雷诺嗪 | 95635-55-5

• 物质功能分类: 生物化工 - 抑制剂 - 跨膜转运体(Transmembrane Transporters)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 雷诺嗪
• 中文别名: N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺；(±)-N-(2, 6-二甲基苯基)-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺
• 英文名称: Ranolazine
• 英文别名: ranexa；1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6,dimethylphenyl)-aminocarbonylmethyl]-piperazine；(+/-)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine acetamide；(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide；N-(2,6-dimethylphenyl)-2-(4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)piperazin-1-yl)acetamide；RAN；N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide
• CAS: 95635-55-5
• 化学式: C₂₄H₃₃N₃O₄
• mdl: MFCD00864690
• 分子量: 427.544
• InChiKey: XKLMZUWKNUAPSZ-UHFFFAOYSA-N

物化性质

• 熔点：
  119-1200C
• 沸点：
  624.1±55.0 °C(Predicted)
• 密度：
  1.174±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  White to off-white solid
• 蒸汽压力：
  4.56X10-16 mm Hg at 25 °C (est)
• 碰撞截面：
  205.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.458
• 拓扑面积：
  74.3
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

拉诺拉嗪在肝脏和胃肠系统中通过CYP3A4酶的活性迅速被大量代谢，CYP2D6也有少量贡献。在血浆中已发现超过40种拉诺拉嗪代谢物，在尿液中已鉴定出超过100种代谢物。拉诺拉嗪及其一些代谢物已知会微弱抑制CYP3A4。然而，拉诺拉嗪代谢物的活性尚未被完全阐明。

Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated.

来源:DrugBank

代谢

拉诺拉嗪在小肠和肝脏中通过细胞色素P-450（CYP）同工酶系统广泛代谢，主要由CYP3A代谢，其次为CYP2D6。体外研究表明，拉诺拉嗪也是P-糖蛋白的底物。已鉴定出至少4种拉诺拉嗪的代谢物。这些代谢物的药理活性尚未完全确定。

Ranolazine is extensively metabolized in the intestine and liver by the cytochrome P-450 (CYP) isoenzyme system, mainly by CYP3A and, to a lesser extent, CYP2D6. In vitro studies indicate that ranolazine also is a p-glycoprotein substrate. At least 4 metabolites of ranolazine have been identified. The pharmacologic activity of these metabolites has not been fully established.

来源:Hazardous Substances Data Bank (HSDB)

代谢

拉诺拉嗪在肝脏和肠道中被迅速和广泛代谢...代谢物的药理活性尚未得到很好的描述。在每日两次服用500毫克至1500毫克达到稳态后，血浆中四种含量最丰富的代谢物的AUC值大约为拉诺拉嗪的5%至33%...

Ranolazine is metabolized rapidly and extensively in the liver and intestine ... The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模预先注册的临床试验中，ranolazine（瑞诺拉唑）治疗期间并未与血清转氨酶和碱性磷酸酶升高有关，并且没有报告出现症状性急性肝损伤的案例。自从其获得批准并更广泛使用以来，ranolazine与一例轻微症状、迅速可逆、无黄疸的肝损伤有关（案例1）。未出现免疫过敏和自身免疫特征。停用ranolazine后，恢复迅速。

In large preregistration clinical trials, ranolazine was not associated with serum aminotransferase and alkaline phosphatase elevations during treatment and no instances of symptomatic acute liver injury were reported. Since its approval and more wide spread use, ranolazine has been linked to a single instance of mildly symptomatic, rapidly reversible, anicteric liver injury (Case 1). Immunoallergic and autoimmune features were not present. Recovery was rapid once ranolazine was discontinued.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：拉诺拉嗪

Compound:ranolazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

达到峰值血清浓度的时间相当可变，但观察到范围在2-6小时之内，3天内达到稳态。美国食品药品监督管理局（FDA）指出Tmax为3-5小时。平均稳态Cmax约为2600 ng/mL。食物消耗对拉诺拉唑的吸收没有显著影响。与拉诺拉唑溶液相比，以片剂形式服用的拉诺拉唑的生物利用度约为76%。

The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

从给药剂量中，大约3/4的剂量通过肾脏排泄，而1/4的剂量通过粪便排泄。估计有5%的摄入剂量以未改变的药物形式排出。

From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

雷诺拉唑的平均表观分布体积报告为53.2升，平均稳态分布体积估计在85到180升之间。

The mean apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L.

来源:DrugBank

吸收、分配和排泄

• 清除

口服给予的拉诺拉齐的报道清除率为45 L/h，当以每日两次500毫克的剂量给药时。拉诺拉齐的清除率与剂量有关，肾功能损害可以增加拉诺拉齐血清浓度40-50%。

The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%.

来源:DrugBank

吸收、分配和排泄

拉诺拉嗪在肠道和肝脏中广泛代谢，其吸收高度可变。例如，在每日两次1000毫克剂量下，平均稳态Cmax为2600 ng/mL，95%置信区间为400至6100 ng/mL。在健康志愿者中，拉诺拉嗪的（+）R-和（-）S-对映体的药代动力学相似...通常在每日两次给药的3天内达到稳态。在500至1000毫克每日两次的剂量范围内，稳态时Cmax和AUC0-t的增加略多于剂量成比例，分别为2.2倍和2.4倍。在每日两次给药的情况下，拉诺拉嗪血浆浓度的谷:峰比为0.3至0.6。拉诺拉嗪的药代动力学不受年龄、性别或食物的影响。

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. ... Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-t increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090
• WGK Germany：
  3
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  -20°C freezer

制备方法与用途

雷诺嗪是一种治疗慢性心绞痛的药物，能够降低心律不齐的发生，包括室性心律失常、新发动脉纤维颤动和因冠状动脉疾病导致的心动过缓。其作用机制是通过部分地抑制脂肪酸代谢并引起葡萄糖代谢，由于葡萄糖代谢比脂肪酸代谢更有效，促进心脏更有效地利用氧气，从而明显改善心绞痛患者的症状。

Ranolazine（CVT 303, RS 43285-003）是一种钙离子通过钠/钙通道摄取的抑制剂抗心绞痛药物。体外研究发现，Ranolazine与失活状态的钠通道结合更紧密，表观解离常数分别为K（DR）=7.47 mM和K（DI）=1.71 mM。在5 mM和10 mM浓度下，它可逆地缩短细胞的动作电位持续时间并废除收缩，在晚期钠增加时抑制钠电流后期分量，并减缓动作电位时程延长。此外，Ranolazine减少了89％由10 nM ATX-Ⅱ诱导的APD变异性。

体内研究显示，在狗左心室肌细胞中，Ranolazine以浓度依赖性的方式显著和可逆地缩短了在0.5或0.25赫兹刺激下的动作电位持续时间（APD）。在工作的大鼠心脏中，Ranolazine (10 mM) 在不同葡萄糖氧化条件下，显著增加了ATP的产生。具体而言，在低钙、高脂肪酸和低胰岛素条件下，Ranolazine将葡萄糖氧化条件下的ATP生成提高了1.5至3倍；在高钙、低脂肪酸和同起搏条件下，或在中间体条件下，它同样增加了葡萄糖氧化（10 mM剂量下，高钙、低脂肪酸，流量为15毫升/分钟）。此外，Ranolazine显著改善了再灌注局部缺血心脏的功能，这与显著增加的葡萄糖氧化相关。

用途：雷诺嗪是一种用于治疗慢性心绞痛的新药。

反应信息

• 作为反应物：
  描述：

  雷诺嗪 在 氢溴酸 作用下， 以 甲醇 、 水 为溶剂， 生成 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrobromide
  参考文献：
  名称：

  [EN] NOVEL SOLID STATE FORMS OF RANOLAZINE SALTS
  [FR] NOUVELLES FORMES SOLIDES DE SELS DE RANOLAZINE

  摘要：

  公开号：

  WO2010029436A3
• 作为产物：
  描述：

  愈创木酚缩水甘油醚 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 雷诺嗪
  参考文献：
  名称：

  An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

  摘要：

  An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

  DOI：

  10.1021/op300056k

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。
• [EN] 1-AKAN-2-OL SUBSTITUTED PIPERAZINE AND PIPERIDINE COMPOUNDS<br/>[FR] COMPOSES PIPERAZINE ET PIPERAZINE 1-AKAN-2-OL SUBSTITUES
  申请人：CV THERAPEUTICS INC

  公开号：WO2005061470A1

  公开（公告）日：2005-07-07

  Disclosed are novel substituted heterocyclic derivatives having the structure of Formula (I): The compounds are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, diabetes, and myocardial infarction.

  揭示了具有以下结构的新型取代杂环衍生物（I）的化合物：这些化合物对于治疗各种疾病状态有用，特别是心血管疾病，如心房和心室心律失常，间歇性跛行，普林兹梅塔（变异）心绞痛，稳定和不稳定心绞痛，运动诱发性心绞痛，充血性心脏病，糖尿病和心肌梗死。
• 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。
• Thiol Activation toward Selective Thiolation of Aromatic C–H Bond
  作者：Jing-Hao Wang、Tao Lei、Hao-Lin Wu、Xiao-Lei Nan、Xu-Bing Li、Bin Chen、Chen-Ho Tung、Li-Zhu Wu

  DOI：10.1021/acs.orglett.0c01050

  日期：2020.5.15

  Direct C-S bond coupling is an attractive way to construct aryl sulfur ether, a building block for a variety of biological active molecules. Herein, we disclose an effective model for regioselective thiolation of the aromatic C-H bond by thiol activation instead of arene activation. Strikingly, this method has been applied into anisole derivatives that are not available in the arene activation approach

  直接CS键偶联是构建芳基硫醚的一种有吸引力的方法，芳基硫醚是多种生物活性分子的基础。在这里，我们公开了通过硫醇活化而不是芳烃活化对芳香族CH键进行区域选择性硫醇化的有效模型。引人注目的是，该方法已被应用到芳烃活化方法中无法获得的苯甲醚衍生物中，从而形成具有高反应活性的单一硫醚异构体。
• [EN] AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRAZINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
  申请人：NOVARTIS AG

  公开号：WO2015162459A1

  公开（公告）日：2015-10-29

  The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.

  本发明提供了一种公式（I）的化合物，该化合物抑制PI 3-激酶γ同工酶的活性，对于治疗由PI 3-激酶γ同工酶激活介导的疾病是有用的。