Paroxetine antidepressant

The chiral reduction of -substituted a,/3-unsaturated lactams with PMHS in the presence of (S)-/ -Tol-BINAP as the chiral ligand with a copper catalyst results in -substituted lactams in excellent yield and with greater than 90% ee.599 This method has been applied in an efficient enantioselective synthesis of the antidepressant (-)-paroxetine (Eq. 356). 

On the other hand, the analgesic phenylbutazone, the antidepressant paroxetine, tetracycline antibiotics doxycycline and chlorotetracycline, the antibiotics tilmico-sin, danofloxacin, enoxacin, nifuroxazide, the (3-blockers betaxolol, carazolol, pindolol, the (3-agonist clenbuterol, barbiturates, the antihypertensive lisinopril, and the drug to treat cancer tamoxifen were never detected. 

SSRI antidepressants (paroxetine = fluoxetine > sertraline > fluvoxamine)... 

Lorazepam is a short-acting benzodiazepine indicated for use in relieving anxiety and insomnia. Lorazepam may also be administered perioperatively to alleviate pain and in status epilepticus. Imipramine is a tricyclic antidepressant, paroxetine is a selective serotonin re-uptake inhibitor, venlafaxine is a serotonin and adrenaline re-uptake inhibitor and moclobemide is a reversible monoamine oxidase inhibitor. Imipramine, paroxetine, venlafaxine and moclobemide are all classified as antidepressants. 

Scheme 15.2 Parallel detoxication pathways that compete with the P450-catalyzed bioactivation pathway of the antidepressant paroxetine as explanation for its wide safety margin.

Keck ME, Welt T, Muller MB, Uhr M, Ohl F, Wigger A, Toschi N, Holsboer F, Landgraf R (2003) Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of the antidepressant paroxetine in a psychopathological rat model. Nem-opsychopharmacology 28 235-243... 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

On March 2, 2004, the Canadian Medical Association Journal reported on a 1998 internal GSK document that had been leaked to it (Kondro et al., 2004). The memorandum advised staff at the international drug giant GlaxoSmithKline (GSK) to withhold clinical trial finds in 1998 that indicated the antidepressant paroxetine... had no beneficial effect in treating adolescents. ... 

Miller A, Musselman D, Pena S, Su C, Pearce B, Nemeroff C. Pretreatment with the antidepressant paroxetine, prevents cytokine-induced depression during IFN-alpha therapy for malignant melanoma. Neuroimmunomodulation 1999 6 237. 

Paroxetine. Paroxetine is a selective serotonin reuptake inhibitor with demonstrated clinical utility as an antidepressant. Paroxetine is completely absorbed after oral ingestion and reaches peak steady-state levels of 30 to 70 ng/mL in approximately 5 hours. It xmdergoes hepatic metabolism by Cyp 2D6, has a half-life of 21 hours, and metabolites are inactive. Steady-state concentrations of paroxetine on a typical dose of 20mg/day are achieved in 10 days. Clinical response appears to be related to serum concentration and a chromatographic method is available. ... 

D6—typical antipsychotics, tricyclic antidepressants, paroxetine, fluoxetine ... 

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

Another Vita-Invest process was developed for the production of enantiop-ure 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ((3S,4i )-64), an intermediate suitable for the preparation of antidepressant Paroxetine (65, Scheme 20) [80]. Lipase from Candida antarctica A was found to catalyze the enantioselective hydrolysis of ester rac-trans-63 best and worked especially well immobilized onto a polyethyleneimine/agar support. The enantiomerically... 

In addition, a general route to substituted piperidines, including the antidepressant (-)-paroxetine, has been developed utilizing the additions to ni-troalkenes (Scheme 51) [105]. 

Andersen BB, Mikkelsen M, Versterager A, Dam MI, Kristensen HB, Pedersen B, Lund J, Mengel H. No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin. Epilepsy Res (1991) 10, 201-4. 

Amperozide, amphetamine, methamphetamine, bambuterol, antidepressants (paroxetine, fluvoxamine, mianserin, and citalopram), anabolic steroids (glucuronides) promethazine, methadone, haloperidol, ibuprofen, naproxen, ketoprofen, propofol, ropivacaine Pb(ll), Mn(ll)... 

A large number of unnatural molecules derived from these heterocycles are of great pharmaceutical importance, many of them being drug molecules currently in the market. Representative examples are shown in Figure 3.2, and include the antipsychotic haloperidol, the antidepressant paroxetine, the anti-HIV palinavir, the antihypertensive amlodipine, the cholesterol-lowering agent torcetrapib, and the mitosis inhibitor monastrol. 

Gill CD, Greenhalgh DA, Simpkins NS. Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine. Tetrahedron 2003 59(46) 9213-9230. 

Buchwald reported asymmetric copper-catalyzed conjugate reductions of a variety of a,/i-unsaturated acceptors [175, 176]. The reactions were demonstrated to proceed with optimal enantioinduction in the presence of a chiral copper catalyst incorporating p-tol-BINAP (240, Scheme 12.20). A convenient feature of these reductions is the use of the inexpensive polymeric polymethyl-hydrosiloxane (PMHS) as the stoichiometric reductant. Unsaturated lactam 239 undergoes reduction in 90% yield and 90% ee to give 241, a key intermediate in a synthesis of the antidepressant (-)-paroxetine (242) [176]. 

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