Other Tricyclic Compounds

CNS effects Because of the drug s relationship to other tricyclic compounds, the possibility of activating latent psychosis, confusion, or agitation in elderly patients may occur. 

There is evidence that doxepin is significantly less cardiotoxic than other tricyclic compounds (53). However, a complete review of all the animal and clinical data has suggested that doxepin overdose can still cause lethal dysrhythmias in man, probably by producing more marked respiratory depression. 

Three different studies have shown that there is less risk of hypotension in patients treated with nortriptyline (54-56) than with other tricyclic compounds. However, a similar claim has been made for doxepin (57). 

Amineptine has a seven-membered carbon side-chain and is reported to have more stimulant and fewer sedative effects than other tricyclic compounds, possibly owing to differential actions on dopaminergic rather than serotonergic mechanisms. Amineptine appears to have an unusual propensity for causing hepatocellular damage, which may limit its clinical use (2). 

Many other tricyclic compounds embracing two as the norcaradiene system can be stable in the closed propellane form certainly when the oxidation state is still lower, the propellane form does not open . 

Some C(3) modifications are described in other sections the preparation of penems in Section 5.11.4.6, and the synthesis of the tricyclic compound (26) in Scheme 10. 

Two rather broad structural classes account for the large majority of drugs that have proven useful in the clinic for treating depression. Each of these has associated with it some clearly recognized side effects the monoamine oxidase inhibitors, most commonly derivatives of hydrazine, tend to have undesirable effects on blood pressure the tricyclic compounds on the other hand may cause undesirable changes in the heart. Considerable effort has thus been expended toward the development of antidepressants that fall outside those structural classes. An unstated assumption in this work is the belief that very different structures will be associated with a novel mechanism of action and a different set of ancillary activities. One such compound, trazodone... 

The de Meijere group [63] prepared interesting spiro-compounds containing a cyclopropyl moiety using a combination of a Heck and a Diels-Alder reaction, with bicyclopropylidene 6/1-115 as the starting material. The transformation can be performed as a three-component process. Thus, reaction of 6/1-115, iodobenzene and acrylate gave 6/1-116 in excellent yield. With vinyliodide, the tricyclic compound 6/1-117 was obtained (Scheme 6/1.31). Several other examples were also described. 

The azatriquinane 36a which may be regarded as an annulated bis-pyrrolizine readily undergoes stereoselective hydrogenation in presence of rhodium on alumina, leading to the fully saturated tricyclic compound with a trans relative orientation between the benzyl group and the two hydrogen atoms located on the two other junctions carbon atoms <2005JA1352>. 

Unfortunately, the situation is even more complicated In bi- and tricyclic compounds the a-SCS may experience further alterations apparently produced by intramolecular strain. The usually large a-SCS(CH3) in 1-methyl-bicyclo[2.2.1]heptane (9) (93) has already been mentioned. The a-effects of other substituents (OH, OCH3, Cl, I, and COOH) in the same molecular system do not correlate with those in bridgehead-substituted bicyclo[2.2.2]octanes or adamantanes again this was attributed to internal strain (125). The a-SCS(F)... 

Tryptophan and its derivatives can be characterized as existing in three possible tautomers the indole form, the indolenine form (hydrogen atom at position 3), and the cyclic form. In neutral solvents only the indole form exists NMR studies indicate no evidence for the other two isomers (60JA2184). However, when dissolved in 85% phosphoric acid or TFA, N-methoxycarbonyltryptophan exists as a pyrrolo[2,3-i]indole derivative 119 (78JA5564 81T1487). Although the tricyclic compound is stable in the crystalline form, it reverts to the starting material when it dissolves in acetic acid or methanolic HCl. 

Many antidepressant drugs have pronounced effects on sleep. Several tricyclic compounds (amitriptyline and others) have sedative actions while others (imipramine and others) are less sedative or even stimulant. Monoamine oxidase inhibitors (MAOIs) have central stimulant effects and may cause insomnia. Specific serotonin reuptake inhibitors (SSRls) and combined serotonin, noradrenaline reuptake inhibitors (SNRIs) can also cause insomnia. 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

The clinical and commercial success of the antidepressant compound fluoxetine (Chapter 2 Prozac) engendered considerable work in other laboratories. A benzo-dioxan based compound that shows similar activity shares only a few stmctural features with the prototype. The benzodioxan nucleus (68-3) is formed by an alkylation reaction between the fluorocatechol (68-1) and the derivative (68-2) from meso, and hence achiral, butanetetrol. The benzyl protecting groups are then removed by hydrogenation over palladium, and the thus-obtained diol is converted to the fiii-toluene-sulfonate (68-4) by reaction with toluenesulfonyl chloride. Treatment of that intermediate with benzylamine leads to fiw-alkylation on the same nitrogen to form a pyrrolidine ring and thus the tricyclic compound (68-5). A second hydrogenolysis step then leads to fluparoxan (68-6) [70]. 

Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well. 

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