38
Y. Pascal et al. / Bioorg. Med. Chem. Lett. 10 (2000) 35±38
Figure 2. Structures of benzodiazepine derivatives in Table 1.
Stereochemistry
Brown-Norway rat. In addition, compound 9 shows no
emetic activity at therapeutic doses unlike Rolipram and
numerous inhibitors related to Rolipram. Since many of
the ®rst generation inhibitors have limited potential due
to side eects, this series of compounds oers a new
class with signi®cant potential for the treatment of
in¯ammatory diseases. More detailed SAR and phar-
macological activity will be communicated at a later
date.
The active isomer is of R con®guration, the S isomer
being completely devoid of inhibitory activity against
PDE4 (5 versus 1).
Derivatives of the phenyl ring D in position 1 of the main
ring B (Fig. 2)
The ortho ¯uoro analogue 2 showed that a slight mod-
i®cation of the D phenyl ring induces a total withdrawal
of the PDE4 inhibiting activity.
Acknowledgements
We thanks Drs. Annette Doherty and Roger Wriggles-
worth for their invaluable information and discussion
and proofreading of the manuscript.
Ring
Substitutions of ring A showed an in¯uence on activity.
Thus, the introduction of a methoxy or a methyl group
at the 9-position increases activity (compounds 7 versus
1, 12 versus 11, 10 versus 11, and 21 versus 20). The
PDE4 potency is further enhanced by the introduction
of a hydroxyl group at the same position (compound
13).
References
1. Beavo, J. A. Physiol. Rev. 1995, 75, 725.
2. Palfreyman, M. N. Drugs Future 1995, 20, 793.
3. Palacios, J. M.; Beleta, J.; Segarra, V. Il Farmaco 1995, 50,
819.
4. Underwood, D. C.; Osborn, R. R.; Novak, L. B.; Matthews,
J. K.; Newsholme, S. J.; Undem, B. J.; Hand, J. M.; Torphy,
T. J. J. Pharmacol. Exp. Ther 1993, 266 (1), 306.
5. Sawanishi, H.; Suzuki, H.; Yamamoto, S.; Waki, Y.; Kasugai,
S.; Ohya, K.; Susuki, N.; Miyamoto, K.; Tagaki, K. J. Med.
Chem 1997, 40, 3248.
6. Schmieden, R.; Schneider, H. H.; Wachtel, H. Psycho-
pharmacology 1990, 102, 17.
7. Barnette, M. S.; Torphy, T. T.; Christensen, S. B. Com-
pounds 1995 WO 00139.
8. Duplantier, A. J.; Biggers, M. S.; Chambers, R. J.; Cheng, J.
B.; Cooper, K.; Damon, D. B.; Eggler, J. F.; Kraus, K. G.;
Marfat, A.; Masamune, H.; Pillar, J. S.; Shirley, J. T.;
Umland, J. P.; Watson, J. W. J. Med. Chem. 1996, 39, 120.
9. Bock, M. G.; Dipardo, R. M.; Evans, B. E.; Rittle, K. E.;
Whitter, D. F.; Veber, P. S.; Anderson, P. S.; Freidinger, R.
M. J. Med. Chem. 1989, 32, 13.
10. Calvet, A.; Pascal, Y.; Junien, J. L.; Pascaud, X.; Roman,
F. J. Eur. Patent 340.064, 1989.
11. Satoh, Y.; Matsuo, T.; Sogabe, H.; Itoh, H.; Tada, T.;
Kinoshita, T.; Yoshida, K.; Takaya, T. Chem. Pharm. Bull.
1994, 42, 2071.
Side chain modi®cations
The nature and substitution of the aromatic ring on
the side chain modulate the inhibitory activity of the
compounds. Among the derivatives of benzoic acid,
the 4-chloro substituted analogue 14 is active, and the
dichloro compounds are equivalent 16 or better 17
than 14. The monomethoxy substituent in the ortho
position (18) shows among the best activities, but the
dimethoxy substitution gives no improvement (19). The
best derivative is the tri-substituted 4-amino-3,5-
dichlorobenzoic analogue 21.
Compounds substituted with heterocyclic moieties
(Table 1) show dierent activities according to the nat-
ure and substitution of the heterocycle. Among hetero-
cycles, a pyrazolotriazine is the best compound in vitro
(8). The 4-pyridine derivative 9 was found very promis-
ing in further pharmacological studies and was selected
for clinical investigations. In summary, a novel series of
benzodiazepine derivatives has been discovered as inhi-
bitors of the enzyme PDE4. We have shown that our
compounds are selective versus other PDE isoenzymes.
Compound 9 was selected for further biological evalua-
tion. This compound shows signi®cant in vivo activity
in a model of antigen induced eosinophilia in the
12. Smith, B. J.; Wales, M. R.; Jappy, J. W. G.; Perry, M. J.
Analytical Biochemistry 1993, 214, 355.
13. Elwood, W.; Sun, J.; Barnes, P. J.; Giembycz, M. A.;
Chung, K. F. In¯ammation Research 1995, 44, 83.
14. Thompson, W. J.; Terasaki, W. L.; Epstein, P. M.; Strada,
S. J. Advances in Cyclic Nucleotide Research 1979, 10, 69.