Rasagiline mesylate

Bezeichnung:Rasagiline mesylate

CAS-Nr161735-79-1

Englisch Name:Rasagiline mesylate

CBNumberCB7501001

SummenformelC13H17NO3S

Molgewicht267.34398

MOL-Datei161735-79-1.mol

Rasagiline mesylate physikalisch-chemischer Eigenschaften

Schmelzpunkt	155-158°C
storage temp.	2-8°C
Löslichkeit	H2O: ≥20mg/mL
Aggregatzustand	powder
Farbe	white to tan
Optische Aktivität	[α]/D +15 to +28°, c = 0.6 mg/mL in H2O
Stabilität	Stable for 2 years from date of purchase as supplied. Solutions in DMSO, distilled water or ethanol may be stored at -20°C for up to 1 month.
InChI	InChI=1/C12H13N.CH4O3S/c1-2-9-13-12-8-7-10-5-3-4-6-11(10)12;1-5(2,3)4/h1,3-6,12-13H,7-9H2;1H3,(H,2,3,4)/t12-;/s3
InChIKey	JDBJJCWRXSVHOQ-ZLBVLXFENA-N
SMILES	C12C=CC=CC=1CC[C@H]2NCC#C.S(C)(O)(=O)=O \|&1:8,r\|
CAS Datenbank	161735-79-1(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	Xn
R-Sätze:	22
S-Sätze:	24/25
WGK Germany	3
HS Code	29214990

Gefahreninformationscode (GHS)

Rasagiline mesylate Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Rasagiline mesylate is a potent and selective irreversible monoamine oxidase B (MAO-B) inhibitor launched in 2005 in Israel by Teva as monotherapy in patients with early Parkinson's disease and as adjuvant treatment in moderate-toadvanced disease. Lundbeck will market the drug throughout Europe. Rasagiline is in phase II clinical trials at Teva and Eisai for the treatment of Alzheimer's type dementia.
Chemische Eigenschaften
White to Off-White Crystalline Solid
Verwenden
Rasagiline is a selective irreversible MAO-B inhibitor. Rasagiline is an Antiparkinsonian agent.
Verwenden
A selective irreversible MAO-B inhibitor. Antiparkinsonian
Verwenden
Rasagiline Mesylate is a new MAO-B inhibitor for the treatment of idiopathic Parkinson's disease.
Indications
Rasagiline mesylate is a novel, potent, second-generation, selective, irreversible MAO-B inhibitor that blocks the breakdown of dopamine. It is approved for the treatment of PD. Indications for use of once-daily rasagiline are as a monotherapy in early PD and as an adjunct to levodopa in moderate to advanced disease. Rasagiline significantly improves symptoms during initial monotherapy in patients with early PD and as an adjunct treatment to levodopa in moderate-to-advanced patients. Rasagiline is well tolerated up to doses as high as 20 mg/day. Evidence for neuroprotective effect of rasagiline is as follows (Jain 2010c):
Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline, which protects mitochondrial viability.
Experimental evidence supports rasagiline's neuroprotective efficacy, showing that neuronal survival is related to the anti-apoptotic properties of its propargyl moiety. Aminoindan metabolite of rasagiline has been shown to have neuroprotective properties (Bar-Am et al. 2010).
Trademarks
Azilect (Teva).
Allgemeine Beschreibung
Rasagiline mesylate, (R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine methanesulfonate(Azilect), belongs to the propargylamine family and is a whiteto off-white powder, soluble in water or ethanol, slightly solublein isopropanol. Rasagiline is rapidly absorbed. Plasmaprotein binding for rasagiline ranges from 88% to 94%, withspecific binding to serum albumin being 61% to 63%. It undergoescomplete biotransformation before excretion, mainlyvia N-dealkylation and hydroxylation, to yield three majormetabolites: 1(R)-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan, and 3-hydroxy-1-aminoindan. Both oxidativepathways are catalyzed by cytochrome P450 (CYP) enzymes,mainly the 1A2 isozyme. Rasagiline and its metabolites undergoglucuronide conjugation with subsequent urinary excretion.Inhibitors of the CYP1A2 may increase plasmaconcentrations of rasagiline up to twofold. Because rasagilineis a selective and irreversible inhibitor of MAO-B, itsduration of action is independent of the drug’s half-life and isinstead determined by the regeneration rate of MAO-B. Thischaracteristic is potentially beneficial in PD, where rasagiline’sprolonged effect may be able to limit the fluctuating responsesthat are characteristic of long-term drug treatmentwith levodopa.
Biochem/physiol Actions
Rasagiline mesylate is an irreversible inhibitor of monoamine oxidase selective for MAO type B over type A by a factor of fourteen. It has anti-apoptotic and neuroprotectant activity and has been used as a treatment for Parkinson′s disease.
Mechanism of action
The specific mechanism of action of Rasagiline mesylate is unknown. One of these mechanisms is thought to be related to its MAO-B inhibitory activity, which leads to elevated extracellular dopamine levels in the striatum. It irreversibly blocks dopamine metabolism, thereby increasing dopamine levels, which can be beneficial for symptoms in Parkinson's disease patients.
Nebenwirkungen
Rasagiline mesylate has been shown to be effective, safe and well tolerated as monotherapy in early Parkinson's disease. The most common are infection, headache, dizziness, weakness, anorexia and vomiting. In rare patients, it may cause new malignancies (melanoma and squamous cell carcinoma of the skin).
Synthese
1-Indanone (122) was condensed with benzyl amine to give corresponding enamine which was reduced with sodium borohydride in ethanol to give racemic Nbenzyl- 1-inda-namine (123) in 82% yield. The racemic benzylamine 123 was resolved with L-tartaric acid and recrystallized from boiling water to give optical pure Rbenzylamine 124 as a tartarate salt. The recovered S-isomer 125 can be racemized under basic condition to give back as the starting racemic 123. Compound 124 was hydrogenated and basified to give free amine 126 in 72 % yield which was alkylated with propargyl chloride and K2CO3 in hot acetonitrile to yield free resagiline. Finally resagiline mesilate (XVII) was obtained by treating resagiline with methanesulfonic acid in refluxing IPA.
Lager
room temperature (desiccate)
Einzelnachweise
1) Youdim?et al.?(2001),?Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B; Br. J. Pharmacol.,?132?500 2) Cereda?et al.?(2017),?Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study; J. Neurol.,?264?1254 3) Cronin and Grealy (2017),?Neuroprotective and Neuro-restorative Effects of Minocycline and Rasagiline in Zebrafish 6-Hydroxydopamine Model of Parkinson’s Disease; Neuroscience,?367?34 4) Kang?et al.?(2017),?TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease; Proc. Natl. Acad. Sci. USA,?114?10773 5) Ledreux?et al.?(2016),?BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson’s disease; Brain Res.,?1631?34

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