Proceedings book download - 5Z.com

R 3H 2 NONHOOHNONH 2R 3 :HNN H N NN NNH14a 14b 14c 14d 14e14H 2 NNOOHNONH 2H 2 NNH 2 NOOHNOHNH 2 N2H 2 NNH15a 15b 15cFig. 1. Structures of urea derivatives and azapeptides.ONOOHNONH 2OHNONOOONH 216treated with amines to produce, upon cleavage, the desired ureas in high HPLC purities.Azapeptides are peptide analogues in which the -CH of one or more amino acidresidue has been substituted by a nitrogen, bearing an appropriate side chain. Theaza-carbonyl bond is much more stable to hydrolysis (both chemical and enzymatic) than anatural peptide bond.For compounds 15 a-c and 16 preparation of the azaglutamine side-chain containingbuilding block was needed. For this tert-butyl carbazate, n-butylamine and Fmoc-aminoacid hydrazides underwent a Michael addition with acrylamide to give substitutedcarbazates having the side-chain of glutamine on nitrogen [5]. Reacting these aza-Glnprecursors with the 2,4-dinitrophenyl carbonate (2,4-DNPC) activated amino group [6] ofthe isoleucine, immobilized on a solid support (Rink amide resin, loading 0.72 mM/g),gave the azaglutamine-containing Ucn3 analogues. 2,4-DNPC was prepared by thenitration of diphenyl carbonate with conc. HNO 3 and H 2 SO 4 [7]. We have found that theAQI short fragment conserves the above mentioned biological action of the longerurocortin III.For improved pharmacokinetic properties we designed and synthesized several ureasand azapeptides by modification of the peptide backbone via formation of a resin boundisocyanate or activated carbamate intermediate, followed by nucleophilic attack with anamine or an amino acid acyl hydrazide. We have found that many of these shorterfragments and analogues show similar or improved antidepressive and anxiolytic action,some of them even on oral administration.References1. Bale, T.L., et al. Nat. Genet. 24, 410-414 (2000).2. Tanaka, M., Telegdy, G. Brain Res. Bulletin 75, 509-512 (2008).3. Telegdy, G., Tóth, G.K., Rákosi, K., Tanaka, M. Patent WO 2010/020825.4. Chong, P.Y., Petillo, P.A. Tetrahedron Letters 40, 4501-4504 (1999).5. Gray, C.J., Quibell,M., Jiang, K.-L., Baggett, N. Synthesis Febr., 141-146 (1991).6. Gray, C.J., Quibell, M., Baggett, N., Hammerle, T. Int. J. Peptide Protein Res. 40, 351-362 (1992).7. Gray, C.J., Ireson, J.C., Parker, R.C. Tetrahedron 33, 739-743 (1977).335