Efficient and beta-stereoselective synthesis of 4(5)-methyl-5(4)-(5-amino-5-deoxy-beta-D-ribofuranosyl)imidazole and related compounds exhibiting antiulcer activity.
The reaction of 2,3,5-tri-O-benzyl-D-ribose with the lithium salt of an imidazole derivative gave an adduct 17RS. Treatment of 17RS with 1.5N HCl in refluxing tetrahydrofuran gave the beta-4(5)-ribofuranosylimidazole 19 (35%) and the ribosylimidazole 18 (51%). The latter was converted into beta-19 in 86% yield by the Mitsunobu cyclization. This synthetic method produced only the desired beta-anomer. Protection of the imidazole nitrogen of 19 with an ethoxycarbonyl group followed by debenzylation gave 21, which was successively derived to the 5'-amino derivative 1 via the 5'-substituted phthalimide 23, followed by hydrazine degradation in excellent yield. Compound 1 was then converted into the 5'-cyanoguanidine 2 in 79% yield. The 5'-amino derivatives 3-9 lacking a methyl group were efficiently synthesized. Among them, the cyanoguanidine 5 and phenylthiourea 8 exhibited antiulcer activities with half the efficacy of cimetidine. The molecular conformation of 5 was determined by X-ray structure analysis.
Harusawa
S
S
Osaka University of Pharmaceutical Sciences, Japan.
Moriyama
H
H
Murai
Y
Y
Imazu
T
T
Ohishi
H
H
Yoneda
R
R
Kurihara
T
T
Hata
H
H
Sakamoto
Y
Y
D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000209:etiology; D013312:Stress, Physiological
C104684:1-cyano-2-methyl-3-(5-deoxy-1-(1H-imidazol-4(5)-yl)ribofuranos-5-yl)guanidine; C104685:4(5)-(5-deoxy-5-(N-phenylthioureido)ribofuranosyl)imidazole; D000897:Anti-Ulcer Agents; D006146:Guanidines; D007093:Imidazoles; D002927:Cimetidine