Paroxetine

Synthesis

Accordingly, methyl acrylate 8 was refluxed with BnNH2 9 in the presence of Et3N to give correspondong double Michael adduct, which upon Dieckmann condensation using NaH in refluxing benzene furnished β-ketoester, which exists as a mixture of 10 and 11. Borohydride reduction of the ketoester followed by mesylation of the resultant alcohol and subsequent elimination provided α,β-unsaturated ester 12. Benzyl protection was then exchanged with methyl carbamate to furnish compound 13 and was subjected to Heck coupling under solvent-free conditions. Delightingly, carbamate 13 furnished the corresponding free amine 14, albiet in moderate yields (scheme 4). Conversion of 14 to paroxetine 7 is reported in the literature. Also, carbamate of 15 was prepared from 14 whose conversion to paroxetine 7 is known.

Description

Paroxetine is a new highly selective serotonin reuptake inhibitor, mechanistically similar to fluoxetine, fluvoxamine and sertraline, introduced for the treatment of all types of depressive illnesses including depression associated with anxiety. It is reportedly non-sedating and non-stimulatory and compared to fluoxetine has a shorter duration of action (half-life of 24 hours versus 2 to 3 days). Paroxetine is also being investigated as a treatment for obesity, alcoholism and obsessive-compulsive disorders.

Chemical Properties

White Solid

Originator

As Ferrosan (Novo-Nordisk) (Denmark)

Uses

A istopically labelled selective serotonin reuptake inhibitor. Used as an antidepressant

Definition

ChEBI: Paroxetine is a benzodioxole that consists of piperidine bearing 1,3-benzodioxol-5-yloxy)methyl and 4-fluorophenyl substituents at positions 3 and 4 respectively; the (3S,4R)-diastereomer. Highly potent and selective 5-HT uptake inhibitor that binds with high affinity to the serotonin transporter (Ki = 0.05 nM). Ki values are 1.1, 350 and 1100 nM for inhibition of [3H]-5-HT, [3H]-l-NA and [3H]-DA uptake respectively. Displays minimal affinity for alpha1-, alpha2- or beta-adrenoceptors, 5-HT2A, 5-HT1A, D2 or H1 receptors at concentrations below 1000 nM, however displays weak affinity for muscarinic ACh receptors (Ki = 42 nM). Antidepressant and anxiolytic in vivo. It has a role as an antidepressant, an anxiolytic drug, a serotonin uptake inhibitor, a hepatotoxic agent and a P450 inhibitor. It is a member of piperidines, a member of benzodioxoles, an organofluorine compound and an aromatic ether. It is functionally related to a monofluorobenzene. It is a conjugate base of a paroxetinium(1+).

Manufacturing Process

251 g of methyl-4-(4-fluorophenyl)-N-methyl-nipecotinate, 8 g of sodium methoxide and 500 ml benzene were refluxed for 2 h. The benzene solution was washed with cold water and evaporated to give the pure α-ester which was dissolved in a mixture of 320 ml of water and 450 ml concentrated hydrochloric acid. The solution was slowly distilled to remove methanol and finally evaporated to dryness in vacuo.
400 ml thionyl chloride were added in small portions to the solid. The mixture was allowed to stand for 3 h at room temperature and was then evaporated to dryness in vacuo with tetrachloroethane giving methyl-4-(4-fluorophenyl)-Nmethylnipecotic acid chloride. The acid chloride was added in small portions to a solution of 160 g (-)-menthol in 800 ml pyridine at a temperature of 0°-5°C. The mixture was allowed to stand at room temperature to the next day. Ice water and 50% sodium hydroxide were added, and the mixture was extracted with ether. The ether was dried with anhydrous magnesium sulphate, filtered and evaporated. Distillation in vacuo gave the menthol ester in a yield of 7580%. Boiling point at 0.05 mm Hg was 165°-170°C.
Racemic 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (50 g) was dissolved in a mixture of 21.6 ml of concentrated sulfuric acid and 50 ml of water. To the solution were added 25 ml of concentrated hydrochloric acid and 22.4 ml of 37% formaldehyde solution. The mixture was refluxed for 5 h, cooled, and 125 ml of concentrated ammonia were added. The mixture was extracted with 50 ml of toluene. Drying of the toluene solution and distillation gave 38 g of 4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine with boiling point 110°-120°C at 0.1 mm Hg.
13 g of the racemic compound and 22 g of (-)-dibenzoyltartaric acid were dissolved in 105 ml of hot methanol. On cooling, 9 g of salt of (-)-4-(4fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine crystallized. Melting point 167°-168°C.
38 g of (-)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6tetrahydropyridine were dissolved in 350 ml of 99% ethanol, 5 g of 5% palladium on carbon were added, and the mixture was treated with hydrogen until 4500 ml were absorbed. The catalyst was filtered off, and the solution was evaporated to yield 37.5 g of (+)-b-4-(4-fluorophenyl)-3-hydroxymethyl1-methylpiperidine.
To a solution of sodium in methanol (125 ml) were added 3,4methylenedioxyphenol (29 g) and the (+)-b-4-(4-fluorophenyl)-3hydroxymethyl-1-methylpiperidine (37,5 g). The mixture was stirred and refluxed. After removal of the solvent in vacuo, the evaporation residue was poured into a mixture of ice (150 g), water (150 ml), and ether (200 ml). The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether solutions were washed with water and dried with anhydrous magnesium sulphate, and the ether was evaporated. The residue was triturated with 200 ml of 99% ethanol and 11.5 ml of concentrated hydrochloric acid, yielding 30 g of (-)-b-4-(4-fluorophenyl-3-(1,3-benzdioxolyl(3)-oxymethyl)-1-methylpiperidine, hydrochloride were obtained. Melting point 202°C.

brand name

Paxil[as hydrochloride] (SmithKline Beecham);Seroxat.

Therapeutic Function

Antidepressant

Biological Functions

Paroxetine (Paxil) has an elimination half-life of 21 hours and is also highly bound to plasma proteins, so it requires special attention when administered with drugs such as warfarin. Paroxetine is a potent inhibitor of the cytochrome P450 2D6 isoenzyme and can raise the plasma levels of drugs metabolized via this route. Of particular concern are drugs with a narrow therapeutic index, such as TCAs and the type 1C antiarrhythmics flecainide, propafenone, and encainide. Additionally, paroxetine itself is metabolized by this enzyme and inhibits its own metabolism, leading to nonlinear kinetics. Weight gain is higher with paroxetine than with the other SSRIs, and it tends to be more sedating, presumably because of its potential anticholinergic effects. Additionally, patients have had difficulty with abrupt discontinuation with this agent, reporting a flulike syndrome; this symptom can be avoided by tapering the medication.

General Description

In the structure of paroxetine (Paxil), an amino group, protonatedin vivo could H-bond with the–CH₂–O– unshared electrons.A β-arylamine–like structure with an extra aryl groupresults. The compound is a very highly selective SERT. Asexpected, it is an effective antidepressant and anxiolytic.

Pharmacokinetics

Paroxetine appears to be slowly but well absorbed from the GItract following oral administration with an oral bioavailability of approximately 50%, suggesting first-pass metabolism, reaching peak plasma concentrations in 2 to 8 hours. Food does not substantially affect the absorption of paroxetine. Paroxetine is distributed into breast milk. Approximately 80% of an oral dose of paroxetine is oxidized by CYP2D6 to a catechol intermediate, which is then either O-methylated or O-glucuronidated. These conjugates are then eliminated in the urine.
Paroxetine exhibits a preincubation-dependent increase in inhibitory potency of CYP2D6 consistent with a mechanism-based inhibition of CYP2D6. The inactivation of CYP2D6 occurs via the formation of an o-quinonoid reactive metabolite.
The methylenedioxy has been associated with mechanism-based inactivation of other CYP isoforms. In contrast, fluoxetine, a potent inhibitor of CYP2D6 activity, did not exhibit a mechanism-based inhibition of CYP2D6. As a result of mechanism-based inhibition, saturation of CYP2D6 at clinical doses appears to account for its nonlinear pharmacokinetics observed with increasing dose and duration of paroxetine treatment, which results in increased plasma concentrations of paroxetine at low doses. The elderly may be more susceptible to changes in doses and, therefore, should be started off at lower doses. Following oral administration, paroxetine and its metabolites are excreted in both urine and feces.
Oral administration of a single dose resulted in unmetabolized paroxetine accounting for 2% and metabolites accounting for 62% of the excretion products. The effect of age on the elimination of paroxetine suggests that hepatic clearance of paroxetine can be reduced, leading to an increase in elimination half-life (e.g., to ~36 hours) and increased plasma concentrations. The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of 5-HT reuptake; therefore, they are essentially inactive.
Because paroxetine is a potent mechanism-based inhibitor of CYP2D6, this type of inhibition yields nonlinear and long-term effects on drug pharmacokinetics, because the inactivated or complexed CYP2D6 must be replaced by newly synthesized CYP2D6 protein. Thus, coadministration of paroxetine with CYP2D6- metabolized medications should be closely monitored or, in certain cases, avoided, as should upward dose adjustment of paroxetine itself.

Clinical Use

In vitro binding studies suggest that paroxetine is a more selective and potent inhibitor of 5-HT reuptake than fluoxetine. The drug essentially has no effect on NE or dopamine reuptake, nor does it show affinity for other neuroreceptors. Its onset of action is 1 to 4 weeks.

Veterinary Drugs and Treatments

Paroxetine may be beneficial for the treatment of canine aggression, and stereotypic or other obsessive-compulsive behaviors. It has been used occasionally in cats as well.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of bleeding with aspirin and NSAIDs; risk of CNS toxicity increased with tramadol; concentration of methadone possibly increased.
Anti-arrhythmics: possibly inhibits propafenone metabolism (increased risk of toxicity).
Anticoagulants: effect of coumarins possibly enhanced; possibly increased risk of bleeding with dabigatran.
Antidepressants: avoid concomitant use with MAOIs and moclobemide (increased risk of toxicity); avoid with St John’s wort; possibly enhanced serotonergic effects with duloxetine; can increase concentration of tricyclics; possible increased risk of convulsions with vortioxetine.
Antiepileptics: antagonism (lowered convulsive threshold); concentration reduced by phenytoin and phenobarbital.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: concentration of clozapine and possibly risperidone increased; metabolism of perphenazine inhibited, reduce dose of perphenazine; possibly inhibits aripiprazole metabolism, reduce aripiprazole dose; concentration possibly increased by asenapine; increased risk of ventricular arrhythmias with pimozide - avoid.
Antivirals: concentration possibly reduced by darunavir and ritonavir.
Beta blockers: concentration of metoprolol possibly increased - increased risk of AV block - avoid in cardiac insufficiency.
Dapoxetine: possible increased risk of serotonergic effects - avoid.
Dopaminergics: increased risk of hypertension and CNS excitation with selegiline - avoid; increased risk of CNS toxicity with rasagiline - avoid.
Hormone antagonists: metabolism of tamoxifen to active metabolite possibly reduced - avoid.
5HT1 agonists: risk of CNS toxicity increased by sumatriptan - avoid; possibly increased risk of serotonergic effects with naratriptan.
Lithium: increased risk of CNS effects - monitor levels.
Methylthioninium: risk of CNS toxicity - avoid if possible.

Metabolism

Paroxetine is extensively metabolised in the liver to pharmacologically inactive metabolites.
Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.