拉贝洛尔 | 36894-69-6

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 拉贝洛尔
• 中文别名: 拉本他乐；2-羟基-5-{1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基}苯甲酰胺；柳胺苄心定；降压乐
• 英文名称: labetaol
• 英文别名: Labetalol；2-hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide
• CAS: 36894-69-6
• 化学式: C₁₉H₂₄N₂O₃
• mdl: MFCD00242941
• 分子量: 328.411
• InChiKey: SGUAFYQXFOLMHL-UHFFFAOYSA-N

物化性质

• 熔点：
  188 °C
• 沸点：
  552.7±50.0 °C(Predicted)
• 密度：
  1.200±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：125 mg/mL（380.62 mM；需要超声波）
• 物理描述：
  Solid
• 稳定性/保质期：

  Labetalol hydrochloride tablets should be stored in well closed containers at 2-30 °C; tablets in unit dose packages should be protected from excessive moisture. Labetalol hydrochloride injection should be stored at 2-30 °C and protected from light and freezing. Labetalol hydrochloride tablets and injection have an expiration date of 3 and 2 years, respectively, after the date of manufacture. /Labetalol hydrochloride/

• 解离常数：
  pKa = 9.3
• 碰撞截面：
  178.1 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.315
• 拓扑面积：
  95.6
• 氢给体数：
  4
• 氢受体数：
  4

ADMET

代谢

拉贝洛尔的代谢在文献中尚未被完全描述，但羊的研究表明存在N-脱烷基化生成3-氨基-1-苯基丁烷。这种代谢物可能进一步代谢为苯甲基乙酮和3-氨基-(4-羟基苯基)丁烷。人体中的拉贝洛尔主要代谢为葡萄糖苷酸代谢物，如O-苯基葡萄糖苷酸和N-葡萄糖苷酸。

The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide.

来源:DrugBank

代谢

拉贝洛尔在口服给药后在肝脏和可能的胃肠道粘膜中广泛代谢，主要是通过与葡萄糖醛酸结合。主要代谢物是O-烷基葡萄糖苷酸，还形成少量的O-苯基葡萄糖苷酸和N-葡萄糖苷酸。口服给药后，拉贝洛尔在肝脏和/或胃肠道粘膜中经历广泛的首过代谢。

Labetalol is extensively metabolized in the liver and possibly in the GI mucosa following oral administration, principally by conjugation with glucuronic acid. The major metabolite is the O-alkylglucuronide, with smaller amounts of the O-phenylglucuronide and N-glucuronide being formed. Following oral administration, labetalol undergoes extensive first pass metabolism in the liver and/or GI mucosa.

来源:Hazardous Substances Data Bank (HSDB)

代谢

主要在肝脏进行，首次通过代谢显著 消除途径：这些代谢物存在于血浆中，并通过尿液排出，以及通过胆汁进入粪便。 半衰期：6-8小时

Primarily hepatic, undergoes significant first pass metabolism Route of Elimination: These metabolites are present in plasma and are excreted in the urine, and via the bile, into the feces. Half Life: 6-8 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

拉贝洛尔有两个不对称中心，因此存在两种对映异构体对的分子复合物。地莱洛尔，即R,R'对映异构体，占消旋拉贝洛尔的25%。拉贝洛尔HCl在单一物质中结合了选择性、竞争性的α-1-肾上腺素能阻滞和非选择性、竞争性的β-肾上腺素能阻滞活性。在人体中，α-与β-阻滞的比例经估计口服后大约为1:3，静脉注射（IV）后为1:7。在动物中已经证实了β-2-激动剂活性，而β-1-激动剂（ISA）活性最小。在动物中，在大于α-或β-肾上腺素能阻滞所需剂量的情况下，已经证实了膜稳定作用。

Labetalol has two asymmetric centers and therefore, exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic labetalol. Labetalol HCl combines both selective, competitive, alpha-1-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta- blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively. Beta-2-agonist activity has been demonstrated in animals with minimal beta-1-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta- adrenergic blockade, a membrane stabilizing effect has been demonstrated.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

拉贝洛尔治疗与高达8%的患者血清转氨酶水平轻至中度升高有关，这一比率远高于其他β受体阻滞剂。然而，这些升高通常是暂时的，不伴随症状，即使在继续治疗的情况下也可以解决。拉贝洛尔引起的特异质、临床上明显的肝损伤是罕见的，但已经有一些个案报告以及病例系列报告。肝损伤通常在治疗4到16周后出现，血清酶升高的模式通常是肝细胞型的，表现为急性肝炎样的发作和过程。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）是不常见的，自身抗体的形成也不常见。尽管大多数病例在停用拉贝洛尔后迅速解决，但已经有一些急性肝衰竭和死亡或需要紧急肝移植的实例与拉贝洛尔使用有关，尤其是如果停药有延迟的话。拉贝洛尔是引起临床上明显肝损伤风险最高的β受体阻滞剂。

Labetalol therapy has been associated with mild-to-moderate elevations of serum aminotransferase levels in up to 8% of patients, a rate far higher than with other beta-blockers. These elevations, however, are usually transient, not associated with symptoms, and can resolve even with continuation of therapy. Idiosyncratic, clinically apparent liver injury from labetalol is rare, but several instances have been reported as isolated case reports as well as in case series. The liver injury typically arises after 4 to 16 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular with an acute hepatitis-like onset and course. Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While most cases resolve rapidly once labetalol is stopped, there have been several instances of acute liver failure and death or need for emergency liver transplantation associated with labetalol use, particularly if there is a delay in its discontinuation. Labetalol is the beta-blocker with the highest apparent risk for causing clinically apparent liver injury.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：拉贝洛尔

Compound:labetalol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

100毫克和200毫克的拉贝洛尔口服剂量，其达峰时间（Tmax）为20分钟至2小时。生物利用度可能低至11%，也可能高达86%，并且可能在老年患者中或与食物同服时增加。

100mg and 200mg oral doses of labetalol have a Tmax of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food.

来源:DrugBank

吸收、分配和排泄

• 消除途径

标记的拉贝洛尔剂量中有55-60%通过尿液回收，12-27%通过粪便回收。

Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在正常血压患者中，分布容积为805L。在高血压患者中，分布容积在188-747L之间，平均为392L。

In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L.

来源:DrugBank

吸收、分配和排泄

• 清除

拉贝洛尔在血浆中的清除率大约为1500毫升/分钟，在全血中的清除率为1100毫升/分钟。

Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min.

来源:DrugBank

吸收、分配和排泄

选择性β-阻滞剂（包括拉贝洛尔）往往具有亲水性，而非选择性β-阻滞剂往往具有亲脂性。亲脂性是非选择性表达的一个关键因素。亲脂性β-阻滞剂通常通过肝脏消除，并在包括大脑在内的所有身体部位分布良好。亲水性β-阻滞剂通常由肾脏以原形排出，难以进入深层身体部位。

Cardioselective beta-blockers /including labetalol/ tend to be hydrophilic, whereas nonselective beta blockers tend to be lipophilic. The property of lipophilicity is an essential factor for the expression of nonselectivity. Lopophilic beta-blockers generally undergo hepatic elimination and distribute well into all body compartments, including the brain. Hydrophilic beta-blockers usually are excreted unchanged by the kidney and enter deep body compartments with difficulty. /From table/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2924299090
• 储存条件：
  | 2-8°C |

制备方法与用途

降压药：拉贝洛尔 概述

高血压是心脑血管疾病的独立危险因素，严重威胁着人们的健康。全球防治工作已经深入展开，并且对其研究也日益广泛。特别是妊娠合并慢性高血压这样的特殊人群，其健康关系到孕妇及胎儿的健康，因此对其防治尤为重要。

拉贝洛尔（Labetalol），又名柳胺苄心定，是一种肾上腺素受体阻断剂，具有选择性α1受体和非选择性β受体拮抗作用。两种作用均有降压效应，其中对β受体的作用比α受体强。通过抑制心肌及血管平滑肌的收缩反应发挥降压作用。在降压的同时伴有心率减慢、冠脉流量增加、外周血管阻力下降。大剂量时具有膜稳定作用，内源性拟交感活性甚微。本品降压强度与剂量及体位有关，立位血压下降较卧位明显，不伴反射性心动过速和心动过缓。

用途

1. 用于治疗各种类型高血压，特别是高血压危象。
2. 适用于伴有冠心病的高血压。
3. 用于外科手术前控制血压。
4. 用于嗜铬细胞瘤的降压治疗。
5. 用于妊娠高血压。

拜新同是钙通道阻滞剂家族中的一员。 主要作用于细胞膜L一型钙通道，抑制钙内流而使细胞内钙离子浓度降低，导致小动脉扩张，总外周阻力下降从而发挥降压作用。对各种类型的高血压均有良好的降压效果，并且在临床试验中证明了其不仅具有降压作用强、速度快等优点，而且不会影响血脂、血糖和电解质水平。拉贝洛尔属于肾上腺受体阻断药，它对α受体的阻断作用选择性不强，临床上主要用于中、重度高血压的治疗。两者合用时，后者能够消除拜新同因扩血管作用所产生的反射性心动过速，从而减少不良反应。

药动学

口服吸收迅速，吸收率为60%～90%，生物利用度为33%。口服后1～2小时内达到血药浓度高峰，血浆蛋白结合率约为50%，半衰期为3.5～5.5小时，维持作用8小时。经肝脏大部分与葡萄糖醛酸结合成为无活性的代谢产物，并通过肾脏排泄。

不良反应

患者偶有头昏、胃肠道不适、疲乏、感觉异常、哮喘加重等症。个别患者可能出现体位性低血压。

禁忌

1. 支气管哮喘患者禁用。
2. 心源性休克、心脏传导阻滞（Ⅱ～Ⅲ度房室传导阻滞）禁用。
3. 重度或急性心力衰竭、窦性心动过缓等患者禁用。

药物相互作用

1. 与三环类抗抑郁药同时应用可产生震颤。
2. 可减弱硝酸甘油的反射性心动过速，但降压作用可协同。
3. 与维拉帕米类钙拮抗剂同用时需十分谨慎。
4. 可增强氟烷对血压的作用。

注意事项

1. 对有下列情况者应慎用：过敏史、充血性心力衰竭、糖尿病、肺气肿或非过敏性支气管炎、肝功能不全、甲状腺功能低下、雷诺综合征或其他周围血管疾病、肾功能减退。
2. 静脉用药时患者应卧位，滴注切勿过速，以防降压过快。注射毕应静卧10～30分钟。
3. 本品尿中代谢产物可造成尿儿茶酚胺和香草基杏仁酸（VMA）假性升高；本品可使尿中苯异丙胺试验呈假阳性。
4. 孕妇（妊娠高血压除外）慎用。FDA对本药的妊娠安全性分级为C级。
5. 本药少量可自乳汁分泌，哺乳期妇女慎用。
6. 儿童用药的安全性和有效性尚不明确。

用途

用于抗高血压治疗。

反应信息

• 作为反应物：
  描述：

  拉贝洛尔 在 吡啶 、 sodium periodate 、 decaborane 、 sodium hydride 、 对甲苯磺酸 、 三乙胺 、 lithium bromide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 16.83h， 生成 4-{3-[4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)but-2-ynyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile
  参考文献：
  名称：

  Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin−Formaldehyde Conjugate

  摘要：

  The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the X-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a 3 H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

  DOI：

  10.1021/jm0303305
• 作为产物：
  描述：

  4-苯基-2-丁醇 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， -10.0~81.0 ℃ 、500.01 kPa 条件下， 反应 8.0h， 生成 拉贝洛尔
  参考文献：
  名称：

  一种盐酸拉贝洛尔的制备方法

  摘要：

  本发明提供了一种盐酸拉贝洛尔的制备方法，属于医药技术领域。本发明提供的制备方法，以5‑卤代乙酰基水杨酰胺作为起始原料与苄胺进行亲核取代反应，然后与3‑卤代丁基苯进行亲核取代反应(或者是与3‑羟基丁基苯和对甲基苯磺酰氯酯化反应产物进行胺酯交换反应)，再进行催化氢化反应反应后成盐，得到盐酸拉贝洛尔。本发明提供的制备方法，采用苄胺替代二苄胺，原料的原子利用率高、对环境友好，体现了绿色化学的原子经济性；胺酯交换反应选择性高，所得产物直接用于下一步反应；采用一步法脱除保护剂和还原羰基缩短了工艺路线；制备方法操作简便且稳定性和可控性高，生产成本高，产率高，适宜工业化生产。

  公开号：

  CN113698316B

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• Dibenzyl Amine Compounds and Derivatives
  申请人：Chang George

  公开号：US20070213371A1

  公开（公告）日：2007-09-13

  Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

  二苯基胺化合物及其衍生物，含有这种化合物的药物组合物以及使用这种化合物提高某些血浆脂质水平，包括高密度脂蛋白胆固醇，并降低其他一些血浆脂质水平，如低密度脂蛋白胆固醇和甘油三酯，并据此治疗由高密度脂蛋白胆固醇水平低和/或低密度脂蛋白胆固醇和甘油三酯水平高加重的疾病，如动脉粥样硬化和心血管疾病在某些哺乳动物，包括人类。
• METHOD FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1-6-NAPHTHYRIDINE-3-CARBOXAMIDE AND THE PURIFICATION THEREOF FOR USE AS AN ACTIVE PHARMACEUTICAL INGREDIENT
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20180244670A1

  公开（公告）日：2018-08-30

  The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)

  本发明涉及一种用于制备式(I)的(4S)-4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啉-3-羧酰胺的新型改进工艺。
• [EN] COMPOUNDS FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTION<br/>[FR] COMPOSÉS POUR LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE B
  申请人：GILEAD SCIENCES INC

  公开号：WO2017205115A1

  公开（公告）日：2017-11-30

  The present disclosure generally relates to compounds and pharmaceutical compositions which may be used in methods of treating a hepatitis B virus infection.

  本公开涉及一般与化合物和药物组合物有关，这些化合物和药物组合物可用于治疗乙型肝炎病毒感染的方法。
• [EN] DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS<br/>[FR] DIARYLURÉES EN TANT QUE MODULATEURS ALLOSTÉRIQUES DE CB1
  申请人：RTI INT

  公开号：WO2018209030A1

  公开（公告）日：2018-11-15

  The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.

  本发明提供了新颖的二芳基脲衍生物（式（I）化合物）及其用途。本发明的化合物被证明是CB1受体的变构调节剂，因此对于治疗由CB1介导的疾病和症状是有用的。