Synthesis of 2-imidazolidinylidenepropanedinitrile derivatives as stimulators of gastrointestinal motility.
Ranitidine (1), the histamine H2-receptor antagonist, has been previously reported to increase gastric emptying and gastric motility by inhibition of acetylcholinesterase (AChE) and enhancement of acetylcholine (ACh) release. In order to obtain potent gastroprokinetic agents, a new series of ranitidine derivatives (5-32) possessing a nitrogen atom instead of a sulfur atom (B) was synthesized and their AChE inhibitory activity and potentiating action on electrically evoked contractions of guinea pig ileum were evaluated. Modification of substituents R1 and R2 markedly influenced the activities. In particular, compound 19, (1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]-ethyl]-2- imidazolidinylidene)propanedinitrile fumarate, showed 20 and 100 times more potent AChE inhibitory activity and potentiating action on the ileal contraction, respectively, than ranitidine. Furthermore, compound 19 (KW-5092) enhanced gastrointestinal motility in anesthetized rabbits along with a negligible histamine H2-receptor blocking activity.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
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S
Sasho
H
H
Obase
S
S
Ichikawa
T
T
Kitazawa
H
H
Nonaka
R
R
Yoshizaki
A
A
Ishii
K
K
Shuto
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004558:Electric Stimulation; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009388:Neostigmine / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D009584:Nitrogen; D011817:Rabbits; D011899:Ranitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D009570:Nitriles; C081341:KW 5092; D009388:Neostigmine; D011899:Ranitidine; D009584:Nitrogen