Synthesis of 2-imidazolidinylidene propanedinitrile derivatives as stimulators of gastrointestinal motility—III

Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 o...

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Veröffentlicht in:Bioorganic & medicinal chemistry 1995-03, Vol.3 (3), p.279-287
Hauptverfasser: Sasho, Setsuya, Obase, Hiroyuki, Ichikawa, Shunji, Kitazawa, Takio, Nonaka, Hiromi, Yoshizaki, Rika, Ishii, Akio, Shuto, Katsuichi
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Sprache:eng
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Zusammenfassung:Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 or 4) at the N-3 position of the moiety (A) significantly increased this activity. In this study, novel 2-imidazolidinylidene propanedinitrile derivatives possessing a thioether 5–15 were prepared and evaluated for in vitro assays; acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically induced contractions of guinea pig ileum. Compound 5, in which a nitrogen atom of compound 2 was replaced by a sulfur atom, was more potent than 2 in these tests. Also, in a series of thioether derivatives, introduction of substituents at the N-3 position of the 2-imidazolidinylidene propanedinitrile moiety markedly influenced both activities. In particular, compounds 12 and 13, which showed an excellent potency during in vitro study (AChE IC 50 = 3.6 and 2.7 nM; ES. EC 30 = 2.1 and 2.5 nM, respectively), were found to be more active in the enhancement of gastrointestinal motility in anesthetized rabbits than their corresponding parent compounds 3 and 4, respectively. In addition, compounds 12 and 13 showed lower affinity for the histamine H 2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility. Compounds 1 2 and 1 3 showed an excellent potency in enhancement of gastrointestinal motility both in vitro and in vivo together with a negligible histamine H 2-receptor blocking property.
ISSN:0968-0896
1464-3391
DOI:10.1016/0968-0896(95)00001-W