methyl (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxylate | 49558-35-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: methyl (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxylate
• 英文别名: methyl (E)-3beta,14beta-dihydroxy-5beta-pregn-20-ene-21-carboxylate；methyl (E)-3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]prop-2-enoate
• CAS: 49558-35-2
• 化学式: C₂₃H₃₆O₄
• 分子量: 376.536
• InChiKey: KJQKBHZKDSBIPI-IFYJLNHVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxylate 在 palladium on activated charcoal 氢气 、 六甲基二硅氮烷 作用下， 以 吡啶 、 甲醇 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 6.0h， 生成 3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-Hydroxy-10,13-dimethyl-3-trimethylsilanyloxy-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-propionic acid methyl ester
  参考文献：
  名称：

  Cardiac glycosides: 2. Synthesis of glucose and galactose analogs

  摘要：

  Five cardioactive steroid genins 1a to 5a of widely varying C17 beta-side groups were converted by modified Koenigs-Knorr reactions into the corresponding beta-D-glucosides 1c to 5c and beta-D-galactosides 1e to 5e. The genins included digitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta-card-20-(22)-enolide, 1a); (20R)-20, 22-dihydrodigitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta, 20R-cardanolde, 2a); 3 beta, 14-dihydroxy-22-methylene-5 beta, 14 beta, 20S-cardanolide (3a); methyl 3 beta, 14-dihydroxy-5 beta, 14 beta-pregn-20(E)-ene-21-carboxylate (4a); and methyl 3 beta, 14-dihydroxy-21-methylene-5 beta, 14 beta-pregnane-21-carboxylate (5a).

  DOI：

  10.1016/s0039-128x(83)90072-7

文献信息

• 17β-<i>O</i>-Aminoalkyloximes of 5β-Androstane-3β,14β-diol with Digitalis-like Activity:  Synthesis, Cardiotonic Activity, Structure−Activity Relationships, and Molecular Modeling of the Na⁺,K⁺-ATPase Receptor
  作者：Alberto Cerri、Nicoletta Almirante、Paolo Barassi、Alessandra Benicchio、Giorgio Fedrizzi、Patrizia Ferrari、Rosella Micheletti、Luisa Quadri、Enzio Ragg、Roberto Rossi、Marco Santagostino、Antonio Schiavone、Fulvio Serra、Maria Pia Zappavigna、Piero Melloni

  DOI：10.1021/jm990627w

  日期：2000.6.1

  with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with

  合成了一系列具有17-氨基烷氧基亚氨基烷基或-烯基取代基的洋地黄样化合物，并评估了其对Na（+），K（+）-ATPase的抑制作用和正性肌力活性。在具有构型17beta的取代基且氨基距洋地黄毒苷骨架的C（17）6或7个键的距离处发现具有最高的抑制作用。肟功能的存在加强了与受体的相互作用，如果α，β-不饱和的话，则更有效，从而模仿了天然洋地黄化合物中不饱和内酯的电子状态。活性最高的化合物显示Na（+），K（+）-ATPase抑制能力（IC（50））比标准地黄毒苷原和地高辛高17-25倍，而正性肌力（EC（50））高3-11倍。孤立的豚鼠左心房。这些特征得到了分子模型的支持，该分子模型暗示了上述基团与Na（+），K（+）-ATPase的H1-H2域中特定氨基酸残基的可能相互作用。一些互动是文献中已经描述的经典互动；发现了碱性基团与Cys138的新的非常强的相互作用，为设计与受体此区域相互作用的
• 17-iminomethylalkenyl-5 .beta., 14 .beta.-androstane and 17-iminoalkyl-5
  申请人：Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.

  公开号：US05583127A1

  公开（公告）日：1996-12-10

  Disclosed are 17-iminomethylalkenyl and 17-iminoalkyl-14.beta.-hydroxy-5.beta.-androstane derivatives of the formula (I): ##STR1## wherein the symbol means .alpha. or .beta. configuration or a Z or E configuration; A represents (CH.sub.2).sub.m or --(CH.dbd.CH).sub.n --; m represents an integer number from 1 to 6; n represents an integer number from 1 to 3; R.sup.2 represents hydrogen or hydroxy; R.sup.1 represents hydrogen, C.sub.2 -C.sub.4 alkyl unsubstituted or substituted by NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5, which may be the same or different, represent hydrogen, C.sub.1 -C.sub.4 alkyl or R.sup.4 and R.sup.5 may form, when taken together with the nitrogen atom, a five- or six- membered heterocyclic ring optionally containing one or more heteroatoms selected from oxygen and nitrogen; R.sup.3 represents NHC(.dbd.X)NR.sup.6 R.sup.7 or OR.sup.8 wherein R.sup.6 and R.sup.7, which may be the same or different, represent hydrogen, methyl, or C.sub.2 -C.sub.4 alkyl unsubstituted or substituted by NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 have the previously defined meanings; R.sup.8 represents hydrogen, methyl, C.sub.2 -C.sub.6 alkyl, unsubstituted or substituted by one or more NR.sup.4 R.sup.5 or NHC(.dbd.NH)NH.sub.2, wherein R.sup.4 and R.sup.5 have the previously defined meanings; X represents O, S, or NR.sup.9 ; R.sup.9 represents hydrogen, methyl, C.sub.2 -C.sub.4 alkyl, C.sub.2 -C.sub.4 acyl or phenyl, where the C.sub.2 -C.sub.4 alkyl and C.sub.2 -C.sub.4 acyl are unsubstituted or substituted by NR.sup.4 R.sup.5, wherein R.sup.4 and R.sup.5 have the previously defined means; and R.sup.6, R.sup.7, and R.sup.9, taken two by two, may form, together with the heteroatoms to which they are linked, a five- , six- , or seven-membered heterocyclic ring; or mixtures of .alpha. and .beta. isomers at the 3-position; or mixtures of Z and E isomers of the group A--CH.dbd.NR.sup.3 ; or pharmaceutically acceptable salts thereof. The compounds are useful for the treatment of cardiovascular disorders, such as heart failure and hypertension. Also, disclosed is a process for preparing the derivatives by reaction of the corresponding 17-alkyl or 17-methylalkenyl aldehyde with a compound of the formula H.sub.2 NNHC(.dbd.X)NR.sup.6 R.sup.7 or H.sub.2 NOR.sup.8.

  揭示了具有以下式(I)的17-亚胺甲基烯基和17-亚胺烷基-14-β-羟基-5-β-雄烷衍生物：其中符号表示α或β构型或Z或E构型；A代表(CH₂)ₘ或--(CH═CH)ₙ--; m表示1到6之间的整数；n表示1到3之间的整数；R²代表氢或羟基；R¹代表氢，未取代或取代的C₂-C₄烷基，取代基为NR⁴R⁵，其中R⁴和R⁵可以相同也可以不同，表示氢，C₁-C₄烷基，或R⁴和R⁵可以与氮原子一起形成含有氧和氮等一种或多种杂原子的五元或六元杂环；R³代表NHC(═X)NR⁶R⁷或OR⁸，其中R⁶和R⁷可以相同也可以不同，表示氢，甲基，或未取代或取代的C₂-C₄烷基，取代基为NR⁴R⁵，其中R⁴和R⁵具有上述定义的含义；R⁸代表氢，甲基，C₂-C₆烷基，未取代或取代的一个或多个NR⁴R⁵或NHC(═NH)NH₂，其中R⁴和R⁵具有上述定义的含义；X表示O，S或NR⁹；R⁹代表氢，甲基，C₂-C₄烷基，C₂-C₄酰基或苯基，其中C₂-C₄烷基和C₂-C₄酰基未取代或取代的NR⁴R⁵，其中R⁴和R⁵具有上述定义的含义；R⁶，R⁷和R⁹，两两结合，可以与它们连接的杂原子一起形成五元、六元或七元杂环；或在3-位置的α和β异构体的混合物；或A--CH═NR³的Z和E异构体的混合物；或其药学上可接受的盐。这些化合物可用于治疗心血管疾病，如心力衰竭和高血压。此外，还揭示了通过将相应的17-烷基或17-甲基烯基醛与式H₂NNHC(═X)NR⁶R⁷或H₂NOR⁸的化合物反应来制备衍生物的方法。
• Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na⁺,K⁺-ATPase Receptor
  作者：Alberto Cerri、Fulvio Serra、Patrizia Ferrari、Elena Folpini、Gloria Padoani、Piero Melloni

  DOI：10.1021/jm970312l

  日期：1997.10.1

  a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both

  合成了一系列洋地黄类化合物，其内酯环通过间隔物从原始位置移位，或被一系列带有胍hydr取代基的链取代，并评估了其对Na +，K（+）-ATPase的抑制作用和正性肌力活动。含乙烯的鸟苷reached 5达到了最高的Na +，K（+）-ATPase抑制（IC50）和正性肌力（EC50），其中17处存在一个心得力样极化的α，β-不饱和系统和碱性胍基团。 beta位置；对于该化合物，IC50和EC50值可与托马斯的母体胍1，洋地黄毒苷和地高辛相媲美或更高。在这个系列中，所需的正性肌力活性相对于有毒的心律失常浓度没有得到实质性的改善。
• Cardenolide analogs. 14. Synthesis and biological activity of glucosides of 17.beta.-modified derivatives of digitoxigenin
  作者：Phillipa Smith、Lindsay Brown、John Boutagy、Richard Thomas

  DOI：10.1021/jm00352a025

  日期：1982.10

  inactivity of the amide, in spite of its favorable shape and high capacity for forming intermolecular hydrogen bonds, is incompatible with some previous structure-activity relationship theories. Of the active genins, glucosidation enhanced activity by a factor of about 2. All glucosides, including those with high potency, showed rapid onset and offset of action. The stepwise fall in potency that occurred

  一种用于合成强心苷的改良方法用于制备洋地黄毒苷衍生物的3个β-葡萄糖苷，其中17个β侧链为CH = CHX（X = COOH，CONH2，COCH3，CN或COOR）。我们使用豚鼠左心房比较了该化合物与洋地黄毒苷葡萄糖苷的正性肌力活性。除酸（7）和酰胺（8）外，所有化合物均具有活性。尽管酰胺具有良好的形状和高的形成分子间氢键的能力，但其无活性与某些先前的结构-活性关系理论不相容。在活性肌苷中，葡糖苷化作用将活性提高了约2倍。所有葡糖苷，包括具有高效力的葡糖苷，均显示出起效快和作用抵消。
• Cardiac glycosides: 2. Synthesis of glucose and galactose analogs
  作者：Masaru Kihara、Kouichi Yoshioka、Eitaro Kitatsuji、Toshihiro Hashimoto、Dwight S. Fullerton、Douglas C. Rohrer

  DOI：10.1016/s0039-128x(83)90072-7

  日期：1983.7

  Five cardioactive steroid genins 1a to 5a of widely varying C17 beta-side groups were converted by modified Koenigs-Knorr reactions into the corresponding beta-D-glucosides 1c to 5c and beta-D-galactosides 1e to 5e. The genins included digitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta-card-20-(22)-enolide, 1a); (20R)-20, 22-dihydrodigitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta, 20R-cardanolde, 2a); 3 beta, 14-dihydroxy-22-methylene-5 beta, 14 beta, 20S-cardanolide (3a); methyl 3 beta, 14-dihydroxy-5 beta, 14 beta-pregn-20(E)-ene-21-carboxylate (4a); and methyl 3 beta, 14-dihydroxy-21-methylene-5 beta, 14 beta-pregnane-21-carboxylate (5a).