(R)-(-)-N-propyl-2-methoxy-11-hydroxynoraporphine | 1012084-77-3

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 阿朴菲
• 英文名称: (R)-(-)-N-propyl-2-methoxy-11-hydroxynoraporphine
• 英文别名: MCL-509；R-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine；2-methoxy-11-hydroxy-N-propylnoraporphine；(6aR)-2-methoxy-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-ol
• CAS: 1012084-77-3
• 化学式: C₂₀H₂₃NO₂
• 分子量: 309.408
• InChiKey: PGKMOUOGPCFQTK-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-(-)-N-propyl-2-methoxy-11-hydroxynoraporphine 在 盐酸 、 potassium carbonate 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (R)-(-)-N-propyl-2-methoxy-11-(2-fluoroethoxy)noraporphine hydrochloride
  参考文献：
  名称：

  Identification of fluorinated (R)-(−)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor

  摘要：

  A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.

  DOI：

  10.1016/j.bmcl.2018.11.050
• 作为产物：
  描述：

  蒂巴因 在 甲烷磺酸 、 偶氮二甲酸二异丙酯 、 palladium on activated charcoal 、 ammonium acetate 、 L-Selectride 、 potassium carbonate 、 magnesium 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 苯 为溶剂， 生成 (R)-(-)-N-propyl-2-methoxy-11-hydroxynoraporphine
  参考文献：
  名称：

  Identification of fluorinated (R)-(−)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor

  摘要：

  A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.

  DOI：

  10.1016/j.bmcl.2018.11.050

文献信息

• 2,4-Disubstituted thiazolyl derivatives
  申请人：——

  公开号：US20030203897A1

  公开（公告）日：2003-10-30

  This invention concerns the use of a compound of formula (I′) 1 a N-oxide, pharmaceutically acceptable addition salt, quaternary amine and stereochemically isomeric form thereof, wherein Q is optionally substituted C 3-6 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl; or Q is a radical of formula 2 wherein X and Y each independently are O, NR 3 , CH 2 or S, with R 3 being hydrogen or C 1-4 alkyl; q is 1 to 4; Z is O or NR 4 with R 4 being hydrogen or C 1-4 alkyl; r is 1 to 3; L is optionally substituted phenyl or L is Het with Het being an optionally substituted five- or six-membered heterocyclic ring or an optionally substituted bicyclic heterocyclic ring; for the manufacture of a medicament for the prevention or the treatment of diseases mediated through cytokines.

  这项发明涉及使用化合物的公式(I′)1a N-氧化物，药学上可接受的加成盐，季铵盐和其立体化学异构体，其中Q是可选择取代的C3-6环烷基，苯基，萘基，吡啶基，嘧啶基，吡嗪基，吡啶并嘧啶基，苯噻唑基，苯氧唑基，苯并咪唑基，吲哚基，或咪唑吡啶基；或Q是公式2的基团，其中X和Y分别独立地是O，NR3，CH2或S，R3为氢或C1-4烷基；q为1到4；Z为O或NR4，其中R4为氢或C1-4烷基；r为1到3；L是可选择取代的苯基或L是Het，其中Het是可选择取代的五元或六元杂环环或可选择取代的双环杂环环；用于制造用于预防或治疗通过细胞因子介导的疾病的药物。
• [EN] 2-ALKOXY-11-HYDROXYAPORPHINE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE 2-ALCOXY-11-HYDROXYAPORPHINE ET LEURS UTILISATIONS
  申请人：MCLEAN HOSPITAL CORP

  公开号：WO2011130530A1

  公开（公告）日：2011-10-20

  The invention features 2-alkoxy-l l-hydroxyaporphine derivatives that selectively bind D2high receptors. The compounds are useful for imaging D2high receptors and for the treatment of diseases, such as Parkinson's disease, sexual dysfunction, and depressive disorders.

  这项发明涉及选择性结合D2高亲和力受体的2-烷氧基-1-羟基吖啶衍生物。这些化合物可用于成像D2高亲和力受体以及用于治疗帕金森病、性功能障碍和抑郁症等疾病。
• R(-)-2-METHOXY-11-HYDROXYAPORPHINE AND DERIVATIVES THEREOF
  申请人：Neumeyer John L.

  公开号：US20110034446A1

  公开（公告）日：2011-02-10

  The invention features derivatives of R(−)-2-methoxy-11-hydroxyaporphines and methods of treating Parkinson's disease, sexual dysfunction, and depressive disorders therewith.

  这项发明涉及R（-）-2-甲氧基-11-羟基阿品啡衍生物及其用于治疗帕金森病、性功能障碍和抑郁症的方法。
• Early Process Development and Scale-Up of Orally Active Apomorphine Drug Candidates
  作者：Ekaterina Y. Melikhova、Nolwenn Derrien、Nadia Fleary-Roberts、Siân M. Forsyth、Sofia Papadouli、Antonio M. Ruda、Vargini G. Thangavadivale、Simon N. G. Tyler、Jonathan D. Moseley

  DOI：10.1021/acs.oprd.2c00297

  日期：2023.1.20

  steps were substantially redeveloped with alternative reagents. Now relying solely on crystallizations for isolation, the yield, purity, and color of each intermediate was greatly improved. All six process steps were easily transferred to the pilot plant with only minimal accommodation work required prior to manufacture on a 20–50 L scale per batch. Thus, the manufacturing campaign performed essentially

  新型阿扑吗啡帕金森氏症候选药物 (MCL-509) 的制造路线已从 mg 实验室规模发展到适用于 20-50 L 规模的规模。虽然无法改进合成顺序，但所有六个反应步骤都需要显着改进才能扩大规模。去除了有害和有毒的试剂以及有害的步骤；去除所有浓缩至干燥和层析纯化；隔离在操作上得到简化，工厂周期时间缩短。两对步骤（1 和 2；5 和 6）被成功地压缩，并且重新设想了步骤 3、4 和 5，以便所有三个步骤都用替代试剂进行了实质性的重新开发。现在完全依靠结晶分离，每个中间体的产率、纯度和颜色都有了很大的提高。所有六个工艺步骤都可以很容易地转移到中试工厂，在以每批次 20-50 L 的规模进行生产之前，只需要进行最少的调整工作。因此，制造活动基本上按预期进行，没有出现问题，同时材料产量增加了大约 10 倍，同时还实现了必要的质量改进。
• Synthesis and Dopamine Receptor Affinities of <i>N</i>-Alkyl-11-hydroxy-2-methoxynoraporphines: <i>N</i>-Alkyl Substituents Determine D1 versus D2 Receptor Selectivity
  作者：Yu-Gui Si、Matthew P. Gardner、Frank I. Tarazi、Ross J. Baldessarini、John L. Neumeyer

  DOI：10.1021/jm701045j

  日期：2008.2.1

  We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxyhoraporphines from thebaine and evaluated their binding affinities at dopamine D-1 and D-2 receptors in rat forebrain tissue. At D-2 receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D-2, K-i = 1.3 nM; D-1, K-i = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D-2, K-i = 44 nM; D-1, K-i = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy: N-methyl-aporphine (D-1 vs D-2, K-i = 46 vs 235 nM) showed higher D-1 than D2 affinity, indicating that N-alkyl substituents have major effects on D2 affinity and D-2/D-1 selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.