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Table 1. In vitro antihypertensive activity of analogues 20, 24-26 in rat uterus assayCompound pA 2Losartan 8.33±0.1320 7.97±0.0724 6.98±0.1925 7.58±0.1526 7.35±0.24The synthesis included the conversion of the commercially available benzonitrile 1 to thestable ortho arylboronic ester 3 by in situ trapping of unstable lithio intermediate using2,2,6,6-tetramethylpiperidine (TMP)/ triisopropylborate in anhydrous THF at -78 o C,followed by transesterification with neopentylglycol [10]. The boronic ester 3 was readilyconverted to the biphenyl compound 4 by Suzuki cross-coupling reaction usingbromotoluene in Tol / EtOH in the presence of catalyst Pd(PPh 3 ) 4 and K 2 CO 3 as base. Theresulting nitrile 4 was converted to the alkylating agent 7 according to an establishedprocedure [11].The synthetic procedure described in Figure 2 was employed to synthesize the targetcompounds 20, 24-26 based on 4(5)-butylimidazole. The key intermediates 17 and 18 wereprepared by two synthetic routes A and B which included the protection of the N-1 of theimidazole ring using appropriate protective groups such as [2-(trimethylsilyl)ethoxy]methyl(SEM) and benzyl (Bn) groups, compatible with the reaction conditions. Theregioselectivity of the N-1 protection was confirmed by 1D NOE experiment. Thus, theformer route included formylation at the 2-position of imidazole ring by treatment withn-BuLi in THF at -78 o C, followed by addition of dry DMF. Reduction of the resultingaldehydes followed by selective alkylation at the 3-position of imidazole ring with thealkylating agent 7, furnished the key intermediates 17 and 18. On the other hand, the latterroute included similarly alkylation at the 3-position followed by direct hydroxymethylationat the 2-position in the presence of formalin in a sealed tube, affording analogues 17 and18. Deprotection of SEM and Bn groups using TBAF·3H 2 O under reflux andhydrogenolysis in the presence of Pd-C, respectively, led to the analogue 19. Halogenationof 19 in the presence of appropriate succinimide NXS (X=Cl, Br, I) at the 4-position ofimidazole ring and removal of the trityl group furnished the final analogues 20 and 24-26.As illustrated in Table 1, the final compounds were evaluated for their antagonistactivity (pA 2 ) in rat uterus assay. The analogue 20 as well as the brominated analogue 25showed high antihypertensive activity (pA 2 =7.97, 7.58, respectively) close to losartan(pA 2 =8.33). It indicates that reorientation of butyl and hydroxymethyl groups on imidazoletemplate retained anti-Ang II activity. However, the chlorine atom is not an optimalsubstitution in this case.AcknowledgmentsWe thank ELDRUG S. A., Patras Science Park, Greece as well as VIANEX Pharmaceutical Companyfor financial support. The work was also supported by the research project No Z40550506 of theInstitute of Organic Chemistry and Biochemistry, AS CR.References1. Carini, D.J., et al. J. Med. Chem. 34, 2525-2546 (1991).2. Matsoukas, J., et al. J. Biol. Chem. 269, 5303-5311 (1994).3. Matsoukas, J., et al. J. Med. Chem. 37, 2958-2969 (1994).4. Aulakh, G.K., et al. Life Sci. 81, 615-639 (2004).5. Matsoukas, J., et al. J. Med. Chem. 38, 4660-4669 (1995).6. Wahhab, A., et al. Drug Res. 43, 1157-1168 (1993).7. Agelis, G., et al. J. Comput.-Aided Mol. Des. 24, 749-758 (2010).8. Agelis, G. Amino Acids (2010) In press.9. Resvani, A., et al. J. Pept. Sci. 16 (2010).10. Kristensen, J., et al. Org. Lett. 3, 1435-1437 (2001).11. Duncia, J.V., et al. J. Org. Chem. 56, 2395-2400 (1991).247