1-benzyl-5-chloro-1H-benzo[d]imidazol-2(3H)-one | 2215-54-5

• 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: 1-benzyl-5-chloro-1H-benzo[d]imidazol-2(3H)-one
• 英文别名: 1-benzyl-5-chloro-1,3-dihydro-benzoimidazol-2-one；1-Benzyl-5-chlor-benzimidazolin-2-on；1-Benzyl-5-chlorbenzimidazolin-2-on；5-Chlor-1-benzylbenzimidazolin-2-on；5-Chloro-1,3-dihydro-1-(phenylmethyl)-2H-benzimidazol-2-one；3-benzyl-6-chloro-1H-benzimidazol-2-one
• CAS: 2215-54-5
• 化学式: C₁₄H₁₁ClN₂O
• 分子量: 258.707
• InChiKey: RREALGGATNQDNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  32.3
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  1-benzyl-5-chloro-1H-benzo[d]imidazol-2(3H)-one 在 盐酸 、 三氯氧磷 作用下， 反应 3.5h， 生成 5-chloro-1-phenylmethyl-2-piperazinyl-1H-benzimidazole
  参考文献：
  名称：

  新的2-哌嗪基苯并咪唑衍生物作为5-HT3拮抗剂。合成和药理评价。

  摘要：

  制备了一系列2-哌嗪基苯并咪唑衍生物，并将其评价为5-HT 3受体拮抗剂。通过放射性配体结合测定法评估了它们的5-HT3受体亲和力，并确定了它们在麻醉大鼠中抑制5-HT诱导的Bezold-Jarisch反射的能力。化合物7e（lerisetron，pKi = 9.2）对5-HT3受体的亲和力高于tropisetron和granisetron，而化合物7q（pKi = 7.5）对该受体的亲和力很低，表明苯并咪唑的N1原子被取代环对于亲和力和活性至关重要。还讨论了不同位置的多个取代基对苯并咪唑芳环的取代作用。建立了所研究化合物的5-HT3拮抗活性与芳香环上取代位置的强相关性。因此，尽管4-甲氧基衍生物7m显示出对5-HT 3受体的弱亲和力（pKi ＝ 6.7），但是7-甲氧基衍生物7n显示出最高的亲和力（pKi ＝ 9.4）。化合物7e和7n作为癌症化疗和放疗引起的恶心和呕吐的治疗药物，目前正在进一步研究中。

  DOI：

  10.1021/jm960442e
• 作为产物：
  描述：

  2-羟基苯并咪唑 在 sodium hydroxide 、 磺酰氯 、 potassium carbonate 作用下， 以 溶剂黄146 、 乙腈 为溶剂， 反应 1.5h， 生成 1-benzyl-5-chloro-1H-benzo[d]imidazol-2(3H)-one
  参考文献：
  名称：

  Regiospecific Functionalization of 1,3-Dihydro-2H-benzimidazol-2-one and Structurally Related Cyclic Urea Derivatives

  摘要：

  Methods for selectively protecting one of the degenerate nitrogen atoms of the cyclic urea derivatives 1,3-dihydro-2H-benzimidazol-2-one (6a), 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11), 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones (20), 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (22), and 1,3-dihydro-4-phenyl-2H-imidazol-2-one (27) were developed. Heating these cyclic ureas with ethyl 2-pyridyl carbonate in the presence of a base in CH3CN at reflux or DMF at 100 degrees C cleanly provided the monoethoxycarbonyl derivatives 7a, 12, 21, 23, and 28, respectively. Alternatively, treatment of 6a with an excess of diethyl pyrocarbonate or di-tert-butyl dicarbonate afforded the bis-alkoxycarbonyl derivatives 8a and 8b, respectively, which underwent disproportionation to 7a and 7b upon heating with 1 mol equiv of 6a and K2CO3 in CH3CN at reflux. The regiochemistry of the introduction of alkoxycarbonyl groups to benzimidazol-2-one derivatives was not significantly influenced by an electron-withdrawing (CF3, 6b) or an electron-donating (OCH3, 6c) substituent at C-5 of the heterocyclic ring. However, the reaction was found to be sensitive to steric factors since a chlorine substituent ortho to one of the urea N atoms (6e) completely directed the alkoxycarbonyl moiety to the less sterically encumbered N atom, affording a single product (7f, 7g). Alkylation of 7a-g proceeded efficiently to provide products 10a-10ag after removal of the protecting group. Halogenation of monoprotected benzimidazol-2-one 7a occurred regiospecifically to give the monohalo derivatives 7h, 7i, and 7k, the identity of which were readily established from the characteristic chemical shift and spin coupling pattern in their 1H NMR spectra. A protecting group interchange strategy that took advantage of the distinctive chemical reactivities of the EtO(2)C and t-BuO(2)C protecting groups toward isopropylamine was developed that provided access to the isomerically substituted series of monohalo, mono-N-alkylated benzimidazol-2-ones 71 and 7m. The efficient derivatization of the unprotected N atom of these monoprotected cyclic urea derivatives was accomplished by treating with activated and unactivated halides in the. presence of K2CO3 or exposure to alcohols under Mitsunobu conditions. In several cases, mixtures of O- and N-alkylated products were produced which were readily separated by chromatography. Alkylation of 7h with activated halides, using K2CO3 in CH3CN at reflux, occurred without protecting group equilibration; however, a mixture of isomeric alkylated products was obtained when 7h was heated at 110 degrees C in DMF with cyclohexylmethyl bromide in the presence of K2CO3 as the base. Derivatization of 7h under Mitsunobu reaction conditions proceeded with retention of the topological substituent relationships. Subsequent removal of the alkoxycarbonyl moiety afforded monoalkylated cyclic urea derivatives.

  DOI：

  10.1021/jo00111a014

文献信息

• Novel Benzo[d]imidazole-2(3H)-thiones as Potent Inhibitors of the .ALPHA.-Melanocyte Stimulating Hormone Induced Melanogenesis in Melanoma B16 Cells
  作者：Jee-Hyun Lee、Pillaiyar Thanigaimalai、Ki-Cheul Lee、Seong-Cheol Bang、Min-Seok Kim、Vinay Kumar Sharma、Cheong-Yong Yun、Eunmiri Roh、Youngsoo Kim、Sang-Hun Jung

  DOI：10.1248/cpb.58.918

  日期：——

  In order to determine the optimum size of heterocycle of lead compound 1 (6-methyl-3-phenethyl-3,4-dihydro-1H-quinoline-2-thione; IC50=0.8 μM) for inhibition of melanogenesis, we have synthesized and evaluated some benzimdazole-2(3H)-thiones 5a—e. The preliminary bioassay has shown that the benzimdazole-2(3H)-thione motif of 5 is essential structural unit for their inhibitory activity. Among all thiones 5a—e, the compound 5d strongly inhibited the formation of melanin with IC50 value of 1.3 μM.

  为了确定先导化合物1（6-甲基-3-苯乙基-3,4-二氢-1H-喹啉-2-硫酮；IC50=0.8 μM）抑制黑色素生成的最佳杂环大小，我们合成并评估了一些苯基咪唑-2(3H)-硫酮5a—e。初步生物检测结果表明，化合物5的苯基咪唑-2(3H)-硫酮构型是其抑制活性的必要结构单元。在所有硫酮5a—e中，化合物5d对黑色素的生成具有强烈抑制作用，其IC50值为1.3 μM。
• Further Exploration of the Benzimidazole Scaffold as TRPC5 Inhibitors: Identification of 1‐Alkyl‐2‐(pyrrolidin‐1‐yl)‐1 <i>H</i> ‐benzo[ <i>d</i> ]imidazoles as Potent and Selective Inhibitors
  作者：Swagat Sharma、Juan L. Pablo、Kirsten T. Tolentino、Wacey Gallegos、Jennifer Hinman、Madison Beninato、MacKenzie Asche、Anna Greka、Corey R. Hopkins

  DOI：10.1002/cmdc.202200151

  日期：2022.7.19

  Inhibitors with potential! Medicinal chemistry optimization of the original hit compound, AC1903, 1, led to the formation of a next-generation transient receptor potential cation channel 5 (TRPC5) inhibitor, 16 f. We profiled this compound in in vitro and in vivo pharmacokinetic assays as well as additional selectivity assays.

  有潜力的抑制剂！原始命中化合物AC1903, 1的药物化学优化导致下一代瞬时受体电位阳离子通道 5 (TRPC5) 抑制剂16 f的形成。我们在体外和体内药代动力学试验以及其他选择性试验中分析了这种化合物。
• Regiospecific Functionalization of 1,3-Dihydro-2H-benzimidazol-2-one and Structurally Related Cyclic Urea Derivatives
  作者：Nicholas A. Meanwell、Sing Yuen Sit、Jinnian Gao、Henry S. Wong、Qi Gao、Denis R. St. Laurent、Neelakantan Balasubramanian

  DOI：10.1021/jo00111a014

  日期：1995.3

  Methods for selectively protecting one of the degenerate nitrogen atoms of the cyclic urea derivatives 1,3-dihydro-2H-benzimidazol-2-one (6a), 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11), 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones (20), 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (22), and 1,3-dihydro-4-phenyl-2H-imidazol-2-one (27) were developed. Heating these cyclic ureas with ethyl 2-pyridyl carbonate in the presence of a base in CH3CN at reflux or DMF at 100 degrees C cleanly provided the monoethoxycarbonyl derivatives 7a, 12, 21, 23, and 28, respectively. Alternatively, treatment of 6a with an excess of diethyl pyrocarbonate or di-tert-butyl dicarbonate afforded the bis-alkoxycarbonyl derivatives 8a and 8b, respectively, which underwent disproportionation to 7a and 7b upon heating with 1 mol equiv of 6a and K2CO3 in CH3CN at reflux. The regiochemistry of the introduction of alkoxycarbonyl groups to benzimidazol-2-one derivatives was not significantly influenced by an electron-withdrawing (CF3, 6b) or an electron-donating (OCH3, 6c) substituent at C-5 of the heterocyclic ring. However, the reaction was found to be sensitive to steric factors since a chlorine substituent ortho to one of the urea N atoms (6e) completely directed the alkoxycarbonyl moiety to the less sterically encumbered N atom, affording a single product (7f, 7g). Alkylation of 7a-g proceeded efficiently to provide products 10a-10ag after removal of the protecting group. Halogenation of monoprotected benzimidazol-2-one 7a occurred regiospecifically to give the monohalo derivatives 7h, 7i, and 7k, the identity of which were readily established from the characteristic chemical shift and spin coupling pattern in their 1H NMR spectra. A protecting group interchange strategy that took advantage of the distinctive chemical reactivities of the EtO(2)C and t-BuO(2)C protecting groups toward isopropylamine was developed that provided access to the isomerically substituted series of monohalo, mono-N-alkylated benzimidazol-2-ones 71 and 7m. The efficient derivatization of the unprotected N atom of these monoprotected cyclic urea derivatives was accomplished by treating with activated and unactivated halides in the. presence of K2CO3 or exposure to alcohols under Mitsunobu conditions. In several cases, mixtures of O- and N-alkylated products were produced which were readily separated by chromatography. Alkylation of 7h with activated halides, using K2CO3 in CH3CN at reflux, occurred without protecting group equilibration; however, a mixture of isomeric alkylated products was obtained when 7h was heated at 110 degrees C in DMF with cyclohexylmethyl bromide in the presence of K2CO3 as the base. Derivatization of 7h under Mitsunobu reaction conditions proceeded with retention of the topological substituent relationships. Subsequent removal of the alkoxycarbonyl moiety afforded monoalkylated cyclic urea derivatives.
• New 2-Piperazinylbenzimidazole Derivatives as 5-HT₃ Antagonists. Synthesis and Pharmacological Evaluation
  作者：Aurelio Orjales、Ramón Mosquera、Luis Labeaga、Rosa Rodes

  DOI：10.1021/jm960442e

  日期：1997.2.1

  of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron

  制备了一系列2-哌嗪基苯并咪唑衍生物，并将其评价为5-HT 3受体拮抗剂。通过放射性配体结合测定法评估了它们的5-HT3受体亲和力，并确定了它们在麻醉大鼠中抑制5-HT诱导的Bezold-Jarisch反射的能力。化合物7e（lerisetron，pKi = 9.2）对5-HT3受体的亲和力高于tropisetron和granisetron，而化合物7q（pKi = 7.5）对该受体的亲和力很低，表明苯并咪唑的N1原子被取代环对于亲和力和活性至关重要。还讨论了不同位置的多个取代基对苯并咪唑芳环的取代作用。建立了所研究化合物的5-HT3拮抗活性与芳香环上取代位置的强相关性。因此，尽管4-甲氧基衍生物7m显示出对5-HT 3受体的弱亲和力（pKi ＝ 6.7），但是7-甲氧基衍生物7n显示出最高的亲和力（pKi ＝ 9.4）。化合物7e和7n作为癌症化疗和放疗引起的恶心和呕吐的治疗药物，目前正在进一步研究中。