2-Hydroxy-8-dechloroclozapine | 156632-07-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 2-Hydroxy-8-dechloroclozapine
• 英文别名: 11-(4-Methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-2-ol；6-(4-methylpiperazin-1-yl)-11H-benzo[b][1,4]benzodiazepin-8-ol
• CAS: 156632-07-4
• 化学式: C₁₈H₂₀N₄O
• 分子量: 308.383
• InChiKey: KBSRARKSRVWNEC-UHFFFAOYSA-N

物化性质

• 沸点：
  515.5±60.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  51.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-Hydroxy-8-dechloroclozapine 在 cyclopentadienylruthenium(II) trisacetonitrile hexafluorophosphate 、 2-氯-1,3-双(2,6-二异丙基苯基)-1H-氯化咪唑 、 cesium fluoride 作用下， 以 乙醇 、 二甲基亚砜 、 乙腈 为溶剂， 反应 1.0h， 以20%的产率得到2-fluoro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
  参考文献：
  名称：

  18F 标记的放射性示踪剂，用于使用正电子发射断层扫描对 DREADD 进行体内成像

  摘要：

  由设计药物独家激活的设计受体 (DREADD) 是一种临床前化学遗传学方法，具有治疗各种疾病的临床潜力。使用11 C 放射性示踪剂通过正电子发射断层扫描 (PET) 实现了 DREADD 的体内可视化。本研究的目的是开发用18 F 标记的 DREADD 放射性示踪剂，以实现更长的同位素半衰期。已经为 PET 合成了一系列对 hM3Dq 和 hM4Di DREADD 受体具有广泛体外结合亲和力的氯氮平非放射性氟化类似物。化合物[ 18 F] 7b通过改进的18 F-脱氧氟化方案用商业钌试剂进行放射性标记。[ 18楼]图7b在 DREADD hM3Dq 转基因小鼠模型中展示了令人鼓舞的 PET 成像特性，而野生型小鼠大脑中的放射性示踪剂摄取量较低。[ 18 F] 7b是 DREADD 放射性示踪剂 [ 11 C]clozapine ([ 11 C]CLZ) 和 [ 11 C]deschloroclozapine

  DOI：

  10.1016/j.ejmech.2020.113047
• 作为产物：
  描述：

  N-甲基哌嗪 在 三氯化铝 、 乙硫醇 作用下， 以 甲苯 为溶剂， 反应 7.0h， 生成 2-Hydroxy-8-dechloroclozapine
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Triflate-Substituted Analogues of Clozapine:  Identification of a Novel Atypical Neuroleptic

  摘要：

  The trifluoromethanesulonyloxy (TfO) analogues 3 and 4 of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine, 1) and its 2-chloro isomer (iso-clozapine, 2), respectively, were synthesized via their OMe and OH analogues with the conventional synthetic method of the tricyclic dibenzodiazepines and evaluated pharmacologically along with their parent drugs. The binding profile of the 2-OTf analogue (4) is comparable to the binding profile of 1, although the affinity for the dopamine (DA) D-2 receptors is higher (IC50 values are 31 nM and 330 nM for compounds 4 and 1, respectively). Interestingly, no notable affinity for muscarinic receptors could be detected in compound 4. On the contrary, the 3-OTf analogue 3 only displayed affinity for muscarinic M-1 receptors (IC50 value 35 nM) and no affinity (IC50 value > 500 nM) for the other receptors tested. The 10 mu mol/kg sc dose, but nod the 10 mu mol/kg po dose, of compound 4 stimulated the output of DA, Increases of 80% and 35% in DOPAC output from the dorsal striatum were seen after sc and po administrations of 10 mu mol/kg of compound 4, respectively. Doses up to 100 mu mol/kg of compound 3 had no effect on either parameter. Doses up to 100 mu mol/kg of compound 4 were not cataleptogenic, but significantly decreased apomorphine-induced locomotor activity. In conclusion, compound 4 (GMC1-169) is a new clozapine-like neuroleptic candidate, which is lacking anticholinergic properties and displays a higher potency, as compared to clozapine (1) itself.

  DOI：

  10.1021/jm9704457

文献信息

• [EN] NEW SULFONE ESTER ANALOGUES OF iso-CLOZAPINE AND RELATED STRUCTURES: ATYPICAL NEUROLEPTICS<br/>[FR] ESTERS DE SULFONE CONSTITUANT DE NOUVEAUX ANALOGUES D'ISO-CLOZAPINE ET STRUCTURES APPARENTEES: NEUROLEPTIQUES ATYPIQUES
  申请人：WIKSTRÖM, Håkan

  公开号：WO1996029316A1

  公开（公告）日：1996-09-26

  (EN) A compound of formula (I), or pharmaceutically acceptable acid addition salts thereof, wherein R1 is H, (C1-C8) alkyl or haloalkyl or hydroxyalkyl, alkenyl, alkynyl, cyclopropylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl; R2 is H, (C1-C8) alkyl, alkenyl, alkynyl, cyclopropylalkyl or (C1-C8) haloalkyl, hydroxyalkyl, hydroxyalkyloxyalkyl or 1-(alkyl-2-imidazolidinone); X is NH, NR1, O, S, SO, SO2. The compounds of this invention possess affinity to one or several receptor systems, e.g. DA (D1-D4), $g(a)1, muscarinic (M1-M4) and 5-HT (5-HT2A, 5-HT2C and 5-HT7). The central nervous system disorders to be treated with the compounds of the present invention include psychoses-schizophrenia, autism, Tourette's syndrome, restless legs, Huntington's chorea, motion sickness, nausea, vomiting and severe anxiety.(FR) Composé de formule (I) ou ses sels à addition d'acide pharmaceutiquement acceptables, où R1 est H, haloalkyle, hydroaxyalkyle ou alkyle (C1-C8), alcényle, alcynyle, cyclopropylalkyle, aryle, arylalkyle, hétéroaryle, hétéroarylalkyle; R2 est H, alcényle, alcynyle, cyclopropylalkyle, alkyle (C1-C8) ou hydroxyalcyle, hydroxyalkyloxyalkyle, haloalkyle (C1-C8) ou 1-(alkyl-2-imidazolidinone); X est NH, NR1, O, S, SO, ou SO2. Les composés réalisés selon cette invention possèdent une affinité avec un ou plusieurs systèmes récepteurs, par exemple DA (D1-D4), $g(a)1, muscariniques (M1-M4) et 5-HT (5-HT2A, 5-HT2C et 5-HT7). Les troubles du système nerveux central pouvant être traités par les composés réalisés selon la présente invention sont notamment la psychose schizophrénique, l'autisme, le syndrome de Tourette, les impatiences des membres inférieurs, la chorée de Huntington, le mal des transports, la nausée, le vomissement et l'anxiété grave.

  化合物式(I)或其药学上可接受的酸盐，其中R1是H，(C1-C8)烷基或卤代烷基或羟基烷基，烯基，炔基，环丙基烷基，芳基，芳基烷基，杂环芳基，杂环芳基烷基; R2是H，(C1-C8)烷基，烯基，炔基，环丙基烷基或(C1-C8)卤代烷基，羟基烷基，羟基烷氧基烷基或1-(烷基-2-咪唑啉酮); X是NH，NR1，O，S，SO，SO2。本发明的化合物具有与一个或多个受体系统的亲和力，例如DA（D1-D4），$g(a)1，肌动蛋白受体（M1-M4）和5-HT（5-HT2A，5-HT2C和5-HT7）。本发明化合物可用于治疗中枢神经系统疾病，包括精神病-精神分裂症，自闭症，图雷特综合症，不宁腿综合症，亨廷顿舞蹈症，晕动病，恶心，呕吐和严重焦虑。
• 18F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography
  作者：Feng Hu、Patrick J. Morris、Jordi Bonaventura、Hong Fan、William B. Mathews、Daniel P. Holt、Sherry Lam、Matthew Boehm、Robert F. Dannals、Martin G. Pomper、Michael Michaelides、Andrew G. Horti

  DOI：10.1016/j.ejmech.2020.113047

  日期：2021.3

  Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using 11C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with 18F for a longer isotope half-life. A series of non-radioactive

  由设计药物独家激活的设计受体 (DREADD) 是一种临床前化学遗传学方法，具有治疗各种疾病的临床潜力。使用11 C 放射性示踪剂通过正电子发射断层扫描 (PET) 实现了 DREADD 的体内可视化。本研究的目的是开发用18 F 标记的 DREADD 放射性示踪剂，以实现更长的同位素半衰期。已经为 PET 合成了一系列对 hM3Dq 和 hM4Di DREADD 受体具有广泛体外结合亲和力的氯氮平非放射性氟化类似物。化合物[ 18 F] 7b通过改进的18 F-脱氧氟化方案用商业钌试剂进行放射性标记。[ 18楼]图7b在 DREADD hM3Dq 转基因小鼠模型中展示了令人鼓舞的 PET 成像特性，而野生型小鼠大脑中的放射性示踪剂摄取量较低。[ 18 F] 7b是 DREADD 放射性示踪剂 [ 11 C]clozapine ([ 11 C]CLZ) 和 [ 11 C]deschloroclozapine
• Synthesis and Pharmacological Evaluation of Triflate-Substituted Analogues of Clozapine:  Identification of a Novel Atypical Neuroleptic
  作者：Yi Liao、Peter DeBoer、Eddie Meier、Håkan Wikström

  DOI：10.1021/jm9704457

  日期：1997.12.1

  The trifluoromethanesulonyloxy (TfO) analogues 3 and 4 of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine, 1) and its 2-chloro isomer (iso-clozapine, 2), respectively, were synthesized via their OMe and OH analogues with the conventional synthetic method of the tricyclic dibenzodiazepines and evaluated pharmacologically along with their parent drugs. The binding profile of the 2-OTf analogue (4) is comparable to the binding profile of 1, although the affinity for the dopamine (DA) D-2 receptors is higher (IC50 values are 31 nM and 330 nM for compounds 4 and 1, respectively). Interestingly, no notable affinity for muscarinic receptors could be detected in compound 4. On the contrary, the 3-OTf analogue 3 only displayed affinity for muscarinic M-1 receptors (IC50 value 35 nM) and no affinity (IC50 value > 500 nM) for the other receptors tested. The 10 mu mol/kg sc dose, but nod the 10 mu mol/kg po dose, of compound 4 stimulated the output of DA, Increases of 80% and 35% in DOPAC output from the dorsal striatum were seen after sc and po administrations of 10 mu mol/kg of compound 4, respectively. Doses up to 100 mu mol/kg of compound 3 had no effect on either parameter. Doses up to 100 mu mol/kg of compound 4 were not cataleptogenic, but significantly decreased apomorphine-induced locomotor activity. In conclusion, compound 4 (GMC1-169) is a new clozapine-like neuroleptic candidate, which is lacking anticholinergic properties and displays a higher potency, as compared to clozapine (1) itself.