Synthesis of C-ribosyl imidazo[2,1-f  ][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

Abstract

The 3-β-D-ribofuranoside 6 of the new imidazo[2,1-f  ][1,2,4]triazine 27 is isomeric and isoelectronic with the nucleoside deaminoformycin 1 which is a good inhibitor of adenosine deaminase (ADA) while its 5′-monophosphate 2 is a good inhibitor of adenosine 5′-monophosphate deaminase (AMPDA). The 6-methylsulfanyl derivative 7 of 6 is synthesized by condensation of the monocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by cyclization to give the protected C-nucleoside 21; the 8-methylsulfanyl group of 21 is removed by replacement by hydrazine and oxidation. The 1,2,4-triazine 9 cyclizes similarly with chloroacetaldehyde or its dimethyl acetal to give 6,8-bis(methylsulfanyl)imidazo[2,1-f  ][1,2,4]triazine 17, which is converted into the parent heterocycle 27 by two routes, and into mono- and di-substituted derivatives (19, 20, 24, 25, 28–30) of the new ring system. Riboside 7 is an inhibitor of mammalian ADA (IC₅₀ 40 µM).

References

1. J. E. Dancer, R. G. Hughes and S. D. Lindell, Plant Physiol., 1997, 114, 119.
2. M. D. Erion, S. R. Kasibhatla, B. C. Bookser, P. D. van Poelje, M. R. Reddy, H. E. Gruber and J. R. Appleman, J. Am. Chem. Soc., 1999, 121, 308.
3. D. W. Hollomon and K. Chamberlain, Pestic. Biochem. Physiol., 1981, 16, 158.
4. R. I. Glazer, Cancer Chemother. Pharmacol., 1980, 4, 227.
5. S. D. Lindell, B. A. Moloney, B. D. Hewitt, C. G. Earnshaw, P. J. Dudfield and J. E. Dancer, Bioorg. Med. Chem. Lett., 1999, 9, 1985.
6. A. J. Sharff, D. K. Wilson, Z. Chang and F. A. Quicho, J. Mol. Biol., 1992, 226, 917.
7. C. G. Earnshaw, AgrEvo UK Ltd., unpublished results. Further details of our calculations can be found in ref. 5 and V.-D. Le, Ph.D. Thesis, University of London, 1997, p. 26See also M. D. Erion and M. R. Reddy, J. Am. Chem. Soc., 1998, 120, 3295.
8. B. Kobe, J. Kobe, D. F. Smee, B. Jerman-Blazic-Dzonova and T. Solmajer, Eur. J. Med. Chem., 1992, 27, 259.
9. V. V. Kuz'menko, T. A. Kuz'menko and A. M. Simonov, Khim. Geterotsikl. Soedin., 1986, 22, 346 (Chem. Heterocycl. Compd. (Engl. Transl.), 1986, 22, 282).
10. L. N. Simon, R. J. Bauer, R. L. Tolman and R. K. Robins, Biochemistry, 1970, 9, 573; C. Frieden, L. C. Kurz and H. R. Gilbert, Biochemistry, 1980, 19, 5303.
11. M. C. Clingerman and J. A. Secrist III, J. Org. Chem., 1983, 48, 3141.
12. A. J. Speziale and K. W. Ratts, J. Org. Chem., 1963, 28, 465.
13. C.-C. Tzeng, N. C. Motola and R. P. Panzica, J. Org. Chem., 1983, 48, 1271.
14. W. Pfleiderer, Tetrahedron, 1988, 44, 3373; H. B. Cottam, Z. Kazimierczuk, S. Geary, P. A. McKernan, G. R. Revankar and R. K. Robins, J. Med. Chem., 1985, 28, 1461; G. A. Howard, B. Lythgoe and A. R. Todd, J. Chem. Soc., 1945, 556.
15. J. Clark, R. K. Grantham and J. Lydiate, J. Chem. Soc., 1968,(C), 1122; T. G. Back, K. Yang and H. R. Krouse, J. Org. Chem., 1992, 57, 1986; T. G. Back, D. L. Baron and K. Yang, J. Org. Chem., 1993, 58, 2407.
16. I. M. Buck, A. Eleuteri and C. B. Reese, Tetrahedron, 1994, 50, 9195.
17. C.-C. Tzeng, D.-C. Wei, L. C. Hwang, M.-C. Cheng and Y. Wang, J. Chem. Soc., Perkin Trans. 1, 1994, 2253.
18. H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T. Christensen and S. K. Byram, J. Am. Chem. Soc., 1975, 97, 4602; J. G. Buchanan, A. R. Edgar, R. J. Hutchison, A. Stobie and R. H. Wightman, J. Chem. Soc., Perkin Trans. 1, 1980, 2567; W.-Y. Ren, M.-I. Lim, B. A. Otter and R. S. Klein, J. Org. Chem., 1982, 47, 4633.
19. S. H. Kang and S. B. Lee, Tetrahedron Lett., 1995, 36, 4089.
20. For a review, see A. Albert, Adv. Heterocycl. Chem., 1976, 20, 117.
21. M. T. Chenon, R. P. Panzica, J. C. Smith, R. J. Pugmire, D. M. Grant and L. B. Townsend, J. Am. Chem. Soc., 1976, 98, 4736.
22. D. J. Williams, Imperial College, unpublished work.
23. Y. Hitoshi and I. Fumiyoshi, Chem. Pharm. Bull., 1982, 30, 326.
24. T. Sasaki, K. Minamoto and K. Harada, J. Org. Chem., 1980, 45, 4587; Y. Nakayama, Y. Sanemitsu, M. Mizutani and H. Yoshioka, J. Heterocycl. Chem., 1981, 18, 631.
25. T. Sasaki and K. Minamoto, Chem. Ber., 1967, 100, 3467; J. Daunis, R. Jacquier and P. Viallefont, Bull. Soc. Chim. Fr., 1969, 3670.
26. W. C. Still, M. Kahn and A. Mitra, J. Org, Chem., 1978, 43, 2923.
27. L. M. Harwood, Aldrichimica Acta, 1985, 18, 25.
28. P. A. Levene and E. T. Stiller, J. Biol. Chem., 1933, 102, 187.