175481-36-4

Basic information

• Product Name: LACOSAMIDE
• Synonyms: LACOSAMIDE;(2R)-2-acetamido-N-benzyl-3-methoxy-propanamide;(2R)-2-(Acetylamino)-3-methoxy-N-(phenylmethyl)propanamide;ADD 243037;Erlosamide;Harkoseride;SPM 927;(R)-2-Acetamido-N-benzyl-3-methoxypropanamide
• CAS NO: 175481-36-4
• Molecular Formula: C13H18N2O3
• Molecular Weight: 250.29362
• EINECS: 1308068-626-2
• Product Categories: Amino Acids 13C, 2H, 15N;Amino Acids & Derivatives;Intermediates & Fine Chemicals;Pharmaceuticals;API;Pharmaceutical raw material;Other APIs;Inhibitors
• Mol File: 175481-36-4.mol

Chemical Properties

• Melting Point: 141-143?C
• Boiling Point: 536.4 °C at 760 mmHg
• Flash Point: 2℃
• Appearance: /
• Density: 1.12 g/cm³
• Vapor Pressure: 1.4E-11mmHg at 25°C
• Refractive Index: 1.52
• Storage Temp.: Refrigerator
• PKA: 14.19±0.46(Predicted)
• CAS DataBase Reference: LACOSAMIDE(CAS DataBase Reference)
• NIST Chemistry Reference: LACOSAMIDE(175481-36-4)
• EPA Substance Registry System: LACOSAMIDE(175481-36-4)

Safety Data

• Hazard Codes: F,Xn
• Statements: 11-20/21/22-36
• Safety Statements: 16-26-36/37
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 2
• Hazardous Substances Data: 175481-36-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Lacosamide is used as an anticonvulsant for the treatment of partial-onset seizures and neuropathic pain. Its anticonvulsant effect is attributed to its selective enhancement of sodium channel inactivation and modulation of CRMP-2, which is involved in neuronal differentiation, control of axonal outgrowth, and possibly epileptogenesis.
Used in Neurological Treatment:
Lacosamide is used as an adjunctive treatment for patients with uncontrolled partial-onset seizures, aged 17 years or older. It is also in development as a monotherapy for epilepsy and neuropathic pain. Its analgesic effect is mediated by its inhibitory effect on sodium channels, leading to neural membrane depolarization.
Used in Epilepsy Management:
Lacosamide is used in the management of epilepsy, particularly for patients with partial-onset seizures. It has been found to be effective in multiple rodent models of seizure activity and is regulated as a Schedule V compound in the United States.
Used in Neuroprotection:
The neuroprotective effects of lacosamide are attributed to its ability to modulate CRMP-2, a member of the semaphorin signal transduction pathway. This modulation may contribute to its efficacy against diabetic neuropathy, possibly as a result of stabilization of neuronal hyperexcitability.
Used in Status Epilepticus Treatment:
Lacosamide can also be used for the treatment of status epilepticus, a life-threatening condition characterized by continuous or near-continuous seizures.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (incl. generic products): It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.

Indications

Epilepsy: Adjunctive treatment of focal seizures with or without secondary generalization.

Dose titration

Epilepsy— adjunctive therapy: 50 mg bd for 7 days, then increased by 50 mg bd every 7 days; usual maintenance 100 mg bd (max. 200 mg bd). Epilepsy— adjunctive therapy (loading dose regimen when it is necessary to rapidly attain therapeutic plasma concentrations, under close medical supervision): 200 mg bd for 1 day, followed by maintenance dose of 100 mg bd after 1 day, then increased if needed by 50 mg bd every 7 days (max. 200 mg bd).

Side effects

Lacosamide was generally well tolerated in adult patients with partial-onset seizures.[11] The side-effects most commonly leading to discontinuation were dizziness, ataxia, diplopia (double vision), nystagmus, nausea, vertigo and drowsiness. These adverse reactions were observed in at least 10% of patients.[9] Less common side-effects include tremors, blurred vision, vomiting and headache.

Cautions

Patients with conduction problems (contraindicated in patients with second- or third- degree A– V block). Patients with severe cardiac disease. Patients at risk of PR- interval prolongation. Elderly patients.

Interactions

With AEDs Concomitant treatment with other AEDs known to be enzyme inducers (such as carbamazepine, phenobarbital, phenytoin) decreases the overall systemic exposure of lacosamide by 25%. With other drugs Nil. With alcohol/food Although no pharmacokinetic data on the interaction of lacosamide with alcohol are available, a pharmacodynamic effect cannot be excluded. There are no specific foods that must be excluded from diet when taking lamotrigine.

Special populations

Hepatic impairment Titrate with caution in mild- to- moderate impairment if co- existing renal impairment. Caution in severe impairment. Renal impairment Loading dose regimen can be considered in mild- to- moderate impairment (titrate above 200 mg with caution). Titrate with caution in severe impairment (max. 250 mg daily). Pregnancy There are no adequate data from the use of lacosamide in pregnant women and the potential risk for humans is unknown. Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). If a woman decides to become pregnant, the use of lacosamide should be carefully re- evaluated. In case of treatment with lacosamide, the dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis. Lacosamide has been found to be present in milk in animal studies and it is recommended that it should be avoided during breastfeeding

Behavioural and cognitive effects in patients with epilepsy

For this third- generation agent, clinical experience is still limited and little is known about its positive and negative psychotropic properties and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of depression, irritability and agitation, and psychotic symptoms. Reports of cognitive effects (mainly affecting attention and memory) are rare and usually not severe.

Psychiatric use

Lacosamide has no indications for the treatment of psychiatric disorders. There is insufficient experience with lacosamide to draw any conclusion regarding its psychotropic profile.

References

[1] B. K. Beyreuther, J. Freitag, C. Heers, N. Krebsf?nger, U. Scharfenecker, T. St?hr (2007) Lacosamide: a review of preclinical properties, CNS Drug Reviews, 13, 21-42 [2] Beyreuther, Bettina K., et al. "Lacosamide: A Review of Preclinical Properties." Cns Drug Reviews 13.1(2007):21. [3]Chung, S, et al. "Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial." Epilepsia 51.6(2010):958–967. [4]Kellinghaus, C, et al. "Intravenous lacosamide for treatment of status epilepticus." Acta Neurologica Scandinavica 123.2(2011):137–141.

Originator

Harris FRC (United States)

Clinical Use

#N/A

Synthesis

The most common adverse events were diplopia, headache, dizziness, and nausea. As typical with AEDs, lacosamide may increase the risk of suicidal thoughts or behavior. Patients should, therefore, be monitored for the emergence or worsening of depression. Caution should also be exercised in patients with known conduction problems or severe cardiac disease (myocardial ischemia or heart failure) since dose-dependent prolongations in PR interval have been observed in clinical studies.

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: anticonvulsant effect antagonised; avoid with St John’s wort. Antimalarials: mefloquine antagonises anticonvulsant effect. Antipsychotics: anticonvulsant effect antagonised. Orlistat: possibly increased risk of convulsions.

Metabolism

The metabolism of lacosamide has not been completely characterised. Lacosamide is a CYP2C19 substrate. Metabolites are inactive. About 95% of a dose is excreted in the urine, about 40% as unchanged drug and less than 30% as the inactive O-desmethyl metabolite. Less than 0.5% of a dose is excreted in the faeces

InChI:InChI=1/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1

Upstream product

• 262845-82-9 N-Benzyl-2-Amino-3-Methoxypropionamide 
• 108-24-7 acetic anhydride 
• 98632-99-6 O-Methyl-N-acetyl-DL-serine 
• 100-46-9 benzylamine 
• 175481-36-4 (2S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide 
• 55299-56-4 N-acetyl serine methyl ester 
• 80-48-8 methyl p-toluene sulfonate 
• 171623-02-2 (R,S)-N-acetylserine-N-benzylamide 
• 16354-58-8 N-acetyl-L-serine 
• 196601-69-1 (R)-2-amino-N-benzyl-3-methoxypropanamide 
• 175481-26-2 2-acetamido-N-benzyl-3-methoxypropionamide 
• 75-36-5 acetyl chloride 
• 474534-78-6 (S)-N-benzyl-2-amino-3-methoxypropionamide 
• 64-19-7 acetic acid 

Downstream Products

• 175481-36-4 (2S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide 
• 175481-36-4 lacosamide 
• 262845-82-9 N-Benzyl-2-Amino-3-Methoxypropionamide 
• 1318767-66-6 C₈H₇ClO₃*C₁₁H₁₆N₂O₂ 

Relevant articles and documents

An enantioselective approach to functionalized amino acids: Total synthesis of antiepileptic drug (R)-lacosamide

A short and highly efficient synthetic approach to enantiopure functionalized amino acids (FAAs) 1 skeleton from racemic butadiene monoepoxide as a starting material and its application to the total synthesis of an antiepileptic drug (R)-lacosamide 2 are described. The synthesis utilizes the palladium catalyzed Trosts Dynamic Kinetic Asymmetric Transformation (DYKAT) as key step.

Chiral pool approach for the synthesis of functionalized amino acids: Synthesis of antiepileptic drug (R)-lacosamide

An efficient total synthesis of (R)-lacosamide 1 has been achieved from N-Boc-N,O-isopropylidene-l-serinol 2 which could easily be obtained from natural l-serine. Our synthesis of 1 starting from 2 using chiral pool strategy resulted in 54% overall yield.

Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid

A catalytic enantioselective three-component Ugi reaction was developed. SPINOL-derived phosphoric acid with bulky 2,4,6-tricyclohexylphenyl groups at the 6,6′ positions was found to be the best catalyst to afford α-amino amide derivatives in good to excellent yields (62% to 99%) and enantiocontrol (81% to >99% enantiomeric excess). This asymmetric reaction was applicable well to an array of aliphatic aldehydes. The gram-scale synthesis, modification of dapsone, and enantioselective synthesis of (R)-Lacosamide underline the general utility of this methodology Influence of dihedral angles and substituents of the chiral phosphoric acids on the enantioselectivity was also discussed in this article.

Synthesis of Lacosamide (Vimpat) and Its Derivatives from Aziridine-(2 R)-carboxylate

An efficient and scalable synthesis of the antiepileptic drug (R)-lacosamide and its derivatives has been achieved from commercially available aziridine-(2R)-carboxylate in three simple sequential steps, including regioselective aziridine ring opening, debenzylation followed by acetylation in one pot, and amide formation. The advantage of this protocol is that the starting material and reagents are commercially available and a single purification by recrystallization is required after all the chemical transformations, providing the final drug in >99.9% ee.

Total synthesis of lacosamide

Total synthesis of anticonvulsant amino acid, lacosamide, is reported. The key step is stereospecific allyl cyanate-to-isocyanate rearrangement, which proceeds with chirality transfer. The enantiopure starting material for the rearrangement step was accessed from ethyl l-lactate.

Synthetic route of lacosamide

The invention discloses a new synthesis route of lacosamide. The new synthesis route comprises the following steps: taking glycine ethyl ester hydrochloride as an initial raw material to react with methylbenzene, benzophenone and p-toluenesulfonic acid to obtain a compound of formula M1; reacting the compound of formula M1 with Xmethyl methyl ether to generate a compound of formula M2; reacting the compound of formula M2 with benzylamine under the catalytic action of sodium ethoxide to generate a compound of formula M3; reacting the compound of formula M3 under the action of acid to generate acompound of formula M4; reacting the compound of formula M4 with Ltartaric acid to generate a compound of formula M5; and enabling the compound of formula M5 to react with acetic anhydride to generate the lacosamide compound. The synthesis route has the advantages that the atom economy is high, the use of isopropyl chloroformate highly toxic products for preparing amide is avoided, the use of methylation reagents methyl iodide or dimethyl sulfate is avoided, the yield is high, and the like.

Novel preparation method of lacosamide

The invention relates to a preparation method of high-purity lacosamide, and belongs to the technical field of organic synthesis. The technical problem to be solved by the invention is to provide a preparation method of lacosamide with mild reaction conditions and high optical purity. The preparation method comprises the following steps: carrying out condensation reaction on a carboxylic acid compound with a protecting group and benzylamine to generate an amide compound, carrying out deprotection under the condition of phosphoric acid, and introducing acetyl to prepare the lacosamide. The invention provides a novel industrial synthesis selection mode, the synthesis mode has the characteristics of simple process, mild reaction conditions, environmental friendliness and the like, can be used for preparing an optical high-purity target compound, and is beneficial to industrial production.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C?C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Preparation method of lacosamide

The invention provides a novel methylation method of a lacosamide synthesis intermediate, which comprises the following steps: methylating a compound I in a reaction solvent at a proper temperature byusing trimethyloxyonium tetrafluoroborate as a methylation reagent under alkaline condition to obtain a methylation product II. The reaction formula is shown in the specification. The method has theadvantages of mild reaction condition, simple post-treatment, green methylation reagent, no high toxicity and high reaction yield, and conforms to the safe and environment-friendly green chemical concept. The method is suitable for laboratory small-scale preparation and large-scale industrial production.

Synthetic method of (by machine translation)

The synthesis method, takes ethyl acetoacetate as a starting material, as a starting raw material and reacts the compound of the formula II with trimethyl orthoformate to form the compound; of the formula III with the compound of the formula III under the action of a catalyst and a ligand H. 2 Of asymmetric hydrogenation to produce compound; of formula IV wherein the compound of formula IV is reacted with sodium azide in Schmidt rearrangement reaction to produce compound; of formula V in which compound of formula V is reacted with benzyl amine (BnNH under alkaline conditions of sodium methoxide. 2 ) The reaction scheme of the invention has the advantages. (: the economical efficiency of the atom is high, the use, of, the methyl tert-butyl carbonate is avoided, the use, of the methyl tert-butyl peroxyformate is avoided, yield is high, and the, like. (by machine translation)