(R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthalene | 220051-78-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthalene
• 英文别名: (R)-5-methyl-8-(N⁴-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ylamine；(R)-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-amine；(2R)-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-amine
• CAS: 220051-78-5
• 化学式: C₁₆H₂₅N₃
• 分子量: 259.395
• InChiKey: IIZNVHAEKCAWCC-CYBMUJFWSA-N

物化性质

• 沸点：
  433.7±45.0 °C(Predicted)
• 密度：
  1.065±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  32.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthalene 在 盐酸 、 溴 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 (R)-N-[7-bromo-1,2,3,4-tetrahydro-5-methyl-8-(4-methylpiperazin-1-yl)-2-naphthyl]-4-morpholinobenzamide
  参考文献：
  名称：

  Synthesis of3H- and14C-labeled AR-A000002, a new and selective 5-HT1B/1D ligand

  摘要：

  AR-A000002是一种新型选择性高亲和力的5-HT1B/1D受体拮抗剂。研究表明，该化合物在豚鼠大脑中能够增强5-HT的周转，并增加豚鼠额叶中5-HT及其代谢物5-羟基吲哚乙酸（5-HIAA）的细胞外浓度。这些观察到的效果表明，该化合物可能用于治疗情感障碍。为进一步药理评估这种选择性5-HT1B/1D拮抗剂所需的标记AR-A000002类似物的合成过程已被描述。版权所有 © 2004 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.810
• 作为产物：
  描述：

  2-溴-5-甲基苯乙酸 在 盐酸 、 甲醇 、 aluminum (III) chloride 、 sodium tetrahydroborate 、 氯化亚砜 、 5%-palladium/activated carbon 、 氢气 、 对甲苯磺酸 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 sodium hydroxide 作用下， 以 乙醇 、 水 、 1,2-二氯乙烷 、 异丙醇 、 甲苯 为溶剂， 反应 26.5h， 生成 (R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthalene
  参考文献：
  名称：

  Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT_1B Receptor Antagonist

  摘要：

  Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C-N bond between an aromatic ring and a heterocyche moiety. The methodology employed a Buchwald-Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)(2) as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110-115 degrees C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.

  DOI：

  10.1021/op8000146

文献信息

• Combination of a 5-HT reuptake inhibitor and a H5-HT1B anatagonist or
  申请人：Astrazeneca AB

  公开号：US06159971A1

  公开（公告）日：2000-12-12

  The invention relates to a combination of a first component (a) which is a 5-HT reuptake inhibitor and a second component (b) which is selective h5-HT.sub.1B antagonist or partial agonist having the formula I ##STR1## wherein X is CH.sub.2, O; Y is CONH, NHCO; R.sub.1 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl; R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen; R.sub.3 is ##STR2## R.sub.4 and R.sub.5 independently are H or C.sub.1 -C.sub.4 alkyl, as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the form of free bases, solvents or pharmaceutically acceptable salts thereof, the preparation thereof, pharmaceutical formulations containing said combination, use of and method of treatment of affective disorders such as depression, anxiety and OCD with said combination as well as a kit containing said combination.

  该发明涉及第一组分(a)为5-HT再摄取抑制剂和第二组分(b)为选择性h5-HT.sub.1B拮抗剂或部分激动剂的组合物，其具有以下式I的结构：其中X为CH.sub.2，O；Y为CONH，NHCO；R.sub.1为H，C.sub.1 -C.sub.6烷基，C.sub.3 -C.sub.6环烷基；R.sub.2为H，C.sub.1 -C.sub.6烷基，C.sub.1 -C.sub.6烷氧基，卤素；R.sub.3为##STR2## R.sub.4和R.sub.5独立地为H或C.sub.1 -C.sub.4烷基，作为拉丁酸酯、R-对映体或S-对映体，所述组分(a)和(b)以其自由碱、溶剂或药学上可接受的盐的形式存在，其制备方法，含有该组合物的药物配方，使用该组合物治疗情感障碍如抑郁症、焦虑症和强迫症的方法，以及含有该组合物的工具包。
• Combination of a selective 5-HT.sub.1A antagonist and a selective ub
  申请人：AstraZeneca AB

  公开号：US06159972A1

  公开（公告）日：2000-12-12

  The invention relates to a combination of a first component (a) which is a selective 5-HT.sub.1A receptor antagonist having the formula I wherein R.sub.1 is n-propyl or cyclobutyl, R.sub.2 is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl and being in the (R)-enantiomer form, with a second component (b) which is a selective h5-HT.sub.1B antagonist or partial agonist having the formula II ##STR1## wherein X is CH.sub.2, O, Y is CONH, NHCO, R.sub.1 is H, C.sub.1 -C.sub.6 alky, C.sub.3 -C.sub.6 cycloalkyl, R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, R.sub.3 is ##STR2## R.sub.4 and R.sub.5 independently are H or C.sub.1 -C.sub.4 alkyl as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the form of free bases, solvates or pharmaceutically acceptable salts thereof, the preparation thereof, pharmaceutical formulations containing said combination, use of and method of treatment of affective disorders such as depression, anxiety and OCD with said combination as well as a kit containing said combination.

  该发明涉及第一组分(a)和第二组分(b)的组合物。第一组分(a)是一种选择性5-HT.sub.1A受体拮抗剂，具有式I，其中R.sub.1为正丙基或环丁基，R.sub.2为异丙基、叔丁基、环丁基、环戊基或环己基，R.sub.3为氢，R.sub.4为氢或甲基，并且为(R)-对映体形式。第二组分(b)是一种选择性h5-HT.sub.1B受体拮抗剂或部分激动剂，具有式II，其中X为CH.sub.2、O，Y为CONH、NHCO，R.sub.1为H、C.sub.1 -C.sub.6烷基、C.sub.3 -C.sub.6环烷基，R.sub.2为H、C.sub.1 -C.sub.6烷基、C.sub.1 -C.sub.6烷氧基、卤素，R.sub.3为，R.sub.4和R.sub.5独立地为H或C.sub.1 -C.sub.4烷基，为消旋体、R-对映体或S-对映体，所述组分(a)和(b)为自由碱、溶剂合物或其药学上可接受的盐形式，其制备方法，含有该组合物的药物配方，使用该组合物治疗情感障碍如抑郁症、焦虑症和强迫症的方法，以及含有该组合物的试剂盒。
• Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis
  作者：Hamish S. Sutherland、Guo-Liang Lu、Amy S.T. Tong、Daniel Conole、Scott G. Franzblau、Anna M. Upton、Manisha U. Lotlikar、Christopher B. Cooper、Brian D. Palmer、Peter J. Choi、William A. Denny

  DOI：10.1016/j.ejmech.2021.114059

  日期：2022.2

  tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC90 <1 μg/mL) in vitro M.tb growth inhibition

  耐药结核病 (TB) 是全球健康危机，需要新的治疗策略。细菌 ATP 合酶抑制剂如贝达喹啉和下一代类似物（如 TBAJ-876）分别在患者群体和临床前研究中显示出有希望的疗效，这表明选择性靶向这种酶是治疗结核病的有效治疗策略。在这项工作中，我们报告了四氢萘酰胺 (THNA) 作为一类新的 ATP 合酶抑制剂，可有效防止培养中的结核分枝杆菌 (M.tb)的生长。描述了大约 80 种 THNA 类似物的设计、合成和综合构效关系研究，其中一小部分化合物表现出强效（在某些情况下为 MIC90 <1 μg/mL) 体外M.tb生长抑制用于药代动力学和脱靶分析研究。最终，我们表明，与贝达喹啉相比，其中一些 THNA 具有降低的亲脂性、降低的 hERG 敏感性、更快的小鼠/人肝微粒体清除率和更短的血浆半衰期，可能解决与贝达喹啉相关的持久性和磷脂沉积的主要问题。
• Combination of a monoamine oxidase inhibitor and a h5-HT.sub.1B
  申请人：Astrazeneca AB

  公开号：US06159970A1

  公开（公告）日：2000-12-12

  The invention relates to a combination of a first component (a) which is a monoamine oxidase inhibitor and a second component (b) which is selective h5-HT.sub.1B antagonist or partial agonist having the formula I ##STR1## wherein X is CH.sub.2, O; Y is CONH, NHCO; R.sub.1 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl; R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen; R.sub.3 is ##STR2## R.sub.4 and R.sub.5 independently are H or C.sub.1 -C.sub.4 alkyl, as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the form of free bases, solvates or pharmaceutically acceptable salts thereof, the preparation thereof, pharmaceutical formulations containing said combination, use of and method of treatment of affective disorders such as depression, anxiety and OCD with said combination as well as a kit containing said combination.

  该发明涉及一种第一组分(a)为单胺氧化酶抑制剂，第二组分(b)为选择性h5-HT.sub.1B拮抗剂或部分激动剂的组合物，其具有以下式I的结构： 其中X为CH.sub.2，O；Y为CONH，NHCO；R.sub.1为H，C.sub.1 -C.sub.6烷基，C.sub.3 -C.sub.6环烷基；R.sub.2为H，C.sub.1 -C.sub.6烷基，C.sub.1 -C.sub.6烷氧基，卤素；R.sub.3为##STR2## R.sub.4和R.sub.5独立地为H或C.sub.1 -C.sub.4烷基，为消旋体，R-对映体或S-对映体，以及该组分(a)和(b)以自由碱、溶剂合物或其药用可接受盐的形式存在，其制备方法，含有该组合物的药物配方，使用该组合物治疗情感障碍如抑郁症、焦虑症和强迫症的方法，以及含有该组合物的套装。
• [EN] SUBSTITUTED 1,2,3,4-TETRAHYDRONAPHTHALENE DERIVATIVES<br/>[FR] DERIVES DE 1,2,3,4-TETRAHYDRONAPHTHALENE SUBSTITUE
  申请人：ASTRA AKTIEBOLAG

  公开号：WO1999005134A1

  公开（公告）日：1999-02-04

  (EN) The present invention relates to new piperidyl-or piperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives having formula (I) wherein X is N or CH; Y is NR2CH2, CH2-NR2, NR2-CO, CO-NR2 or NR2SO2 wherein R2 is H or C1-C6 alkyl; R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted, n is 0-4; R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein R6, R7 and R8 are as defined above, as ($i(R))-enantiomers, ($i(S))-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.(FR) L'invention concerne de nouveaux dérivés de 1,2,3,4-tétrahydronaphthalène substitué par pipérihyl ou pipérazinyl ayant la formule (I) où X représente N ou CH; Y représente NR2HC2, CH2-NR2, NR2-CO, CO-NR2 ou NR2SO2, R2 représentant H ou alkyle C1-C6; R1 représente H, un alkyle C1-C6 ou un cycloalkyle C3-C6; R3 représente un alkyle C1-C6, un cycloalkyle C3-C6 ou (CH2)n-aryle, aryle étant du phényle ou un noyau hétéroaromatique contenant un ou deux hétéroatomes sélectionnés parmi N, O et S, et pouvant être mono-substitué ou di-substitué; n vaut 0 à 4; R9 représente un alkyle C1-C6, cycloalkyle C3-C6, OCF3, OCHF2, OCH2F, halogène, CN, CF3, OH, alcoxy C1-C6, alcoxy C1-C6-alkyle C1-C6, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, un noyau hétéroaromatique ou hétérocyclique non substitué ou substitué contenant un ou deux hétéroatomes sélectionnés parmi N et O, les substituants étant alkyle C1-C6; ou COR8; R6, R7 et R8 étant définis plus haut. Lesdits composés se présentent sous la forme de (R)-énantiomères, (S)-énantiomères ou racémates sous forme d'une base libre ou de sels pharmaceutiquement tolérables de ceux-ci. L'invention concerne un procédé de leur préparation, des compositions pharmaceutiques contenant ces composés thérapeutiquement actifs et l'utilisation de ces composés actifs en thérapie.

  本发明涉及具有式（I）的新的哌啶基或哌嗪基取代的1,2,3,4-四氢萘衍生物，其中X为N或CH; Y为NR2CH2，CH2-NR2，NR2-CO，CO-NR2或NR2SO2，其中R2为H或C1-C6烷基; R1为H，C1-C6烷基或C3-C6环烷基; R3为C1-C6烷基，C3-C6环烷基或（CH2）n-芳基，其中芳基为苯基或含有N、O和S中的一种或两种杂原子的杂芳环，并且可能是单取代或双取代的，n为0-4; R9为C1-C6烷基，C3-C6环烷基，OCF3，OCHF2，OCH2F，卤素，CN，CF3，OH，C1-C6烷氧基，C1-C6烷氧基C1-C6烷基，NR6R7，SO3CH3，SO3CF3，SO2NR6R7，未取代或取代的杂环或杂芳环，其中含有N和O中的一种或两种杂原子，取代基为C1-C6烷基; 或COR8; 其中R6，R7和R8如上所定义，以（$i(R))-对映体，（$i(S))-对映体或光学异构体的形式呈现为自由碱基或药物可接受的盐，以及其制备方法，含有所述治疗活性化合物的制药组合物以及所述活性化合物在治疗中的使用。