2430
R. J. Cherney et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2425–2430
4. Feria, M.; Diaz-Gonzalez, F. Expert Opin. Ther. Patents 2006, 16, 49.
5. Tak, P. P. Best Pract. Res. Clin. Rheumatol. 2006, 20, 929.
6. (a) Coll, B.; Alonso-Villaverde, C.; Joven, J. Clin. Chim. Acta 2007, 383, 21; (b)
Peters, W.; Charo, I. F. Curr. Opin. Lipidol. 2001, 12, 175.
carbonate cyclization conditions afforded lactam 50, even in the
presence of the aryl sulfide. Subsequent reduction of the azide fol-
lowed by our standard transformations gave the desired racemic
diastereomers 20 and 21.
With the ‘end game’ chemistry firmly established (see Schemes
2–4), other core modifications were produced as shown in Scheme
5. The six-membered lactam necessary for analog 23 started from
the racemic amine 51.10c A reductive amination with (S)-2-N-tert-
butoxycarbonyl-5-oxopentanoic acid methyl ester20 followed by
saponification and cyclization yielded 52, which was taken to 23
using our standard chemistry. Following this same sequence, but
7. Mahad, D. J.; Ransohoff, R. M. Semin. Immunol. 2003, 15, 23.
8. Kamei, N.; Tobe, K.; Suzuki, R.; Ohsugi, M.; Watanabe, T.; Kubota, N.; Ohtsuka-
Kowatari, N.; Kumagai, K.; Sakamoto, K.; Kobayashi, M.; Yamauchi, T.; Ueki, K.;
Oishi, Y.; Nishimura, S.; Manabe, I.; Hashimoto, H.; Ohnishi, Y.; Ogata, H.;
Tokuyama, K.; Tsunoda, M.; Ide, T.; Murakami, K.; Nagai, R.; Kadowaki, T. J. Biol.
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10. (a) Cherney, R. J.; Mo, R.; Meyer, D. T.; Nelson, D. J.; Lo, Y. C.; Yang, G.; Scherle, P.
A.; Mandlekar, S.; Wasserman, Z. R.; Jezak, H.; Solomon, K. A.; Tebben, A. J.;
Carter, P. H.; Decicco, C. P. J. Med. Chem. 2008, 51, 721; (b) Cherney, R. J.;
Brogan, J. B.; Mo, R.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.; Molino, B. F.;
Carter, P. H.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2009, 19, 597; (c) Cherney, R.
J.; Mo, R.; Meyer, D. T.; Voss, M. E.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.;
Tebben, A. J.; Carter, P. H.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2009, 19, 3418.
11. (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R.
Science 1980, 210, 656; (b) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org.
Chem. 1982, 47, 104.
substituting
(S)-2-N-tert-butoxycarbonyl-5-oxohexanoic
acid
methyl ester21 into the reductive amination, gave the seven-mem-
bered lactam analog of 52, which was used to synthesize 24. In a
similar way, a reductive amination of 53 and (S)-3,3-dimethyl-4-
oxo-2-[(9-phenylfluoren-9-yl)-amino]-butyric acid methyl ester22
was followed by phenylfluorenyl removal and cyclization to yield
54, which was used in the production of 22. Finally, amine 53
was also coupled to N-Boc-L-aspartic acid, thus directly forming
the imide 55, which was used in the formation of analog 25.
12. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
1997, 23, 3.
13. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D.
J. Med. Chem. 2002, 45, 2615.
14. Carter, P. H.; Cherney, R. J. Diamines as modulators of chemokine receptor
activity. WO 2002050019, 2002.
In summary, we have demonstrated that c-lactams are viable gly-
cinamide replacements within a series of cyclohexane-based CCR2
antagonists. Lactam-containing trisubstituted cyclohexanes were
more promising, and this led to the potent and selective CCR2 antag-
onist 13, whichalsoshowedoralbioavailabilityindog. The five-mem-
bered lactam of compound 13 proved to be more active than the six-
or seven-membered lactams, and additional substitution about the
lactam ring of 13 was not tolerated. As glycinamide-based CCR2
15. Wacker, D. A.; Santella, J. B., III; Gardner, D. S.; Varnes, J. G.; Estrella, M.;
DeLucca, G. V.; Ko, S. S.; Tanabe, K.; Watson, P. S.; Welch, P. K.; Covington, M.;
Stowell, N. C.; Wadman, E. A.; Davies, P.; Solomon, K. A.; Newton, R. C.; Trainor,
G. L.; Friedman, S. M.; Decicco, C. P.; Duncia, J. V. Bioorg. Med. Chem. Lett. 2002,
12, 1785.
16. Stereochemistry based on previous SAR.10
17. Wu, C.; Kobayashi, H.; Sun, B.; Yoo, T. M.; Paik, C. H.; Gansow, O. A.;
Carrasquillo, J. A.; Pastan, I.; Brechbiel, M. W. Bioorg. Med. Chem. 1997, 5, 1925.
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1994, 59, 5328; (b) Hayashi, Y.; Rhode, J. J.; Corey, E. J. J. Am. Chem. Soc. 1996,
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Fortunak, J. M.; Nugent, W. A.; Radesca, L. A.; Tang, L.; Xiang, C. D. Org. Process
Res. Dev. 2006, 10, 262.
antagonists are quite prevalent, these c-lactams could find additional
use in the design and development of future antagonists.
References and notes
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21. (S)-2-N-tert-butoxycarbonyl-5-oxohexanoic acid methyl ester was produced
by an esterification (trimethylsilyldiazomethane in 92% yield) of the
commercially available (S)-2-N-tert-butoxycarbonyl-5-oxohexanoic acid.
22. Kawahata, N.; Weisberg, M.; Goodman, M. J. Org. Chem. 1999, 64, 4362.
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