Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors

Tetrahedron Letters

Volumn 51, Issue 14, 2010, Pages 1880-1883

  Mascitti, Vincent ^a   Robinson, Ralph P ^a   Préville, Cathy ^a   Thuma, Benjamin A ^a   Carr, Christopher L ^a   Reese, Matthew R ^a   Maguire, Robert J ^a   Leininger, Michael T ^a   Lowe, André ^a   Steppan, Claire M ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOSIDE; PROTEIN INHIBITOR; SODIUM GLUCOSE COTRANSPORTER 1; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; UNCLASSIFIED DRUG;

ALDOL REACTION; ARTICLE; CANNIZZARO REACTION; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; IC 50; ONE POT SYNTHESIS;

EID: 77549085827     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2010.02.024     Document Type: Article

References (34)

1. +/glucose cotransporter found primarily in the gut and to a smaller extent in the liver, the lungs, and in the S3 domain of the kidneys
2. Idris I., and Donnelly R. Diabetes Obes. Metab. 11 (2009) 79
3. Phlorizin is a weak and non-specific SGLT inhibitor. For a recent review see:. Ehrenkranz J.R.L., Lewis N.G., Kahn C.R., and Roth J. Diabetes Metab. Res. Rev. 21 (2005) 31
4. Chassis H., Joliffe N., and Smith H.W. J. Clin. Invest. 12 (1933) 1083
5. +/glucose cotransporter SGLT1 see also:. Lee W.S., Kanai Y., Wells R.G., and Hediger M.A. J. Biol. Chem. 269 (1994) 12032
6. Fujimori Y., Katsuno K., Nakashima I., Ishikawa-Takemura Y., Fujikura H., and Isaji M. J. Pharmacol. Exp. Ther. 327 (2008) 268
7. Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J., Patel M., Girotra R.N., Wu G., Sher P.M., Morrison E.P., Biller S.A., Zahler R., Deshpande P.P., Pullockaran A., Hagan D.L., Morgan N., Taylor J.R., Obermeier M.T., Humphreys W.G., Khanna A., Discenza L., Robertson J.G., Wang A., Han S., Wetterau J.R., Janovitz E.B., Flint O.P., Whaley J.M., and Washburn W.N. J. Med. Chem. 51 (2008) 1145
8. Sato, T.; Honda, K.; Kawai, T.; Ahn, K. H., Patent application WO 013280, 2008.
9. See also Chen, Y.; Feng, Y.; Xu, B.; Lv, B.; Dong, J.; Seed, B.; Hadd, M. J. US Patent application 0275907, 2007.
10. Xu B., Lv B., Feng Y., Xu G., Du J., Welihinda A., Sheng Z., Seed B., and Chen Y. Bioorg. Med. Chem. Lett. 19 (2009) 5632
11. Detailed reviews on SGLT2 inhibitors have recently appeared:. Washburn W.N. J. Med. Chem. 52 (2009) 1785
12. Washburn W.N. Expert Opin. Ther. Patents 19 (2009) 1485
13. Schaffer R. J. Am. Chem. Soc. 81 (1959) 5452
14. See also. Amigues E.J., Greenberg M.L., Ju S., Chen Y., and Migaud M.E. Tetrahedron 63 (2007) 10042
15. Compounds 6a, 6b, 6e, and 6f were prepared as described in the literature via addition of the appropriately substituted 3-benzylphenyllithium to 2,3,4,6-tetra-O-trimethylsilyl-β-d-gluconolactone; see for instance Ref. 7. Interestingly, nucleophilic additions onto an adequately protected form of gluconolactone using organometallic species derived from 1,3-dithiane-containing aryl bromides of the kind below led to moderate yields of the corresponding methyl ketal intermediate:{A figure is presented}
16. Lipták A., Jodál I., and Nánási P. Carbohydr. Res. 44 (1975) 1
17. Mancuso A.J., and Swern D. Synthesis (1981) 165
18. 1H NMR (400 MHz, chloroform-d) δ ppm 1.98 (dd, J = 10.0, 4.1 Hz, 1H), 2.24-2.27 (m, 1H), 2.28 (s, 3H), 3.51-3.59 (m, 1H), 3.70-3.78 (m, 1H), 3.77 (s, 3H), 3.80-4.02 (m, 6H), 4.07 (d, J = 4.3 Hz, 2H), 4.39 (d, J = 10.5 Hz, 1H), 4.53 (d, J = 9.8 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.87 (d, 1H), 4.96 (d, J = 10.9 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.87-7.05 (m, 4H), 7.17-7.38 (m, 16H).
19. For oxetane synthesis see:. Picard P., Leclercq D., Bats J.-P., and Moulines J. Synthesis (1981) 550
20. 4) δ ppm 2.19 (s, 3H), 3.25-3.38 (m, 3H), 3.74 (s, 3H), 3.92 (s, 2H), 4.04 (d, J = 8.8 Hz, 1H), 4.49 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.4 Hz, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.93 (d, J = 6.6 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.11-7.19 (m, 3H).
21. 4) δ ppm 7.16-6.96 (m, 7H), 4.89 (d, 1H, J = 6.8 Hz), 4.79 (d, 1H, J = 6.8 Hz), 4.59 (d, 1H, J = 6.4 Hz), 4.45 (d, 1H, J = 7.2 Hz), 4.00 (d, 1H, J = 9.6 Hz), 3.92 (s, 2H), 3.36-3.20 (m, 3H), 2.54 (q, 2H, J = 7.6 Hz), 2.16 (s, 3H), 1.15 (t, 3H, J = 7.6 Hz).
22. 4): δ ppm 3.20-3.28 (m, 2H), 3.34-3.38 (m, 1H), 3.75 (s, 3H), 3.99-4.08 (m, 3H), 4.48 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 4.82 (d, J = 6.8 Hz, 1H), 4.92 (d, J = 6.8 Hz, 1H), 6.79-6.84 (m, 2H), 7.09-7.11 (m, 2H), 7.23-7.29 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H).
23. 4) δ ppm 1.35 (t, J = 7.0 Hz, 3H), 3.20-3.34 (m, 3H), 3.92-4.09 (m, 5H), 4.48 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.92 (d, J = 6.8 Hz, 1H), 6.76-6.86 (m, 2H), 7.02-7.13 (m, 2H), 7.21-7.30 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H).
24. Anisole avoids the unwanted formation of side products arising from Friedel-Craft-type reactions between the PMB cation and the electron-rich aryl ring of the substrate.
25. For the synthesis of spiro nucleosides see:. Roy A., Achari B., and Mandal S.B. Tetrahedron Lett. 47 (2006) 3875
26. 4) δ ppm 7.22-6.99 (m, 7H), 4.55 (d, 1H, J = 13.6 Hz), 4.46 (d, 1H, J = 14 Hz), 4.20 (dd, 1H, J = 13.6 and 4.8 Hz), 4.15 (d, 1H, J = 9.6 Hz), 4.03 (dd, 1H, J = 14 and 4.8 Hz), 3.96 (s, 2H), 3.53 (d, 1H, J = 9.6 Hz), 3.41 (t, 1H, J = 9.2 Hz), 3.23 (t, 1H, J = 9.2 Hz), 2.58 (q, 2H, J = 7.6 Hz), 2.19 (s, 3H), 1.17 (t, 3H, J = 7 Hz).
27. 4) δ ppm 8.43 (s, 1H), 7.19-6.99 (m, 7H), 4.37 (d, 1H, J = 11.0 Hz), 4.28 (d, 1H, J = 11.1 Hz), 4.12-4.06 (m, 2H), 3.99-3.91 (m, 3H), 3.48-3.33 (m, 3H), 2.58 (q, 2H, J = 7.6 Hz), 2.20 (s, 3H), 1.19 (t, 3H, J = 7.6 Hz).
28. Hanessian S. In: Hanessian S. (Ed). Preparative Carbohydrate Chemistry (1997), Marcel Dekker, New York 389-412 Chapter 17
29. Hanessian S., Lu P.-P., and Ishida H. J. Am. Chem. Soc. 120 (1998) 13296
30. Hanessian S., and Lou B. Chem. Rev. 100 (2000) 4443
31. Hanessian S., Mascitti V., Lu P.-P., and Ishida H. Synthesis (2002) 1959
32. Moitessier N., Englebienne P., and Chapleur Y. Tetrahedron 61 (2005) 6839 and references cited therein
33. 14C]glucopyranoside (AMG) uptake in CHO cells stably expressing human SGLT1 or 2; Han, S.; Hagan, D. L.; Taylor, J. R.; Xin, L.; Meng, W.; Biller, S. A.; Wetterau, J. R.; Washburn, W. N.; Whaley, J. M. Diabetes 2008, 57, 1723-1729.
34. For a broader discussion of the structure activity relationship around the carbohydrate motif of SGLT2 inhibitors see: Robinson, R. P.; Mascitti, V.; Boustany-Kari, C. M.; Carr, C. L.; Foley, P. M.; Kimoto, E.; Leininger, M. T.; Lowe, A.; Klenotic, M. K.; MacDonald, J. I.; Maguire, R. J.; Masterson, V. M.; Maurer, T. S.; Miao, Z.; Patel, J. D.; Préville, C.; Reese, M. R.; She, L.; Steppan, C. M.; Thuma, B. A.; Zhu, T. Bioorg. Med. Chem. Lett. 2010, doi:10.1016/j.bmcl.2010.01.075.