(E)-3-(4-amino-3-chloro-5-fluorophenyl)acrylonitrile

• 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: (E)-3-(4-amino-3-chloro-5-fluorophenyl)acrylonitrile
• 英文别名: 4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamine；(E)-3-(4-amino-3-chloro-5-fluorophenyl)prop-2-enenitrile
• 化学式: C₉H₆ClFN₂
• 分子量: 196.611
• InChiKey: GLYJKIFQZAXMPY-OWOJBTEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-3-(4-amino-3-chloro-5-fluorophenyl)acrylonitrile 、 2,4-二氯-5 硝基嘧啶 反应 0.08h， 以35%的产率得到2-chloro-4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine
  参考文献：
  名称：

  [EN] HIV INHIBITING 5-SUBSTITUTED PYRIMIDINES
  [FR] PYRIMIDINES 5-SUBSTITUEES INHIBITRICES DE HIV

  摘要：

  公式（I）的HIV复制抑制剂，其中A为-CH2-CH2-，-CH=CH-，-C≡C-；R1为氢，芳基，甲酰基，C1-6烷基羰基，C1-6烷基，C1-6烷氧羰基，R2为羟基，卤素，C1-6烷基，羧基，氰基，-C（=O）R6，硝基，氨基，单或双（C1-6烷基）氨基，多卤甲基；X1为-NR1-，-O-，-S-，-S（=O）p-；R3为H，C1-6烷基，卤素；R4为H，C1-6烷基，卤素；R5为硝基，氨基，单和双C1-4烷基氨基，芳基，卤素，-CHO，-CO-R6，-COOR7，-NH-C（=O）H，-NH-C（=O）R6，-CH=N-O-R8；R6为C1-4烷基，氨基，单或双（C1-4烷基）氨基或多卤代C1-4烷基；R7为氢，C1-6烷基，芳基C1-6烷基；R8为氢，C1-6烷基，芳基；p为1或2；芳基为可选取代苯基；含有这些化合物作为活性成分的药物组合物以及制备这些化合物和组合物的过程。

  公开号：

  WO2006035069A1
• 作为产物：
  描述：

  2-氯-6-氟苯胺 在 palladium 10% on activated carbon 、 四丁基溴化铵 、 sodium acetate 、 一氯化碘 、 碳酸氢钠 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 18.0h， 生成 (E)-3-(4-amino-3-chloro-5-fluorophenyl)acrylonitrile
  参考文献：
  名称：

  Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

  摘要：

  Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnudeoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound lid, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 mu L/min/mg (human) and 33.2 mu L/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 mu L/min/mg; rat, 33.2 mu L/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.

  DOI：

  10.1021/acsinfecdis.9b00229

文献信息

• [EN] HIV INHIBITING 5-SUBSTITUTED PYRIMIDINES<br/>[FR] PYRIMIDINES 5-SUBSTITUEES INHIBITRICES DE HIV
  申请人：TIBOTEC PHARM LTD

  公开号：WO2006035069A1

  公开（公告）日：2006-04-06

  HIV replication inhibitors of formula (I) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein A is -CH2-CH2- , -CH=CH- , -C≡C- ; R1 is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, R2 hydroxy, halo, C1-6alkyl, carboxyl, cyano, -C(=O)R6, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl; X1 is -NR1-, -O-, -S-, -S(=O)p-; R3 is H, C1-6alkyl, halo ; R4 is H, C1-6alkyl, halo ; R5 is nitro, amino, mono- and diC1-4alkylamino, aryl, halo, -CHO, -CO-R6, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 is C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or polyhaloC1-4alkyl; R7 is hydrogen, C1-6alkyl, arylC1-6alkyl; R8 is hydrogen, C1-6alkyl, aryl; p is 1 or 2; aryl is optionally substituted phenyl; pharmaceutical compositions containing these compounds as active ingredient and processes for preparing said compounds and compositions.

  公式（I）的HIV复制抑制剂，其中A为-CH2-CH2-，-CH=CH-，-C≡C-；R1为氢，芳基，甲酰基，C1-6烷基羰基，C1-6烷基，C1-6烷氧羰基，R2为羟基，卤素，C1-6烷基，羧基，氰基，-C（=O）R6，硝基，氨基，单或双（C1-6烷基）氨基，多卤甲基；X1为-NR1-，-O-，-S-，-S（=O）p-；R3为H，C1-6烷基，卤素；R4为H，C1-6烷基，卤素；R5为硝基，氨基，单和双C1-4烷基氨基，芳基，卤素，-CHO，-CO-R6，-COOR7，-NH-C（=O）H，-NH-C（=O）R6，-CH=N-O-R8；R6为C1-4烷基，氨基，单或双（C1-4烷基）氨基或多卤代C1-4烷基；R7为氢，C1-6烷基，芳基C1-6烷基；R8为氢，C1-6烷基，芳基；p为1或2；芳基为可选取代苯基；含有这些化合物作为活性成分的药物组合物以及制备这些化合物和组合物的过程。
• HIV inhibiting bicyclic pyrimidine derivatives
  申请人：Janssen Sciences Ireland UC

  公开号：US10072015B2

  公开（公告）日：2018-09-11

  HIV replication inhibitors of formula wherein a1=a2-a3=a4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b1=b2-b3=b4- is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; n and m is 0-4, R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; R2 is OH; halo; C1-6alkyl, C2-6alkenyl or C2-6alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; polyhalomethyl; polyhalomethylthio; —S(═O)pR6; C(═NH)R6; R2a is CN; amino; substituted amino; C1-6alkyl; halo; C1-6alkyloxy; carbonyl; —CH═N—NH—C(═O)—R16; C1-6alkyloxyC1-6alkyl; C2-6alkenyl or C2-6alkynyl; —C(═N—O—R8)—C1-4alkyl; R7 or —X—R7; R3 is CN; amino; C1-6alkyl; halo; C1-6alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R16; substituted C1-6alkyl; C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl or C2-6alkynyl; —C(═N—O—R8)—C1-4alkyl; R7; —X—R7; R4 is halo; OH; C1-6alkyl, C2-6alkenyl or C2-6alkynyl; C3-7cycloalkyl; C1-6alkyloxy; CN; nitro; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C1-4alkyl)amino or R7; A-B- is —CR5═N—, —N═N—, —CH2—CH2—, —CS—NH—, —CO—NH—, —CH═CH—; and the use of these compounds for the prevention or the treatment of HIV infection.

  艾滋病毒复制抑制剂配方 其中 a1=a2-a3=a4- 是-CH═CH═CH-、-N═CH═CH-、-N═CH═CH-N═CH-、-N═CH═CH-； -b1=b2-b3=b4- 是-CH═CH═CH-、-N═CH═CH-、-N═CH═CH-、-N═CH═CH-、-N═CH═CH-； n 和 m 为 0-4、 R1 是氢；芳基；甲酰基；C1-6烷基羰基；C1-6烷基；C1-6烷氧基羰基； R2 是 OH；卤素；C1-6烷基、C2-6烯基或 C2-6 烷炔基；取代的羰基；羧基；CN；硝基；氨基；多卤甲基；多卤甲硫基；-S(═O)pR6；C(═NH)R6； R2a 是 CN；氨基；取代氨基；C1-6烷基；卤素；C1-6烷氧基；羰基；-CH═N-NH-C(═O)-R16；C1-6烷氧基 C1-6烷基；C2-6烯基或 C2-6炔基；-C(═N-O-R8)-C1-4烷基；R7 或-X-R7； R3是CN；氨基；C1-6烷基；卤素；C1-6烷氧基；取代的羰基；-CH═N-NH-C(═O)-R16；取代的C1-6烷基；C1-6烷氧基C1-6烷基；取代的C2-6烯基或C2-6炔基；-C(═N-O-R8)-C1-4烷基；R7；-X-R7； R4 是卤素；OH；C1-6 烷基、C2-6 烯基或 C2-6 烷炔基；C3-7 环烷基；C1-6 烷氧基；CN；硝基；多卤代 C1-6 烷基；多卤代 C1-6 烷氧基；取代的羰基；甲酰基；氨基；单-或二(C1-4 烷基)氨基或 R7； A-B-是-CR5═N-、-N═N-、-CH2-CH2-、-CS-NH-、-CO-NH-、-CH═CH-；以及这些化合物用于预防或治疗HIV感染。
• [EN] HIV INHIBITING 5-CARBO- OR HETEROCYCLIC SUBSTITUTED PYRIMIDINES<br/>[FR] 5-CARBO- OU HETEROCYCLIQUES PYRIMIDINES SUBSTITUEES INHIBITRICES DE VIH
  申请人：TIBOTEC PHARM LTD

  公开号：WO2006035068A3

  公开（公告）日：2006-08-31
• HIV INHIBITING 5-SUBSTITUTED PYRIMIDINES
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：EP1797047A1

  公开（公告）日：2007-06-20
• HIV INHIBITING BICYCLIC PYRIMIDINE DERIVATIVES
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：EP1807430A1

  公开（公告）日：2007-07-18