Tranylcypromine

CgHjiN. Liquid, b.p. 79 C. Used as the hydrochloride, C HnN HCI, with m.p. 164°C. Tranylcypromine is an inhibitor of monamine oxidase and is administered orally in the treatment of depressive illness. 

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

Like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. For example, the antidepressant drug tranylcypromine is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride. 

Hammond postulate and, 197-199 Translation (RNA), 1109-1111 Tranylcypromine, synthesis of, 935 Tree diagram (NMR), 466 Triacylglycerol, 1061... 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Benazepril Docetaxel Fluazacort Imiquimod Irbesartan Midodtine Oseltamivir Paclitaxel Pemirolast Pranlukast Tazanolast Tranylcypromine Zanamivir Zidovudine sodium benzenesultinate... 

With the exception of tranylcypromine (a phenylcycloalkylamine), the first MAOIs (e.g. iproniazid, isoniazid, phenelzine, isocarboxazid) were derivatives of hydrazine (originally used as a rocket fuel) (Fig. 20.2). All are irreversible inhibitors of the enzyme and restoration of MAO activity requires the synthesis of new enzyme. 

MAO has been inhibited. As a result, transmitter accumulates in the cytoplasm and is exported into the synapse via the membrane-bound transporter. The ensuing (impulse-independent) sympathetic arousal can be disastrous, culminating in a hypertensive crisis and stroke. Although this process is a pharmacological curiosity and certainly contributed to the demise of MAOIs, it is possibly overrated (Tyrer 1979) it has been estimated that the number of deaths associated with the use of the MAOI, tranylcypromine, amounts to only 1 per 14000 patient years. However, this sequence of events echoes exactly the acute actions of methylenedioxymethamphetamine (MDMA, Ecstasy ) and undoubtedly accounts for some of the deaths attributed to this drug. 

Ferrer, A and Artigas, F (1994) Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain. Eur. J. Pharmacol. 263 227-234. 

Fillenz, M and Stanford, SC (1981) Vesicular noradrenaline stores in peripheral nerves of the rat and their modification by tranylcypromine. Brit. J. Pharmacol. 73 401-404. 

Isocarboxizid, phenelzine, selegiline, tranylcypromine, moclobemide, clorgiline, and linezolid... 

Monoamine oxidase inhibitors (phenelzine, tranylcypromine, possibly linezolicl)... 

Clinical success with the monoamine oxidase inhibitor and amphetamine analogue tranylcypromine (27) led to... 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

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