F. Bennett et al. / Bioorg. Med. Chem. Lett. 16 (2006) 186–190
189
7. Still, W. C.; Schneider, J. A. Tetrahedron Lett. 1980, 21,
1035.
8. Enders, D.; Nakai, S. Chem. Ber. 1991, 124, 219.
RX: PO-1xDx4D- 10MG/KG
100
80
60
40
20
0
• • • •
25
9. Selected analytical data: Sch 56588: ½aꢁD ꢀ20.1 (c 1.02,
25
CHCl3); ½aꢁD ꢀ20.8 (c 0.35, CHCl3). 1H NMR (CDCl3,
•
400 Hz) d 8.11 (s, 1H), d 7.80 (s, 1H), d 7.64 (s, 1H), d 7.42
(m, 2H), d 7.39 (m, 1H), d 7.03 (m, 2H), d 6.94 (m, 2H), d
6.86 (m, 1H), d 6.83 (m, 1H), d 6.78 (m, 2H), d 4.65–4.51
(d, J = 14.4 Hz, d, J = 14.4 Hz, 2H), d 4.17 (m, 1H), d
4.12–3.78 (dd, J = 8.7, 7.4 Hz, dd, J = 8.7, 3.8 Hz, 2H), d
4.07 (dt, J = 10.9, 3.4, 3.4 Hz, 1H), d 3.71–3.62 (dd,
J = 8.9, 5.5 Hz, dd, J = 8.9, 7.1 Hz, 2H), d 3.38 (m, 4H), d
3.30 (d, J = 2.6 Hz, 1H), d 3.23 (m, 4H), d 2.61 (m, 1H), d
2.56–2.08 (m, J = 12.3, 8.0, 2.5 Hz, dd, J = 12.3, 8.0 Hz,
2H), d 2.02–1.87 (mm, 2H), d 1.25 (d, J = 6.5 Hz, 3H), d
0.91 (t, J = 7.4 Hz, 3H). HR-FABMS calcd for
C37H43N8O4F2: 701.3375. Found: 701.3385 (M+H)+.
•
• •
56592
• • • • • • •
56588
• • •
56984
51048
• •
ITZ
•
(100MPK)
• • •
•
4
VEHICLE • •
•
8
21
0
2
6
10
10. Selected analytical data: Sch 56592: mp 170–172 ꢁC. ½aꢁD
DAYS
1
ꢀ23.3 (c 1, CHCl3). H NMR (CDCl3, 400 Hz) d 8.11 (s,
1H), d 7.80 (s, 1H), d 7.66 (s, 1H), d 7.43 (m, 2H), d 7.39
(m, 1H), d 7.03 (m, 2H), d 6.95 (m, 2H), d 6.86 (m, 1H), d
6.83 (m, 1H), d 6.78 (m, 2H), d 4.65–4.51 (d, J = 14.5 Hz,
d, J = 14.5 Hz, 2H), d 4.11–3.78 (dd, J = 8.7, 7.4 Hz, dd,
J = 8.7, 6.8 Hz, 2 H), d 4.06 (m, 1H), d 4.02 (m, 1H), d
3.70–3.62 (dd, J = 9.0, 5.6 Hz, dd, J = 9.0, 7.3 Hz, 2H), d
3.38 (m, 4H), d 3.24 (m, 4H), d 3.08 (d, J = 9.0 Hz, 1H), d
2.61 (m, 1H), d 2.55–2.08 (m, J = 12.7, 7.9, 2.5 Hz, dd,
J = 12.7, 8.3 Hz, 2H), d 2.00–1.89 (mm, 2H), d 1.22 (d,
J = 6.3 Hz, 3H), d 0.94 (t, J = 7.4 Hz, 3H). HR-FABMS
calcd for C37H43N8O4F2: 701.3375. Found: 701.3378
(M+H)+.
Chart 4. Aspergillus fumigatus, ND159 pulmonary infection in mice.
In summary, based on previous leads, a series of hydrox-
ylated potential antifungal agents were synthesized. All
alcohols proved to be extremely potent in vitro. A select-
ed number of these analogues were evaluated in vivo
and based on an overall superior profile, Sch 56592
was selected for clinical studies. Extension of this work
including the evaluation of water-soluble prodrugs of
posaconazole will be published elsewhere.
11. Selected analytical data: Sch 56984: [a]D ꢀ23.65 (c 1,
1
CHCl3). H NMR (CDCl3, 300 Hz) d 8.11 (s, 1H), d 7.80
References and notes
(s, 1H), d 7.63 (s, 1H), d 7.40 (m, 2H), d 7.39 (m, 1H), d
7.03 (m, 2H), d 6.94 (br, 2H), d 6.84 (m, 1H), d 6.84 (m,
1H), d 6.78 (m, 2H), d 4.65–4.51 (d, J = 14.4 Hz, d,
J = 14.4 Hz, 2H), d 4.28–4.19 (m, 1H), d 4.28–4.19 (m,
1H), d 4.11–3.77 (mm, 2H), d 3.63 (mm, 2H), d 3.36 (m,
4H), d 3.23 (m, 4H), d 2.61 (m, 1H), d 2.54–2.07 (m,
J = 12.5, 7.8, 2.3 Hz, dd, J = 12.5, 7.7 Hz, 2H), d 1.42 (d,
J = 6.9 Hz, 3H), d 1.24 (d, J = 6.2 Hz, 3H). MS m/z: 687.5
(M+H)+.
1. (a) Viscoli, C.; Girmenia, A.; Marinus, A. Clin. Infect. Dis.
1999, 28, 1071; (b) Rangel-Frausto, M. S.; Wiblin, T.;
Blumberg, H. M. Clin. Infect. Dis. 1999, 29, 253; (c)
Edmond, M. B.; Wallace, M. E.; McClish, D. K. Clin.
Infect. Dis. 1999, 27, 887; (d) Richards, M. J.; Edwards, J.
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12. (a) Dodge, J. A.; Tujillo, J. I.; Presnell, M. J. Org. Chem.
1994, 59, 234; (b) Saiah, M.; Bessodes, M.; Antonakis, K.
Tetrahedron Lett. 1992, 33, 4317; (c) Martin, S. F.; Dodge,
J. A. Tetrahedron Lett. 1991, 32, 3017.
13. Loebenberg, D.; Cacciapuoti, A.; Parmegiani, R.; Moss,
E. L., Jr.; Antonacci, B.; Norris, C.; Yarosh-Tomaine, T.;
Hare, R. S.; Miller, G. H. Antimicrob. Agents Chemother.
1992, 36, 498.
14. Methods. Drugs were administered orally to mice (Charles
River CF1 white males, ca. 20 g) which had been fasted for
18 h. Six mice were used per time point. The AUC was
calculated from 0 to 24 h. The compounds were prepared
in methyl cellulose (0.4%) containing polysorbate 80
(0.5%) and NaCl (0.9%), except for Sch 51048, which
was prepared in 40% hydroxypropyl-b-cyclodextrin.
HPLC was used to determine the drug concentrations in
serum.
15. Methods. Drugs were administered orally to cynomolgus
monkeys (weight range 5.9–7.3 kg). The compounds were
prepared in methyl cellulose (0.4%) containing polysor-
bate 80 (0.5%) and NaCl (0.9%), except for Sch 51048,
which was prepared in 40% hydroxypropyl-b-cyclodextrin.
HPLC was used to determine the drug concentrations in
serum.
2. (a) De Beule, K.; Van Gestel, J. Drugs 2001, 61, 27; (b)
Barone, J. A.; Moskovitz, B. L.; Guarnieri, J. Antimicrob.
Agents Chemother. 1998, 42, 1862; (c) Stevens, D. A.
Pharmacotherapy 1999, 19, 603; (d) Hostetler, J. S.;
Hanson, L. H.; Stevens, D. A. Antimicrob. Agents
Chemother. 1992, 36, 447.
3. (a) Van Etten, E. W. N.; Stearne-Cullen, L. E. T.; Ten
Kate, M. T.; Bakker-Woudenberg, I. A. J. M. Antimicrob.
Agents Chemother. 2000, 44, 540; (b) Otsubo, T.; Maruy-
ama, K.; Maesaki, S.; Miyazaki, Y.; Tanaka, E.; Takiz-
awa, T.; Moribe, K.; Kazunori, T.; Tashiro, T.; Kohno, S.
Antimicrob. Agents Chemother. 1998, 42, 40.
4. Sabo, J. A.; Abdel-Rahman, S. M. Ann. Pharmacother.
2000, 34, 1032.
5. Fung-Tomc, J. C.; Huczko, E.; Minassian, B.; Bonner, D.
P. Antimicrob. Agents Chemother. 1998, 42, 313.
6. (a) Lovey, R.; Saksena, A.; Girijavallabhan, V.; Blundell,
P.; Guzik, H.; Loebenberg, D.; Parmegiani, R.; Cacciapu-
oti, A. Bioorg. Med. Chem. Lett. 2002, 12, 1739; (b)
Saksena, A.; Girijavallabhan, V.; Wang, H.; Liu, Y.-T.;
Pike, R.; Ganguly, A. Tetrahedron Lett. 1996, 37, 5657; (c)
Saksena, A.; Girijavallabhan, V.; Lovey, R.; Pike, R.;
Wang, H.; Ganguly, A.; Morgan, B.; Zaks, A.; Puar, M.
Tetrahedron Lett. 1995, 3, 787; (d) Saksena, A.; Girijaval-
labhan, V.; Lovey, R.; Desai, J.; Pike, R.; Jao, E.; Wang,
H.; Ganguly, A.; Loebenberg, D.; Hare, R. Bioorg. Med.
Chem. Lett. 1995, 5, 127.
16. Methods. Immunocompromised mice (c-irradiated,
500 rads, 3 days prior to infection) were infected intrave-
nously with 1 · 106 CFU/mouse of C. albicans C72.