143322-58-1 Usage
Description
Eletriptan, the seventh member of the triptan class of antimigraine drugs was launched in Switzerland for the acute treatment of migraine. The 5-step synthesis of this
conformationally restricted analog of sumatriptan involves the deprotonation of 5-
bromoindole with Grignard reagent at the position C3 followed by a condensation with NCbz-
D-proline acid chloride to afford the key Cbz-D-prolyl intermediate. After reduction
with LiAIH4, the sulfone moiety was introduced in postion 5 by a palladium cross-coupling
Heck reaction using the phenylvinyl sulfone. Eletriptan is a 5-HT receptor agonist that
binds to 5-HT1B, 5HT1D and 5HT1F receptors with high potency. Activation of these
receptors causes constriction of extracerebral intracranial vessels, abolition of the dural
extravasation and neurogenic inflammation, and inhibition of trigeminal neuronal
discharge. Eletriptan was found to be the most potent agonist at the 5-HT1D receptor
compared to the other triptans with pEC50 value of 9.2. In thousands of participants in
clinical trials, eletriptan has acted more effectively and more rapidly than sumatriptan to
relieve pain from mild to severe attacks of migraine. Eletriptan also reduced time lost for
ordinary activity to patients with migraine attacks when compared to placebo and when
compared to sumatriptan. Eletriptan was also superior to sumatriptan in terms of relieving
functional disability, nausea, photophobia and phonophobia. Unlike other compounds of its
class, eletriptan has a positive logD value, that could underlie its rapid and complete oral
absorption and may be suggestive of a good brain penetration. The oral biovailability of
Eletriptan is approximately 50% (14% for Sumatriptan) with a half life of 5.7h (2h for
Sumatriptan). Eletriptan was well tolerated with mild to moderate adverse events including
asthenia, somnolence, dizziness and nausea. Eletriptan is a new potent and fast-acting
triptan for the treatment of migraine attacks.
Chemical Properties
Yellow Foam
Originator
Pfizer (US)
Uses
Different sources of media describe the Uses of 143322-58-1 differently. You can refer to the following data:
1. A serotonin 5-HTIB/ID receptor agonist. Antimigrene
2. Eletriptan is a selective serotonin 5-HT1B and 5-HT1D receptor agonist and used to treat migraines (1,2,3).
Definition
ChEBI: Eletriptan is an N-alkylpyrrolidine, being N-methylpyrrolidine in which the pro-R hydrogen at position 2 is substituted by a {5-[2-(phenylsulfonyl)ethyl]-1H-indol-3-yl}m
thyl group.
Manufacturing Process
A mixture of the appropriate phenyl vinyl sulfone, tri-o-tolylphosphine,
palladium (II) acetate, triethlamine and (R)-5-bromo-3-(Nmethylpyrrolidinylmethyl)-1H-indole in anhydrous acetonitrle was heated at
reflux under nitrogen. The resultant reaction mixture was evaporated under
reduced pressure, and the residue was column chromatographed using silica
gel and elution with methylene chloride/absolute ethanol/ammonia to afford
the (R )-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-
1H-indole.A solution of (R)-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-
ylmethyl)-1H-indole and 10% Pd/C in ethanolic hydrogen chloride (prepared
from absolute ethanol and acetyl chloride and N,N-dimethylformamide was
shaken under a hydrogen atmosphere at room temperature). The resultant
reaction mixture was filtered through diatomaceous earth (Celite trademark),
washed with absolute ethanol, and the combined filtrates were evaporated
under reduced pressure. The residue was partitioned between ethyl acetate
and water. The organic phase was separated, washed with water, brine, dried(Na2SO4), and evaporated under reduced pressure to afford a oil product.
Column chromatography of this product using silica gel and elution with
methylene chloride/absolute ethanol/ammonia afforded the appropriate (R)-5-
(2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.The salt eletriptan hydrobromide may be produced by reaction of the (R)-5-
(2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with
hydrobromic acid.
Brand name
Relpax
Therapeutic Function
Serotonin agonist
General Description
Eletriptan, introduced into the market in 2002, is the newesttriptan with highest affinity for 5-HT1B, 5-HT1D, and 5-HT1Freceptors. It is one of the most lipophilic triptans marketedto date and is well tolerated and safe across its dosing rangeof 20 to 80 mg. However, it is metabolized primarily(>90%) by CYP3A4 isozyme to its active metabolite, theN-desmethyleletriptan, which accounts for approximately10% to 20% of the plasma concentration of that observedfor parent drug. Thus, coadministration of eletriptan withpotent CYP3A4 inhibitors such as ketoconazole, itraconazole,nefazodone, troleandomycin, clarithromycin, ritonavir,and nelfinavir may require dose reduction and closer monitoringfor CNS side effects. Furthermore, becauseeletriptan and its active metabolite, N-desmethyleletriptan,are also substrates for the P-glycoprotein efflux pumps thatare responsible for their removal from the brain, coadministrationof eletriptan with a known P-glycoprotein inhibitorand/or inducer such as digoxin, diltiazem, verapamil, or St.John’s Worth would result in higher brain levels of its activemetabolite, and thus a higher rate of the CNS side effectsreported for this drug.
Clinical Use
5HT1
receptor agonist:Acute relief of migraine
Drug interactions
Potentially hazardous interactions with other drugsAntibacterials: concentration increased by
clarithromycin and erythromycin - avoid.Antidepressants: increased risk of CNS toxicity with
citalopram - avoid; possibly increased serotonergic
effects with duloxetine and venlafaxine; increased
serotonergic effects with St John’s wort - avoidAntifungals: concentration increased by itraconazole
and ketoconazole - avoid.Antivirals: concentration increased by indinavir and
ritonavir - avoid.Dapoxetine: possible increased risk of serotonergic
effects - avoid for 2 weeks after stopping 5HT1
agonistsErgot alkaloids: increased risk of vasospasm - avoid.
Metabolism
In vitro studies indicate that eletriptan is primarily
metabolised by hepatic cytochrome P-450 enzyme
CYP3A4. This finding is substantiated by increased
plasma concentrations of eletriptan followingknown selective and potent CYP3A4 inhibitors. In vitro
studies also indicate a small involvement of CYP2D6
although clinical studies do not indicate any evidence of
polymorphism with this enzyme.There are two major circulating metabolites identified
that significantly contribute to plasma radioactivity
following administration of 14C-labelled eletriptan. The
metabolite formed by N-oxidation, has demonstrated no
activity in animal in vitro models. The metabolite formed
by N-demethylation, has been demonstrated to have
similar activity to eletriptan in animal in vitro models.
A third area of radioactivity in plasma has not been
formally identified, but is most likely to be a mixture of
hydroxylated metabolites which have also been observed
excreted in urine and faeces.The plasma concentrations of the N-demethylated
active metabolite are only 10-20% of those of parent,
so would not be expected to significantly contribute to
the therapeutic action of eletriptan. Non-renal clearance
accounts for approximately 90% of the total clearance
indicating that eletriptan is eliminated primarily by
metabolism.
Check Digit Verification of cas no
The CAS Registry Mumber 143322-58-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,3,3,2 and 2 respectively; the second part has 2 digits, 5 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 143322-58:
(8*1)+(7*4)+(6*3)+(5*3)+(4*2)+(3*2)+(2*5)+(1*8)=101
101 % 10 = 1
So 143322-58-1 is a valid CAS Registry Number.
InChI:InChI=1/C22H26N2O2S.BrH/c1-24-12-5-6-19(24)15-18-16-23-22-14-17(9-10-21(18)22)11-13-27(25,26)20-7-3-2-4-8-20;/h2-4,7-10,14,16,19,23H,5-6,11-13,15H2,1H3;1H/t19-;/m1./s1
143322-58-1Relevant articles and documents
Investigational study into the formation of methoxy derivative and other impurities during the optimization of eletriptan hydrobromide
Kumar, U. Sampath,Sankar, V. Ravi,Rao, M. Malleswara,Jaganathan,Buchi Reddy
, p. 1917 - 1920 (2012)
During the process development of eletriptan hydrobromide, we have observed formation of an unknown impurity in the final product at enhanced levels which was identified as a methoxy substituted derivative on the side chain of the product. The present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production of eletriptan hydrobromide substantially free from the methoxy impurity and other impurities.
A synthesis method according to sets up qu tan hydrobromide
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Paragraph 0061-0063, (2017/10/22)
The invention discloses a synthesis method of eletriptan hydrobromate, which comprises the following steps: reacting (R)-1-acetyl-3-(N-methylpyrrolidinyl-2-methy)-5-bromo-1H-indole and metal in an organic solvent to form a metal complex, reacting the metal complex with a boron reagent in an organic solvent to form aryl borane or aryl borate, carrying out acid-catalyzed hydrolysis to obtain aryl boric acid, and carrying out coupling and hydrolysis on the aryl boric acid and 2-chloroethylphenyl sulfone under the actions of a catalyst and an alkali to obtain eletriptan, or directly carrying out coupling and hydrolysis on the metal complex and 2-chloroethylphenyl sulfone to obtain eletriptan; and carrying out salification on the eletriptan and hydrobromic acid in an organic solvent to finally obtain the eletriptan hydrobromate. The method is simple to operate, has the advantages of high safety, high stability, low cost and higher yield, and is suitable for industrial production.
A NOVEL PROCESS FOR THE PREPARATION OF ELETRIPTAN
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Paragraph 0033, (2013/07/25)
The present invention relates to a novel process for the preparation of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole and its intermediates thereof.