3-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-propionic acid ethyl ester | 856895-07-3

• 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: 3-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-propionic acid ethyl ester
• 英文别名: ethyl 3-[[1-[(3-hydroxy-6-methylpyridin-2-yl)methyl]-4,6-dimethylbenzimidazol-2-yl]amino]propanoate
• CAS: 856895-07-3
• 化学式: C₂₁H₂₆N₄O₃
• 分子量: 382.462
• InChiKey: MDIOMOJVOSXFML-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  89.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-propionic acid ethyl ester 在 lithium aluminium tetrahydride 、 水 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 4.0h， 以73%的产率得到2-[2-(3-hydroxypropylamino)-4,6-dimethyl-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol
  参考文献：
  名称：

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

  摘要：

  本发明涉及具有对呼吸道合胞病毒复制具有抑制活性的氨基苯并咪唑化合物，其具有式（I），它们的前药、N-氧化物、加成盐、季铵盐、金属络合物和立体化异构体形式，其中Q为Ar1或C1-6烷基，其上取代有一个或多个取代基，所选取代基包括三氟甲基、C3-7环烷基、Ar2、羟基、C1-4烷氧基、C1-4烷硫基、Ar2-氧基、Ar2-硫基、Ar2(CH2)noxy、Ar2(CH2)nthio、羟基羰基、氨基羰基、C1-4烷基羰基、Ar2羰基、C1-4烷氧羰基、Ar2(CH2)n羰基、氨基羰氧基、C1-4烷基羰氧基、Ar2羰氧基、Ar2(CH2)n羰氧基、羟基-C2-4-烷氧基、C1-4烷氧基羰基(CH2)noxy、单或双(C1-4烷基)-氨基羰基、单或双(C1-4烷基)氨基羰氧基、氨基磺酰基、单或双(C1-4烷基)氨基磺酰基、二氧杂环己基，可选地取代有一或两个C1-6烷基基团，以及从吡咯烷基、吡咯基、二氢吡咯基、噻唑烷基、咪唑基、三唑基、哌啶基、环戊哌啶基、哌嗪基、吡啶基和四氢吡啶基中选择的杂环，每个可能可选地取代有氧代或C1-6烷基；G为直链键或可选地取代的C1-10烷二基，R1为Ar1或单环或双环杂环；R2a和R3a中的一个为C1-6烷基，另一个为氢；如果R2a不同于氢，则R2b为氢或C1-6烷基，且R3b为氢；如果R3a不同于氢，则R3b为氢或C1-6烷基，且R2b为氢；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。

  公开号：

  WO2005058870A1
• 作为产物：
  描述：

  ethyl 3-[(4,6-dimethyl-1H-benzimidazol-2-yl)amino]propanoate 、 2-(氯甲基)-6-甲基吡啶-3-醇盐酸盐 在 potassium carbonate 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 4.0h， 以21%的产率得到3-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-propionic acid ethyl ester
  参考文献：
  名称：

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

  摘要：

  本发明涉及具有对呼吸道合胞病毒复制具有抑制活性的氨基苯并咪唑化合物，其具有式（I），它们的前药、N-氧化物、加成盐、季铵盐、金属络合物和立体化异构体形式，其中Q为Ar1或C1-6烷基，其上取代有一个或多个取代基，所选取代基包括三氟甲基、C3-7环烷基、Ar2、羟基、C1-4烷氧基、C1-4烷硫基、Ar2-氧基、Ar2-硫基、Ar2(CH2)noxy、Ar2(CH2)nthio、羟基羰基、氨基羰基、C1-4烷基羰基、Ar2羰基、C1-4烷氧羰基、Ar2(CH2)n羰基、氨基羰氧基、C1-4烷基羰氧基、Ar2羰氧基、Ar2(CH2)n羰氧基、羟基-C2-4-烷氧基、C1-4烷氧基羰基(CH2)noxy、单或双(C1-4烷基)-氨基羰基、单或双(C1-4烷基)氨基羰氧基、氨基磺酰基、单或双(C1-4烷基)氨基磺酰基、二氧杂环己基，可选地取代有一或两个C1-6烷基基团，以及从吡咯烷基、吡咯基、二氢吡咯基、噻唑烷基、咪唑基、三唑基、哌啶基、环戊哌啶基、哌嗪基、吡啶基和四氢吡啶基中选择的杂环，每个可能可选地取代有氧代或C1-6烷基；G为直链键或可选地取代的C1-10烷二基，R1为Ar1或单环或双环杂环；R2a和R3a中的一个为C1-6烷基，另一个为氢；如果R2a不同于氢，则R2b为氢或C1-6烷基，且R3b为氢；如果R3a不同于氢，则R3b为氢或C1-6烷基，且R2b为氢；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。

  公开号：

  WO2005058870A1

文献信息

• [EN] AMINO-BENZIMIDAZOLES DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION<br/>[FR] DERIVES AMINO-BENZIMIDAZOLES UTILISES EN TANT QU'INHIBITEURS DE LA REPLICATION DU VIRUS SYNCYTIAL RESPIRATOIRE
  申请人：TIBOTEC PHARM LTD

  公开号：WO2005058870A1

  公开（公告）日：2005-06-30

  The present invention concerns 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 Ar1 or C1-6alkyl substituted with one or more substituents selected from trifluoromethyl, C3-7cycloalkyl, Ar2, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar2-oxy-, Ar2-thio-, Ar2(CH2)„oxy, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4 alkylcarbonyl, Ar2carbonyl, C1-4alkoxycarbonyl, Ar2(CH2)n carbonyl, aminocarbonyloxy, C1-4 alkylcarbonyloxy, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, hydroxy-C2- 4-alkyloxy, C1-4 alkoxycarbonyl(CH2)noxy, mono­or di(C1-4alkyl)-aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(C1-4alkyl)aminosulfonyl, dioxolanyl optionally substituted with one or two C1-6alkyl radicals, and a heterocycle selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, thiazolidinyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, which each may optionally be substituted with oxo or C1-6alkyl; G is a direct bond or optionally substituted C1-10alkanediyl R1 is Ar1 or a monocyclic or bicyclic heterocycle; one of R2a and R3a is C1-6alkyl 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 C 1-6alkyl, and R2b is hydrogen; 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.

  本发明涉及具有对呼吸道合胞病毒复制具有抑制活性的氨基苯并咪唑化合物，其具有式（I），它们的前药、N-氧化物、加成盐、季铵盐、金属络合物和立体化异构体形式，其中Q为Ar1或C1-6烷基，其上取代有一个或多个取代基，所选取代基包括三氟甲基、C3-7环烷基、Ar2、羟基、C1-4烷氧基、C1-4烷硫基、Ar2-氧基、Ar2-硫基、Ar2(CH2)noxy、Ar2(CH2)nthio、羟基羰基、氨基羰基、C1-4烷基羰基、Ar2羰基、C1-4烷氧羰基、Ar2(CH2)n羰基、氨基羰氧基、C1-4烷基羰氧基、Ar2羰氧基、Ar2(CH2)n羰氧基、羟基-C2-4-烷氧基、C1-4烷氧基羰基(CH2)noxy、单或双(C1-4烷基)-氨基羰基、单或双(C1-4烷基)氨基羰氧基、氨基磺酰基、单或双(C1-4烷基)氨基磺酰基、二氧杂环己基，可选地取代有一或两个C1-6烷基基团，以及从吡咯烷基、吡咯基、二氢吡咯基、噻唑烷基、咪唑基、三唑基、哌啶基、环戊哌啶基、哌嗪基、吡啶基和四氢吡啶基中选择的杂环，每个可能可选地取代有氧代或C1-6烷基；G为直链键或可选地取代的C1-10烷二基，R1为Ar1或单环或双环杂环；R2a和R3a中的一个为C1-6烷基，另一个为氢；如果R2a不同于氢，则R2b为氢或C1-6烷基，且R3b为氢；如果R3a不同于氢，则R3b为氢或C1-6烷基，且R2b为氢；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。
• AMINO-BENZIMIDAZOLES DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION
  申请人：Bonfanti Jean-Francois

  公开号：US20090036466A1

  公开（公告）日：2009-02-05

  The present invention concerns 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 Ar 1 or C 1-6 alkyl substituted with one or more substituents selected from 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, hydroxy-C 2-4 -alkyloxy, C 1-4 alkoxycarbonyl(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, dioxolanyl optionally substituted with one or two C 1-6 alkyl radicals, and a heterocycle selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, thiazolidinyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, which each 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; 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氨基苯并咪唑，其具有以下结构式： 其中Q是Ar1或C1-6烷基，其被一个或多个从三氟甲基，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，羟基羧酸基，氨基羧酸基，C1-4烷基羧酸基，Ar2-羧酸基，C1-4烷氧羧酸基，Ar2(CH2)ncarbonyl，氨基羧酸酯基，C1-4烷基羧酸酯基，Ar2-羧酸酯基，Ar2(CH2)ncarbonyloxy，羟基-C2-4-烷氧基，C1-4烷氧羧酸基(CH2)noxy，单烷基或双烷基氨基羧酸基，单烷基或双烷基氨基羧酸酯基，氨基磺酰基，单烷基或双烷基氨基磺酰基，二氧杂环己烷基，其可选地被一个或两个C1-6烷基基团取代，以及从吡咯烷基，吡咯基，二氢吡咯基，噻唑烷基，咪唑基，三唑基，哌啶基，同型哌啶基，哌嗪基，吡啶基和四氢吡啶基中选择的杂环，每个杂环都可以选择性地被氧代或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; 如果R2a与氢不同，则R2b是氢或C1-6烷基，而R3b是氢; 如果R3a与氢不同，则R3b是氢或C1-6烷基，而R2b是氢; Ar1是苯基或取代苯基，而Ar2是苯基或取代苯基。本发明还涉及其制备和包含它们的组合物，以及它们作为药物的用途。
• 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.