非氨酯 | 25451-15-4

• 物质功能分类: 原料药 - 神经系统用药 - 抗癫痫及抗惊厥药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 非氨酯
• 中文别名: 非吧吗特；非尔氨酯；2-苯基-1,3-丙二醇二氨基甲酸酯；非巴马特
• 英文名称: felbamate
• 英文别名: 2-phenyl-1,3-propanediol dicarbamate；(3-carbamoyloxy-2-phenylpropyl) carbamate；1,3-bis-carbamoyloxy-2-phenyl-propane；1,3-Bis-carbamoyloxy-2-phenyl-propan；2-phenylpropane-1,3-diyl dicarbamate
• CAS: 25451-15-4
• 化学式: C₁₁H₁₄N₂O₄
• mdl: MFCD00865296
• 分子量: 238.243
• InChiKey: WKGXYQFOCVYPAC-UHFFFAOYSA-N

物化性质

• 熔点：
  148-1500C
• 沸点：
  511.9±50.0 °C(Predicted)
• 密度：
  1.275±0.06 g/cm3(Predicted)
• 闪点：
  9℃
• 溶解度：
  酒精：可溶
• 物理描述：
  Solid
• 颜色/状态：
  White powder
• 气味：
  Odorless
• 蒸汽压力：
  1.6X10-5 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic vapors of /nitrogen oxides/.
• 保留指数：
  2157

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.272
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

生物转化主要发生在肝脏，可能通过细胞色素P-450系统；主要是通过羟基化和与代谢物结合，这些代谢物既不具有药理活性也不具有神经毒性。

/Biotransformation is/ hepatic, probably by the cytochrome P-450 system; primarily by hydroxylation and conjugation to metabolites that are neither pharmacologically active nor neurotoxic.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大约40-50%的吸收剂量以不变的形式出现在尿液中，另外40%以未识别的代谢物和结合物形式存在。大约15%以对羟基苯甲酸、2-羟基苯甲酸和苯甲酸单碳酰胺的形式存在，这些物质均不具有显著的抗惊厥活性。

About 40-50% of absorbed dose appears in unchanged in urine, an additional 40% is present as unidentified metabolites and conjugates. About 15% is present parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) 是一种被批准的抗癫痫药物，对其他治疗方法无效的多种癫痫障碍显示出有效性。然而，由于与其罕见发生的再生障碍性贫血和肝功能衰竭有关联，其使用受到了限制。由于已经证明FBM的代谢需要谷胱甘肽（GSH），我们使用了两种实验方案来确定特定代谢物对氧化还原途径的敏感性。在0.1 mg/mL的浓度下，FBM及其代谢物W873（2-phenyl-1,3-propanediol monocarbamate）与B10.BR小鼠相比，诱导了B10.AKM小鼠骨髓细胞的凋亡增加。研究该药物对人类前单核细胞系U937细胞的影响表明，在较高浓度（0.5 mg/mL）下，FBM和代谢物W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate]诱导了该细胞系的凋亡。我们还观察到，虽然FBM及其代谢物诱导了内源性GSH水平降低的B细胞凋亡增加，但添加外源性GSH减少了W873诱导的凋亡，而FBM或W2986诱导的凋亡没有显著影响。作者的结果表明，在目前调查中使用的浓度下，FBM代谢物通过氧化还原敏感和氧化还原独立途径诱导凋亡。

Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug shown to be effective in a variety of seizure disorders refractory to other treatments. However, its use has been restricted because of association with occurrence of rare cases of aplastic anemia and hepatic failure. Since it was shown that FBM metabolism requires glutathione (GSH), we used two experimental protocols to determine if the effects of specific metabolites were sensitive to redox pathways. FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate), at 0.1 mg/mL, induced increased apoptosis of bone marrow cells from B10.AKM mice as compared with B10.BR mice. Study of the effects of the drug on human promonocytic cell line U937 cells showed that FBM and the metabolite W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate], at higher concentrations (0.5 mg/mL), induced apoptosis in this cell line. We also observed that while FBM and its metabolites induced increased apoptosis of B cells with reduced intracellular GSH levels, addition of exogenous GSH decreased apoptosis induced by W873 but did not significantly affect apoptosis induced by FBM or W2986. /The authors/ results suggest that, at concentrations used during the present investigations, FBM metabolites induce apoptosis via redox-sensitive and redox-independent pathways.

来源:Hazardous Substances Data Bank (HSDB)

代谢

抗癫痫药物felbamate（FBM）的广泛使用受到了限制，因为与其使用相关的肝脏毒性和再生障碍性贫血的报告。有人提出，FBM的生物激活形成α,β-不饱和醛，atropaldehyde（ATPAL）可能是与母药相关的毒性的原因。这类化合物中的其他成员，丙烯醛和4-羟基壬醛（HNE），以其反应性和毒性而闻名。已经提出，FBM到ATPAL的生物激活是通过一个更稳定的环化产物，4-羟基-5-苯基四氢-1,3-恶嗪-2-酮（CCMF）进行的，其形成最近已经被证实。乙醛脱氢酶（ALDH）和谷胱甘肽转移酶（GST）是解毒酶和反应性醛类的靶点。本研究检查了ATPAL及其前体CCMF对ALDH、GST和细胞活力的影响，以及它们在肝脏中的代谢和毒性。已知毒素HNE，也是ALDH和GST的底物，用于比较。FBM的种间代谢差异已有详细记录，因此，人组织被认为是最相关的，并用于这些研究。ATPAL抑制了ALDH和GST的活性，并导致肝细胞活力的丧失。需要几倍于ATPAL的CCMF浓度才能观察到类似的ALDH抑制或细胞毒性。这与CCMF需要先转化为更接近毒素的ATPAL一致。已经证明GSH可以保护ALDH免受ATPAL的抑制。在这种情况下，ALDH和GST是解毒途径，它们的抑制会导致FBM代谢或其他内源性和外源性化合物的代谢产生的反应性物质的积累，并导致或倾向于毒性。因此，反应性醛类毒性的机制可能包括与关键细胞大分子的直接相互作用或间接干扰细胞的解毒机制。

Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia associated with its use. It was proposed that a bioactivation of FBM leading to formation of alpha,beta-unsaturated aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities associated with the parent drug. Other members of this class of compounds, acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examined effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metabolism and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metabolism of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concentrations of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as observed with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metabolism and/or metabolism of other endogenous or exogenous compounds and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with critical cellular macromolecules or indirect interference with cellular detoxification mechanisms.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

felbamate发挥其抗惊厥活性的机制尚不清楚，但在旨在检测抗惊厥活性的动物测试系统中，felbamate具有与其他市场上抗惊厥药物共同的特性。体外受体结合研究建议felbamate可能是N-甲基-D-天门冬氨酸（NMDA）受体-离子通道复合物中strychnine不敏感的甘氨酸识别位点的拮抗剂。拮抗NMDA受体的甘氨酸结合位点可能阻止兴奋性氨基酸的效果并抑制癫痫活动。动物研究表明，felbamate可能增加癫痫阈值并可能减少癫痫扩散。还表明felbamate对GABA受体结合、苯二氮卓受体结合有微弱的抑制作用。

The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. <i>In vitro</i> receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，慢性felbamate治疗并未伴随血清转氨酶水平的显著升高。尽管如此，felbamate引起的临床明显肝毒性已有详细描述，虽然不常见，估计在每18,500到25,000次暴露中发生一次，通常结果严重。损伤发生的时间是在开始治疗后的1到6个月，酶升高的模式通常是肝细胞型的。在对其使用实施严格限制之前，已有超过十几例急性肝衰竭和死亡归因于felbamate。Felbamate并未与抗惊厥药物超敏反应综合征相关联，并且可能是对其他抗惊厥药物产生该综合征的人的一种潜在替代疗法。

Prospective studies suggest that chronic felbamate therapy is not accompanied by significant elevations in serum aminotransferase levels. Nevertheless, clinically apparent hepatotoxicity from felbamate is well described, although uncommon, estimated to occur in 1 in 18,500 to 25,000 exposures, often with severe outcome. The onset of injury is 1 to 6 months after starting therapy and the pattern of enzyme elevations is typically hepatocellular. More than a dozen instances of acute liver failure and death were attributed to felbamate before severe restrictions were placed upon its use. Felbamate has not been associated with anticonvulsant hypersensitivity syndrome and is a potential alternative for persons who have developed that syndrome from other anticonvulsants.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：Felbamate（芬巴胺）

Compound:felbamate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

大于90%

>90%

来源:DrugBank

吸收、分配和排泄

• 分布容积

756±82 毫升/千克

756±82 mL/kg

来源:DrugBank

吸收、分配和排泄

• 清除

26 ± 3 毫升/小时/千克 [单次 1200 毫克剂量]

26 +/- 3 mL/hr/kg [single 1200 mg dose]

来源:DrugBank

吸收、分配和排泄

吸收是完全的（>90%）。食物不影响吸收，并且片剂和悬浮液的剂型表现出相似的动力学特性。

/Absorption is/ complete (>90%). Absorption is unaffected by food, and both tablet and suspension dosage forms exhibit similar kinetics.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Felbamate 进入中枢神经系统（CNS），脑/血浆系数大约为0.9。在单次和多次剂量研究中，表观分布容积（Vol D）范围为0.73至0.85升/每公斤体重（L/kg）。

Felbamate enters the central nervous system (CNS), with a brain/plasma coefficient of approximately 0.9. The apparent volume of distribution (Vol D) ranged from 0.73 to 0.85 L per kg of body weight (L/kg) in single and multiple dose studies.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  2
• 海关编码：
  2924299090
• RTECS号：
  TZ1070000
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存储于室温下

制备方法与用途

生物活性

Felbamate（Felbatol, ADD-03055）是一种抗惊厥药，主要用于治疗癫痫，并且是NMDAR拮抗剂。

靶点

Target	Value
NMDAR	1.8 mM

化学性质

Felbamate 是一种白色粉末，无气味。熔点为151～152℃。它易溶于二甲亚砜、1-甲醇-2-吡咯烷酮或二甲基甲酰胺，并且微溶于甲醇、乙醇、丙酮、氯仿或水。

用途

Felbamate 是一种新型抗癫痫药，与传统抗癫痫药物相比，它没有镇静、抑郁、敌对行为、体重增加和认知能力减弱等副作用。它可以作为单一治疗或附加治疗用于14岁及以上患者的部分性癫痫发作的起始阶段；在儿童中，则可以用来治疗由于类小发作引起的部分性发作或全身性发作。

用途

Felbamate 主要用作抗癫痫药物。

生产方法

Felbamate 的制备涉及以下步骤：首先，50克2-苯基丙二酸二乙酯（I）在500毫升无水乙醚中使用12克氢化铝锂进行还原，得到23克2-苯基-1,3-丙二醇（II）和31克N,N-二甲基苯胺。将该混合物溶于100毫升甲苯中，在-10℃下加入光气（在150毫升无水甲苯中的溶液），并在-5至-5℃条件下维持反应20分钟，之后用5%盐酸洗涤并用无水硫酸钠干燥。然后通入氨气至饱和，并加热至回流。经过过滤后得到非尔氨酯。

反应信息

• 作为产物：
  描述：

  2-fluoro-2-phenyl-1,3-propanediol 以82%的产率得到非氨酯
  参考文献：
  名称：

  Felbamate derived compounds

  摘要：

  本发明涉及新型费巴酯衍生物及其用于治疗癫痫等神经系统疾病和治疗因缺血事件导致的组织损伤的用途。费巴酯衍生物经过改良，以防止形成被认为与费巴酯疗法相关的毒性代谢物。

  公开号：

  US20020156070A1

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• 4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
  申请人：Dunn Robert

  公开号：US20080318941A1

  公开（公告）日：2008-12-25

  The present disclosure provides compounds having affinity for the 5-HT 6 receptor which are of the formula (I): wherein R 1 , R 2 , R 5 , R 6 , B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

  本公开提供了具有亲和力的化合物，其对5-HT 6 受体具有亲和力，其化学式为（I）： 其中R1、R2、R5、R6、B、D、E、G、Q、x和n如本文所定义。本公开还涉及制备这种化合物的方法、含有这种化合物的组合物以及使用这些化合物的方法。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
  申请人：ARENA PHARM INC

  公开号：WO2009128907A1

  公开（公告）日：2009-10-22

  Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.

  根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
• [EN] SUBSTITUTED PIPERIDINE COMPOUND AND USE THEREOF<br/>[FR] COMPOSÉ DE PIPÉRIDINE SUBSTITUÉE ET SON UTILISATION
  申请人：TAKEDA PHARMACEUTICALS CO

  公开号：WO2017135306A1

  公开（公告）日：2017-08-10

  Provided is a substituted piperidine compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as a prophylactic or therapeutic agent for narcolepsy.

  提供的是一种替代哌啶化合物，具有促进俐克脑肽2型受体激动剂活性。公式（I）所代表的化合物：其中每个符号如描述中所述，或其盐具有促进俐克脑肽2型受体激动剂活性，并且可用作嗜睡症的预防或治疗药物。

表征谱图