2-{3-[3-(cyclopenlyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}-N,N-bis(2-hydroxyethyl)acetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-{3-[3-(cyclopenlyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}-N,N-bis(2-hydroxyethyl)acetamide
• 英文别名: 2-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}-N,N-bis(2-hydroxyethyl)acetamide；2-[3-(3-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydro-1,2-oxazol-5-yl]-N,N-bis(2-hydroxyethyl)acetamide
• 化学式: C₂₁H₃₀N₂O₆
• 分子量: 406.479
• InChiKey: VUQABPCUWUTWEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-(cyclopentyloxy)-4-methoxybenzaldehyde oxime 在 N-氯代丁二酰亚胺 、 三乙胺 作用下， 以 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 2-{3-[3-(cyclopenlyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}-N,N-bis(2-hydroxyethyl)acetamide
  参考文献：
  名称：

  New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment

  摘要：

  Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.018

文献信息

• [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。
• 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。
• NEW COMPOUNDS HAVING A SELECTIVE PDE4D INHIBITING ACTIVITY
  申请人：Universita' degli Studi di Genova

  公开号：EP3105206A1

  公开（公告）日：2016-12-21
• New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment
  作者：Chiara Brullo、Roberta Ricciarelli、Jos Prickaerts、Ottavio Arancio、Matteo Massa、Chiara Rotolo、Alessia Romussi、Claudia Rebosio、Barbara Marengo、Maria Adelaide Pronzato、Britt T.J. van Hagen、Nick P. van Goethem、Pasqualina D'Ursi、Alessandro Orro、Luciano Milanesi、Sara Guariento、Elena Cichero、Paola Fossa、Ernesto Fedele、Olga Bruno

  DOI：10.1016/j.ejmech.2016.08.018

  日期：2016.11

  Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. (C) 2016 Elsevier Masson SAS. All rights reserved.