A variety of fused membered

A variety of fused 6–5-membered ring chemotypes have arisen such as 7-azaindole acetic acids, benzimidazolyl acetic acids, spiro-indolinone acetic acids, and indolizine acetic acids, however, to the best of our knowledge, fused 5,5-membered ring systems have not been reported.
Prostaglandin D (PGD) produced by mast cells is a key mediator of asthmatic and allergic inflammatory responses. There are two known receptors of PGD: DP1 and DP2 (also known as CRTh2)., , The latter receptor is expressed on the surface of eosinophils, basophils, and Th2 cells and is responsible for PGD-induced chemotaxis in all three cell types. Moreover, CRTh2 is involved in cytokine release from Th2 cells and degranulation of eosinophils., This has led to widespread interest in antagonists of CRTh2 as potential agents for the treatment of asthma and related allergic diseases., , , , , Recent publication of the effect of CRTh2 antagonists in various animal models of asthma and allergic rhinitis have spurred further interest in the exploration of this target., , Ramatroban and its acetic ZD 7288 receptor analog (, ) have been reported to be potent antagonists of CRTh2., We previously disclosed the SAR of a series of ‘reverse Ramatroban’ analogs with similar potency to compound . In our attempts to design additional novel CRTh2 antagonists, we hypothesized that the saturated ring of compound could be excised from the tetrahydrocarbazole and instead form a bicyclic sulfonamide, as shown in . One such embodiment of this hypothesis is benzosultam . This analog seemed especially fitting given that it would retain and rigidify the cisoid geometry that sulfonamides such as Ramatroban naturally adopt. The synthesis of compound and related compounds is illustrated in . The synthesis begins with AlCl promoted electrophilic addition of compound (derived in one step from saccharin) to an indole, giving intermediate . The indole nitrogen of is alkylated with -butyl bromoacetate and the sulfonyl imine is subsequently reduced to give the benzosultam . Deprotection of the -butyl group is accomplished with TFA giving compounds . Compound proved to be only weakly active as an antagonist of CRTh2, with binding affinity () of approximately 9.2μM (). Incorporation of various substituents at the 5-position () improved affinity by 2–3-fold. Incorporation of methyl at the 2-position () also increased binding by threefold. The effect of substituents at the 2- and 5-positions proved to be additive, as can be seen by comparing compounds with compounds . Combining a methyl at the 2-position with a halogen at the 5-position gave our first sub-μM compounds in this series, and . We next set about to explore substitution on the sultam nitrogen. The nitrogen of intermediate () was alkylated by standard conditions ultimately giving compounds and after deprotection of the carboxylic acid. Alternatively, an Ullmann-like coupling gave direct aryl substitution on nitrogen (). We began our explorations with various alkylations on the unsubstituted indole scaffold (R=H, ). Small alkyl groups, such as methyl () and neopentyl () gave little improvement over the parent compound (). However, larger groups such as 2-phenylethyl () gave more than a 10-fold improvement in affinity. To our astonishment, a dimethyl isoxazole () gave nearly a 500-fold boost in receptor-binding. This compound was greater than 10-fold more potent than any other compound in the series. Combining a 2-methyl indole core with -alkyl substituents generally improved the affinity of compounds by 2–3-fold (e.g., see / and /). Interestingly, however, the addition of a 2-methyl group to compound had little effect on the potency (). Rather, the presence of the isoxazole ring itself seems to drive the exceptional potency. Substitution of the isoxazole () and substitution of the indole core () had only minor effects on potency. Interestingly, the incorporation of a hydrogen bond acceptor into compound resulted in compounds (/) with similar potency to the isoxazoles. Movement of the hydrogen bond acceptor further from the core () or replacement of the acceptor with a donor () resulted in compounds with significantly decreased potency. Taken together, these results clearly indicate that optimal potency can be obtained by incorporation of a strategically placed hydrogen bond acceptor within a few bond lengths of the sultam nitrogen.