3-(1,4'-bipiperidin-1'-ylmethyl)-2-phenyl-4-quinolinecarboxylic acid | 473248-87-2

• 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-(1,4'-bipiperidin-1'-ylmethyl)-2-phenyl-4-quinolinecarboxylic acid
• 英文别名: 3-[1,4']Bipiperidinyl-1'-ylmethyl-2-phenyl-quinoline-4-carboxylic acid；2-phenyl-3-[(4-piperidin-1-ylpiperidin-1-yl)methyl]quinoline-4-carboxylic acid
• CAS: 473248-87-2
• 化学式: C₂₇H₃₁N₃O₂
• 分子量: 429.562
• InChiKey: QBZXRNVBCRLMGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 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-苯基环丙胺 、 3-(1,4'-bipiperidin-1'-ylmethyl)-2-phenyl-4-quinolinecarboxylic acid 在 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以22%的产率得到3-(1,4'-bipiperidin-1'-ylmethyl)-2-phenyl-N-(1-phenylcyclopropyl)-4-quinolinecarboxamide
  参考文献：
  名称：

  [EN] TRPV4 ANTAGONISTS
  [FR] ANTAGONISTES DE TRPV4

  摘要：

  本发明涉及喹啉类似物、含有它们的药物组合物以及它们作为TRPV4拮抗剂的用途。

  公开号：

  WO2011119704A1
• 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-(1,4'-bipiperidin-1'-ylmethyl)-2-phenyl-4-quinolinecarboxylic 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。
• Novel compounds
  申请人：——

  公开号：US20040102633A1

  公开（公告）日：2004-05-27

  Certain compounds of formula (I) below or a pharmaceutically acceptable salt or hydrate thereof: wherein: R 1 is H or alkyl; R 2 is —R 8 R 9 ; R 8 is a single bond or alkyl, optionally substituted one or more times by hydroxy; R 9 is aryl or cycloalkyl or heteroaryl, optionally substituted one or more times by hydroxy, alkoxy, or alkoxyalkyl; R 3 is H or alkyl or cycloalkyl or cycloalkylalkyl, optionally substituted one or more times by hydroxy or by one or more fluorines; R 4 is —NR 10 R 11 ; R 10 and R 11 are independently selected from H or alkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring comprising 3-8 ring members, which heterocyclic ring is unsubstituted or is substituted one or more times by one or more substituents R 12 ; R 12 is oxo or —R 13 R 14 R 15 , wherein R 13 is a single bond or alkyl, R 14 is OC(O) or C(O)O, and R 15 is H or alkyl; R 5 is an alkyl, cycloalkyl, cycloalkylalkyl, aryl, or single or fused ring aromatic heterocyclic group, which group is unsubstituted or is substituted one or more times by one or more substituents selected from halo such as fluoro, alkyl or haloalkyl such as fluoroalkyl; R 6 represents H or up to three substituents independently selected from the list consisting of: alkyl, alkenyl, aryl, alkoxy or a hydroxylated derivative thereof, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, alkoxycarbonyl, haloalkyl such as trifluoromethyl, acyloxy, amino, mono- or di-alkylamino, alkoxyamido, alkoxycarboxylate or an esterified derivative thereof; R 7 is H or halo; a is 1-6; and any of R 1 , R 3 , R 5 , R 8 , R 9 , R 10 , R 11 and R 12 may optionally be substituted one or more times by halo, hydroxy, amino, cyano, nitro, carboxy or oxo; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

  以下式（I）的某些化合物或其药学上可接受的盐或水合物： 其中： R1为H或烷基； R2为—R8R9； R8为单键或烷基，可以被羟基替代一次或多次； R9为芳基或环烷基或杂环烷基，可以被羟基、烷氧基或烷氧基烷基替代一次或多次； R3为H或烷基或环烷基或环烷基烷基，可以被羟基或一次或多次氟原子替代； R4为—NR10R11； R10和R11独立选择自H或烷基，或者R10和R11连同它们连接的氮原子形成一个由3-8个环成员组成的饱和或不饱和杂环，该杂环未被取代或被一个或多个取代基R12取代一次或多次； R12为氧代或—R13R14R15，其中R13为单键或烷基，R14为OC（O）或C（O）O，R15为H或烷基； R5为烷基、环烷基、环烷基烷基、芳基或单环或融合环芳基杂环基，该基未被取代或被一个或多个取代基选自卤素如氟、烷基或卤代烷基如氟代烷基取代一次或多次； R6代表H或最多三个独立选择自以下列表中的取代基：烷基、烯烃基、芳基、烷氧基或其羟基衍生物、羟基、卤素、硝基、氰基、羧基、羧胺基、磺胺基、烷氧羰基、卤代烷基如三氟甲基、酰氧基、氨基、单烷基或二烷基氨基、烷氧胺基、烷氧羧酸酯或其酯化衍生物； R7为H或卤素； a为1-6； 以及R1、R3、R5、R8、R9、R10、R11和R12中的任何一个可以选择性地被卤素、羟基、氨基、氰基、硝基、羧基或氧代基取代一次或多次； 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应用。
• Stepwise Modulation of Neurokinin-3 and Neurokinin-2 Receptor Affinity and Selectivity in Quinoline Tachykinin Receptor Antagonists
  作者：Frank E. Blaney、Luca F. Raveglia、Marco Artico、Stefano Cavagnera、Catherine Dartois、Carlo Farina、Mario Grugni、Stefania Gagliardi、Mark A. Luttmann、Marisa Martinelli、Guy M. M. G. Nadler、Carlo Parini、Paola Petrillo、Henry M. Sarau、Mark A. Scheideler、Douglas W. P. Hay、Giuseppe A. M. Giardina

  DOI：10.1021/jm000501v

  日期：2001.5.1

  Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant

  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）
• [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。
• 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