Archives
Synthesis of and is described in Scheme Compounds and
Synthesis of 5–7, 12–14, and 18 is described in Scheme 3. Compounds 5–7 and 18 were prepared as outlined in Scheme 3a. Reaction of 4-bromomethylbenzoic N1-Methylpseudouridine (36) with thionyl chloride yielded the corresponding acid chloride, which was converted to the corresponding amide 40a by the usual ammonolysis with aqueous ammonia. O-Alkylation of 34 (Scheme 2) with 40a gave 41a. N-Acylation of the amide function of 41a yielded N-acetylcarboxyamide 5. Ammonolysis of 4-bromomethyl benzenesulfonyl chloride (37) gave the sulfonamide 40b. O-Alkylation of 34 (Scheme 2) with 40b, in the presence of potassium carbonate, yielded 41b. N-Methanesulfonylation of the primary sulfonamide residue of 41b resulted in N-methanesulfonylsulfonamide 6. N-Acetylation of the sulfonamide residue of 41b produced N-acetyl sulfonamide 7. O-Alkylation of the phenol residue of 38 with methyl chloroacetate yielded 39. Bromination reaction of benzyl alcohol 39 with phosphorus tribromide provided 40c. O-Alkylation of 34 (Scheme 2) with 40c yielded 41c, alkaline hydrolysis of which resulted in the corresponding carboxylic acid 18.
Compound 12 was prepared as shown in Scheme 3b. Bromination of 42 with N-bromosuccinimide yielded 43. O-Alkylation of 34 (Scheme 2) with the bromide 43 produced 44, alkaline hydrolysis of which yielded 45. Heating of 45 in the presence of acetic anhydride, followed by ammonolysis and then heating in toluene, resulted in the phthalimide analog 12.
Synthesis of 13 and 14 is described in Scheme 3c. Partial alkaline hydrolysis of 46 yielded 47, reduction of which with diborane-dimethylsulfide complex produced 48. O-Alkylation of 34 (Scheme 2) with 48, using the Mitsunobu reaction, gave 49. Reduction of 49 with iron powder, followed by alkaline hydrolysis, produced 51.
Cyclization of 51 with imidoformamide hydrochloride, with heating, resulted in 4-hydroxyquinazoline 13. Cyclization of 51 with urea, with heating, resulted in 2,4-dihydroxyquinzoline 14.
Results and discussion
The test compounds listed in Table 1, Table 2, Table 3, Table 4, Table 5 were biologically evaluated for their inhibition of the specific binding of a radiolabeled ligand, [3H]PGE2, to membrane fractions prepared from cells stably expressing each mouse prostanoid receptor. The EP1 antagonist properties of these compounds were determined by a Ca2+ assay using mouse EP1 receptor expressed on CHO cells in the presence of 0.1% of bovine serum albumin.
Furan-2-sulfonyl analogs 2a and b were synthesized and evaluated (Table 1). Among these, 5-methylfuran-2-sulfonyl analog 2b showed much stronger antagonist activity relative to the chemical lead 1, while demethylated analog 2a showed nearly the same potency as 1 in terms of both receptor affinity and antagonist activity. Based on these results, further optimization of 5-methylfuran-2-sulfonyl analogs, instead of the phenylsulfonyl and furan-2-sulfonyl analogs, was carried out as shown in Table 2, Table 3, Table 4, Table 5.
In proceeding the optimization process, focus was placed on the nitrile analog 3 (Table 2), in which a carboxylic acid residue was replaced by a nitrile residue. The marked reduction in the activity of this transformation strongly suggested a structural requirement for an acid residue at this position, which was supposed to correspond to the carboxylic acid residue of PGE2. For this reason, synthesis and biological evaluation of the acid analogs listed in Table 2, Table 3, Table 4, Table 5 are of great interest to medicinal chemists.
The bioisostere is known as one of the useful transformations for improving the activity and/or pharmacokinetic profiles of chemical leads in medicinal chemistry. In an effort to further optimize the acid residue of the chemical lead 2b, the carboxylic acid was replaced by various bioisosteres, as illustrated in Table 2, Table 3, Table 4, Table 5. As shown in Table 2, replacement of the carboxylic acid of 2b with an N-acylsulfonamide and an N-acylacetoamide (imide) yielded 4 and 5, respectively. Compound 4 exhibited 11-fold less EP1 receptor affinity and 6.8-fold less antagonist activity relative to 2b, while 5 exhibited less receptor affinity and antagonist activity. Replacement of the carboxylic acid residue of 2b with a N-sulfonyl methanesulfonamide and a N-sulfonyl acetoamide yielded 6 and 7, respectively, which showed less receptor affinity relative to 4 and 5, respectively.