Other phenylpropylamines

The very slow onset of action and side effects which follow from the anticholinergic side effects characteristic of the tricyclic antidepressants has led to a continuing effort to find replacements from other structural classes which might thus be devoid of this defect. A series of alkoxy phenylpropylamines has been investigated extensively in this search for non-tricyclic antidepressants. The most recent analogue, tomoxetine (69), is accessible by the same route [15] used to prepare the earlier analogue, nisoxetine, in which methoxyl replaces the ortho methyl group. 

The (n)-propylamine counterpart (as if one were to move the amine function the other direction, from the beta-carbon to the gamma-carbon of the three carbon chain of the amphetamine molecule) is gamma-3,4-methylenedioxy-phenylpropylamine or 1 -amino-3-(3,4-methylenedioxyphenyl)propane, GAMMA. The hydrochloride salt has a mp of 204-205 °C. At oral levels of 200 milligrams there was some physical ill-at-ease, possible time distortion, and a feeling of being keenly aware of one s surroundings. The duration of effects was 4 hrs. 

Although the above commercial process succeeded in providing R-l-methyl-3-phenylpropylamine (VIII) for significantly less than 100/kg several other companies carried out research to find even lower cost processes based on the RS raw material. A few of these processes will be described later. 

These effects are produced mostly by phenylpropanolamines present in the leaves. These include cathinone [4] (5 -a-aminopropiophenone), cathine [5] [(-)-IS, 2S-norpseudoephedrine] and (-) -IR, 2S-norephedrine (8). These substances have pharmacological properties similar to those of amphetamine [6] (81), as they induce the release and inhibit the uptake of dopamine and norepinephrine in CNS (82). In addition to the known phenylpropylamines, the presence of other amines such as meracathine, pseudomeracathine and meracathinone have been identified (83, 84). Cathinone, being a ketoamine base, is extremely unstable and, in particular, it can be transformed into (+)-norpseudoephedrine and (-)-norephedrine by an enzymatic reduction. It can also be oxidized to give 1-phenyl-l,2-propandione, while the cathinone dimers, such as 3,6-dimethyl-2,5-diphenylpyrazine are purely artifacts of the isolation (85). 

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