8-(4-氯丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮 | 21098-11-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 中文名称: 8-(4-氯丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮
• 中文别名: 丁螺环酮杂质
• 英文名称: 8-(4-chlorobutyl)-8-azaspiro<4.5>decane-7,9-dione
• 英文别名: 8-(4-chlorobutyl)-8-azaspiro[4.5]decane-7,9-dione
• CAS: 21098-11-3
• 化学式: C₁₃H₂₀ClNO₂
• 分子量: 257.76
• InChiKey: BCNBRBQCDHLCBD-UHFFFAOYSA-N

物化性质

• 沸点：
  429.4±28.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、乙酸乙酯（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• WGK Germany：
  3

反应信息

• 作为反应物：
  描述：

  8-(4-氯丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮 以 甲苯 为溶剂， 反应 32.0h， 生成 8-<4-<4-(1,2-benzisothiazol-3-yl)-3-methyl-1-piperazinyl>butyl>-8-azaspiro<4.5>decane-7,9-dione
  参考文献：
  名称：

  Synthesis and biological evaluation of 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents

  摘要：

  Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound's lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

  DOI：

  10.1021/jm00153a010
• 作为产物：
  描述：

  1-溴-4-氯丁烷 、 3,3-四亚甲基戊二酰亚胺 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以93%的产率得到8-(4-氯丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮
  参考文献：
  名称：

  一系列具有潜在抗精神病作用的多目标N-取代环酰亚胺衍生物的合成和生物学评价

  摘要：

  在本研究中，其具有强效的多巴胺d一系列多目标的N-取代环状酰亚胺衍生物的2，血清素5-HT 1A和5-HT 2A受体的性质，合成并评价潜在的抗精神病药物。在这些化合物中，（3aR，4R，7S，7aS）-2-（4-（4-（4-苯并[ b ]噻吩-4-基）哌嗪-1-基）丁基）-3a，4,7,7a-四氢-1H-4,7-甲基异吲哚-1,3（2H）-二酮盐酸盐（3d）具有良好的药理作用。3d不仅在D 2 / 5-HT 1A / 5-HT 2A上显示出强大而平衡的体外活性受体，但在5-HT 2C，H 1，α1A，M 3受体和hERG通道上也具有低至中度的活性，提示引起副作用（如体重增加，体位性低血压和QT延长）的责任低。在动物行为研究中，3d降低了苯环利定诱发的运动过度，并导致僵直症的诱导阈值较高。化合物3d被选作潜在的抗精神病药物，可用于进一步开发。

  DOI：

  10.1016/j.ejmech.2017.12.099

文献信息

• Polycyclic spiroimides with psychotropic activity
  申请人：American Home Products Corporation

  公开号：US04812567A1

  公开（公告）日：1989-03-14

  There are disclosed compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 taken together represent ##STR2## with the proviso that in ##STR3## when X is lower alkylene or O, m is other than 1; and when R.sup.1 and R.sup.2 taken together represent ##STR4## R.sup.3 is other than unsubstituted or substituted 2-pyridinyl or 2-pyrimidinyl; R.sup.3 is unsubstituted or substituted 2-pyridinyl, 2-pyrimidinyl, 2-pyrazinyl or 3-pyridazinyl, where the substituents are selected from the group lower alkyl, lower alkoxy, halo, cyano and nitro; Z is --(CH.sub.2).sub.n -- or vinylene; X is lower alkylene, vinylene or O; m is 1-4; n is 1-3; o is 1-5; p is 0-1; and the pharmaceutically acceptable salts thereof and their use as antipsychotic/anxiolytic agents having a low liability for extrapyramidal side effects.

  揭示了具有以下结构的化合物 ##STR1## 其中 R.sup.1 和 R.sup.2 一起表示 ##STR2## 前提是在 ##STR3## 中，当 X 是较低的烷基或 O 时，m 不等于 1；当 R.sup.1 和 R.sup.2 一起表示 ##STR4## 时，R.sup.3 不是未取代或取代的 2-吡啶基或 2-嘧啶基；R.sup.3 是未取代或取代的 2-吡啶基、2-嘧啶基、2-吡啶啉基或 3-吡啶啉基，其中取代基选自较低烷基、较低烷氧基、卤素、氰基和硝基；Z 是 --(CH.sub.2).sub.n -- 或乙烯基；X 是较低烷基、乙烯基或 O；m 是 1-4；n 是 1-3；o 是 1-5；p 是 0-1；以及它们的药用盐及其作为具有低外周神经副作用的抗精神病/抗焦虑剂的用途。
• Verfahren zur Herstellung von 8-(4'-(4"-(Pyrimidin-2'''-yl)-piperazin-1"-yl)-butyl)-8-aza-spiro(4,5) decan-7,9-dion und von dessen Hydrochloriden hoher Reinheit
  申请人：EGIS GYOGYSZERGYAR RT.

  公开号：EP0634411A1

  公开（公告）日：1995-01-18

  Gegenstand der Erfindung ist ein Verfahren zur Herstellung von 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}- 8-aza-spiro[4,5]decan-7,9-dion Buspiron} der Formel und von dessen Hydrochloriden durch Hydrieren von 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-but-2'-inyl}- 8-aza-spiro[4,5]decan-7,9-dion der Formel in Gegenwart eines Palladium- oder Raney-Nickel-Katalysators in einem organischen Lösungsmittel und gegebenenfalls Überführen des erhaltenen 8-4'-[4''-(Pyrimidin-2'''-yl)- piperazin-1''-yl]-butyl}-8-aza-spiro[4,5]decan-7,9-diones in ein Hydrochlorid, bei welchem eine Lösung von 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]- but-2'-inyl}-8-aza-spiro[4,5]decan-7,9-dion der Formel II in einem organischen Lösungsmittel, deren Konzentration mindestens 40 Gew.-/Gew.-% ist, einer Suspension des Katalysators in einem organischen Lösungsmittel zugesetzt wird, der Katalysator entfernt wird und a) die 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}- 8-aza-spiro[4,5]decan-7,9-dion-Base der Formel I isoliert wird und/oder b) die 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}- 8-aza-spiro[4,5]decan-7,9-dion-Base der Formel I bei 15 bis 40°C in Äthanol oder Isopropanol mit Chlorwasserstoff behandelt und das bei 188 bis 191°C schmelzende 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}-8- aza-spiro[4,5]decan-7,9-dion-hydrochlorid isoliert wird oder c) die 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}- 8-aza-spiro[4,5]decan-7,9-dion-Base der Formel I bei höchstens 70°C in Äthylacetat oder Isopropanol mit Chlorwasserstoff behandelt und das bei 201 bis 203°C schmelzende 8-4'-[4''-(Pyrimidin-2'''-yl)-piperazin-1''-yl]-butyl}-8- aza-spiro[4,5]decan-7,9-dion-hydrochlorid isoliert wird.

  本发明的主题是制备 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮丁螺环酮}的工艺，其式为 及其盐酸盐的氢化反应，氢化 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁-2'-基}-8-氮杂螺[4,5]癸烷-7,9-二酮的式 在钯或雷尼镍催化剂存在下，在有机溶剂中，将得到的 8-4'-[4''-(嘧啶-2''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7、将式 II 的 8-4'-[4''-(嘧啶-2''-基)-哌嗪-1''-基]-丁-2'-炔基}-8-氮杂螺[4,5]癸烷-7,9-二酮在浓度至少为 40 wt.% 的有机溶剂中的溶液转化为盐酸盐。-/按重量百分比将催化剂加入到有机溶剂中的催化剂悬浮液中，然后移除催化剂并 a) 分离出式 I 的 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮碱和/或 b) 式 I 的 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮碱在 15 至 40°C 下在乙醇或异丙醇中分离出来。 乙醇或异丙醇与氯化氢反应，分离出 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮盐酸盐，其熔点为 188 至 191°C，或 c) 式 I 的 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮碱基，在不超过 70°C 的温度下 在乙酸乙酯或异丙醇中加入氯化氢，分离出 8-4'-[4''-(嘧啶-2'''-基)-哌嗪-1''-基]-丁基}-8-氮杂螺[4,5]癸烷-7,9-二酮盐酸盐，其熔点为 201 至 203°C。
• 7-[3-(1-Piperidinyl)propoxy]chromenones as Potential Atypical Antipsychotics
  作者：Jordi Bolós、Santiago Gubert、Lluís Anglada、Josep M. Planas、Carme Burgarolas、Josep M. Castelló、Aurelio Sacristán、José A. Ortiz

  DOI：10.1021/jm950894b

  日期：1996.1.1

  Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)- a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.
• 1,9-Alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines with affinity for the .alpha.2-adrenoceptor and the 5-HT1A receptor
  作者：Robin D. Clark、Klaus K. Weinhardt、Jacob Berger、Lawrence E. Fisher、Christine M. Brown、Alison C. MacKinnon、Andrew T. Kilpatrick、Michael Spedding

  DOI：10.1021/jm00164a026

  日期：1990.2

  A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.
• BOAVENTURA, ANNA-MARIA;GASC, JEAN-CLAUDE;HUMBERT, DANIEL
  作者：BOAVENTURA, ANNA-MARIA、GASC, JEAN-CLAUDE、HUMBERT, DANIEL

  DOI：——

  日期：——