Tranylcypromine: Tranylcypromine, (±)-irans-2-phenylcyclopropylamine (7.2.10), differs from the drugs described above in that it is not a derivative of hydrazine. It is synthesized from the ethyl ester of 2-phenylcyclopropan carboxylic acid (7.2.7), which is synthesized by the reaction of styrene with ethyl diazoacetate. 2-phenylcyclopropan-carboxylic acid ethyl ester (7.2.7) is hydrolyzed by alkali to 2-phenylcyclopropancar-boxylic acid (7.2.8) and the trans-isomer is separated for further reactions. The reaction of the trans-isomer with thionyl chloride gives trans-2-phenylcyclopropancarboxylic acid chloride (7.2.9), which upon reaction with sodium azide gives the respective acid azide, which undergoes Curtius rearrangement to the transcyclopropylamine (7.2.10) [48,49].
As with the MAO inhibitor drugs described above, tranylcypromine is also used for depressions that do not respond to other drugs. Synonyms of this drug are transamin, par-modalin, parnate, and others.
7.3 SECOND-GENERATION ANTIDEPRESSANTS (ATYPICAL ANTIDEPRESSANTS)
A number of chemically dissimilar compounds that are not classified and do belong to either the class of tricyclic antidepressants or to the class of MAO inhibitors, exhibit very effective antidepressant activity.
It is very likely that their action is also due to the ability to inhibit the intake of norepinephrine or serotonin. However, because of the diversity of this group, the mechanism of action of each drug will be examined separately.
Amoxapine: Amoxapine, 2-chloro-11-(1-piperazinyl)-dibenz[b,f]oxazepine (7.3.2), is a direct analog of the neuroleptic loxapine (6.5.3), differing only in the absence of a methyl group in the piperazine region of the molecule. On the other hand, it could be included in the class of tricyclic antidepressants, the main difference being the presence of a side chain on the central 7-membered ring of the tricyclic system. Amoxapine, like loxapine, is synthesized from 2-(4-chlorobenzoxy)aniline, which as in loxapine synthesis is acidified with chlorocarbonic acid into (6.5.1) and further transformed into ureide (7.3.1) upon reaction with 1-carboethoxypiperazine. Cyclization by a mixture of phosphorous pentoxide and phosphorous oxychloride into the dibenzoxazepine and subsequent alkaline hydrolysis gives amoxapine (7.3.2) [50-53].
The antidepressant action of amoxapine is comparable to that of imipramine and amitripty-line. It exhibits antagonistic activity on dopamine (D2) receptors. Amoxapine is intended more for relieving symptoms in patients with neurotic or situational depression. It has a number of serious side effects. Synonyms of this drug are asendin, amoxan, moxadil, and others.
Bupropion: The synthesis of bupropion, 1-3(-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone (7.3.5), begins with the reaction of 3-chlorobenzonitrile, with ethylmagnesium bromide to give 3-chloropropiophenone (7.3.3). Brominating this with bromine gives 3-chloro-a-bromopropiophenone (7.3.4), which on reaction with ieri-butylamine gives bupropion (7.3.5) [54-58].
¿ h—CSEN -^-CH^CH3 -» ^C^CH3-►¿;>-C-CH-NH-C(CH3)3
Bupropion is an a-aminoketone that is structurally related to amphetamines, and it exhibits unique activity comparable to that of other antidepressants. It is believed that bupropion restores the total amount of norepinephrine in the body. This compound is a poor reuptake inhibitor of dopamine, and does not exhibit anticholinergic activity or inhibit MAO. Its efficacy as an antidepressant is comparable to that of tricyclic antidepressants, and as a serotonin uptake inhibitor it is comparable to fluoxetine. It is preferable to use amoxapine. Synonyms of bupropion are amphebutamon and wellbutrin.
Fluoxetine: Fluoxetine, 3-[p-(trifluoromethyl)-phenoxy]-N-methyl-3-phenylpropylamine (7.3.6), is synthesized by reaction of p-trifluoromethylphenol with 3-(chloro)-N-methyl-3-phenylpropylamine in the presence of potassium carbonate [59,60].
Fluoxetine is a phenylpropylamine that inhibits the neuronal reuptake of serotonin, which presumably has a direct relationship on antidepressant activity. This compound has either no effect or a small effect on the neuronal reuptake of norepinephrine and dopamine. In addition, it does not bind to cholinergic, histaminergic, or a-adrenergic receptors, which is believed to be the cause of tricyclic antidepressant side effects.
The efficacy of fluoxetine in treating patients with moderate depression is comparable to the efficacy of tricyclic antidepressants. It is capable of elevating mood and removing feelings of fear and stress. It does not have a sedative effect. Fluoxetine is used in depression as well as in bulemic neuroses. Use of fluoxetine is preferred in cases when sedative, hypotensive, and anticholinergic side effects caused by other antidepressants are con-traindicative to patients. Prozac is a synonym for fluoxetine.
Trazodone: Trazodone, 2-[3-[4-(m-chlorophenyl)-1-piperazineyl]propyl]-s-triazolo[4,3-a] piridine-3(2H)-one (7.3.8), is synthesized from 2-chloropiridine, the reaction of which with semicarbazide gives s-triazolo-3-one[4,3-a]pyridine (7.3.7). Alkylation of this product using 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine gives trazodone (7.3.8) [61,62].
CY-'CI H2N-HN-C-NH2 xíVÍN ^—' ^—' ^-„sN . .
T —-^ i II N-H -»■ I IT N—CH2—CH2—N N—(\ /)
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