Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000084.xml
Download PDF
Synthesis 2007(7): 1047-1053
DOI: 10.1055/s-2007-965962
DOI: 10.1055/s-2007-965962
PAPER
© Georg Thieme Verlag Stuttgart · New YorkSimple Approach to Highly Functionalized Trisubstituted Tetrahydropyrimidine-2,4-diones from Perhydropyrazino[1,2-f]pyrimidine-3,6,8-trione Precursors
Further Information
Received
3 November 2006
Publication Date:
28 February 2007 (online)
Publication History
Publication Date:
28 February 2007 (online)
Abstract
Unprecedented trisubstituted tetrahydropyrimidine-2,4-diones were easily synthesized in two steps involving Boc-amide protection and controlled ring opening, from perhydropyrazino[1,2-f]pyrimidine-3,6,8-triones. These bicyclic derivatives were prepared by reaction of 2-oxopiperazines derived from dipeptides with isocyanates, followed by cyclization. The monocyclic pyrimidinone derivatives were further elaborated to potential CCK ligands that have contributed to a better understanding of the structural requirements for efficient binding at the CCK1 receptor.
Key words
heterocycles - peptides - bicyclic compounds - ring opening - medicinal chemistry
- Selected applications in medicinal chemistry of dihydropyrimidinones include: Antivirals:
- 1a
Botta M.Occhionero F.Nicoletti R.Mastromarino P.Conti C.Magrini M.Saladino R. Bioorg. Med. Chem. Lett. 1999, 7: 1925 - 1b
Botta M.Corelli F.Maga G.Manetti F.Renzulli M.Spadari S. Tetrahedron 2001, 57: 8357 - 1c
Balzarini J.McGuigan C. J. Antimicrob. Chemother. 2002, 50: 5 - 1d
McGuigan C.Pathirana RN.Snoeck R.Andrei G.De Clercq E.Balzarini J. J. Med. Chem. 2004, 47: 1847 - 1e
Stray SJ.Bourne CR.Punna S.Lewis WG.Finn MG.Zlotnick A. Proc. Natl. Acad. Sci. U.S.A. 2005, 102: 8138 - 1f
Semaine W.Johar M.Lorne D.Tyrrell J.Kumar R.Agrawal B. J. Med. Chem. 2006, 49: 2049 - Calcium channel blockers:
- 1g
Atwal KS.Rovnyak GC.Schwartz J.Moreland S.Hedberg A.Gougoutas JZ.Malley MF.Floyd DM. J. Med. Chem. 1990, 33: 1510 - α1a-Antagonists:
- 1h
Barrow JC.Nantermet PG.Selnick HG.Glass KL.Rittle KE.Gilbert KF.Steele TG.Homnick CF.Freidinger RM.Ransom RW.Kling P.Reiss D.Broten TP.Schorn TW.Chang RSL.O’Malley SS.Olah TV.Ellis JD.Barrish A.Kassahun K.Leppert P.Nagarathnam D.Forray C. J. Med. Chem. 2000, 43: 2703 - 1i
Patanè E.Pittalà V.Guerrera F.Salerno L.Romeo G.Siracusa MA.Russo F.Manetti F.Botta M.Mereghetti I.Cagnotto A.Mennini T. J. Med. Chem. 2005, 48: 2420 - Angitensin II receptor antagonists:
- 1j
Atwal KS.Ahmed SZ.Bird JE.Delaney CL.Dickinson KE.Ferrara FN.Hedberg A.Miller AV.Moreland S.O’Reilly BC. J. Med. Chem. 1992, 35: 4751 - Tetrahydropyrimidin-2-ones have shown to exhibit a range of interesting biological activities: Anti-HIV
- 2a
De Lucca GV.Liang J.De Lucca I. J. Med. Chem. 1999, 42: 135 - Antitumoral:
- 2b
Adams JL.Meek TD.Mong S.-M.Johnson RK.Wetcalf BW. J. Med. Chem. 1988, 31: 1355 - Antiallergic agents:
- 2c
Cohan VL, andPettipher ER. inventors; Eur. Pat. Appl. E.P. 636369. ; Chem. Abstr. 1995, 122, 178386 - 3
Embrey MW.Wai JS.Funk TW.Homnick CF.Perlow DS.Young SD.Vacca JP.Hazuda DJ.Felock PJ.Stillmock KA.Witmer MV.Moyer G.Schleif WA.Gabryelski LJ.Jin L.Chen I.-W.Ellis JD.Wong BK.Lin JH.Leonard YM.Tsou NN.Zhuang L. Bioorg. Med. Chem. Lett. 2005, 15: 4550 - 4
Jones KA,Weaver DF, andTiedje KE. inventors; Pat. Appl. WO 2004009559. ; Chem. Abstr. 2004, 140, 146155MissingFormLabel - 5
Poitout L,Thurieau C, andBrault V. inventors; Pat. Appl. WO 2001009090. ; Chem. Abstr. 2001, 134, 163050MissingFormLabel - 6
Tewari N.Tiwari VK.Mishra RC.Tripathi RP.Srivastava AK.Ahmad R.Srivastava R.Srivastava BS. Bioorg. Med. Chem. Lett. 2003, 11: 2911 - 7
Konopelski JP.Filonova LK.Olmstead MM. J. Am. Chem. Soc. 1997, 119: 4305 - 8
Hopkins SA.Ritsema TA.Konopelski JP. J. Org. Chem. 1999, 64: 7885 - 9
Martins MAP.Teixeira MVM.Cunico W.Scapin E.Mayer R.Pereira CMP.Zanatta N.Bonacorso HG.Peppe C.Yuan Y.-F. Tetrahedron Lett. 2004, 45: 8991 - 10a
Agami C.Dechoux L.Melaimi M. Tetrahedron Lett. 2001, 42: 8629 - 10b
Scannell MP.Prakash G.Falvey DE. J. Phys. Chem. A 1997, 101: 4332 - 11
Hakkou H.Vanden Eynde JJ.Hamelin J.Bazureau JP. Tetrahedron 2004, 60: 3745 - 12a
Martín-Martínez M.Bartolomé-Nebreda JM.Gómez-Monterrey I.González-Muñiz R.García-López MT.Ballaz S.Barber A.Fortuño A.Del Río J.Herranz R. J. Med. Chem. 1997, 40: 3402 - 12b
Ballaz S.Barber A.Fortuño A.Del Río J.Martín-Martínez M.Gómez-Monterrey I.Herranz R.González-Muñiz R.García-López MT. Br. J. Pharmacol. 1997, 121: 759 - 13a
Bartolomé-Nebreda JM.Gómez-Monterrey I.García-López MT.González-Muñiz R.Martín-Martínez M.Ballaz S.Cenarruzabeitia E.Latorre M.Del Río J.Herranz R. J. Med. Chem. 1999, 42: 4659 - 13b
Bartolomé-Nebreda JM.Patiño-Molina R.Martín-Martínez M.Gómez-Monterrey I.García-López MT.González-Muñiz R.Cenarruzabeitia E.Latorre M.Del Río J.Herranz R. J. Med. Chem. 2001, 44: 2219 - 14
Bartolomé-Nebreda JM.García-López MT.González-Muñiz R.Cenarruzabeitia E.Latorre M.Del Río J.Herranz R. J. Med. Chem. 2001, 44: 4196 - 15
Martín-Martínez M.García-López MT.Herranz R.González-Muñiz R. Tetrahedron Lett. 1996, 37: 2471 - 16
Gerona-Navarro G.García-López MT.González-Muñiz R. Tetrahedron Lett. 2003, 44: 6145 - 17 Compounds 3, 4, and 5 were synthesized by reductive amination of β-keto esters derived from Z-Xaa-Gly dipeptides
(Xaa = Gly, Ala, and Phe, respectively). Compounds 4 and 5 were obtained as separable mixtures of diastereoisomers due to the induction by the
Ala and Phe stereogenic centers. However, analogue 3 was obtained as racemic due to the achiral nature of the starting β-keto ester:
Patiño-Molina R.Herranz R.García-López MT.González-Muñiz R. Tetrahedron 1999, 55: 15001 - 20
Martín-Martínez M.Marty A.Jourdan M.Escrieut C.Archer E.González-Muñiz R.García-López MT.Maigret B.Herranz R.Fourmy D. J. Med. Chem. 2005, 48: 4842
References
An authentic sample of compound 19b, prepared by an alternative stereospecific synthetic route, allows the unequivocal assignment of the configuration at C6 in the diastereoisomeric pairs 19a,b and 20a,b: Patiño-Molina, R.; Cubero, J.; Pérez de Vega, M. J.; García-López, M. T.; González-Muñiz, R., unpublished results.
19The increased shielding (Δβ = δ19b - δ21b) was 0.36 ppm for the H-5eq and 1.67 ppm for the H-5ax.