Duloxetine hydrochloride

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

Duloxetine hydrochloride Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.

• Beschreibung

  Duloxetine is a selective serotonin (5-HT) and norepinephrine reuptake inhibitor (SSNRI) for oral administration, and it is currently approved in the US and in Europe for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain (DPN). Additionally, it is indicated for the treatment of stress urinary incontinence (SUI) in Europe. However, the US approval for SUI is still pending, and Lilly recently withdrew the NDA for this indication. It is expected that additional clinical trials may be required to secure FDA approval for SUI treatment due to concern over the potential of duloxetine to prolong the QT interval in patients taking concomitant CYP2D6 or CYP1A2 inhibitors such as tricyclic antidepressants, type 1C antiarrhythmics and phenothiazines. Duloxetine is the second SSNRI to enter the market. Its predecessor, venlafaxine, has been available since 1994 for the treatment of depression. Duloxetine has a higher affinity for human norepinephrine (K_i=7.5 nM) and 5-HT transporters (K_i=0.8 nM) than venlafaxine (K_i=2480nM and 82nM, respectively). Additionally, it shows a more balanced ratio of 5-HT to norepinephrine uptake inhibition than venlafaxine. Duloxetine is a moderate inhibitor of dopamine reuptake (K_i=300nM in rat brain preparations) and shows only weak affinity for muscarinic, α1-and α2 adrenergic and histamine H1 receptors （K_i=＞2.3μ）. It is devoid of any activity against monoamine oxidase. In vivo, duloxetine inhibits 5-HT and norepinephrine uptake in rats, with ED₅₀ values of 12 mg/kg and 22 mg/kg p.o., respectively, and has no effect on dopamine uptake at doses up to 30 mg/kg. The antidepressant and central paininhibitory action of SSNRIs are derived from the inhibition of both 5-HT and norepinephrine uptake, which increases the availability of neurotransmitters and ultimately increases serotonergic and noradrenergic function within the CNS. In the treatment of SUI with duloxetine, the increased neurotransmitter concentration is believed to increase the tone and contractions of the urethral sphincter at the opening of the bladder, helping to prevent accidental urine leakage. The absolute stereochemistry of duloxetine is shown to be S(+). It is prepared in four steps starting from 2-acetylthiophene. A key intermediate in the synthesis of duloxetine is (S)-3-dimethylamino-1-(2-thienyl)-1-propanol, which is obtained from the corresponding ketone, either by reduction with sodium borohydride and subsequent chiral resolution of the alcohol product with S-mandelic acid, or by enantioselective reduction with a chiral amine complex of lithium aluminum hydride. Etherification of this intermediate with 1-fluoronaphthalene, followed by N-demethylation with trichloroethylchloroformate affords duloxetine. Orally administered duloxetine is well absorbed, with C_max achieved in 6 hours post dose. It exhibits dose-proportional pharmacokinetics at doses of 20–40 mg twice daily, with an average bioavailability of about 50% and an elimination half-life of about 12 hours. The volume of distribution is high (1943 L) and steady-state plasma levels are achieved after 3 days of dosing. Duloxetine is extensively metabolized, mainly by CYP2D6 and CYP1A2. The primary routes of elimination are in the urine (70%) and in the feces (20%). The recommended dosages of duloxetine are 20 mg to 30 mg twice daily for treating MDD, 60 mg once daily for treating DPN, and 40 mg twice daily for treating SUI. In clinical trials with adult MDD outpatients (n =1059), duloxetine at doses of 40–120 mg daily for 8 to 9 weeks demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale total score. In trials involving 791 DPN patients, 60 and 120 mg once daily dose of duloxetine statistically significantly improved the endpoint mean pain scores from baseline, and increased the proportion of patients with at le

• Chemische Eigenschaften

  White Crystalline Solid

• Originator

  Lilly (US)

• Verwenden

  Duloxetine Hydrochloride acts as an antidepressant and a dual serotonin and norepinephrine reuptake inhibitor (SNRI) (1,2). Exhibits linear pharmacokinetics in mice and is not associated in any drastic changes of blood pressure or heart rate (3).

• Verwenden

  solubility H2O: soluble5 mg/mL (clear solution, warmed)

• Verwenden

  anti-depressant, analgesic for osteoarthiritis and musculoskeletal pain

• Verwenden

  An antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Used in treatment of stress urinary incontinence.

• Verwenden

  leucotriene antagonist, antiasthmatic

• Verwenden

  Labelled Duloxetine, which is used as an antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Current lot is 97% d7 with no d0, d1 or d2

• Definition

  ChEBI: A duloxetine hydrochloride in which the duloxetine moiety has S configuration.

• Trademarks

  Cymbalta (Lilly).

• Allgemeine Beschreibung

  Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards

• Biochem/physiol Actions

  Duloxetine hydrochloride is a dual serotonin/norepinephrine reuptake inhibitor (SNRI), widely used clinically as an antidepressant and anxiolytic.

• Synthese

  The synthesis from Lilly?ˉs group is depicted in Scheme 4. Friedel-Crafts acylation of thiophene (24) by 3- chloropropanoyl chloride (25) with SnCl4 as Lewis acid gave ketone 26 which was then enantioselectively reduced with (R )-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2- c][1,3,2]oxazaborole (27) in the presence of borane in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (28). Compound 28 was subjected to Finkelstein reaction to give (S)-3-iodio-1-(2-thienyl)-1-propanol which was reacted with methylamine in THF to give compound 29. The alcohol 29 was then used in a nucleophilic displacement reaction with 1-fluoronaphthalene (30) in the presence of sodium hydride in DMA to give duloxetine free base in 88% yield. Finally, the free base was treated with HCl to yield duloxetine hydrochloride (IV).

  

• Lager

  Room temperature

Duloxetine hydrochloride Upstream-Materialien And Downstream Produkte

Duloxetine hydrochloride Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(714)Suppliers

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