Synthesis of 6‐amino‐1‐benzyl‐4‐methylhexahydro‐1<i>H</i>‐1,4‐diazepine

Kato, Shiro; Harada, Hiroshi; Morie, Toshiya

doi:10.1002/jhet.5570320244

Cited by 12 publications

(4 citation statements)

References 9 publications

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“…The following known 6-aminohexahydro-1,4-diazepines and benzoic acids were prepared according to the cited literature: 6-amino-1-benzyl-4-methylhexahydro-1,4-diazepine 23,37) (61). Methyl 4-acetylamino-5-chloro-2-methoxybenzoate (22a), 4-amino-5-chloro-2-methoxybenzoic acid (23a), 2,4,5-trifluorobenzoic acid (63), and 4-chloro-2-methoxybenzoic acid (67) are commercially available.…”

Section: Methodsmentioning

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: Methodsmentioning

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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“…118 (102) in a good yield. Treatment of 102 with diisobutylaluminum hydride (DIBAL-H) at Ϫ70ЊC, followed by further reduction of the iminium salt 103b derived from the aminoaldehyde 103a, with NaBH 4 afforded the desired hexahydro-1,4-diazepine 104 in 81% yield.…”

Section: Synthesis Of 6-amino-1-benzyl-4-methylhexahydro-14-diazepinementioning

confidence: 91%

“…63,118 On the basis of these results, we hoped that reaction of the chiral 2,3-diaminopropionic esters with DIBAL-H at low temperature followed by NaBH 4 reduction of the chiral iminium salts would produce the chiral 6-(substituted amino)hexahydro-1,4-diazepines without racemization. As the optically active form of the 2,3-diaminopropionic ester intermediates such as 101, the chiral 1-substituted aziridine-2-carboxylic esters were selected.…”

Section: Synthesis Of (R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydrmentioning

confidence: 94%

“…Next, we investigated the development of an alternative synthetic route to the chiral hexahydro-1,4-diazepine (R)-106 from the 2,3-diaminopropionic ester 127 (Scheme 18). Based on our previous results, 118 we adopted the method involving the intramolecular amidation reaction. Hydrolysis of 127 with 2N NaOH solution gave the 2,3-diaminopropionic acid 129, which was then treated with WSC to afford the hexahydro-1,4-diazepin-5-one 130 in 52% two steps yield.…”

Section: Synthesis Of (R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydrmentioning

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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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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Synthesis of 6‐amino‐1‐benzyl‐4‐methylhexahydro‐1H‐1,4‐diazepine

Cited by 12 publications

References 9 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

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

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