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 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 IC50 = 3.6 and 2.7 nM; ES. EC30 = 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 H2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility.
Sasho
S
S
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
Obase
H
H
Ichikawa
S
S
Kitazawa
T
T
Nonaka
H
H
Yoshizaki
R
R
Ishii
A
A
Shuto
K
K
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011899:Ranitidine / Q000031:analogs & derivatives; D051381:Rats; D011970:Receptors, Histamine H2 / Q000378:metabolism; D013440:Sulfides / Q000032:analysis
D002800:Cholinesterase Inhibitors; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D009570:Nitriles; D011970:Receptors, Histamine H2; D013440:Sulfides; D011899:Ranitidine; D000110:Acetylcholinesterase