(S)-2-氨基-1-环己基-(R)-3,(S)-4-二羟基-6-甲基庚烷盐酸盐 | 104882-45-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: (S)-2-氨基-1-环己基-(R)-3,(S)-4-二羟基-6-甲基庚烷盐酸盐
• 英文名称: (S)-2-amino-1-cyclohexyl-(R)-3,(S)-4-dihydroxy-6-methylheptane hydrochloride
• 英文别名: (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane hydrochloride；2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane hydrochloride；(2S,3R,4S)-2-Amino-1-cyclohexyl-6-methyl-3,4-heptanediol hydrochloride；2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride；(2S,3R,4S)-2-amino-1-cyclohexyl-6-methylheptane-3,4-diol;hydrochloride
• CAS: 104882-45-3
• 化学式: C₁₄H₂₉NO₂*ClH
• 分子量: 279.851
• InChiKey: OMFWCVXLDHXOOG-NPTJMSEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.47
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  66.5
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-2-氨基-1-环己基-(R)-3,(S)-4-二羟基-6-甲基庚烷盐酸盐 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (S)-N-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-3-thiophen-2-ylmethyl-succinamic acid
  参考文献：
  名称：

  Discovery of non-peptidic P 2 –P 3 butanediamide renin inhibitors with high oral efficacy

  摘要：

  A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P-2 and P-3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00265-x
• 作为产物：
  描述：

  (4R,5R)-4-<(S)-(1-N-Benzylamino-2-cyclohexyl)ethyl>-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane 在 palladium dihydroxide 吡啶 、 盐酸 、 氢氧化钾 、 copper(l) iodide 、 氨 、 氢气 、 sodium methylate 、 sodium 、 potassium carbonate 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， -78.0~80.0 ℃ 、101.33 kPa 条件下， 反应 139.0h， 生成 (S)-2-氨基-1-环己基-(R)-3,(S)-4-二羟基-6-甲基庚烷盐酸盐
  参考文献：
  名称：

  (2S, 3R, 4S)-4-Amino-5-cyclohexyl-1-morpholino-2,3-pentanediol 和 (2S, 3R, 4S)-2-Amino-1-cyclohexyl-6-methyl-3 的新合成,4-庚二醇，肾素抑制剂的 C 端成分

  摘要：

  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。

  DOI：

  10.1246/cl.1990.1709

文献信息

• 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。
• Renin inhibitors containing .alpha.-heteroatom amino acids as P2 residues
  作者：Joseph T. Repine、James S. Kaltenbronn、Annette M. Doherty、James M. Hamby、Richard J. Himmelsbach、Brian E. Kornberg、Michael D. Taylor、ELizabeth A. Lunney、Christine Humblet

  DOI：10.1021/jm00084a008

  日期：1992.3

  A series of renin inhibitors having alpha-heteroatom amino acids as P2 substitutions has been prepared. Examples where the heteroatom is oxygen, sulfur, or nitrogen are described. Many of the compounds exhibit subnanomolar potency when tested in vitro against monkey renin. When selected compounds were tested orally in conscious, salt-depleted, normotensive, Cynomolgus monkeys, low to moderate blood

  已经制备了一系列具有α-杂原子氨基酸作为P2取代的肾素抑制剂。描述了杂原子为氧，硫或氮的实例。在体外针对猴肾素进行测试时，许多化合物均表现出亚纳摩尔效价。当在有意识的，盐分稀少，血压正常的食蟹猴中对选定的化合物进行口服测试时，观察到低至中度的血压降低。在口服剂量为30 mg / kg时，化合物53a在给药后2.5小时最大降低了18 mmHg的血压。
• A Practical Synthesis of the Dihydroxyethylene Dipeptide Isostere, (2S, 3R, 4S) 2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane, from D-Isoascorbic Acid
  作者：William R. Baker、Stephen L. Condon

  DOI：10.1016/s0040-4039(00)91679-4

  日期：1992.3

  )-5-hydroxymethyl-1,3-dioxolane (3b), in 24 and 32% overall yield, respectively. Alcohol 3b was readily prepared from inexpensive and commercially available D-isoascorbic acid in four steps. The synthesis featured a stereoselective addition of cyclohexylmethyllithium to the dimethyl hydrazone of (4S,5S)-2,2-dimethyl-4-(2-methylpropyl)-5-formyl-1,3-dioxolane (4).

  将N-Boc二羟基二肽等排7和它的N-Boc 3-（噻唑-4-基）丙氨酰基衍生物8合成，无需纯化中间体，由（4S，5R）-2,2-二甲基-4-（2- -甲基丙基）-5-羟甲基-1,3-二氧戊环（3b）的总收率分别为24％和32％。醇3b可以很容易地从便宜且可商购的D-异抗坏血酸分四个步骤制备。该合成的特征在于将环己基甲基锂立体选择性地加成到（4S，5S）-2，2-二甲基-4-（2-甲基丙基）-5-甲酰基-1，3-二氧戊环（4）的二甲基中。
• Non-peptide renin inhibitors
  申请人：ABBOTT LABORATORIES

  公开号：EP0364804A1

  公开（公告）日：1990-04-25

  A renin inhibiting compound of the formula: wherein A is a substituent; R1 is hydrogen, loweralkyl, substituted loweralkyl or loweralkenyl; X is CH2, CHOH, C(O), O, S, S(O), S02, NH, N(O) or -P(O)O-; R3 is loweralkyl, loweralkenyl or substituted loweralkyl; and T is mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.

  式中的肾素抑制化合物： 其中 A 是取代基；R1 是氢、低级烷基、取代的低级烷基或低级烯基；X 是 CH2、CHOH、C(O)、O、S、S(O)、S02、NH、N(O)或-P(O)O-；R3 是低级烷基、低级烯基或取代的低级烷基；T 是血管紧张素原的 Leu-Val 裂解位点的模拟物；或其药学上可接受的盐、酯或原药。
• Renin inhibitors
  申请人：ABBOTT LABORATORIES

  公开号：EP0456185A2

  公开（公告）日：1991-11-13

  A renin inhibiting compound of the formula: wherein R₁ is 4-piperazinyl, 1-methyl-4-piperazinyl, 1-methyl-1-oxo-4-piperazinyl, 2-oxo-4-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl or 1-methyl-4-homopiperazinyl; R₂ is benzyl, 2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl; R₃ is 4-thiazolyl, 2-amino-4-thiazolyl, 2-thiazolyl, 5-thiazolyl, 1-pyrazolyl, 3-pyrazolyl, 1-imidazolyl, n-propyl, isopropyl, CH₃S- or CH₃SCH₂-; R₄ is isobutyl or cyclopropyl; R₅ is hydrogen or loweralkyl; and X is CH₂ or NH; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that when X is NH and R₃ is 2-amino-4-thiazolyl, then R₄ is cyclopropyl.

  式中的肾素抑制化合物： 其中 R₁ 是 4-哌嗪基、1-甲基-4-哌嗪基、1-甲基-1-氧代-4-哌嗪基、2-氧代-4-哌嗪基、4-吗啉基、4-硫代吗啉基或 1-甲基-4-高哌嗪基； R₂ 是苄基、2-苯基乙基、1-萘甲基或 2-萘甲基； R₃ 是 4-噻唑基、2-氨基-4-噻唑基、2-噻唑基、5-噻唑基、1-吡唑基、3-吡唑基、1-咪唑基、正丙基、异丙基、CH₃S- 或 CH₃SCH₂-； R₄ 是异丁基或环丙基； R₅ 是氢或低级烷基；和 X为CH₂或NH；或其药学上可接受的盐、酯或原药；但当X为NH且R₃为2-氨基-4-噻唑基时，R₄为环丙基。