Uses
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
Description
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 (Ki=7.5 nM) and 5-HT transporters (Ki=0.8 nM)
than venlafaxine (Ki=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 (Ki=300nM in rat brain
preparations) and shows only weak affinity for muscarinic, α1-and α2 adrenergic
and histamine H1 receptors （Ki=＞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 Cmax 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 least 50%
reduction in pain score from baseline. All doses of duloxetine resulted in superior
results than placebo. In phase III studies of adult women with predominant symptoms of SUI (n=1635), duloxetine 40 mg twice daily reduced the median
incontinence episode frequency from baseline to a significantly greater extent than
placebo (50.0–53.6% versus 27.5–40.0%). In addition, duloxetine recipients experienced
significantly greater increases in their average voiding interval than placebo
recipients (15.0–20.4 versus 1.7–8.5 minutes). The most commonly observed adverse
events associated with duloxetine therapy are nausea, dry mouth, constipation,
decreased appetite, fatigue, somnolence, and increased sweating. As with other
5-HT reuptake inhibitors, duloxetine is contraindicated in patients taking MAO
inhibitors. Additionally, it is contraindicated in patients with uncontrolled narrowangle
glaucoma.
Synthesis
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).
