5-fluoro-N-[(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-3-methylbenzothiophene-2-sulphonamide | 1417309-76-2

• 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: 5-fluoro-N-[(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-3-methylbenzothiophene-2-sulphonamide
• 英文别名: (S)-5-fluoro-N-(1-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)pyrrolidin-3-yl)-3-methylbenzo[b]thiophene-2-sulfonamide；5-fluoro-N-[(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-3-methyl-1-benzothiophene-2-sulfonamide
• CAS: 1417309-76-2
• 化学式: C₂₃H₂₃F₂N₃O₃S₂
• 分子量: 491.583
• InChiKey: QMWKPHNSQXMTEQ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-(3-chloropropyl)-6-fluorobenzo[d]isoxazole 在 盐酸 、 4-二甲氨基吡啶 、 potassium carbonate 、 caesium carbonate 、 potassium iodide 作用下， 以 二氯甲烷 、 乙酸乙酯 、 乙腈 为溶剂， 反应 78.0h， 生成 5-fluoro-N-[(3S)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-3-methylbenzothiophene-2-sulphonamide
  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

文献信息

• SULPHONAMIDE DERIVATIVES OF ALICYCLIC AMINES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISEASES
  申请人：Kolaczkowski Marcin

  公开号：US20140135310A1

  公开（公告）日：2014-05-15

  Sulphonamide derivatives of alicyclic amines of formula (I), wherein A represents naphthyl or 9- or 10-membered bicyclic group, consisting of benzene ring fused with 5- or 6-membered heterocyclic ring; D represents phenyl, naphthyl, 5-membered aromatic heterocyclic group, bicyclic group consisting of a ring selected from benzene and pyridine, fused with aromatic or non-aromatic 5-membered heterocyclic ring; p, r independently represent 0 or 1; x, z independently represent 1 or 2; n is 2 or 3; and enancjomers, pharmaceutically acceptable salts and solvates thereof. The compounds may be useful for the treatment and/or prevention of the central nervous system disorders.

  环脂肪胺的磺胺衍生物的化学式(I)，其中A代表萘基或9-或10-成员双环基团，由苯环与5-或6-成员杂环环融合而成；D代表苯基，萘基，5-成员芳香杂环基团，由苯环和吡啶中选择的环融合而成，与芳香或非芳香5-成员杂环环融合；p，r独立地代表0或1；x，z独立地代表1或2；n为2或3；其对映体，药学上可接受的盐及溶剂化合物。这些化合物可能对中枢神经系统疾病的治疗和/或预防有用。
• [EN] SULPHONAMIDE DERIVATIVES OF ALICYCLIC AMINES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISEASES<br/>[FR] DÉRIVÉS SULPHONAMIDE D'AMINES ALICYCLIQUES UTILISÉS DANS LE TRAITEMENT DE MALADIES DU SYSTÈME NERVEUX CENTRAL
  申请人：ADAMED SP ZOO

  公开号：WO2013001505A2

  公开（公告）日：2013-01-03

  Sulphonamide derivatives of alicyclic amines of formula (I), wherein A represents naphthyl or 9- or 10-membered bicyclic group, consisting of benzene ring fused with -or 6-membered heterocyclic ring; D represents phenyl, naphthyl, 5-membered aromatic heterocyclic group, bicyclic group consisting of a ring selected from benzene and pyridine, fused with aromatic or non-aromatic 5-membered heterocyclic ring; r represents 0 or 1; x, z independently represent 1 or 2; n represents 3 and p represents 0, or n represents 2 and p represents 1;and enantiomers, pharmaceutically acceptable salts and solvates thereof. The compounds may be useful for the treatment and/or prevention of the central nervous system disorders (Formula I).
• Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)
  作者：Adam Bucki、Monika Marcinkowska、Joanna Śniecikowska、Agnieszka Zagórska、Marek Jamrozik、Maciej Pawłowski、Monika Głuch-Lutwin、Agata Siwek、Magdalena Jakubczyk、Karolina Pytka、Magdalena Jastrzębska-Więsek、Anna Partyka、Anna Wesołowska、Paweł Mierzejewski、Marcin Kołaczkowski

  DOI：10.1016/j.ejmech.2020.112149

  日期：2020.4

  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/).