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

solubility 

DMF: 30 mg/ml; DMF:PBS(pH7.2) (1:2): 0.33 mg/ml; DMSO: 20 mg/ml; Ethanol: 1 mg/ml

Water Solubility 

Insoluble in water

form 

powder to crystal

pka

10.49±0.40(Predicted)

color 

White to Almost white

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

HS Code 

2934990002

Hazardous Substances Data

99755-59-6(Hazardous Substances Data)

ROTIGOTINE Usage And Synthesis

Description

While 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.

Description

Rotigotine 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.

Originator

Aderis (US)

Uses

It is a non-ergot dopamine agonist drug and is indicated for the treatment of Parkinson disease.

Definition

ChEBI: Rotigotine is a member of tetralins.

brand name

Neupro

General Description

Rotigotine, (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 D_2L receptors (variants in the D₂ receptor subtypeare caused by insertion of the 29 amino acids into thethird loop to give D_2s and D_2L).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)

Synthesis

The 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.

Drug interactions

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

Metabolism

Rotigotine 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.

ROTIGOTINE(99755-59-6)Related Product Information

• Varenicline tartrate
• Naratriptan Hydrochloride
• Lenalidomide
• Lopinavir
• D-Glutamine
• 5,5-Diphenylhydantoin
• (6S)-6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol hydrochloride
• 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-
• ROTIGOTINE