(-)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (-)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylic acid
• 英文别名: 2,6-Dimethyl-5-nitro-4-pyridin-2-yl-1,4-dihydropyridine-3-carboxylic acid
• 化学式: C₁₃H₁₃N₃O₄
• 分子量: 275.264
• InChiKey: CONWAHGITICZPH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  溴代环己烷 、 (-)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylic acid 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以12%的产率得到Cyclohexyl 2,6-dimethyl-5-nitro-4-pyridin-2-yl-1,4-dihydropyridine-3-carboxylate
  参考文献：
  名称：

  烷基（或环烷基）1,4-二氢-2,6-二甲基-3-硝基-4-吡啶基-5-吡啶羧酸酯的外消旋物和对映异构体的合成和钙通道调节作用。

  摘要：

  一组外消旋烷基（或环烷基）1,4-二氢-2,6-二甲基-3-硝基-4-（2-，3-或4-吡啶基）-5-吡啶羧酸酯异构体（6-14）为使用改进的Hantzsch反应制备的方法，该反应涉及硝基丙酮与3-氨基巴豆酸烷基酯（或环烷基）和2-，3-或4-吡啶甲醛的缩合反应。使用豚鼠回肠纵向平滑肌（GPILSM）和豚鼠左心房（GPLA）分析测定其体外钙通道调节活性，结果表明2-吡啶基异构体可作为双心脏选择性钙通道激动剂（GPLA）/平滑肌选择性钙通道拮抗剂（GPILSM）。相反，3-吡啶基和4-吡啶基异构体在GPLA和GPILSM上均充当钙通道激动剂。在化合物的C-4 2-吡啶基中 C-5烷基（或环烷基）酯取代基的大小是GPILSM拮抗剂活性的决定因素，其中相对活性分布为环戊基和环己基> t-Bu，i-Bu，并且Et> MeOCH2CH2> Me。C-4吡啶基取代基的连接点是GPLA激动剂活性的决定因

  DOI：

  10.1021/jm9704006
• 作为产物：
  描述：

  吡啶-2-甲醛 、 (1R,2S)-2-(4-tolylsulfamoyl)-2-(methoxycarbonyl)-1-methylethyl acetoacetate 生成 (-)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylic acid 、 (-)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridinyl)pyridine-5-carboxylic acid
  参考文献：
  名称：

  Syntheses, Calcium Channel Agonist-Antagonist Modulation Activities, and Voltage-Clamp Studies of Isopropyl 1,4-Dihydro-2,6-dimethyl-3-nitro- 4-pyridinylpyridine-5-carboxylate Racemates and Enantiomers

  摘要：

  A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/-)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity an both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (I-Ca), that (+)-12A increased slightly I-Ca; and that (+/-)-12 inhibited I-Ca but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited I-Ca at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

  DOI：

  10.1021/jm00015a007

文献信息

• Synthesis and biological evaluation of 1,4-dihydropyridine calcium channel modulators having a diazen-1-ium-1,2-diolate nitric oxide donor moiety for the potential treatment of congestive heart failure
  作者：Carlos Velázquez、Edward E Knaus

  DOI：10.1016/j.bmc.2004.05.008

  日期：2004.7

  potent smooth muscle calcium channel antagonist activity (IC(50)'s in the 0.37-1.09 microM range) than related analogs having a C-4 3-pyridyl substituent (IC(50)'s=3.03-9.14 microM range) relative to the reference drug nifedipine (IC(50)=9.13 nM). The point of attachment of C-4 isomeric pyridyl substituents was a determinant of smooth muscle calcium channel antagonist activity where the relative potency

  一组具有一氧化氮供体O（2）-乙酰氧基甲基-1-（N-乙基-N-甲基氨基）或4的外消旋4-芳基（杂芳基）-1,4-二氢-2,6-二甲基-3-硝基吡啶-乙基哌嗪-1-基）重氮-1-1,2-二醇酸酯，通过偶联各自的4-芳基（杂芳基）-1,4-二氢-2,6-二甲基-3合成C-5酯取代基-硝基吡啶-5-羧酸与O（2）-乙酰氧基甲基-1- [N-（2-甲基磺酰氧基乙基）-N-甲基氨基]重氮-1-1,2-二醇酸酯或O（2）-乙酰氧基甲基-1- [4-（2-甲基磺酰氧基乙基）哌嗪-1-基]重氮-1-1,2-二醇盐。具有C-4 2-吡啶基，4-吡啶基，2-三氟甲基苯基或苯并呋喃山-4-基取代基的化合物显示出比在0.37-1.09 microM范围内更强的平滑肌钙通道拮抗剂活性（IC（50）在0.37-1.09 microM范围内）具有C-4 3-吡啶基取代基的相关类似物（IC（50）'s = 3.03-9。相对于参考药物硝苯地平为14
• Resolution of 1,4-dihydropyridine derivatives
  申请人：LABORATOIRES SYNTEX S.A.

  公开号：EP0273349A2

  公开（公告）日：1988-07-06

  Optically active compounds of the formula or a salt thereof wherein R, is H or lower alkyl; R2 and R6 are each independently lower alkyl, aryl, or arylalkyl; R3 is CN, N02, C02R5, CONHR5, SO2R5, or P(O)(OR5)2, where R5 is lower alkyl, lower alkoxyalkyl, aryl, or arylalkyl; R4 is aryl, heterocyclyl, or fused-ring heterocyclyl, optionally substituted with one, two, or three halo, N02, CN, lower alkyl, lower alkoxy, lower alkylamino, CF3, OCH2F, or OCF3; are formed from a salt mixture of the compound with a resolving agent in a hot solvent mixture of an organic solvent and water.

  式中的光学活性化合物 或其盐，其中 R 是 H 或低级烷基 R2 和 R6 各自独立地为低级烷基、芳基或芳烷基； R3 是 CN、N02、C02R5、CONHR5、SO2R5 或 P(O)(OR5)2，其中 R5 是低级烷基、低级烷氧基烷基、芳基或芳基烷基； R4 是芳基、杂环基或融合环杂环基，可任选被 1、2 或 3 个卤素、N02、CN、低级烷基、低级烷氧基、低级烷基氨基、CF3、OCH2F 或 OCF3 取代； 在有机溶剂和水的热混合溶剂中，由化合物与溶解剂的盐混合物形成。
• US4920225A
  申请人：——

  公开号：US4920225A

  公开（公告）日：1990-04-24
• Synthesis and Calcium Channel-Modulating Effects of Alkyl (or Cycloalkyl) 1,4-Dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate Racemates and Enantiomers
  作者：Manian Ramesh、Wandikayi C. Matowe、Murthy R. Akula、Dean Vo、Lina Dagnino、Moy Cheong Li-Kwong-Ken、Michael W. Wolowyk、Edward E. Knaus

  DOI：10.1021/jm9704006

  日期：1998.2.1

  that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity

  一组外消旋烷基（或环烷基）1,4-二氢-2,6-二甲基-3-硝基-4-（2-，3-或4-吡啶基）-5-吡啶羧酸酯异构体（6-14）为使用改进的Hantzsch反应制备的方法，该反应涉及硝基丙酮与3-氨基巴豆酸烷基酯（或环烷基）和2-，3-或4-吡啶甲醛的缩合反应。使用豚鼠回肠纵向平滑肌（GPILSM）和豚鼠左心房（GPLA）分析测定其体外钙通道调节活性，结果表明2-吡啶基异构体可作为双心脏选择性钙通道激动剂（GPLA）/平滑肌选择性钙通道拮抗剂（GPILSM）。相反，3-吡啶基和4-吡啶基异构体在GPLA和GPILSM上均充当钙通道激动剂。在化合物的C-4 2-吡啶基中 C-5烷基（或环烷基）酯取代基的大小是GPILSM拮抗剂活性的决定因素，其中相对活性分布为环戊基和环己基> t-Bu，i-Bu，并且Et> MeOCH2CH2> Me。C-4吡啶基取代基的连接点是GPLA激动剂活性的决定因
• Syntheses, Calcium Channel Agonist-Antagonist Modulation Activities, and Voltage-Clamp Studies of Isopropyl 1,4-Dihydro-2,6-dimethyl-3-nitro- 4-pyridinylpyridine-5-carboxylate Racemates and Enantiomers
  作者：Dean Vo、Wandikayi C. Matowe、Manian Ramesh、Nadeem Iqbal、Michael W. Wolowyk、Susan E. Howlett、Edward E. Knaus

  DOI：10.1021/jm00015a007

  日期：1995.7

  A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/-)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity an both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (I-Ca), that (+)-12A increased slightly I-Ca; and that (+/-)-12 inhibited I-Ca but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited I-Ca at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.