Cyclic urea HIV protease inhibitors containing alkynyl- and alkenyl-tethered heterocycles in the P2 region

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 7, 1996, Pages 797-802

  Dax, Scott L ^a   Cook, Stacy C ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4,7 DIBENZYL 1 CYCLOPROPYLMETHYL 2 OXO 3 [3 (4 PYRAZOLYL) 2 PROPENYL]PERHYDRO 1,4 DIAZEPINE 5,6 DIOL; 4,7 DIBENZYL 2 OXO 1,3 BIS[3 (4 PYRAZOLYL) 2 PROPENYL] PERHYDRO 1,4 DIAZEPINE 5,6 DIOL; ANTIVIRUS AGENT; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; UREA DERIVATIVE; XU 348; XU 430;

ARTICLE; CONTROLLED STUDY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 0029933347     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00108-4     Document Type: Article

References (11)

1. SCRIP, December 27, 1995, pg. 21.
2. For an excellent review on anti-HIV chemotherapy, see: De Clercq, E. J. Med. Chem. 1995, 38, 2491.
3. Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C-H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-Vittanen, S. Science 1994, 263, 380.
4. 3): δ 1.56 (s, 6H), 2.22 (t, 2H), 2.80 (d, 2H), 3.00 (m, 4H), 4.06 (br dd, 2H), 4.24 (app. s, 2H), 4.50 (d, 2H), 7.18 - 7.37 (m, 10H).
5. Representative reaction conditions: Bis-alkynyl cyclic urea 2 (4.0 g, 9.0 mmol, 1.0 equiv) is dissolved in oxygen-free tetrahydrofuran (50 mL) under nitrogen. Diethylamine (2.8 mL, 26.7 mmol, 1.5 equiv) is added followed by the halo-heterocycle (e.g., 4-iodo-(N-methoxyethoxmethyl)pyrazole) (7.52 g, 26.7 mmol, 1.5 equiv). Copper (I) iodide (0.36 g, 1.9 mmol, 0.2 equiv) and tetrakis(triphenylphosphine)palladium (0) (1.04 g, 0.9 mmol, 0.1 equiv) are added as solids. The mixture is heated at reflux overnight, cooled and product extracted into ethyl acetate and then purified via flash column chromatography.
6. 3): δ 1.52 (s, 6H), 3.00 - 3.10 (m, 6H), 3.38 (s, 6H), 3.49 (m, 4H), 3.60 (m, 4H), 4.06 (m, 2H), 4.30 (app. s, 2H), 4.64 (d, 2H), 5.41 (s, 4H), 7.20 - 7.35 (m, 10H).
7. 3): δ 1.50 (s,6H), 1.30 - 1.60 (m, 12H), 2.40 - 2.51 (m, 8H), 2.83 (d, 2H), 2.96 - 3.04 (m, 4H), 3.25 (s, 4H), 4.06 (m, 2H), 4.22 (app. s, 2H), 4.53 (d, 2H), 7.17 - 7.37 (m, 10H).
8. 6): δ 2.83 (d, 2H), 2.90 - 3.11 (m, 4H), 3.73 (br d, 2H), 3.95 (app. s, 2H), 4.41 (br s, 2H), 4.50 (d, 2H), 7.10 - 7.20 (m, 10H), 7.43 (s, 4H), 12.25 (br s, 2H).
9. Erickson-Viitanen, S.; Manfredi, J.; Viitanen, P.; Tribe, D. E.; Tritch, R.; Hutchison (III) C. A.; Loeb, D. D.; Swanstrom, R. AIDS Res. Hum. Retroviruses 1989, 5, 577.
10. 3OD): δ 2.81 - 3.11 (m, 4H), 3.01 (d, 2H), 3.50 - 3.70 (br s, 2H), 3.67 (br d, 2H), 3.92 (app. s, 2H), 4.17 (dd, 2H), 5.77 -5.82 (m, 2H), 6.17 (d, 2H), 7.10 - 7.30 (m, 10H), 7.60 (br s, 4H).
11. 90 as described in ref 3.