1410
J. Pontillo, C. Chen / Bioorg. Med. Chem. Lett. 15 (2005) 1407–1411
4. (a) Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.;
Suzuki, N.; Furuya, S.; Fujino, M. J. Med. Chem. 2003,
46, 113; (b) Devita, R. J.; Walsh, T. F.; Young, J. R.;
Jiang, J.; Ujjainwalla, F.; Toupence, R. B.; Parikh, M.;
Huang, S. X.; Fair, J. A.; Goulet, M. T.; Wyvratt, M. J.;
Lo, J. L.; Ren, N.; Yudkovitz, J. B.; Yang, Y. T.; Cheng,
K.; Cui, J.; Mount, G.; Rohrer, S. P.; Schaeffer, J. M.;
Rhodes, L.; Drisko, J. E.; McGowen, E.; MacIntyre, D.
E.; Vincent, S.; Carlin, J. R.; Cameron, J.; Smith, R. G. J.
Med. Chem. 2001, 44, 917, and references cited therein; (c)
Young, J. R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J.;
Yang, Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren,
R. N.; Wu, T. J.; Shen, X.; Lyons, K. A.; Mao, A. H.;
Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Cheng, K.;
Goulet, M. T. Bioorg. Med. Chem. Lett. 2002, 12, 827, and
references cited therein; (d) Luthin, D. R.; Hong, Y.;
Tompkins, E.; Anderes, K. L.; Paderes, G.; Kraynov, E.
A.; Castro, M. A.; Nared-Hood, K. D.; Castillo, R.;
Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B.
Bioorg. Med. Chem. Lett. 2002, 12, 827; (e) Tucci, F. C.;
Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Conners, P. J.;
Struthers, R. S.; Reinhart, G. J.; Wang, X.; Saunders, J.;
Chen, C. Bioorg. Med. Chem. Lett. 2002, 12, 3491, and
references cited therein; (f) Zhu, Y.-F.; Guo, Z.; Gross, T.
D.; Gao, Y.; Conners, P. J.; Struthers, R. S.; Xie, Q.;
Tucci, F. C. J. Med. Chem. 2003, 46, 1769, and references
cited therein; (g) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci,
F. C.; Gao, Y.; Moorjani, M.; Connors, P. J., Jr.;
Rowbottom, M. W.; Chen, Y.; Struthers, R. S.; Xie, Q.;
Saunders, J.; Reinhart, G.; Chen, T. K.; Killam-Bonne-
ville, A. L.; Chen, C. J. Med. Chem. 2004, 47, 1259; (h)
Reinhart, G. J.; Xie, Q.; Liu, X.-J.; Zhu, Y.; Fan, J.; Chen,
C.; Struthers, R. S. J. Biol. Chem. 2004, 33, 34115.
5. Neurocrine, unpublished result.
micromolar range. Other compounds 12a–d and 13b–e
were tested as mixtures of diastereomers.
In comparing the oxazolino[3,2-c]pyrimidin-5,7-dione
cases 12a and 12b, incorporation of a 2-fluoro substitu-
ent on the bottom phenyl ring slightly increased activity
to 230 nM. The 3-methoxyphenyl derivative 12c showed
modest activity (870 nM). However, incorporation of
the 2-fluoro, 3-methoxyphenyl substitution pattern in
12d resulted in good binding activity (125 nM).
The thiazolino[3,2-c]pyrimidin-5,7-diones 13 showed
somewhat similar SAR patterns. The sulfur derivative
13b (220 nM) was equipotent to oxo-derivative 12b.
Incorporation of the (2-fluoro, 3-methoxy)phenyl moi-
ety in 13c increased binding activity to 40 nM, an almost
6-fold increase. Interestingly, incorporation of the 2-
chlorophenyl substituent (13d) also slightly improved
binding affinity over the 2-fluorophenyl case. Moreover,
the best substitution pattern in this series is the (2-
chloro, 3-methoxy)phenyl of 13e. This potent compound
displayed a hGnRH binding affinity of 4.5 nM.
In summary, we have shown that reaction of substituted
2-methyl oxazolines or thiazolines with chlorocarbonyl
isocyanate gives the oxazolino- or thiazolino[3,2-c]pyr-
imidin-5,7-dione derivatives in very good yield. This
reaction has been applied to the rapid syntheses of sub-
strates active against the hGnRH receptor. The first syn-
thesis ends with a Suzuki coupling, making the synthesis
ideally suited to the development of SAR on the right
side of the molecule, while the second synthesis ends
with a Mitsunobu coupling, rendering the synthesis well
suited to development of SAR on the left side of the sys-
tem. The best compound in the series displayed binding
in the low nanomolar range with 13e having a Ki of
4.5 nM. Further SAR studies of these systems will be
reported in due course.
6. For examples, see: (a) Otter, B. A.; Falco, E. A.; Fox, J. J.
J. Org. Chem. 1968, 33, 3593; (b) Tanai, K.; Maruyama,
O. J. Carbohydr. Nucleos. Nucleot. 1976, 3, 25; (c)
Maruyama, T.; Sato, S.; Honjo, M. Chem. Pharm. Bull.
1982, 30, 2688; (d) Urata, H.; Miyagoshi, H.; Kakuya, H.;
Tokumoto, H.; Kawahata, T.; Otake, T.; Akagi, M.
Chem. Pharm. Bull. 1998, 46, 458.
7. Bayer Patent (Germany) DE 2126148; Chem. Abstr. 1972,
78, 11360.
8. The oxazolines 4a, 4c–d and thiazoline 5a were purchased
from Sigma-Aldrich. The oxazoline 4b was purchased
from Lancaster Synthesis.
Acknowledgements
9. (a) The oxazoline 4e was synthesized according to known
literature procedures, see: Shafer, C. M.; Molinski, T. F. J.
Org. Chem. 1996, 61, 2044; (b) The thiazolines 5b–f were
synthesized according to known literature procedures, see:
Aitken, R. A.; Armstrong, D. P.; Galt, R. H. B.; Mesher,
S. T. E. J. Chem. Soc., Perkin Trans. 1 1997, 2139.
We thank Qiu Xie (Neurocrine Biosciences) for per-
forming the hGnRH binding assays.
References and notes
1
10. All new compounds were characterized by H NMR, 13C
1. Schally, A. V.; Arimura, A.; Kastin, A. J.; Matsuo, H.;
Baba, Y.; Redding, T. W.; Nair, R. M. G.; Debeljuk, L.;
White, W. F. Science 1971, 173, 1036.
NMR, LCMS, and elemental analysis or HRMS.
11. Representative procedure (see Scheme 1): To (S)-2-
methyl-4-phenyl-4,5-dihydrooxazole (4f) (1.82 g, 11.3
mmol) and dry N,N-dimethylaniline (1.49 g, 12.3 mmol)
in dry dichloromethane (8 mL) under N2 at 0 ꢁC was
added dropwise chlorocarbonyl isocyanate (1.24 g,
11.8 mmol). The mixture was allowed to warm to room
temperature and stirred for 14 h, during which time a thick
white precipitate formed. The suspension was filtered, and
the solid triturated with cold dichloromethane (3 · 2 mL)
to give 3-phenyl-2,3-dihydroxazolo[3,2-c]pyrimidine-5,7-
(6H)-dione (6f) as a white amorphous powder (2.11 g,
2. (a) Kutscher, B.; Bernd, M.; Beckers, T.; Polymeropoulos,
E. E.; Engel, J. Angew. Chem., Int. Ed. 1997, 36, 2149, and
references cited therein; (b) Cui, J.; Smith, R. G.; Mount,
G. R.; Lo, J. L.; Yu, J.; Walsh, T. F.; Singh, S. B.; DeVita,
R. J.; Goulet, M. T.; Schaeffer, J. M.; Cheng, K. Mol.
Endocrinol. 2000, 14, 671; (c) Zhou, W.; Rodic, V.;
Kitanovic, S.; Flanagan, C. A.; Chi, L.; Weinstein, H.;
Maayani, S.; Millar, R. P.; Sealfon, S. C. J. Biol. Chem.
1995, 270, 18853.
3. Kardamakis, E.; Tzingounis, V. In Biomedical Health
Research: Bioactive Peptides in Drug Discovery and
Design: Medical Aspects; Marsoukas, J., Mavromousta-
kos, T., Eds.; IOS: Amsterdam, 1999; Vol. 22, pp 275–285.
1
81%). H NMR (DMSO-D6, 500 MHz): d 10.95 (s, 1H);
7.42–7.39 (m, 2H); 7.37–7.33 (m, 1H); 7.28–7.26 (m, 2H);
5.57 (dd, J = 3.7, 8.3 Hz, 1H), 5.11 (s, 1H); 5.00 (dd,
J = 8.8, 8.8 Hz, 1H); 4.54 (dd, J = 3.4, 8.8 Hz, 1H). 13C