tert-butyl 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)- carboxylate | 167159-80-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: tert-butyl 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)- carboxylate
• 英文别名: 7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester；tert-butyl 7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 167159-80-0
• 化学式: C₁₅H₂₁NO₄
• 分子量: 279.336
• InChiKey: NXGLYAKMESSSPJ-UHFFFAOYSA-N

物化性质

• 熔点：
  123.6-124.2 °C
• 沸点：
  420.3±45.0 °C(Predicted)
• 密度：
  1.178±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)- carboxylate 在 吡啶 、 三氟甲磺酸酐 作用下， 以 乙醚 为溶剂， 生成 tert-butyl 6-methoxy-7-(((trifluoromethyl)sulfonyl)oxy)-3,4- dihydroisoquinoline-2(1H)-carboxylate
  参考文献：
  名称：

  MDR reversal agents

  摘要：

  通式为：##STR1## 其中R.sub.1、R.sub.2、R.sub.3、R.sub.4和R.sub.5如本文所述，A是直链或支链(C.sub.2 -C.sub.12)烷基或苯基基团，B是式的基团：##STR2## 这些化合物能够通过增加多药耐药细胞对化疗药物的敏感性，增强化疗抗癌药物的活性。

  公开号：

  US05387685A1
• 作为产物：
  描述：

  6,7-二甲氧基-3,4-二氢异喹啉 在 sodium tetrahydroborate 、 氢溴酸 作用下， 以 甲醇 为溶剂， 生成 tert-butyl 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)- carboxylate
  参考文献：
  名称：

  Variabiline（一种使鲍曼不动杆菌和肺炎克雷伯菌对粘菌素敏感的阿朴啡生物碱）的合成、立体化学拆分和类似合成

  摘要：

  抗菌素耐药性的增加，加上新抗生素的缺乏，导致医生依赖粘菌素（一种已知具有肾毒性的多粘菌素）作为治疗革兰氏阴性菌感染的最后手段。提高抗生素功效并从而减少剂量的一种方法是使用增强抗生素活性的小分子增效剂。我们最近鉴定出了阿朴啡生物碱 (±)-variabiline，它可以降低粘菌素对鲍曼不动杆菌和肺炎克雷伯菌的最低抑菌浓度。在此，我们报告了 (±)-variabiline 的首次全合成，以确认结构和活性、两种对映体作为粘菌素增效剂的分离和评估，以及鉴定更有效的 variabiline 衍生物的结构-活性关系研究。初步机制研究表明，(±)-variabiline 及其衍生物通过靶向革兰氏阴性外膜来增强粘菌素。

  DOI：

  10.1021/acsinfecdis.4c00026

文献信息

• [EN] APOPTOSIS SIGNAL-REGULATING KINASE 1 INHIBITORS AND METHODS OF USE THEREOF<br/>[FR] INHIBITEURS DE LA KINASE 1 RÉGULANT LE SIGNAL D'APOPTOSE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：ENANTA PHARM INC

  公开号：WO2020198214A1

  公开（公告）日：2020-10-01

  The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).

  本发明揭示了式(I)的化合物，及其药学上可接受的盐和酯，其抑制与自身免疫性疾病、神经退行性疾病、炎症性疾病、慢性肾脏疾病、心血管疾病相关的细胞凋亡信号调节激酶1（ASK-1）。本发明还涉及包含上述化合物的药物组合物，用于给患有ASK-1相关疾病的受试者使用。该发明还涉及通过给予包含本发明化合物的药物组合物来治疗受试者的ASK-1相关疾病的方法。本发明特别涉及治疗与肝脏脂肪变性相关的ASK-1的方法，包括非酒精性脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）。
• Tariquidar-Related Chalcones and Ketones as ABCG2 Modulators
  作者：Diana Peña-Solórzano、Matthias Scholler、Günther Bernhardt、Armin Buschauer、Burkhard König、Cristian Ochoa-Puentes

  DOI：10.1021/acsmedchemlett.8b00289

  日期：2018.8.9

  ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone 16d (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound 17f from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.
• Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2)
  作者：Cristian Ochoa Puentes、Peter Höcherl、Matthias Kühnle、Stefanie Bauer、Kira Bürger、Günther Bernhardt、Armin Buschauer、Burkhard König

  DOI：10.1016/j.bmcl.2011.04.094

  日期：2011.6

  Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor. (C) 2011 Elsevier Ltd. All rights reserved.
• INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
  申请人：Merck & Co., Inc.

  公开号：EP0783518A1

  公开（公告）日：1997-07-16
• APOPTOSIS SIGNAL-REGULATING KINASE 1 INHIBITORS AND METHODS OF USE THEREOF
  申请人：ENANTA PHARMACEUTICALS, INC.

  公开号：US20200308193A1

  公开（公告）日：2020-10-01

  The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof: which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).