Ramatroban a thromboxane A receptor TP antagonist currently
Ramatroban (), a thromboxane A2 receptor (TP) antagonist currently used for the treatment of allergic rhinitis, was shown to be a potent CRTH2 antagonist. Indomethacin (), a well-known analgesic and cyclooxygenase 1 and 2 (COX-1 and COX-2) enzyme inhibitor, was reported to show CRTH2 agonist potency. Since then, a large number of CRTH2 antagonists including several series of indole acids have been reported. These CRTH2 antagonists have a variety of fused 6–5-membered ring chemotypes as a core structure such as indole (),, , , 5-azaindole (), 7-azaindole (), benzimidazole,, indolizine, spiro–indoline; in addition, they have an acetic flunixin meglumine moiety (). In the course of our program, which was aimed at developing CRTH2 antagonists for the treatment of allergic diseases, we have been pursuing a new class of potent and selective CRTH2 antagonist lead based on the structures of CRTH2 antagonists known to date (, , ). Using a fused 6–6-membered ring system as a core structure, we newly designed a 1,4-disubstituted isoquinoline lead bearing a benzoyl group at the 1-position and an acetic acid moiety essential to CRTH2 potency at the 4-position (). As a result, we have identified a novel compound showing moderate binding affinity for the CRTH2 receptor in a radioligand binding assay (H-PGD) using CHO cells stably transfected with the human CRTH2 receptor (IC=330nM). In this paper, we describe the synthesis and structure–activity relationship (SAR) of the new class of isoquinoline derivatives. shows the synthesis of compounds –, , and from commercially available 2-(4-aminophenyl)acetonitrile (). Protection of the starting material with di--butyl dicarbonate afforded . The reaction of with methyl 1-chloroisoquinoline-4-carboxylate in the presence of sodium hexamethyldisilazane, followed by oxidative decyanation under oxygen atmosphere produced in 83% yields. The carboxylic acid , prepared by the basic hydrolysis of , was converted into the corresponding acid chloride, and was treated with trimethylsilyldiazomethane to afford the diazoketone intermediate. Wolff rearrangement of the diazoketone intermediate followed by methylation of the resulting carboxylic acid moiety with trimethylsilyldiazomethane provided in 69% yield from . Deprotection of the -butoxycarbonyl group in under an acidic condition (TFA), and the subsequent acylation of the resulting aniline intermediate with various kinds of acid chlorides gave . Finally, hydrolysis of the ester moiety afforded the target isoquinoline derivatives –, , and in 22–96% yields. On the other hand, compound was obtained by the treatment of with acetic anhydride and the subsequent basic hydrolysis. summarizes the synthesis of compounds –. Compound was prepared by selective N-methylation of the amide of . With regard to the synthesis of compound , the common intermediate was treated with 3,4-dichlorobenzylbromide in the presence of potassium carbonate, and the ester moiety was hydrolyzed by sodium hydroxide. Compound was synthesized by the reaction of the aniline intermediate with 3,4-dichlorobenzene-1-sulfonyl chloride in the presence of pyridine followed by basic hydrolysis of the ester moiety. Synthesis of compound was achieved by demethylation of by boron tribromide, which was derived from methyl 1-chloroisoquinoline-4-carboxylate and 2-(4-methoxyphenyl)acetonitrile in a procedure similar to the synthesis of (), and the subsequent 3,4-dichlorobenzylation of the resulting phenol. Intermediate was prepared from methyl 1-chloroisoquinoline-4-carboxylate and -butyl 4-(cyanomethyl)benzoate, in a manner similar to the synthesis of as described in . By using , compound was prepared as follows: (1) acidic removal of the ester moiety (TFA), (2) conversion into acyl chloride (oxalyl chloride), (3) condensation of the acyl chloride with 3,4-dichloroaniline.