3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid | 746637-40-1

• 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: 3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
• 英文别名: 2-phenyl-3-[(4-propan-2-ylpiperazin-1-yl)methyl]quinoline-4-carboxylic acid
• CAS: 746637-40-1
• 化学式: C₂₄H₂₇N₃O₂
• 分子量: 389.497
• InChiKey: XVCUUIZNQPLPSL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  56.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-氨基高哌啶 、 3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 18.0h， 以17%的产率得到3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenylquinoline-4-carboxylic acid azepan-1-ylamide
  参考文献：
  名称：

  [EN] SUBSTITUTED QUINOLINE-4-CARBOXYLIC HYDRAZIDES AS NK-2/NK-3 RECEPTOR LIGANDS
  [FR] HYDRAZIDES D'ACIDE CARBOXYLIQUE DE 4-QUINOLEINE SUBSTITUES EN TANT QUE LIGANDS DU RECEPTEUR DE NK-2/NK-3

  摘要：

  本发明公开了一种化合物，其化学式为（I）：其中：R1是芳基或杂环芳基；R2是羟基，C1-6烷氧基，C1-6烷基，氨基，NR'R'或C1-6烷基-NR'R'，其中R'和R'分别选择自氢和C1-4烷基，且R'和R'与它们连接的氮原子一起形成一个饱和的含氮3-7成员杂环，该杂环可以包含另一个氮原子，并且可以被上述定义的NR'R'取代，或者R2是被上述定义的NR'R'取代的C1-6烷氧基；R3是氢或C1-6烷基；R4是氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基或芳基C1-6烷基；R5是氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基，芳基C1-6烷基或C1-6烷氧羰基；或者R4和R5，与它们连接的氮原子一起形成一个C3-C10单环或双环饱和环；X和Y分别选择自氢，羟基，硝基，氨基，氰基，三氟甲基，卤素和C1-4烷基；或其药用盐；作为治疗精神分裂症、COPD、哮喘或肠易激综合征的NK-2/NK-3配体。

  公开号：

  WO2004072045A1
• 作为产物：
  描述：

  3-溴甲基-2-苯基喹啉-4-羧酸甲酯 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid
  参考文献：
  名称：

  逐步调节喹啉速激肽受体拮抗剂中神经激肽3和神经激肽2受体的亲和力和选择性。

  摘要：

  描述了使用相同的2-苯基喹啉模板从人神经激肽3受体（hNK-3R）选择拮抗剂逐步转化为有效和组合的hNK-3R和hNK-2R拮抗剂的逐步化学修饰方法。用hNK-3和hNK-2受体的3-D模型对接研究来驱动化学设计并加快对两种受体的有效和联合拮抗作用的鉴定。（S）-（+）-N-（1-环己基乙基）-3-[（4-吗啉-4-基）哌啶-1-基]甲基-2-苯基喹啉-4-羧酰胺（化合物25，SB-400238 ：hNK-3R结合亲和力，K（i）= 0.8 nM； hNK-2R结合亲和力，K（i）= 0.8 nM）成为这种方法的最佳例子。进一步的研究导致鉴定（S）-（+）-N-（1,2,2-三甲基丙基）-3-[（4-哌啶-1-基）哌啶-1-基]甲基-2-苯基喹啉-4-羧酰胺（化合物28，SB-414240：hNK-3R结合亲和力，K（i）= 193 nM；hNK-2R结合亲和力，K（i）= 1.0 nM）

  DOI：

  10.1021/jm000501v

文献信息

• Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
  申请人：SmithKline Beecham S.p.A.

  公开号：US20030212101A1

  公开（公告）日：2003-11-13

  A compound, or a solvate or a salt thereof, of formula (I): 1 wherein, Ar is an optionally substituted aryl or a C 5-7 cycloalkdienyl group, or an optionally substituted C 5-7 cycloalkyl group, or an optionally substituted single or fused ring aromatic heterocyclic group; R is hydrogen, linear or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl; R 1 represents hydrogen or up to three optional substituents 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, amino or mono- and di-C 1-6 alkylamino; R 2 represents a moiety —(CH 2 ) n —NY 1 Y 2 wherein n is an integer in the range of from 1 to 9, Y 1 and Y 2 are independently selected from C 1-6 -alkyl; C 1-6 alkyl substituted with hydroxy, alkoxy, C 1-6 alkylamino or bis (C 1-6 alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C 1-6 -alkenyl; aryl or aryl-C 1-6 -alkyl or Y 1 and Y 2 together with the nitrogen atom to which they are attached represent 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, R 5 represents hydrogen or halogen; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

  式（I）的化合物，或其溶剂化物或盐，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C5-7环烷基基团，或可选择取代的单环或融合环芳香杂环基团；R是氢，直链或支链的C1-6烷基，C3-7环烷烷基，C3-7环烷烷基烷基；R1代表氢或来自以下列表中选择的最多三个可选取代基：C1-6烷基，C1-6烯基，芳基，C1-6烷氧基，羟基，卤素，硝基，氰基，羧基，羧胺基，磺胺基，C1-6烷氧羰基，三氟甲基，酰氧基，氨基或单-和双-C1-6烷基氨基；R2代表一个基团—（CH2）n—NY1Y2，其中n是1到9范围内的整数，Y1和Y2独立选择自C1-6烷基；C1-6烷基取代羟基，烷氧基，C1-6烷基氨基或双（C1-6烷基）氨基；C3-6环烷基；C4-6氮杂环烷基；C1-6烯基；芳基或芳基-C1-6烷基或Y1和Y2与它们连接的氮原子一起代表一个可选择取代的N-连接的单环或融合环杂环基团；R3是支链或直链的C1-6烷基，C3-7环烷烷基，C4-7环烷烷基烷基，可选择取代的芳基，或可选择取代的单环或融合环芳香杂环基团；和R4代表氢或C1-6烷基，R5代表氢或卤素；制备这种化合物的过程，包括这种化合物的药物组合物以及这种化合物和组合物在医学中的用途。
• [EN] QUINOLINE DERIVATIVES AS NK-2 AND NK-3 RECEPTOR LIGANDS<br/>[FR] DERIVES DE QUINOLINE UTILISES COMME LIGANDS DES RECEPTEURS NK-2 ET NK-3
  申请人：SMITHKLINE BEECHAM SPA

  公开号：WO2000031038A1

  公开（公告）日：2000-06-02

  A compound, or a solvate or a salt thereof, of formula (I), wherein R is linear or branched alkyl; R1 represents hydrogen or up to four optional substituents selected from the list consisting of: C1-6 alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino or mono- and di-C1-6 alkylamino; R2 represents a moiety -(CH2)n-NY1Y2 wherein n is an integer in the range of from 1 to 9, Y1 and Y2 are independently selected from hydrogen; C1-6-alkyl; C1-6 alkyl substituted with hydroxy, C1-6 alkylamino or bis (C1-6 alkyl) amino; C1-6-alkenyl; aryl or aryl-C1-6-alkyl or Y1 or Y2 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group; R3 is branched or linear C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and R4 represents hydrogen or alkyl or R4 and R together with the carbon atom to which they are attached form an optionally substituted C3-12 cycloalkyl group; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds as NK-2 or NK-3 receptor ligands.

  公式（I）的化合物，或其溶剂化物或盐，其中R是直链或支链烷基；R1代表氢或最多四个可选的取代基，所选自以下列表：C1-6烷基，C1-6烯基，芳基，C1-6烷氧基，羟基，卤素，硝基，氰基，羧基，羧酰胺基，磺酰胺基，C1-6烷氧羰基，三氟甲基，酰氧基，邻苯二甲酰亚胺基，氨基或单-和双-C1-6烷基氨基；R2代表一个基团-(CH2)n-NY1Y2，其中n是1至9范围内的整数，Y1和Y2是独立选择的氢；C1-6烷基；C1-6烷基被羟基，C1-6烷基氨基或双（C1-6烷基）氨基取代；C1-6烯基；芳基或芳基-C1-6-烷基或Y1或Y2与它们附着的氮原子一起表示一个可选取代的N-连接的单环或融合环杂环基；R3是支链或直链C1-6烷基，C3-7环烷基，C4-7环烷基烷基，可选取代的芳基，或可选取代的单环或融合环芳香杂环基；R4表示氢或烷基，或R4和R与它们附着的碳原子形成一个可选取代的C3-12环烷基基团；制备这种化合物的方法，包括这种化合物的制药组合物以及将这种化合物用作NK-2或NK-3受体配体的用途。
• Substituted quinoline-4-carboxylic hydrazides as nk-2/nk-3 receptor ligands
  申请人：Chambers Stuart Mark

  公开号：US20060089348A1

  公开（公告）日：2006-04-27

  The present invention discloses a compound of formula (I): wherein: R 1 is an aryl or heteroaryl ring; R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkyl, amino, NR′R″ or C 1-6 alkyl-NR′R″ where R′ and R″ are independently chosen from hydrogen and C 1-4 alkyl and where R′ and R″, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 3-7 membered heterocycle optionally containing a further nitrogen atom and optionally substituted by NR′R″ as defined above or R 2 is C 1-6 alkoxy substituted by NR′R″ as defined above; R 3 is hydrogen or C 1-6 alkyl; R 4 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, aryl or aryl C 1-6 alkyl; R 5 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -8 cycloalkyl, aryl, aryl C 1-6 alkyl or C 1-6 alkoxycarbonyl; or R 4 and R 5 , together with the nitrogen atom to which they are attached, form a C 3 -C 10 mono- or bicyclic saturated ring; X and Y are independently chosen from hydrogen, hydroxy, nitro, amino, cyano, CF 3 , halogen and C 1-4 alkyl; or a pharmaceutically acceptable salt thereof; as NK-2/NK-3 ligands for treating schizophrenia, COPD, asthma or irritable bowel syndrome.

  本发明揭示了一种化合物，其化学式为（I）：其中：R1为芳基或杂环芳基环；R2为羟基，C1-6烷氧基，C1-6烷基，氨基，NR′R″或C1-6烷基-NR′R″，其中R′和R″分别选择氢和C1-4烷基，且R′和R″与它们所连接的氮原子一起形成一个饱和的含氮3-7成员杂环，可选地含有进一步的氮原子，并可选地被上述定义的NR′R″或R2为C1-6烷氧基所取代；R3为氢或C1-6烷基；R4为氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基或芳基C1-6烷基；R5为氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基，芳基C1-6烷基或C1-6烷氧羰基；或R4和R5与它们所连接的氮原子一起形成C3-C10单环或双环饱和环；X和Y分别选择自氢，羟基，硝基，氨基，氰基，CF3，卤素和C1-4烷基；或其药学上可接受的盐；作为NK-2 / NK-3配体，用于治疗精神分裂症，慢性阻塞性肺疾病，哮喘或肠易激综合征。
• Substituted quinoline-4-carboxylic hydrazides as NK-2/NK-3 receptor ligands
  申请人：Merck Sharp & Dohme

  公开号：US07482457B2

  公开（公告）日：2009-01-27

  The present invention discloses a compound of formula (I): wherein: R1 is an aryl or heteroaryl ring; R2 is hydroxy, C1-6 alkoxy, C1-6 alkyl, amino, NR′R″ or C1-6 alkyl-NR′R″ where R′ and R″ are independently chosen from hydrogen and C1-4 alkyl and where R′ and R″, together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing 3-7 membered heterocycle optionally containing a further nitrogen atom and optionally substituted by NR′R″ as defined above or R2 is C1-6 alkoxy substituted by NR′R″ as defined above; R3 is hydrogen or C1-6 alkyl; R4 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, aryl or aryl C1-6 alkyl; R5 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, aryl, aryl C1-6 alkyl or C1-6 alkoxycarbonyl; or R4 and R5, together with the nitrogen atom to which they are attached, form a C3-C10 mono- or bicyclic saturated ring; X and Y are independently chosen from hydrogen, hydroxy, nitro, amino, cyano, CF3, halogen and C1-4 alkyl; or a pharmaceutically acceptable salt thereof; as NK-2/NK-3 ligands for treating schizophrenia, COPD, asthma or irritable bowel syndrome.

  本发明揭示了化合物（I）的结构：其中：R1是芳基或杂环芳基环；R2是羟基，C1-6烷氧基，C1-6烷基，氨基，NR′R″或C1-6烷基-NR′R″，其中R′和R″分别选择氢和C1-4烷基，R′和R″与它们所连接的氮原子一起形成一个饱和的含氮3-7环杂环，该杂环可选择性地含有进一步的氮原子，并可选择性地被上述定义的NR′R″取代，或者R2是被上述定义的NR′R″取代的C1-6烷氧基；R3是氢或C1-6烷基；R4是氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基或芳基C1-6烷基；R5是氢，C1-8烷基，C2-8烯基，C2-8炔基，C3-8环烷基，芳基，芳基C1-6烷基或C1-6烷氧羰基；或者R4和R5，与它们所连接的氮原子一起，形成C3-C10单环或双环饱和环；X和Y分别选择自氢，羟基，硝基，氨基，氰基，CF3，卤素和C1-4烷基；或其药学上可接受的盐；作为NK-2/NK-3配体，用于治疗精神分裂症，慢性阻塞性肺疾病，哮喘或肠易激综合症。
• QUINOLINE DERIVATIVES AS NK-2 AND NK-3 RECEPTOR LIGANDS
  申请人：Smithkline Beecham S.p.A.

  公开号：EP1131294A1

  公开（公告）日：2001-09-12