甲磺酸盐;甲磺酸溴隐亭 USP标准品;甲磺酸溴隐亭 EP标准品

英文名称:

Bromocriptine mesylate

英文同义词:

(5A)-2-BROMO-12-HYDROXY-2-(1-METHYLETHYL)-5-(2-METHYLPROPYL)ERGOTAMAN-3,6,18-TRIONE MESYLATE;BCT;BRC;(+)-BROMOCRIPTINE MESYLATE;BROMOCRIPTINE MESYLATE;(+)-BROMOCRIPTINE METHANESULFONATE;BROMOCRIPTINE METHANESULPHONATE;BROMOCRYPTINE MESYLATE METHANESULFONATE SALT

CAS号:

22260-51-1

分子式:

C33H44BrN5O8S

分子量:

750.7

EINECS号:

244-881-1

相关类别:

医药原料药;医用原料;医药原料;医药原料;原料药;原料;PARLODEL;Aromatics;Dopamine receptor;Heterocycles;Inhibitors;Intermediates Fine Chemicals;Pharmaceuticals

Mol文件:

22260-51-1.mol

熔点 

192-196° (dec)

比旋光度 

D20 +95° (c = 1 in methanol-methylene chloride)

储存条件 

2-8°C

溶解度 

H2O: 0.8 mg/mL

酸度系数(pKa)

4.90(at 25℃)

形态

solid

颜色

white

旋光性 (optical activity)

[α]20/D +95°, c = 1 in methanol: methylene chloride (1:1)(lit.)

Merck 

13,1400

BRN 

4115238

InChIKey

NOJMTMIRQRDZMT-JGYCFGIMSA-N

CAS 数据库

22260-51-1(CAS DataBase Reference)

背景

甲磺酸溴隐亭最早由诺华公司开发，主要用于抗震颤麻痹，抑制生理性泌乳和治疗催乳激素过高引起的经前期综合征、肢端肥大症、女性不育症和亨丁顿舞蹈病。临床用于治疗帕金森病，与催乳素有关的生殖系统功能异常，如闭经、溢乳症、经前综合征、产褥期乳腺炎、纤维囊性乳腺瘤、男性阳痿或性欲减退，还可用于垂体腺瘤等。甲磺酸溴隐亭快速释放的口服制剂辅助用于Ⅱ型糖尿病的治疗，该药2009年5月获得ＦＤＡ批准。

作用

本品又称溴麦亭、溴化麦角隐亭、溴克丁、麦角克碱、麦角环肽、抑乳停、甲磺酸溴隐亭，是麦角生物碱的半合成衍生物，能特异地兴奋中枢多巴胺受体，对其他受体有拮抗作用。无麦角类的收缩子宫和血管作用。可抑制PRL、LH的分泌，激活脑内新纹状体的多巴胺受体，控制震颤麻痹综合征；通过中枢或外周的作用松弛血管平滑肌，减低交感神经兴奋性，进而使血压下降，脉率不增加。

适应症

适用于治疗高泌乳素血症及泌乳素瘤，或作为泌乳素瘤的术前准备或术后治疗；亦用于治疗垂体生长激素瘤、巨人症及肢端肥大症；或用于垂体促皮质素瘤及库欣(Cushing)病合并血糖升高者的治疗。可用于治疗多囊卵巢综合征，对排卵功能障碍性不孕症有效。对乳腺增生、回乳、月经紊乱、经前紧张综合征、肝性脑病、糖尿病、特发性水肿、垂体性甲亢及甲状腺功能减退症均有一定效果。

制备

1）溴隐亭的合成 将α-麦角隐亭12g（20.8mmoL）和二氯甲烷120mL加入反应瓶中，搅拌溶清后依次加入5，5-二溴巴比妥酸3.69g（12.9mmoL）、33％氢溴酸的冰乙酸溶液0.2mL，控温25～30℃反应5～6h，过滤，滤液依次用1moL／L的硫代硫酸钠（30mL），5％的碳酸氢钠溶液（30mL），20％氯化钠溶液（30mL）洗涤。有机相用无水硫酸镁干燥，过滤，并加入硅胶36g浓缩将溶剂完全拉干。柱层析：流动相先为二氯甲烷，后为V（二氯甲烷）∶V（丙酮）＝6∶1的混合溶液。得10.6g溴隐亭，收率７8％。 2）甲磺酸溴隐亭的合成 将溴隐亭6.0g用二氯甲烷120mL溶清后加入2-丁酮200mL，控制内温20～30℃，加入甲磺酸1.14g，生成结晶型沉淀，搅拌1h。滤出固体，用2-丁酮30mL洗涤，干燥得6.13g甲磺酸溴隐亭，收率86％。

生物活性

Bromocriptine mesylate 是一种有效的多巴胺 D2/D3 受体激动剂，结合多巴胺 D2 受体，pKi 为 8.05±0.2。

靶点

pKi: 8.05±0.2 (dopamine D2 receptor)

体外研究

Bromocriptine stimulates [ 35 S]-GTPγS binding at D2 dopamine receptor expressed in CHO cells with pEC 50 of 8.15±0.05. Bromocriptine also is a strong inhibitor of brain nitric oxide synthase. The ergot alkaloid Bromocriptine (BKT) is found to act as a strong inhibitor of purified neuronal nitric oxide synthase (NOS) (IC 50 =10±2 μM) whereas it is poorly active towards inducible macrophage NOS (IC 50 >100 μM) . Bromocriptine is found to inhibit the activity of at least one human cytochrome P450 enzyme. Bromocriptine is a potent inhibitor of CYP3A4 with a calculated IC 50 value for the interaction of 1.69 μM.

体内研究

Bromocriptine mesylate (2 mg/kg, i.p.) is administered for 7 days in groups of mice in forced swimming test (FST) and tail suspension test (TST). Bromocriptine group shows significant anti-immobility action as compared to control. When Bromocriptine administered 30 min after the last dose of 7 days MPE treatment and subjected to FST, this dopaminergic agonist produces significant and dose dependent potentiation of anti-immobility action of MPE (200 mg/kg, p.o.) as compared to MPE treatment alone. Bromocriptine treatment group shows a significant reduction of immobility time as compared to control. Bromocriptine administration after 7 days pretreatment with MPE (100 and 200 mg/kg, p.o.) shows significant and dose dependent potentiation of anti-immobility action of MPE as compared to MPE treatment alone. Intracisternal administration of Bromocriptine decreases significantly the static mechanical allodynia (SMA) score compared to that of sham (saline-injected rats) and its effect lasted for 30 min. Intraperitoneal administration of Bromocriptine induces a significant, dose dependent (0.1 mg and 1 mg/kg) decrease in pain scores in CCI-IoN group when compared to sham and its effect lasted for 6 h. The highest dose induces the highest score decrease (P<0.01). Bromocriptine effect lasts for 20 min. Intraperitoneal administration of Bromocriptine induces a significant dose dependent decrease in SMA score in CCI-IoN+6-OHDA lesioned group compared to that of sham. Its effect lasts for 6 h.

类别

有毒物质

毒性分级

中毒

急性毒性

口服-小鼠 LD50: 2502 毫克/公斤; 静脉-大鼠 LD50: 10.5 毫克/公斤

可燃性危险特性

热分解排出有毒氮氧化物,硫氧化物和溴化物烟雾

储运特性

库房通风干燥低温

灭火剂

水,干粉,二氧化碳,泡沫,沙土

危险品标志 

Xn

危险类别码 

20/21/22

安全说明 

22-24/25-36

危险品运输编号 

UN 3077 9 / PGIII

WGK Germany 

3

RTECS号

KE1595000

F 

3-10

海关编码 

29396900

毒性

LD50 in mice, rats, rabbits (mg/kg): 190, 72, 12.5 i.v. (Parkes)