1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane | 134069-68-4

• 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: 1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane
• 英文别名: 1-Oxa-3,8-diazaspiro(4.5)decan-2-one, 8-(4,4-bis(4-fluorophenyl)butyl)-3-(1,1-dimethylethyl)-4-methylene-；8-[4,4-bis(4-fluorophenyl)butyl]-3-tert-butyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one
• CAS: 134069-68-4
• 化学式: C₂₈H₃₄F₂N₂O₂
• 分子量: 468.587
• InChiKey: OFRYIDMZALXALS-UHFFFAOYSA-N

物化性质

• 沸点：
  556.2±60.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃

制备方法与用途

生物活性

TDN345 A 是一种 Ca2+ 拮抗剂，主要用于血管和老年痴呆疾病的研究，例如阿尔茨海默症。

体外研究

在时间进程的实验中，10 μM 的 TDN-345 显著增加了细胞内 NGF 内容。TDN-345 在浓度为 0.1 μM 时诱导 NGF 合成/分泌，在 1 μM 浓度下具有统计学意义。其半数有效剂量（ED50）为 0.88 μM。

体内研究

口服给药 TDN-345（0.1-1.0 mg/kg，60 分钟前和 90 分钟后各一次），可剂量依赖性地减少缺血性神经功能缺损评分，并降低死亡率。此外，在中风发作后连续三周每日口服 0.2 或 1.0 mg/kg 的 TDN-345 可以降低 SHRSP 中的死亡率和中风复发率。

反应信息

• 作为反应物：
  描述：

  1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane 在 盐酸 、 甲酸 作用下， 以95%的产率得到
  参考文献：
  名称：

  1-Oxa-3,8-diazaspiro[4.5]decan-2-one derivatives with a potent inhibitory effect on neural Ca-uptake and protecting action against TET-induced brain edema and memory and learning deficits

  摘要：

  A series of novel 1-oxa-3,8-diazaspiro[4.5]decan-2-one derivatives 8-71 were synthesized. Several representatives were examined for their in vitro inhibitory action on Ca-45-uptake into cerebrocortical synaptosomes depolarized by potassium and veratrine and on triethyltin-induced brain edema. Of the compounds displaying most potent inhibitory action on veratrine-induced Ca-45-uptake into cerebrocortical synaptosomes and outstanding protection against triethyltin chloride (TET) induced brain edema in rats, four were tested for their antihypoxic action and prevention of learning and memory deficits elicited by various agents leg, electroshock, diazepam, scopolamine, carbon dioxide and normobaric hypoxia). In some of these tests the four compounds showed remarkable protecting/restoring activity. It is assumed that the beneficial effects of these compounds in brain edema formation are probably related to their actions on intracellular Ca2+- and Na+-movements. These cellular effects may also play role in their antiamnesic actions, but other mechanisms may also be involved. On the basis of results obtained in the tests used, the pharmacological profile of the novel 1-oxa-3,8-diazaspiro [4.5]decan-2-one derivatives seems to differ from that of known Ca2+-antagonists such as flunarizine or nimodipine and Na+-channel blocker, phenytoin. Out of the four most active compounds tested, one (44) was selected for further investigation and this compound is currently under preclinical development with the code name of RGH-2716 or TDN-345.

  DOI：

  10.1016/s0223-5234(97)84359-0
• 作为产物：
  描述：

  4,4,-二(4-氟苯)氯丁烷 、 3-tert-Butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]-decane 在 potassium carbonate 、 potassium iodide 作用下， 以 various solvent(s) 为溶剂， 反应 19.0h， 以85%的产率得到1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane
  参考文献：
  名称：

  1-Oxa-3,8-diazaspiro[4.5]decan-2-one derivatives with a potent inhibitory effect on neural Ca-uptake and protecting action against TET-induced brain edema and memory and learning deficits

  摘要：

  A series of novel 1-oxa-3,8-diazaspiro[4.5]decan-2-one derivatives 8-71 were synthesized. Several representatives were examined for their in vitro inhibitory action on Ca-45-uptake into cerebrocortical synaptosomes depolarized by potassium and veratrine and on triethyltin-induced brain edema. Of the compounds displaying most potent inhibitory action on veratrine-induced Ca-45-uptake into cerebrocortical synaptosomes and outstanding protection against triethyltin chloride (TET) induced brain edema in rats, four were tested for their antihypoxic action and prevention of learning and memory deficits elicited by various agents leg, electroshock, diazepam, scopolamine, carbon dioxide and normobaric hypoxia). In some of these tests the four compounds showed remarkable protecting/restoring activity. It is assumed that the beneficial effects of these compounds in brain edema formation are probably related to their actions on intracellular Ca2+- and Na+-movements. These cellular effects may also play role in their antiamnesic actions, but other mechanisms may also be involved. On the basis of results obtained in the tests used, the pharmacological profile of the novel 1-oxa-3,8-diazaspiro [4.5]decan-2-one derivatives seems to differ from that of known Ca2+-antagonists such as flunarizine or nimodipine and Na+-channel blocker, phenytoin. Out of the four most active compounds tested, one (44) was selected for further investigation and this compound is currently under preclinical development with the code name of RGH-2716 or TDN-345.

  DOI：

  10.1016/s0223-5234(97)84359-0

文献信息

• [EN] ARYL IMIDAZOLE COMPOUNDS AND THEIR USE AS BETA AMYLOID PRODUCTION INHIBITORS<br/>[FR] COMPOSÉ ARYLIMIDAZOLE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PRODUCTION DE LA PROTÉINE AMYLOÏDE BÊTA
  申请人：EISAI R&D MAN CO LTD

  公开号：WO2010098488A1

  公开（公告）日：2010-09-02

  A compound represented by the formula (I): or a pharmacologically acceptable salt or ester thereof, wherein Ring A represents a triazolyl group or the like which may be substituted, Ring B represents a phenyl group or the like which may be substituted, X1 represents a single bond or the like, R1 and R2 each represent a C1-6 alkyl group or the like, m represents an integer of 0 to 3, and n represents an integer of 0 to 2, is effective as a therapeutic agent for a disease caused by Aβ.

  一种由化学式(I)表示的化合物，或其药理学上可接受的盐或酯，其中环A代表可能被取代的三唑基团或类似物，环B代表可能被取代的苯基团或类似物，X1代表单键或类似物，R1和R2分别代表C1-6烷基或类似物，m代表0到3的整数，n代表0到2的整数，对于由Aβ引起的疾病具有治疗作用。
• MULTI-CYCLIC COMPOUNDS
  申请人：KIMURA Teiji

  公开号：US20090062529A1

  公开（公告）日：2009-03-05

  A compound represented by the formula (I): or a pharmacologically acceptable salt thereof, wherein Ar 1 represents an imidazolyl group or the like which may be substituted with a C1-6 alkyl group, Ar 2 represents a phenyl group or the like which may be substituted with a C1-6 alkoxy group, X 1 represents a double bond or the like and Het represents a triazolyl group or the like which may be substituted with a C1-6 alkyl group or the like, is effective as a therapeutic or prophylactic agent for a disease caused by Aβ.

  一种由化学式(I)表示的化合物或其药理学可接受的盐，其中Ar1代表可用C1-6烷基基团取代的咪唑基团或类似基团，Ar2代表可用C1-6烷氧基团取代的苯基团或类似基团，X1代表双键或类似基团，Het代表可用C1-6烷基基团或类似基团取代的三唑基团或类似基团，对由Aβ引起的疾病具有治疗或预防作用。
• [EN] NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUNDS AND THEIR USE AS BETA AMYLOID PRODUCTION INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES CONDENSÉS CONTENANT DE L'AZOTE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PRODUCTION DE LA BÊTA-AMYLOÏDE
  申请人：EISAI R&D MAN CO LTD

  公开号：WO2010098487A1

  公开（公告）日：2010-09-02

  A compound represented by the formula [I]: or a pharmacologically acceptable salt or ester thereof, wherein Ring A represents a five-membered aromatic heterocyclic group or the like fused with a non-aromatic ring group, which may be substituted, Ring B represents a phenyl group or the like which may be substituted, X1 represents a single bond or the like, R1 and R2 each represent a C1-6 alkyl group or the like, m represents an integer of 0 to 3, and n represents an integer of 0 to 2, is effective as a therapeutic agent for a disease caused by Aβ.

  化合物的分子式为[I]：或其药理学可接受的盐或酯，其中环A代表一个五元芳香杂环基团或类似于非芳香环基团的融合物，可以被取代，环B代表一个苯基或类似的基团，可以被取代，X1代表一个单键或类似物，R1和R2分别代表一个C1-6烷基基团或类似物，m表示0到3的整数，n表示0到2的整数，对由Aβ引起的疾病具有治疗作用。
• [EN] IMIDAZOLYLPYRAZINE DERIVATIVES<br/>[FR] DÉRIVÉS D'IMIDAZOLYLPYRAZINE
  申请人：EISAI R&D MAN CO LTD

  公开号：WO2010098495A1

  公开（公告）日：2010-09-02

  To provide a novel low-molecular-weight compound that inhibits the production of amyloid-β (Aβ ). A compound represented by the formula [I]: or a pharmacologically acceptable salt or ester thereof, wherein R1 and R2 are the same or different and each represent a substituent selected from the following Substituent Group a1; m represents an integer of 0 to 3; n represents an integer of 0 to 2; X1 represents a single bond or the like; X2 represents a single bond or the like; Ring A represents a five-membered aromatic heterocyclic group or the like which contains two or more nitrogen atoms and may have 1 to 3 substituents selected from the following Substituent Group b1; and Ring B represents a monocyclic or fused cyclic aromatic ring group such as the formula [2] which may have 1 to 3 substituents selected from the following Substituent Group c1, is effective as a therapeutic agent for a disease such as Alzheimer's disease. Substituent Group a1: a C1-6 alkyl group and the like Substituent Group b1: a C1-6 alkyl group and the like Substituent Group c1: an amino group and the like

  提供一种新型低分子量化合物，该化合物能够抑制淀粉样蛋白-β（Aβ）的产生。表示为化学式[I]的化合物，或其药理学上可接受的盐或酯，其中R1和R2相同或不同，每个代表以下取代基团a1中选择的取代基；m代表0到3的整数；n代表0到2的整数；X1代表单键或类似物；X2代表单键或类似物；环A代表含有两个或更多氮原子并且可能具有1到3个取代基团b1中选择的取代基的五元芳香杂环基团或类似物；环B代表可能具有1到3个取代基团c1中选择的取代基的单环或融合环芳香环基团，如化学式[2]所示，对于阿尔茨海默病等疾病具有治疗作用。取代基团a1：C1-6烷基基团等；取代基团b1：C1-6烷基基团等；取代基团c1：氨基团等。
• Nitrogen-Containing Fused Heterocyclic Compounds and Their use as Beta Amyloid Production Inhibitors
  申请人：Kitazawa Noritaka

  公开号：US20120053171A1

  公开（公告）日：2012-03-01

  A compound represented by the formula [I]: or a pharmacologically acceptable salt or ester thereof, wherein Ring A represents a five-membered aromatic heterocyclic group or the like fused with a non-aromatic ring group, which may be substituted, Ring B represents a phenyl group or the like which may be substituted, X1 represents a single bond or the like, R1 and R2 each represent a C1-6 alkyl group or the like, m represents an integer of 0 to 3, and n represents an integer of 0 to 2, is effective as a therapeutic agent for a disease caused by Aβ.

  化合物的化学式为[I]，或其药理学上可接受的盐或酯，其中环A代表一个五元芳香杂环基团或类似物，与非芳香环基团融合，可以被取代，环B代表苯基或类似物，可以被取代，X1代表单键或类似物，R1和R2各代表C1-6烷基或类似物，m代表0至3的整数，n代表0至2的整数，该化合物对由Aβ引起的疾病具有治疗作用。