lumateperone | 313369-37-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: lumateperone
• 英文别名: 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone；1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one；4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one；ITI-007；1-(4-fluorophenyl)-4-[(10R,15S)-4-methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one
• CAS: 313369-37-8
• 化学式: C₂₄H₂₈FN₃O
• 分子量: 393.504
• InChiKey: HOIIHACBCFLJET-SFTDATJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  26.8
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

Lumateperone被广泛代谢。其羰基侧链通过酮还原酶还原，产生主要活性代谢物。[A189093,A188991] 细胞色素P450 3A4酶将Lumateperone代谢为2种代谢物：活性N-去甲基羰基代谢物（IC200161）或N-去甲基醇代谢物（IC200565）。[A189093,A188991]

Lumateperone is extensively metabolized. The carbonyl side chain is reduced by ketone reductase to produce the primary active metabolite.[A189093,A188991] Cytochrome P450 3A4 enzymes metabolize lumateperone to 2 metabolites: the active N-desmethylated carbonyl metabolite (IC200161) or the N-desmethylated alcohol metabolite (IC200565).[A189093,A188991]

来源:DrugBank

毒理性

• 毒性总结

由于 lumateperone 是一种新批准的药物，目前没有可用的上市后数据。[A189093] 毒性症状可能包括更强烈的 lumateperone 不良反应，如过度镇静。

Since lumateperone is a newly approved medication, there is no post-marketing data available at this time.[A189093] It is likely that symptoms of toxicity will include more intense lumateperone adverse effects such as excessive sedation.

来源:DrugBank

毒理性

• 蛋白质结合

Lumateperone大约有97.4%与血浆蛋白结合。[A189093,L10860]

Lumateperone is approximately 97.4% plasma protein bound.[A189093,L10860]

来源:DrugBank

吸收、分配和排泄

• 吸收

Lumateperone能够渗透多重药物耐药蛋白1（MDR1），在pH为7.4时具有很高的脂溶性，这些特性使得抗精神病药物能够被小肠和血脑屏障吸收。[A189093] Tmax出现在口服给药后3-4小时。[A189093]

Lumateperone is able to permeate multidrug resistance protein 1 (MDR1) and is very lipophilic at a pH of 7.4, which are characteristics that allow the antipsychotic to be absorbed in the small intestine and the blood brain barrier.[A189093] Tmax occurs 3-4 hours after oral administration.[A189093]

来源:DrugBank

吸收、分配和排泄

• 消除途径

由于其分子量，几乎所有的未经改变的卢马特珀隆都会通过粪便排出体外。卢马特珀隆的代谢物非常水溶性，这一特性使得其能够被完全排出体外。大约58%的卢马特珀隆剂量可以在尿液中回收，而29%可以在粪便中回收。

Due to it's molecular weight, virtually all unchanged lumateperone is excreted in the feces.[L10860,A189093] Lumateperone's metabolites are very water soluble which is a property that allows for complete elimination.[A189093] Approximately 58% of a lumateperone dose can be recovered in the urine, while 29% can be recovered in the feces.[L10860]

来源:DrugBank

吸收、分配和排泄

• 分布容积

在静脉给药后，卢马特珀酮的分布容积大约为4.1升/千克。[L10860]

The volume of distribution of lumateperone is approximately 4.1 L/Kg after intravenous administration.[L10860]

来源:DrugBank

吸收、分配和排泄

• 清除

Lumateperone的清除率估计为27.9升/小时。[L10860]

Lumateperone's clearance is estimated to be 27.9 L/hour.[L10860]

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  lumateperone 在 盐酸 作用下， 以 醋酸异丙酯 为溶剂， 反应 1.5h， 以10.77 g的产率得到1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one hydrochloride
  参考文献：
  名称：

  [EN] SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SYNTHESIS
  [FR] SYNTHÈSE DE GAMMA-CARBOLINES FUSIONNÉES À HÉTÉROCYCLES SUBSTITUÉS

  摘要：

  本发明提供了改进的方法，用于制备取代杂环融合γ-咔啉，这些中间体在生产中很有用，并提供了制备这些中间体和这些杂环融合γ-咔啉的方法。

  公开号：

  WO2019241278A1
• 作为产物：
  描述：

  2-溴苯肼盐酸盐 在 盐酸 、 三乙基硅烷 、 硼烷四氢呋喃络合物 、 rac-BINAP 、 sodium hydride 、 sodium carbonate 、 三乙胺 、 三氟乙酸 、 potassium iodide 、 potassium hydroxide 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 生成 lumateperone
  参考文献：
  名称：

  ITI-007. 5-HT2A receptor antagonist, dopamine D2 receptor modulator, treatment of schizophrenia, treatment of insomnia

  摘要：

  A great deal has been achieved in the treatment of schizophrenia in recent decades, especially the treatment of the positive symptoms by targeting dopamine D-2 receptors. But the disease has a range of other symptoms which gravely affect quality of life and which require other strategies or additional targets. Among the agents gradually filling the empty therapeutic space is ITI-007, which has an unusual mechanistic profile: it targets 5-HT2A and dopamine D-2 receptors, but has a much higher affinity for the former receptors. This may allow the drug's effects to be modified by dose adjustments, with effects on sleep disturbances, depression and anxiety seen with lower doses and higher doses affecting the positive symptoms of schizophrenia through dopamine D-2 receptor modulation. Higher doses can also inhibit serotonin transporters and produce glutamatergic modulation which could improve positive and negative symptoms, depressive symptoms and cognitive impairments. The findings of preclinical studies have supported this view of the drug, and a phase II study found effects on positive and negative symptoms with a safety profile distinct from atypical antipsychotics. Phase III investigation in schizophrenia has begun, and clinical investigation in insomnia and dementia is also under way.

  DOI：

  10.1358/dof.2015.040.10.2387229

文献信息

• Substituted heterocycle fused gamma-carbolines
  申请人：——

  公开号：US20040220178A1

  公开（公告）日：2004-11-04

  The present invention is directed to methods of treating addictive behavior and sleep disorders by administering compounds represented by structural Formula (I) 1 or pharmaceutically acceptable salt forms thereof, wherein R 1 , R 5 , R 6a , R 6b , R 7 , R 8 , R 9 , X, b, k, m, and n, and the dashed lines are described herein. The compounds used in the method of treatment of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including addictive behavior and sleep disorders.

  本发明涉及通过给予由结构式（I）表示的化合物或其药学上可接受的盐形式来治疗成瘾行为和睡眠障碍的方法，其中R1、R5、R6a、R6b、R7、R8、R9、X、b、k、m和n以及虚线如本文所述。本发明治疗方法中使用的化合物是5-羟色胺激动剂和拮抗剂，对于控制或预防包括成瘾行为和睡眠障碍在内的中枢神经系统疾病是有用的。
• [EN] ORGANIC COMPOUNDS<br/>[FR] COMPOSÉS ORGANIQUES
  申请人：INTRA CELLULAR THERAPIES INC

  公开号：WO2014145192A1

  公开（公告）日：2014-09-18

  The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D2 receptor signaling systems.

  该发明涉及特定的取代杂环融合的γ-咖啡碱，其前药，以自由的、药学上可接受的盐和/或基本纯净形式描述，以及其药物组合物，以及在治疗涉及5-HT2A受体、5-羟色胺转运体（SERT）和/或涉及多巴胺D2受体信号系统的疾病中的使用方法。
• Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders
  作者：Peng Li、Qiang Zhang、Albert J. Robichaud、Taekyu Lee、John Tomesch、Wei Yao、J. David Beard、Gretchen L. Snyder、Hongwen Zhu、Youyi Peng、Joseph P. Hendrick、Kimberly E. Vanover、Robert E. Davis、Sharon Mates、Lawrence P. Wennogle

  DOI：10.1021/jm401958n

  日期：2014.3.27

  We report the synthesis and structure–activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT2A and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which

  我们报告了一类四环丁苯酮的合成与结构-活性关系，这些四环丁酮显示了对5-羟色胺5-HT 2A和多巴胺D 2受体的强结合亲和力。这项工作导致了4-（（6b R，10a S）-3-methyl-2,3,6b，9,10,10 a -hexahydro -1 H，7 H -pyrido [3'，4 ′：4,5]吡咯并[1,2,3- de ]喹喔啉-8-基）-1-（4-氟苯基）-丁-1-酮4-甲基苯磺酸盐（ITI-007），其有效值为5 -HT 2A拮抗剂，突触后D 2素和5-羟色胺转运蛋白的抑制剂。该多功能候选药物具有口服生物利用度，并且在体内表现出良好的抗精神病功效。目前，这种正在研究中的新药正在临床开发中，用于治疗神经精神疾病和神经疾病。
• [EN] NOVEL SALTS AND CRYSTALS<br/>[FR] NOUVEAUX SELS ET CRISTAUX
  申请人：INTRA-CELLULAR THERAPIES INC

  公开号：WO2017172784A1

  公开（公告）日：2017-10-05

  The disclosure provides new, stable, pharmaceutically acceptable salt forms of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.

  该披露提供了1-(4-氟苯基)-4-((6bR,10aS)-3-甲基-2,3,6b,9,10,10a-六氢-1H,7H-吡啶[3',4':4,5]吡咯[1,2,3-de]喹喔杂环8-基)-丁酮的新型、稳定、药用可接受的盐形式，以及制备和使用它们的方法，以及包含它们的药物组合物。
• [EN] METHOD FOR THE MANUFACTURE OF LUMATEPERONE AND ITS SALTS<br/>[FR] PROCÉDÉ POUR LA FABRICATION DE LUMATÉPÉRONE ET DE SES SELS
  申请人：EGYT GYOGYSZERVEGYESZETI GYAR

  公开号：WO2019102240A1

  公开（公告）日：2019-05-31

  Method for the production of formula (I) lumateperone or its acid addition salts so that the enantiomer compound with stereochemistry 6bR, 10aS is separated form the cis racemate using resolution and the formula (II) stereoisomer is alkylated with 4-halo-4'-fluoro butyrophenone (X = I, Br, CI) to produce the formula (I) lumateperone, or optionally its acid addition salt. The object of the invention also relates to the amorphous form of the morphologically uniform p-toluenesulfonic acid salt of lumateperone and to the naphthalene-2-sulfonic acid salt of lumateperone, to the 1 :2 stoichiometry salt of lumateperone formed with naphthalene-2-sulfonic acid.

  生产配方（I）卢马特贝隆或其酸盐的方法，以便通过分辨法将立体化学为6bR，10aS的对映异构体与顺式混合物分离，使用配方（II）立体异构体与4-卤代-4'-氟丁酮苯（X = I，Br，Cl）烷基化，制备配方（I）卢马特贝隆，或可选择其酸盐。本发明的目的还涉及卢马特贝隆形态上均匀的对甲苯磺酸盐和卢马特贝隆的萘-2-磺酸盐，以及与萘-2-磺酸形成的1：2化学计量比的卢马特贝隆盐。