齐洛那平 | 170381-16-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 中文名称: 齐洛那平
• 英文名称: Zicronapine
• 英文别名: 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine；trans-4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine；trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine；4-[(1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl]-1,2,2-trimethylpiperazine
• CAS: 170381-16-5
• 化学式: C₂₂H₂₇ClN₂
• 分子量: 354.923
• InChiKey: BYPMJBXPNZMNQD-PZJWPPBQSA-N

物化性质

• 沸点：
  443.8±45.0 °C(Predicted)
• 密度：
  1.125±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  6.5
• 氢给体数：
  0
• 氢受体数：
  2

制备方法与用途

齐克罗纳平是一种抗精神病药物，在动物模型中显示出强大的促认知作用，可能用于治疗多种神经和精神疾病。它对多巴胺D1/D2和5-羟色胺5-HT2A受体具有强烈的拮抗作用。

反应信息

• 作为反应物：
  描述：

  丙二酸 、 齐洛那平 以 异丙醇 为溶剂， 以84%的产率得到trans-4-((1R,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine hydrogen malonate
  参考文献：
  名称：

  [EN] SUCCINATE AND MALONATE SALT OF TRANS-4-(IR,3S)-6-CHLORO-3-PHENYLINDAN-1-YL)-1,2,2-TRIMETHYLPIPERAZINE AND THE USE AS A MEDICAMENT
  [FR] SEL DE SUCCINATE ET DE MALONATE DE TRANS-4-((1R,3S)-6-CHLORO-3-PHENYLINDAN-1-YL)-1,2,2-TRIMETHYLPIPERAZINE ET SON UTILISATION EN TANT QUE MEDICAMENT

  摘要：

  4-((1R,3S)-6-氯-3-苯基茚-1-基)-1,2,2-三甲基哌嗪氢丁二酸盐或氢丁二酸盐，含有这些盐的药物组合物及其医疗用途，包括用于治疗精神分裂症和其他精神疾病。还描述了制备4-((1R,3S)-6-氯-3-苯基茚-1-基)-1,2,2-三甲基哌嗪和其医疗用途的方法。

  公开号：

  WO2005016900A1
• 作为产物：
  描述：

  3,5-dichloro-1-phenyl-2,3-dihydro-1H-indene 在 甲酸 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 20.0h， 生成 齐洛那平
  参考文献：
  名称：

  Enhanced D1 Affinity in a Series of Piperazine Ring Substituted 1-Piperazino-3-Arylindans with Potential Atypical Antipsychotic Activity

  摘要：

  A study of the effect of aromatic substitution on D-1 and D-2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro- or B-fluoro-substituted derivatives show preference for D-1 receptors. D-1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D-1 and D-2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl, 2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chlorosubstituted derivatives have potent D-1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED(50) values about 1 mu mol/kg. In vitro all compounds show preference for D-1 receptors, but in vivo they are equally effective as D-1 and D-2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha(1) adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being ''atypical'' antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D-2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D-1 receptor site.

  DOI：

  10.1021/jm00022a004

文献信息

• DEUTERATED 1-PIPERAZINO-3-PHENYL-INDANES FOR TREATMENT OF SCHIZOPHRENIA
  申请人：JORGENSEN Morten

  公开号：US20120322811A1

  公开（公告）日：2012-12-20

  The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D 1 and D 2 as well as the 5HT 2 receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

  本发明涉及氘代1-哌嗪基-3-苯基茚烷及其盐，具有在中枢神经系统中对多巴胺受体D1和D2以及5HT2受体的活性，涉及包含这些化合物作为活性成分的药物、将这些化合物用于治疗中枢神经系统疾病的用途，以及包括给予这些化合物的治疗方法。
• [EN] METHOD FOR RESOLUTION OF 4-((1R,3S)-6-CHLORO-3-PHENYL-INDAN-1-YL)-1,2,2-TRIMETHYL-PIPERAZINE AND 1-((1R,3S)-6-CHLORO-3-PHENYL-INDAN, 1-YL)-3,3-DIMETHYL-PIPERAZINE<br/>[FR] PROCÉDÉ DE DÉDOUBLEMENT DE LA 4-((1R,3S)-6-CHLORO-3-PHÉNYL-INDAN-1-YL)- 1,2,2-TRIMÉTHYL-PIPÉRAZINE ET DE LA 1-((1R,3S)-6-CHLORO-3-PHÉNYL-INDAN- 1-YL)-3,3-DIMÉTHYL-PIPÉRAZINE
  申请人：LUNDBECK & CO AS H

  公开号：WO2012093165A1

  公开（公告）日：2012-07-12

  The present invention relates to resolution methods for manufacture of 4-((1R,3S)-6- chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and 1-((1R,3S)-6-chloro-3- phenyl-indan-1-yl)-3,3-dimethyl-piperazine and pharmaceutically acceptable salts thereof.

  本发明涉及用于制造4-((1R,3S)-6-氯-3-苯基-茚-1-基)-1,2,2-三甲基哌嗪和1-((1R,3S)-6-氯-3-苯基-茚-1-基)-3,3-二甲基哌嗪及其药学上可接受的盐的分辨方法。
• [EN] MANUFACTURE OF 4-((1R,3S)-6-CHLORO-3-PHENYL-INDAN-1-YL)-1,2,2-TRIMETHYL-PIPERAZINE AND 1-((1R,3S)-6-CHLORO-3-PHENYL-INDAN-1-YL)-3,3-DIMETHYL-PIPERAZINE<br/>[FR] FABRICATION DE LA 4-((1R,3S)-6-CHLORO-3-PHÉNYL-INDAN-1-YLE)-1,2,2-TRIMÉTHYL-PIPÉRAZINE ET DE LA 1-((1R,3S)-6-CHLORO-3-PHÉNYL-INDAN-1-YLE)-3,3-DIMÉTHYL-PIPÉRAZINE
  申请人：LUNDBECK & CO AS H

  公开号：WO2011003423A1

  公开（公告）日：2011-01-13

  The present invention relates to a process for the manufacture of 4-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine or a pharmaceutically acceptable salt thereof and a process for the manufacture of 1-((1R,3S)-6-Chloro-3-phenyl-indan-1-yl)-3,3-dimethyl-piperazine or a pharmaceutically acceptable salt thereof.

  本发明涉及制备4-((1R,3S)-6-氯-3-苯基-茚烷-1-基)-1,2,2-三甲基哌嗪或其药学上可接受的盐的方法，以及制备1-((1R,3S)-6-氯-3-苯基-茚烷-1-基)-3,3-二甲基哌嗪或其药学上可接受的盐的方法。
• [EN] 1-PIPERAZINO-1,2-DIHYDROINDENE DERIVATIVES<br/>[FR] DERIVES DE 1-PIPERAZINO-1,2-DIHYDROINDENE
  申请人：H. LUNDBECK A/S

  公开号：WO1993022293A1

  公开（公告）日：1993-11-11

  (EN) Trans isomers of 1-piperazino-1,2-dihydroindene compounds having general formula (I), wherein X and Y are hydrogen, halogen, trifluoromethyl, alkyl, alkylthio, trifluoromethylthio, alkoxy, hydroxy, alkylsulfonyl, amino, alkylamino, nitro or cyano; Ar is a phenyl, thienyl or furyl group, each optionally substituted; R1 is hydrogen, or optionally hydroxy substituted alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; R2 is alkyl, alkenyl, cycloalkyl, or cycloalkylalkyl; or R1 and R2 together form a 5 to 7-membered heterocyclic ring fused with the piperazine ring, which ring may be substituted with hydroxy; R3 is hydrogen, alkyl, r alkenyl, cycloalkyl or cycloalkylalkyl; or R2 and R3 together form a 3 to 7-membered carbocyclic ring which is spirofused to the piperazine ring; and R4 is hydrogen or alkyl; have potent antagonistic action on dopamine D1 receptors. The compounds are useful in the treatment of diseases in the central nervous system, in particular psychoses, schizophrenia (positive as well as negative symptoms), anxiety, depression, sleep disturbances, migraine, Parkinson's disease or cocaine abuse.(FR) Trans-isomères de composés de 1-pipérazine-1,2-dihydroindène répondant à la formule générale (I) dans laquelle X et Y représentent hydrogène, halogène, trifluorométhyle, alkyle, alkylthio, trifluorométhylthio, alcoxy, hydroxy, alkylsulfonyle, amino, alkylamino, nitro ou cyano; Ar représente un groupe phényle, thiényle ou furyle, chacun éventuellement substitué; R1 représente hydrogène ou alkyle, alcényle, cycloalkyle ou cycloalkylalkyle éventuellement substitué par hydroxy; R2 représente alkyle, alcényle, cycloalkyle ou cycloalkylalkyle; ou R1 et R2 forment ensemble un noyau hétérocyclique comprenant 5 à 7 éléments, fusionné avec le noyau pipérazine, ce noyau pouvant être substitué par hydroxy; R3 représente hydrogène, alkyle, alcényle, cycloalkyle ou cycloalkylalkyle; ou R2 et R3 forment ensemble un noyau carbocyclique comprenant 3 à 7 éléments qui est spiro-fusionné au noyau pipérazine; et R4 représente hydrogène ou alkyle. Ces composés présentent une activité antagoniste puissante par rapport aux récepteurs de dopamine D1. Ces composés peuvent être utilisés dans le traitement de maladies du système nerveux central, en particulier les psychoses, la schizophénie (symptômes positifs aussi bien que négatifs), l'anxiété, la dépression, les troubles du sommeil, la migraine, la maladie de Parkinson ou l'abus de cocaïne.

  (I)式中的1-哌嗪基-1,2-二氢茚化合物的顺式异构体，其中X和Y为氢、卤素、三氟甲基、烷基、烷硫基、三氟甲基硫基、烷氧基、羟基、烷基磺酰基、氨基、烷基氨基、硝基或氰基；Ar为苯基、噻吩基或呋喃基，每个基团均可选地被取代；R1为氢或可选地被羟基取代的烷基、烯基、环烷基或环烷基烷基；R2为烷基、烯基、环烷基或环烷基烷基；或R1和R2共同形成与哌嗪环融合的5到7元杂环，该环可能被羟基取代；R3为氢、烷基、烯基、环烷基或环烷基烷基；或R2和R3共同形成与哌嗪环融合的3到7元碳环，该环与哌嗪环螺合；R4为氢或烷基。这些化合物对多巴胺D1受体具有强烈的拮抗作用。这些化合物在治疗中枢神经系统疾病，特别是精神病、精神分裂症（正向和负向症状）、焦虑、抑郁、睡眠障碍、偏头痛、帕金森病或可卡因滥用方面有用。
• 1-piperazino-1,2-dihydroindene derivatives
  申请人：H. Lundbeck A/S

  公开号：US05807855A1

  公开（公告）日：1998-09-15

  Trans isomers of 1-piperazino-1,2-dihydroindene compounds having formula (I), ##STR1## wherein X and Y are hydrogen, halogen, trifluoromethyl, alkyl, alkylthio, trifluoromethylthio, alkoxy, hydroxy, alkylsulfonyl, amino, alkylamino, nitro or cyano; Ar is a phenyl, thienyl or furyl group, each optionally substituted; R.sub.1 is hydrogen, or optionally hydroxy substituted alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; R.sub.2 is alkyl, alkenyl, cycloalkyl, or cycloalkylalkyl; or R.sub.1 and R.sub.2 together form a 5 to 7-membered heterocyclic ring fused with the piperazine ring, which ring may be substituted with hydroxy; R.sub.3 is hydrogen, alkyl, alkenyl, cycloalkyl or cycloalkylalkyl; or R.sub.2 and R.sub.3 together form a 3 to 7-membered carbocyclic ring which is spiro-fused to the piperazine ring; and R.sub.4 is hydrogen or alkyl. The compounds of the invention have potent antagonist action on dopamine D.sub.1 receptors and are useful in the treatment of diseases of the central nervous system, such as psychoses, schizophrenia (positive as well as negative symptoms), anxiety, depression, sleep disturbances, migraine, Parkinson's disease or cocaine abuse.

  具有公式（I）的1-哌嗪基-1,2-二氢吲哚化合物的反式异构体，其中X和Y是氢，卤素，三氟甲基，烷基，烷基硫，三氟甲基硫，烷氧基，羟基，烷基磺酰基，氨基，烷基氨基，硝基或氰基；Ar是苯基，噻吩基或呋喃基，每个基团均可选择性地被取代；R1是氢，或可选地羟基取代的烷基，烯基，环烷基或环烷基烷基；R2是烷基，烯基，环烷基或环烷基烷基；或R1和R2共同形成与哌嗪环融合的5至7成员杂环，该环可以被羟基取代；R3是氢，烷基，烯基，环烷基或环烷基烷基；或R2和R3共同形成与哌嗪环螺合的3至7成员碳环，该环与哌嗪环融合；R4是氢或烷基。该发明的化合物在多巴胺D1受体上具有强大的拮抗作用，并且在治疗中枢神经系统疾病，如精神病，精神分裂症（正性和负性症状），焦虑，抑郁，睡眠障碍，偏头痛，帕金森病或可卡因滥用方面具有用处。