6-(4-(methylsulfonyl)phenyl)-2H-benzo[d]1,3-dioxolane-5-carbaldehyde | 445039-81-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: 6-(4-(methylsulfonyl)phenyl)-2H-benzo[d]1,3-dioxolane-5-carbaldehyde
• 英文别名: 6-(4-Methylsulfonylphenyl)-1,3-benzodioxole-5-carbaldehyde
• CAS: 445039-81-6
• 化学式: C₁₅H₁₂O₅S
• 分子量: 304.323
• InChiKey: GZGZKFIPJFMDPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  78
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(4-(methylsulfonyl)phenyl)-2H-benzo[d]1,3-dioxolane-5-carbaldehyde 在 palladium on activated charcoal potassium tert-butylate 、 氢气 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 为溶剂， 20.0 ℃ 、137.9 kPa 条件下， 反应 3.25h， 生成 5-Cyclopentylmethyl-6-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxole
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationship of Novel, Highly Potent Metharyl and Methcycloalkyl Cyclooxygenase-2 (COX-2) Selective Inhibitors

  摘要：

  A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo-[3,4-d] 1,3-dioxolan-5-yl)-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC50 for 22c = 1 muM and COX-1 IC50 for 22c = 20 muM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 muM in an in vitro HWB assay.

  DOI：

  10.1021/jm030268b
• 作为产物：
  描述：

  6-溴-3,4-亚甲基二氧苯甲醛 在 aluminum oxide 、 Oxone 、 sodium tetrahydroborate 、 四(三苯基膦)钯 、 sodium carbonate 、 pyridinium chlorochromate 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 6-(4-(methylsulfonyl)phenyl)-2H-benzo[d]1,3-dioxolane-5-carbaldehyde
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationship of Novel, Highly Potent Metharyl and Methcycloalkyl Cyclooxygenase-2 (COX-2) Selective Inhibitors

  摘要：

  A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo-[3,4-d] 1,3-dioxolan-5-yl)-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC50 for 22c = 1 muM and COX-1 IC50 for 22c = 20 muM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 muM in an in vitro HWB assay.

  DOI：

  10.1021/jm030268b

文献信息

• Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use related applications
  申请人：——

  公开号：US20020119977A1

  公开（公告）日：2002-08-29

  The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent, such as, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H 2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobaxcter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity or other toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

  该发明描述了新型的取代芳基化合物，这些化合物是环氧合酶2（COX-2）选择性抑制剂，以及包含至少一种环氧合酶2（COX-2）选择性抑制剂的新型组合物。此外，还可以选择性地包含至少一种提供、转移或释放一氧化氮、刺激内源性一氧化氮合成、提高内源性内皮衍生松弛因子水平或是一氧化氮合酶底物的化合物，以及可选地包含至少一种治疗剂，如类固醇、非类固醇抗炎化合物（NSAID）、5-脂氧合酶（5-LO）抑制剂、白三烯B4（LTB4）受体拮抗剂、白三烯A4（LTA4）水解酶抑制剂、5-HT受体激动剂、3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）抑制剂、H2受体拮抗剂、抗肿瘤药物、抗血小板药物、凝血酶抑制剂、前列腺素抑制剂、去充血剂、利尿剂、镇静或非镇静抗组胺药、诱导型一氧化氮合酶抑制剂、阿片类药物、镇痛剂、幽门螺杆菌抑制剂、质子泵抑制剂、异前列腺素抑制剂等，以及它们的混合物。该发明还提供了包含至少一种COX-2选择性抑制剂、可选地至少一种一氧化氮供体和/或可选地至少一种治疗剂的新型试剂盒。该发明中的新型环氧合酶2选择性抑制剂可以选择性地硝化和/或硝酰化。此外，该发明还提供了治疗炎症、疼痛和发热的方法；用于治疗和/或改善COX-2选择性抑制剂的胃肠特性；促进伤口愈合；用于治疗和/或预防肾毒性或其他毒性；用于治疗和/或预防由于环氧合酶-2水平升高而导致的其他疾病；以及用于改善COX-2选择性抑制剂的心血管特性的方法。
• Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
  申请人：NitroMed, Inc.

  公开号：US20040116431A1

  公开（公告）日：2004-06-17

  The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent, such as, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H 2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof.. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity or other toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

  该发明描述了一种新型的取代芳基化合物，它们是环氧合酶2（COX-2）选择性抑制剂，并且包括至少一种环氧合酶2（COX-2）选择性抑制剂的新型组合物，以及可选择地包括至少一种捐赠、转移或释放一氧化氮、刺激内源性一氧化氮合成、提高内源性内皮源性松弛因子水平或是一氧化氮合酶底物的化合物，和/或可选择地包括至少一种治疗剂，如类固醇、非甾体抗炎化合物（NSAID）、5-脂氧合酶（5-LO）抑制剂、白三烯B4（LTB4）受体拮抗剂、白三烯A4（LTA4）水解酶抑制剂、5-HT激动剂、3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）抑制剂、H2拮抗剂、抗肿瘤剂、抗血小板剂、凝血酶抑制剂、血栓素抑制剂、解充血剂、利尿剂、镇静或非镇静抗组胺药、诱导型一氧化氮合酶抑制剂、阿片类药物、镇痛剂、幽门螺杆菌抑制剂、质子泵抑制剂、异前列腺素抑制剂以及它们的混合物。该发明还提供了至少一种COX-2选择性抑制剂，并可选择地包括至少一种一氧化氮供体和/或至少一种治疗剂的新型试剂盒。该发明的新型环氧合酶2选择性抑制剂可选择性地硝化和/或亚硝化。该发明还提供了治疗炎症、疼痛和发热的方法；用于治疗和/或改善COX-2选择性抑制剂的胃肠道性质；促进伤口愈合的方法；用于治疗和/或预防肾毒性或其他毒性的方法；用于治疗和/或预防由于COX-2水平升高而引起的其他疾病的方法；以及用于改善COX-2选择性抑制剂的心血管特性的方法。
• SUBSTITUTED ARYL COMPOUNDS AS NOVEL CYCLOOXYGENASE-2 SELECTIVE INHIBITORS, COMPOSITIONS AND METHODS OF USE
  申请人：Nitromed, Inc.

  公开号：EP1406609A2

  公开（公告）日：2004-04-14
• EP1406609A4
  申请人：——

  公开号：EP1406609A4

  公开（公告）日：2004-04-14
• US6706724B2
  申请人：——

  公开号：US6706724B2

  公开（公告）日：2004-03-16