1,4,5,6-四氢-5-嘧啶羰基氯化物 | 189361-35-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 1,4,5,6-四氢-5-嘧啶羰基氯化物
• 中文别名: 5-嘧啶羰基氯化,1,4,5,6-四氢-(9CI)
• 英文名称: 1,4,5,6-tetrahydropyrimidine-5-carboxylic acid chloride
• 英文别名: (5S)-1,4,5,6-tetrahydropyrimidine-5-carbonyl chloride
• CAS: 189361-35-1
• 化学式: C₅H₇ClN₂O
• mdl: MFCD13173498
• 分子量: 146.576
• InChiKey: IBXBKDHUEWHPBO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  9
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  41.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-丁炔-2-醇 、 1,4,5,6-四氢-5-嘧啶羰基氯化物 以54%的产率得到5-(1-methylpropynyloxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride
  参考文献：
  名称：

  Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

  摘要：

  Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

  DOI：

  10.1021/jm960467d
• 作为产物：
  描述：

  1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride 在 草酰氯 作用下， 以 苯 为溶剂， 反应 2.5h， 生成 1,4,5,6-四氢-5-嘧啶羰基氯化物
  参考文献：
  名称：

  Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

  摘要：

  Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

  DOI：

  10.1021/jm960467d

文献信息

• Muscarinic agonists
  申请人：The University of Toledo

  公开号：US05726179A1

  公开（公告）日：1998-03-10

  A muscarinic agonist compound having the formula (I) or (II) below or a pharmaceutically acceptable salt thereof: ##STR1## where R is (trans) 3-methyl-2-penten-4-ynyl, (cis)3-methyl-2-penten-4-ynyl, 2-butynyl, 2-methylbutenyl, 3-methylpropynyl, phenylpropynyl, butynyl; or ##STR2## where R' is butynyl.

  一种具有以下化学式(I)或(II)或其药学上可接受的盐的毒蕈碱激动剂化合物： ##STR1## 其中R为(trans)3-甲基-2-戊烯-4-炔基，(cis)3-甲基-2-戊烯-4-炔基，2-丁炔基，2-甲基丁烯基，3-甲基丙炔基，苯基丙炔基，丁炔基; 或 ##STR2## 其中R'为丁炔基。
• US5726179A
  申请人：——

  公开号：US5726179A

  公开（公告）日：1998-03-10
• [EN] MUSCARINIC AGONISTS<br/>[FR] AGONISTES MUSCARINIQUES
  申请人：THE UNIVERSITY OF TOLEDO

  公开号：WO1998046232A1

  公开（公告）日：1998-10-22

  (EN) A muscarinic agonist compound having formula (I) or (II) or a pharmaceutically acceptable salt thereof. In formula (I) R is (trans) 3-methyl-2-penten-4-ynyl, (cis) 3-methyl-2-penten-4-ynyl, 2-butynyl, 2-methylbutenyl, 3-methylpropynyl, phenylpropynyl, butynyl. In formula (II) R' is butynyl.(FR) L'invention concerne un composé agoniste muscarinique correspondant à la formule (I) ou (II), ou bien un sel pharmaceutiquement acceptable de ce composé. Dans la formule (I), R représente (trans)3-méthyl-2-pentèn-4-ynyle, (cis)3-methyl-2-pentén-4-ynyle, 2-butynyle, 2-méthylbutenyl, 3-méthylpropynyl, phénylpropynyle, butynyle. Dans la formule (II) , R' représente butynyle.
• Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists
  作者：William S. Messer,、Yahaya F. Abuh、Yang Liu、Sumudra Periyasamy、Dan O. Ngur、Michael A. N. Edgar、Afif A. El-Assadi、Sbeih、Philip G. Dunbar、Scott Roknich、Taikyun Rho、Zheng Fang、Babatunde Ojo、Hao Zhang、James J. Huzl、Peter I. Nagy

  DOI：10.1021/jm960467d

  日期：1997.4.1

  Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.