反式-10-羟基去甲替林 | 47132-16-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 二苯并环庚烯
• 中文名称: 反式-10-羟基去甲替林
• 英文名称: (E)-10-Hydroxynortriptyline
• 英文别名: 10-Hydroxynortriptyline；(R,S)-(E)-N-methyl-(10,11-dihydro-10-hydroxy-5H-dibenzocycloheptene)-δ^5,γ-propylamine；(E)-N-methyl-3-(10,11-dihydro-10-hydroxy-5H-dibenzocycloheptene)-Δ^5,γ-propylamine；E-10-hydroxynortriptyline；5-[3-methylamino-propylidene]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol；(E)-N-methyl-3-(10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]cycloheptene)-Δ^5,γ-propylamine；(2E)-2-[3-(methylamino)propylidene]tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaen-9-ol
• CAS: 47132-16-1；112839-35-7；112839-36-8
• 化学式: C₁₉H₂₁NO
• 分子量: 279.382
• InChiKey: VAGXZGJKNUNLHK-LFIBNONCSA-N

物化性质

• 沸点：
  462.3±45.0 °C(Predicted)
• 密度：
  1.164±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：轻微； DMSO：1mg/mL；乙醇：3mg/mL； PBS (pH 7.2)：不溶

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  2

制备方法与用途

(E)-10-羟氮卓特林 ((E)-10-OH-NT) 是诺 tripletline (HY-B1417) 的代谢产物。而诺 tripletline 是一种三环类抗抑郁药，其主要活性代谢物为氨 tripletline (HY-B0527A)。

反应信息

• 作为反应物：
  描述：

  反式-10-羟基去甲替林 在 human liver cytosol 芦丁 、 还原型辅酶II(NADPH)四钠盐 作用下， 反应 0.08h， 生成 (E)-N-methyl-3-(10,11-dihydro-10-oxo-5H-dibenzocycloheptene)-Δ^5,γ-propylamine
  参考文献：
  名称：

  Stereoselective reversible ketone formation from 10-hydroxylated nortriptyline metabolites in human liver

  摘要：

  1. E- and Z-10-hydroxynortriptyline are major metabolites of amitriptyline and nortriptyline in man. Upon incubation with human liver microsomes or cytosol, these metabolites were oxidized to the corresponding ketones, E- and Z-10-oxonortriptyline. (+)-E- and (+)-Z-10-hydroxynortriptyline were distinctly preferred over the (-)-isomers as substrates. NADP(+) supported the oxidation in cytosol whereas in microsomes NAD(+) was the best cofactor.2. Incubation of E- and Z-10-oxonortriptyline with NADPH and cytosol resulted in the nearly exclusive formation of (+)-E- and (+)-Z-10-hydroxynortriptyline. Kinetic analysis revealed high-affinity reduction (K-m 1-2 mu M) of the two ketones and an additional low-affinity component with the E-isomer. 10-Oxonortriptyline reduction was also catalysed by rabbit, but not by rat or guinea pig liver cytosol.3. With [4-H-3]NADPH as cosubstrate, tritium was incorporated into E- and Z-10-hydroxynortriptyline preferentially from the pro-4R position. Redox cycling of (+)-E- and (+)-Z-10-hydroxynortriptyline in cytosol in the presence of NAD(+) and NADPH was indicated by H-3 incorporation from [pro-4R-H-3]NADPH.4. Recombinant human carbonyl reductase catalysed low-affinity reduction of E-10-oxonortriptyline with preferential transfer of the pro-4S-H-3 of labelled NADPH.5. Ketone reduction in cytosol was strongly inhibited by 9,10-phenanthrenequinone and dehydrolithocholic acid and moderately by other 3-oxo steroids and some antiinflammatory drugs.6. The high-affinity reduction of E- and Z-10-oxonortriptyline and the oxidation of the alcohols in cytosol are probably mediated by a member of the aldo-keto reductase family of enzymes.

  DOI：

  10.3109/00498259509061920
• 作为产物：
  描述：

  10-bromo-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene 在 盐酸 、 sodium tetrahydroborate 、 potassium dihydrogenphosphate 、 potassium tert-butylate 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 水 、 甲苯 为溶剂， 反应 10.5h， 生成 反式-10-羟基去甲替林
  参考文献：
  名称：

  Synthesis and NMR Studies of Z- and E-Isomers of 10-Oxo and 10-Hydroxy Derivatives of Amitriptyline and Nortriptyline.

  摘要：

  DOI：

  10.3891/acta.chem.scand.37b-0335

文献信息

• A novel strategy for spectrophotometric simultaneous determination of amitriptyline and nortriptyline based on derivation with a quinonoid compound in serum samples
  作者：Amir Farnoudian-Habibi、Bakhshali Massoumi、Mehdi Jaymand

  DOI：10.1016/j.saa.2016.06.013

  日期：2016.11

  strategy. Acetaldehyde (AC), and 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil; CL) were used as chemical reagents for reaction with NT, while AT did not react with these reagents. This method is based on the condensation reaction between secondary amine group of NT and AC to afford an enamine, and subsequently reaction with CL to produce a chlorinated quinone-substituted enamine. The final product exhibited

  通过磁性固相萃取（MSPE）和分光光度法联合测定两种三环抗抑郁药（TCA）[阿米替林（AT）及其主要代谢物（去甲替林； NT）]的新颖有效策略建议。为此，使用咪唑鎓离子液体（Imz）改性的Fe 3 O 4 @SiO 2纳米颗粒（Fe 3 O 4 @SiO 2-Imz）用作MSPE的吸附剂。在优化条件下进行了预浓缩（负载-解吸）研究，包括pH，吸附剂量，接触时间，洗脱液体积和解吸时间。之后，通过特定策略确定每种药物。乙醛（AC）和2,3,5,6-四氯-1,4-苯醌（氯腈; CL）用作与NT反应的化学试剂，而AT不与这些试剂反应。该方法基于NT的仲胺基和AC之间的缩合反应，得到烯胺，随后与CL反应，生成氯化醌取代的烯胺。最终产物在556 nm处显示出最大吸收，而AT在240 nm处测定。血清样品中NT和AT的检出限（LOD）为0.19和0。− 1。NT和AT的定量限（LOQs）分别为0.63和2
• SUBSTITUTED THIAZOLIDINEDIONE INDAZOLES, INDOLES AND BENZOTRIAZOLES AS ESTROGEN-RELATED RECEPTOR-a MODULATORS
  申请人：Bignan Gilles

  公开号：US20110294780A1

  公开（公告）日：2011-12-01

  The present invention relates to compounds of Formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter's syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

  本发明涉及式(I)的化合物，制备这些化合物的方法，组合物，中间体及其衍生物，并用于治疗包括但不限于强直性脊柱炎，动脉粥样硬化，关节炎（如类风湿关节炎，感染性关节炎，儿童关节炎，银屑病性关节炎，反应性关节炎），与骨相关的疾病（包括与骨形成有关的疾病），乳腺癌（包括对抗雌激素治疗无效的癌症），心血管疾病，软骨相关疾病（如软骨损伤/丧失，软骨退化以及与软骨形成有关的疾病），软骨发育不良，软骨肉瘤，慢性腰部损伤，慢性支气管炎，慢性炎症性气道疾病，慢性阻塞性肺疾病，糖尿病，能量稳态紊乱，痛风，假性痛风，脂质紊乱，代谢综合征，多发性骨髓瘤，肥胖，骨关节炎，遗传性骨发育不全，骨溶解性骨转移，软骨软化症，骨质疏松症，帕金森病，牙周病，多肌痛风，Reiter综合征，重复性应激损伤，高血糖，血糖水平升高和胰岛素抵抗等病症的方法。
• Regioselectivity and Substrate Concentration-dependency of Involvement of the CYP2D Subfamily in Oxidative Metabolism of Amitriptyline and Nortriptyline in Rat Liver Microsomes
  作者：Yasuhiro Masubuchi、Takashi Iwasa、Shoichi Fujita、Tokuji Suzuki、Toshiharu Horie、Shizuo Narimatsu

  DOI：10.1111/j.2042-7158.1996.tb06003.x

  日期：2011.4.12

  Kinetic analysis of the metabolism of amitriptyline and nortriptyline using liver microsomes from Wistar rats showed that more than one enzyme was involved in each reaction except for monophasic amitriptyline N-demethylation. The Vmax values particularly in the high-affinity sites for E-10-hydroxylation of both drugs were larger than those for Z-10-hydroxylations. Their E- and Z-10-hydroxylase activities in Dark-Agouti rats, which are deficient for CYP2D1, were significantly lower than those in Wistar rats at a lower substrate concentration (5 μM). The strain difference was reduced at a higher substrate concentration (500 μM). A similar but a smaller strain difference was also observed in nortriptyline N-demethylase activity, and a pronounced sex difference (male > female) was observed in N-demethylation of both drugs in Wistar and Dark-Agouti rats. The reactions with the strain difference were inhibited concentration-dependently by sparteine, a substrate of the CYP2D subfamily, and an antibody against a CYP2D isoenzyme. The profiles of these decreased metabolic activities corresponded to that of the lower metabolic activities in Dark-Agouti rats.

  These results indicated that a cytochrome P450 isozyme in the CYP2D subfamily was involved in E- and Z- 10-hydroxylations of amitriptyline and nortriptyline in rat liver microsomes as a major isozyme in a low substrate concentration range. It seems likely that the CYP2D enzyme contributes to nortriptyline N-demethylation.

  摘要：对Wistar大鼠肝微粒体中阿米替林和诺替林代谢的动力学分析表明，除了单相阿米替林N-去甲基化反应外，每个反应中涉及多种酶。尤其是在高亲和位点上，两种药物的E-10-羟基化的Vmax值比Z-10-羟基化的要大。在缺乏CYP2D1的Dark-Agouti大鼠中，这两种药物的E-和Z-10-羟化活性在较低底物浓度（5 μM）下明显低于Wistar大鼠。在较高底物浓度（500 μM）下，品系差异减小。在诺替林N-去甲基酶活性中也观察到类似但较小的品系差异，而在Wistar和Dark-Agouti大鼠中，两种药物的N-去甲基化反应中观察到明显的性别差异（男性>女性）。具有品系差异的反应受到CYP2D亚家族底物斯帕替因和抗CYP2D同工酶抗体的浓度依赖性抑制。这些降低的代谢活性的特征与Dark-Agouti大鼠中较低的代谢活性相符。 这些结果表明，在低底物浓度范围内，CYP2D亚家族的一种细胞色素P450同工酶参与了大鼠肝微粒体中阿米替林和诺替林的E-和Z-10-羟基化作用，作为一个主要同工酶。CYP2D酶可能有助于诺替林N-去甲基化。
• COMPOSITIONS OF (-)-E-10-OH-NT AND METHODS FOR THEIR SYNTHESIS AND USE
  申请人：LE BOURDONNEC Bertrand

  公开号：US20080275131A1

  公开（公告）日：2008-11-06

  This present disclosure provides compositions comprising E-10-OH-NT metabolites of AT and NT, methods for their synthesis and methods for their use.

  本公开提供了包含AT和NT的E-10-OH-NT代谢物的组合物，以及它们的合成方法和使用方法。
• Facile Synthesis of (R,S)-(Z) and (R,S)-(E)-N-Methyl-(10,11-dihydro-10-hydroxy-5H-Dibenzo[a,d]cycloheptene)-Δ^8,γ-propylamine. The Major Metabolites of Amitriptyline and Nortriptyline
  作者：Bertrand J. Jean-Claude、George Just

  DOI：10.1080/00397919408010157

  日期：1994.6

  Abstract Efficient methods for the syntheses of amines 6b and 9b, the major metabolites of the antidepressant drugs amitriptyline 1a and nortriptyline 1b, are described.

  摘要 描述了合成胺 6b 和 9b（抗抑郁药物阿米替林 1a 和去甲替林 1b 的主要代谢物）的有效方法。