Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Abstract

In the previous paper, 1) we reported the design and synthesis of Pratosartan (Chart 1), which is an orally active angiotensin II (AII) antagonist, exhibiting selective and potent antagonistic activity to AT 1 subtype. Furthermore, long duration was shown in various animal models in vivo experiment. Clinical trials of Pratosartan are now in progress as an antihypertensive agent.Clarification of the possible metabolites and their therapeutic or toxic effects during the development process of new drugs is mandatory. For this purpose, we have tried to synthesize possible metabolites in human and rat to identify their structures and activities. In a pharmacokinetic study of Pratosartan, three hydroxylated metabolites were observed as major metabolites in human and rat after oral administration. These structures were characterized on the basis of MS and NMR spectra. Metabolite 1 isolated from human urine was estimated as a hydroxylated metabolite at the propyl side chain of Pratosartan. A similar hydroxlated metabolite was also reported for Losartan.2) Metabolite 2 and 3 isolated from rat bile were estimated as 8-and 5-hydroxylated metabolites on the cycloheptane ring of Pratosartan, respectively. In this paper, we describe the synthesis of these metabolites to identify their structures and to study their pharmacological properties. ChemistryMetabolite 1 was synthesized as shown in Chart 2. Protection of 2-propyl-3H-cycloheptimidazol-4-one 4 3,4) with chloromethyl methyl ether (MOMCl) gave 5, which was treated with N-bromosuccinimide (NBS) to give the brominated product 6. The bromo group was converted to an acetoxy group using sodium acetate to yield 7. Removal of the MOM group and subsequent ester exchange of the acetate gave the corresponding alcohol 9. Hydrogenation of 9 provided 10, and it was alkylated with 11 5) to afford the desired intermediate compound 12. N-Alkylation of 3H-cycloheptimidazol-4-one in the presence of K 2 CO 3 in N,N-dimethylformamide (DMF) gave an N3-alkylated compound preferentially similarly to the biphasic reaction condition 6) and the regioisomer was separated easily by silica gel column chromatography. The N-benzylic proton of compound 12 and 20 was observed at lower field characteristically (0.4-0.5 ppm) compared to their regioisomers, which was caused by the anisotropic effect of the C4-carbonyl group. For the purpose of optical resolution, the racemic trityl compound 12 was converted to a-methoxy-a-(trifluoromethyl)phenylacetate (MTPA) 13 with (ϩ)-MTPA-Cl. 7) Each diastereomer could be separated by silica gel column chromatography. Hydrolysis of the isolated single isomer 13a gave an optically active hydroxy intermediate, and finally (ϩ)-1 was obtained by the successive deprotection of MTPA and trityl groups. Enantiomer (Ϫ)-1 was obtained from 13b in the same manner.In order to confirm the structure, the human main metabolite was led to MTPA ester (Chart 3). The human main metabolite was protected with trityl chloride to give trityl compound 12, and then it was converted to MTPA est...

Design and Synthesis of Crown Ether Functionalized Imidazoles as a New type of Building Blocks

“…Imidazoles can be conveniently N-alkylated when treated with base followed by an alkyl halide or sulfonate, However, N-alkylation of substituted imidazoles gives regioisomers in most cases. The ratio of isomers is difficult to predict, as the regiochemical outcome generally is dependent on the structure of both imidazole and alkylating agent as well as the exact reaction conditions used [13][14][15][16][17][18][19][20][21][22] .…”