| Identification | More | [Name]
Tiagabine hydrochloride | [CAS]
145821-59-6 | [Synonyms]
TIAGABINE HCL
TIAGABINE HYDROCHLORIDE
THYMOL IODIDE-PURIFIED GRADE
(3R)-1-[4,4-Bis(3-methylthiophen-2-yl)but-3-enyl]piperidine-3-carboxylic acid hydrochloride
GABITRIL | [EINECS(EC#)]
200-659-6 | [Molecular Formula]
C20H26ClNO2S2 | [MDL Number]
MFCD07369025 | [Molecular Weight]
412.01 | [MOL File]
145821-59-6.mol |
| Chemical Properties | Back Directory | [Melting point ]
>192oC dec. | [alpha ]
D20 -11° | [Fp ]
9℃ | [storage temp. ]
2-8°C | [solubility ]
H2O: soluble10mg/mL, clear | [form ]
powder | [pka]
pKa1 3.3; pKa2 9.4(at 25℃) | [color ]
white to beige | [optical activity]
[α]/D -9 to -12°, c = 1 in H2O | [Merck ]
14,9417 | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO, ethanol, or distilled water may be stored at -20° for up to 3 months. | [InChIKey]
YUKARLAABCGMCN-PKLMIRHRSA-N | [CAS DataBase Reference]
145821-59-6(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
Xn | [Risk Statements ]
R20/21/22:Harmful by inhalation, in contact with skin and if swallowed . | [Safety Statements ]
S36/37:Wear suitable protective clothing and gloves . | [RIDADR ]
UN1230 - class 3 - PG 2 - Methanol, solution | [WGK Germany ]
3 | [RTECS ]
TM6128245 | [HS Code ]
2934.99.3000 |
| Questions And Answer | Back Directory | [Chemical Properties]
Tiagabine hydrochloride is a whitish, odorless, crystalline powder with a molecular formula of C20H25NO2S2HCl and a molecular weight of 412.0. Tiagabine hydrochloride was originally synthesized by Novo Nordisk Pharmaceuticals in Denmark.
It was licensed in Europe in 1996 and in the United States in 1997, under the brand name Gabitril1. Gabitril1 is available in the form of 2, 4, 12, and 16 mg tablets. It is marketed by Cephalon.
The antiepileptic drug tiagabine is a lipophilic derivative of nipecotic acid. Nipecotic acid inhibits GABA reuptake, but does not cross the blood brain barrier and is effective against seizures in animal models only when injected in the cerebral ventricles (Croucher et al. 1983). Tiagabine’s lipophilic anchor permits the passage of nipecotic acid from the systemic circulation across the blood brain barrier to the central nervous system (Krogsgaard-Larsen et al. 2000). | [Indications]
Tiagabine is licensed by the United States Food and Drug Administration (FDA) for adjunctive therapy in adults, and children of 12 years and older in the treatment of partial seizures with or without secondary generalization. There is no evidence to support a broader spectrum of action in epilepsy (Ben-Menachem 1995; Bialer et al. 2007). Tiagabine is also licensed in Europe by the European Medicines Agency (EMEA) for the same indications. | [Clinical Applications]
Tiagabine is currently used as adjunctive treatment in adults and children 12 years and older, suffering from partial-onset seizures, which cannot be satisfactorily controlled with other antiepileptic drugs. This indication was based on the results of five multi-center, double-blind, placebo-controlled clinical trials (two cross over and three parallel group studies) that proved its efficacy in patients with refractory partial seizures. These studies included a total of 951 adult and adolescent patients treated with add-on tiagabine at doses ranging from 16 to 56 mg compared to placebo (Ben-Menachem 1995; Richens et al. 1995; Sachdeo et al. 1997; Kalviainen et al. 1998; Uthman et al. 1998; Crawford et al. 2001). An integrated analysis of these studies demonstrated a significant 50% reduction in all seizure types in 23% of the tiagabine-treated group compared to 9% of the placebotreated group during a 7–12 week period (Ben-Menachem 1995). Doses between 32 and 56 mg in three or four divided doses were more effective than placebo (Sachdeo et al. 1997; Uthman et al. 1998). There was a dose–response relationship with greater efficacy at 56 mg/day (Uthman et al. 1998). | [Drug Interactions]
Tiagabine has minimal potential interaction with other drugs (Leppik et al. 1999). Tiagabine is not known to cause either induction or inhibition of hepatic microsomal enzyme systems. Consequently tiagabine does not alter the plasma concentrations of other drugs including antiepileptic drugs that undergo hepatic metabolism (Gustavson et al. 1998a, b). However, enzyme-inducing drugs accelerate the hepatic metabolism of tiagabine (So et al. 1995). There is no clinically relevant interaction between tiagabine and digoxin (Snel et al. 1998). |
| Hazard Information | Back Directory | [Description]
Tiagabine (145821-59-6) is a clinically useful anticonvulsant.1?It is also used to treat anxiety/panic disorder2?and neuropathic pain3. Tiagabine inhibits GABA-reuptake (IC50?[3H]GABA uptake = 67 nM)?via?inhibiting GABA transporter 1(GAT1) blocking both neuronal and glial GABA re-uptake.4,5 | [Originator]
Gabitril,Cephalon, Inc.,USA | [Uses]
Tiagabine hydrochloride was used to study serotoninergic transmission in G1 cells. It has also been used to study its anti-aging effects on the sensory neurons of C. elegans. | [Uses]
A GABA uptake inhibitor. Anticonvulsant. | [Uses]
Tiagabine Hydrochloride is a GABA uptake inhibitor and an anticonvulsant (1,2,3). It is used to treat epilepsy, anxiety disorders, and panic disorder. Neuroprotective & Neuroresearch Product. | [Definition]
ChEBI: A hydrochloride resulting from the reaction of equimolar amounts of tiagabine and hydrogen chloride. A GABA reuptake inhibitor, it is used for the treatment of epilepsy. | [Manufacturing Process]
A solution of 34 ml of n-butyl lithium in 30 ml of anhydrous ether was cooled
to -65°C under nitrogen and 5.3 ml of 3-methyl-2-bromothiophene in 10 ml
anhydrous ether was added dropwise over a period of 10 min. The reaction
mixture was stirred at -65°C for 1 h and 2.7 ml of ethyl 4-bromo-butyrate in
10 ml of anhydrous ether was added slowly. The reaction was stirred for 4 h
while the temperature raised to -20°C, 20 ml water was added, and the
mixture was stirred for 5 min after which the aqueous layer was removed. The
ether layer was washed with 20 ml of water, and the combined aqueous
phases were extracted with 50 ml of ether. The combined organic phases were
dried over anhydrous sodium sulfate, which after evaporation yielded 9 g of 1-
bromo-4,4-bis(3-methylthien-2-yl)but-3-ene as an oil.
This compound was without further purification used for coupling with ethyl
nipecotate.
A suspension of 5.0 g of 1-bromo-4,4-bis(3-methylthien-2-yl)but-3-ene, 3.4 g
of nipecotic acid ethyl ester and 3.3 g of potassium carbonate in 150 ml of dry
acetone was kept under reflux for 15 h. The reaction mixture was evaporated
and, after addition of 30 ml of water, the resulting solution was extracted
twice with 50 ml of ethyl acetate. The ethyl acetate extracts were dried and
evaporated leaving 7.3 g of an oil. By column chromatography on silica gel
using methanol as eluent, N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic
acid ethyl ester was isolated.
5.3 g of N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid ethyl ester
was dissolved in 100 ml of ethanol and 200 ml of an 8 N sodium hydroxide
solution was added. The mixture was heated at reflux for 1 h, cooled and
acidified by adding 10% hydrochloric acid. The resulting solution was
evaporated and 100 ml of water was added to the residue. The resulting acid
solution was extracted with ethyl acetate and the dried extract was
evaporated to give (R)-N-(4,4-bis(3-methylthien-2-yl)but-3-enyl)nipecotic acid
hydrochloride, melting point 187°-189°C. | [Therapeutic Function]
Antiepileptic | [Biochem/physiol Actions]
Tiagabine increases the synaptic GABA and enhances the neuronal inhibition. It is effective as adjunctive treatment of epilepsy and anxiety disorders. | [storage]
Room temperature (desiccate) | [References]
1) Schacter (1999)?A Review of the Antiepileptic Drug Tiagabine, Clin. Neuropharmacol.?22?312
2) Schwartz and Nihalani (2006)?Tiagabine in anxiety disorders, Expert Opin. Pharmacother.?7?1977
3) Novak?et al.?(2001)?Treatment of Painful Sensory Neuropathy With Tiagabine: A Pilot Study, Clin. Auton. Res.?11?357
4) Braestrup?et al.?(1990)?(R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl)nipecotic Acid Binds With High Affinity to the Brain Gamma-Aminobutyric Acid Uptake Carrier, J. Neurochem. 54 639
5) Nielsen?et al.?(1991)?Characterization of Tiagabine (NO-328), a New Potent and Selective GABA Uptake Inhibitor, Eur. J. Pharmacol.?196?257 |
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