(2S)-2-[N-[2-(N-methyl-N-morpholinocarbonylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid | 124074-88-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2S)-2-[N-[2-(N-methyl-N-morpholinocarbonylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid
• 英文别名: 2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionic acid；(2S)-2-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionic acid；(2S)-2-[methyl-[2-[methyl(morpholine-4-carbonyl)amino]ethyl]carbamoyl]oxy-3-phenylpropanoic acid
• CAS: 124074-88-0
• 化学式: C₁₉H₂₇N₃O₆
• 分子量: 393.44
• InChiKey: IMUHTFFBOWKSAW-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  99.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S)-2-[N-[2-(N-methyl-N-morpholinocarbonylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid 、 (2S)-N-[(2S,3S,5S)-1-cyclohexyl-3,5-dihydroxy-6-methylheptan-2-yl]-3-(1H-imidazol-5-yl)-2-(methylamino)propanamide 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 [(2S)-1-[[(2S)-1-[[(2S,3S,5S)-1-cyclohexyl-3,5-dihydroxy-6-methylheptan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-methylamino]-1-oxo-3-phenylpropan-2-yl] N-methyl-N-[2-[methyl(morpholine-4-carbonyl)amino]ethyl]carbamate
  参考文献：
  名称：

  Novel Renin Inhibitors Containing (2S,3S,5S)-2-Amino-1-cyclohexyl-6-methyl-3,5-heptanediol Fragment as a Transition-state Mimic at the P1-P1' Cleavage Site.

  摘要：

  合成了一系列含有(2S, 3S, 5S)-2-氨基-1-环己基-6-甲基-3, 5-庚二醇（2-氨基-3, 5-反-二醇）片段作为新型过渡态模拟物的新型肾素抑制剂，并评价了它们的生物活性。所有在P1-P1'位置含有2-氨基-3, 5-反-二醇片段的合成化合物均表现出高体外肾素抑制活性，IC50值在10-8至10-10M范围内，并且大多数化合物在口服给盐缺乏的清醒狨猴时能降低血压。在P4位置含有4-羟基哌啶残基的抑制剂（29）在降低血压作用的强度和持续时间方面表现出最高的活性。

  DOI：

  10.1248/cpb.45.1631
• 作为产物：
  描述：

  N-[(叔-丁氧基)羰基]-N,N'-二甲基乙二胺 在 吡啶 、 盐酸 、 sodium hydroxide 作用下， 以 乙二醇二甲醚 、 乙醇 为溶剂， 反应 80.0h， 生成 (2S)-2-[N-[2-(N-methyl-N-morpholinocarbonylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid
  参考文献：
  名称：

  Renin inhibitory pentols showing improved enteral bioavailability

  摘要：

  Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.

  DOI：

  10.1021/jm00081a019

文献信息

• Renin inhibitors containing a pyridyl amino diol derived C-terminus
  作者：Holger Heitsch、Rainer Henning、Heinz Werner Kleemann、Wolfgang Linz、Wolf Ulrich Nickel、Dieter Ruppert、Hansjoerg Urbach、Adalbert Wagner

  DOI：10.1021/jm00071a009

  日期：1993.9

  the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected

  基于过渡态类似物的概念，一系列具有新的（2S，3R，4S）-2-氨基-1-环己基-3,4-二羟基-6-（2-吡啶基）己烷部分的非肽肾素抑制剂合成了在C-末端的C末端功能，并在体外和体内评估了对肾素的抑制。当与人肾素进行体外测试时，所有化合物均显示出纳摩尔或什至亚纳摩尔范围的效力。在麻醉的，钠缺乏的恒河猴中评估选定的抑制剂，并在十二指肠内给予2 mg / kg的剂量后，平均动脉血压（MAP）明显降低。含有氨基哌啶基琥珀酸衍生的N端的化合物38（S 2864）是该系列中最有希望的成员。38种抑制人肾素的IC50为0.38 nM，不影响其他人天冬氨酸蛋白酶，
• Novel amino acid derivatives possessing renin-inhibitory activities
  申请人：Japan Tobacco Inc.

  公开号：EP0396065A1

  公开（公告）日：1990-11-07

  An amino acid derivative of the general formula: wherein R1 is wherein, R10 is a lower alkyl group and R" is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R'° and R" are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+1-O-CO- (n is as defined above) or R'3 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H2C)n-O-, R12- NH- (n and R12 are as defined above) and pyridyl group; X is -CH2-, -O- or -NH- and Y is -O- or -NH-; wherein (wherein Z is -0-, -S-, -S(O)-. -S(O)2-, -CH2-, -CH(OH)-, or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R4 is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.

  通用公式的氨基酸衍生物： 其中R1为 其中，R10为较低的烷基基团，R"为 （其中R111为较低的烷基基团，n为1至5的整数）或者可以被羟基或甲氧乙氧甲氧基取代的较低烷基基团，或者R'°和R"与相邻的氮原子 结合在一起； R12为氢原子，CnH2n+1-O-CO-（n如上定义）或者 R'3为可以被HOOC-(H2C)n-O-、R12-NH-（n和R12如上定义）和吡啶基取代的较低烷基基团； X为-CH2-、-O-或-NH-，Y为-O-或-NH-；其中 （其中Z为-0-、-S-、-S(O)-、-S(O)2-、- -、-CH(OH)-， 或 a和b分别独立为1至4的整数，且a和b的总和不超过5）； R2为可以被较低烷基基团取代的芳基烷基基团； R3为氢原子或较低烷基基团； R4为较低烷基基团； A为羟基，B为氢原子，或者A和B与相邻的碳原子结合在一起，描述了一种药学上可接受的酸盐或其酯。本发明的化合物具有对肾素的抑制活性，并可用作降压药。
• New amino acid derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0300189A2

  公开（公告）日：1989-01-25

  A compound of the formula : wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl,hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R5 is hydrogen or acyl and R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R2 is hydrogen or lower alkyl; or R1 and R2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R3 is hydrogen or lower alkyl; and R4 is lower alkyl; and its pharmaceutically acceptable salt, processes for the preparation thereof and pharmaceutical composition comprising the same.

  一种式如下的化合物 其中 R1 是低级烷基，可任选被选自以下组别的取代基取代：酰基、羟基、低级烷氧基、芳基、低级烷硫基和一个式......的基团： 其中 R5 为氢或酰基，且 R6 是氢或低级烷基；芳基；或被选自低级烷基和酰基的取代基任选取代的氨基；以及 R2 是氢或低级烷基；或 R1 和 R2 与所连接的氮原子一起形成杂环基团，该杂环基团可任选被选自由低级烷基、羟基（低级）烷基、低级烷氧基（低级）烷基、酰基（低级）烷基、氧代和酰基组成的取代基取代； R3 是氢或低级烷基；和 R4 是低级烷基； 及其药学上可接受的盐、制备工艺和包含这些成分的药物组合物。
• NOVEL INTERMEDIATE FOR SYNTHESIS AND PRODUCTION OF AMINO ACID DERIVATIVE
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0648747A1

  公开（公告）日：1995-04-19

  A novel intermediate (II) for use in synthesis which is useful for the production of an amino acid derivative (I) having a renin-inhibiting activity, and a process for producing the derivative (I) which involves the reaction step represented by the figure, wherein R¹ represents lower alkyl, etc., which may be substituted by -NR⁷-CO-NR⁸R⁹ (wherein R⁷ represents hydrogen or lower alkyl, and R⁸ and R⁹ may be combined together with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group), etc.; R² represents hydrogen, lower alkyl, etc., R³ represents hydrogen or lower alkyl; R⁴ represents hydrogen or an N-protecting group; R⁵ represents hydrogen or a carboxyl-protecting group; and R¹⁰ represents lower alkyl. This process, proceeding via the intermediate (II), is industrially advantageous because the final product (I) can be obtained in a high yield from an inexpensive starting material as compared with the conventional processes and hence the production cost can be reduced remarkably.

  一种用于合成的新型中间体（II），该中间体可用于生产具有肾素抑制活性的氨基酸衍生物（I），以及一种生产该衍生物（I）的工艺，该工艺涉及如图所示的反应步骤，其中 R¹ 代表低级烷基等、R⁷-CO-NR⁸R⁹（其中 R⁷ 代表氢或低级烷基，R⁸ 和 R𠞙 可与相邻的氮原子结合在一起代表任选取代的杂环基团）等取代；R² 代表氢、低级烷基等、R³ 代表氢或低级烷基；R⁴ 代表氢或 N 保护基团；R⁵ 代表氢或羧基保护基团；R¹⁰ 代表低级烷基。与传统工艺相比，这种通过中间体（II）进行的工艺具有工业优势，因为可以从廉价的起始原料中以高产率获得最终产品（I），从而显著降低生产成本。
• US4921855A
  申请人：——

  公开号：US4921855A

  公开（公告）日：1990-05-01