1369764-02-2

Basic information

• Product Name: Lemborexant
• Synonyms: Lemborexant;lemborexant,E2006;(1R,2S)-2-[[(2,4-Dimethyl-5-pyrimidinyl)oxy]methyl]-2-(3-fluorophenyl)-N-(5-fluoro-2-pyridinyl)cyclopropanecarboxamide;E 2006;lemborexant / E-2006, CID 56944144
• CAS NO: 1369764-02-2
• Molecular Formula: C₂₂H₂₀F₂N₄O₂
• Molecular Weight: 410.4166064
• EINECS: -0
• Product Categories: API
• Mol File: 1369764-02-2.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 596.1±50.0 °C(Predicted)
• Appearance: /
• Density: 1.347±0.06 g/cm3(Predicted)
• Storage Temp.: -20°C, Inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 12.30±0.40(Predicted)
• CAS DataBase Reference: Lemborexant(CAS DataBase Reference)
• NIST Chemistry Reference: Lemborexant(1369764-02-2)
• EPA Substance Registry System: Lemborexant(1369764-02-2)

Safety Data

• Hazardous Substances Data: 1369764-02-2(Hazardous Substances Data)

Usage

Description

Lemborexant is a newer orexin receptor antagonist which is submitted to US FDA for review as new drug application for the treatment of insomnia after completing two key Phase 3 studies of lemborexant – SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303).

Chemical Properties

Lemborexant is a white to off-white powder that is practically insoluble in water.

Uses

Lemborexant is a novel orexin receptor antagonist and is used in the treatment of insomnia, characterised by difficulties with sleep onset or sleep maintenance. Orexins are neuropeptides involved in regulating sleep and arousal by promoting wakefulness. Lemborexant blocks the binding of orexins A and B to their receptors 1 and 2 thereby reducing wakefulness and promoting sleep. Suvorexant is the other orexin receptor antagonist marketed in Australia for insomnia.

Pharmacokinetics

Effect of food High-fat & high-calorie meal delay Tmax & reduce Cmax Tmax 1 to 3 hours Half-life 17 hours (5 mg) and 19 hours (10 mg) Metabolism primarily metabolized by CYP3A4 Excretion Urine (29%); feces (57%)

Effect of food

High-fat & high-calorie meal delay Tmax & reduce Cmax

Tmax

1 to 3 hours

Half-life

17 hours (5 mg) and 19 hours (10 mg)

Metabolism

primarily metabolized by CYP3A4

Excretion

Urine (29%); feces (57%)

Drug interactions

Lemborexant is metabolized by CYP3A4 and is susceptible to interactions with medications such as amiodarone, amlodipine, carbamazepine, clarithromycin, diltiazem, fluoxetine and phenytoin. Lemborexant may affect other medications metabolised by CYP2B6, such as bupropion and methadone. Alcohol should be avoided: a single dose of alcohol can increase lemborexant concentrations up to 70%.

Mode of action

The mechanism of action of lemborexant in the treatment of insomnia is Blocks the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R, presumed to suppress wake drive.

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdfhttps://www.smchealth.org/sites/main/files/file-attachments/dayvigo_for_publish.pdf?1592332002https://www.superiorhealthplan.com/content/dam/centene/Superior/policies/pharmacy-policies/Lemborexant%20(Dayvigo)%20(CP.PMN.233)%20(PDF).pdf

Upstream product

• 412003-95-3 5-hydroxy-2,4-dimethylpyrimidine 
• 1369766-72-2 5-methoxy-2,4-dimethylpyrimidine 
• 31301-51-6 2-chloro-5-fluoropyridine 
• 1369769-04-9 C₁₇H₁₈FN₃O₂ 
• 1450904-98-9 (1S,2R)-1-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carbonitrile 
• 501-00-8 3-fluorophenylacetonitrile 
• 1450904-96-7 5-methoxy-2,6-dimethylpyrimidin-1-ium chloride 
• 1369769-35-6 (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid 
• 21717-96-4 2-amino-5-fluoropyridine 
• 1369767-26-9 (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarbaldehyde 
• 1369767-24-7 ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol 
• 1450904-94-5 C₁₉H₂₁FN₂O₃ 
• 1450904-92-3 ((1R,2S)-2-(3-fluorophenyl)-2-((p-tosyloxy)methyl)cyclopropyl)methyl acetate 
• 1369768-29-5 [(1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]-methyl acetate 

Downstream Products

• 1369768-78-4 (1R,2S)-2-(((2-methyl-4-bromomethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide 
• 1369765-96-7 (1R,2S)-2-(((2-methyl-4-hydroxymethylpyrimidin-5-yl)oxy)-methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)-cyclopropanecarboxamide 
• 1369766-44-8 (1R,2S)-2-{[(4-fluoromethyl-2-methylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide 

Relevant articles and documents

METHOD FOR MANUFACTURING CYCLOPROPANE COMPOUND

The present invention provides an industrially advantageous production method of (1R,2S)-2-{[((2,4-dimethylpyrimidin-5-yl)oxy}methyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide. (1R,2S)-2-{[((2,4-Dimethylpyrimidin-5-yl)oxyl}methyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide (compound [A]) is produced by an industrially advantageous method by a route via a novel compound. wherein each symbol is as described in the description.

Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor

Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4- methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl) -2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [11C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [11C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.

CYCLOPROPANE COMPOUND

A cyclopropane compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof has orexin receptor antagonism, and therefore has a potencial of usefulness for the treatment of sleep disorder for which orexin receptor antagonism is effective, for example, insomnia: wherein Q represents —CH— or a nitrogen atom, R1a and R1b each independently represent a C1-6 alkyl group and the like, R1c represents a hydrogen atom and the like, R2a, R2b, R2c and R2d each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group and the like, R3a, R3b and R3c each independently represent a hydrogen atom, a halogen atom and the like, and R3d represents a hydrogen atom and the like.