ROTIGOTINE

ROTIGOTINE Basic information
Product Name:ROTIGOTINE
Synonyms:()-(S)-5,6,7,8-Tetrahydro-6-(propyl(2-(2-thienyl)ethyl)amino)-1-napht hol;(6S)-5,6,7,8-Tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthalenol;N 0923;Neupro;SPM 962;(S)-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol;[2S,(-)]-N-Propyl-N-[2-(2-thienyl)ethyl]-5-hydroxy-1,2,3,4-tetrahydro-2β-naphthalenamine;[S,(-)]-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol
CAS:99755-59-6
MF:C19H25NOS
MW:315.47
EINECS:
Product Categories:Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
Mol File:99755-59-6.mol
ROTIGOTINE Structure
ROTIGOTINE Chemical Properties
Melting point 78 °C
Boiling point 470.1±45.0 °C(Predicted)
density 1.15±0.1 g/cm3(Predicted)
storage temp. room temp
Water Solubility Insoluble in water
solubility DMF: 30 mg/ml; DMF:PBS(pH7.2) (1:2): 0.33 mg/ml; DMSO: 20 mg/ml; Ethanol: 1 mg/ml
pka10.49±0.40(Predicted)
form powder to crystal
color White to Almost white
Safety Information
Hazard Codes Xn
Risk Statements 22
HS Code 2934990002
Hazardous Substances Data99755-59-6(Hazardous Substances Data)
MSDS Information
ROTIGOTINE Usage And Synthesis
DescriptionWhile levodopa is still considered the cornerstone of treatment of Parkinson’s disease, many patients begin to experience treatment-related problems, such as a wearing-off phenomenon and the development of dyskinesias as the disease progresses. Continuous dopaminergic stimulation by means of a dopamine agonist has been recognized as being associated with a lower incidence of dyskinesias. Using a selective dopamine agonist as monotherapy in early disease may delay the onset of levodopa therapy, or at a minimum, lower its dose in adjunctive situations to minimize the adverse neurotoxic effects of levodopa. Rotigotine is a nonergolinic dopamine D3/D2/D1 receptor agonist, and it is the first dopamine agonist to be launched as a transdermal patch.
DescriptionRotigotine is a non-selective dopamine receptor agonist with pEC50 values of 9.6, 10.4, 8.2, 7.7, and 7.7 for D1, D2, D3, D4, and D5, respectively. It demonstrates a high-affinity for D1, D2, and D3 with lesser affinity for D4 and D5 receptor subtypes. This binding profile is similar to that of apomorphine and pergolide but differentiated from that of pramipexole and ropinirole, which have a more narrow profile of receptor specificity. Each of these agonists demonstrates anti-Parkinsonian effects in animal and clinical models through their ability to directly activate dopamine receptors.
OriginatorAderis (US)
UsesIt is a non-ergot dopamine agonist drug and is indicated for the treatment of Parkinson disease.
DefinitionChEBI: Rotigotine is a member of tetralins.
Brand nameNeupro
General DescriptionRotigotine, (6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol (Neupro),is a nonergoline that is available as a silicone-based, selfadhesivematrix, transdermal system for continuous delivery over a 24-hour period. Approximately 45% of the drug is releasedwithin 24 hours. The terminal half-life of rotigotine is5 to 7 hours after removal of the patch. Rotigotine is 90%bound to plasma proteins. The compound undergoes extensivemetabolism and has low bioavailability by the oralroute. The major metabolites of rotigotine are the glucuronideand sulfate conjugates of rotigotine and sulfateconjugates of N-despropylrotigotine and N-desthienylethylrotigotine. Rotigotine is excreted in the urine (71%) andfeces (11%).Studies using human liver microsomes didnot find any interactions with CYP1A2, CYP2C9,CYP2C19, CYP2D6, and CYP3A4 substrates.Rotigotinetransdermal system contains sodium metabisulfite, and individualssensitive to sulfite could be at risk for allergic reactions.Additionally, somnolence is a common adverse reactionwith individuals on rotigotine, and patients should beclosely monitored during therapy.In transfected Chinesehamster ovary (CHO) cells, rotigotine binds with high affinityat D3 and D2L receptors (variants in the D2 receptor subtypeare caused by insertion of the 29 amino acids into thethird loop to give D2s and D2L).Using rat CHO cells,rotigotine shows over 30-fold selectivity at D3 versus D2 receptors.48 Rotigotine was approved in May 2007 for thetreatment of early-stage PD.
Clinical Use
Treatment of Parkinson’s disease
Restless legs syndrome (RLS)

SynthesisThe synthesis described by the originators at Discovery Therapeutics Inc. (now known as Aderis Pharmaceuticals) is shown in the scheme. The synthesis utilizes the chiral methoxy tetralin 62 as starting precursor which was obtained via chiral crystallization procedure described in a patent literature [34]. Demethylation of tetraline 62 with refluxing 40% HBr solution for several hours provided phenol 63 in 96% yield. Reaction of the amine 63 with 2- thiophenylethyl tosylate 64 in refluxing xylene for 24-32 h in the presence of 0.6 equiv sodium carbonate gave the desired rotigotine (IX) without requiring chromatographic purification. The ratio of sodium carbonate to the amine was critical to achieving good yields (59-84% yield) without requiring extensive purification. Rotigotine was isolated as the HCl salt.

Synthesis_99755-59-6

Drug interactionsPotentially hazardous interactions with other drugs
Antipsychotics: avoid concomitant use (antagonism of effect).
Metoclopramide: avoid concomitant use (antagonism of effect).

MetabolismRotigotine is metabolised in the gut wall and liver by N-dealkylation as well as direct and secondary conjugation. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl-metabolites, which are biologically inactive. Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is excreted in faeces.
5,5-Diphenylhydantoin D-Glutamine Lopinavir Lenalidomide Naratriptan Hydrochloride Varenicline tartrate 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]- (6S)-6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol hydrochloride ROTIGOTINE

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