1-tert-butoxycarbonyl-4(R)-hydroxy-L-proline tert-butylamide | 143978-73-8

• 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: 1-tert-butoxycarbonyl-4(R)-hydroxy-L-proline tert-butylamide
• 英文别名: (4R)-1-t-butoxycarbonyl-N-t-butyl-4-hydroxy-L-prolinamide；N'-t-butyl-N-Boc-4(R)-hydroxy-L-prolineamide；Boc-Hyp-NH-tBu；tert-butyl (2S,4R)-2-(tert-butylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate
• CAS: 143978-73-8
• 化学式: C₁₄H₂₆N₂O₄
• 分子量: 286.371
• InChiKey: JMAXTWCTIHZZLL-ZJUUUORDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-tert-butoxycarbonyl-4(R)-hydroxy-L-proline tert-butylamide 在 盐酸 、 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.42h， 生成 (S)-4,4-Dimethoxy-pyrrolidine-2-carboxylic acid tert-butylamide
  参考文献：
  名称：

  Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA—II. Modification of pyrrolidine ring at P1′ proline

  摘要：

  Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1' proline was carried out. Compound 26, which has a C1 atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed K-i = 4.5 nM against HIV PR and IC(50)s 0.58 mu M and 0.06 mu M in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-Cl atom and fused bicyclic heterocycles may be effective in improving their cellular penetration. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0968-0896(96)00130-7
• 作为产物：
  描述：

  Boc-L-羟脯氨酸 在 N-甲基吗啉 作用下， 以 四氢呋喃 为溶剂， 反应 24.5h， 生成 1-tert-butoxycarbonyl-4(R)-hydroxy-L-proline tert-butylamide
  参考文献：
  名称：

  Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA—II. Modification of pyrrolidine ring at P1′ proline

  摘要：

  Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1' proline was carried out. Compound 26, which has a C1 atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed K-i = 4.5 nM against HIV PR and IC(50)s 0.58 mu M and 0.06 mu M in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-Cl atom and fused bicyclic heterocycles may be effective in improving their cellular penetration. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0968-0896(96)00130-7

文献信息

• An Enantioselective Biginelli Reaction Catalyzed by a Simple Chiral Secondary Amine and Achiral Brønsted Acid by a Dual-Activation Route
  作者：Junguo Xin、Lu Chang、Zongrui Hou、Deju Shang、Xiaohua Liu、Xiaoming Feng

  DOI：10.1002/chem.200701581

  日期：2008.3.27

  An enantioselective Biginelli reaction that proceeds by a dual-activation route has been developed by using a combined catalyst of a readily available trans-4-hydroxyproline-derived secondary amine and a Bronsted acid. Aromatic, heteroaromatic, and fused-ring aldehydes were found to be suitable substrates for this multicomponent reaction. The corresponding dihydropyrimidines were obtained in moderate-to-good

  通过使用容易获得的反式4-羟基脯氨酸衍生的仲胺和布朗斯台德酸的组合催化剂，已经开发了通过双活化途径进行的对映选择性比吉内利反应。发现芳族，杂芳族和稠环醛是该多组分反应的合适底物。在温和条件下，以中等至良好的收率获得了相应的二氢嘧啶，收率高达98％ee。根据实验结果和观察到的产物的绝对构型，提出了一个合理的过渡态来解释激活和不对称诱导的起源。
• Inhibitors of HIV protease
  申请人：Sankyo Company, Limited

  公开号：US05629406A1

  公开（公告）日：1997-05-13

  Compounds of formula (I): ##STR1## wherein: R.sup.1 is hydrogen, alkyl, aralkyl, --COR.sup.a, --COR.sup.b, --CSR.sup.a, --CSR.sup.b, --SO.sub.2 R.sup.b, --CONHR.sup.b, --CSNHR.sup.b, --CONR.sup.b R.sup.b or --CSNR.sup.b R.sup.b ; R.sup.2 is hydrogen or alkyl; R.sup.3 is hydrogen, alkylidene, substituted alkyl, or R.sup.b ; R.sup.4 is optionally substituted alkyl, cycloalkyl, or aryl; R.sup.5 is R.sup.b O--, R.sup.b R.sup.b N--, R.sup.b HN--, aralkyloxycarbonyloxy or aralkyloxycarbonylamino, or R.sup.5 is --(CH.sub.2).sub.p --D--(CH.sub.2).sub.r --, where D is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH.sub.2 .dbd.CH.sub.2)-- or --NHCO--; and p and r are each 0 or an integer from 1 to 5; A is --(CH.sub.2).sub.m --B--(CH.sub.2).sub.n -- where B is a single bond, carbonyl, oxygen, sulfur, --NH--, --(CH.sub.2 .dbd.CH.sub.2)-- or --NHCO--; and m and n are each 0 or an integer from 1 to 5; R.sup.a is alkoxy, aralkyloxy, aryloxy or alkoxycarbonyl; R.sup.b is optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or arylalkenyl; and pharmaceutically acceptable salts and esters thereof and pro-drugs therefor, have the ability to inhibit the activity of HIV protease and may thus be used for the treatment and prophylaxis of AIDS.

  式(I)的化合物：其中：R.sup.1为氢，烷基，芳基甲基，-COR.sup.a，-COR.sup.b，-CSR.sup.a，-CSR.sup.b，-SO.sub.2R.sup.b，-CONHR.sup.b，-CSNHR.sup.b，-CONR.sup.b R.sup.b或-CSNR.sup.b R.sup.b；R.sup.2为氢或烷基；R.sup.3为氢，烷基亚烷基，取代烷基，或R.sup.b；R.sup.4为可选择取代的烷基，环烷基，或芳基；R.sup.5为R.sup.b O--，R.sup.b R.sup.b N--，R.sup.b HN--，芳基氧羰氧基或芳基氧羰氨基，或R.sup.5为--(CH.sub.2).sub.p--D--(CH.sub.2).sub.r--，其中D为单键，羰基，氧，硫，-NH--，-(CH.sub.2.dbd.CH.sub.2)-或-NHCO--；p和r分别为0或1至5的整数；A为-(CH.sub.2).sub.m--B--(CH.sub.2).sub.n--，其中B为单键，羰基，氧，硫，-NH--，-(CH.sub.2.dbd.CH.sub.2)-或-NHCO--；m和n分别为0或1至5的整数；R.sup.a为烷氧基，芳基甲氧基，芳氧基或烷氧羰基；R.sup.b为可选择取代的烷基，环烷基，杂环烷基，芳基或芳基烯基；其药学上可接受的盐和酯以及其前药，具有抑制HIV蛋白酶活性的能力，因此可用于治疗和预防艾滋病。
• HIV protease inhibitors useful for the treatment of AIDS
  申请人：Merck & Co., Inc.

  公开号：US05413999A1

  公开（公告）日：1995-05-09

  Compounds of formula ##STR1## where R.sup.1 and R.sup.2 are independently hydrogen or optionally-substituted C.sub.1-4 alkyl or aryl, or R.sup.1 and R.sup.2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of treating infection by HIV are also described.

  化合物的结构式为##STR1##，其中R.sup.1和R.sup.2分别是氢或选择性取代的C.sub.1-4烷基或芳基，或者R.sup.1和R.sup.2结合在一起形成单环或双环环系统，这些化合物是HIV蛋白酶抑制剂。这些化合物在治疗HIV感染和艾滋病方面非常有用，无论是作为化合物、药学上可接受的盐、药用组合成分，还是与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了治疗艾滋病和治疗HIV感染的方法。
• Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents
  作者：John Kitchin、Richard C. Bethell、Nicholas Cammack、Simon Dolan、Derek N. Evans、Stuart Holman、Duncan S. Holmes、Peter McMeekin、Chi L. Mo

  DOI：10.1021/jm00048a007

  日期：1994.10

  As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide

  作为我们基于单个青霉素衍生的噻唑烷部分的早期工作的扩展，我们发现十氢异喹啉基团（也存在于Ro 31-8959中）可有效替代C2对称青霉素衍生的二聚体中的噻唑烷单元之一。外消旋环氧化合物6与[3S- [3α，4aα，8aα]]-十氢-N-（1，1-二甲基乙基）-3-异喹啉羧酰胺的反应得到非对映异构体34a和34b。确定34a的羟基的立体化学为（S）。衍生自34a和34b的胺与噻唑烷8a的反应分别得到50和51。化合物50是有效的HIV蛋白酶抑制剂（IC50 = 23 nM），在体外具有针对HIV-1的抗病毒活性（EC50 C8166细胞= 50 nM）。但是，狗体内化合物50及其类似物的药代动力学较差，
• [EN] HIV PROTEASE INHIBITORS USEFUL FOR THE TREATMENT OF AIDS
  申请人：MERCK & CO., INC.

  公开号：WO1993009096A1

  公开（公告）日：1993-05-13

  (EN) Compounds of formula (I) where R1 and R2 are independently hydrogen or optionally-substituted C1-4alkyl or aryl, or R1 and R2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.(FR) L'invention décrit des composés ayant la formule (I) dans laquelle R1 et R2 représentent indépendamment l'hydrogène ou un groupe aryle ou alkyle de C1-4 éventuellement substitué, ou bien R1 et R2 forment ensemble un système d'anneau monocyclique ou bicyclique, ces composés étant des inhibiteurs de protéase du VIH efficace. Ces composés sont utiles dans la prévention ou le traitement de l'infection par le virus d'immunodéficience humaine et dans le traitement du SIDA, soit en tant que composés, en tant que sels pharmaceutiquement acceptables, ingrédients d'une composition pharmaceutique, combinés ou non à d'autres agents antiviraux, des immunomodulateurs, des antibiotiques ou des vaccins. Des procédés de traitement du SIDA et des procédés de prévention ou de traitement de l'infection par VIH sont également décrits.

  化合物的化学式为(I)，其中R1和R2独立地代表氢或可选取代的C1-4烷基或芳基，或R1和R2结合形成单环或双环环系统，是HIV蛋白酶抑制剂。这些化合物可用于预防或治疗HIV感染以及治疗艾滋病，无论是作为化合物、药学上可接受的盐、药物组成成分，还是与其他抗病毒、免疫调节剂、抗生素或疫苗组合使用。还描述了治疗艾滋病的方法和预防或治疗HIV感染的方法。