Yoshitaka Ohishi

Syntheses of 3-acetoacetylaminobenzo[b]furan derivatives having cysteinyl leukotriene 2 receptor antagonistic activity

Novel 3-acetoacetylaminobenzo[b]furan derivatives having a modified triene system at the 3-position were synthesized starting with 3-aminobenzo[b]furans. The enol isomers, 3-[(3-hydroxybut-2-enonyl)amino]benzo[b]furans (), of the 3-acetoacetylaminobenzo[b]furans were obtained as stable isomers owing to formation of a hydrogen bonding between the enol hydroxyl group and the amidocarbonyl group. The planarity of the C-2 substituent through the C-3 side chain suggested the existence of a modified conjugational triene system in the enol compound. Cysteinyl leukotriene 1 and 2 receptor antagonistic activities for these compounds were evaluated. 2-(4-Cyanobenzoyl or ethoxycarbonyl)-3-[(2-cyano-3-hydroxybut-2-enonyl)amino]benzo[b]furans (, ) were moderately active.

Preparation of 3-acetoacetylaminobenzo[b]furan derivatives with cysteinyl leukotriene receptor 2 antagonistic activity

Novel 3-acetoacetylaminobenzo[b]furan derivatives with a modified triene system at the 3-position were prepared through acylation of the 3-aminobenzo[b]furans with 5-methylisoxazole-4-carboxylic acid chloride followed by basic cleavage of the isoxazole ring and several of these compounds showed moderate cysteinyl leukotriene receptor 2 antagonistic activity.

Preparation of novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their biological activity.

Abstract A reaction of 2-acetyl-3-acylaminobenzo[b]furans (9d–o) with Vilsmeier (VM) reagent afforded a mixture of (E)- and (Z)-{(E)-2-aralkenylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylidene}acetaldehydes (5) with a characteristic exo-formylmethylene group on the oxazine ring. The Z-isomer was more stable than the E-isomer. The Z-isomers ((Z)-5) were reacted with phosphonate reagents under two different conditions to obtain various butadiene derivatives (12) containing benzo[b]furo[3,2-d][1,3]oxazine skeleton. Typical compounds (5 and 12) were evaluated for their anti-osteoclastic bone resorption activity, antagonistic activity for the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7. Compounds 12f and 12j showed potent anti-osteoclastic bone resorption activity comparable to E2 (17β-estradiol).

Synthesis and biological activities of novel furo[2,3,4-jk][2]benzazepin-4(3H)-one derivatives.

A novel seven-membered lactam formation method has been established by intramolecular ring closure reaction of 4-bromo-(E)-3-[(2-alkylvinyl)carbonylamino]benzo[b]furans under Heck coupling conditions. A number of furo[2,3,4-jk][2]benzazepin-4(3H)-ones, tricyclicbenzo[b]furans, have been prepared by this method and evaluated for their leukotriene B(4) (LTB(4)) receptor and poly(ADP-ribose)polymerase-1 (PARP-1) inhibitory activities.

Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B4 receptor antagonistic activity

Variable 7-carboxylpropoxy or (1-phenyl)ethoxybenzo[b]furan derivatives with (E)- and (Z)-2-alkylcarbamoyl-1-methylvinyl groups at the 2-, 4-, and 5-positions were prepared to find novel and selective leukotriene B(4) (LTB(4)) receptor antagonists. (E)-2-(2-Diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4v) showed selective inhibition of the human BLT(2) receptor (hBLT(2)). On the other hand, (E)-2-acetyl-4-(2-diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (7c) inhibited both human BLT(1) receptor (hBLT(1)) and hBLT(2). The (E)-2-(2-diethylcarbamoyl-1-methylvinyl) group lay on approximately the same plane as the benzo[b]furan ring, whereas the (E)-4-(2-diethylcarbamoyl-1-methylvinyl) group had a torsion angle (45.7 degrees ) from the benzo[b]furan ring plane. However, the (Z)-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans were inactive. The inhibitory activity depended on the conformation of the 2-alkylcarbamoyl-1-methylvinyl groups.

Preparation of 2- and 4-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans having potent antagonistic activity against human leukotriene B4 BLT1 and/or BLT2 receptors

(E)-2-Acetyl-4-(2-diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4b) with a characteristic conformation and (E)-2-(2-morpholinocarbo-1-methylvinyl)-7-ethoxycarbopropoxybenzo[b]furan ((E)-3b) were prepared and evaluated for their leukotriene B4(LTB4) antagonistic activity. Compound 4b showed potent antagonistic activity against human BLT1 and BLT2 receptors. Compound (E)-3b displayed selective BLT2 receptor antagonistic activity. Both compounds were inactive to cysteinyl LT receptors.

Synthesis of a regio-isomer of kealiiquinone, a marine benzimidazole alkaloid

Treatment of 1,3-dialkyl-2-(phenylthio)benzimidazolium salts 3 and 1,3-dialkyl-2-phenylthio-1H-imidazolium salts 7 with aq. K2CO3 gives 1,3-dialkyl-1,3-dihydrobenzimidazol-2-ones 4 and 1,3-dialkyl-1,3-dihydroimidazol-2-ones 8, respectively, in 22–94% yield. A regio-isomer 17 of kealiiquinone, a marine benzimidazole alkaloid, where the 4-methoxyphenyl group at the 4-position migrates to the 9-position, is synthesized by application of the reaction. Cytotoxity of 17 and kealiiquinone against 39 human cancer cells is evaluated. They have weak activity but a unique mechanism of action.

Preparation of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)-5-methoxybenzo[b]furan derivatives and their leukotriene B4 inhibitory activity

A series of 3-(4-chlorophenyl)-2-(2-aminothiazol-4-yl)benzo[b]furan derivatives 6-10 were prepared and their leukotriene B(4) inhibitory activity was evaluated. We found that several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors. Among them, 3-(4-chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 9b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252.

Anti-osteoporosis Effect of 5-Bromo-2-(4-chlorobenzoyl)-(Z)-3-(2-cyano-3-hydroxybut-2-enonyl)aminobenzo[b]furan: a Novel Selective Estrogen Receptor Modulator

Abstract. The benzo[b]furan derivative MU314 inhibits in vitro bone resorption as potently as β-estradiol (E2). Here, we examined the point of action on the anti-osteoporotic effects of MU314. MU314 (10 nM) suppressed lacunae formation by osteoclastic cells and ICI-182,780, a pure E2 antagonist, inhibited this effect. Specifically, we ovariectomized (OVX) Wistar female rats and subcutaneously injected them with either MU314 (30 or 100 μg/kg) or E2 (100 μg/kg) over an 8-week period. Bone mineral content (BMC) in the proximal end of the tibia was significantly decreased (14%) in OVX rats, and MU314 (100 μg/kg) and E2 significantly suppressed the decline in BMC. OVX rats exhibited decreased cancellous bone in the proximal end of the tibia and induced destruction of its trabecular structure. MU314 suppressed these changes. OVX also reduced the mechanical strength of the femoral neck, which was also recovered by MU314 and E2. E2 completely protected against OVX-induced uterine atrophy, but MU314 had no effect. These results strongly indicate that MU314 acts as a selective estrogen receptor modulator.