Duloxetine Chemical Properties

Boiling point:

466.2±40.0 °C(Predicted)

Density 

1.158±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

Soluble in DMSO

pka

10.02±0.10(Predicted)

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 Substance Registry System

2-Thiophenepropanamine, N-methyl-?-(1-naphthalenyloxy)-, (?S)- (116539-59-4)

Safety Information

Hazardous Substances Data

116539-59-4(Hazardous Substances Data)

Duloxetine Usage And Synthesis

Uses

Antidepressant.

Definition

ChEBI: (S)-duloxetine is a duloxetine. It is an enantiomer of a (R)-duloxetine.

brand name

Cymbalta (Lilly).

General Description

Duloxetine (Cymbalta) is a newer antidepressant. It islargely like venlafaxine, which is an SNERI (selective norepinephrinereuptake inhibitor).

Pharmacokinetics

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.

Synthesis

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 .

Drug interactions

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.

Metabolism

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(116539-59-4)Related Product Information

• Paroxetine
• Duloxetine intermediate
• Duloxetine intermediate AA
• Duloxetine hydrochoride
• (rs)-duloxetine hydrochloride,(rs)-n-methyl-gama-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride
• (r)-duloxetine,R-DULOXETINE HCL,(r)-n-methyl-gama-(1-naphthalenyloxy)-2-thiophenepropanamine
• (S)-(+)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
• Duloxetine
• Duloxetine hydrochloride
• 4-Hydroxy Duloxetine
• 4-Hydroxy Duloxetine -D-Glucuronide,4-Hydroxy Duloxetine b-D-Glucuronide
• S-(+)-N,N-DIMETHYL-3-(1-NAPHTHLENYLOXY)-3-(2-THIENYL)-PROPANAMINE
• Duloxetine-d3 HCl
• R-DULOXETINE HYDROCHLORIDE
• Duloxetine-naphthyl-D7 Maleate
• DULOXETINE MALEATE
• 5-Hydroxy-6-methoxy Duloxetine
• 5-Hydroxy-6-methoxy duloxetine sulfate