占诺美林 | 131986-45-3

• 物质功能分类: 原料药 - 呼吸系统用药 - 平喘药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 占诺美林
• 中文别名: 5-(4-己氧基-[1,2,5]噻二唑-3-yl)-1-甲基-1,2,3,6-四氢吡啶；3-[4-(己基氧)-1,2,5-噻二唑-3-基]-1,2,5,6-四氢-1-甲基吡啶；呫诺美林
• 英文名称: xanomeline
• 英文别名: 3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine；3-(hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole；3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methyl-5,6-dihydro-2H-pyridine；3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine；3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole
• CAS: 131986-45-3
• 化学式: C₁₄H₂₃N₃OS
• mdl: MFCD00867179
• 分子量: 281.422
• InChiKey: JOLJIIDDOBNFHW-UHFFFAOYSA-N

物化性质

• 沸点：
  397.0±42.0 °C(Predicted)
• 密度：
  1.101±0.06 g/cm3(Predicted)
• 溶解度：
  H2O: 可溶10mg/mL, 透明 (加热)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.714
• 拓扑面积：
  66.5
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• WGK Germany：
  3
• 海关编码：
  2934999090
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  | 2-8°C |

制备方法与用途

化学性质
草酸咕诺美林 (Xanomeline Oxalate)：C₁₄H₂₃N₃OS·C₂H₂O₄。[141064-23-5]。从丙酮结晶，熔点为148℃。
(+)-L-酒石酸咕诺美林 (Xanomeline Tartrate)：C₁₄H₂₃N₃OS·C₄H₆O₆。[152854-19-8]。从2-丙醇结晶，熔点为95.5℃。

用途
拟胆碱药物，是一种选择性的毒蕈碱M₁受体激动剂。

生产方法
将S₂Cl₂溶解于二甲基甲酰胺中，加入α-氨基-α-3-吡啶基乙腈反应得到化合物(Ⅱ)。再与己醇钠作用得到化合物(Ⅲ)，接着与碘甲烷反应形成吡啶衍生物(Ⅳ)，最后用硼氢化钠还原得到产物。

反应信息

• 作为反应物：
  描述：

  占诺美林 以 甲醇 、 水 、 乙酸乙酯 为溶剂， 生成 xanomeline pamoate
  参考文献：
  名称：

  CN114853750

  摘要：

  公开号：
• 作为产物：
  描述：

  3-(3-Pentyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridinium iodide 在 甲醇 、 sodium tetrahydroborate 作用下， 以75%的产率得到占诺美林
  参考文献：
  名称：

  Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors

  摘要：

  We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M-1/M-4 preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M-1 mAChRs by exploring the interaction of G alpha(q)-PLC-beta 3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M-1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.

  DOI：

  10.1016/j.bioorg.2020.103633

文献信息

• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• [EN] QUINOLIZIDINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1 DE LA QUINOLIZIDINONE
  申请人：MERCK & CO INC

  公开号：WO2009051715A1

  公开（公告）日：2009-04-23

  The present invention is directed to spiropiperidine compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的螺环哌啶化合物，这些化合物是M1受体阳性变构调节剂，并且在治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍方面有用。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• Piperazine-piperidine antagonists and agonists of the 5-HT1A receptor
  申请人：Asselin Magda

  公开号：US20070027160A1

  公开（公告）日：2007-02-01

  The present invention relates to novel piperazine-piperidine compounds. The compounds are useful as 5-HT 1A binding agents, particularly as 5-HT 1A receptor antagonists and agonists. These compounds are useful in treating central nervous system disorders, such as cognition disorders, anxiety disorders, depression and sexual dysfunction.

  本发明涉及新型哌嗪-哌啶化合物。这些化合物可用作5-HT1A结合剂，特别是作为5-HT1A受体拮抗剂和激动剂。这些化合物在治疗中枢神经系统疾病方面很有用，如认知障碍、焦虑症、抑郁症和性功能障碍。
• Piperidine compounds and their preparation and use
  申请人：Novo Nordisk A/S

  公开号：US05041455A1

  公开（公告）日：1991-08-20

  The present invention relates to therapeutically active piperidine compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease, severe painful conditions and glaucoma.

  本发明涉及治疗活性哌啶化合物，一种制备该化合物的方法以及包含该化合物的药物组合物。这些新颖化合物可用作哺乳动物前脑和海马体认知功能的刺激剂，特别适用于治疗阿尔茨海默病、严重疼痛症状和青光眼。
• [EN] 3-(1H-PYRAZOL-4-YL)PYRIDINE ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE TYPE 3-(1H-PYRAZOL-4-YL)PYRIDINE DU RÉCEPTEUR MUSCARINIQUE M4 DE L'ACÉTYLCHOLINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2019005588A1

  公开（公告）日：2019-01-03

  The present invention is directed to pyrazol-4-yl-pyridine compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

  本发明涉及吡唑并[4,3-b]吡啶化合物，其为M4毒蕈碱型乙酰胆碱受体的变构调节剂。本发明还涉及在可能治疗或预防神经和精神障碍以及涉及M4毒蕈碱型乙酰胆碱受体的疾病中使用所述化合物。本发明还涉及包含这些化合物的组合物。本发明还涉及在可能预防或治疗涉及M4毒蕈碱型乙酰胆碱受体的疾病中使用这些组合物。