NKH477 | 113462-26-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: NKH477
• 英文别名: 6-(3-dimethylaminopropionyl)forskolin；Colforsin daropate；[(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-5-acetyloxy-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-5,6,6a,8,9,10-hexahydro-2H-benzo[f]chromen-6-yl] 3-(dimethylamino)propanoate
• CAS: 113462-26-3
• 化学式: C₂₇H₄₃NO₈
• 分子量: 509.64
• InChiKey: RSOZZQTUMVBTMR-XGUNBQNXSA-N

物化性质

• 沸点：
  582.7±50.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  NKH477 在 溶剂黄146 作用下， 反应 24.0h， 以66%的产率得到Acrylic acid (3R,4aR,5S,6S,6aS,10S,10aR,10bS)-5-acetoxy-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-3-vinyl-dodecahydro-benzo[f]chromen-6-yl ester
  参考文献：
  名称：

  The Pharmacodynamics of 6-(3-Dimethylaminopropionyl)forskolin and a Possible Metabolite in Beagles

  摘要：

  A specific gas chromatography mass spectroscopy method with a detection limit of 0.1 ng/mL was developed for the measurement of 6-(3-dimethylaminopropionyl)forskolin (1) in beagle plasma. Using this method, plasma concentrations of 1 in beagles given pharmacologically effective intravenous doses of 1.HCl were determined. The observed maximal plasma concentrations rapidly decreased with time, and half-lives of the alpha-phases were less-than-9 min. Pharmacological effects of 1 on the cardiovascular parameters were simultaneously evaluated in one of the studies. Decreases of the pharmacological effects were slower than decreases in plasma concentrations of 1. In addition, 6-(3-methylaminopropionyl)forskolin (N-monodemethyl 1), an expected initial metabolite of 1, was prepared and found to be as pharmacologically active as 1 in beagles. These results and others suggest that a metabolite(s) of 1 contributes to the pharmacological effects of 1 in beagles.

  DOI：

  10.1021/js930234z
• 作为产物：
  描述：

  1-(tert-butyldimethylsilyl)-7-deacetylforskolin 在 吡啶 、 sodium hydroxide 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 52.42h， 生成 NKH477
  参考文献：
  名称：

  Forskolin Derivatives. I. Synthesis, and Cardiovascular and Adenylate Cyclase-Stimulating Activities of Water-Soluble Forskolins.

  摘要：

  制备了在 6-或 7-位具有氨基乙酰基、3-氨基丙酰基或 4-氨基丁酰基的水溶性毛喉素和 7-去乙酰基毛喉素衍生物，并在麻醉狗中评估了它们的正性肌力和血管舒张活性。将7-脱乙酰基毛喉素(2)和7-脱乙酰基-1-甲硅烷基毛喉素(6)转化为相应的7-氯酰基衍生物(3,7,10),与胺反应得到7-氨酰基-7-脱乙酰基毛喉素(4a- f、9a、b、11)。在乙腈-水中，用氢氧化钠将 7-酰基取代基迁移到 6-位，得到 6-氨基酰基-7-脱乙酰基毛喉素 (12a-f)。用乙酰氯选择性乙酰化12a、d-f的7位，得到相应的6-氨基酰基毛喉素(13a-d)。6-氨基酰基毛喉素中，6-(3-二甲基氨基丙酰基)毛喉素(13b)和6-(4-毛喉素)二甲氨基丁酰)forskolin (13d) 表现出与 forskolin (1) 相当的强正性肌力和血管舒张活性。13b 和 13d 的活性比 7-氨酰基-和 6-氨酰基-7-脱乙酰基 forskolin 的活性大约强十倍（ 4a-f、9a、12a-c、f)。 6-二甲氨基乙酰基毛喉素 (13a) 和 6-(3-二乙氨基丙酰基)毛喉素 (13c) 的效力低于 1。可溶性毛喉素对腺苷酸环化酶活性的影响也在体外进行了检测。 6-氨基酰基毛喉素 (13a-d) 表现出有效的腺苷酸环化酶刺激活性，与 1 相当。

  DOI：

  10.1248/cpb.44.2274

文献信息

• CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
  申请人：Cerulean Pharma Inc.

  公开号：US20130196906A1

  公开（公告）日：2013-08-01

  Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

  提供了关于使用CDP-治疗剂偶联物治疗疾病或紊乱的方法，例如自身免疫疾病、炎症性疾病、中枢神经系统紊乱、心血管疾病或代谢紊乱。还提供了CDP-治疗剂偶联物、包含CDP-治疗剂偶联物的颗粒以及包含CDP-治疗剂偶联物的组合物。
• [EN] PYRAZOLE DERIVATIVES AS SGC STIMULATORS<br/>[FR] DÉRIVÉS DE PYRAZOLE UTILISÉS COMME STIMULATEURS DE SGC
  申请人：IRONWOOD PHARMACEUTICALS INC

  公开号：WO2016044447A1

  公开（公告）日：2016-03-24

  There are described imidazole and pyrazole derivatives which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

  描述了咪唑和吡唑衍生物，它们可作为sGC的刺激剂，特别是NO独立、依赖血红素的刺激剂。这些化合物还可用于治疗、预防或管理本文中披露的各种疾病。
• [EN] SGC STIMULATORS<br/>[FR] STIMULATEURS DE LA SGC
  申请人：IRONWOOD PHARMACEUTICALS INC

  公开号：WO2015089182A1

  公开（公告）日：2015-06-18

  The present patent application discloses at least the compounds according to Formula 1 shown below, or pharmaceutically acceptable salts thereof, wherein ringjB,n, JD, J,0, X, X1, J, RC, and W are as defined herein. These compounds are useful as simulators of soluble sGC.

  本专利申请至少揭示了如下所示的符合Formula 1的化合物，或其药用可接受盐，其中ringjB，n，JD，J，0，X，X1，J，RC和W的定义如本文所述。这些化合物可用作可溶性sGC的模拟物。
• [EN] JAK INHIBITORS CONTAINING A 4-MEMBERED HETEROCYCLIC AMIDE<br/>[FR] INHIBITEURS DE JAK CONTENANT UN AMIDE HÉTÉROCYCLIQUE À 4 CHAÎNONS
  申请人：THERAVANCE BIOPHARMA R&D IP LLC

  公开号：WO2018165392A1

  公开（公告）日：2018-09-13

  The invention provides compounds of formula (I): which contain a 4-membered heterocyclic amide, where the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are useful as JAK kinase inhibitors. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat respiratory diseases, and processes and intermediates useful for preparing such compounds.

  该发明提供了式(I)的化合物：其中包含一个4-成员杂环酰胺，其中变量在规范中定义，或其药用可接受盐，这些化合物可用作JAK激酶抑制剂。该发明还提供了包含这些化合物的药物组合物，使用这些化合物治疗呼吸道疾病的方法，以及用于制备这些化合物的过程和中间体。
• [EN] POLYMERIC HYPERBRANCHED CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À DES EXCIPIENTS POLYMÉRIQUES HYPERBRANCHÉS
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024048A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble carrier-linked prodrugs of formula (I),wherein POL is a polymeric moiety,each Hyp is independently a hyperbranched moiety,each moiety SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, m is 0 or 1, each n is independently an integer from 2 to 200 and each x is independently 0 or 1. It further relates to pharmaceutical compositions comprising said water- soluble carrier-linked prodrugs and methods of treatment.

  本发明涉及水溶性载体连接的前药，其化学式为（I），其中POL是聚合物基团，每个Hyp是独立的超支化基团，每个基团SP是独立的间隔基团，每个L是独立的可逆前药连接基团，m为0或1，每个n是独立的整数，范围从2到200，每个x是独立的0或1。此外，还涉及包含所述水溶性载体连接的前药的药物组合物和治疗方法。