(1R,3R)-cis-methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate | 303984-25-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: (1R,3R)-cis-methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
• 英文别名: methyl (1R,3R)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate；methyl (1R,3R)-1-(4-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate；methyl 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate
• CAS: 303984-25-0
• 化学式: C₂₀H₂₀N₂O₃
• 分子量: 336.39
• InChiKey: YCCPHMBIMIJBPW-QZTJIDSGSA-N

物化性质

• 熔点：
  117-119 °C(Solv: ligroine (8032-32-4))
• 沸点：
  520.2±50.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  63.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1R,3R)-cis-methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 在 碳酸氢钠 作用下， 以 甲醇 、 氯仿 为溶剂， 生成 (+/-) cis-2-ethyl-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione Analogues

  摘要：

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

  DOI：

  10.1021/jm0300577
• 作为产物：
  描述：

  L-色氨酸 在 盐酸 、 硫酸 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 (1R,3R)-cis-methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate
  参考文献：
  名称：

  一些 1-芳基-1,2,3,4-四氢-β-咔啉-3-羧酸及其甲酯的顺式和反式异构体的 1H 和 13C NMR 光谱归属

  摘要：

  根据 1H NMR 中 C-1 质子的化学位移和 13C NMR 光谱中 C-1 和 C-3 碳的化学位移，通过分级结晶获得的 3 和 4 的异构体是顺式并归为反式。

  DOI：

  10.1002/ardp.19803130414

文献信息

• [EN] NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF<br/>[FR] NOUVEAUX ACTIVATEURS DE LA GUANYLATE CYCLASE SOLUBLE À DOUBLE MODE D'ACTION ET INHIBITEURS DE PHOSPHODIESTÉRASE ET LEURS UTILISATIONS
  申请人：TOPADUR PHARMA AG

  公开号：WO2021245192A1

  公开（公告）日：2021-12-09

  The present invention relates to compounds of formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula (I) comprises at least one covalently bound -ONO2 or -ONO moiety and at most four covalently bound -ONO2 or -ONO moieties, and wherein AR, R1, X, R3 and R4 are as defined in claim 1; and pharmaceutical compositions thereof, and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.

  本发明涉及式(I)的化合物，或其药学上可接受的盐、溶剂或水合物，其中所述式(I)的化合物至少包括一个共价结合的-ONO2或-ONO基团，最多包括四个共价结合的-ONO2或-ONO基团，其中AR、R1、X、R3和R4如权利要求1所定义；以及其药物组合物，以及它们在治疗或预防通过抑制人类或非人类哺乳动物中的PDE5而缓解的疾病的方法中的使用。
• Synthesis of 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines as a new class of antimalarial agents
  作者：Leena Gupta、Kumkum Srivastava、Shubhra Singh、S.K. Puri、Prem M.S. Chauhan

  DOI：10.1016/j.bmcl.2008.04.030

  日期：2008.6

  A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-beta-carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05-0.11 microM and are in vitro several folds more active than chloroquine

  合成了一系列杂化分子2- [3-（7-氯喹啉-4-基氨基）-烷基] -1-（取代的苯基）-2,3,4,9-四氢-1H-β-咔啉并筛选了它们对恶性疟原虫氯喹敏感菌株的体外抗疟活性。化合物26、32和34的MIC在0.05-0.11 microM的范围内，并且在体外具有比氯喹高几倍的活性。
• 4-甲氧基苯基取代四氢-β-咔啉哌嗪二酮类衍 生物及其应用
  申请人：华东理工大学

  公开号：CN108409737B

  公开（公告）日：2020-07-03

  本发明涉及一种4‑甲氧基苯基取代四氢‑β‑咔啉哌嗪二酮类衍生物及其应用。具体地，本发明公开了式I所示的化合物或其立体异构体，或其药学上可接受的盐，各基团的定义详见说明书。本发明的化合物具有乙酰胆碱酯酶和磷酸二酯酶5的双重抑制活性，具有良好的血脑屏障透过率。因此，本发明化合物可用于制备治疗和/或预防阿尔茨海默病药物。
• Pictet-spengler cyclization in room temperature ionic liquid: A convenient access to tetrahydro β-carbolines
  作者：M. Muthukrishnan、Shivaji V. More、Dinesh R. Garud、C. V. Ramana、R. R. Joshi、R. A. Joshi

  DOI：10.1002/jhet.5570430337

  日期：2006.5

  1,2,3,4-Tetrahydro-β-carbolines have been synthesized in moderate to good yields in short reaction time using the ionic liquid [bbim] BF4 as reaction medium and promoter. There was no need for the use of an additional catalyst normally employed in Pictet-Spengler condensation.

  使用离子液体[bbim] BF 4作为反应介质和促进剂，已在较短的反应时间内以中等至良好的产率合成了1,2,3,4-四氢-β-咔啉。无需使用通常在Pictet-Spengler缩合反应中使用的其他催化剂。
• Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity
  作者：Xin Chen、Jiayun Wang、Peng Zhao、Baiyun Dang、Ting Liang、Raphael R. Steimbach、Aubry K. Miller、Jia Liu、Xin Wang、Tongtong Zhang、Xiaofa Luan、Jiadong Hu、Jinming Gao

  DOI：10.1016/j.ejmech.2023.115776

  日期：2023.11

  application of scaffold hopping strategy. Several THβC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chloro

  应用支架跳跃策略合理设计并合成了一系列基于四氢β-咔啉（TH β C）的异羟肟酸作为新型选择性HDAC6抑制剂（sHDAC6is）。几种 TH β C 类似物对 HDAC6 酶具有高效能（IC 50 < 5 nM）和选择性，并对人多发性骨髓瘤(MM) 细胞表现出良好的抗增殖活性。分子对接解释了结构活性关系（SAR）。使用 WB 测定在 RPMI-8226 细胞中证实了 HDAC6 的靶标参与。体外，(1 S , 3 R )-1-(4-氯苯基) -N -(4-(羟基氨基甲酰基)苄基)-2,3,4,9-四氢-1H-吡啶并[3, 4- b ] indole-3-carboxamide ( 14g ) 对各种肿瘤（包括白血病、结肠癌、黑色素瘤和乳腺癌细胞系）表现出有效、广泛的抗增殖活性，优于 ACY-1215。此外， 14g在小鼠口服给药中也表现出良好的药代动力学特性。