(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidine-3-amine hydrochloride | 1417311-95-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并异恶唑
• 英文名称: (3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidine-3-amine hydrochloride
• 英文别名: (S)-1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-amine hydrochloride
• CAS: 1417311-95-5
• 化学式: C₁₄H₁₈FN₃O*ClH
• 分子量: 299.776
• InChiKey: XKKXHPMGHAZZCI-MERQFXBCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.35
• 重原子数：
  20.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  55.29
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidine-3-amine hydrochloride 、 6-chloro-1-benzothiophene-2-sulfonyl chloride 在 4-二甲氨基吡啶 、 caesium carbonate 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 (S)-6-chloro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)benzo[b]thiophene-2-sulfonamide
  参考文献：
  名称：

  Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

  摘要：

  Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant.A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D-2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT(6)Rs and 5-HT(7)Rs ( potential procognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker.N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pK(i) = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pK(B) = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD. (c) 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

  DOI：

  10.1016/j.ejmech.2020.112149
• 作为产物：
  描述：

  (S)-tert-butyl (1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)carbamate 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 18.0h， 以91%的产率得到(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidine-3-amine hydrochloride
  参考文献：
  名称：

  Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

  摘要：

  Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant.A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D-2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT(6)Rs and 5-HT(7)Rs ( potential procognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker.N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pK(i) = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pK(B) = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD. (c) 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

  DOI：

  10.1016/j.ejmech.2020.112149