1-(1-氮杂双环[2.2.1]庚-4-基)乙酮 | 126344-06-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 1-(1-氮杂双环[2.2.1]庚-4-基)乙酮
• 英文名称: 4-acetyl-1-azabicyclo[2.2.1]heptane
• 英文别名: 1-(1-azabicyclo[2.2.1]heptan-4-yl)ethanone
• CAS: 126344-06-7
• 化学式: C₈H₁₃NO
• 分子量: 139.197
• InChiKey: VVHIDANWMHPNPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  甲氧基胺盐酸盐 、 1-(1-氮杂双环[2.2.1]庚-4-基)乙酮 以 甲醇 为溶剂， 生成 4-acetyl-1-azabicyclo[2.2.1]heptane O-methyloxime
  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 吡啶 、 盐酸 、 氯化亚砜 、 氢溴酸 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醚 、 乙腈 为溶剂， 反应 24.5h， 生成 1-(1-氮杂双环[2.2.1]庚-4-基)乙酮
  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。
• Novel compounds
  申请人：BEECHAM GROUP PLC

  公开号：EP0338723A1

  公开（公告）日：1989-10-25

  Novel compounds of formula (I), a process for their preparation, and their use as pharmaceutical agents are described: wherein R₁ represents 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; R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a group OCOR₅ where R₅ is hydrogen or R₄, or a group NHR₆ or NR₇R₈ where R₆, R₇ and R₈ are independently C₁₋₂ alkyl; and R₃ is hydrogen or C₁₋₄ alkyl, subject to the proviso that when R₂ is a group OCOR₅ or a group NHR₆, R₃ is C₁₋₄ alkyl.

  本研究描述了式 (I) 的新型化合物、其制备方法及其作为药剂的用途： 其中 R₁ 代表 其中 p 和 q 各自独立地代表 2 至 4 的整数，r 代表 2 至 4 的整数，s 代表 1 或 2，t 代表 0 或 1； R₂ 是基团 OR₄，其中 R₄ 是 C₁₋₄ 烷基、C₂₋₄ 烯基、C₂₋₄ 烷炔基、基团 OCOR₅（其中 R₅ 是氢或 R₄）或基团 NHR₆ 或 NR₇（其中 R₆、R₇ 和 R₈ 独立地是 C₁₋₂ 烷基）；以及 R₃ 是氢或 C₁₋₄ 烷基，但当 R₂ 是基团 OCOR₅ 或基团 NHR₆ 时，R₃ 是 C₁₋₄ 烷基。
• Heterocyclic derivatives, process for their preparation and pharmaceutical compositions containing them
  申请人：BEECHAM GROUP PLC

  公开号：EP0366304A2

  公开（公告）日：1990-05-02

  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 one heteroatom selected from oxygen, nitrogen and sulphur or two heteroatoms selected from sulphur and nitrogen, any amino nitrogen being optionally substituted by a C1 -2 alkyl, and at least one ring carbon atom being substituted by a group Ri; or a group in which A1, A2 and As complete a 5-membered aromatic ring and A1 is oxygen or sulphur, A2 is CR2 and As is nitrogen or CH, or A2 is oxygen or sulphur, A1 is CH and As is CR2; and R1 and R2 are selected from, halogen, CN, OR4, SR4, N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2Hs, NHOR4, NHNH2, N02, COR4, CORs, C2-4 alkenyl, C2-4 alkynyl or C1-2 alkyl substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-2 alkyl and Rs is OR4, NH2 or NHR4; 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 5 元芳香环的 3 元二价残基，包含一个选自氧、氮和硫的杂原子或两个选自硫和氮的杂原子，任何氨基氮可选择被 C1 -2 烷基取代，至少一个环碳原子被基团 Ri 取代；或一个基团 其中 A1、A2 和 As 组成一个 5 元芳香环，且 A1 为氧或硫，A2 为 CR2，As 为氮或 CH，或 A2 为氧或硫，A1 为 CH，As 为 CR2；R1 和 R2 选自卤素、CN、OR4、SR4、N(R4)2、NHCOR4、NHCOOCH3、NHCOOC2Hs、NHOR4、NHNH2、N02、COR4、CORs、C2-4 烯基、C2-4 炔基或被 OR4、N(R4)2、SR4、CO2R4、CON(R4)2 或一个、两个或三个卤原子取代的 C1-2 烷基，其中每个 R4 独立地为氢或 C1-2 烷基，Rs 为 OR4、NH2 或 NHR4；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。
• 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。
• US5110828A
  申请人：——

  公开号：US5110828A

  公开（公告）日：1992-05-05