(2R,3S)-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol | 1164498-31-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (2R,3S)-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol
• 英文别名: 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol；(2R,3S)-5-{2-hydroxy-3-[(2-methyl-2-propanyl)amino]propoxy}-1,2,3,4-tetrahydro-2,3-naphthalenediol；(2R,3S)-5-{[3-(tert-butylamino)-2-hydroxypropyl]oxy}-1,2,3,4 tetrahydro-naphthalene-2,3-diol；1-(tert-butyamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)oxy]-2-propanol；Corgard；nadolol；(2R,3S)-5-[3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydronaphthalene-2,3-diol
• CAS: 1164498-31-0
• 化学式: C₁₇H₂₇NO₄
• mdl: MFCD00079476
• 分子量: 309.406
• InChiKey: VWPOSFSPZNDTMJ-UCWKZMIHSA-N

物化性质

• 沸点：
  526.4±50.0 °C(Predicted)
• 密度：
  1.189±0.06 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  White to off-white, crystalline powder
• 气味：
  Odorless
• 熔点：
  130.0 °C
• 溶解度：
  8330 mg/L (at 25 °C)
• Caco2细胞的药物渗透性：
  -5.41
• 解离常数：
  pKa= 9.67
• 碰撞截面：
  172 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)：
  0.7
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.647
• 拓扑面积：
  82
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

Nadolol 在人体内不由肝脏代谢。

Nadolol is not metabolized by the liver in humans.

来源:DrugBank

代谢

Nadolol 不被代谢。

Nadolol is not metabolized.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清转氨酶水平轻至中度升高发生在少于1%的纳多洛尔治疗患者中，通常是暂时的且无症状的，即使在继续治疗的情况下也会解决。尽管纳多洛尔被广泛使用，但没有确凿的证据将其与临床上明显的肝脏损伤病例联系起来；报道的少数病例通常发生在接受其他已知对肝脏有毒性的药物的患者中，或者仅与血清酶水平升高有关。其他β受体阻滞剂已被牵涉在引起急性肝损伤的罕见病例中，发病潜伏期从4周到24周不等，表现为血清酶水平升高呈肝细胞模式，病程轻微，自我限制，没有超敏反应或自身免疫反应的证据。

Mild-to-moderate elevations in serum aminotransferase levels occur in less than 1% of patients on nadolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its widespread use, nadolol has not been convincingly linked to instances of clinically apparent liver injury; the few cases reported have generally occurred in patients who were receiving other well known hepatotoxic agents or were associated with serum enzyme elevations only. Other beta-blockers have been implicated in causing rare instances of acute liver injury, with latency to onset ranging from 4 to 24 weeks, a hepatocellular pattern of serum enzyme elevations, and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.

来源:LiverTox

毒理性

• 药物性肝损伤

纳多洛尔

Compound:nadolol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

纳多洛尔口服剂量的吸收率大约为30%。在健康受试者中，纳多洛尔在服用60毫克口服剂量后的达峰时间为2.7小时，血药峰浓度为69±15ng/mL，而在服用120毫克口服剂量后的血药峰浓度为132±27ng/mL。服用60毫克口服剂量的药时曲线下面积为1021ng*h/mL，服用120毫克口服剂量的药时曲线下面积为1913±382ng*h/mL。

Oral doses of nadolol are approximately 30% absorbed. In healthy subjects, nadolol has a Tmax of 2.7h with a Cmax or 69±15ng/mL following a 60mg oral dose and 132±27ng/mL after a 120mg oral dose. The AUC following a 60mg oral dose was 1021ng\*h/mL and following a 120mg oral dose was 1913±382ng\*h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Nadolol 在肝脏不进行代谢，主要通过尿液排出。在健康受试者中，静脉给药后，72小时内60%的剂量通过尿液排出，15%通过粪便排出。随后，剩余的剂量预计将通过粪便排出。

Nadolol is not metabolized in the liver and excreted mainly in the urine. In healthy subjects, following intravenous dosing, 60% of a dose is eliminated in the urine and 15% in the feces after 72 hours. The remainder of the dose is expected to be eliminated in the feces afterwards.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在健康受试者中，纳多洛尔的分布容积为147-157升。

In healthy subjects, the volume of distribution of nadolol is 147-157L.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康受试者中，纳多洛尔的总体清除率为219-250毫升/分钟，肾清除率为131-150毫升/分钟。

In healthy subjects, the total body clearance of nadolol is 219-250mL/min and the renal clearance is 131-150mL/min.

来源:DrugBank

吸收、分配和排泄

口服纳多洛尔后，吸收情况不稳定，平均约为剂量的30-40%。胃肠道中的食物不影响吸收的速度或程度。口服2毫克纳多洛尔（胶囊形式）后，通常在2-4小时内达到血浆峰值浓度。在一项针对接受每日80毫克、160毫克或320毫克纳多洛尔的高血压成年人的研究中，平均稳态血浆浓度分别为25.5-35.5 ng/ml、51.7-74.1 ng/ml和154-191.4 ng/ml。在每日剂量为40-320毫克的情况下，纳多洛尔的抗高血压和抗心绞痛效果持续时间至少为24小时。

Following oral administration of nadolol, absorption is variable and averages about 30-40% of a dose. The presence of food in the GI tract does not affect the rate or extent of absorption. After oral administration of 2 mg of nadolol (in a capsule), peak plasma concentrations usually occur in 2-4 hours. In one study in hypertensive adults who received 80 mg, 160 mg, or 320 mg of nadolol daily, mean steady state plasma concentrations were 25.5-35.5 ng/ml, 51.7-74.1 ng/ml, and 154-191.4 ng/ml, respectively. With doses of 40-320 mg daily, the duration of nadolol's antihypertensive and antianginal effects is at least 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (2R,3S)-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol 在 sodium hypochlorite 、 sodium nitrate 、 borate buffer 作用下， 反应 120.0h， 生成
  参考文献：
  名称：

  Transformation of Aromatic Ether- and Amine-Containing Pharmaceuticals during Chlorine Disinfection

  摘要：

  Many of the human pharmaceuticals detected in municipal wastewater effluent, surface water, and groundwater contain functional groups that could undergo transformation reactions during chlorine disinfection. To assess the potential importance of these reactions to the environmental fate of pharmaceuticals, the rate of transformation of a group of compounds was measured over a pH range of 5-10. Several of the pharmaceuticals reacted rapidly with free chlorine (i.e., HOCl/OCl-) and would be expected to undergo transformation under the conditions typically encountered in many chlorine disinfection systems. For compounds containing aromatic ether functional groups, the rate of transformation was strongly affected by the other substituents on the ring. The amine-containing pharmaceuticals underwent a rapid reaction with hypochlorous acid to form chlorinated amines, which could be converted back into the parent compound by reaction with thiosulfate. In the absence of thiosulfate, the chlorinated amines slowly decomposed to form species that could not be converted back into the parent compound. The reaction rates of the pharmaceuticals with combined chlorine (i.e., chloramines) were significantly slower, and transformation of the compounds would not be expected under the conditions encountered during chloramination.

  DOI：

  10.1021/es035368l
• 作为产物：
  描述：

  diacetyl nadolol 在 phosphate buffer 作用下， 生成 (2R,3S)-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol
  参考文献：
  名称：

  二乙酰基萘多酚的水解动力学。

  摘要：

  二乙酰基纳多洛尔是纳多洛尔的前药和β受体阻滞剂，由于其更高的亲脂性，其角膜通透性比其母体化合物高约20倍。在各种升高的温度和pH值下对二乙酰基萘多酚进行了水解研究，以提供其眼科制剂的稳定性信息。确定了二乙酰基萘多酚水解成乙酰基萘多酚和萘多洛尔的表观速率常数。在中性pH值范围（6.8至8.2）内，可以建议将二乙酰基萘多酚水解作为特定的碱催化方法。二乙酰基萘多酚水解为乙酰基萘多酚和乙酰基萘多酚水解为纳多洛尔的各种常数分别列出如下：活化能为9.78和11.39kcal / mol；在25℃，-9.78和-5.86cal / mol.deg下的熵；二阶速率常数在75摄氏度，3。47 X 10（4）和2.22 X 10（4）M-1h-1。根据这些动力学常数，可以制备pH为6.5的二乙酰基纳多洛尔水溶液作为抗青光眼剂。在室温（25摄氏度）下，保质期估计仅为43天。然而，当储存温度降低到5摄氏度时，保质期可以延长到2年以上。

  DOI：

  10.1002/jps.2600761215

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。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED PYRROLOTRIAZINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] PYRROLOTRIAZINES À SUBSTITUTION SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2015091156A1

  公开（公告）日：2015-06-25

  This invention relates to novel sulfoximine substituted pyrrolotriazine derivatives of formula wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的噻氧亚胺取代吡咯三嗪衍生物，其化学式中Ar、R1和R2的定义如描述和权利要求中所定义，并且它们作为MNK1（MNK1 a或MNK1 b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1 a或MNK1 b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR UNE SULFOXIMINE DESTINÉES À DES COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2015169677A1

  公开（公告）日：2015-11-12

  The application relates to novel sulfoximine substituted quinazoline derivatives of formula (I) wherein Ar, R1, R2 and R3 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  该申请涉及式(I)的新型磺酰胺取代喹唑啉衍生物，其中Ar、R1、R2和R3如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有相同化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。