Duloxetine

Bezeichnung:Duloxetine

CAS-Nr116539-59-4

Englisch Name:Duloxetine

CBNumberCB8670379

SummenformelC18H19NOS

Molgewicht297.41

MOL-Datei116539-59-4.mol

Duloxetine physikalisch-chemischer Eigenschaften

Siedepunkt	466.2±40.0 °C(Predicted)
Dichte	1.158±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
Löslichkeit	Soluble in DMSO
Aggregatzustand	Oil
pka	10.02±0.10(Predicted)
Farbe	Light brown to yellow
BCS Class	2
InChI	InChI=1/C18H19NOS.ClH/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16;/h2-10,13,17,19H,11-12H2,1H3;1H/t17-;/s3
InChIKey	BFFSMCNJSOPUAY-VOPAOICTNA-N
SMILES	C1(=CC=CS1)[C@H](CCNC)OC1=CC=CC2=CC=CC=C12.Cl \|&1:5,r\|
EPA chemische Informationen	2-Thiophenepropanamine, N-methyl-?-(1-naphthalenyloxy)-, (?S)- (116539-59-4)

Sicherheit

Giftige Stoffe Daten

116539-59-4(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Duloxetine Chemische Eigenschaften,Einsatz,Produktion Methoden

History
Duloxetine is a second-generation antidepressant. Its mechanism of action involves inhibiting the reuptake of serotonin and norepinephrine by neurons, thereby increasing the concentration of these two neurotransmitters in the synaptic cleft, thus improving mood and relieving pain.
Initial Approval (2004): Cymbalta was initially approved for the treatment of major depressive disorder (MDD). In the same year, it also received approval for the treatment of diabetic peripheral neuropathy (DPNP), making it a unique drug capable of simultaneously addressing two common and frequently co-occurring conditions: depression and neuropathic pain.
Expansion of Indications: Subsequently, Eli Lilly expanded its indications through clinical trials, making it a multi-functional drug. The most significant expansions include generalized anxiety disorder (GAD) (2007), fibromyalgia (2008), and chronic musculoskeletal pain (2010). The approval of these indications secured Cymbalta a significant position in the pain management market, making it one of Eli Lilly's blockbuster drugs.
Patent Expiration (2013): In December 2013, Cymbalta's primary patent in the United States expired, a phenomenon known as the "patent cliff."
Following the patent expiration, the FDA quickly approved several generic versions (generic name: duloxetine), leading to a significant drop in sales, but also enabling wider use of the drug at a lower price.
Verwenden
Antidepressant.
Definition
ChEBI: (S)-duloxetine is a duloxetine. It is an enantiomer of a (R)-duloxetine.
Trademarks
Cymbalta (Lilly).
Allgemeine Beschreibung
Duloxetine (Cymbalta) is a newer antidepressant. It islargely like venlafaxine, which is an SNERI (selective norepinephrinereuptake inhibitor).
Pharmakokinetik
Duloxetine appears to be fairly well absorbed after oral doses, with peak plasma levels in 6 to 10 hours and linear pharmacokinetics. The drug is extensively metabolized in the liver to active metabolites, with 72% of an oral dose primarily excreted in the urine as conjugated metabolites and up to 15% appearing in the feces.
N-demethylation to an active metabolite (CYP2D6) and hydroxylation of the naphthyl ring (CYP1A2) at either the 4-, 5-, or 6-positions are the main metabolic pathways for duloxetine. Its metabolites are primarily excreted into the urine as glucuronide, sulfate, and O-methylated conjugation products. The major metabolites found in plasma also were found in the urine. Preclinical data for 4-hydroxyduloxetine suggests it has a similar pharmacological profile to duloxetine, with selective inhibition of SERT but less activity at the NET.
Clinical Use
Duloxetine has been approved for the treatment of depression and diabetic peripheral neuropathic pain. It is another analogue in the line of fluoxetine-based products from Lilly, in which the phenyl and phenoxy groups of fluoxetine have been respectively replaced with the benzene isostere, thiophene, and a naphthyloxy group (previously described under fluoxetine). Duloxetine exhibits dual inhibition with high affinity for the SERTs and NETs, with a five times preferential inhibition of the SERT. Duloxetine appears to be a more potent in vitro blocker of SERTs and NETs than venlafaxine. In humans, duloxetine has a low affinity for the other neuroreceptors, suggesting low incidence of unwanted adverse effects.
Synthese
Reaction of 2-acetylthiophene with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)- 1-propanone, which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)- 3-methyl-1,2-diphenyl-2-butanol and LiAlH4 in toluene to yield (S)-3-(dimethylamino)- 1-(2-thienyl)-1-propanol. The condensation of (S)-3-(dimethylamino)-1-(2- thienyl)-1-propanol with 1-fluoronaphthalene catalyzed by NaH in DMSO affords the corresponding naphthyl ether (S)-N,N-dimethyl-3- (naphthalen-1-yloxy)-3-(thiophen-2-yl)propan- 1-amine, which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and zinc in toluene and treated with oxalic acid .
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: metabolism inhibited by ciprofloxacin - avoid.
Anticoagulants: possibly increased risk of bleeding with dabigatran.
Other CNS medication: enhanced effect.
Antidepressants: avoid with MAOIs, moclobemide, St John’s wort, tryptophan, venlaflaxine, amitriptyline, clomipramine and SSRIs due to increased risk of serotonin syndrome; increased risk of side effects with tricyclic antidepressants; fluvoxamine decreases the clearance of duloxetine by 77% - avoid; possible increased risk of convulsions with vortioxetine.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Dapoxetine: avoid concomitant use.
Methylthioninium: risk of CNS toxicity - avoid if possible.
Stoffwechsel
Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites, glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy, 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive

Duloxetine Upstream-Materialien And Downstream Produkte

Duloxetine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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