Synthesis and Structure-Activity Relationships of 4-Amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide Derivatives, Novel and Potent Serotonin 5-HT3 and Dopamine D2 Receptors Dual Antagonist.

Abstract

A number of the 2-alkoxy-4-amino-5-chlorobenzamide family possessing a potent serotoninergic or dopaminergic activity has been reported.1) The potency and selectivity of the benzamides are dependent upon the structure of their basic moiety. The classic and parent benzamide of this family is metoclopramide, which is used clinically as a stimulant of upper gastrointestinal motility and an antiemetic agent. 2,3) Effects of metoclopramide are believed to be due to a combination of a relatively weak serotonin (5-hydroxytryptamine) 5-HT 3 (5-HT 3 ) and dopamine D 2 receptors antagonism and a serotonin 5-HT 4 receptor agonism. The weak affinity and lack of selectivity of metoclopramide for these receptors can be explained by the large number of permissible conformers due to the flexibility of the 2-(diethylamino)ethyl chain. To date, several benzamide derivatives with potent and selective activity for the dopamine D 2 , and the serotonin 5-HT 4 , and 5-HT 3 receptors have been reported. Thus, zacopride, 4) BRL 24682, 5) renzapride, 6) SC 53116, 7) and mosapride 8,9) with a rigid folded framework as the amine moiety showed good affinity for the 5-HT 3 and/or serotonin 5-HT 4 receptors. On the other hand, clebopride, a compound 1, and BRL 25594 having a benzyl group on the nitrogen atom in the amine moiety had high affinity for the dopamine D 2 and D 3 receptors. 10)Several potent and selective 5-HT 3 receptor antagonists such as ondansetron and granisetron have been used clinically to prevent nausea and emesis induced by cancer chemotherapeutic agents such as cisplatin and radiation treatment. [11][12][13][14] The nausea and emesis are common side effects that can cause patients to refuse subsequent chemotherapeutic sessions.15) On the other hand, dopamine D 2 receptor antagonists such as phenothiazines and butyrophenones are known to be effective in the treatment of emesis and vomiting induced by centrally acting emetic stimuli such as antiparkinsonian drugs, loperamide, apomorphine, and morphine. 16) In addition, the traditional antiemetic agent domperidone, a peripheral dopamine D 2 receptor antagonist, has been shown to be effective for the treatment of chronic upper gastrointestinal distress and the prevention of nausea and vomiting resulting from variety of causes. 17,18) However, dopamine D 2 receptor antagonists including domperidone are only minimally effective against chemotherapy-or radiationinduced nausea and vomiting.19) Previously, we reported that the structurally novel 4-amino-N-(1-benzyl-4-methylhexahydro-1,4-diazepin-6-yl)-5-chloro-2-methoxybenzamide (2x) and the corresponding 4-amino-5-chloro-2-ethoxybenzamide (2y) are potent and selective 5-HT 3 receptor antagonists. 20) In the course of our studies on the structure-activity relationships (SARs) of 2x, y, we found that replacement of the benzyl group in the hexahydro-1,4-diazepine ring by an alkyl group results in a significant increase in the dopamine D 2 receptor binding affinity along with a potent 5-HT 3 receptor antagonistic activity. 21) Thu...

Alkalinity Initiated Decomposition of Mediating Imidazolium Ions in High Current Density CO2 Electrolysis

“…Finally, examination of the remaining signals suggests the presence of N 1 ‐ethyl‐ N 2 ‐methylethane‐1,2‐diamine. On one hand, the triplet at δ =1.11 ppm is attributed to the terminal methyl group of the ethyl residue at the nitrogen atom (Figure c) . On the other hand, a variety of overlaying and unresolved signals between δ =2.74 and 3.00 ppm, which are of similar intensity, are likely to correspond to the other four positions of N 1 ‐ethyl‐ N 2 ‐methylethane‐1,2‐diamine.…”

“…On one hand, the triplet at d = 1.11ppm is attributed to the terminal methyl group of the ethyl residue at the nitrogen atom ( Figure 5c). [43] On the other hand, av ariety of overlaying and unresolved signals between d = 2.74 and 3.00 ppm, which are of similar intensity,a re likely to correspond to the other four positions of N 1 -ethyl-N 2 -methylethane-1,2-diamine. It should be noted that furthermultiplets with comparativel ower intensitya re detected at approximately d = 8.02 ppm (see the Supporting Information, S7).…”

Non‐metathesis reactions of ruthenium carbene catalysts and their application to the synthesis of nitrogen‐containing heterocycles

“…Finally, treatment of 52 with conc. H 2 SO 4 at 0°C23 gave the deprotected product 53a quantitatively in crude form (Scheme ). 3‐Indolinone 53a was pure and stable enough to characterize the structure by spectral analyses.…”

Development of Environmentally Benign Organometallic Catalysis for Drug Discovery and Its Application

“…Finally, treatment of 78 with conc. H 2 SO 4 at 0°C 119) gave the deprotected product 79a quantitatively in crude form (Chart 15). 3-Indolinone 54a was pure and stable enough to characterize the structure by spectral analyses.…”