Imipramine preparations

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

The antidepressant agent tampramine (44-6) can be viewed as a distant analogue of imipramine that contains an extra benzene ring and two additional nitrogen atoms. The preparation of this compound starts by Ullman coupling of chloropyridine (44-1) with the aminobenzophenone (44-2) more frequently used for benzodiazepine syntheses. Reduction of the nitro group in the product (44-3) leads to a diamine (44-4) that readily cyclizes to form the pyridodiazepine (44-5). Alkylation of the anion from the treatment of this with sodium hydride with 3-chloro-1 -dimethylaminopropane affords tampramine (44-6) [44]. 

However some researchers challenged the view that antidepressants were disease-specific drugs. In 1964, a psychiatrist called E.H. Hare and his colleagues published a report of a controlled trial comparing Drinamyl a widely used preparation containing barbiturates and amphetamine, with imipramine. They found no difference between the two treatments and concluded that imipramine has no specific... 

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones (Khan 1999). Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action (Lahti Maickel 1971). In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin (Frazer Mendels 1977 Heydorn, Frazer, Mendels 1980 Schildkraut, Winokur, Applegate 1970). 

Tofranil [Novartis]. Proprietary preparation of imipramine hydrochloride. 

A number of variations of a tricyclic indole structure were prepared. Compound (8) was comparable in activity to imipramine in reversing ptosis and anticholinergic activity. Compound (9), which has the terminal N-benzyl function, was active in reversing reserpine ptosis and showed no anticholinergic and antihistaminic activity. Compound (10) was significant in that it demonstrated the importance of the location of the side chain, this form being inactive. 11... 

Conversely, in the tricyclic antidepressant series, the passage from the basic imipramine to the acidic amineptine conserved the antidepressant properties. In other words, there are no general rules available for the selection of the most appropriate solubilizing moiety. It is therefore recommended, that for each new solubilization problem, acidic, basic and neutral solubilized versions of the parent molecule be prepared. 

Carbamazepine is structurally related to phenytoin and to the tricyclic antidepressant, imipramine. The oral bioavailability of carbamazepine, which may depend on a particular pharmaceutical preparation, is 75 to 85%. After absorption, it is bound to plasma proteins to the extent of 60 to 70%. Carbamazepine is metabolized to its 10,11-epoxide and 10,11-dihydroxide derivatives, some of which are... 

In the early 1960s, there was a near-simultaneous introduction of carbamazepine and valproic acid and its derivatives, as new treatments for epilepsy. Although in 1882 Beverly S. Burton, an American working in Europe, had prepared valproic acid, its antiepileptic utility was not appreciated until this was serendipitously discovered 65 years later by Meunier in France. Carbamazepine was first synthesized in 1960, in the United States by Schindler — who, a decade earlier, had patented the stmcturally closely related imipramine and it was found to have antiepileptic properties. When concurrent remedial effects on mood and behaviour were noted with both carbamazepine and valproic acid in the very early epilepsy trials, both drags were soon appropriated by psychiatrists, first by Lambert in France (1966), using the amide derivative of valproic acid. 

However when high micromolar concentrations (200 micro M) of 5-HT or of 5-HT uptake inhibitors were used in determining the dissociation half life of H-imipramine, H-paroxetine and H-dtalopram dissociating from human platelet membrane preparations it appears that not only the dissociation half life was prolonged but also that the prolongation was different for each of the three labeled uptake inhibitors [24]. This led to the conclusion that the three labeled ligands each bind to a different domain on the 5-HT transporter. 

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