诺阿斯米唑 | 75970-99-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 中文名称: 诺阿斯米唑
• 英文名称: norastemizole
• 英文别名: 1-(4-fluorobenzyl)-N-(piperidin-4-yl)-1H-benzo[d]imidazol-2-amine；N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-N-(piperidin-4-yl)-amine；Tecastemizole；1-[(4-fluorophenyl)methyl]-N-piperidin-4-ylbenzimidazol-2-amine
• CAS: 75970-99-9
• 化学式: C₁₉H₂₁FN₄
• 分子量: 324.401
• InChiKey: SFOVDSLXFUGAIV-UHFFFAOYSA-N

物化性质

• 熔点：
  290.2 °C
• 沸点：
  519.8±60.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：100 mg/mL（308.26 mM；超声波加热至 60°C）

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  41.9
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

Norastemizole 是 astemizole 的人体代谢物。

Norastemizole is a known human metabolite of astemizole.

来源:NORMAN Suspect List Exchange

安全信息

• 储存条件：
  2-8°C

制备方法与用途

替卡斯咪唑（Norastemizole）是阿司咪唑的主要代谢产物，是一种有效的选择性H1受体拮抗剂，并展现出抗炎活性。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  4-[[1-[(4-氟苯基)甲基]-1H-苯并咪唑-2-基]氨基]哌啶-1-甲酸乙酯	ethyl 4-((1-(4-fluorobenzyl)-1H-benzo[d]imidazol-2-yl)amino)piperidine-1-carboxylate	84501-68-8	C22H25FN4O2	396.465
  阿司咪唑	astemizole	68844-77-9	C28H31FN4O	458.579
  阿司咪唑-d3	Astemizole-d3	1189961-39-4	C28H31FN4O	461.555
  1-(4-氟苄基)-2-氯苯并咪唑	2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole	84946-20-3	C14H10ClFN2	260.698
  2-溴-1-[(4-氟苯基)甲基]苯并咪唑	2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole	111782-98-0	C14H10BrFN2	305.149

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineethanol	90519-49-6	C21H25FN4O	368.454
  ——	4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile	——	C23H26FN5	391.491
  ——	N-[1-[2-(ethenyloxy)ethyl]-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine	99796-65-3	C23H27FN4O	394.492
  ——	N-(1-cyclohexyl-4-piperidinyl)-1-<(4-fluorophenyl)methyl>-1H-benzimidazol-2-amine	73735-89-4	C25H31FN4	406.546
  ——	1-(4-fluorobenzyl)-N-(1-phenethylpiperidin-4-yl)-1H-benzo[d]imidazol-2-amine	98088-84-7	C27H29FN4	428.552
  ——	1-(4-fluorobenzyl)-N-(1-(4-fluorophenethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-amine	98088-85-8	C27H28F2N4	446.543
  ——	N-(1-cyclohexyl-4-piperidinyl)-1-(phenylmethyl)-1H-benzimidazol-2-amine	73735-96-3	C25H32N4	388.556
  ——	1-<(4-fluorophenyl)methyl>-N-<1-<2-(4-pyridinyl)ethyl>-4-piperidinyl>-1H-benzimidazol-2-amine	73735-71-4	C26H28FN5	429.54
  4-(2-(4-((1-((4-氟苯基)甲基)-1H-苯并咪唑-2-基)氨基)-1-哌啶基)乙基)-苯酚	O-desmethyl astemizole	73736-50-2	C27H29FN4O	444.552
  ——	R 58639	99157-83-2	C29H33FN8	512.633

反应信息

• 作为反应物：
  描述：

  诺阿斯米唑 在 potassium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 丙酮 、 乙腈 为溶剂， 反应 3.5h， 生成 (4-(2-(4-(1-(4-fluorobenzyl)-1H-benzo[d]imidazol-2-ylamino)piperidin-1-yl)ethyl)piperazin-1-yl)(1H-indol-2-yl)methanone
  参考文献：
  名称：

  Mepyramine–JNJ7777120-hybrid compounds show high affinity to hH1R, but low affinity to hH4R

  摘要：

  In literature, a synergism between histamine H-1 and H-4 receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H-1 antagonist and JNJ7777120, a H-4 receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H-1 and one H-4 pharmacophor, connected by an appropriate spacer, in order to address both, H1R and H4R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH(1)R and hH(4)R. The new compounds revealed (high) affinity to hH(1)R, but showed only low affinity to hH(4)R. Additionally, we performed molecular dynamic studies for some selected compounds at hH(1)R, in order to obtain information about the binding mode of these compounds on molecular level. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.001
• 作为产物：
  描述：

  阿司咪唑 在 cytochrome P₄₅₀ BM₃ variant 2C₁₁ 作用下， 反应 1.0h， 以100%的产率得到诺阿斯米唑
  参考文献：
  名称：

  一组细胞色素 P450 BM3 变体用于生产药物代谢物并使先导化合物多样化

  摘要：

  在此，我们证明来自巨大芽孢杆菌的细胞色素 P450 BM3 的一小部分变体通过产生两种市售药物维拉帕米和阿司咪唑以及一种研究化合物的 13 种哺乳动物代谢物中的 12 种，涵盖了人类 P450 的反应范围。最活跃的酶支持制备单个代谢物以进行临床前生物活性和毒理学评估。工程化的 P450 BM3 变体还强调了其在药物先导多样化方面的潜在用途，通过催化碳中心的反应，产生超出动物和人类 P450 靶向范围的反应，从而产生新的代谢物。通过酶催化剂的定向进化可以改善特定代谢物的产生。一些变体对疏水性更强的母体药物比其代谢物更活跃，这限制了多羟基化物质的产生，这种偏好似乎取决于 P450 变体的进化历史。

  DOI：

  10.1002/chem.200900643

文献信息

• Imidazole and benzimidazole derivatives useful as histamine H3 antagonists
  申请人：Aslanian G. Robert

  公开号：US20060166960A1

  公开（公告）日：2006-07-27

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: n is 2-5; R is R 3 -aryl, R 3 -heteroaryl, R 3 -cycloalkyl, R 3 -heterocycloalkyl, alkyl, haloalkyl, —OR 4 , —SR 4 or —S(O) 1-2 R 5 ; R 1 and R 2 are H or optionally substituted phenyl or optionally substituted and X is —O— or —S—; or R 1 and R 2 , together with the carbon atoms to which they are attached form optionally substituted and X is —O—, —S— or —NR 7 —; Z is and the remaining variables are as defined in the specification; also disclosed are pharmaceutical compositions comprising the compounds of formula I; also disclosed are methods of treating allergy, allergy-induced airway responses, congestion, obesity and metabolic syndrome using the compounds of Formula I, as well as combinations with other drugs useful for treating those diseases.

  揭示了以下公式化合物或其药学上可接受的盐或溶剂，其中：n为2-5；R为R3-芳基，R3-杂环芳基，R3-环烷基，R3-杂环烷基，烷基，卤代烷基，—OR4，—SR4或—S(O)1-2R5；R1和R2为H或可选择地取代的苯基或可选择地取代的，X为—O—或—S—；或R1和R2，连同它们连接的碳原子形成可选择地取代的，X为—O—，—S—或—NR7—；Z为，其余变量如规范中所定义；还揭示了包括公式I化合物的药物组合物；还揭示了使用公式I化合物治疗过敏、过敏引起的气道反应、充血、肥胖和代谢综合征的方法，以及与其他用于治疗这些疾病的药物的组合。
• [EN] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS<br/>[FR] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES UTILISES EN TANT QU'ANTAGONISTES DU RECEPTEUR H3 DE L'HISTAMINE
  申请人：SCHERING CORP

  公开号：WO2003103669A1

  公开（公告）日：2003-12-18

  Disclosed are histamine H3 antagonists of the formula (I) wherein R1 is benzimidazolone derivative, M1 and M2 are optionally substituted carbon or nitrogen, R2 includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula (I) in combination with a H1 receptor antagonist.

  揭示了公式（I）中的组胺H3拮抗剂，其中R1是苯并咪唑酮衍生物，M1和M2是可选择地取代的碳或氮，R2包括可选择地取代的芳基或杂环基，其余变量如规范中所定义。还揭示了包括公式（I）化合物的药物组合物。还揭示了使用公式（I）化合物治疗各种疾病或症状的方法，例如过敏、过敏引起的气道反应和充血（例如，鼻塞）的方法。还揭示了使用公式（I）化合物与H1受体拮抗剂结合治疗各种疾病或症状的方法，例如过敏、过敏引起的气道反应和充血（例如，鼻塞）。
• [EN] N-PYRAZOLYL CARBOXAMIDES AS CRAC CHANNEL INHIBITORS<br/>[FR] CARBOXAMIDES N-PYRAZOLYL EN TANT QU'INHIBITEURS DU CANAL CRAC
  申请人：GLAXO GROUP LTD

  公开号：WO2010122089A1

  公开（公告）日：2010-10-28

  The present invention relates to amide compounds, processes for their preparation, pharmaceutical compositions containing these compounds and to their use in the treatment of disorders, conditions or disorders such as allergic disorders, inflammatory disorders and disorders of the immune system.

  本发明涉及酰胺化合物，其制备方法，含有这些化合物的药物组合物，以及它们在治疗过敏性疾病、炎症性疾病和免疫系统疾病等疾病、状况或障碍中的应用。
• Carbon-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists
  申请人：Aslanian G. Robert

  公开号：US20070010513A1

  公开（公告）日：2007-01-11

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt thereof, wherein: M 1 and M 3 are CH or N; M 2 is CH, CF or N; Y is —C(═O)—, —C(═S)—, —(CH 2 ) q —, —C(═NOR 7 )— or —SO 1-2 —; Z is a bond or optionally substituted alkylene or alkenylene; R 1 is H, alkyl, alkenyl, or optionally substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl or a group of the formula: where ring A is a monoheteroaryl ring; R 1 is optionally substituted alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods of treating allergy-induced airway responses, congestion, obesity, metabolic syndrome nonalcoholic fatty liver disease, hepatic steatosis, nonalcoholic steatohepatitis, cirrhosis, hepatacellular carcinoma or cognition deficit disorders using said compounds, alone or in combination with other agents.

  揭示了以下化合物的结构式或其药学上可接受的盐，其中： M1和M3为CH或N； M2为CH、CF或N； Y为—C(═O)—、—C(═S)—、—(CH2)q—、—C(═NOR7)—或—SO1-2—；Z为键或可选择地取代的烷基或烯基； R1为H、烷基、烯基，或可选择地取代的环烷基、芳基、杂芳基、杂环烷基或下式的基团： 其中环A为单杂芳基环； R1为可选择地取代的烷基、烯基、芳基、杂芳基、环烷基或杂环烷基；其余变量如规范中所定义；使用这些化合物，单独或与其他药剂结合，治疗过敏引起的气道反应、充血、肥胖、代谢综合征、非酒精性脂肪肝病、肝脂肪变性、非酒精性脂肪性肝炎、肝硬化、肝细胞癌或认知缺陷症状的组合物和治疗方法。
• Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
  申请人：Mutahi W. Mwangi

  公开号：US20070167435A1

  公开（公告）日：2007-07-19

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: M is CH or N; U and W are each CH, or one of U and W is CH and the other is N; X is a bond, alkylene, —C(O)—, —C(N—OR 5 )—, —C(N—OR 5 )—CH(R 6 )—, —CH(R 6 )—C(N—OR 5 )—, —O—, —OCH 2 —, —CH 2 O— or —S(O) 0-2 —; Y is —O—, —(CH 2 ) 2 —, —C(═O)—, —C(═NOR 7 )— or —SO 0-2 —; Z is a bond, optionally substituted alkylene or alkylene interrupted by a heteroatom or heterocyclic group; R 1 is optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, or benzimidazolyl or a derivative thereof; R 2 is optionally substituted alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods for treating an allergy-induced airway response, congestion, diabetes, obesity, an obesity-related disorder, metabolic syndrome and a cognition deficit disorder using said compounds, alone or in combination with other agents.

  揭示了以下化合物的结构式或其药学上可接受的盐或溶剂，其中：M为CH或N；U和W分别为CH，或者U和W中的一个为CH，另一个为N；X为键，烷基，—C(O)—，—C(N—OR5)—，—C(N—OR5)—CH(R6)—，—CH(R6)—C(N—OR5)—，—O—，—OCH2—，—CH2O—或—S(O)0-2—；Y为—O—，—(CH2)2—，—C(═O)—，—C(═NOR7)—或—SO0-2—；Z为键，可选择地取代的烷基或被杂原子或杂环基中断的烷基；R1为可选择地取代的烷基，环烷基，芳基，芳基烷基，杂芳基，杂环烷基或苯并咪唑基或其衍生物；R2为可选择地取代的烷基，烯基，芳基，芳基烷基，杂芳基，杂芳基烷基，环烷基或杂环烷基；其余变量如规范中所定义；使用这些化合物，单独或与其他药剂联合使用，治疗由过敏引起的气道反应、充血、糖尿病、肥胖症、与肥胖有关的疾病、代谢综合征和认知缺陷障碍的组合物和方法。