噻加宾 - CAS号 115103-54-3

物化性质

熔点：

192oC dec.
沸点：

568.0±50.0 °C(Predicted)
密度：

1.208±0.06 g/cm3(Predicted)
物理描述：

Solid
溶解度：

In water, 6.6X10-1 mg/L at 25 °C (est)
蒸汽压力：

7.2X10-14 mm Hg at 25 °C (est)
解离常数：

pKa1 = 3.56 (carboxylic acid); pKa2 = 9.49 (secondary amine) (est)
碰撞截面：

184.5 Å² [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
稳定性/保质期：

盐酸噻加宾(Tiagabine Hydrochloride)：C20H25NO2S2·HCl，[145820-59-6]。这是一种白色至类白色的结晶性粉末，无气味，熔点为192℃（分解），[α]D20 -11°，pKa1 3.3，pKa2 9.4，辛醇/水分配系数（pH值7.4）为39.3。在水中溶解度为3%，几乎不溶于己烷。

计算性质

辛醇/水分配系数(LogP)：

2.7
重原子数：

25
可旋转键数：

6
环数：

3.0
sp3杂化的碳原子比例：

0.45
拓扑面积：

97
氢给体数：

1
氢受体数：

5

ADMET

代谢

Tiagabine 很可能主要通过肝脏细胞色素 P450 的 3A 亚型同系物进行代谢。

Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450.

来源:DrugBank

代谢

尽管尚未完全阐明tiagabine的代谢途径，但体内和体外研究表明，在人体中已经确定了至少两种tiagabine的代谢途径：1）噻吩环氧化导致5-氧代-tiagabine的形成；2）葡萄糖苷酸化。5-氧代-tiagabine代谢物并不对tiagabine的药理活性产生影响。

Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

基于体外数据，tiagabine很可能主要通过肝脏细胞色素P450的3A亚型同系物（CYP 3A）进行代谢，尽管尚未排除CYP 1A2、CYP 2D6或CYP 2C19对tiagabine代谢的贡献。

Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP 3A), although contributions to the metabolism of tiagabine from CYP 1A2, CYP 2D6 or CYP 2C19 have not been excluded.

来源:Hazardous Substances Data Bank (HSDB)

代谢

替加滨主要通过肝脏细胞色素P450的3A亚型家族进行代谢。消除途径：口服剂量的替加滨大约有2%以原形排泄，剩余剂量的25%和63%分别通过尿液和粪便排出，主要是以代谢物的形式。半衰期：7-9小时。

Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450. Route of Elimination: Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites. Half Life: 7-9 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

毒性总结

尽管提加宾对人体产生作用的精确机制尚不清楚，但它似乎作为一种选择性GABA再摄取抑制剂发挥作用。

Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

肝毒性

关于替加滨对肝脏的毒性数据有限。在临床试验中，使用替加滨治疗并未增加血清转氨酶升高或肝脏毒性的发生率。目前尚未有关于替加滨导致肝脏损伤的个案报告发表，其使用也未曾与超敏反应综合征或自身免疫性疾病有关联。然而，替加滨的总使用量还是有限的。

Limited data are available on the hepatotoxicity of tiagabine. In clinical trials, therapy with tiagabine was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. No individual case reports of liver injury from tiagabine have been published and its use has not been associated with hypersensitivity syndromes or autoimmunity. However, its overall use has been limited.

来源:LiverTox

毒理性

药物性肝损伤

化合物：提加宾

Compound:tiagabine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

药物性肝损伤

DILI 注解：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

吸收、分配和排泄

吸收

Tiagabine几乎完全吸收（>95%）。

Tiagabine is nearly completely absorbed (>95%).

来源:DrugBank

吸收、分配和排泄

消除途径

大约2%的口服剂量以原形排泄，其余剂量中有25%和63%分别通过尿液和粪便排出，主要是以代谢产物的形式。

Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites.

来源:DrugBank

吸收、分配和排泄

清除

109毫升/分钟 [健康受试者]

109 mL/min [Healthy subjects]

来源:DrugBank

吸收、分配和排泄

吸收迅速，空腹状态下口服剂量后约45分钟达到血浆峰浓度。几乎完全吸收(>95%)，绝对口服生物利用度约为90%。高脂肪餐会减慢吸收速率（平均达峰时间延长至2.5小时，平均峰浓度降低约40%），但不会影响吸收程度（AUC）。

Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean T max was prolonged to 2.5 hours, and mean C max was reduced by about 40%) but not the extent (AUC) of tiagabine absorption.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在2至24毫克的单一剂量范围内，tiagabine的药代动力学呈线性。在多次给药后，2天内达到稳态。

The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

危险品标志：

Xi
危险类别码：

R36/37/38
WGK Germany：

3
安全说明：

S22,S26,S36/37,S37/39
储存条件：

-20℃

SDS

SDS：376a75eb0aa0351f24b37f9c7837b49b

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制备方法与用途

生物活性

Tiagabine（Gabitril, NO050328, NO328, TGB）是一种抗惊厥药物，作为GABA重吸收的抑制剂。

靶点

Target	Value
GABA reuptake

体外研究

Tiagabine在神经元细胞和胶质细胞中是GABA吸收的抑制剂。它参与调节GABA水平，特别是在海马和丘脑中。Tiagabine不仅影响IPSCs的衰减动力学，还减少自发的微型IPSCs出现频率。

体内研究

在沙鼠全脑缺血30分钟前处理以tiagabine（而不是全脑缺血发生3小时后），Tiagabine可以提供显著的神经保护作用。

化学性质

盐酸噻加宾(Tiagabine Hydrochloride)：C₂₀H₂₅NO₂S₂·HCl。[145820-59-6]。白色至类白色结晶性粉末，无臭。熔点192℃（分解）；[α]²₀D -11°。pKa₁ 3.3；pKa₂ 9.4。辛醇/水（pH值7.4）分配系数：39.3。水中溶解度：3%。几不溶于己烷。

用途

抗惊厥剂。为γ-氨基丁酸(GABA)吸收抑制剂，用于12岁以下儿童及成人的癫痫治疗维持用药。

生产方法

二(3-甲基-2-噻嗯基)甲酮(I)和环丙基镁溴化物反应，得到化合物(Ⅱ)。再在HBr作用下脱水开环，得到化合物(Ⅲ)。接着和3-哌啶酸乙酯(Ⅳ)进行酰胺化反应，生成物(V)水解得到产物。

上下游信息

上游原料

中文名称	英文名称	CAS号	化学式	分子量
噻加宾乙酯	ethyl (R)-1-<4,4-bis(3-methyl-2-thienyl)-3-butenyl>-3-piperidinecarboxylate	145821-58-5	C₂₂H₂₉NO₂S₂	403.61
——	1-(4,4-bis(3-methylthiophen-2-yl)but-3-en-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid	——	C₂₀H₂₃NO₂S₂	373.54
——	4,4-bis(3-methyl-2-thienyl)but-3-en-1-ol	847233-27-6	C₁₄H₁₆OS₂	264.412
2,2’-(4-溴-1-亚丁烯基)双[3-甲基噻吩]	4,4-bis(3-methyl-thiophen-2-yl)-but-3-en-1-yl bromide	109857-81-0	C₁₄H₁₅BrS₂	327.309
——	1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl methanesulfonate	847233-13-0	C₁₅H₁₈O₃S₃	342.504

反应信息

作为反应物：

描述：

噻加宾在氢溴酸作用下，以异丙醚、乙酸乙酯、乙腈为溶剂，以94%的产率得到tiagabine hydrobromide

参考文献：

名称：

Crystalline and amorphous forms of tiagabine

摘要：

本发明提供了24种新的替加巴嗪形式，包括22种新的替加巴嗪和其盐的晶体形式，替加巴嗪游离碱的非晶形式，以及替加巴嗪盐酸盐与2-呋喃羧酸的共晶形式。本发明还提供了制备每种新替加巴嗪形式的方法。本发明还提供了含有至少一种新替加巴嗪形式的药物组合物，以及其制备方法。本发明还提供了一种治疗与哺乳动物GABA摄取相关疾病的方法，包括向哺乳动物投与至少一种新替加巴嗪形式的治疗有效量。

公开号：

US20080051435A1
作为产物：

描述：

氢溴酸槟榔碱在 C₆₃H₇₈IrNOP⁽²⁺⁾*C₃₂H₁₂BF₂₄^(1-) 、水、氢气、 potassium carbonate 、 potassium iodide 、 sodium hydroxide 作用下，以甲醇、水、丙酮为溶剂， 20.0~60.0 ℃ 、607.99 kPa 条件下，反应 134.5h，生成噻加宾

参考文献：

名称：

铱催化不饱和杂环酸的对映选择性加氢

摘要：

螺旋结合：一种高度对映选择性的不饱和杂环羧酸的加氢已经通过使用手性铱/ spirophosphino恶唑啉催化剂开发（参见方案; BAR ˚F - =四[3,5-双（三氟甲基）苯基]硼酸盐，的Boc =叔丁氧羰基）。该反应提供了制备具有优异对映选择性的旋光杂环酸的有效方法。

DOI：

10.1002/anie.201301341

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文献信息

[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS [FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE

申请人：MERCK SHARP & DOHME

公开号：WO2016089721A1

公开（公告）日：2016-06-09

The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
[EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS [FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1

申请人：MERCK SHARP & DOHME

公开号：WO2011149801A1

公开（公告）日：2011-12-01

The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
[EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS [FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME

申请人：MERCK SHARP & DOHME

公开号：WO2013169567A1

公开（公告）日：2013-11-14

The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
[EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE [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] FUSED QUINOLINE DERIVATIVE AND USE THEREOF [FR] DÉRIVÉ DE QUINOLINE FUSIONNÉE ET UTILISATION DE CELUI-CI

申请人：TAKEDA PHARMACEUTICAL

公开号：WO2005105802A1

公开（公告）日：2005-11-10

The present invention aims at provision of a quinoline derivative having a neurokinin 2 (NK2) receptor antagonistic action and relates to a compound represented by the formula (I) wherein Rl is a hydrogen atom and the like; R2 is a hydrogen atom, a hydrocarbon group optionally having substituent(s) and the like; R3 is unsubstituted (i.e., absence), a hydrogen atom and the like; R4 and R5 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s), and the like; R6 is (cyclic group optionally having substituent(s)) -carbonyl, and the like; R7, R8, R9 and R10 are the same or different and each is a hydrogen atom, halogen and the like; or R7 and R8, R8 and R9, and R9 and R10 may form a ring together with the adjacent carbon atoms; n is an integer of 1 to 5; --- represents unsubstituted (i.e., absence) or a single bond; and --- represents a single bond or a double bond, or a salt thereof, and the like.

本发明旨在提供一种具有神经激肽2（NK2）受体拮抗作用的喹啉衍生物，并涉及一种由式（I）表示的化合物，其中R1是氢原子等；R2是氢原子，可选地具有取代基的碳氢基团等；R3是未取代的（即缺失），氢原子等；R4和R5相同或不同，每个是氢原子，可选地具有取代基的碳氢基团等；R6是（环状基团，可选地具有取代基）-羰基等；R7、R8、R9和R10相同或不同，每个是氢原子，卤素等；或R7和R8、R8和R9、以及R9和R10可以与相邻的碳原子一起形成环；n是1到5的整数；---表示未取代的（即缺失）或单键；---表示单键或双键，或其盐等。

噻加宾 | 115103-54-3

分子结构分类

物化性质

计算性质

ADMET

安全信息

SDS

制备方法与用途

上下游信息

反应信息

文献信息

同类化合物

相关结构分类

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