(z)-(9ci)-2-[(羟基亚氨基)甲基]-1-甲基-吡啶(盐) | 6735-59-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: (z)-(9ci)-2-[(羟基亚氨基)甲基]-1-甲基-吡啶(盐)
• 英文名称: pralidoxime
• 英文别名: Pralidoxime cation, (Z)-；(NZ)-N-[(1-methylpyridin-1-ium-2-yl)methylidene]hydroxylamine
• CAS: 6735-59-7；45765-69-3
• 化学式: C₇H₉N₂O
• 分子量: 137.161
• InChiKey: JBKPUQTUERUYQE-UHFFFAOYSA-O

物化性质

• 物理描述：
  Solid
• 熔点：
  215-225°C
• 溶解度：
  In water, 1.0X10+6 mg/L at 25 °C (est)
• 蒸汽压力：
  6.74X10-4 mm Hg at 25 °C (est)
• 稳定性/保质期：

  No evidence of significant degradation products appears up to 48 hr after pralidoxime autoinjector discharge. Concentration without degradation of the solution was noted over time when the autoinjector needle caused coring of the vial closure ... Mark-1 autoinjectors are not suitable for administering pralidoxime to small children. However, the autoinjectors are a readily available source of concentrated pralidoxime for administering weight-adjusted doses in small children. The pralidoxime solution obtained in this manner remains chemically intact for at least 48 hr.

• 解离常数：
  pKa = 5.78 (pyridine) (est)
• 亨利常数：
  Henry's Law constant = 9.98X10-15 atm-cu m/mol at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  36.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

尽管普瑞洛酶的确切代谢命运尚未完全阐明，但人们认为这种药物是在肝脏中代谢的。最近的一项研究表明，积极的管状分泌可能参与其中，尽管具体的机制尚未确定。

Although the exact metabolic fate of pralidoxime has not been completely elucidated, the drug is believed to be metabolized in the liver. ... A recent study has suggested that active tubular secretion may be involved, although the specific mechanism has not been identified.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究评估了急性肾功能衰竭对大鼠模型中氯磷定动力学的影响，该模型通过注射重铬酸钾诱导。在第一天，斯普拉格-道利大鼠皮下注射重铬酸钾（研究组）或生理盐水（对照组）。注射后48小时，动物肌肉注射氯磷定甲磺酸盐（以氯磷定碱计50毫克/千克）。在注射后180分钟内采集血液样本。在研究的3天内，每天收集尿液。血浆中氯磷定的浓度通过液相色谱与电化学检测法测量。与对照组相比，研究组的平均消除半衰期增加了2倍，平均药时曲线下面积增加了2.5倍。与对照组相比，研究组的平均总清除率减少了一半。我们的研究表明，急性肾功能衰竭不会改变氯磷定的分布，但会显著改变其从血浆中的消除。这些结果提示，在使用高剂量氯磷定方案治疗有机磷酸酯中毒的人类患者时，应调整氯磷定的剂量。

There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague-Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received pralidoxime methylsulfate (50 mg/kg of pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of pralidoxime.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：普拉立多辛是一种解毒剂和胆碱酯酶复活剂，用于治疗由于具有抗胆碱酯酶活性的杀虫剂和化学物质引起的中毒。它还用于治疗用于治疗重症肌无力的抗胆碱酯酶药物的过量。氯化普拉立多辛与阿托品联合使用，用于治疗化学战或恐怖主义背景下的神经毒剂中毒。氯化普拉立多辛必须在接触神经毒剂后几分钟到几小时内给药才能有效。人体研究：正常受试者中过量的表现包括头晕、视力模糊、复视、头痛、调节障碍、恶心和轻微的心率加快。在治疗中，很难区分是药物引起的副作用还是毒物引起的效应。当阿托品和氯化普拉立多辛一起使用时，阿托品化的迹象（潮红、瞳孔扩大、心率加快、口鼻干燥）可能比单独使用阿托品时预期的要早出现。动物研究：普拉立多辛用于治疗有机磷中毒，在开胸麻醉的狗中，所有剂量的普拉立多辛都显著增加了心脏输出量。在α-肾上腺素能阻断的动物中也得到了类似的反应，但在β-肾上腺素能阻断或使用利血平治疗的动物中则没有。普拉立多辛的所有剂量在对照组、β-肾上腺素能阻断和α-肾上腺素能阻断的动物中显著增加了平均动脉压。20和40 mg/kg的普拉立多辛在利血平处理的动物中也增加了动脉压。除了α-肾上腺素能阻断的动物外，所有动物在使用普拉立多辛时心率都降低。β阻断的动物的总外周阻力随着普拉立多辛每一剂量的增加而增加，尽管在对照组中没有观察到显著的增加。在利血平处理的和α-肾上腺素能阻断的动物中，总外周阻力的增加较小。所有动物的心搏出量和心搏功的变化都显著增加，每种变化都发生在不同的心房压力下，取决于治疗。结果表明，普拉立多辛直接刺激心脏和血管平滑肌。在高剂量时，狗的普拉立多辛会引起与其自身抗胆碱酯酶活性相关的体征。狗的临床毒性症状可能表现为肌肉无力、共济失调、呕吐、过度换气、癫痫、呼吸暂停和死亡。

IDENTIFICATION AND USE: Pralidoxime is an antidote and cholinesterase reactivator used in the treatment of poisoning due to pesticides and chemicals which have anticholinesterase activity. It is also used to treatment overdoses by anticholinesterase drugs used in the treatment of myasthenia gravis. Pralidoxime chloride is used concomitantly with atropine for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism. Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective. HUMAN STUDIES: Manifestations of overdosage in normal subjects include dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and slight tachycardia. In therapy, it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison. When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. ANIMAL STUDIES: Pralidoxime, used in the treatment of organophosphate poisoning, significantly increased cardiac output at all doses in open chest anesthetized dogs. A similar response was obtained in alpha-adrenergic blocked animals, but not with beta-adrenergic blocked or reserpine treated animals. All doses of pralidoxime significantly increased mean arterial pressure in control, beta-adrenergic blocked, and alpha-adrenergic blocked animals. Pralidoxime at 20 and 40 mg/kg also increased arterial pressure in reserpine treated animals. Heart rate was decreased in all but the alpha-adrenergic blocked animals with pralidoxime. The total peripheral resistance of the beta-blocked animals increased with every subsequent dose of pralidoxime although no significant increase was observed in controls. A smaller increase in total peripheral resistance was observed in reserpine-treated and alpha-adrenergic blocked animals. Significant increases in stroke volume and changes in stroke work were noted with all animals, each occurring at different atrial pressures depending on the treatment. The results suggest that pralidoxime directly stimulates the heart and vascular smooth muscle. Pralidoxime in dogs at high dosages, causes signs associated with its own anticholinesterase activity. Clinical signs of toxicity in dogs may be exhibited as muscle weakness, ataxia, vomiting, hyperventilation, seizures, respiratory arrest, and death.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物的名称:普拉立多姆

Compound:pralidoxime

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

药物在尿液中迅速排泄，部分未改变，部分作为肝脏产生的代谢物。

The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver.

来源:DrugBank

吸收、分配和排泄

尚不清楚肟吡啶是否穿过人类胎盘到达胚胎或胎儿。氯解磷定是一种季铵化合物，但自由碱基的分子量（约137）足够低，可以穿过胎盘。该药物的快速消除应该减轻这种转移。

It is not known if pralidoxime crosses the human placenta to the embryo or fetus. Pralidoxime chloride is a quaternary ammonium compound, but the molecular weight of the free base (about 137) is low enough for passage across the placenta. The rapid elimination of the drug should mitigate this transfer.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

肾脏小管如何处理普拉立多克斯姆（一种用于重新激活被有机磷抑制的胆碱酯酶的季铵化合物）的具体机制，已经通过对22名受试者的研究得到了探讨。在研究过程中，每个受试者都被置于特定的条件下。所有22名受试者在强制水合和卧床休息的条件下作为对照组接受了普拉立多克斯姆（5 mg/kg，静脉注射，2分钟内）。8名受试者在强制水合和卧床休息的条件下，一次在氯化铵酸化36小时后，另一次在碳酸氢钠碱化后接受了普拉立多克斯姆。9名受试者在强制脱水和卧床休息的条件下，在注射有机碱硫胺素（总共200毫克，肌肉注射）20-30分钟后接受了普拉立多克斯姆。8名受试者在强制水合和卧床休息的同时，注射了有机酸对氨基马尿酸（总共900毫克，静脉注射）后接受了普拉立多克斯姆。4名受试者在禁食8-12小时后，卧床休息条件下接受了普拉立多克斯姆。该药物通过肾脏小管分泌从血浆中迅速清除。与对氨基马尿酸给药后相比，注射硫胺素后普拉立多克斯姆的清除率降低和生物半衰期延长，表明普拉立多克斯姆作为有机碱被分泌。在尿液碱化和尿液酸化的条件下普拉立多克斯姆的排泄减少，表明普拉立多克斯姆存在一种此前未描述的主动重吸收。

The specific mechanism by which the renal tubule handles pralidoxime, a quaternary ammonium compound used to reactivate organophosphate-inhibited cholinesterase, has been studied using 22 subjects. Each subject was placed under certain conditions in the course of the study. All 22 received pralidoxime (5 mg/kg, IV, over a 2-min interval) under conditions of forced hydration and bed rest to serve as controls. Eight subjects received pralidoxime under conditions of forced hydration and bed rest, one time after 36 hr of ammonium chloride acidification, and another time after sodium bicarbonate alkalinization. Nine subjects received pralidoxime under forced dehydration and bed rest, 20-30 min after thiamine (200 mg total, IM), organic base. Eight received pralidoxime under forced hydration and bed rest simultaneously with p-aminohippurate (900 mg total, IV), organic acid. Four received pralidoxime under bed rest, after 8-12 hr of fasting, NPO. The drug is rapidly cleared from the plasma by renal tubular secretion. Reduction of pralidoxime clearance rates and prolongation of the biologic half-life after thiamine administration as compared to those after PAH administration suggest that pralidoxime is secreted as an organic base. Reduction of the excretion of pralidoxime under conditions of both urine alkalinization and urine acidification implicates an active reabsorption of pralidoxime not heretofore described.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氯化普立多克斯（2-PAM）在大鼠体内的药代动力学进行了研究。不同组的大鼠接受了三种剂量（20、40或80 mg/kg）之一的2-PAM肌肉注射。这个剂量范围通常用于研究2-PAM对强效有机磷胆碱酯酶抑制剂中毒的疗效。在实验过程中收集了个体连续的血样。从这些血样中确定了每个动物随时间变化的2-PAM血浆浓度。接下来，血浆浓度与时间的关系用标准药代动力学模型表示。使用开放一室模型计算了各种药代动力学参数的估计值：分布体积（Vd）、最大血浆浓度（Cmax）、消除速率常数（k10）、吸收速率常数（k01）、曲线下面积（AUC）和清除率（CL）。在比较所有剂量的药代动力学估计值时，只有Cmax和AUC被发现具有统计学意义（p小于0.0001）；这些药代动力学估计值与剂量高度相关，相关系数分别为r = 0.998和r = 0.997。然而，当AUC和Cmax通过除以剂量进行归一化时，转化数据中没有发现显著差异。这项在大鼠中的研究结果表明，2-PAM的药代动力学与在治疗研究中使用的剂量范围内呈线性关系。

The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

背景：目前治疗有机磷中毒的方法涉及使用拟除虫菊酯类药物，如普拉立多（2-PAM），来重新激活乙酰胆碱酯酶。动物模型的研究表明，系统性注射后大脑中的浓度较低。 方法：为了评估2-PAM的传输，我们研究了三种Madin-Darby犬肾（MDCKII）细胞系和干细胞来源的人脑微血管内皮细胞（BC1-hBMECs）的跨孔渗透性。为了确定2-PAM是否为常见大脑外排泵的底物，我们在MDCKII-MDR1细胞系中进行了实验，该细胞系过表达了P-糖蛋白外排泵，以及MDCKII-FLuc-ABCG2细胞系，该细胞系过表达了BCRP外排泵。为了确定跨细胞传输如何影响酶的重新激活，我们开发了一种改良的跨孔分析，其中将抑制的乙酰胆碱酯酶酶、底物和报告器引入基底侧室。使用对氧磷和巴拉硫磷抑制酶活性。 结果：2-PAM在MDCK细胞中的渗透性约为2 x 10(-6) cm/s，在BC1-hBMECs中约为1 x 10(-6) cm/s。渗透性不受阿托品预处理的 影响。此外，2-PAM不是P-糖蛋白或BCRP外排泵的底物。 结论：较低的渗透性解释了2-PAM在大脑中渗透不足，因此酶的重新激活速度缓慢。这阐明了在有机磷中毒反应中进行持续静脉（IV）输注的必要性之一。

BACKGROUND: Current therapies for organophosphate poisoning involve administration of oximes, such as pralidoxime (2-PAM), that reactivate the enzyme acetylcholinesterase. Studies in animal models have shown a low concentration in the brain following systemic injection. METHODS: To assess 2-PAM transport, we studied transwell permeability in three Madin-Darby canine kidney (MDCKII) cell lines and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs). To determine whether 2-PAM is a substrate for common brain efflux pumps, experiments were performed in the MDCKII-MDR1 cell line, transfected to overexpress the P-gp efflux pump, and the MDCKII-FLuc-ABCG2 cell line, transfected to overexpress the BCRP efflux pump. To determine how transcellular transport influences enzyme reactivation, we developed a modified transwell assay where the inhibited acetylcholinesterase enzyme, substrate, and reporter are introduced into the basolateral chamber. Enzymatic activity was inhibited using paraoxon and parathion. RESULTS: The permeability of 2-PAM is about 2 x 10(-6) cm/s in MDCK cells and about 1 x 10(-6) cm/s in BC1-hBMECs. Permeability is not influenced by pre-treatment with atropine. In addition, 2-PAM is not a substrate for the P-gp or BCRP efflux pumps. CONCLUSIONS: The low permeability explains poor brain penetration of 2-PAM and therefore the slow enzyme reactivation. This elucidates one of the reasons for the necessity of sustained intravascular (IV) infusion in response to organophosphate poisoning.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (z)-(9ci)-2-[(羟基亚氨基)甲基]-1-甲基-吡啶(盐) 、 diethylphosphoryl-human serum butyrylcholinesterase conjugate 生成 diethyl [(1-methylpyridin-1-ium-2-yl)methylideneamino] phosphate 、 human serum butyrylcholinesterase
  参考文献：
  名称：

  摘要：

  DOI：

文献信息

• CARBALDEHYDE OXIMES AS BUTYRYLCHOLINESTERASE REACTIVATORS
  申请人：Etat Français représenté par la Direction Centrale Du Service de Santé des Armées

  公开号：EP3945092A1

  公开（公告）日：2022-02-02

  The present invention relates to compounds for their use in the reactivation of butyrylcholinesterase. Such compounds are useful in the treatment or prevention of the intoxication with at least one organophosphorus nerve agent. The invention also relates to pharmaceutical compositions and kits comprising said compounds, and compounds per se.

  本发明涉及化合物，用于重新激活丁酰胆碱酯酶。这些化合物在治疗或预防至少一种有机磷神经毒剂中毒方面是有用的。该发明还涉及包含所述化合物的药物组合物和试剂盒，以及化合物本身。
• MULTIFUNCTIONAL SMALL MOLECULES
  申请人：The Regents of the University of Michigan

  公开号：US20150216993A1

  公开（公告）日：2015-08-06

  The present invention relates to novel therapeutic dendrimer conjugates configured for the treatment and/or prevention of organophosphate poisoning. In particular, the present invention is directed to dendrimers complexed with organophosphate poisoning antidotes (e.g., pralidoxime (2-PAM) (4-PAM), obidoxime, trimedoxime, asoxime (HI-6), hydroxamate, and related analogs, salts and derivatives thereof), compositions comprising such dendrimer conjugates, related methods of synthesizing such dendrimer conjugates, as well as systems and methods utilizing such dendrimer conjugates (e.g., in diagnostic and/or therapeutic settings (e.g., for the delivery of therapeutics, imaging, and/or targeting agents (e.g., in the treatment and/or prevention of organophosphate poisoning)).

  本发明涉及用于治疗和/或预防有机磷酸盐中毒的新型治疗性树状大分子偶联物。特别是，本发明涉及与有机磷酸盐中毒解毒剂（例如，普瑞洛霉素（2-PAM）（4-PAM），奥比多西姆，三甲多西姆，阿索西姆（HI-6），羟基酰胺以及相关的类似物，盐和衍生物）复合的树状大分子，包含这样的树状大分子偶联物的组合物，合成这样的树状大分子偶联物的方法，以及利用这样的树状大分子偶联物（例如，在诊断和/或治疗环境中（例如，用于治疗剂，成像和/或靶向剂（例如，在治疗和/或预防有机磷酸盐中毒）的递送））的系统和方法。
• [EN] BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS<br/>[FR] PRO-FRAGMENTS BIORÉVERSIBLES POUR MÉDICAMENTS CONTENANT DE L'AZOTE ET DE L'HYDROXYLE
  申请人：BAIKANG SUZHOU CO LTD

  公开号：WO2015081891A1

  公开（公告）日：2015-06-11

  Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.

  披露了以下公式的促销性质，它们可用于形成含有氮或羟基的药物或药物活性剂的的前药：(I)以及包含这些前药的药物组合物。
• [EN] CATALYTIC SCAVENGERS OF ORGANOPHOSPHATES TO POTENTIATE BUTYRYLCHOLINESTERASE (BCHE) AS A CATALYTIC BIOSCAVENGER AND METHODS FOR MAKING AND USING THEM<br/>[FR] PIÉGEURS CATALYTIQUES D'ORGANOPHOSPHATES POUR POTENTIALISER LA BUTYRYLCHOLINESTÉRASE (HBCHE)
  申请人：UNIV CALIFORNIA

  公开号：WO2015057822A1

  公开（公告）日：2015-04-23

  Provided are N-alkyl imidazole 2-aldoximes, including cationic imidazolium and uncharged tertiary imidazole aldoximes, and compositions and methods for making and using them, including methods for reactivating human butyrylcholinesterase (hBChE) or acetylcholinesterase (hAChE ) inhibited by organophosphate (OP). By administration of a composition of the invention, the inactive or conjugated hBChE-OP or hAChE-OP is reactivated and the catalytic cycle of turnover and inactivation of the OP is completed; and in alternative embodiments, secondary mechanisms of reversible protection of hBChE and hAChE from irreversible inactivation by OPs and reactivation of tissue AChE also contribute to overall efficacy.

  提供了N-烷基咪唑-2-醛肟，包括阳离子咪唑盐和不带电的三级咪唑醛肟，以及制备和使用它们的组合物和方法，包括重新激活被有机磷酸酯（OP）抑制的人丁酰胆碱酯酶（hBChE）或乙酰胆碱酯酶（hAChE）的方法。通过给予本发明的组合物，不活性或结合的hBChE-OP或hAChE-OP被重新激活，完成了OP的催化周转和失活循环；在替代实施方案中，可逆保护hBChE和hAChE免受OP不可逆失活的次要机制以及再激活组织AChE也有助于整体功效。
• [EN] BENZODIAZEPINE DERIVATIVES, COMPOSITIONS, AND METHODS FOR TREATING COGNITIVE IMPAIRMENT<br/>[FR] DÉRIVÉS DE BENZODIAZÉPINE, COMPOSITIONS ET MÉTHODES DE TRAITEMENT DE LA DÉFICIENCE COGNITIVE
  申请人：MEKONNEN BELEW

  公开号：WO2016205739A1

  公开（公告）日：2016-12-22

  This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of a α5- containing GABAA receptor agonist (e.g., a α5-containing GABAA receptor positive allosteric modulator) as described herein in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age- Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer' s Disease(AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson' s disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction.

  这项发明涉及苯二氮卓啉衍生物，包括含有这些苯二氮卓啉衍生物的治疗有效量的组合物，以及使用这些衍生物或组合物治疗与中枢神经系统（CNS）疾病相关的认知障碍的方法。具体而言，它涉及在需要或有风险的受试者中治疗与中枢神经系统（CNS）疾病相关的认知障碍，包括但不限于具有或有风险患上与年龄相关的认知障碍、轻度认知障碍（MCI）、遗忘性MCI（aMCI）、年龄相关记忆障碍（AAMI）、年龄相关认知衰退（ARCD）、痴呆症、阿尔茨海默病（AD）、前驱期AD、创伤后应激障碍（PTSD）、精神分裂症、躁郁症、肌萎缩侧索硬化（ALS）、癌症治疗相关认知障碍、智力障碍、帕金森病（PD）、自闭症谱系障碍、脆性X综合症、雷特综合症、强迫行为和物质成瘾。

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