Substituted benzamides

Reaction 12, the acid-catalyzed hydrolysis of substituted benzamides, has p = — 0.22, so the reaction is modestly facilitated by electron-donating groups. This suggests that protonation of the amide is kinetically important ... 

Amisulpride is a substituted benzamide, which acts as a highly selective blocker of D2 and D3 receptors (Kerwin, 2000). As with all the other drugs, it can easily be demonstrated to be effective compared with placebo and haloperidol, with a lower extrapyramidal symptom profile (Moller et al, 1995). The strength of amisulpride lies in the quality of the evidence to show that it is effective against primary negative symptoms and affective symptoms. Two studies have shown convincing superiority for negative symptoms... 

Now that steric parameters have been introduced in this way, the treatment can be extended to include the reactions of o-substituted benzene derivatives as well. Thus for the acid-catalysed hydrolysis of o-substituted benzamides (43), the value of 8 is found to be 0-81 so this reaction is apparently slightly less susceptible to the steric... 

Domestic ferret, Mustelus putorius 2, 4, or 6 Gy single brief exposure adult males All doses depressed locomotion vomiting in 22 min at 2 Gy, 13 min at 4 Gy, and 11 min at 6 Gy. Various substituted benzamides reduced vomiting 36... 

Substituted benzamides + OH - CTABr + OH -. Possible micellar effects on mechanism Broxton et al., 1981... 

Many DA receptor antagonists (neuroleptics) for treating psychoses (for example, schizophrenia) have become efficient medicines. However, most of them induce severe extrapyramidal side-effects (EPS) akin to parkinsonian symptoms and also, more seriously, they induce tardive dyskinesias (TD). There is a need for improvements in the neuroleptics in the clinic. The substituted benzamides are D2 antagonists, some of which display a high degree of limbic selectivity. Such a regional selectivity has been suggested to be beneficial from the side-effects point of view [11,12]. 

Birch reduction-methylation of the 2,3-dialkyl substituted benzamide 85 (Scheme 19) provided the cyclohexa-1,4-diene 86 with diastereoselectivity comparable to that observed with the 2-alkylbenzamides illustrated in Scheme 4. Cyclohexadiene 86 was converted to iodolactone 87 and reduction of 87 with BusSnH occurred with exclusive equatorial delivery of hydrogen to give the axial methoxyethyl derivative 88. Lactone 88 was converted to the Caribbean fruit fly pheromone (+)-epia-nastrephin 90 (> 98% ee) in 9.5% overall yield from the chiral benzamide 85. °... 

The reactions of a limited number of Af,Af-dialkoxyamides have been investigated . While they are relatively stable at RT, at temperatures above 100 °C in mesitylene, Af,A-dimethoxy-4-substituted benzamides (194) have been found to undergo unimolec-ular decomposition giving parent hydroxamic ester (195), methyl esters (196) and N-methoxy-Af-(3,5-dimethylbenzyl)benzamides (197) (equation 25). 

TABLE 12. Arrhenius parameters and rate constants at 373 K for radical decomposition of A,A-dimethoxy-4-substituted benzamides (194a-d) ... 

Tiapride and sulpiride are neuroleptics of the substituted benzamide class. These selective Dj blockers have weak antipsychotic properties and are not available in the United States, although they are commonly used in Europe for the treatment of tics. In a pair of 6-week controlled trials involving 27 children with TS, at doses ranging from 4 to 6 mg/kg/day, tiapride was superior to placebo and produced a 30%-44% decrease in videotaped tic counts (Eggers et ah, 1988). 

Substituted benzamides produce substituted aniline, and show the following order of reactivity Y = —OCH3 > —CH3 > —H > —Cl > —NO2. 

Substituted benzamides include metodopramide (discussed previously) and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide also has weak antihistaminic activity. For prevention and treatment of nausea and vomiting, metodopramide may be given in the relatively high dosage of 10-20 mg orally or intravenously every 6 hours. The usual dose of trimethobenzamide is 250 mg orally, 200 mg rectally, or 200 mg by intramuscular injection. The principal adverse effects of these central dopamine antagonists are extrapyramidal restlessness, dystonias, and parkinsonian symptoms. 

This small family is found in North America and eastern Asia. A substituted benzamide has been isolated from a species of Ilnuttuy-nia, but in the present study no positive alkaloid tests were obtained on testing Anemopsis califomica, Houttuynia enrdata, Saururus cernuus, and S. chinensis. 

To facilitate the nitro group displacement reaction, the thioethers 7, obtained by treatment of difluoride 6 with thiols, were oxidized with 3-chloroperbenzoic acid to afford the corresponding sulfones 8 (Fig. 4). The resulting sulfones 8 showed the expected high reactivity toward nucleophiles, as demonstrated by the efficient displacement of both the second fluoride and the nitro group with two different aliphatic amines to yield the highly substituted benzamides 10. 

As illustrated by the examples sketched in Fig. 5, pharmacophore-rich thiols and amines could be used in all three displacement reactions to yield substituted benzamides displaying highly variable arrangements of different pharmacophoric groups. 

Fig. 5. Examples of substituted benzamides prepared by 3-fold sequential nucleophilic substitution on an insoluble support.

The technical assistance of Henrik Stephensen during the development of sequential nucleophilic substitutions at support-bound 2,3-dichloropropionic acid is gratefully acknowledged. Thanks are also extended to Marie Grimstrup, who optimized the synthesis of substituted benzamides. 

Substituted benzamides include metoclopramide and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide... 

Brownlee, R.T.C. and Sadek, M., Natural abundance 15N chemical shifts in substituted benzamides and thiobenzamides, Magn. Reson. Chem., 24, 821, 1986. 

Because of the wide range of specificity of sulpiride and other substituted benzamides, it is possible to administer these drugs intravenously and differentiate renal or mesenteric vasodilation produced by DA from non-specific vasodilating agents such as bradykinin (18,Jj)). However, we disagree with Shepperson et al 20) who estimated the relative potency of less specific antagonists by the intravenous route. 

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