ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate hydrobromide | 129656-27-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate hydrobromide
• 英文别名: ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate;hydrobromide
• CAS: 129656-27-5
• 化学式: BrH*C₉H₁₅NO₂
• 分子量: 250.136
• InChiKey: VOSFCWXPVNUZFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.22
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate hydrobromide 在 盐酸 作用下， 反应 5.0h， 生成 1-氮杂双环[2.2.1]庚烷-4-羧酸
  参考文献：
  名称：

  Design of [R-(Z)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere

  摘要：

  Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

  DOI：

  10.1021/jm9702903
• 作为产物：
  描述：

  7-苄基-2-噁-7-氮杂螺[4.4]-1-壬酮 在 palladium on activated charcoal 氢溴酸 、 氢气 、 potassium carbonate 作用下， 生成 ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate hydrobromide
  参考文献：
  名称：

  Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands

  摘要：

  The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl-, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands ha, been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.

  DOI：

  10.1021/jm00091a007

文献信息

• Azabicyclic compounds for treating dementia
  申请人：Beecham Group p.l.c.

  公开号：US05217975A1

  公开（公告）日：1993-06-08

  A compound of formula (I) useful for treating dementia or a pharmaceutically acceptable salt thereof: ##STR1## in which one of X and Y represents hydrogen and the other represents Z, where Z is a group in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a C.sub.1-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1.

  一种化合物的分子式（I），或其药学上可接受的盐，可用于治疗痴呆症：##STR1## 其中X和Y中的一个表示氢，另一个表示Z，其中Z是一个基团，其中Q表示完成5-成员芳香环的3-成员二价残基，并包括两个或三个氮原子，任何氨基氮均被C.sub.1-2烷基，环丙基或丙炔基取代，r表示2或3的整数，s表示1或2的整数，t表示0，但当Y为氢时，s为1。
• Azabicylo oxime compounds
  申请人：Beecham Group p.l.c.

  公开号：USRE035593E1

  公开（公告）日：1997-08-19

  A compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein R.sup.1 represents ##STR2## in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; R.sub.2 is a group OR.sub.4, where R.sub.4 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a group OCOR.sub.5 where R.sub.5 is hydrogen or R.sub.4, or a group NHR.sub.6 or NR.sub.7 R.sub.8 where R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-2 alkyl; and R.sub.3 is chloro, fluoro, bromo, cyclopropyl, C.sub.1-3 alkyl substituted by one, two or three halogen atoms, or R.sub.3 is a group (CH.sub.2).sub.n R.sub.9 where R.sub.9 is --CN, --OH, --OCH.sub.3, --SH, --SCH.sub.3, --C.tbd.CH or --CH.dbd.CH.sub.2 and n is O or 1, with the proviso that when n is 0, R.sub.9 is not --OH or --SH.

  化合物的式子(I)或其药学上可接受的盐：##STR1## 其中R.sup.1代表##STR2## 其中p和q各自表示2到4的整数，r表示2到4的整数，s表示1或2，t表示0或1; R.sub.2是一个OR.sub.4基团，其中R.sub.4是C.sub.1-4烷基，C.sub.2-4烯基，C.sub.2-4炔基，OCOR.sub.5基团，其中R.sub.5是氢或R.sub.4，或NHR.sub.6或NR.sub.7R.sub.8基团，其中R.sub.6，R.sub.7和R.sub.8分别是C.sub.1-2烷基; R.sub.3是氯，氟，溴，环丙基，C.sub.1-3烷基，被一个，两个或三个卤原子取代的，或R.sub.3是(CH.sub.2).sub.nR.sub.9基团，其中R.sub.9是--CN，--OH，--OCH.sub.3，--SH，--SCH.sub.3，--C.tbd.CH或--CH.dbd.CH.sub.2，n为0或1，但当n为0时，R.sub.9不是--OH或--SH。
• 1-aza-bicyclico(2.2.1)heptanes
  申请人：Beecham Group p.l.c.

  公开号：US05091397A1

  公开（公告）日：1992-02-25

  A compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## in which one of X and Y represents hydrogen and the other represents --CH.sub.2 --Z where Z is a group ##STR2## in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being optionally substituted by a C.sub.1-2 alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group R.sub.1 ; or a group ##STR3## in which A.sub.1, A.sub.2 and A.sub.3 complete a 5-membered aromtic ring and A.sub.1 is oxygen or sulphur, one of A.sub.2 and A.sub.3 is CR.sub.2 and the other is nitrogen or CR.sub.3, or A.sub.2 is oxygen or sulphur, one of A.sub.1 and A.sub.3 is CR.sub.2 and the other is CR.sub.3 ; and R.sub.1, R.sub.2 and R.sub.3 are independently selected from hydrogen, halogen, CN, OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, NHCOR.sub.4, NHCOOCH.sub.3, NHCOOC.sub.2 H.sub.5, NHOR.sub.4, NHNH.sub.2, NO.sub.2, COR.sub.4, COR.sub.5, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, cyclopropyl or C.sub.1-2 alkyl optionally substituted with OR.sub.4, N(R.sub.4).sub.2, SR.sub.4, CO.sub.2 R.sub.4, CON(R.sub.4).sub.2 or one, two or three halogen atoms, in which each R.sub.4 is independently hydrogen or C.sub.1-2 alkyl and R.sub.5 is OR.sub.4, NH.sub.2 or NHR.sub.4 ; r represents an integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0 or 1, with the proviso that when Y is hydrogen s is 1.

  化合物的式子为（I）或其药学上可接受的盐：##STR1## 其中X和Y中的一个表示氢，另一个表示--CH.sub.2--Z，其中Z是一个团体##STR2## 其中Q表示一个3元二价残基，完成一个5元芳香环，并包括从氧、氮和硫中选择的一个或两个杂原子，或三个氮原子，任何氨基氮可以被C.sub.1-2烷基、环丙基或丙炔基取代，任何环碳原子可以被一个基团R.sub.1取代；或一个团体##STR3## 其中A.sub.1、A.sub.2和A.sub.3完成一个5元芳香环，A.sub.1是氧或硫，A.sub.2和A.sub.3中的一个是CR.sub.2，另一个是氮或CR.sub.3，或A.sub.2是氧或硫，A.sub.1和A.sub.3中的一个是CR.sub.2，另一个是CR.sub.3；R.sub.1、R.sub.2和R.sub.3分别选择自氢、卤素、CN、OR.sub.4、SR.sub.4、N(R.sub.4).sub.2、NHCOR.sub.4、NHCOOCH.sub.3、NHCOOC.sub.2 H.sub.5、NHOR.sub.4、NHNH.sub.2、NO.sub.2、COR.sub.4、COR.sub.5、C.sub.2-4烯基、C.sub.2-4炔基、环丙基或C.sub.1-2烷基，可以选择用OR.sub.4、N(R.sub.4).sub.2、SR.sub.4、CO.sub.2 R.sub.4、CON(R.sub.4).sub.2或一个、两个或三个卤素原子取代，其中每个R.sub.4独立地表示氢或C.sub.1-2烷基，R.sub.5表示OR.sub.4、NH.sub.2或NHR.sub.4；r表示2或3的整数，s表示1或2的整数，t表示0或1，但当Y为氢时，s为1。
• Azabicyclic compounds, process for their preparation and pharmaceutical compositions containing them
  申请人：Beecham Group p.l.c.

  公开号：EP0402056A2

  公开（公告）日：1990-12-12

  A compound of formula (I) or a pharmaceutically acceptable salt thereof: in which one of X and Y represents hydrogen and the other represents Z, where Z is a group in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a C1-2 alkyl, cyclopropyl or propargyl group, r represents an integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0 or 1, with the proviso that when Y is hydrogen s is 1.

  式 (I) 的化合物或其药学上可接受的盐： 其中 X 和 Y 的一个代表氢，另一个代表 Z，其中 Z 是一个基团 其中 Q 代表完成五元芳香环的三元二价残基，包含两个或三个氮原子，任何氨基氮均被 C1-2 烷基、环丙基或丙炔基取代，r 代表 2 或 3 的整数，s 代表 1 或 2 的整数，t 代表 0 或 1，但当 Y 为氢时，s 为 1。
• Novel compounds
  申请人：Beecham Group p.l.c.

  公开号：EP0392803B1

  公开（公告）日：2004-06-16