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  • The following are the supplementary

    2019-08-12

    The following are the supplementary data related to this article.
    Acknowledgments
    Introduction Cyclooxygenases metabolize arachidonic bethanechol chloride to five primary prostanoids, PGE2, PGF2, PGI2, TXA2 (TX), and PGD2. These lipid mediators interact with specific members of a family of distinct G-protein-coupled prostanoid receptors. Coleman et al. proposed the existence of specific receptors for TX, PGI, PGE, PGF, and PGD, named TP, IP, EP, FP, and DP receptors, respectively. They further classified the EP receptor into four subtypes (EP1, EP2, EP3, and EP4), all of which respond to PGE2 in different ways. A number of specific ligands for these receptors and their therapeutic potential have already been described in the literature. Discovery of selective EP1 receptor antagonists would offer an opportunity to elucidate the role of this receptor in various pathological conditions such as hyperalgesia and pollakisuria. In one of our previous papers, we reported on the discovery of 1 as a new lead compound in the EP1 receptor antagonists. Compound 1 demonstrated remarkably weak antagonist activity (IC50, 0.13μM) for its strong receptor affinity (Ki, 0.0005μM). In an effort to improve this weak antagonist activity, we incorporated bioisosteres into our further optimization process because this methodology has been frequently used for such a purpose in conventional medicinal chemistry. Accordingly, the phenylsulfonyl moiety and the carboxylic acid residue were replaced with a furan-2-sulfonyl moiety and acid residue, respectively (Fig. 1). We here report on further optimization efforts for the newly found EP1 receptor antagonist 1.
    Chemistry The synthesis of the test compounds listed in Table 1, Table 2, Table 3, Table 4, Table 5 is outlined in Scheme 1, Scheme 2, Scheme 3. Compounds 2b, 4, and 15–17 were synthesized as described in Schemes 1a and b. O-Alkylation of 19 with methyl 4-(bromomethyl) benzoate in the presence of potassium carbonate yielded 20a, reduction of which, with lithium borohydride, gave alcohol 21. Oxidation of 21 with DMSO yielded an aldehyde 22, C2 homologation of which, using malonic acid reaction followed by esterification, gave an α,β-unsaturated methyl ester 20b. Reduction of the nitro residue of 20a and b yielded anilines 24a and b, respectively. Hydrogenation of 24b gave 24c.N-Sulfonylation of 24a–c with 5-methylfuran-2-sulfonyl chloride 29, which was prepared from 27 according to a previously reported method (Scheme 1b), gave sulfonamides 25a–c, respectively. N-Alkylation of 25a–c with isobutyl iodide in the presence of potassium carbonate yielded 26a–c, respectively. Alkaline hydrolysis of 26a gave a carboxylic acid 2b. Compound 2b was converted to the corresponding acid chloride with thionyl chloride. Wittig reaction of the resulting acid chloride with methyl (triphenylphosphoranylidene) acetate, followed by heating, yielded 26d. Alkaline hydrolysis of 26d gave the corresponding carboxylic acid 17. Condensation of 2b with methanesulfonamide in the presence of EDC yielded 4. Alkaline hydrolysis of 26b and c gave 16 and 15, respectively. Synthesis of 3 and 8–11 is outlined in Scheme 2. Catalytic hydrogenation of a protected O-nitrophenol 30, which was prepared by O-alkylation of 19 with methoxymethyl chloride, yielded 31. N-Sulfonylation of 31 with 5-methylfuran-2-sulfonyl chloride gave 32, N-alkylation of which with isobutyl iodide in the presence of potassium carbonate yielded 33. Acidic deprotection of 33 gave 34, O-alkylation of which with 4-(bromomethyl)benzonitrile, in the presence of potassium carbonate, produced the nitrile 3. Reaction of the nitrile 3 with sodium azide, in the presence of triethylamine, resulted in the tetrazole 11. Reaction of the nitrile 3 with hydroxylamine, in the presence of triethylamine, produced the N-hydroxy amidine 35. Reaction of 35 with thionyl chloride yielded 3H-1,2,3,5-oxathiadiazole 2-oxide 8. Reaction of 35 with 2-ethylhexyl chloroformate, followed by heating in xylene, gave oxadiazol-5-one 9. Reaction of 35 with thiocarbonyl diimidazole, followed by cyclization with boron trifluoride etherate, yielded thiadiazol-5-one 10.