PDF herunterladen
Synthesis 2007(7): 1047-1053  
DOI: 10.1055/s-2007-965962
PAPER
© Georg Thieme Verlag Stuttgart · New York

Simple Approach to Highly Functionalized Trisubstituted Tetrahydro­pyrimidine-2,4-diones from Perhydropyrazino[1,2-f]pyrimidine-3,6,8-trione Precursors

Rosario Patiño-Molinaa,b, M. Teresa García-Lópeza, Edurne Cenarruzabeitiac, Joaquín Del Ríoc, Rosario González-Muñiz*a
a Instituto de Química Médica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34(91)5644853; e-Mail: iqmg313@iqm.csic.es;
b Escuela Técnica Superior de Ingenieros Industriales, Universidad de Valladolid, Paseo del Cauce s/n, 4701 Valladolid, Spain
c Departamento de Farmacología-Unidad Asociada al CSIC, Universidad de Navarra, Irunlarrea 1, 31080 Pamplona, Spain
Weitere Informationen

Publikationsverlauf

Received 3 November 2006
Publikationsdatum:
28. Februar 2007 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

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

    References

  • 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 
    CrossrefSuche in Google Scholar
  • 1b Botta M. Corelli F. Maga G. Manetti F. Renzulli M. Spadari S. Tetrahedron  2001,  57:  8357 
    CrossrefSuche in Google Scholar
  • 1c Balzarini J. McGuigan C. J. Antimicrob. Chemother.  2002,  50:  5 
    CrossrefSuche in Google Scholar
  • 1d McGuigan C. Pathirana RN. Snoeck R. Andrei G. De Clercq E. Balzarini J. J. Med. Chem.  2004,  47:  1847 
    CrossrefSuche in Google Scholar
  • 1e Stray SJ. Bourne CR. Punna S. Lewis WG. Finn MG. Zlotnick A. Proc. Natl. Acad. Sci. U.S.A.  2005,  102:  8138 
    CrossrefSuche in Google Scholar
  • 1f Semaine W. Johar M. Lorne D. Tyrrell J. Kumar R. Agrawal B. J. Med. Chem.  2006,  49:  2049 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • Antitumoral:
  • 2b Adams JL. Meek TD. Mong S.-M. Johnson RK. Wetcalf BW. J. Med. Chem.  1988,  31:  1355 
    CrossrefSuche in Google Scholar
  • Antiallergic agents:
  • 2c Cohan VL, and Pettipher ER. inventors; Eur. Pat. Appl. E.P.  636369.  ; Chem. Abstr. 1995, 122, 178386
    Crossref
  • 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 
    CrossrefSuche in Google Scholar
  • 4 Jones KA, Weaver DF, and Tiedje KE. inventors; Pat. Appl. WO  2004009559.  ; Chem. Abstr. 2004, 140, 146155
  • 5 Poitout L, Thurieau C, and Brault V. inventors; Pat. Appl. WO  2001009090.  ; Chem. Abstr. 2001, 134, 163050
  • 6 Tewari N. Tiwari VK. Mishra RC. Tripathi RP. Srivastava AK. Ahmad R. Srivastava R. Srivastava BS. Bioorg. Med. Chem. Lett.  2003,  11:  2911 
    CrossrefSuche in Google Scholar
  • 7 Konopelski JP. Filonova LK. Olmstead MM. J. Am. Chem. Soc.  1997,  119:  4305 
    CrossrefSuche in Google Scholar
  • 8 Hopkins SA. Ritsema TA. Konopelski JP. J. Org. Chem.  1999,  64:  7885 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 10a Agami C. Dechoux L. Melaimi M. Tetrahedron Lett.  2001,  42:  8629 
    CrossrefSuche in Google Scholar
  • 10b Scannell MP. Prakash G. Falvey DE. J. Phys. Chem. A  1997,  101:  4332 
    CrossrefSuche in Google Scholar
  • 11 Hakkou H. Vanden Eynde JJ. Hamelin J. Bazureau JP. Tetrahedron  2004,  60:  3745 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 15 Martín-Martínez M. García-López MT. Herranz R. González-Muñiz R. Tetrahedron Lett.  1996,  37:  2471 
    CrossrefSuche in Google Scholar
  • 16 Gerona-Navarro G. García-López MT. González-Muñiz R. Tetrahedron Lett.  2003,  44:  6145 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
  • 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 
    CrossrefSuche in Google Scholar
18

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.

19

The increased shielding (Δβ = δ19b - δ21b) was 0.36 ppm for the H-5eq and 1.67 ppm for the H-5ax.