Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1781
Then 0.5 g of the nitro compound was dissolved in 4 mL of EtOH,
and 2.9 g of ZnCl2 ·2H2O was added and stirred for 2 h at 70 °C.
After cooling to room temperature, 20 mL of ice-water was added
and alkalinized with NaOH (20%). The aqueous phase was extracted
with EtOAc, the organic layer was evaporated under reduced
pressure, and the residue was purified by column chromatography
(SiO2 60, DCM/MeOH, 95/5). Yield, 0.14 g (23%).
of 5” in contrast to most of the target compounds of the carbon
analogue series, suggesting improved bioavailability for aza-
dibenzoheptenones. The anti-inflammatory activity of the tested
compounds was determined in vitro by measuring the inhibitory
effect of p38 MAPK in a cell-free enzyme assay.20 Our earlier
work indicated that the three most potent phenylamino-substit-
uents of the dibenzepinone-series were the 2-aminophenylamino
(22a, 23a, 28a), the 2-amino-4-fluorophenylamino (22b, 28b),
and the 2,4-difluorophenylamino (22c, 23b, 28c) residues, and
we introduced these same functionalities into the aza-analogues.
On the basis of the inhibition of the p38 enzyme as assessed
by the immunosorbent assay (Table 1), the potency of the
substituted dibenzepinones (IC50 ) 40-1020 nM) was equal
compared to the reference compound 32 (50 nM). The aza-
dihydro-dibenzoheptenones (25a, 25b, 25c, 27) were less potent,
and the IC50 values were elevated by 3- to 8-fold as compared
to the corresponding carbon analogues (22a, 22b, 22c). Variation
of the nitrogen position in ring A had no effect on the IC50
values of the target compounds. The activity of the aza-
dibenzoheptenone series (24a, 24b, 26) was slightly superior
to the dibenzoheptenones (23a, 23b). However, compounds of
the unsaturated dibenzoheptenone series (23a, 23b) were
generally less potent than those of the dibenzoheptanone series
(22a-c) and dibenzoxepinone series (28a-c). The IC50 values
of the aza-analogues of the oxepine series (29a-c) range from
0.2 µM (2,4-difluorphenylamino derivative) to 2.8 µM (2-amino-
4-fluor-phenylamino derivative) in the p38 enzyme assay and
are therefore markedly less potent than the corresponding
dibenzoxepinones (28a-c). Taken together, our results indicated
that despite improved solubility of the aza-analogues, as based
on the log P, CHI(MeOH) values, and measured aqueous
solubility, these compounds are less potent inhibitors of p38
MAP kinase. Introduction of nitrogen into the dibenzepinone
scaffold had a negative effect on the potency of the aza-
analogues class of potential p38 inhibitors that is directly related
to their structure. The nitrogen in ring A clearly reduced potency
of the compounds in inhibiting p38 MAP kinase, and this effect
could be attributed to decreased hydrophobic interaction in the
binding pocket dependent upon changes in the electronic
properties of ring A. In summary, we have synthesized aza-
analogues with improved aqueous solubility. Although aza-
analogues dibenzepinones were less potent in inhibiting the p38
in the enzyme assay compared to the pyridinyl-imidazoles, they
may be better tolerated at higher doses in vivo.
Compound 29b was prepared in a manner similar to 25b.
Acknowledgment. We thank S. Luik, M Goettert, and K.
Bauer for biological testing.
Supporting Information Available: General synthetic proce-
dures, spectral and analytical data, HPLC purity and HRMS data
of test compounds, and lipophilicity measurements. This material
References
(1) Halpert, J. R. Structural basis of selective cytochrome P450 inhibition.
Annu. ReV. Pharmacol. Toxicol. 1995, 35, 29–53.
(2) Miranda, C. L.; Henderson, M. C.; Buhler, D. R. Evaluation of
chemicals as inhibitors of trout cytochrome P450s. Toxicol. Appl.
Pharmacol. 1998, 148, 237–244.
(3) Hooper, W. D. Metabolic drug interactions. In Handbook of Drug
Metabolism; Woolf T. F. Ed.; Marcel Dekker: New York, 1999; pp
229-238.
(4) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. Tetrasubstituted imidazole
inhibitors of cytokine release: probing substituents in the N-1 position.
J. Med. Chem. 2004, 47, 6311–6325.
(5) Laufer, S. A.; Ahrens, G. M.; Karcher, S. C.; Hering, J. S.; Niess, R.
Design, Synthesis, and Biological Evaluation of Phenylamino-
Substituted 6,11-Dihydro-dibenzo[b,e]oxepin-11-ones and Diben-
zo[a,d]cycloheptan-5-ones: Novel p38 MAP Kinase Inhibitors. J. Med.
Chem. 2006, 49, 7912–7915.
(6) Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar,
S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heyes, J. R. A protein
kinase involved in the regulation of inflammatory cytokine biosyn-
thesis. Nature (London) 1994, 372, 739–746.
(7) Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram,
H.; Hiestand, P.; Manning, U.; Rucklin, G. SAR of benzoylpyridines
and benzophenones as p38a MAP kinase inhibitors with oral activity.
Bioorg. Med. Chem. Lett. 2004, 14, 3601–3605.
(8) Brenner, D. G.; Halczenko, W.; Shepard, K. L. Imino-bridged
heterocycles. II. (1). Regiospecific synthesis of the 11H-benzo
[5,6]cyclohepta[1,2-c]pyridin-6,11-imineand5H-benzo[4,5]cyclohepta[1,2-
b]pyridin-5,10-imine systems. J. Heterocycl. Chem. 1982, 19, 897–
900.
(9) Villani, F. J.; Wefer, E. A.; Mann, T. A.; Mayer, J.; Peer, L.; Levy,
A. S. Derivatives of 10,11-dihydro-5H-benzo(a,d)cycloheptane and
related compounds. VII. Improved syntheses of 11H-
benzo(5,6)cyclohepta(1,2-c)pyridin-11-one. J. Heterocycl. Chem.
1972, 9, 1203–1207.
(10) Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann,
T. A. Superacid cyclodehydration of ketones in the production of
tricyclic antihistamines. J. Org. Chem. 1989, 54, 2242–2244.
(11) Piwinski, J. J.; Wong, J. K.; Chan, T. M.; Green, M. J.; Ganguly,
A. K. Hydroxylated metabolites of loratadine: an example of confor-
mational diastereomers due to atropisomerism. J. Org. Chem. 1990,
55, 3341–3350.
(12) Krimen, L. I.; Cota, D. J. Ritter reaction. In Organic Reactions, 17th
ed.; Wiley-Interscience: New York, 1969; pp 213-325.
(13) Inoue, K.; Sugaya, T.; Ogase, T.; Tomioka, S. A facile synthesis of
substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines. Synthesis
1997, 113–116.
(14) Jensen, T. A.; Liang, X.; Tanner, D.; Skjaerbaek, N. Rapid and efficient
microwave-assisted synthesis of aryl aminobenzophenones using Pd-
catalyzed amination. J. Org. Chem. 2004, 69, 4936–4947.
(15) van de, W. H.; Jones, B. C. Predicting oral absorption and bioavail-
ability. Prog. Med. Chem. 2003, 41, 1–59.
(16) Valko, K.; Bevan, C.; Reynolds, D. Chromatographic hydrophobicity
index by fast-gradient RP HPLC: a high-throughput alternative to log
P log D. Anal. Chem. 1997, 69, 2022–2029.
(17) Karger, B. L.; Gant, J. R.; Hartkopf, A.; Weiner, P. H. Hydrophobic
effects in reversed-phase liquid chromatography. J. Chromatogr. 1976,
128, 65–78.
(18) Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Hatley, R. J. D.;
Hughes, J. A.; Irving, W. R.; Livermore, D. G.; Sollis, S. L.;
Nerozzi, F.; Valko, K. L.; Allen, M. J.; Perren, M.; Shabbir, S. S.;
Woollard, P. M.; Price, M. A. 2,5-Diketopiperazines as Potent,
Selective, and Orally Bioavailable Oxytocin Antagonists. 3.
Experimental Section
8-(2-Amino-phenylamino)-benzo[4,5]cyclohepta[1,2-b]pyridin-
5-one (24a). A mixture of 0.44 g (1.8 mmol) of 5, 1.0 g (9.2 mmol)
of 1,2-phenylendiamine, 0.05 g of (0.22 mmol) Pd(OAc)2, 0.10 g
of (0.21 mmol) 2-(dicyclohexylphosphino)-2′-, 4′-, 6′-triisopropyl-
biphenyl, 1.40 g of (12.4 mmol) KOtert-Bu, 5 mL of toluene, and
1 mL of tert-BuOH was heated at 90 °C under argon. After stirring
at this temperature for 6 h, the reaction mixture was poured into
water and extracted with 3 × 200 mL ethyl acetate. The residue
was purified by flash chromatography (SiO2, dichloromethane/
ethanol, 95 /5). Yield 0.04 g (7%).
Compounds 24b, 25a, 25c, 26, 27, 29a, and 29c were prepared
in a manner similar to 24a.
8-(2-Amino-4-fluoro-phenylamino)-10,11-dihydro-benzo[4,5]-
cyclohepta[1,2-b]pyridin-5-one (25b). Compound 6 (44 g, 1.8
mmol), 0.3 g (1.9 mmol) of 2-nitro-4-fluoroaniline, 0.05 g (0.22
mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphos-
phino)-2′-, 4′-, 6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of
KOtert-Bu, 5 mL of toluene, and 1 mL of tert-BuOH were used as
starting materials. The crude product was recrystallized from
methanol and was used in the next step without further purification.