Novel 5-(N-Alkylaminouracil) Acyclic Nucleosides

Abstract

Protocols for the two-step syntheses of new 5-(N-hydroxyalkyl- and 5-N-benzylamino)uracil acyclic nucleosides bearing various functional groups (alkoxy/hydroxy and cyano/ester) are presented. Two groups of the title compounds were synthesised via aminolysis of 5-bromouracil and, subsequently, either coupling with an alkylating agent (2-chloromethoxyethyl acetate), or Michael­-type addition to acrylonitrile/methyl acrylate. The reverse sequences for both syntheses were also studied. The target molecules were designed as non-nucleoside reverse transcriptase inhibitors (NNRTI) and are analogues of 1-(hydroxyethoxymethyl)-6-thiophenylthymine (HEPT) and 3-benzyl-1-cyanomethyluracils. The obtained compounds will be used in screening tests for anti-HIV-1 activity.

Key words

acyclic nucleosides - 5-(N-alkylamino)uracil - aminolysis - N-alkylation - Michael-type addition

References

• 1 Gumina G. Choi Y. Chu CK. Antiviral Nucleosides - Chiral Synthesis and Chemotherapy   Elsevier; Amsterdam: 2003.  p.46 
• 2 Miyasaka T. Tanaka H. Baba M. Hayakawa H. Walker RT. Balzarini J. De Clercq E. J. Med. Chem.  1989,  32:  2507 
• 3 De Clercq E. Field HJ. Br. J. Pharmacol.  2006,  147:  1 
• 4 Faulds D. Heel RC. Drugs  1990,  39:  597 
• 5 Baraldi PG. Romagnoli R. Guadix AE. Pineda de las Infantas MJP. Gallo MA. Espinosa A. Martinez A. Bingham JP. Hartley JA. J. Med. Chem.  2002,  45:  3630 
• 6 Ozarov AA. Novikov MS. Chem. Heterocycl. Compd.  2005,  41:  766 
• 7 Ozarov AA. Novikov MS. Brel’ AK. Solodunova GN. Chem. Heterocycl. Compd.  1998,  34:  611 
• 8 Zemlicka J. In Nucleosides and Nucleotides as Antitumor and Antiviral Agents   Chu CK. Baker DC. Plenum Press; New York: 1993. 
• 9 Maruyama T. Kozai S. Demizu Y. Witvurow M. Pannecouque C. Balzarini J. Snoecks R. Andrei G. De Clercq E. Chem. Pharm. Bull.  2006,  54:  325 
• 10 Philips AP. J. Am. Chem. Soc.  1951,  73:  1061 
• 11 Gerns FR. Perrota A. Hitchings GH. J. Med. Chem.  1966,  9:  108 
• 12 Majmudar KC. Das U. Jana NK. J. Org. Chem.  1998,  63:  3550 
• 13 Fang W.-P. Cheng Y.-T. Cheng Y.-R. Czerng Y.-J. Tetrahedron  2005,  61:  3107 
• 14 Senda S. Hirota K. Banno K. J. Med. Chem.  1972,  15:  471 
• 15 Vorbrüggen H. Ruh-Pohlenz C. Org. React.  2000,  55:  1 
• 16 Boncel S. Gondela A. Walczak K. Synthesis  2010,  1573 
• 17 Boncel S. Mączka M. Walczak KZ. Tetrahedron  2010,  66:  8450 
• 18 Foye WO. Kauffman JM. Kim YH. J. Heterocycl. Chem.  1982,  19:  497 
• 19 Bobkov GV. Brilliantov KV. Mikhailov SN. Rozenski J. Aerschot AV. Herdewijn P. Collect. Czech. Chem. Commun.  2006,  71:  804 
• 20 Senkus M. J. Am. Chem. Soc.  1946,  68:  734 
• 21 Rosowsky A. Kim S.-H. Wick M. J. Med. Chem.  1981,  24:  1177