ethyl (1R,2S)-2-ethenyl-1-[[(2S,4S)-4-hydroxy-1-non-8-enoylpyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate | 923289-03-6

• 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: ethyl (1R,2S)-2-ethenyl-1-[[(2S,4S)-4-hydroxy-1-non-8-enoylpyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate
• CAS: 923289-03-6
• 化学式: C₂₂H₃₄N₂O₅
• 分子量: 406.522
• InChiKey: SQGYITFLNXHXNR-BZDHPDOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl (1R,2S)-2-ethenyl-1-[[(2S,4S)-4-hydroxy-1-non-8-enoylpyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate 、 对硝基苯甲酸 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 以50%的产率得到[(3R,5S)-5-[[(1R,2S)-2-ethenyl-1-ethoxycarbonylcyclopropyl]carbamoyl]-1-non-8-enoylpyrrolidin-3-yl] 4-nitrobenzoate
  参考文献：
  名称：

  WO2007/14919

  摘要：

  公开号：
• 作为产物：
  描述：

  [(3S,5S)-5-[[(1R,2S)-2-ethenyl-1-ethoxycarbonylcyclopropyl]carbamoyl]-1-non-8-enoylpyrrolidin-3-yl] 4-nitrobenzoate 在 lithium hydroxide 、 水 作用下， 以 四氢呋喃 为溶剂， 以87%的产率得到ethyl (1R,2S)-2-ethenyl-1-[[(2S,4S)-4-hydroxy-1-non-8-enoylpyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate
  参考文献：
  名称：

  Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors

  摘要：

  Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061 (1), we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl) sulfonamide 19l an extremely potent (K-i = 0.20 nM, EC50 = 3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.07.124

文献信息

• MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
  申请人：Simmen Kenneth Alan

  公开号：US20100240698A1

  公开（公告）日：2010-09-23

  Inhibitors of HCV of formula al and the N-oxides, salts, and stereochemically isomeric forms thereof, wherein R 1 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 8 to 12 membered bicyclic heterocyclic ring system containing one nitrogen, and optionally one to three oxygen, sulfur or nitrogen, wherein said ring system may be optionally substituted; L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—CO—, —O—C(═O)—NR 5a — or —O—C(═O)—NR 5a —C 1-4 alkanediyl-; R 2 is hydrogen, —OR 6 , —C(═O)OR 6 , —C(═O)R 7 , —C(═O)NR 5a R 5b , —C(═O)NHR 5c , —NR 5a R 5b , —NHR 5c , —NHSO p NR 5a R 5b , —NR 5a SO p R 8 , or —B(OR 6 ) 2 ; R 3 and R 4 are hydrogen or C 1-6 alkyl; or R 3 and R 4 taken together may form a C 3-7 cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式aland及其N-氧化物、盐和立体化学同分异构体的HCV抑制剂，其中R1是芳基或饱和、部分不饱和或完全不饱和的5或6元单环或8到12元双环杂环环系统，其中含有一个氮，以及可选的1到3个氧、硫或氮，其中该环系统可以选择性地被取代；L是直接键，-O-，-O-C1-4烷二基，-O-CO-，-O-C（═O）-NR5a-或-O-C（═O）-NR5a-C1-4烷二基；R2是氢、-OR6、-C（═O）OR6、-C（═O）R7、-C（═O）NR5aR5b、-C（═O）NHR5c、-NR5aR5b、-NHR5c、-NHSOpNR5aR5b、-NR5aSOpR8或-B（OR6）2；R3和R4是氢或C1-6烷基；或R3和R4一起可以形成C3-7环烷基；n为3、4、5或6；p为1或2；芳基是苯基、萘基、茚基或1,2,3,4-四氢萘基，每个基团可以选择性地被取代；Het是一个5或6元饱和、部分不饱和或完全不饱和的杂环环，其中每个单独选择的1到4个杂原子分别来自氮、氧和硫，可选择性地与苯环融合，整个Het基团可以选择性地被取代；含有化合物（I）的制药组合物以及制备化合物（I）的过程。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。
• MACROCYLIC INHIBITORS OF HEPATITIS C VIRUS
  申请人：Tibotec Pharmaceuticals

  公开号：EP1912995B1

  公开（公告）日：2011-07-27
• US7989471B2
  申请人：——

  公开号：US7989471B2

  公开（公告）日：2011-08-02
• [EN] MACROCYLIC INHIBITORS OF HEPATITIS C VIRUS<br/>[FR] INHIBITEURS MACROCYCLIQUES DU VIRUS DE L'HÉPATITE C
  申请人：TIBOTEC PHARM LTD

  公开号：WO2007014919A1

  公开（公告）日：2007-02-08

  [EN] Inhibitors of HCV of formula (I), and the N-oxides, salts, and stereochemically isomeric forms thereof, wherein R¹ is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 8 to 12 membered bicyclic heterocyclic ring system containing one nitrogen, and optionally one to three oxygen, sulfur or nitrogen, wherein said ring system may be optionally substituted; L is a direct bond, -O-. -O-C_1-4alkanediyl-, -O-CO-, -O-C(=O)-NR^5a- or -O-C(=O)-NR^5a-C_1-4alkanediyl-; R² is hydrogen, -OR⁶, -C(O)OR⁶, -C(=O)R⁷, -C(=O)NR^5aR^5b, -C(=O)NHR^5c, -NR^5aR^5b, -NHR^5c, -NHSO_pNR^5aR^5b, -NR^5aSO_pR⁸, or -B(OR⁶)₂; R³ and R⁴ are hydrogen or C_1-6alkyl; or R³ and R⁴ taken together may form a C_3-7cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted ; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
  [FR] Inhibiteurs du VHC de formule (I) et N-oxydes, sels et formes isomériques du point de vue stéréochimique de ceux-ci, dans laquelle formule R¹ est un aryle ou un système hétérocyclique monocyclique ayant 5 ou 6 chaînons ou bicyclique ayant 8 à 12 chaînons, saturé, partiellement insaturé ou complètement insaturé, contenant un azote et facultativement un à trois atomes d'oxygène, de soufre ou d'azote, ledit système cyclique pouvant être facultativement substitué ; L est une liaison directe, -O-, un -O-(alcane en C_1-4)diyle-, -O-CO-, -O-C(=O)-NR^5a- ou un -O-C(=O)-NR^5a-(alcane en C_1-4)diyle- ; R² est un hydrogène, -OR⁶, -C(O)OR⁶, -C(=O)R⁷, -C(=O)NR^5aR^5b, -C(=O)NHR^5c, -NR^5aR^5b, -NHR^5c, -NHSO_pNR^5aR^5b, -NR^5aSO_pR⁸ ou -B(OR⁶)₂ ; R³ et R⁴ sont chacun un hydrogène ou un alkyle en C_1-6 ; ou bien R³ et R⁴ pris ensemble peuvent former un cycle cycloalkyle en C_3-7 ; n est 3, 4, 5 ou 6 ; p est 1 ou 2 ; un aryle est un phényle, un naphtyle, un indanyle ou un 1,2,3,4-tétrahydronaphtyle, chacun desquels pouvant être facultativement substitué ; Het est un hétérocycle saturé, partiellement insaturé ou complètement insaturé à 5 ou 6 chaînons contenant 1 à 4 hétéroatomes sélectionnés chacun indépendamment entre l'azote, l'oxygène et le soufre, ledit hétérocycle étant facultativement condensé avec un noyau benzénique et le groupe Het pris dans son ensemble pouvant être facultativement substitué ; compositions pharmaceutiques contenant les composés (I) et procédés servant à préparer les composés (I). L'invention concerne également des associations biodisponibles des inhibiteurs du VHC de formule (I) avec du ritonavir.
• Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors
  作者：Pierre Raboisson、Tse-I Lin、Herman de Kock、Sandrine Vendeville、Wim Van de Vreken、David McGowan、Abdellah Tahri、Lili Hu、Oliver Lenz、Frederic Delouvroy、Dominique Surleraux、Piet Wigerinck、Magnus Nilsson、Åsa Rosenquist、Bertil Samuelsson、Kenneth Simmen

  DOI：10.1016/j.bmcl.2008.07.124

  日期：2008.9

  Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061 (1), we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl) sulfonamide 19l an extremely potent (K-i = 0.20 nM, EC50 = 3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development. (C) 2008 Elsevier Ltd. All rights reserved.