| Identification | Back Directory | [Name]
ROTIGOTINE | [CAS]
99755-59-6 | [Synonyms]
N 0923
Neupro
CS-110
SPM 962
Rotigotine
S(-)-N-0437
Rotigotine (Base)
ROTIGOTINE USP/EP/BP
(S)-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol
[S,(-)]-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol
()-(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
(6S)-6-(Propyl(2-(2-thienyl)ethyl)amino)-5,6,7,8-tetrahydro-1-naphthalenol
5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-(6S)-1-naphthalenol
(6S)-6-{propyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol
1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]aMino]-, (6S)-
(?)-(S)-5,6,7,8-Tetrahydro-6-(propyl(2-(2-thienyl)ethyl)amino)-1-naphthol hydrochloride
[2S,(-)]-N-Propyl-N-[2-(2-thienyl)ethyl]-5-hydroxy-1,2,3,4-tetrahydro-2β-naphthalenamine | [Molecular Formula]
C19H25NOS | [MDL Number]
MFCD00906149 | [MOL File]
99755-59-6.mol | [Molecular Weight]
315.47 |
| Chemical Properties | Back Directory | [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 | [Major Application]
pharmaceutical
pharmaceutical small molecule | [InChI]
InChI=1S/C19H25NOS/c1-2-11-20(12-10-17-6-4-13-22-17)16-8-9-18-15(14-16)5-3-7-19(18)21/h3-7,13,16,21H,2,8-12,14H2,1H3/t16-/m0/s1 | [InChIKey]
KFQYTPMOWPVWEJ-INIZCTEOSA-N | [SMILES]
C1(O)=C2C(C[C@@H](N(CCC)CCC3SC=CC=3)CC2)=CC=C1 |
| Hazard Information | Back Directory | [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. | [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 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) | [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. | [References]
[1] MARTYN WOOD. Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors[J]. British Journal of Pharmacology, 2014, 172 4: 1124-1135. DOI: 10.1111/bph.12988 |
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