(S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide | 191796-74-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide
• 英文别名: (S)-3-(2-aminoethoxy)-2-phenyl-N-(1-phenylpropyl)quinoline-4-carboxamide；(S)-N-(alpha-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide；3-(2-aminoethoxy)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide
• CAS: 191796-74-4
• 化学式: C₂₇H₂₇N₃O₂
• 分子量: 425.53
• InChiKey: ABPUPHVEUMCNPO-QFIPXVFZSA-N

物化性质

• 沸点：
  611.2±55.0 °C(Predicted)
• 密度：
  1.178±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  77.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide 在 ammonium hydroxide 、 sodium hydroxide 、 NaCNBH3 作用下， 以 甲醇 、 甲苯 、 柠檬酸 为溶剂， 生成 (S)-N-(a-ethylbenzyl)-3-[2-(N-methyl-8-azabicyclo[3.2.1]oct-3-yl)aminoethoxy]-2-phenylquinoline-4-carboxamide hydrochloride
  参考文献：
  名称：

  Quinoline derivatives

  摘要：

  一种化合物，或其溶剂合物或盐，其化学式为（I），其中Ar是可选择取代的芳基或C5-7环烯基基团，或可选择取代的单环或融合环芳香杂环基团；R，R1，R2和R3如描述中定义；一种制备这种化合物的方法，包含这种化合物或组合物的药物组合物在医学上的应用。

  公开号：

  US06277862B1
• 作为产物：
  描述：

  (-)-(S)-N-(alpha-乙基苄基)-3-羟基-2-苯基喹啉-4-羧酰胺 在 potassium carbonate 、 一水合肼 、 potassium iodide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 17.5h， 生成 (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide
  参考文献：
  名称：

  在新型多功能μ/δ-阿片激动剂-神经激肽拮抗剂肽模拟物的设计中利用NK2和NK3配体的抗伤害感受潜力

  摘要：

  阿片类激动剂是公认的镇痛剂，广泛用于治疗急性和慢性疼痛。然而，它们的效率伴随着极大影响副作用的代价，这些副作用与其长期使用有着内在的联系。为了解决这些问题，设计的多配体 (DML) 通过共同靶向涉及伤害感受的阿片类和非阿片类信号通路提供了一种有前景的策略。尽管与物质 P (SP)/神经激肽 1 (NK1) 系统密切相关，该系统被广泛用于疼痛治疗，但神经激肽受体 NK2 和 NK3 迄今为止在此类 DML 中被忽视。在此，报道了一系列新设计的阿片类激动剂-NK2 或-NK3 拮抗剂。一系列报道的肽、假肽、d -Arg-Phe-Lys-NH 2 ) 和双重 μ/δ 阿片类激动剂 H-Dmt- d -Arg-Aba-βAla-NH 2 (KGOP01)。阿片类药物结合测定明确表明，只有SBL-OPNK-5、SBL-OPNK-7和SBL-OPNK-9 的杂交体，带有 KGOP01 支架，保守的纳摩尔范围

  DOI：

  10.3390/molecules26175406

文献信息

• Quinoline-4-carboxamide derivatives, their preparation and their use as neurokinin 3 ( NK-3 ) - and neurokinin 2 ( NK-3 ) receptor antagonists
  申请人：SmithKline Beecham S.p.A.

  公开号：US20020068827A1

  公开（公告）日：2002-06-06

  A compound of formula (I): 1 or a salt thereof, or a solvate thereof, wherein, Ar is an optionally substituted aryl or a C 5-7 cycloalkdienyl group, or an optionally substituted single or fused ring aromatic heterocyclic group; R is C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, optionally substituted phenyl or phenyl C 1-6 alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylaminoalkyl, di C 1-6 alkylaminoalkyl, C 1-6 acylaminoalkyl, C 1-6 alkoxyalkyl, C 1-6 alkylcarbonyl, carboxy, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl C 1-6 alkyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di C 1-6 alkylaminocarbonyl, halogeno C 1-6 alkyl; or R is a group —(CH 2 ) p — wherein p is 2 or 3 which group forms a ring with a carbon atom of Ar; R 1 represents hydrogen or up to four optional subtitutents selected from the list consisting of: C 1-6 alkyl, C 1-6 alkenyl, aryl, C 1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C 1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino or mono- and di-C 1-6 alkylamino; R 2 represents hydrogen, C 1-6 -alkyl, hydroxy, halogen, cyano, amino, mono- or di-C 1-6 -alkylamino, alkylsulphonylamino, mono- or di-C 1-6 -alkanoylamino wherein any alkyl group is optionally substituted with an amino group or with a mono- or di-alkylamino group, or R 2 is a moiety —X—(CH 2 ) n —Y wherein X is a bond or —O— and n is an integer in the range of from 1 to 5 providing that when X is —O— n is only an integer from 2 to 5 and Y represents a group NY 1 Y 2 wherein Y 1 and Y 2 are independently selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkenyl, aryl or aryl-C 1-6 -alkyl or Y is hydroxy, halogen or an optionally substituted N-linked single or fused ring, heterocyclic group, R 3 is branched or linear C 1-6 alkyl, C 3-7 cycloalkyl, C 4-7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and R 4 represents hydrogen or C 1-6 alkyl; a process for the preparation of such a compound, a pharmaceutical compositon containing such a compound and the use of such a compound or composition in medicine.

  一个式为（I）的化合物： 或其盐，或其溶剂合物，其中，Ar是可选择取代的芳基或C 5-7 环烯烃基团，或可选择取代的单个或融合环芳香杂环基团； R是C 1-6 烷基，C 3-7 环烷基，C 3-7 环烷基烷基，可选择取代的苯基或苯基C 1-6 烷基，可选择取代的含有最多四个来自O和N的杂原子的五元杂芳环，羟基C 1-6 烷基，氨基C 1-6 烷基，C 1-6 烷基氨基烷基，二C 1-6 烷基氨基烷基，C 1-6 酰胺基烷基，C 1-6 烷氧基烷基，C 1-6 烷基羰基，羧基，C 1-6 烷氧羰基，C 1-6 烷氧羰基C 1-6 烷基，氨基羰基，C 1-6 烷基氨基羰基，二C 1-6 烷基氨基羰基，卤代C 1-6 烷基；或R是一个基团—(CH 2 ) p —其中p为2或3，该基团与Ar的一个碳原子形成环； R 1 代表氢或来自以下列表中选择的最多四个可选取代基：C 1-6 烷基，C 1-6 烯基，芳基，C 1-6 烷氧基，羟基，卤素，硝基，氰基，羧基，羧胺基，磺胺基，C 1-6 烷氧羰基，三氟甲基，酰氧基，邻苯二甲酰胺基，氨基或单-和双-C 1-6 烷基氨基； R 2 代表氢，C 1-6 -烷基，羟基，卤素，氰基，氨基，单-或双-C 1-6 -烷基氨基，烷基磺酰氨基，单-或双-C 1-6 -酰胺基，其中任何烷基基团可选择地取代为氨基基团或单-或双-烷基氨基基团，或R 2 是一个基团—X—(CH 2 ) n —Y，其中X是键或—O—，n是在1到5范围内的整数，要求当X为—O—时，n仅为2到5之间的整数，Y代表一个基团NY 1 Y 2 ，其中Y 1 和Y 2 分别选择自氢，C 1-6 -烷基，C 1-6 -烯基，芳基或芳基-C 1-6 -烷基，或Y为羟基，卤素或可选择取代的N-连接的单个或融合环杂环基团， R 3 是支链或直链C 1-6 烷基，C 3-7 环烷基，C 4-7 环烷基烷基，可选择取代的芳基，或可选择取代的单个或融合环芳香杂环基团；和 R 4 代表氢或C 1-6 烷基；一种制备这种化合物的方法，含有这种化合物的药物组合物以及这种化合物或组合物在医学中的用途。
• Combination, for treating depression and anxiety, containing an NK-3 receptor antagonist and a CNS penetrant NK-1 receptor antagonist
  申请人：Pfizer Products Inc.

  公开号：EP1192952A2

  公开（公告）日：2002-04-03

  The present invention relates to a method of treating depression or anxiety in a mammal, including a human, by administering to the mammal a CNS-penetrant NK-1 receptor antagonist (e.g. a substance P receptor antagonist) in combination with an NK-3 antagonist agent. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a CNS-penetrant NK-1 receptor antagonist and an NK-3 antagonist.

  本发明涉及一种治疗哺乳动物（包括人类）抑郁症或焦虑症的方法，其方法是向哺乳动物施用中枢神经系统穿透性NK-1受体拮抗剂（例如P物质受体拮抗剂）与NK-3拮抗剂联合制剂。它还涉及含有药学上可接受的载体、中枢神经系统穿透性 NK-1 受体拮抗剂和 NK-3 拮抗剂的药物组合物。
• Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 2. Identification of (<i>S</i>)-<i>N</i>-(1-Phenylpropyl)-3-hydroxy-2- phenylquinoline-4-carboxamide (SB 223412)
  作者：Giuseppe A. M. Giardina、Luca F. Raveglia、Mario Grugni、Henry M. Sarau、Carlo Farina、Andrew D. Medhurst、Davide Graziani、Dulcie B. Schmidt、Roberto Rigolio、Mark Luttmann、Stefano Cavagnera、James J. Foley、Vittorio Vecchietti、Douglas W. P. Hay

  DOI：10.1021/jm980633c

  日期：1999.3.1

  Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SE 223412, hNK-3-CHO binding K-i = 1.4 nM) and 55 (3-NHz, hNK-3-CHO binding K-i = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-8-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 mu M. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SE 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
• QUINOLINE DERIVATIVES
  申请人：Smithkline Beecham S.p.A.

  公开号：EP0876347A1

  公开（公告）日：1998-11-11
• QUINOLINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS NEUROKININ 3 (NK-3)- AND NEUROKININ 2 (NK-2) RECEPTOR ANTAGONISTS.
  申请人：Smithkline Beecham S.p.A.

  公开号：EP1019377A1

  公开（公告）日：2000-07-19