Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides

Kato, Shiro; Morie, Toshiya; Hino, Ken‐ichi; Kon, Tatsuya; Naruto, Shunsuke; Yoshida, Naoyuki; Karasawa, Tadahiko; Matsumoto, Junichi

doi:10.1021/jm00167a020

Cited by 27 publications

(29 citation statements)

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“…20,32) Effect on Apomorphine-Induced Emesis in Dogs 48) Male beagle dogs, weighing 10-16 kg, were used. Groups of three to six dogs received a subcutaneous injection of apomorphine hydrochloride (0.3 mg/kg) 2 h after pretreatment with test compounds (1.0 mg/kg, p.o.).…”

Section: (R)-and (S)-81 (R)-and (S)-82 (R)-and (S)-110 (R)-and (S)mentioning

confidence: 99%

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.

Hirokawa

Harada

Yoshikawa

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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Section: (R)-and (S)-81 (R)-and (S)-82 (R)-and (S)-110 (R)-and (S)mentioning

confidence: 99%

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.

Hirokawa

Harada

Yoshikawa

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Among several candidates, 2-aminomethyl-4-benzylmorpholine (1) emerged as an interesting lead compounds. 40 …”

Section: Design Of Novel Benzamidementioning

confidence: 99%

“…The result suggests that the 4-amino-5-chloro-2-methoxybenzoyl moiety is essential for the gastric emptying activity. 40 The effect of a variation of the 2-methoxy group of 2 was examined (Table III). Compounds 8b-8r were prepared from 2 as shown in Scheme 5.…”

Section: Structure-activity Relationships Of Morpholinyl Benzamides (1)mentioning

confidence: 99%

“…47 The structure-activity relationships (SARs) associated with substituents at the N-4 position of the morpholine ring were examined (Tables IV and V). The 4-amino-5-chloro-2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides 15a-15l and 16a-16n were prepared by the reaction of 4-amino-5-chloro-2-ethoxybenzoic acid 48 with appropriate 4-substituted 2-aminomethylmorpho- …”

Section: Structure-activity Relationships Of Morpholinyl Benzamides (1)mentioning

confidence: 99%

“…The morpholine derivatives E and 14 were derived as follows: hydrogenation of 2-acetylaminomethyl-4-benzylmorpholine 40 (9) prepared from 1 over palladium on carbon afforded the debenzylmorpholine 10, which was subsequently treated with appropriate alkyl and aryl halides to give the 2-acetylaminomethylmorpholines D. Acid-or alkaline-hydrolysis of D produced the amines E. 49 Hydrogenation of 8b over the palladium catalyst caused not only debenzylation but also removal of the chlorine atom to give the morpholine 11. Reaction of 11 with Ac 2 O, followed by chlorination of the resulting diacetyl derivative 12 with NCS, gave the 4-acetylmorpholine derivative 13.…”

Section: Scheme 4 Synthesis Of N-[(4-benzyl-2-morpholinyl)methyl]benmentioning

confidence: 99%

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Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: Development of gastroprokinetic and antiemetic agents

1999

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To obtain gastroprokinetic agents with more potent and selective activity than metoclopramide and cisapride, a series of N‐(4‐benzyl‐2‐morpholinylmethyl)benzamides were designed and prepared. Their synthesis and structure‐activity relationships were described. As a result, mosapride was selected as a promising candidate for potent gastroprokinetic activity with selective 5‐HT4 receptor agonistic activity. As an extension to this project, the novel benzamide and the carboxamide derivatives having 1‐benzyl‐4‐methylhexahydro‐1,4‐diazepine ring in the amine moiety were prepared and evaluated for 5‐HT3 receptor antagonistic activity. DAT‐582 was identified as an antiemetic agent in cancer chemotherapy. The asymmetric synthesis of DAT‐582 and the SAR studies were briefly reviewed. In further modifications of the N‐(1‐benzyl‐4‐methylhexahydro‐1,4‐diazepin‐6‐yl)benzamides, the novel nicotinamides with 1‐ethyl‐4‐methylhexahydro‐1,4‐diazepin ring were found to have potent 5‐HT3 and dopamine D2 and D3 receptor antagonistic activities and to show weak central nervous system depression and extrapyramidal syndrome. After extensive SARs, AS‐8112 was selected as a broad antiemetic agent. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 1, 25–73, 1999.

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TheMitsunobu Reaction

1992

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Alkyl and aryl phosphites and phosphines react with compounds having weak heteroatom–heteroatom bonds, such as SS, OO, etc., and with azo compounds to form reactive phosphonium salts. These phosphonium salts in turn promote “redox” condensation reactions with compounds having active hydrogens. The condensation reaction of alcohols using the redox couple of a triaryl‐ or trialkylphosphine and a dialkyl azodicarboxylate has become known as the Mitsunobu reaction, based on his pioneering work in the late 1960s. The overall reaction is summarized, wherein the alcohol (R 1 OH) and acidic compound (H–Nu) are condensed to form product (R 1 –Nu), while triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate is reduced to the hydrazine. Although the typical redox combination is diethyl azodicarboxylate (DEAD) and triphenylphosphine, many other combinations have found selected use. The reaction is generally limited to primary and secondary alcohols, although tertiary alcohols react in a few intramolecular and intermolecular reactions. For secondary alcohols the reaction usually proceeds with clean inversion of stereochemistry. The acidic component of the reaction generally has an aqueous p K a < 15, with intramolecular reactions providing the exceptions. Examples of H–Nu include oxygen nucleophiles such as carboxylic acids and phenols; nitrogen nucleophiles such as imides, hydroxamates, and heterocycles; sulfur nucleophiles such as thiols and thioamides; and carbon nucleophiles such as β‐ketoesters. Major reviews of the Mitsunobu reaction were published in 1981 by Mitsunobu and in 1983 by Castro. The former review concentrated on reactions using DEAD/triphenylphosphine, while the latter review focused on reactions in which halogens replaced the hydroxy group using reagents such as triphenylphosphine/carbon tetrachloride, triphenyl phosphite/iodomethane, and triphenylphosphine/ N ‐halosuccinimide. Reactions involving the DEAD/triphenylphosphine redox system are the principal subject of this chapter, with emphasis on the literature between 1981 and 1988.

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Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides

Cited by 27 publications

References 6 publications

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.

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.

Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: Development of gastroprokinetic and antiemetic agents

TheMitsunobu Reaction

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