Stereoselective synthesis and biological activity of cis azetidinones as cholesterol absorption inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 16, 1996, Pages 1947-1950

  McKittrick, Brian A ^a   Ma, Ke ^a   Dugar, Sundeep ^a   Clader, John W ^a   Davis Jr , Harry ^a   Czarniecki, Michael ^a   McPhail, Andrew T ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b DUKE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 2 AZETIDINONE DERIVATIVE; 3 (1 HYDROXY 3 PHENYLPROPYL) 4 (4 METHOXYPHENYL) 1 PHENYL 2 AZETIDINONE; ANTILIPEMIC AGENT; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG STRUCTURE; DRUG SYNTHESIS; HAMSTER; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HYPERCHOLESTEROLEMIA; NONHUMAN; ORAL DRUG ADMINISTRATION; REACTION ANALYSIS;

ANIMALIA; CRICETINAE;

EID: 0030594964     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00347-2     Document Type: Article

References (16)

1. 1. (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733;
2. (b) Salisbury, B. G.; Davis, H. R.; Burrier, R.; Burnett, D. A.; Boykow, G.; Caplen, M. A.; Clemmons, A. L.; Compton, D. S.; Hoos, L. M.; McGregor, D. G.; Schnitzer-Polokoff, R.; Smith, A. A.; Weig, B. C.; Zilli, D. L.; Clader, J. W.; Sybertz, E. J. Atherosclerosis 1995, 115, 45.
3. 2. Dugar, S.; Clader, J. W.; Chan, T.; Davis, H. J. Med. Chem. 1995, 38, 4875.
4. 3. (a) 3 was prepared in 70% yield according to Bose, A. K.; Gupta, K.; Manhas, M. S. J. Chem. Soc. Chem. Comm. 1984, 2, 86.
5. 20 = - 157.6 °, 2.5 mg/ml MeOH) was assigned based on the X-ray crystallographic structure determination of the brosylate prepared from the enantiomeric alcohol 2g. The relative stereochemistry of 2b was established by direct x-ray analysis and the absolute configuration was assigned by comparison of the CD spectra with SCH 48461.
6. 2/dM at 241nm determined as solutions in MeOH: 2a, -4.6, 2b,-5.2, 2c,-5.4, 2d,-5.6, 2e,+4.5, 2f, + 4.8, 2g, + 5.2, 2h, + 5.8. (coordinates for both X-ray structures have been deposited with Cambridge Crystallographic Data Centre).
7. 4. For a similar transformation see: Tschaen, D. M.; Fuentes, L. M.; Lynch, J. E.; Lasweel, W. L.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 23, 2779.
8. 5. (a) SCH 51812, single enantiomer.
9. 50 for the single stereoisomer of the deshydroxy analog of 2c was estimated to be ≥4 mg/kg/day. This estimate was used for the SAR comparison with 2c.
10. 1,11 had demonstrated only weak ACAT activity for a series of structurally related azetidinones. Therefore it is highly unlikely that the weak ACAT activity that these compounds may have would account for the potent CAI activity observed.
11. 7. Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M. J. Am. Chem. Soc. 1981, 103, 6765.
12. 8. (a) Attempted deprotonation/kinetic protonation of 2a/b (using 2 equiv of LDA followed by AcOH) or 4 (using NaH, followed by AcOH) gave only the recovered trans isomers. For additional routes to cis azetidinones see: Georg, G. I.; Akgün, E. Tetrahedron Lett. 1990, 23, 3267, and ref 4.;
13. (b) Aimetti, J. A.; Hamanaka, E. S.; Johnson, D. A.; Kellog, M. S. Tetrahedron Lett. 1979, 48, 4631
14. 2 column with EtOAc:Hexane, 1:10.
15. 10. Kanabus-Kaminska, J. M.; Hawari, J. A.; Griller, D.; Chatglialoglu, C. J. Am. Chem. Soc. 1987, 109, 5267.
16. 11. John W. Clader, Duane A. Burnett, Mary Ann Caplen, Martin S. Domalski, Sundeep Dugar, Wayne Vaccaro, Rosy Sher, Margaret E. Browne, Hongrong Zhao, Robert E. Burrier, Brian Salisbury, and Harry R. Davis, Jr., J. Med. Chem 1996 in press.