2788
V. Chiroli et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2785–2788
18. Chang, S. C.; Bundgaard, H.; Buur, A.; Lee, V. H. Invest. Ophthalmol. Vis. Sci. 1987,
and 12, 15.5
of ODQ (11, 56.3
l
M) and comparable with that of timolol in presence
M and 12, 32.7 M), implying that these com-
28, 487.
l
l
19. Shan, D.; Nicolaou, M. G.; Borchardt, R. T.; Wang, B. J. Pharm. Sci. 1997, 86, 765.
20. Representative procedures and sequence for the synthesis of compound 11.
(S)-3-(tert-Butylamino)-1-(4-morpholino-1,2,5-thiadiazol-3-yloxy)propan-2-yl 2-
(Chloromethyl)-4,6-dimethoxybenzoate (c).To a solution of 2-(chloromethyl)-
4,6-dimethoxybenzoic acid21 (1.5 g, 6.6 mmol) in DCM (10 mL) at 0 °C was
added oxalyl chloride (0.61 ml, 7.2 mmol) and stirred 1 h. In turn this mixture
was added to a solution of timolol (free base,22 1.4 g, 4.4 mmol) in DCM (30 ml)
at 0 °C. The mixture was kept to 0 °C for 30 min and then was allowed to warm
to ambient temperature and stir for 24 h. The crude mixture was evaporated to
dryness. The crude material was purified over silica gel eluting with EtOAc/
MeOH/TEA 95:5:0.5 to give 0.850 g of ester c as a colorless foam.
pounds combine timolol- and NO-mediated properties. Thus, in
this biological assay the selected compounds show properties
dependent on their expected dual mechanism of action.
In conclusion, new conjugates of timolol with NO-donating
capability were made. They are stable in solution and yet also la-
bile to enzymatic hydrolysis, by way of a ‘trigger strategy’ that al-
lows the release of the core drug (timolol) and NO. These
compounds may manifest improved in vivo IOP lowering activ-
ity—related studies of the in vivo activity are underway and will
be reported in due course.
(1S)-3-(tert-Butylamino)-1-{[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}
ethyl 2,4-Dimethoxy-6-({[6-(nitroxy)hexanoyl]oxy}methyl)benzoate (d).To
solution of (S)-3-(tert-butylamino)-1-(4-morpholino-1,2,5-thiadiazol-3-
yloxy)propan-2-yl 2-(chloromethyl)-4,6-dimethoxybenzoate (c; 1.1 g,
a
2.07 mmol) and 6-nitroxyhexanoic acid23 (0.55 g, 3.1 mmol) in DMSO, was
added Cs2CO3 (1.0 g, 3.1 mmol) whereupon an exotherm was observed
(CAUTION: low molecular weight nitrated compounds, that is, 6-
nitroxyhexanoic acid, might be explosive: keep temperature under control and
use diluted solution). The mixture stirred at ambient temperature for 8 h, then
diluted with EtOAc and washed with water. The separated organic phase was
dried over Na2SO4 and evaporated in vacuo. The residue was purified over silica
gel eluting with EtOAc/Hexane 2:1 to give 0.85 g of the title compound as a
colorless oil.
Acknowledgments
The authors are very grateful to Laura Carzaniga, Rebecca
Steele, and Feng Zhou for invaluable support towards the synthesis
of the compounds.
References and notes
(1S)-3-(tert-Butylamino)-1-{[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}
ethyl 2,4-dimethoxy-6-({[6-(nitroxy)hexanoyl]oxy}methyl)benzoate maleate
(11).To a solution of free base d (0.55 g, 0.82 mmol) in EtOAc (20 ml) was added a
solution of maleic acid (0.095 g, 0.82 mmol) in EtOAc (3 ml). The solution stirred for
30 min and hexane added whereupon an oil separated at the bottom. The upper
phase was removed. The lower oil was concentrated under vacuum and crystallized
from EtOAc to give 0.45 g of the title compound as a white solid.
Selected data forcompound 11. 1H NMR (300 MHz, DMSO-d6): d1.32 (s, 11H), 1.45–
1.56 (m, 2H), 1.61–1.71 (m, 2H), 2.31 (t, J = 7.16 Hz, 2H), 3.39–3.52 (m, 6H), 3.64 (t,
J = 4.43 Hz, 4H), 3.70 (s, 3H), 4.50 (t, J = 6.50 Hz, 2H), 4.58–4.67 (m, 1H), 4.73–4.83
(m, 1H), 5.11 (s, 2H), 5.71 (s, 1H), 6.07 (s, 2H), 6.64 (s, 1H), 6.67 (d, J = 1.70 Hz, 1H),
8.45 (br s, 1H), 8.58 (br s, 1H). LC MS: (M+H)+ = 670.2. HRMS Calcd for
(M+H)+ = 670.27525, found 670.28691. Anal. Calcd for C33H47N5O15S: C, 50.44; H,
6.03; N, 8.91. Found: C, 50.35; H, 6.13; N, 8.75.
1. Ferrer, E.; Bozzo, J. Drugs Future 2006, 31, 355.
2. Topper, J. E.; Brubaker, R. F. Invest. Ophthalmol. Vis. Sci. 1985, 26, 1315.
3. Nelson, W. P.; Fraunfelder, F. T.; Sills, J. M.; Arrowsmith, J. B.; Kuritsky, J. N. Am.
J. Ophthalmol. 1986, 102, 606.
4. Blanksma, L. J. Doc. Ophthalmol. 1991, 78, 255.
5. Chang, S. C.; Lee, V. H. J. Ocul. Pharmacol. 1987, 3, 159.
6. Chien, D. S.; Sasaki, H.; Bundgaard, H.; Buur, A.; Lee, V. H. L. Pharm. Res. 1991, 8,
728.
7. Bundgaard, H.; Buur, A.; Chang, S. C.; Lee, V. H. L. Int. J. Pharm. 1986, 33, 15.
8. This 3-dimensional model was computer-generated with a Pfizer proprietary
graphic interface utilizing the AMBER 7.0 (2002 release) suite of programs,
particularly minimization to local minimum pictured in Figure 1, with standard
parameters. The thiadiazole was generated by sulfur replacement of the oxygen
in an oxadiazole actually used for minimization. Amber literature reference:
Pearlman, D. A.; Case, D. A.; Caldwell, J. W.; Ross, W. S.; Cheatham, T. E.; DeBolt, S.;
Ferguson, D.; Seibel, G.; Kollman, P. Comput. Phys. Commun. 1995, 91, 1.
9. Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563.
10. Nathanson, J. A. J. Pharmacol. Exp. Ther. 1992, 260, 956.
11. Galassi, F.; Renieri, G.; Sodi, A.; Ucci, F.; Vannozzi, L.; Masini, E. Br. J.
Ophthalmol. 2004, 88, 757.
12. Kanno, M.; Araie, M.; Koibuchi, H.; Masuda, K. Br. J. Ophthalmol. 2000, 84, 293.
13. Kanno, M.; Araie, M.; Masuda, K.; Takase, M.; Kitazawa, Y.; Shiose, Y.; Azuma,
I.; Ogawa, N.; Ohdo, S. Arzneim.-Forsch. 2006, 56, 820.
21. Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem.
Soc. 2001, 123, 10903.
22. Kai, T.; Isami, T.; Kobata, K.; Kurosaki, Y.; Nakayama, T.; Kimura, T. Chem.
Pharm. Bull. 1992, 40, 2498.
23. Piermatti, O.; Fringuelli, F.; Pochini, L.; Indiveri, C.; Palmerini, C. A. Biorg. Med.
Chem. 2008, 16, 1444.
24. Isosorbide mononitrate (ISMN) is a well known NO donor25 used for the
treatment of angina pectoris.26
25. Buccellati, C.; Sala, A.; Rossoni, G.; Capra, V.; Rovati, G. E.; Di Gennaro, A.; Folco,
G.; Colli, S.; Casagrande, C. J. Pharmacol. Exp. Ther. 2006, 317, 830.
26. Parker, J. D.; Parker, J. O. N. Engl. J. Med. 1998, 338, 520.
27. Garthwaite, J.; Southam, E.; Boulton, C. L.; Nielsen, E. B.; Schmidt, K.; Mayer, B.
Mol. Pharmacol. 1995, 48, 184.
14. Kanno, M.; Araie, M.; Masuda, K.; Takase, M.; Kitazawa, Y.; Shiose, Y.; Azuma,
I.; Ogawa, N.; Ohdo, S. Arzneim.-Forsch. 2006, 56, 729.
15. Bundgaard, H.; Buur, A.; Chang, S. C.; Lee, V. H. L. Int. J. Pharm. 1988, 46, 77.
16. John, G. T.; Heinzle, E. Biotechnol. Bioeng. 2001, 72, 620.
28. Mostaghim, R.; Maddox, Y. T.; Ramwell, P. W. J. Pharmacol. Exp. Ther. 1986, 239,
797.
17. Mauger, J. P.; Worcel, M. Br. J. Pharmacol. 1980, 68, 731.