4-(3-氯丙酰基)-2,6-二甲基吗啉 | 915920-51-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 中文名称: 4-(3-氯丙酰基)-2,6-二甲基吗啉
• 中文别名: 吗啉)丙-1-酮
• 英文名称: 4-(3-chloropropanoyl)-2,6-dimethylmorpholine
• 英文别名: 3-chloro-1-(2,6-dimethylmorpholin-4-yl)propan-1-one
• CAS: 915920-51-3
• 化学式: C₉H₁₆ClNO₂
• 分子量: 205.685
• InChiKey: YBQWWSMRKQHSIL-UHFFFAOYSA-N

物化性质

• 沸点：
  323.4±37.0 °C(Predicted)
• 密度：
  1.095±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2934999090

反应信息

• 作为反应物：
  描述：

  4-(3-氯丙酰基)-2,6-二甲基吗啉 、 3-(cyclopentyloxy)-4-methoxybenzaldehyde oxime 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以52%的产率得到3-(cyclopentyloxy)-4-methoxybenzaldehyde O-[3-(2,6-dimethylmorpholin-4-yl)-3-oxopropyl]oxime
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of New 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) Related Phosphodiesterase 4D (PDE4D) Inhibitors

  摘要：

  A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.

  DOI：

  10.1021/jm500855w
• 作为产物：
  描述：

  2,6-二甲基吗啉 、 3-氯丙酰氯 在 potassium carbonate 作用下， 以 甲苯 为溶剂， 反应 2.0h， 以80%的产率得到4-(3-氯丙酰基)-2,6-二甲基吗啉
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling of New 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) Related Phosphodiesterase 4D (PDE4D) Inhibitors

  摘要：

  A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.

  DOI：

  10.1021/jm500855w

文献信息

• Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors
  作者：Chiara Brullo、Federica Rapetti、Sara Abbate、Tommaso Prosdocimi、Archimede Torretta、Marta Semrau、Matteo Massa、Silvana Alfei、Paola Storici、Emilio Parisini、Olga Bruno

  DOI：10.1016/j.ejmech.2021.113638

  日期：2021.11

  phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a

  记忆和认知功能取决于大脑中环磷酸腺苷 (cAMP) 的水平，该水平由磷酸二酯酶 4 (PDE4) 家族的酶调节。选定的咯利普兰相关 PDE4 抑制剂（GEBR 库的成员）已被证明可增加海马 cAMP 水平，提供具有安全药理学特征的促认知益处。在最近一项涉及 GEBR 库化合物子集的 SAR 研究中，我们已经证明，根据长度和灵活性，配体可以采用扭曲、延伸或突出的构象，后者允许配体与监管机构形成稳定的接触。酶的结构域。在此，基于这些发现，我们描述了突出的 GEBR 库抑制剂子集的进一步化学修饰及其对配体构象和效力的影响。特别是，我们证明在连接儿茶酚部分和分子基本末端的柔性接头区域中插入甲基可增强配体与酶的催化域和调节域相互作用的能力。
• [EN] NEW COMPOUNDS HAVING A SELECTIVE PDE4D INHIBITING ACTIVITY<br/>[FR] NOUVEAUX COMPOSÉS PRÉSENTANT UNE ACTIVITÉ D'INHIBITION SÉLECTIVE VIS-À-VIS DE PDE4D
  申请人：UNIVERSIT DEGLI STUDI DI GENOVA

  公开号：WO2015121212A1

  公开（公告）日：2015-08-20

  Compounds of formula (I), wherein Z = cyclopentyl. cyclopropylmethyl, -CH3; R' = -CH3, CHF2, X= formula (II) (III) (IV) (V) Y = - CO; -C=O(CH2), -CH(OH)-CH2, -CH2-C=O, -CH2-CH2-C=O; -CH2-CH(OH)-CH2, -CH2- CH(OCOR1)-CH2 NR2 = -N(CH2-CH2OH)2, formula (VI) (VII) (VIII) (IX) (X) (XI) R1 = optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof; these compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.

  化合物的化学式（I），其中Z = 环戊基，环丙甲基，-CH3；R' = -CH3，CHF2，X = 化学式（II）（III）（IV）（V），Y = -CO；-C=O（CH2），-CH（OH）-CH2，-CH2-C=O，-CH2-CH2-C=O；-CH2-CH（OH）-CH2，-CH2-CH（OCOR1）-CH2，NR2 = -N（CH2-CH2OH）2，化学式（VI）（VII）（VIII）（IX）（X）（XI），R1 = 可选择地取代的C1-C8烷基，可选择地取代的芳基；可选择地取代的芳基烷基，优选C1-C3烷基，更优选CH3；以及其对映体，异构体和药学上可接受的盐；这些化合物具有PDE4D抑制活性，可用作治疗痴呆症，特别是阿尔茨海默病，并改善记忆的药物。
• Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents
  作者：Elena Cichero、Federica Rapetti、Matteo Lusardi、Naomi Scarano、Silvana Alfei、Paola Altieri、Silvano Garibaldi、Pietro Ameri、Maria Grazia Signorello、Chiara Brullo

  DOI：10.1002/cmdc.202300046

  日期：——

  Based on the X-ray data of previous phosphodiesterase 4 (PDE4) inhibitors, compounds 1–3 were designed, synthesized, and screened in silico as putative PDE4 inhibitors to exploit structural variation at the catechol group to gain further contacts, especially with the flat aromatic residues of PDE4. Subsequent in vitro biological assays on platelets and endothelial cells provided evidence for antioxidant

  基于先前磷酸二酯酶 4 (PDE4) 抑制剂的 X 射线数据，化合物1-3被设计、合成并在计算机中筛选为推定的 PDE4 抑制剂，以利用儿茶酚基团的结构变异以获得进一步的接触，尤其是与平面PDE4 的芳香族残基。随后对血小板和内皮细胞进行的体外生物测定为抗氧化和抗炎活性提供了证据。
• New compounds as selective PDE4D inhibitors
  申请人：UNIVERSITA DEGLI STUDI DI GENOVA

  公开号：EP2907806A1

  公开（公告）日：2015-08-19

  Compounds of formula (I), wherein Z = cyclopentyl, cyclopropylmethyl, -CH3; R' = -CH3, CHF2, X= Y = -CO; -C=O(CH2), -CH(OH)-CH2, -CH2-C=O, -CH2-CH2-C=O; -CH2-CH(OH)-CH2, -CH2-CH(OCOR1)-CH2; NR2 = -N(CH2-CH2OH)2, R1 = optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof. These compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.

  式(I)化合物、 其中 Z = 环戊基、环丙基甲基、-CH3； R' = -CH3、CHF2、 X= y = -co；-c=o(ch2)，-ch(oh)-ch2，-ch2-c=o，-ch2-ch2-c=o；-ch2-ch(oh)-ch2，-ch2-ch(ocor1)-ch2； NR2 = -N（CH2-CH2OH）2、 R1 = 任选取代的 C1-C8 烷基，任选取代的芳基；任选取代的芳烷基，优选 C1-C3 烷基，更优选 CH3； 及其对映体、非对映异构体和药学上可接受的盐。 这些化合物具有 PDE4D 抑制活性，可用作治疗痴呆症（尤其是阿尔茨海默病）和改善记忆的药物。
• Compounds having a selective PDE4D inhibiting activity
  申请人：UNIVERSITÂ DEGLI STUDI DI GENOVA

  公开号：US10017480B2

  公开（公告）日：2018-07-10

  Compounds of formula (I), wherein Z=cyclopentyl. cyclopropylmethyl, —CH3; R′═—CH3, CHF2, X=formula (II) (III) (IV) (V) Y=—CO; —C═O(CH2), —CH(OH)—CH2, —CH2—C═O, —CH2—CH2—C═O; —CH2—CH(OH)—CH2, —CH2—CH(OCOR1)—CH2 NR2═ —N(CH2—CH2OH)2, formula (VI) (VII) (VIII) (IX) (X) (XI) R1=optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof; these compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.

  式 (I) 的化合物，其中 Z= 环戊基。环丙基甲基，-CH3；R′═-CH3，CHF2，X=式(II) (III) (IV) (V) Y=-CO；-C═O(CH2)，-CH(OH)-CH2，-CH2-C═O，-CH2-CH2-C═O；-CH2-CH(OH)-CH2，-CH2-CH(OCOR1)-CH2 NR2═ -N(CH2-CH2OH)2，式(VI) (VII) (VIII) (IX) (X) (XI) R1=任选取代的 C1-C8 烷基，任选取代的芳基；任选取代的芳烷基，优选 C1-C3 烷基，更优选 CH3；及其对映体、非对映异构体和药学上可接受的盐；这些化合物具有 PDE4D 抑制活性，可用作治疗痴呆症，特别是阿尔茨海默病和改善记忆的药物。