N-(2-methoxyethyl)-1-<(phenylmethoxy)carbonyl>-4-piperidinecarboxamide | 73415-78-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-methoxyethyl)-1-<(phenylmethoxy)carbonyl>-4-piperidinecarboxamide
• 英文别名: 1-Benzyloxycarbonyl-4-[N-(2-methoxyethyl)carbamoyl]piperidine；benzyl 4-(2-methoxyethylcarbamoyl)piperidine-1-carboxylate
• CAS: 73415-78-8
• 化学式: C₁₇H₂₄N₂O₄
• mdl: MFCD22123733
• 分子量: 320.389
• InChiKey: YNAKQZLBMNLANV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.529
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(2-methoxyethyl)-1-<(phenylmethoxy)carbonyl>-4-piperidinecarboxamide 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 正丁醇 为溶剂， 50.0 ℃ 、344.73 kPa 条件下， 反应 24.0h， 生成 1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid 2-methoxy-ethylamide
  参考文献：
  名称：

  2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents

  摘要：

  A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.

  DOI：

  10.1021/jm00389a007
• 作为产物：
  描述：

  4-氯羰酰四氢-吡啶羧酸苄酯 、 2-甲氧基乙胺 以 氯仿 为溶剂， 生成 N-(2-methoxyethyl)-1-<(phenylmethoxy)carbonyl>-4-piperidinecarboxamide
  参考文献：
  名称：

  2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents

  摘要：

  A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.

  DOI：

  10.1021/jm00389a007

文献信息

• 4-Amino-2-piperidino-quinazolines
  申请人：Pfizer Inc.

  公开号：US04243666A1

  公开（公告）日：1981-01-06

  Regulators of the cardiovascular system and, in particular, in the treatment of hypertension having the formula ##STR1## wherein R is lower alkyl; X, is a 3- or 4-position substituent and is --(CH.sub.2).sub.n CONR.sup.1 R.sup.2, --O(CH.sub.2).sub.n CONR.sup.1 R.sup.2 or ##STR2## wherein n is 0, 1 or 2; R.sup.1 is hydrogen or lower alkyl, and R.sup.2 is lower alkyl; lower alkenyl, lower alkynyl, phenyl, substituted phenyl, C.sub.3 -C.sub.7 cycloalkyl; lower alkyl substituted by phenyl, substituted phenyl, C.sub.3 -C.sub.7 cycloalkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, phenoxy, substituted phenoxy or --NR.sup.3 R.sup.4 wherein R.sup.3 and R.sup.4 each represent hydrogen, lower alkyl, lower alkanoyl or lower alkylsulfonyl; with the proviso that any O, N or halogen atom in R.sup.2 is separated by at least 2 carbon atoms from the nitrogen atom to which R.sup.2 is attached; or R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached form a morpholino group optionally substituted by one or two lower alkyl groups, or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring portion by one or two lower alkoxy groups; the pharmaceutically acceptable bioprecursors therefor, and the pharmaceutically acceptable acid addition salts thereof.

  心血管系统的调节剂，尤其是治疗高血压的化合物的公式为##STR1##其中R是较低的烷基；X是3-或4-位取代基，为--(CH.sub.2).sub.n CONR.sup.1 R.sup.2，--O(CH.sub.2).sub.n CONR.sup.1 R.sup.2或##STR2##其中n为0、1或2；R.sup.1为氢或较低的烷基，而R.sup.2为较低的烷基；较低的烯基，较低的炔基，苯基，取代苯基，C.sub.3-C.sub.7环烷基；较低的烷基被苯基，取代苯基，C.sub.3-C.sub.7环烷基，卤素，三氟甲基，羟基，较低的烷氧基，较低的烷氧羰基，苯氧基，取代苯氧基或--NR.sup.3 R.sup.4取代的；其中R.sup.3和R.sup.4分别表示氢，较低的烷基，较低的烷酰基或较低的烷基磺酰基；但R.sup.2中的任何O、N或卤原子与R.sup.2连接的氮原子至少相隔2个碳原子；或R.sup.1和R.sup.2与它们连接的氮原子一起形成一个吗啡基，该吗啡基可以选择地被一个或两个较低的烷基取代，或者一个1,2,3,4-四氢异喹啉基，该基可以选择地在苯环部分被一个或两个较低的烷氧基取代；其药用上可接受的生物前体，以及其药用上可接受的酸加盐。
• US4243666A
  申请人：——

  公开号：US4243666A

  公开（公告）日：1981-01-06
• US4248618A
  申请人：——

  公开号：US4248618A

  公开（公告）日：1981-02-03
• 2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as .alpha.1-adrenoceptor antagonists and antihypertensive agents
  作者：Valerie A. Alabaster、Simon F. Campbell、John C. Danilewicz、Colin W. Greengrass、Rhona M. Plews

  DOI：10.1021/jm00389a007

  日期：1987.6

  A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.