25451-15-4 Usage
Description
Felbamate, also known as Felbatol, is a white powder with low toxicity and a wide margin of safety. It is an anticonvulsant used in the treatment of epilepsy, particularly for refractory patients with generalized tonic-clonic and complex partial seizures. It can be used as monotherapy or adjunctive therapy and has been shown to have neuroprotective effects in cerebral ischemia and hypoxia. Its anticonvulsant activity is believed to be due to an interaction with the strychnine-insensitive receptor site on the NMDA receptor complex.
Uses
Used in Pharmaceutical Industry:
Felbamate is used as an anticonvulsant medication for the treatment of epilepsy, specifically in patients with refractory generalized tonic-clonic and complex partial seizures. It is administered as monotherapy or adjunctive therapy to help control seizures and improve the quality of life for those affected by this neurological disorder.
Additionally, Felbamate has been demonstrated to have neuroprotective properties, making it a potential candidate for use in the treatment of cerebral ischemia and hypoxia. Its mechanism of action involves interaction with the strychnine-insensitive receptor site on the NMDA receptor complex, which may contribute to its therapeutic effects in these conditions.
Originator
Carter-Wallace (U.S.A.)
Biological Functions
Felbamate (Felbatol) was introduced with the expectation
that it would become a major drug in the treatment
of epilepsy. Felbamate exhibited few manifestations of
serious toxicity in early clinical trials. Soon after its introduction,
however, it became apparent that its use was
associated with a high incidence of aplastic anemia.
Consequently, felbamate is indicated only for patients
whose epilepsy is so severe that the risk of aplastic anemia
is considered acceptable.
While its mechanism of action has not been clearly
established, felbamate shows some activity as an inhibitor
of voltage-dependent sodium channels in a manner
similar to that of phenytoin and carbamazepine.
Felbamate also interacts at the strychnine-insensitive
glycine recognition site on the NMDA receptor–
ionophore complex.Whether this effect is important to
its anticonvulsant activity is not clear.
Hazard
Low toxicity by ingestion. Human systemic
effects.
Biological Activity
Anticonvulsant, acting as an antagonist at the NMDA-associated glycine binding site.
Biochem/physiol Actions
Anticonvulsant agent that is an allosteric antagonist at the NR2B subunit of the NMDA glutamate receptor; also has γ-aminobutyric acid (GABAA) receptor agonist properties.
Mechanism of action
Gabapentin is a water-soluble amino acid originally designed to be a GABA-mimetic analogue capable of penetrating the CNS.
Surprisingly, it has no direct GABA-mimetic activity, nor is it active on sodium channels. The mechanism of action remains
unknown, although it has been suggested that gabapentin may alter the metabolism or release of GABA. Gabapentin
raises brain GABA levels in patients with epilepsy. Recent studies have demonstrated gabapentin binding to calcium
channels in a manner that can be allosterically modulated.
Gabapentin is indicated as an adjunct for use against partial seizures with or without secondary generalization, in patients
older than 12 years, and as adjunct for the treatment of partial seizures in children 3 to 12 years of age. It also is approved for
the treatment of postherpetic neuralgia.
Pharmacokinetics
The pharmacokinetic properties for gabapentin generally are favorable, with a bioavailability of 60% when given in low doses
and somewhat less when given at higher doses because of saturable intestinal uptake by the L-amino-acid transporter.
The L-amino-acid transporter is very susceptible to substrate saturation (low Km value). Its absorption and distribution into the
CNS appears to be dependent on this amino acid transporter. Following the administration of an oral dose, gabapentin reaches
peak plasma concentration in 2 to 3 hours. Additionally, it exhibits linear pharmacokinetics. Moreover, it is not extensively
metabolized, nor is it an inducer of hepatic metabolizing enzymes. The elimination of unmetabolized gabapentin occurs by the
renal route. Although its therapeutic range is not well characterized, gabapentin has a broad therapeutic index. This implies
that a wide range of doses can be used, based on individual patient needs, without significant limitation because of
dose-dependent side effects. Protein binding is negligible. Its elimination half-life of 5 to 7 hours is not affected by the dose or
by other drugs, and its short half-life necessitates multiple daily administration.
Clinical Use
Felbamate is a dicarbamate that is structurally similar to the antianxiety drug meprobamate. It was approved by the U.S. FDA
for antiseizure use in 1993. Following the occurrence of rare cases of aplastic anemia and of severe hepatotoxicity associated
with the use of felbamate during early 1994, however, a black box warning was added to the drug's package insert).
Despite this, felbamate continues to be used in many patients, although not as a first-line treatment. These toxicity effects may
be attributed to the formation of toxic metabolites. Although felbamate use is now uncommon, it is used for severe
refractory seizures, either partial, myoclonic, or atonic, or in Lennox-Gastaut syndrome
Side effects
Adverse effects of gabapentin are uncommon and not serious. The CNS effects include mild to moderate sedation, fatigue,
ataxia, headache, dizziness, and diplopia. Gabapentin may exacerbate myoclonus, but the effect is mild and does not require
discontinuance of the drug. It has been associated with the development of neuropsychiatric adverse events in
children.
Drug interactions are infrequent with gabapentin. It does not induce hepatic metabolizing enzymes, nor do other AEDs affect its
metabolism and elimination. Antacids may decrease absorption. Gabapentin dosage may need to be decreased in patients with
renal disease or in the elderly.
Veterinary Drugs and Treatments
Felbamate is an anticonvulsant agent that may useful for treating
seizure disorders (especially complex partial seizures) in dogs. A
potential advantage of felbamate therapy is that when used alone
or in combination with phenobarbital and/or bromides, it does not
appear to cause additive sedation.
Metabolism
Although the metabolism of felbamate has not been fully characterized, felbamate is esterase hydrolyzed to its monocarbamate
metabolite, 2-phenyl-1,3-propanediol monocarbamate, which subsequently is oxidized via aldehyde dehydrogenase to its major
human metabolite 3-carbamoyl-2-phenylpropionic acid. Other metabolites include the p-hydroxy and mercapturic
acid metabolites of felbamate, which have been identified in human urine. Felbamate is a substrate for CYP2C19, with minor
activity for CYP3A4 and CYP2E1. Thompson et al. has provided evidence for the formation of the reactive metabolite,
3-carbamoyl-2-phenylpropionaldehyde (CBMA), from the alcohol oxidation of 2-phenyl-1,3-propanediol monocarbamate. CBMA
then undergoes spontaneous elimination to another reactive intermediate, 2-phenylpropenal (more commonly known as
atropaldehyde), which is proposed to play a role
in the development of toxicity during felbamate therapy. CBMA or a further product has been shown to provoke an immune
response in mice. Evidence for in vivo atropaldehyde formation was confirmed with the identification of its mercapturic acid
conjugates in human urine after felbamate administration. This is consistent with the hypothesis that atropaldehyde reacts
rapidly with thiol nucleophiles, such as glutathione, to form mercapturates. More recently, a fluorine analogue
of felbamate was synthesized in which the benzylic C2 hydrogen of the propane chain was replaced with fluorine, preventing
the formation of atropaldehyde and confirming that the acidic benzylic hydrogen plays a pivotal role in its formation. This
analogue is presently undergoing drug development. Felbamate administration exhibited linear kinetics, with a half-life of 20 to
23 hours in the absence of enzyme-inducing AEDs. Approximately 50% of an oral dose of felbamate is excreted unchanged.
Check Digit Verification of cas no
The CAS Registry Mumber 25451-15-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,5,4,5 and 1 respectively; the second part has 2 digits, 1 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 25451-15:
(7*2)+(6*5)+(5*4)+(4*5)+(3*1)+(2*1)+(1*5)=94
94 % 10 = 4
So 25451-15-4 is a valid CAS Registry Number.
InChI:InChI=1/C11H14N2O4/c12-10(14)16-6-9(7-17-11(13)15)8-4-2-1-3-5-8/h1-5,9H,6-7H2,(H2,12,14)(H2,13,15)
25451-15-4Relevant articles and documents
PROCESS FOR THE SYNTHESIS OF ISOCYANATE-FREE OMEGA-HYDROXY-URETHANES, ALPHA-OMEGA-DIURETHANES AND OLIGO (POLY)URETHANES
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Page/Page column 11, (2021/11/26)
The synthesis of omega-hydroxyalkyl-urethanes, and of alfa-omega-diurethanes is reported which includes the reaction of diols with urea in presence of catalysts based on Ce at temperatures between 125 and 170°C over 4-8 h reaction time. A process for the production of oligomers of omega-hydroxyalkyl-urethanes is also reported based on the reaction of urea with diols in presence of Ce or Zr catalysts or Ce mixed oxides at 125-170°C over 4-20 h.
PROCESS FOR THE PREPARATION OF 2-PHENYL-1,3-PROPANEDIOL
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, (2012/03/27)
The present invention is related to a novel synthetic procedure that provides a simple, safe and commercially valuable method for the preparation of 2-phenyl-1,3-propanediol. The process for the preparation of 2-phenyl-1,3-propanediol involves reducing diethyl phenylmalonate with sodium borohydride (NaBH4) in the presence of an alkali metal dihydrogen phosphate buffer or the hydrate thereof.
Methods for synthesis of dicarbamate compounds and intermediates in the formation thereof
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Page/Page column 8, (2008/06/13)
Disclosed is a method of making 2-substituted-2-halo-1,3-propanediols via reduction of corresponding malonate compounds. Also disclosed is a method of making 2-substituted-2-halo-1,3-dicarbamate compounds (such as halo derivatives of felbamate, including fluorofelbamate) via reduction of malonate compounds, followed by carbamoylation. Reduction of the malonate compounds is carried out using an electrophilic hydride reagent.