The nitrophenols b d were prepared as
The nitrophenols 34b–d were prepared as described in Scheme 3b. Nitration of phenols 39b–d with 1equiv of sodium nitrate in the presence of hydrochloric Tasquinimod gave an inseparable mixture of 34b–d and 40b–d (1:1). This synthetic problem was successfully avoided as described below. Nitration of 39b–d with 2equiv of sodium nitrate afforded a separable mixture of 34b–d and 41b–d (1:1) because preferential nitration of the byproducts 40b–d gave dinitro compounds 41b–d.
Synthesis of 11 is described in Scheme 4. O-Protection of 2-aminonaphthol 42 as TBS ether provided a TBS ether 43. N-Sulfonylation of 43 with 5-methylfuran-2-sulfonyl chloride afforded a sulfonamide 44, N-alkylation of which with isobutanol under Mitsunobu reaction conditions provided 45. Deprotection of TBS ether afforded 46. O-Alkylation of 46 with methyl 4-(bromomethyl)benzoate gave 47, alkaline hydrolysis of which resulted in 11.
Results and discussion Further optimization of the carboxylic acid analogs was carried out because of their less potent P450 enzyme inhibition. Table 3 shows the effect of substituting the benzoic acid moiety on activity profiles. 2-Chlorobenzoic acid, 3-chlorobenzoic acid, 3-methylbenzoic acid, and 3,5-dimethylbenzoic acid analogs 3, 4, 5, and 6 were tested for their receptor affinities and were found to be less potent than 1. They were also tested for their antagonist activities. Predictably, compound 3 had nearly 15-fold less potent activity than 1, because of the presumed masking effect of hydrophilic carboxylic acid function by the hydrophobic 2-chloro substituent, whereas 3- and/or 5-substituted benzoic acid analogs 4–6 without such a masking effect had equipotent antagonist activity with 1 regardless of their reduced receptor affinities. As reported in our previous paper, the aminophenoxy moiety showed a tendency to prefer more hydrophobic substituents. Based on the information, 5-methyl analog 7 and 4,5-disubstituted analogs 8–13 were synthesized and evaluated. Table 4 shows the effect of substituting the aminophenoxy moiety on activity profiles. Replacement of the trifluoromethyl residue of 1 with a methyl residue afforded 7, which had a 3.5-fold less potent receptor affinity and a 3-fold less potent antagonist activity. Introduction of another methyl residue into position 4 of the 2-aminophenoxy moiety of7 produced 8, which had a slightly more potent receptor affinity and a nearly 8-fold more potent antagonist activity. Indane analog 9 had nearly 3-fold less potent receptor affinity relative to 8, but it had equipotent antagonist activity. Tetrahydronaphthalene analog 10 had slightly less potent activity relative to 9 with respect to both receptor affinity and antagonist activity. Naphthalene analog 11 had an increased receptor affinity relative to 10, although it had a reduced antagonist activity. Introduction of another methyl residue into position 3 of the benzoic acid residue of 8 afforded 12, which had a reduced receptor affinity but a similar antagonist activity. Introduction of another methyl residue into position 3 of the benzoic acid moiety of9 produced13, which had a reduced receptor affinity but a nearly equipotent antagonist activity. Table 5 shows the structure–activity relationships (SAR) of N-thiazole-2-sulfonyl analogs 14–18, because N-thiazole-2-sulfonyl residue is one of the optimized heteroaryl sulfonyl residues as reported previously.N-Thiazole-2-sulfonyl analogs 14–18 had equipotent to slightly more potent antagonist activity compared with their corresponding N-5-methylfuran-2-sulfonyl analogs 1, 8–9, and 12–13, respectively, whereas their EP1 receptor affinities were not always consistent with the potency of their functional activities. In particular, N-thiazole-2-sulfonyl analogs 16–18 did not show increased functional activities in tandem with their increases in EP1 receptor affinities relative to their corresponding N-5-methylfuran-2-sulfonyl analogs 9 and 12 and 13.