8,13-epoxy-6β-(piperidinoacetoxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

• 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: 8,13-epoxy-6β-(piperidinoacetoxy)-1α,7β,9α-trihydroxylabd-14-en-11-one
• 英文别名: 6β-piperidinoacetyloxy-1α,7β,9α-trihydroxy-8,13-epoxy-labd-14-en-11-one；[(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-ethenyl-5,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-5,6,6a,8,9,10-hexahydro-2H-benzo[f]chromen-6-yl] 2-piperidin-1-ylacetate
• 化学式: C₂₇H₄₃NO₇
• 分子量: 493.641
• InChiKey: BKGCWFFZEATAAG-XGUNBQNXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1alpha,6beta,7beta,9alpha-四羟基-8,13-环氧-赖百当-14-烯-11-酮 以 吡啶 、 二氯甲烷 为溶剂， 反应 14.0h， 生成 8,13-epoxy-6β-(piperidinoacetoxy)-1α,7β,9α-trihydroxylabd-14-en-11-one
  参考文献：
  名称：

  Cardiovascular effects of new water-soluble derivatives of forskolin

  摘要：

  A series of 6- and 7-aminoacyl derivatives of 7-deacetylforskolin was prepared to provide water-soluble derivatives of the potent cardioactive diterpenoid forskolin. The compounds were evaluated for positive inotropic and blood pressure lowering properties in pharmacological models. Several derivatives displayed potent positive inotropic activity in guinea pig atria (EC50 = 0.16-3.0 micrograms/mL). In the most active compounds, the amino moiety of the aminoacyl chain corresponded to a cyclic amine, and the acyl moiety to a C2-C4 alkanoyl group. In vivo biological evaluation led to the selection of 6-(piperidinoacetyl)-7-deacetylforskolin hydrochloride (49) as a candidate for clinical development.

  DOI：

  10.1021/jm00118a002

文献信息

• Forskolin Derivatives. I. Synthesis, and Cardiovascular and Adenylate Cyclase-Stimulating Activities of Water-Soluble Forskolins.
  作者：Tochiro TATEE、Aya NARITA、Kazuhisa NARITA、Giichi IZUMI、Takashi TAKAHIRA、Masao SAKURAI、Akira FUJITA、Makoto HOSONO、Kouwa YAMASHITA、Keiko ENOMOTO、Akira SHIOZAWA

  DOI：10.1248/cpb.44.2274

  日期：——

  Water-soluble forskolin and 7-deacetylforskolin derivatives with an aminoacetyl, a 3-aminopropionyl, or a 4-aminobutyryl group at the 6- or 7-position were prepared, and their positive inotropic as well as vasodilative activities were evaluated in anesthetized dogs.7-Deacetylforskolin (2) and 7-deacetyl-1-silylforskolin (6) were converted to the corresponding 7-chloroacylderivatives (3, 7, 10), which were reacted with amines to obtain 7-aminoacyl-7-deacetylforskolins (4a-f, 9a, b, 11). The 7-acyl substituents migrated to the 6-position with sodium hydroxide in acetonitrile-water to afford 6-aminoacyl-7-deacetylforskolins (12a-f). The 7-position of 12a, d-f was selectively acetylated with acetyl chloride to obtain the corresponding 6-aminoacylforskolins (13a-d).Among the 6-aminoacylforskolins, 6-(3-dimethylaminopropionyl)forskolin (13b) and 6-(4-dimethylaminobutyryl)forskolin (13d) exhibited potent positive inotropic and vasodilative activities comparable to those of forskolin (1).The activities of 13b and 13d were approximately ten times more potent than those of 7-aminoacyl- and 6-aminoacyl-7-deacetylforskolins (4a-f, 9a, 12a-c, f). 6-Dimethylaminoacetylforskolin (13a) and 6-(3-diethylaminopropionyl)forskolin (13c) were less potent than 1. The effects of the soluble forskolins on adenylate cyclase activity were also examined in vitro. 6-Aminoacylforskolins (13a-d) exhibited potent adenylate cyclase-stimulating activity, comparable to that of 1.

  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。
• Neue polyoxygenierte Labdan-Derivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Medikamente
  申请人：HOECHST AKTIENGESELLSCHAFT

  公开号：EP0217372A2

  公开（公告）日：1987-04-08

  Die vorliegende Erfindung betrifft polyoxygenierte Labdan-Derivate. die als Substituenten eine oder mehrere Aminoacyigruppen tragen, sowie ein Verfahren zu ihrer Herstellung. Die pharmakologischen Eigenschaften der erfindungsgemäßen Verbindungen machen sie für die Verwendung bei der Behandlung von Herz- und Kreisiauferkrankungen, Hypertonie. Glaukom, Aliergien, Bronchokonstriktion und als immunomodulatoren geeignet.

  本发明涉及以一个或多个氨基酰基为取代基的聚氧拉布烷衍生物及其制备方法。 本发明化合物的药理特性使其适用于治疗心脏和循环系统疾病、高血压、青光眼、过敏、支气管收缩和心血管疾病。本发明的化合物还可用于治疗高血压、青光眼、过敏、支气管收缩和免疫调节剂。
• Process for the preparation of 6-acyl, 7-acyl and 6,7-diacyl analogues of forskolin and intermediates thereof
  申请人：HOECHST AKTIENGESELLSCHAFT

  公开号：EP0468444A1

  公开（公告）日：1992-01-29

  Process for the preparation of 6-acyl-, 7-acyl- or 6,7-diacyl analogues of forskolin of the general formula

  通式为 6-酰基、7-酰基或 6,7-二酰基的福斯克林类似物的制备工艺
• METHODS AND COMPOSITIONS FOR TREATING URINARY TRACT INFECTIONS USING AGENTS THAT MIMIC OR ELEVATE CYCLIC AMP
  申请人：DUKE UNIVERSITY

  公开号：US20140128399A1

  公开（公告）日：2014-05-08

  Methods and compositions are provided for treating a urinary tract infection (UTI). The methods involve administering to a subject in need thereof a cAMP elevator or agent that mimics cAMP, particularly a labdane diterpene such as forskolin or a derivative or analog thereof in a therapeutically effective amount to treat a UTI. The methods may further include administration of at least one cAMP elevator in combination with one or more additional active compounds from other classes of therapeutic agents, such as antimicrobial agents or cholesterol lowering drugs. Compositions of the invention include pharmaceutical compositions and kits for treating a UTI in a subject in need thereof that include therapeutically effective amounts of at least two cAMP elevators, particularly where one of the cAMP elevators is a labdane diterpene such as forskolin or a derivative or analog thereof. In particular, the compositions and kits may also include at least one cAMP elevator in combination with one or more additional active compounds from other classes of therapeutic agents, such as antimicrobial agents or cholesterol lowering drugs.
• US5268471A
  申请人：——

  公开号：US5268471A

  公开（公告）日：1993-12-07