(4S,5S)-3-tert-butoxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-vinyloxazolidine | 121533-55-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: (4S,5S)-3-tert-butoxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-vinyloxazolidine
• 英文别名: (4S,5S)-3-(tert-butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-vinyloxazolidine；(4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-vinyloxazolidine；(4S.5S)-3-tert-Butoxycarbonyl-4-cyclohexyl-methyl-2.2-dimethyl-5-vinyloxazolidine；tert-butyl (4S,5S)-4-(cyclohexylmethyl)-5-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 121533-55-9
• 化学式: C₁₉H₃₃NO₃
• 分子量: 323.476
• InChiKey: FDHUDLULPYXQKV-HOTGVXAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (4S,5S)-3-tert-butoxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-vinyloxazolidine 在 sodium tetrahydroborate 、 二甲基硫 、 臭氧 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 9.0h， 生成 (4S,5R)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-<(mesyloxy)methyl>-2,2-dimethyloxazolidine
  参考文献：
  名称：

  Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'

  摘要：

  A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega-mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

  DOI：

  10.1021/jm00097a010
• 作为产物：
  描述：

  (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyloxazolidine-5-ethanol 在 potassium tert-butylate 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 反应 6.5h， 生成 (4S,5S)-3-tert-butoxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-vinyloxazolidine
  参考文献：
  名称：

  Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'

  摘要：

  A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega-mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

  DOI：

  10.1021/jm00097a010

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，
• N-acylamino acid derivatives and their use
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP0309766A2

  公开（公告）日：1989-04-05

  An N-acylamino acid derivative of the formula: wherein each of R¹, R², R⁴ and R⁶ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or a monocyclic or bicyclic heterocyclic group containing from 1 to 4 hetero atoms; each of R³ and R⁵ is hydrogen or lower alkyl; A is -CH(OH)-(CH₂)qR⁷ wherein R⁷ is hydrogen, lower alkyl, cycloalkyl, cyloalkylalkyl, aryl, aralkyl, a monocyclic or bicyclic heterocyclic group containing from 1 to 4 hetero atoms or -E-R¹⁰ wherein E is -S(O)i- wherein i is 0, 1 or 2, oxygen, -NR¹¹- wherein R¹¹ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, or wherein each of R¹² and R¹³ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, and R¹⁰ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or a monocyclic or bicyclic heterocyclic group containing from 1 to 4 hetero atoms provided that when R¹⁰ is hydrogen, i is 0, and q is an integer of from 0 to 5; or -CH₂-CHR⁸-CO-R⁹ wherein R⁸ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or a monocyclic or bicyclic heterocyclic group containig from 1 to 4 hetero atoms, and R⁹ is hydroxyl, -OX wherein X is alkyl, aryl, lower alkoxycarbonyloxyalkyl or 1-phthalidyl, or -N(Y¹)(Y²) wherein each of Y¹ and Y² is hydrogen, lower alkyl, aryl, aralkyl or cycloalkyl, or Y¹ and Y² form together with the adjacent nitrogen atom a 5- or 6-membered heterocyclic group which may contain a further hetero atom; m is 0, 1 or 2; and n is an integer of from 1 to 5, provided that when R¹ is hydrogen, m is 0; or a salt thereof, which is useful as hypotensive drugs.

  一种 N-酰基氨基酸衍生物，其式如下 其中 R¹、R²、R⁴ 和 R⁶ 各为氢、低级烷基、环烷基、环烷基烷基、芳基、芳烷基或含有 1 至 4 个杂原子的单环或双环杂环基团；R³ 和 R⁵ 各为氢或低级烷基；A 是 -CH(OH)-(CH₂)qR⁷，其中 R⁷ 是氢、低级烷基、环烷基、环烷基烷基、芳基、芳烷基、含有 1 至 4 个杂原子的单环或双环杂环基团或 -E-R¹⁰ ，其中 E 是 -S(O)i- 其中 i 是 0、1或2、氧、-NR¹¹- 其中R¹¹是氢、低级烷基、环烷基、环烷基烷基、芳基或芳烷基，或 其中 R¹² 和 R¹³ 均为氢、低级烷基、环烷基、环烷基烷基、芳基或芳烷基，且 R¹⁰ 为氢、低级烷基、环烷基、环烷基烷基、芳基、芳烷基或含有 1 至 4 个杂质原子的单环或双环杂环基团，但当 R¹⁰ 为氢时，i 为 0，q 为 0 至 5 的整数；或-CH₂-CHR⁸-CO-R⁹，其中 R⁸ 是氢、低级烷基、环烷基、环烷基烷基、芳基、芳烷基或含有 1 至 4 个杂原子的单环或双环杂环基团，且 R𠞙 是羟基、-OX，其中 X 是烷基、芳基、或-N(Y¹)(Y²)，其中 Y¹ 和 Y² 分别为氢、低级烷基、芳基、芳烷基或环烷基，或 Y¹ 和 Y² 与邻近的氮原子一起形成 5 或 6 元杂环基团，该杂环基团可能含有另一个杂原子；m为0、1或2；n为1至5的整数，但当R¹为氢时，m为0；或其盐，可用作降血压药物。
• Macrocyclic lactones having renin inhibiting properties
  申请人：MERCK & CO. INC.

  公开号：EP0431972A2

  公开（公告）日：1991-06-12

  Compounds of the formula :

  式中的化合物：
• Cyclic renin inhibitors
  申请人：MERCK & CO. INC.

  公开号：EP0432974A1

  公开（公告）日：1991-06-19

  Compounds of the formuia : are disclosed. These compounds inhibit the angiotensinogen-cleaving action of the natural proteolytic enzyme, renin, and are useful in treating, preventing or managing renin-associated hypertension, hyperaldosteronism, congestive heart failure, and glaucoma.

  的化合物： 的化合物。这些化合物能抑制天然蛋白分解酶肾素的血管紧张素原分解作用，可用于治疗、预防或控制肾素相关性高血压、高醛固酮症、充血性心力衰竭和青光眼。
• Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors
  作者：Ann E. Weber、Thomas A. Halgren、John J. Doyle、Robert J. Lynch、Peter K. S. Siegl、William H. Parsons、William J. Greenlee、Arthur A. Patchett

  DOI：10.1021/jm00113a005

  日期：1991.9

  Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65-mu-M, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.