2-{4-[1-(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-ethanol | 856706-30-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-{4-[1-(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-ethanol
• 英文别名: 2-[4-[[4-Methyl-1-[(6-methyl-3-phenylmethoxypyridin-2-yl)methyl]benzimidazol-2-yl]amino]piperidin-1-yl]ethanol
• CAS: 856706-30-4
• 化学式: C₂₉H₃₅N₅O₂
• 分子量: 485.629
• InChiKey: IEUTZZYGTIHJHQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  75.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-{4-[1-(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-ethanol 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 40.0 ℃ 、500.01 kPa 条件下， 反应 3.0h， 以43%的产率得到2-[[2-[[1-(2-Hydroxyethyl)-4-piperidyl]amino]-4-methyl-benzimidazol-1-yl]methyl]-6-methyl-pyridin-3-ol
  参考文献：
  名称：

  Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate, Part 1:  Improving the Pharmacokinetic Profile Using the Structure−Property Relationship

  摘要：

  We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R 17059 1, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pK(a) of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.

  DOI：

  10.1021/jm070143x
• 作为产物：
  描述：

  {4-[1-(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-acetic acid ethyl ester 在 lithium aluminium tetrahydride 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以71.6%的产率得到2-{4-[1-(3-benzyloxy-6-methyl-pyridin-2-ylmethyl)-4-methyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-ethanol
  参考文献：
  名称：

  [EN] PIPERIDINE-AMINO-BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION
  [FR] DERIVES PIPERIDINE-AMINO-BENZIMIDAZOLE EN TANT QU'INHIBITEURS DE LA REPLICATION DU VIRUS RESPIRATOIRE SYNCYTIAL

  摘要：

  本发明涉及具有抑制呼吸道合胞病毒复制活性的哌啶-氨基-苯并咪唑类化合物，其具有通式(I)，及其前药、N-氧化物、加成盐、季铵盐、金属络合物和立体化学异构体，其中Q为C1-6烷基，可选择性地被三氟甲基、C3-7环烷基、Ar2、羟基、C1-4烷氧基、C1-4烷基硫基、Ar2-氧-、Ar2-硫-、Ar2(CH2)n氧、Ar2(CH2)n硫、羟基羰基、氨基羰基、C1-4烷基羰基、Ar2羰基、C1-4烷氧基羰基、Ar2(CH2)n羰基、氨基羰基氧、C1-4烷基羰基氧、Ar2羰基氧、Ar2(CH2)n羰基氧、C1-4烷氧基羰基(CH2)n氧、单或二(C1-4烷基)氨基羰基、单或二(C1-4烷基)氨基羰基氧、氨基磺酰基、单或二(C1-4烷基)氨基磺酰基或选自吡咯烷基、吡咯基、二氢吡咯基、咪唑基、三唑基、哌啶基、高哌啶基、哌嗪基、吗啉基、硫代吗啉基、1-氧代-硫代吗啉基、1,1-二氧代-硫代吗啉基、吡啶基和四氢吡啶基的杂环，其中所述的每个杂环可选择性地被羰基或C1-6烷基取代；G为直接键或可选择性取代的C1-10亚烷基；R1为Ar1或单环或双环杂环；R2a和R3a中的一个是C1-6烷基，另一个是氢；如果R2a不同于氢，则R2b为氢或C1-6烷基，R3b为氢；如果R3a不同于氢，则R3b为氢或C1-6烷基，R2b为氢；t为1、2或3；Ar1为苯基或取代苯基；Ar2为苯基或取代苯基。本发明还涉及它们的制备方法和包含它们的组合物，以及它们作为药物的用途。

  公开号：

  WO2005058873A1

文献信息

• Piperdine-amino-benzimidazole derivatives as inhibitors of respiratory syncytial virus replication
  申请人：Bonfanti Jean-Francois

  公开号：US20070093659A1

  公开（公告）日：2007-04-26

  The present invention concerns piperidine-amino-benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein Q is C 1-6 alkyl optionally substituted with trifluoromethyl, C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, Ar 2 -oxy-, Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, Ar 2 carbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxy-carbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)-aminocarbonyloxy, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycles selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl; G is a direct bond or optionally substituted C 1-10 alkanediyl; R 1 is Ar 1 or a monocyclic or bicyclic heterocycle; one of R 2a and R 3a is C 1-6 alkyl and the other one of R 2a and R 3a is hydrogen; in case R 2a is different from hydrogen then R 2b is hydrogen or C 1-6 alkyl, and R 3b is hydrogen; in case R 3a is different from hydrogen then R 3b is hydrogen or C 1-6 alkyl, and R 2b is hydrogen; t is 1, 2 or 3; Ar 1 is phenyl or substituted phenyl; and Ar 2 is phenyl or substituted phenyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

  本发明涉及具有对呼吸合胞病毒复制具有抑制活性的哌啶基氨基苯并咪唑，其具有以下式子，它们的前药，N-氧化物，加成盐，季铵盐，金属配合物和立体化学异构体形式，其中Q是C1-6烷基，可选地被三氟甲基取代，C3-7环烷基，Ar2，羟基，C1-4烷氧基，C1-4烷基硫基，Ar2-氧基，Ar2-硫基，Ar2(CH2)noxy，Ar2(CH2)nthio，羟基羧酸，氨基羧酸，C1-4烷基羧酸，Ar2羧酸，C1-4烷氧羧酸，Ar2(CH2)ncarbonyl，氨基羧酸氧酯，C1-4烷基羧酸氧酯，Ar2羧酸氧酯，Ar2(CH2)ncarbonyloxy，C1-4烷氧基羧酸(CH2)noxy，单一或二(C1-4烷基)氨基羧酸，单一或二(C1-4烷基)氨基羧酸氧酯，氨基磺酰基，单一或二(C1-4烷基)氨基磺酰基或从吡咯烷基，吡咯基，二氢吡咯基，咪唑基，三唑基，哌啶基，同源哌啶基，哌嗪基，吗啉基，噻吗啉基，1-氧代噻吗啉基，1,1-二氧代噻吗啉基，吡啶基和四氢吡啶基中选择的杂环，其中每个所述杂环可选地被氧代或C1-6烷基取代；G是直接键或可选地取代的C1-10烷二基；R1是Ar1或单环或双环杂环；R2a和R3a中的一个是C1-6烷基，另一个是氢；在R2a与氢不同的情况下，R2b是氢或C1-6烷基，R3b是氢；在R3a与氢不同的情况下，R3b是氢或C1-6烷基，R2b是氢；t为1、2或3；Ar1为苯基或取代苯基；Ar2为苯基或取代苯基。本发明还涉及它们的制备和包含它们的组合物，以及它们作为药物的用途。
• PIPERIDINE-AMINO-BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION
  申请人：BONFANTI Jean-Francois

  公开号：US20080146613A1

  公开（公告）日：2008-06-19

  The present invention concerns piperidine-amino-benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein Q is C 1-6 alkyl optionally substituted with trifluoromethyl, C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, Ar 2 -oxy-, Ar 2 -thio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH 2 ) n thio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyl-carbonyl, Ar 2 -carbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 -carbonyloxy, Ar 2 (CH 2 ) n carbonyloxy, C 1-4 alkoxy-carbonyl(CH 2 ) n oxy, mono- or di(C 1-4 alkyl)aminocarbonyl, mono- or di(C 1-4 alkyl)-aminocarbonyloxy, aminosulfonyl, mono- or di(C 1-4 alkyl)aminosulfonyl or a heterocycles selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C 1-6 alkyl; G is a direct bond or optionally substituted C 1-10 alkanediyl; R 1 is Ar 1 or a monocyclic or bicyclic heterocycle; one of R 2a and R 3a is C 1-6 alkyl and the other one of R 2a and R 3a is hydrogen; in case R 2a is different from hydrogen then R 2b is hydrogen or C 1-6 alkyl, and R 3b is hydrogen; in case R 3a is different from hydrogen then R 3b is hydrogen or C 1-6 alkyl, and R 2b is hydrogen; t is 1, 2 or 3; Ar 1 is phenyl or substituted phenyl; and Ar 2 is phenyl or substituted phenyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

  本发明涉及对呼吸道合胞病毒复制具有抑制活性的哌啶基氨基苯并咪唑，其具有以下式子： 其中Q是C1-6烷基，可选地取代三氟甲基，C3-7环烷基，Ar2，羟基，C1-4烷氧基，C1-4烷基硫基，Ar2-氧基，Ar2-硫基，Ar2(CH2)noxy，Ar2(CH2)nthio，羟基羧酸，氨基羧酸，C1-4烷基羧酸，Ar2-羧酸，C1-4烷氧基羧酸，Ar2(CH2)ncarbonyl，氨基羧酸氧酸酯，C1-4烷基羧酸氧酸酯，Ar2-羧酸氧酸酯，Ar2(CH2)ncarbonyloxy，C1-4烷氧基-羧酸(CH2)noxy，单烷基或双烷基氨基羧酸，单烷基或双烷基氨基羧酸氧酸酯，氨基磺酰基，单烷基或双烷基氨基磺酰基或从吡咯烷基，吡咯基，二氢吡咯基，咪唑基，三唑基，哌啶基，同型哌啶基，哌嗪基，吗啉基，硫代吗啉基，1-氧代硫代吗啉基，1,1-二氧代硫代吗啉基，吡啶基和四氢吡啶基中选择的杂环，其中每个所述杂环可以选择地用氧代或C1-6烷基取代；G是直接键或可选取代的C1-10烷基二基基；R1是Ar1或单环或双环杂环；R2a和R3a中的一个是C1-6烷基，另一个是氢；如果R2a不同于氢，则R2b是氢或C1-6烷基，而R3b是氢；如果R3a不同于氢，则R3b是氢或C1-6烷基，而R2b是氢；t为1、2或3；Ar1为苯基或取代苯基；Ar2为苯基或取代苯基。本发明还涉及它们的制备和包含它们的组合物，以及它们作为药物的用途。
• US7355051B2
  申请人：——

  公开号：US7355051B2

  公开（公告）日：2008-04-08
• Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate, Part 1:  Improving the Pharmacokinetic Profile Using the Structure−Property Relationship
  作者：Jean-François Bonfanti、Frédéric Doublet、Jérôme Fortin、Jean Lacrampe、Jérôme Guillemont、Philippe Muller、Laurence Queguiner、Eric Arnoult、Tom Gevers、Peggy Janssens、Heidi Szel、Rudy Willebrords、Philip Timmerman、Koen Wuyts、Frans Janssens、Cois Sommen、Piet Wigerinck、Koen Andries

  DOI：10.1021/jm070143x

  日期：2007.9.1

  We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R 17059 1, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pK(a) of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
• [EN] PIPERIDINE-AMINO-BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION<br/>[FR] DERIVES PIPERIDINE-AMINO-BENZIMIDAZOLE EN TANT QU'INHIBITEURS DE LA REPLICATION DU VIRUS RESPIRATOIRE SYNCYTIAL
  申请人：TIBOTEC PHARM LTD

  公开号：WO2005058873A1

  公开（公告）日：2005-06-30

  The present invention concerns piperidine-amino-benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula (I) their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein Q is C1-6alkyl optionally substituted with trifluorornethyl, C3-7cycloalkyl, Ar2, hydroxy, C1-4 alkoxy, C1-4alkylthio, Ar2-oxy-, Ar2-thio-, Ar2(CH2)noxy, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4alkyl­carbonyl, Ar2carbonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyloxy, C1-4alkylcarbonyloxy, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, C1-4alkoxy­ carbonyl(CH2)noxy, mono- or di(C1-4alkyl)aminocarbonyl, mono- or di(C1-4alkyl)-­aminocarbonyloxy, aminosulfonyl, mono-odi(C1-4alkyl)aminosulfonyl or a heterocycles selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or C1-6alkyl; G is a direct bond or optionally substituted Cl-10 loalkanediyl; R1 is Ar1 or a monocyclic or bicyclic heterocycle; one of R2a and R3a is C1-6 salkyl and the other one of R2a and R3a is hydrogen; in case R2a is different from hydrogen then R2b is hydrogen or C1-6alkyl, and R3b is hydrogen; in case R3a is different from hydrogen then R3b is hydrogen or C1-6alkyl, and R2b is hydrogen; t is 1, 2 or 3; Ar1 is phenyl or substituted phenyl; and Ar2 is phenyl or substituted phenyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

  本发明涉及具有抑制呼吸道合胞病毒复制活性的哌啶-氨基-苯并咪唑类化合物，其具有通式(I)，及其前药、N-氧化物、加成盐、季铵盐、金属络合物和立体化学异构体，其中Q为C1-6烷基，可选择性地被三氟甲基、C3-7环烷基、Ar2、羟基、C1-4烷氧基、C1-4烷基硫基、Ar2-氧-、Ar2-硫-、Ar2(CH2)n氧、Ar2(CH2)n硫、羟基羰基、氨基羰基、C1-4烷基羰基、Ar2羰基、C1-4烷氧基羰基、Ar2(CH2)n羰基、氨基羰基氧、C1-4烷基羰基氧、Ar2羰基氧、Ar2(CH2)n羰基氧、C1-4烷氧基羰基(CH2)n氧、单或二(C1-4烷基)氨基羰基、单或二(C1-4烷基)氨基羰基氧、氨基磺酰基、单或二(C1-4烷基)氨基磺酰基或选自吡咯烷基、吡咯基、二氢吡咯基、咪唑基、三唑基、哌啶基、高哌啶基、哌嗪基、吗啉基、硫代吗啉基、1-氧代-硫代吗啉基、1,1-二氧代-硫代吗啉基、吡啶基和四氢吡啶基的杂环，其中所述的每个杂环可选择性地被羰基或C1-6烷基取代；G为直接键或可选择性取代的C1-10亚烷基；R1为Ar1或单环或双环杂环；R2a和R3a中的一个是C1-6烷基，另一个是氢；如果R2a不同于氢，则R2b为氢或C1-6烷基，R3b为氢；如果R3a不同于氢，则R3b为氢或C1-6烷基，R2b为氢；t为1、2或3；Ar1为苯基或取代苯基；Ar2为苯基或取代苯基。本发明还涉及它们的制备方法和包含它们的组合物，以及它们作为药物的用途。