N-[(3R，4S)-3,4-二氢-3-羟基-2,2-二甲基-6-(4,4,4-三氟丁氧基)-2H-1-苯并吡喃-4-基]-N-甲基甲磺酰胺 | 223749-46-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: N-[(3R，4S)-3,4-二氢-3-羟基-2,2-二甲基-6-(4,4,4-三氟丁氧基)-2H-1-苯并吡喃-4-基]-N-甲基甲磺酰胺
• 英文名称: HMR 1556
• 英文别名: (3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide；HMR-1556；HMR1556；Methanesulfonamide, N-((3R,4S)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)-2H-1-benzopyran-4-yl)-N-methyl-；N-[(3R,4S)-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydrochromen-4-yl]-N-methylmethanesulfonamide
• CAS: 223749-46-0
• 化学式: C₁₇H₂₄F₃NO₅S
• 分子量: 411.442
• InChiKey: SRZRLJWUQFIZRH-LSDHHAIUSA-N

物化性质

• 熔点：
  178-179 °C
• 沸点：
  469.0±55.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  84.4
• 氢给体数：
  1
• 氢受体数：
  9

制备方法与用途

生物活性

HMR 1556 是一种色氨醇衍生物，作为有效的 IKs 阻滞剂，在犬和豚鼠的左心室肌细胞中的 IC50 值分别为 10.5 nM 和 34 nM。

靶点

• IC50: 10.5 nM (I_Ks 在犬左心室肌细胞中)，34 nM (I_Ks 在豚鼠左心室肌细胞中)

体外研究

HMR 1556 能抑制 I_to、I_Ca,L 和 IKr，其 IC50 值分别为 33.9 μM、27.5 μM 和 12.6 μM，在犬左心室肌细胞中分别测得。

反应信息

• 作为产物：
  描述：

  2,5-二羟基苯乙酮 在 四氢吡咯 、 sodium hypochlorite 、 sodium tetrahydroborate 、 disodium hydrogenphosphate 、 R,R-Jacobsen's catalyst 、 sodium hydride 、 对甲苯磺酸 作用下， 以 甲醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 32.33h， 生成 N-[(3R，4S)-3,4-二氢-3-羟基-2,2-二甲基-6-(4,4,4-三氟丁氧基)-2H-1-苯并吡喃-4-基]-N-甲基甲磺酰胺
  参考文献：
  名称：

  Synthesis and Activity of Novel and Selective I_Ks-Channel Blockers

  摘要：

  Since the discovery of the I-Ks-potassium channel as the slowly activating component of the delayed rectifier current (I-k) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K-ATP-channel openers of the chromanol type we found that chromanol 293B was able to block I-Ks. Chromanol 293B is a sulfonamide analogue of the K-ATP-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.

  DOI：

  10.1021/jm0109255

文献信息

• Sulfonamide-substituted benzopyran derivatives, processes for their
  申请人：Hoechst Marion Roussel Deutschland GmbH

  公开号：US06008245A1

  公开（公告）日：1999-12-28

  Sulfonamide-substituted benzopyran derivatives, processes for their preparation, their use as a medicament, and pharmaceutical preparations comprising them Compounds of the formula I ##STR1## having the meanings of the substituents indicated in the claims are outstandingly active substances for the production of medicaments for the prophylaxis and for the therapy of cardiovascular disorders, in particular arrhythmias, for the treatment of ulcers of the gastrointestinal region or for the treatment of diarrheal diseases.

  磺酰胺取代的苯并吡喃衍生物，其制备方法，它们作为药物的用途以及包括它们的制药制剂。式I的化合物##STR1## 具有声明中所指代的取代基的含义，是用于生产预防和治疗心血管疾病，特别是心律失常，治疗胃肠道溃疡或腹泻疾病药物的杰出活性物质。
• Treatment of neurological and neurodevelopmental diseases and disorders associated with aberrant ion channel expression and activity
  申请人：LIEBER INSTITUTE FOR BRAIN DEVELOPMENT

  公开号：US11221329B2

  公开（公告）日：2022-01-11

  Provided are methods for treating and/or reducing the symptoms of a neurological or neurodevelopmental disease or disorder characterized by ectopic expression of certain ion channels, in particular, the Nav1.8 subtype SCN10a sodium channel, or the KCNQ1 potassium channel, in neuronal cells of the central nervous system (CNS) of a subject by administering to a subject in need an antagonist of one or both of these ion channels, and in particular, an antagonist of SCN10a, to block, reduce, or suppress the aberrant CNS neuronal ion channel expression and/or activity and normalize behavioral and cognitive defects associated with the neurological and neurodevelopmental disease or disorder, so as to treat and/or reduce the symptoms of the neurological or neurodevelopmental disease or disorder. Examples of such diseases or disorders that may be treated by the described methods include, for example, Pitt-Hopkins Syndrome (PTHS), autism, autism spectrum disorder, schizophrenia, 18q syndrome and the like.

  本发明提供了用于治疗和/或减轻神经或神经发育疾病或紊乱症状的方法，该疾病或紊乱的特征是某些离子通道的异位表达，特别是 Nav1.8 亚型 SCN10a 钠通道或 KCNQ1 钾通道在中枢神经系统（CNS）神经细胞中的异位表达。8亚型SCN10a钠通道或KCNQ1钾通道的方法，该方法通过向有需要的受试者施用一种或两种这些离子通道的拮抗剂，特别是SCN10a的拮抗剂，以阻断、减少或抑制异常的中枢神经系统（CNS）离子通道、或抑制异常的中枢神经系统神经元离子通道表达和/或活性，使与神经系统和神经发育疾病或紊乱相关的行为和认知缺陷正常化，从而治疗和/或减轻神经系统或神经发育疾病或紊乱的症状。可通过所述方法治疗的此类疾病或紊乱的例子包括皮特-霍普金斯综合征（PTHS）、自闭症、自闭症谱系障碍、精神分裂症、18q 综合征等。
• Use of inhibitors of the KQT1 channel and methods of controlling and treating diseases caused by helminths and ectoparasites
  申请人：Aventis Pharma Deutschland GMBH

  公开号：US20020055537A1

  公开（公告）日：2002-05-09

  Use of inhibitors of the KQT1 channel for preparing a medicament for treating diseases caused by helminths and ectoparasites Inhibitors of the KQT1 channel are a novel way of destroying helminths and ectoparasites. For this reason, blockers of the cellular KQT1 channel, which is present in helminths and ectoparasites, are used for preparing a medicament for the treatment of vertebrates and humans infested by helminths or ectoparasites. These KQT1 blockers are used as medicaments on their own or in combination with other medicaments and therapeutic measures. Inhibitors of the KQT1 channel are likewise a novel mechanism of action for phytoparasites such as insects, arachnids, molluscs and nematodes, and consequently, they are used for preparing a crop protection composition.

  使用 KQT1 通道抑制剂制备治疗蠕虫和体外寄生虫引起的疾病的药物 KQT1 通道抑制剂是消灭蠕虫和体外寄生虫的一种新方法。因此，蠕虫和体外寄生虫体内的细胞 KQT1 通道阻断剂可用于制备治疗脊椎动物和人类蠕虫或体外寄生虫疾病的药物。这些 KQT1 阻断剂可单独用作药物，也可与其他药物和治疗措施结合使用。 KQT1 通道抑制剂同样也是一种针对植物寄生虫（如昆虫、蛛形纲动物、软体动物和线虫）的新型作用机制，因此可用于制备作物保护组合物。
• Sulfonamid-substituierte Benzopyranderivate, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
  申请人：Aventis Pharma Deutschland GmbH

  公开号：EP0913396B1

  公开（公告）日：2003-09-17
• VERWENDUNG VON INHIBITOREN DES KQT1-KANALS ZUR HERSTELLUNG EINES MEDIKAMENTS ZUR BEHANDLUNG VON KRANKHEITEN, DIE DURCH HELMINTHEN UND EKTOPARASITEN HERVORGERUFEN WERDEN
  申请人：Sanofi-Aventis Deutschland GmbH

  公开号：EP1140042B1

  公开（公告）日：2008-03-26