(2S,3R,4S)-2-[(tert-butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane | 104882-10-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,3R,4S)-2-[(tert-butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane
• 英文别名: (2S,3R,4S)-2-[(tert-Butyloxycarbonyl)-amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane；(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane；(2S,3R,4S)-2-[(tert-Butyloxycarbonyl) amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane；tert-butyl N-[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]carbamate
• CAS: 104882-10-2
• 化学式: C₁₉H₃₇NO₄
• 分子量: 343.507
• InChiKey: ZHAZNVULMASDSK-YESZJQIVSA-N

物化性质

• 熔点：
  128.5-129.5 °C
• 沸点：
  493.5±35.0 °C(Predicted)
• 密度：
  1.027±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  78.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,3R,4S)-2-[(tert-butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.5h， 生成 N-[2-Azido-1-(1-cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexylcarbamoyl)-ethyl]-2-benzyl-4-morpholin-4-yl-4-oxo-butyramide
  参考文献：
  名称：

  Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides

  摘要：

  A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.

  DOI：

  10.1021/jm00056a005
• 作为产物：
  描述：

  2-甲基-2-丙基[(2S)-1-环己基-3-氧代-2-丙基]氨基甲酸酯 在 四氧化锇 、 potassium tert-butylate 、 N-甲基吗啉氧化物 作用下， 以 异丙醇 、 甲苯 为溶剂， 反应 24.5h， 生成 (2S,3R,4S)-2-[(tert-butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane
  参考文献：
  名称：

  Diastereoselectivity in the osmium-catalyzed dihydroxylation of allylic amides and carbamates

  摘要：

  The stereochemistry of the osmium-catalyzed dihydroxylation of a series of chiral allylic amides and carbamates has been studies. The diastereoselectivity of these reactions was found to be dependent upon the solvent and the nitrogen protecting group as well as the geometry and substitution pattern of the olefin substrate. In contrast to the erythro selectivity observed with allylic alcohols, osmylations of the allylic amides and carbamates in this study were threo selective. Stoichiometric osmylations were consistently more selective than the corresponding catalytic reactions. Control experiments suggest this is due to the presence of a second catalytic cycle based upon an osmium glycolate catalyst which accumulates as the reaction proceeds to completion. Double diastereoselective dihydroxylations of allylic carbamates were also briefly examined.

  DOI：

  10.1016/0957-4166(94)80024-3

文献信息

• Novel Synthesis of (2<i>S</i>, 3<i>R</i>, 4<i>S</i>)-4-Amino-5-cyclohexyl-1-morpholino-2,3-pentanediol and (2<i>S</i>, 3<i>R</i>, 4<i>S</i>)-2-Amino-1-cyclohexyl-6-methyl-3,4-heptanediol, the C-Terminal Components of Renin Inhibitors
  作者：Yuko Kobayashi、Kazuhiko Nakatani、Yoshio Ito、Shiro Terashima

  DOI：10.1246/cl.1990.1709

  日期：1990.9

  The title synthesis could be accomplished in a highly stereo- and regioselective manner by employing epoxide formation with inversion of configuration followed by epoxide opening with a nucleophile.

  标题合成可以以高度立体和区域选择性的方式完成，方法是采用环氧化物形成和构型反转，然后用亲核试剂打开环氧化物。
• Novel Synthesis of Three Types of C-Terminal Components of Renin Inhibitors from Unnatural (2S,3S)-Tartaric Acid.
  作者：Yuko KOBAYASHI、Teruyo MATSUMOTO、Yoshiji TAKEMOTO、Kazuhiko NAKATANI、Yoshio ITO、Tetsuhide KAMIJO、Hiromu HARADA、Shiro TERASHIMA

  DOI：10.1248/cpb.39.2550

  日期：——

  The addition reaction of cyclohexylmethylmagnesium bromide with the imine prepared from unnatural(2S, 3S)-tartaric acid was found to proceed in a highly stereoselective manner in the presence of cerium(III) chloride. A chelation-controlled mechanism could explain the stereochemical outcome of the addition reaction. The addition product could be elaborated into three types of C-terminal components of renin inhibitors by employing oxidative cleavage of the 1, 2-diol moiety, epoxide formation with inversion of configuration, and epoxide opening with a nucleophile.

  环己基甲基溴化镁与非天然（2S, 3S）-酒石酸制备的亚胺的加成反应，在氯化铈（III）存在下，表现出高度的立体选择性。螯合控制机制可以解释加成反应的立体化学结果。加成产物可以通过1, 2-二醇部分的氧化断裂、构型反转的环氧化反应和与亲核试剂的环氧化开环反应，进一步转化为三种类型的血管紧张素转化酶抑制剂的C端部分。
• Endothelin converting enzyme inhibitors
  申请人：Abbott Laboratories

  公开号：US05338726A1

  公开（公告）日：1994-08-16

  Compounds are disclosed which inhibit endothelin converting enzyme. These compounds are useful for treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma and atherosclerosis.

  抑制内皮素转化酶的化合物已被披露。这些化合物可用于治疗高血压、充血性心力衰竭、心肌梗死、再灌注损伤、冠状动脉狭窄、脑血管痉挛、急性肾衰竭、非甾体抗炎药诱导的胃溃疡、环孢霉素诱导的肾毒性、内毒素诱导的毒性、哮喘和动脉粥样硬化。
• Renin inhibitors. Dipeptide analogs of angiotensinogen utilizing a dihydroxyethylene transition-state mimic at the scissile bond to impart greater inhibitory potency
  作者：Jay R. Luly、Nwe BaMaung、Jeff Soderquist、Anthony K. L. Fung、Herman Stein、Hollis D. Kleinert、Patrick A. Marcotte、David A. Egan、Barbara Bopp

  DOI：10.1021/jm00120a005

  日期：1988.12

  extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin. At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes. Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal

  含二醇的肾素抑制剂的合成表明，与人血管紧张素原中易裂的Leu-Val键相对应的简单邻位二醇官能团能够以与相应的醛或羟甲基官能团相当或更高的水平赋予抑制活性（比较抑制剂2a-c或3a-c）。这一发现通过在Leu-Val替代物中包含第二个羟基，从而在200-700-pM范围内抑制人肾素的化合物（例如43）进一步优化了一系列小型过渡态类似物抑制剂。 ，45，63，66）。第二羟基对效能的影响大小不仅由二醇的绝对立体化学决定，而且由P1残基的侧链决定。含二醇抑制剂的分子模型表明，一个羟基氢键与Asp 32和Asp 215，而另一个氢键与Asp215。这些二醇抑制剂对人肾素的选择性超过相关的组织蛋白酶D，胃蛋白酶和胃蛋白酶。在高浓度下，在P2位上含有亮氨酸或苯丙氨酸而不是组氨酸的化合物对其他酶的抑制作用很小。在静脉内和十二指肠内给药后，抑制剂43完全抑制了血浆血浆肾素活性，并降低了猴子的平均血压，但
• Time-Resolved Ligand Exchange Reactions: Kinetic Models for Competitive Inhibitors with Recombinant Human Renin
  作者：Maurice M. Morelock、Christopher A. Pargellis、Edward T. Graham、Daniel Lamarre、Grace Jung

  DOI：10.1021/jm00010a019

  日期：1995.5

  peptidomimetic, competitive inhibitors of human renin using a novel binding assay. The method entails analyzing a pair of ligand exchange reactions in which a dansylated inhibitor serves as the fluorescent probe. The first in the pair of reactions involves preincubating renin with the probe and initiating the reaction by addition of a sample inhibitor; the second reaction involves preincubating renin with the

  使用新型结合测定法，确定了一系列人肾素的拟肽竞争性抑制剂的开和关速率常数（kon和koff）。该方法需要分析一对配体交换反应，其中以丹磺酰化的抑制剂作为荧光探针。该对反应中的第一个涉及将肾素与探针预孵育，并通过添加样品抑制剂来引发反应；第二个反应包括将肾素与样品抑制剂预孵育，然后通过添加探针来引发反应。这两个反应均产生了进度曲线，其中包含有关每个配体的kon和koff的补充信息。使用从描述配体交换过程的微分速率方程式衍生的模型同时拟合两条曲线。探针的kon和koff速率常数分别为6.85 x 10（6）M-1 s-1和2.96 x 10（-4）s-1，得出的Kd为43.2 pM。抑制剂系列的Kd值变化超过2个数量级（27-2320 pM），而单个kon（10（6）-10（7）M-1 s-1）和koff（10（-4）- 10（-3）s-1）常数仅在1个数量级上变化。