N-(2-bromo-5-chloro-benzyl)-2,2-diethoxy-acetamidine | 1338254-52-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-bromo-5-chloro-benzyl)-2,2-diethoxy-acetamidine
• 英文别名: N-(2-bromo-5-chlorobenzyl)-2,2-diethoxyacetamidine；N'-[(2-bromo-5-chlorophenyl)methyl]-2,2-diethoxyethanimidamide
• CAS: 1338254-52-6
• 化学式: C₁₃H₁₈BrClN₂O₂
• 分子量: 349.655
• InChiKey: NXFRHTUWMITRRZ-UHFFFAOYSA-N

物化性质

• 沸点：
  383.1±52.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(2-bromo-5-chloro-benzyl)-2,2-diethoxy-acetamidine 在 吡啶 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium aluminium tetrahydride 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 硫酸 、 叠氮磷酸二苯酯 、 sodium acetate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 三环己基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， -50.0~90.0 ℃ 、303.99 kPa 条件下， 反应 82.5h， 生成 [3-(3-ethyl-ureido)-5-(2-methyl-pyridin-4-yl)-isoquinolin-8-ylmethyl]-carbamic acid methyl ester
  参考文献：
  名称：

  Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents

  摘要：

  Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

  DOI：

  10.1021/acs.jmedchem.6b01834
• 作为产物：
  描述：

  (2-bromo-5-chlorophenyl)methanamine 、 甲基2,2-二乙氧基乙亚氨酸酯 以 甲醇 为溶剂， 反应 10.0h， 生成 N-(2-bromo-5-chloro-benzyl)-2,2-diethoxy-acetamidine
  参考文献：
  名称：

  Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents

  摘要：

  Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

  DOI：

  10.1021/acs.jmedchem.6b01834

文献信息

• [EN] 3-UREIDOISOQUINOLIN-8-YL DERIVATIVES<br/>[FR] DÉRIVÉS DE 3-URÉIDOISOQUINOLÉIN-8-YLE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2012131588A1

  公开（公告）日：2012-10-04

  The invention relates to 3-ureidoisoquinolin-8-yl derivatives of formula I I wherein R is alkyl, haloalkyl or cyclopropyl; R 2 is H, halogen, pyridazin-4-yl, pyrimidin-5-yl or an optionally substituted pyridin-3-yl, pyridin-4-yl or phenyl group; R 3 is alkyl, alkynyl, aminoalkyl, carbamoylalkyl, methylcarbamoylalkyl, alkoxy, haloalkoxy, alkynyloxy, (4-hydroxybut-2-yn-1-yl)oxy, (4-aminobut-2-yn-1-yl)oxy, dimethylaminoalkoxy, carbamoylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, carboxyalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, aryl, heteroaryl, benzyl, benzyloxy, 2-cyanoethoxy, 2,3-dihydroxypropoxy, 3,4-dihydroxybutoxy, -CH 2 R a, -CH 2 CH 2 R b, -(CH 2 ) n -C(O)O-R d, -(CH 2 ) n -N(R c )C(O)O-R d, -O-(CH 2 ) n -N(R c )C(O)O-R d, -(CH 2 ) n -R e or -O-(CH 2 ) n -R e; R a is cyano, acetylamino or N,N-dimethylamino; R b is cyano or carbamoyl; R c is H or methyl; R d is alkyl; R e is pyrrolidin-1-yl, piperidin-1-yl, piperidin-3-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl, 5-oxopyrrolidin-2-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 4-(aminomethyl)cyclohexyl or heteroaryl; R 4 is H or methyl; and to the salts of such compounds. These compounds are useful for the prevention or the treatment of bacterial infections.

  该发明涉及式I的3-脲基异喹啉-8-基衍生物，其中R为烷基、卤代烷基或环丙基；R2为H、卤素、吡啶并[4,5-d]嘧啶-4-基、嘧啶-5-基或可选择取代的吡啶-3-基、吡啶-4-基或苯基；R3为烷基、炔基、氨基烷基、氨基甲酰烷基、甲基氨基甲酰烷基、烷氧基、卤代烷氧基、炔基氧基、(4-羟基丁-2-炔-1-基)氧基、(4-氨基丁-2-炔-1-基)氧基、二甲胺基烷氧基、甲酰胺烷氧基、烷基氨基、环烷基、环烷基烷基、环烷基烷氧基、羟基烷基、羟基烷氧基、烷氧基烷基、烷氧基烷氧基、羧基烷基、羧基烷氧基、烷氧羰基烷氧基、芳基、杂环芳基、苄基、苄氧基、2-氰基乙氧基、2,3-二羟基丙氧基、3,4-二羟基丁氧基、- Ra、- Rb、-(CH2)n-C(O)O-Rd、-( )n-N(Rc)C(O)O-Rd、-O-( )n-N(Rc)C(O)O-Rd、-( )n-Re或-O-( )n-Re；Ra为氰基、乙酰氨基或N,N-二甲基氨基；Rb为氰基或甲酰基；Rc为H或甲基；Rd为烷基；Re为吡咯烷-1-基、哌啶-1-基、哌啶-3-基、吗啉-1-基、2-氧代吡咯烷-1-基、5-氧代吡咯烷-2-基、2,5-二氧代吡咯烷-1-基、2-氧代咪唑烷-1-基、4-(叔丁氧羰基)哌嗪-1-基、4-(氨甲基)环己基或杂环芳基；R4为H或甲基；以及这些化合物的盐。这些化合物对于预防或治疗细菌感染是有用的。
• [EN] ANTIBACTERIAL ISOQUINOLIN-3-YLUREA DERIVATIVES<br/>[FR] DÉRIVÉS D'ISOQUINOLÉIN-3-YLURÉE ANTIBACTÉRIENS
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2011121555A1

  公开（公告）日：2011-10-06

  The invention relates to isoquinolin-3-ylurea derivatives of formula (I) wherein R1 represents (C1-C3)alkyl, (C1-C3)haloalkyl or cyclopropyl, R4 represents H and the substituents R2 and R3 and R5 have the meanings disclosed in the specification; and to the salts of such compounds. These compounds are useful for the prevention or the treatment of bacterial infections.

  这项发明涉及式（I）的异喹啉-3-基脲衍生物，其中R1代表（C1-C3）烷基，（C1-C3）卤代烷基或环丙基，R4代表H，取代基R2、R3和R5的含义在说明书中披露；以及这些化合物的盐。这些化合物可用于预防或治疗细菌感染。
• Isoquinolin-3-Ylurea Derivatives
  申请人：Bur Daniel

  公开号：US20130096119A1

  公开（公告）日：2013-04-18

  The invention relates to isoquinolin-3-ylurea derivatives of formula (I) wherein R 1 represents (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl or cyclopropyl, R 4 represents H and the substituents R 2 and R 3 and R 5 have the meanings disclosed in the specification; and to the salts of such compounds. These compounds are useful for the prevention or the treatment of bacterial infections.

  本发明涉及通式（I）的异喹啉-3-基脲衍生物，其中R1代表（C1-C3）烷基、（C1-C3）卤代烷基或环丙基，R4代表H，取代基R2、R3和R5具有说明书中披露的意义；以及涉及这些化合物的盐。这些化合物对于预防或治疗细菌感染有用。
• 3-UREIDOISOQUINOLIN-8-YL DERIVATIVES
  申请人：Gude Markus

  公开号：US20140038961A1

  公开（公告）日：2014-02-06

  The invention relates to 3-ureidoisoquinolin-8-yl derivatives of formula I wherein R 1 is alkyl, haloalkyl or cyclopropyl; R 2 is H, halogen, pyridazin-4-yl, pyrimidin-5-yl or an optionally substituted pyridin-3-yl, pyridin-4-yl or phenyl group; R 3 is alkyl, alkynyl, aminoalkyl, carbamoylalkyl, methylcarbamoylalkyl, alkoxy, haloalkoxy, alkynyloxy, (4-hydroxybut-2-yn-1-yl)oxy, (4-aminobut-2-yn-1-yl)oxy, dimethylaminoalkoxy, carbamoylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, carboxyalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, aryl, heteroaryl, benzyl, benzyloxy, 2-cyanoethoxy, 2,3-dihydroxypropoxy, 3,4-dihydroxybutoxy, —CH 2 R a , —CH 2 CH 2 R b , —(CH 2 ) n —C(O)O—R d , —(CH 2 ) n —N(R c )C(O)O—R d , —O—(CH 2 ) n —N(R c )C(O)O—R d , —(CH 2 ) n —R e or —O—(CH 2 ) n —R e ; R a is cyano, acetylamino or N,N-dimethylamino; R b is cyano or carbamoyl; R c is H or methyl; R d is alkyl; R e is pyrrolidin-1-yl, piperidin-1-yl, piperidin-3-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl, 5-oxopyrrolidin-2-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 4-(aminomethyl)cyclohexyl or heteroaryl; R 4 is H or methyl; and to the salts of such compounds. These compounds are useful for the prevention or the treatment of bacterial infections.

  本发明涉及式I的3-尿素异喹啉-8-基衍生物，其中R1是烷基、卤代烷基或环丙基；R2是H、卤素、吡啶并[4,5-d]嘧啶-4-基、嘧啶并[4,5-d]嘧啶-5-基或可选取代的吡啶-3-基、吡啶-4-基或苯基；R3是烷基、炔基、氨基烷基、氨基甲酰烷基、甲基氨基甲酰烷基、烷氧基、卤代烷氧基、炔基氧基、(4-羟基丁-2-炔-1-基)氧基、(4-氨基丁-2-炔-1-基)氧基、二甲基氨基烷氧基、甲酰氨基烷氧基、烷基氨基、环烷基、环烷基烷基、环烷基氧基、羟基烷基、羟基烷氧基、烷氧基烷基、烷氧基氧基、羧基烷基、羧基烷氧基、烷氧羰基烷氧基、芳基、杂环芳基、苄基、苄氧基、2-氰乙氧基、2,3-二羟基丙氧基、3,4-二羟基丁氧基、- Ra、- Rb、-(CH2)n-C(O)O-Rd、-( )n-N(Rc)C(O)O-Rd、-O-( )n-N(Rc)C(O)O-Rd、-( )n-Re或-O-( )n-Re；Ra是氰基、乙酰氨基或N,N-二甲基氨基；Rb是氰基或甲酰基；Rc是H或烷基；Rd是吡咯烷-1-基、哌啶-1-基、哌啶-3-基、吗啉-1-基、2-氧代吡咯烷-1-基、5-氧代吡咯烷-2-基、2,5-二氧代吡咯烷-1-基、2-氧代咪唑烷-1-基、4-(叔丁氧羰基)哌嗪-1-基、4-(氨甲基)环己基或杂环芳基；R4是H或烷基；以及这些化合物的盐。这些化合物可用于预防或治疗细菌感染。
• ANTIBACTERIAL ISOQUINOLIN-3-YLUREA DERIVATIVES
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2552893A1

  公开（公告）日：2013-02-06