Doxepin

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Double resonance modulated spectroscopy pyridines and benzo derivatives, 2, 104 Dowicil S-13 as fungicide, 2, 515 Doxepin... 

Cyclization of 2-benzyloxybenzoic acid (66) by means of poly-phosphoric acid affords the dibenzoxepinone, 67. Condensation with the Grignard reagent from 3-dimethylaminopropyl chloride, followed by dehydration of the alcohol thus produced affords doxepin (68), presumably as a mixture of geometrical isomers. 

Figure 15.3 Separation of tricyclic antidepressants by using multidimensional LC-LC. Peak identification is as follows DOX, doxepin DES, desipramine NOR, noitryptylene IMI, imipramine AMI, amiti yptyline. Adapted from Journal of Chromatography, 507, J. V. Posluszny et al., Optimization of multidimensional high-performance liquid cliromatography for the deterTnination of drugs in plasma by direct injection, micellar cleanup and photodiode array detection , pp. 267 - 276, copyright 1990, with permission from Elsevier Science.

C) Preparation of Doxepin 1,530 grams of the product from step (B) is suspended in 4.5 liters dry tetrahydrofuran and 6.0 mols of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 483 grams of 6,1 I dihydrodibenz-lb.eloxepin-ll-one, prepared as described in Belgian Patent 641,49B, is added to the deep red solution and the reaction was maintained at reflux for 10 hours. Water, 500 ml, is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 1.5 liters benzene is added. After stirring, the mixture separates into 3 phases (an insoluble hydrochloride salt product phase, an aqueous phase and an organic phase). 

Butyl lithium Doxepin HCI Gemfibrozil Thiothixene Zimel idine... 

Benzethonium chloride Bephenium hydroxynaphthoate Camazepam Dibutoline sulfate Doxepin HCI Furtrethonium iodide Loperamide HCI Thiothixene... 

Dow-lsoniazid Isoniazid Dowmycin - Erythromycin Dow-Sulfisoxazole - Sulfisoxazole Doxal - Doxepin HCI Doxaprii - Doxapram HCI Doxedyn - Doxepin HCI Doxergan - Dxomemazine Doxidan Docusate calcium Doxi-OM - Dobesilate calcium Doxitard -Doxycycline Doxium - Dobesilate calcium Doxy - Doxycycline Doxy 200 - Doxycycline Doxylin - Doxycycline Doxy-Puren - Doxycycline Doxyremed - Doxycycline Doxytrex - Dobesilate calcium... 

NET Desipramine Maprotiline. mianserin Amoxapin. doxepine. nortriptyiine, duloxetine... 

Older tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipmmine, doxepine, noitriptyline, maprotiline) is limited because at therapeutic levels ihese drugs also block receptors (H t-histamine, a,-adrenergic, muscarinic). 

CiyH23N02 see Doxepin 9 i3-(dimethylamino)propyl]-9,10-dihydro-10,10-di-methyl-9-anthraceno]... 

Wikler A Opioid Dependence Mechanisms and Treatment. New York, Plenum, 1980 Williams JT, Christie MJ, Manzoni O Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 81 299—343, 2001 Woody GE, O Brien CR, Rickels K Depression and anxiety in heroin addicts a placebo-controlled study of doxepin in combination with methadone. Am J Psychiatry 132 447--i50, 1975... 

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