(4R)-1-[(2S,3S)-3-(N2-Benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-hydroxy-L-prolinamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (4R)-1-[(2S,3S)-3-(N2-Benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-hydroxy-L-prolinamide
• 英文别名: (2S)-N-((1S,2S)-3-{(5S,3R)-5-[N-(tert-butyl)carbamoyl]-3-hydroxypyrrolidinyl}-2-hydroxy-3-oxo-1-benzylpropyl)-3-carbamoyl-2-[(phenylmethoxy)carbonylamino]propanamide；benzyl N-[(2S)-4-amino-1-[[(2S,3S)-4-[(2S,4R)-2-(tert-butylcarbamoyl)-4-hydroxypyrrolidin-1-yl]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]amino]-1,4-dioxobutan-2-yl]carbamate
• 化学式: C₃₁H₄₁N₅O₈
• 分子量: 611.695
• InChiKey: AKVZXIQLWXMCLX-VEGWMBEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  44
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  200
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (2S,4R)-1-benzyloxycarbonyl-2-tert-butylaminocarbonyl-4-hydroxypyrrolidine 在 palladium on activated charcoal 氰基磷酸二乙酯 、 氢气 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 44.0h， 生成 (4R)-1-[(2S,3S)-3-(N2-Benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-hydroxy-L-prolinamide
  参考文献：
  名称：

  Syntheses of HIV Protease Inhibitors Having a Peptide Moiety Which.

  摘要：

  设计并合成了一些含有N-羧甲氧羰基-脯氨酰-苯丙氨酸苄酯（CPF）部分作为gp120结合位点的HIV蛋白酶抑制剂衍生物。几乎所有在苯氧乙酰基上带有CPF的化合物都显示出蛋白酶抑制活性。化合物25a和25b分别在苯氧乙酰基的邻位和对位上具有CPF部分，它们具有抗HIV活性，尽管其他化合物仅显示出蛋白酶抑制活性。这些结果表明25b能与gp120结合并抑制HIV蛋白酶。

  DOI：

  10.1248/cpb.46.697

文献信息

• Peptides capable of inhibiting the activity of HIV protease, their preparation and their therapeutic use
  申请人：SANKYO COMPANY LIMITED

  公开号：EP0587311A1

  公开（公告）日：1994-03-16

  Compounds of formula (I) : [wherein: R¹ is hydrogen, alkyl, aralkyl, -CORa, -CORb, -CSRa, -CSRb, -SO₂Rb, -CONHRb, -CSNHRb, -CONRbRb or -CSNRbRb; R² is hydrogen or alkyl; R³ is hydrogen, alkylidene, substituted alkyl, or Rb; R⁴ is optionally substituted alkyl, cycloalkyl, or aryl; R⁵ is RbO-, RbRbN-, RbHN-, aralkyloxycarbonyloxy or aralkyloxycarbonylamino, or R⁵ is -(CH₂)p-D-(CH₂)r- [where D is a single bond, carbonyl, oxygen, sulphur, -NH-, -(CH₂=CH₂)- or -NHCO-; and p and r are each 0 or an integer from 1 to 5]; A is -(CH₂)m-B-(CH₂)n- [where B is a single bond, carbonyl, oxygen, sulphur, -NH-, -(CH₂=CH₂)- or -NHCO-; and m and n are each 0 or an integer from 1 to 5]; Ra is alkoxy, aralkyloxy, aryloxy or alkoxycarbonyl; Rb 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.

  化合物的化学式为(I)：[其中：R¹为氢，烷基，芳基烷基，-CORa，-CORb，-CSRa，-CSRb，-SO₂Rb，-CONHRb，-CSNHRb，-CONRbRb或-CSNRbRb；R²为氢或烷基；R³为氢，烷基亚甲基，取代烷基或Rb；R⁴为可选取代的烷基，环烷基或芳基；R⁵为RbO-，RbRbN-，RbHN-，芳基烷氧羰氧基氧或芳基烷氧羰氨基，或R⁵为-(CH₂)p-D-(CH₂)r- [其中D为单键，酰基，氧，硫，-NH-，-(CH₂=CH₂)-或-NHCO-；p和r分别为0或1到5的整数]；A为-(CH₂)m-B-(CH₂)n- [其中B为单键，酰基，氧，硫，-NH-，-(CH₂=CH₂)-或-NHCO-；m和n分别为0或1到5的整数]；Ra为烷氧基，芳基烷氧基，芳氧基或烷氧羰基；Rb为可选取代的烷基，环烷基，杂环，芳基或芳基烷烯基]；以及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。
• 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.

  化学式（I）的复合物：##STR1## 其中：R.sup.1是氢，烷基，芳基烷基，--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或--CSNR.sup.b R.sup.b; R.sup.2是氢或烷基; R.sup.3是氢，烷基，取代烷基或R.sup.b; R.sup.4是可选的取代烷基，环烷基或芳基; R.sup.5是R.sup.b O--，R.sup.b R.sup.b N--，R.sup.b HN--，芳基烷氧羰氧基或芳基烷氧羰氨基，或R.sup.5是--(CH.sub.2).sub.p --D--(CH.sub.2).sub.r --，其中D是单键，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是--(CH.sub.2).sub.m --B--(CH.sub.2).sub.n --，其中B是单键，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是烷氧基，芳基烷氧基，芳氧基或烷氧羰基; R.sup.b是可选的取代烷基，环烷基，杂环基，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。
• Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA—II. Modification of pyrrolidine ring at P1′ proline
  作者：Tomoaki Komai、Susumu Higashida、Mitsuya Sakurai、Tamayo Nitta、Atsushi Kasuya、Shuichi Miyamaoto、Ryuichi Yagi、Yuji Ozawa、Hiroshi Handa、Hiroshi Mohri、Akira Yasuoka、Shinichi Oka、Takashi Nishigaki、Satoshi Kimura、Kaoru Shimada、Yuichiro Yabe

  DOI：10.1016/0968-0896(96)00130-7

  日期：1996.8

  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
• [EN] CYCLIC AMIDES OF 3-AMINO-2-HYDROXY-CARBOXYLIC ACIDS AS HIV-PROTEASE INHIBITORS
  申请人：SYNTEX (U.S.A.) INC.

  公开号：WO1993013066A1

  公开（公告）日：1993-07-08

  (EN) Compounds of formula (I) wherein R1 is alkoxycarbonyl, aralkoxycarbonyl, optionally substituted aralkanoyl, optionally substituted aroyl, optionally substituted heterocyclylcarbonyl, optionally substituted aryloxyalkanoyl, or optionally substituted heterocyclyloxyalkanoyl; R2 is hydrogen; R3 is alkyl optionally substituted by hydroxy, carbamoyl, monoalkylcarbamoyl, or dialkylcarbamoyl; R4 is optionally substituted aryl or optionally substituted aralkyl; R5 is hydrogen; R6 is hydroxy; or R5 and R6 together form oxo, and R7 is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h) and (i), wherein n is 0, 1 or 2; each R14 is independently hydroxy, alkyl, alkoxy, or phenyl; and R10 is alkoxycarbonyl or optionally substituted monoalkylcarbamoyl; as a single stereoisomer or as a mixture thereof; or as pharmaceutically acceptable salts thereof, are useful in treating disease-states which are alleviated by treatment with an HIV protease inhibitor.(FR) Des composés de la formule (I) dans laquelle R1 représente alcoxycarbonyle, aralcoxycarbonyle, aralcanoyle éventuellement substitué, aroyle éventuellement substitué, hétérocyclylcarbonyle éventuellement substitué, aryloxyalcanoyle éventuellement substitué, ou hétérocyclyloxyalcanoyle éventuellement substitué; R2 représente hydrogène; R3 représente alkyle éventuellement substitué par hydroxy, carbamoyle, monoalkylcarbamoyle ou dialkylcarbamoyle; R4 représente aryle éventuellement substitué ou aralkyle éventuellement substitué; R5 représente hydrogène; R6 représente hydroxy; ou R5 et R6 forment ensemble oxo; et R7 est sélectionné dans le groupe comprenant les formules (a), (b), (c), (d), (e), (f), (g), (h) et (i) dans lesquelles n vaut 0, 1 ou 2; chaque R14 représente indépendamment hydroxy, alkyle, alcoxy, ou phényle; et R10 représente alcoxycarbonyle ou monoalkylcarbamoyle éventuellement substitué; sous la forme d'un seul stéréoisomère ou d'un mélange de ceux-ci; ou bien sous la forme de sels pharmaceutiquement acceptables, sont utiles dans le traitement d'états pathologiques qui sont soulagés par traitement avec un inhibiteur de la protéase du VIH.
• Syntheses of HIV Protease Inhibitors Having a Peptide Moiety Which.
  作者：Akira ASAGARASU、Taketo UCHIYAMA、Kazuo ACHIWA

  DOI：10.1248/cpb.46.697

  日期：——

  Some HIV-protease inhibitor derivatives having an N-carbomethoxycarbonyl-prolyl-phenylalanine benzyl ester (CPF) moiety as a binding site to gp120 were designed and synthesized. Almost all the compounds bearing CPF on the phenoxyacetyl group showed protease-inhibitory activity. Compounds 25a and 25b, which have the CPF moiety at the ortho- and meta-positions of the phenoxyacetyl group, respectively, had anti-HIV activity, although the others showed only protease-inhibitory activity. These results suggest that 25b binds to gp120 and inhibits HIV protease.

  设计并合成了一些含有N-羧甲氧羰基-脯氨酰-苯丙氨酸苄酯（CPF）部分作为gp120结合位点的HIV蛋白酶抑制剂衍生物。几乎所有在苯氧乙酰基上带有CPF的化合物都显示出蛋白酶抑制活性。化合物25a和25b分别在苯氧乙酰基的邻位和对位上具有CPF部分，它们具有抗HIV活性，尽管其他化合物仅显示出蛋白酶抑制活性。这些结果表明25b能与gp120结合并抑制HIV蛋白酶。