Sugar-substituted 2-azetidinones as cholesterol absorption inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 1, 1998, Pages 35-40

  Vaccaro, Wayne D ^a   Sher, Rosy ^a   Davis Jr , Harry R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 2 AZETIDINONE; CHOLESTEROL; GLUCURONIDE; UNCLASSIFIED DRUG;

ARTICLE; CONJUGATE; CONTROLLED STUDY; DRUG SYNTHESIS; METHODOLOGY; NONHUMAN; STEREOCHEMISTRY;

ANIMALS; ANTICHOLESTEREMIC AGENTS; AZETIDINES; CARBOHYDRATES; CRICETINAE; MOLECULAR STRUCTURE;

EID: 0032488621     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)10185-8     Document Type: Article

References (28)

1. 1. Discovery of Sch 48461: Burnett, D. A.; Caplan, M. A.; Davis, H. R., Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733. SAR studies of Sch 48461: Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, E. R.; Salisbury, B.; Davis, H. R., Jr. J. Med. Chem. 1996, 39, 3684.
2. 1. Discovery of Sch 48461: Burnett, D. A.; Caplan, M. A.; Davis, H. R., Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733. SAR studies of Sch 48461: Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, E. R.; Salisbury, B.; Davis, H. R., Jr. J. Med. Chem. 1996, 39, 3684.
3. 2. Metabolism studies of Sch 48461: Van Heek, M.; France, C. F.; Compton, D. S.; Mcleod, R. L.; Yumbie, N. P.; Alton, K. B.; Sybertz, E. J.; Davis, H. R., Jr. J. Pharmacol. Exp. The. 1997, Accepted for publication.
4. 3): 7.38 (5H, m). 7.21 (9H, m), 6.96 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 9.1 Hz), 5.04 (2H, s), 4.55 (1H, d, J = 2.2 Hz), 3.06 (1H, m), 2.64 (2H, m), 1.97 (1H, m), 1.82 (3H, m).
5. 4. Burnett, D. A. Tetrahedron Lett. 1994, 35, 7339. The stereochemistry of 1, Sch 48461 was determined to be 3R,4S by independent chiral synthesis and by X-ray analysis of a crystalline analog. The stereochemical assignment of phenol 2 was confirmed by independent synthesis from 1, boron tribromide demethylation of 1 gave a phenol which was identical to 2 by NMR and chiral HPLC.
6. 3)
7. 6. Useful discussions of methods of glucuronidation: (a) van Boeckel, C. A. A.; Kasperson, F. M. Xenobiotica 1987, 17, 1451.
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11. 3: Smith, A. B.; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092.
12. 2
13. (d) NaH, DMF
14. 3, DMF.
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16. 8. Attempted coupling of 2 and 10. (a) p-TSA, 110 °C, vacuum: Bollenback, G. N.; Long, J. W.; Benjamin, D. G.; Lindquist, J. A. J. Am. Chem. Soc. 1955, 77, 3310. Nicolaou, K. C.; Daines, R. C.; Ogawa, Y.; Chakraorty, T. K. J. Am. Chem. Soc. 1988, 110, 4696.
17. 8. Attempted coupling of 2 and 10. (a) p-TSA, 110 °C, vacuum: Bollenback, G. N.; Long, J. W.; Benjamin, D. G.; Lindquist, J. A. J. Am. Chem. Soc. 1955, 77, 3310. Nicolaou, K. C.; Daines, R. C.; Ogawa, Y.; Chakraorty, T. K. J. Am. Chem. Soc. 1988, 110, 4696.
18. 2: Fischer, B.; Nudelman, A.; Ruse, M.; Herzig, J.; Gottlied, H. E. J. Org. Chem. 1984, 49, 4988.
19. 3H: Murphy, G. J. Pharm. Science 1972, 61, 811.
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21. (b) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639.
22. 9 924.4112, found 924.4119. HPLC: Analytical Chiracel OD column (20% isopropanol/hexane, 1.0 mL/min, Rt = 15.13 min).
23. 12. Available from the Sigma Chemical Company.
24. 13. Tietze, L. F.; Seele, R. Carbohydr. Res. 1986, 148, 349.
25. 4Ac pH 6 Buffer/30% Acetonitrile gradient to 100% acetonitrile over 40 min.) Rt 3: 10 min. Rt 1: 43 min.
26. 15. Nudelman, A.; Gottlied, H. E.; Fischer, B.; Herzig, J. J. Org. Chem. 1986, 51, 727.
27. 16. Structure determination of glucuronides. See ref 5a and Mutlib, A. E.; Abbott, F. S. Drug Metab. Dispos. 1992, 20, 451.
28. 17. For a discussion of the seven day cholesterol fed hamster assay see ref 1.