Lamotrigine Chemical Properties

Melting point:

177-181°C

Boiling point:

503.1±60.0 °C(Predicted)

Density 

1.572±0.06 g/cm3(Predicted)

Flash point:

9℃

storage temp. 

2-8°C

solubility 

DMSO: 20 mg/mL at 60 °C, soluble

pka

5.7(at 25℃)

form 

powder

color 

white

Merck 

14,5353

BCS Class

2

InChI

InChI=1S/C9H7Cl2N5/c10-5-3-1-2-4(6(5)11)7-8(12)14-9(13)16-15-7/h1-3H,(H4,12,13,14,16)

InChIKey

PYZRQGJRPPTADH-UHFFFAOYSA-N

SMILES

N1C(C2=CC=CC(Cl)=C2Cl)=C(N)N=C(N)N=1

CAS DataBase Reference

84057-84-1(CAS DataBase Reference)

Safety Information

Hazard Codes 

T,Xi,F

Risk Statements 

25-36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

45-36-26-36/37-16

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

XY5850700

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29336990

Hazardous Substances Data

84057-84-1(Hazardous Substances Data)

Toxicity

LD50 in mice, rats (mg/kg): 250, >640 orally (Sawyer)

MSDS

• Language:English Provider:6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
• Language:English Provider:SigmaAldrich

Lamotrigine Usage And Synthesis

Description

Lamotrigine, also known by the brand name Lamictal®, is a second-generation antiepileptic drug (AED) manufactured by GlaxoSmithKline in the UK and USA. Lamotrigine is a new mazine, glutamate inhibitor anticonvulsant that significantly reduces the incidence of refractory partial seizures. The drug is reported to produce fewer CNS side effects than diazepam or sodium phenytoin. It is also indicated as add-on therapy for the treatment of generalized seizures not satisfactorily controlled by other anti-epileptics.

Chemical Properties

It is a white to cream coloured powder that is soluble in isopropanol and somewhat soluble in water. It has a melting point of 216-218°C and readily dissolves in organic solvents like benzene, toluene, and hot ethanol.

Originator

Burroughs Wellcome (United Kingdom)

Uses

Lamotrigine is an anticonvulsant that works by Inhibits glutamate release, possibly through inhibition of Sodium, Potassium, and Calcium currents. Used in the treatment of bipolar depression, partial seizures in epilepsy, and generalized seizures of Lennox-Gastaut syndrome. Additionally, it is used for the maintenance treatment of bipolar I disorder and depression.

Definition

ChEBI: Lamotrigine is a member of the class of 1,2,4-triazines in which the triazene skeleton is substituted by amino groups at positions 3 and 5, and by a 2,3-dichlorophenyl group at position 6. It has a role as an anticonvulsant, an antimanic drug, an antidepressant, a non-narcotic analgesic, a calcium channel blocker, an excitatory amino acid antagonist, an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor, an environmental contaminant, a xenobiotic and a geroprotector. It is a member of 1,2,4-triazines, a primary arylamine and a dichlorobenzene.

Preparation

The preparation method of Lamotrigine involves several steps. 2,3-dichlorobenzoic acid is chlorinated to 2,3-dichlorobenzoyl chloride, then reacted with cuprous cyanide, condensed with aminoguanidine, and finally cyclized under the action of potassium hydroxide Lamotrigine.
Two key methods for the synthesis of lamotrigine have been reported.
https://www.sciencedirect.com/topics/chemistry/lamotrigine
A novel process for the synthesis of lamotrigine and its intermediate
https://patents.google.com/patent/WO2007069265A1/en

brand name

Lamictal (Glax oSmithKline).

Therapeutic Function

Anticonvulsant

World Health Organization (WHO)

Lamotrigine is a relatively new antiepilepsy agent acting through stabilization of neuronal membranes and preventing liberation of neurotransmitters.

Biological Functions

Lamotrigine has a broad spectrum of action and is effective in generalized and partial epilepsies. Its primary mechanism of action appears to be blockage of voltagedependent sodium channels, although its effectiveness against absence seizures indicates that additional mechanisms may be active. Lamotrigine is almost completely absorbed from the gastrointestinal tract, and peak plasma levels are achieved in about 2 to 5 hours. The plasma half-life after a single dose is about 24 hours. Unlike most drugs, lamotrigine is metabolized primarily by glucuronidation. Therefore, it appears likely that lamotrigine will not induce or inhibit cytochrome P450 isozymes, in contrast to most AEDs.

General Description

Lamotrigine is an antiepileptic drug belonging in the phenyltriazine class. It is used in the treatment of both epilepsy and as a mood stabilizer in bipolar disorder. Lamotrigine is the first medication since lithium granted Food and Drug Administration (FDA) approval for the maintenance treatment of bipolar type I. It is approved for use in more than 30 countries.

Biological Activity

Anticonvulsant. Inhibits glutamate release, possibly through inhibition of Na + , K + and Ca 2+ currents.

Mechanism of action

Lamotrigine has been found effective against refractory partial seizures. Like phenytoin and CBZ, its main mechanism of action appears to be a blockade of sodium channels that is both voltage- and used-dependent. It also inhibits the high-threshold calcium channel, possibly through inhibition of presynaptic N-type calcium channels, and also blocks glutamate release. The most probable explanation for lamotrigine's efficacy is its ability to produce a blockade of sodium channel repetitive firing. In addition, lamotrigine appears to reduce glutaminergic excitatory transmission, although the mechanism for this action remains unclear.

Pharmacokinetics

Following oral administration, lamotrigine is absorbed rapidly and completely, exhibiting linear pharmacokinetics and modest protein binding (55%). Lamotrigine is metabolized predominantly by N-glucuronidation and subsequent urinary elimination of its major metabolite, the quaternary 2-N-glucuronide (80–90%), the minor 5-amino-N-glucuronide (8–10%), and unchanged drug (8–10%). Lamotrigine's usual elimination half-life of 24–35 hours is reduced to 13–15 hours in patients taking enzymeinducing AEDs. The presence of valproate increases the lamotrigine half-life substantially by inhibiting N-glucuronidation, necessitating a reduction in dose to avoid toxicity. Hepatic disease patients may demonstrate a reduced capacity to for lamotrigine glucuronidation, thus reducing its rate of clearance.

Clinical Use

Lamotrigine is a 5-phenyl-1,2,4-triazine derivative indicated as monotherapy or as an adjunct for partial seizures in adults, as adjunct in patients with Lennox-Gastaut syndrome, and as adjunct for partial seizures in children 2 years of age and older. Lamotrigine may have additional benefit in combating myoclonic and typical absence seizures. It is approved for use in the maintenance treatment of bipolar disorder.

Side effects

The usefulness of lamotrigine is limited by the increased incidence of serious rashes, particularly in children or patients taking valproate. This increase, however, may be attenuated by very slow dose escalation, because most rashes appear within the first 8 weeks of treatment. The drug should be discontinued if a rash appears at any time. Additionally, lamotrigine may be associated with development of myoclonus after 2 to 3 years of drug treatment. Additional common side effects associated with lamotrigine therapy include dizziness, diplopia, headache, ataxia, blurred vision, somnolence, and nausea.

Synthesis

The reaction of the Grignard compound of 2,3-dichloroiodobenzene with CO2 in diethyl ether gives 2,3-dichlorobenzoic acid, which is converted to the corresponding acyl chloride by refluxing with SOCl2. The reaction of 2,3-dichlorobenzoyl chloride with cuprous cyanide and KI in refluxing xylene yields 2,3-dichlorobenzoyl cyanide. Finally, this compound is cyclized with aminoguanidine in DMSO to yield lamotrigine .

Metabolism

Lamotrigine is extensively metabolised in the liver by UDP-glucuronyl transferases and excreted almost entirely in urine, principally as an inactive glucuronide conjugate. It slightly induces its own metabolism. Only about 2% of lamotrigine-related material is excreted in faeces.

storage

Room temperature

References

https://my.clevelandclinic.org/health/drugs/20217-lamotrigine-tablets
https://pubchem.ncbi.nlm.nih.gov/compound/Lamotrigine
https://go.drugbank.com/drugs/DB00555
The_Renal_Drug_Handbook_The_Ultimate

Lamotrigine(84057-84-1)Related Product Information

• Lamotrigine N2-Glucuronide
• 2-AMINO-1-PHENYLETHANOL
• Dichlormid
• Dichlorodiphenylsilane
• Dichloromethylphenylsilane
• 1,3,5-Triazine
• 3-Dechloro-4-chloro Lamotrigine
• (Z)-[cyano(2,3-dichlorophenyl)methylene]carbazamidine
• 2,3-Dichlorobenzoic acid
• LaMotrigine IMpurity D
• Lamotrigine N2-Oxide
• 2,4-Dichlorobenzoyl Cyanide
• Lamotrigine Impurity 3
• 2,3-Dichlorobenzoyl cyanide
• (E)-3-[cyano(2,3-dichlorophenyl)methylene]carbazamidine
• Amines, N-tallow alkyltrimethylenedi-
• Lamotrigine Impurity 4
• LaMotrigine Related CoMpound D