Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis

Journal of Medicinal Chemistry

Volumn 49, Issue 11, 2006, Pages 3060-3063

  Vachal, Petr ^a   Hale, Jeffrey J ^a   Lu, Zhe ^a   Streckfuss, Eric C ^a   Mills, Sander G ^a   MacCoss, Malcolm ^a   Yin, Daniel H ^a   Algayer, Kimberly ^a   Manser, Kimberly ^a   Kesisoglou, Filippos ^a   Ghosh, Soumojeet ^a   Alani, Laman L ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALENDRONIC ACID; N MYRISTOYLALENDRONIC ACID; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE DENSITY; CONCEPT FORMATION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG EXPOSURE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; EVALUATION; NONHUMAN; OSTEOPOROSIS; PREDICTION; RAT; STRUCTURE ANALYSIS;

ALENDRONATE; ANIMALS; BONE DENSITY; BONE DENSITY CONSERVATION AGENTS; OSTEOPOROSIS; PRODRUGS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33744811701     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060398v     Document Type: Article

References (38)

1. Carmona, R. H. Report on Bone Health and Osteoporosis. United States Department of Human Health Services Press Release, October 14, 2004.
2. In this report, we do not investigate tri-, di-, or monoalkyl alendronates because the in vivo hydrolysis of the second alkyl ester of either phosphonate functionality was expected to be very slow and therefore not considered an effective prodrug based on our concept. The ultimate goal for tetraalkyl alendronate prodrugs was to design structures in which the hydrolysis of the first ester would automatically trigger the release of the second one for each of the two phosphonates.
3. Study of alendronate prodrugs derived from N-linked peptides: Ezra, A.; Hoffman, A.; Breuer, E.; Alferiev, I. S.; Moenkkoenen, J.; El Hanany-Rozen, N.; Weiss, G.; Stepensky, D.; Gati, I.; Cohen, H.; Toermaelehto, S.; Amidon, G. L.; Golomb, G. J. Med. Chem. 2000, 43, 3641.
4. (a) Xie, Y.; Ding, H.; Qian, L.; Yan, X.; Yang, C.; Xie, Y. Bioorg. Med. Chem. Lett. 2005, 15, 3267.
5. (b) Migianu, E.; Guenin, E.; Lecouvey, M. Synlett 2005, 425.
6. (c) Turhanen, P. A.; Vepsalainen, J. J. Synthesis 2005, 2119.
7. (d) Turhanen, P. A.; Vepsalainen, J. J. Synthesis 2004, 992.
8. (e) Even, P.; Guenin, E.; Benramdame, M.; Quidu, P.; El Manouni, D.; Lecouvey, M. Lett. Org. Chem. 2004, 1, 75.
9. (f) Ye, Y.; Xu, G.; Zheng, Y.; Liu, L. Heteroat. Chem. 2003, 14, 309.
10. (g) Orstad, E.; Hoff, P.; Skattebol, L.; Skretting, A.; Breistol, K. J. Med. Chem. 2003, 46, 3021.
11. (h) Mizrahi, D. M.; Waner, T.; Segall, Y. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 173, 1.
12. (i) Turhanen, P. A.; Ahlgren, M. J.; Jarvinen, T.; Vepsalainen, J. J. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 170, 115.
13. (j) Turhanen, P. A.; Ahlgren, M. J.; Jarvinen, T.; Vepsalainen, J. J. Synthesis 2001, 633.
14. (k) Mallard, I.; Benech, J.; Lecouvey, M.; Leroux, Y. Phosphorus. Sulfur Silicon Relat. Elem.s 2000, 162, 15.
15. (l) Niemi, R.; Turbanen, P. A.; Vepsalainen, J. J.; Taipale, H.; Jarvinen, T. Eur. J. Pharm. Sci. 2000, 11, 173. Reviews of literature prior to 2000:
16. (m) Lecouvey, M.; Leroux, Y. Heteroat. Chem. 2000, 11, 556.
17. (n) McKenna, C. E.; Kashemirov, B. A. Top. Curr. Chem. 2002, 220, 201.
18. There are several synthetic strategies for the preparation of alendronic acid. Of these, the most notable is the work of Kieczykowski et al., which serves as a basis for the large-scale production of alendronate sodium: Kieczykowski, G. R.; Jobson, R. B.; Melillo, D. G.; Reinhold, D. F.; Grenda, V. J.; Shinkai, I. J. Org. Chem. 1995, 60, 8310.
19. Fitch, S. J.; Moedritzer, K. J. Am. Chem. Soc. 1962, 84, 1876.
20. 31P NMR analysis of the reaction mixture along with the rearranged 1-phosphonate-1-phosphate byproduct. The desired product was never isolated in substantial yield.
21. Ruel, R.; Bouvier, J. P.; Young, R. J. Org. Chem. 1995, 60, 5209.
22. Review of the Michaelis-Arbuzov reaction: Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
23. Review of Pudovik reaction: Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81.
24. For examples, see the introduction of ref 6.
25. We were unable to reproduce several published procedures that relied on the use of catalytic amounts of secondary and tertiary amines as sufficient to promote the reaction. When 0.1 and 0.2 equiv of various bases were used, an average conversion of only 9.3 ± 1.2% and 21.1 ± 2.3% was observed, respectively.
26. The role of solvent polarity on the rearrangement of monophosphonates to monophosphates follows a trend similar to that reported here for bisphosphonates. Compare this to a recent disclosure for monophosphonates: El Kaim, L.; Gaultier, L.; Grimaud, L.; Dos Santos, A. Synlett 2005, 2335.
27. March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons: New York, 1992.
28. 31P NMR for a sample stored under an inert atmosphere of argon at 20 ± 3 °C.
29. The intramolecular mechanism of the 7-exo-trig O → N acyl transfer was established by a crossover experiment in which a mixture of 3 equiv of 6b and 1 equiv of 7a was hydrogenated. No cross-acylation to produce N-acetyl 9b was observed, and the sole product of this reaction was N-myristoyl 9a.
30. While the use of DMAP afforded a ratio of the desired O-TBS-alendronate to the rearranged 1-phosphonate-1-phosphate of 9:1, the use of other bases provided the following ratios: imidazole, 5:1; triethylamine, 6:1; Hunigs base, 8:1; DABCO, 6:1; DBU, 0.5:1. In addition, the use of imidazole did not affect completion of the silylation step and the use of the Huenigs base led to undesired formation of silylenolethers from the α-ketophosphonate, effectively reducing the overall yield. The use of less polar solvents such as cyclohexane or toluene with a potential of increasing the content of desired Pudovik adduct over undesired rearranged byproduct prior to silylation (see Table 1) led to heterogeneous reaction mixtures and irreproducible overall yields.
31. 2, were prepared in 57%, 89%, and 71% overall isolated yield, respectively, using the same general strategy.
32. 3) δ 19.21; HRMS calcd m/z 494.1785, obsd m/z 494.1789.
33. (a) Tatsuoka, T.; Imao, K.; Suzuki, K. Heterocydes 1986, 24, 617.
34. (b) Blackburn, G. M.; Kent, D. E. J. Chem. Soc., Perkin Trans. 1 1986, 913.
35. (c) Streicher, W.; Werner, G.; Rosenwirth, B Chem. Scr. 1986, 26, 179.
36. Intravenous dosing was chosen over oral administration to circumvent potential errors in the overall biomarker readout due to any phase I metabolism of N-acylalendronates or substantial variations in their oral bioavailability compared to the parent drug.
37. (a) Lin, J. H.; Russell, G.; Gertz, B. Int. J. Clin. Pract. 1999, 101, 18.
38. (b) Lin, J. H. Bone 1996, 18, 75.