Improved synthesis of antibacterial 3-substituted 6-anilinouracils

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 11, 2008, Pages 3215-3218

  Svenstrup, Niels ^a   Kuhl, Alexander ^a   Ehlert, Kerstin ^a   Häbich, Dieter ^a  

^a BAYER PHARMA AG   (Germany)

Author keywords

Anilinouracils; Antibacterials; DNA polymerase IIIC; Gram positive bacteria; Resistance

Indexed keywords

3 (CYCLOPROPHYLMETHYL) 6 (2,3 DIHYDRO 1H INDEN 5 YLAMINO)URACIL; ANILINOURACIL; CHLOROURACIL; URACIL DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL CELL WALL; CONTROLLED STUDY; DRUG EFFICACY; DRUG SYNTHESIS; GRAM POSITIVE BACTERIUM; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANILINE COMPOUNDS; ANTI-BACTERIAL AGENTS; DNA POLYMERASE III; ENZYME INHIBITORS; GRAM-POSITIVE BACTERIA; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

BACTERIA (MICROORGANISMS); POSIBACTERIA;

EID: 44149123363     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.04.061     Document Type: Article

References (20)

1. Coates A., Hu Y., Bax R., and Page C. Nat. Rev. Drug Disc. 1 (2002) 895
2. Infectious Disease Society of America (IDSA): http://www.idsociety.org.
3. Wright G.D. Curr. Opin. Chem. Biol. 7 (2003) 1
4. EARSS Annual Report 2006, http://www.rivm.nl.
5. von Nussbaum F., Brands M., Hinzen B., Weigand S., and Häbich D. Angew. Chem. 118 (2006) 5194
6. Angew. Chem. Int. Ed. 45 (2006) 5072
7. Kuhl A., Svenstrup N., Ladel C., Otteneder M., Binas A., Schiffer G., Brands M., Lampe T., Ziegelbauer H., Haebich D., and Ehlert K. Antimicrob. Agents Chemother. 49 (2005) 987
8. Sun H., Zhi C., Wright G.E., Ubiali D., Pregnolato M., Verri A., Focher F., and Spadari S. J. Med. Chem. 42 (1999) 2344
9. Cowden W.B., Halladay P.K., Cunningham R.B., Hunt N.H., and Clark I.A. J. Med. Chem. 34 (1991) 1818
10. Müller C.E., Shi D., Manning Jr. M., and Daly J.W. J. Med. Chem. 36 (1993) 3341
11. Focher F., Ubiali D., Pregnolato M., Zhi C., Gambino J., Wright G.E., and Spadari S. J. Med. Chem. 43 (2000) 2601
12. Tobe M., Isobe Y., Goto Y., Obara F., Tsuchiya M., Matsui J., Hirota K., and Hayashi H. Biorg. Med. Chem. 8 (2000) 2037
13. Tarantino Jr. P.M., Zhi C., Gambino J.J., Wright G.E., and Brown N.C. J. Med. Chem. 42 (1999) 2035
14. Wright N.E., and Brown N.C. Curr. Opin. Anti-Infect. Investig. Drugs 1 (1999) 45
15. Link P.A., van der Plas H.C., and Müller F. J. Heterocycl. Chem. 22 (1985) 873
16. Jursic B.S., and Neumann D.M. Tetrahedon Lett. 42 (2001) 8435
17. Zhi C., Long Z., Manikowski A., Brown N.C., Tarantino Jr. P.M., Holk K., Dix E.J., Wright G.E., Foster K.A., Butler M.M., LaMarr W.A., Skow D.J., Motorina I., Lamothe S., and Storer R. J. Med. Chem. 48 (2005) 7063
18. Edstrom E.D., and Wei Y. J. Org. Chem. 59 (1994) 6902
19. 4) and evaporated in vacuo to give the product 4b as a solid, yield 1.76 g (86%). 6-Chloro-3-cyclopropylmethyluracil 1b: a suspension of 1-(benzyloxy)methyl-6-chloro-3-cyclo-propyl-methyl-uracil 4 b (600 mg, 1.9 mmol) was suspended in TFA (30 mL) and heated at reflux for 45 min. The reaction mixture was cooled to rt and evaporated in vacuo, whereupon MeOH (10 mL) was added and subsequently removed in vacuo. Ethylacetate (5 mL) was added, and the sample was left overnight to crystallize. The solid was filtered off, washed with ether and dried in vacuo to give 1b as colorless crystals, yield 320 mg (85%). 3-Cyclopropylmethyl-6-(2,3-dihydro-1H-inden-5-ylamino)uracil 2b: a mixture of 6-Chloro-3-(cyclo-propylmethyl)uracil 1b (120 mg, 0.6 mmol) and 5-aminoindane (320 mg, 2.4 mmol) was heated under argon at 160 °C for 30 min. The reaction mixture was cooled to rt, 2-propanol (5 mL) was added, and the resulting precipitate was filtered off and dried to give a crude product, which was purified by reverse-phase preparative HPLC to give the product 2b as a solid, yield 123 mg (68%).
20. The aqueous solubility of 2b is 3.3 mg/L.