Design, synthesis, and biological evaluation of phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones and dibenzo[a,d]cycloheptan-5-ones: Novel p38 MAP kinase inhibitors

Article abstract of DOI:10.1021/jm061072p

The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo-[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.

Full text of DOI:10.1021/jm061072p

7912
J. Med. Chem. 2006, 49, 7912-7915
Design, Synthesis, and Biological Evaluation of Phenylamino-Substituted
6,11-Dihydro-dibenzo[b,e]oxepin-11-ones and Dibenzo[a,d]cycloheptan-5-ones: Novel p38 MAP
Kinase Inhibitors
Stefan A. Laufer,* Gabriele M. Ahrens, Solveigh C. Karcher, Jo¨rg S. Hering, and Raimund Niess
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-UniVersita¨t, Auf der Morgenstelle 8,
72076 Tu¨bingen, Germany
ReceiVed September 12, 2006
The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines.
p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both
transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy
lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo-
[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of
selected compounds are described.
Introduction
11-one, 8b, 3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-11-one, 8a
(Scheme 1), and 8-amino-6,11-dihydrodibenzo[b,e]oxepin-11-
one, 14 (Scheme 2), were performed via either 7c, 7b, 7a, or
12 in a modified synthetic pathway according to Kluge et al.13
Preparation of the scaffold 2-amino-dibenzosuberone 23 and
the corresponding 2-fluoro-dibenzosuberenone 24 (Scheme 3)
was derived from a modified synthesis according to Eicher et
al.14 and Kluge et al.
Coupling of the resulting ketones with any respective residues
was carried out with the suitable fluoronitrobenzene or amino
compound using sodium hydride and a polar aprotic solvent or
by melting the reactants in the absence of reagents or solvent
(Scheme 4). Any resulting nitro compound was reduced to the
corresponding amine by the use of tin and HCl or tin(II)-
chloride-dihydrate.
First generation compounds like the pyridinyl-imidazole 2
(SB-203580)1,2 (Figure 1) targeted the kinase’s binding site for
its cosubstrate ATP.3 Compound 2-type compounds are fully
competitive with ATP, occupying essentially the same molecular
interaction sites as ATP itself at the binding site of the kinase.4,5
Both pyridinyl and imidazol rings are known to bind to
cytochrome P-450 (CYP-450) enzymes, implicating hepatotox-
icity as well as drug-drug interaction potential. Thus, there is
a continuous need for structurally novel inhibitors that overcome
the intrinsic problems of the common diaryl-substituted het-
erocyclic compounds. More recently developed second genera-
tion p38 MAP kinase6 inhibitors differ insofar as they do not
directly compete with ATP for its binding site; they are
exemplified by the pyrazolyl-urea derivatives like 4 (BIRB-
796;7 Figure 1) and the 4-phenylamino-diarylketones 3 (LEO;8,9
Figure 1). For 4, Regan et al.10-12 described a novel binding
mode based on an X-ray structure.
In this study, we describe the synthesis and biological testing
of novel 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-ones, 26,
N-substituted 3- and 8-amino-6,11-dihydro-dibenzo[b,e]oxepin-
11-ones, 27 and 28, 2-amino-10,11-dihydro-dibenzo[a,d]cyclo-
hepten-5-ones, 29, and 2-amino-dibenzo-[a,d]cyclohepten-5-
ones, 30. Kinase structures are quite flexible as they undergo
substantial conformational changes during activation. Together
with flexible inhibitor structures, there is considerable room for
induced fits that may reduce the selectivity of the compounds.
Therefore, the aim of our work was to design very rigid
structures. SAR from benzophenone derivates make it obvious
that inhibitory potency is related to limited ability of rotation
due to steric hindrance. In consequence, we proposed to fix the
torsion angle between the two phenyl rings by introduction of
condensed ring systems. To keep the molecular geometry and
the spatial conformation similar to those of the benzophenones,
we chose the moieties ethano, etheno, methylenoxy, and
methylsulfanyl as linkers.
Biological Testing
All compounds were primarily screened in an isolated p38R
kinase assay.15 CYP interactions were investigated by BD-
Gentest Corp.16
Results and Discussion
From the results of p38 MAP kinase enzyme assays,15
summarized in Table 1, we deduced several SARs. Any ortho-
Chemistry
Synthesis of the scaffolds 3-amino-6,11-dihydro-dibenzo[b,e]-
thiepin-11-one, 8c, 3-amino-6,11-dihydrodibenzo[b,e]oxepin-
* To whom correspondence should be addressed. Telephone: +49-7071-
2972459. Fax: +49-7071-295037. E-mail: stefan.laufer@uni-tuebingen.de.
Figure 1. MAP kinase p38 inhibitors.
10.1021/jm061072p CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/21/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7913
Scheme 3. Preparation of 2-Amino-dibenzosuberonea
Scheme 1. Preparation of
6,11-Dihydrodibenzo[b,e]oxepin-11-one Derivatesa
a Reagents: (a) NaH, DMF; (b) PPA, sulfolan.
Scheme 2. Preparation of
8-Amino-6,11-dihydrodibenzo[b,e]oxepin-11-onea
a Reagents and conditions: (a) NBS, AIBN, CHCl3, reflux; (b) P(Ph)3,
acetone, reflux; (c) NaOMe, MeOH, reflux; (d) NaOH (20%), MeOH, reflux;
(e) H2 (4 bar), Pd/C, ethyl acetate, rt; (f) acetic anhydride, rt; (g) PPA,
sulfolan, reflux; (h) HCl (20%), reflux.
a Reagents: (a) NBS, AIBN/Br2; (b) K2CO3, acetone; (c) KOH, ethanol;
(d) PPA, sulfolan; (e) SnCl2, ethanol.
Scheme 4. Coupling of the Ketones with Respective Residues
anilino-substituted 2-aminodibenz[a,d]epines inhibited p38 MAP
kinase with medium to good IC50 values ranging from ∼1 µM
30b to 0.1 µM 29b. Interestingly, 28d, the isomeric structure
to 27i, resulted in almost total loss in activity. Moving the amino
substituent to either the meta- or the para-position led to reduced
activity (cf. 27i vs 27k and 27j and, correspondingly, cf. 29b
vs 29d); note that even the potency of ortho-anilino compound
27n deteriorated due to the 4-amino substituent. Because other
4-substituents are less detrimental, steric reasons cannot fully
explain the reduction in inhibitor potency; hydrogen bond donor/
acceptor functions of the amino group might be responsible.
Comparing 27l to 27j and 27n, it is surprising that inhibitory
activity of the para-compounds is improved by the introduction
of fluorine instead of an amino group in position 2. Conse-
quently, we replaced the 4-amino substituent of 27n with
In summary, our 3-phenylamino-dibenzo[a,d]thiepin-11-ones,
3-phenylamino-dibenzo[b,e]oxepin-11-ones, and 2-phenylamino-
dibenzosuberones represent a structurally novel class of p38
MAP kinase inhibitors that have good activities.
fluorine, leading to the potent p38 kinase inhibitor 27a (IC50
)
Experimental Section
0.239 µM). Subsequently, the other 2,4-dihalogen substituted
compounds 27b and 27c were investigated and found to lose
activity as the size of the halogen increased. The combination
of the substitution patterns of both 27a and 27i led us finally to
the best inhibitor in this series. Compound 27m gave an IC50
of 38 nM, surpassing both reference compounds 2 and 3 (Figure
1).
General. All commercially available reagents and solvents are
used without further purification. Melting points were determined
with a Bu¨chi melting point B-545, IR data were determined with
a Perkin-Elmer Spectrum One (ATR Technik), and 1H NMR
(200 MHz) and 13C NMR (50 MHz) were determined with a Bruker
Advance 200 using TMS as internal standard. The chemical shifts
are reported in ppm.
For the preparation of the 3-fluoro or 3- or 8-amino-6,11-dihydro-
dibenzo[b,e]oxepin-11-one and -thiepinone templates and of the
2-aminodibenzosuberones and 2-aminodibenzosuberenones, we
used the method published by Kluge et al.
For further investigations, we selected 29b as a candidate
with good activity in p38 enzyme assay and first in vivo
experiments (data not shown). The second target activity in the
development of novel p38 inhibitors was CYP interaction.
Concerning this parameter, compound 29b was only slightly
superior to 2. The most relevant isoenzyme, 2D6, was only
inhibited by 42%, whereas 2 inhibited this same enzyme variant
by 73%. (Table 2).
2-(3-Fluoro-phenoxymethyl)-benzoic Acid (7a). Yield 48.5%;
mp 90-92 °C. 2-(3-Acetylamino-phenoxymethyl)-benzoic Acid
(7b). Yield 50.0%; mp 200-202 °C. 2-(3-Acetylamino-phenyl-
sulfanylmethyl)-benzoic Acid (7c). Mp 161-163 °C. 2-Bromo-

7914 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Brief Articles
Table 1. Inhibitory Activity in MAP Kinase p38 Alpha Enzyme Assay
5H), 7.29-7.17 (m, 1H), 6.81-6.74 (m, 1H), 6.70-6.64 (m, 1H),
6.27 (s, 1H), 5.19 (s, 2H); IR 1589 cm-1 (CdO); 13C NMR (CDCl3)
δ 188.73, 162.95, 148.45, 140.45, 136.06, 135.31, 134.12, 132.29,
129.65, 129.51, 129.14, 127.59 (2C’), 127.16, 125.01, 120.54,
119.24, 111.68, 105.20, 73.60; IR (ATR) (cm-1) 1589, 1573, 1514,
1468, 1326, 1298, 1278, 1253, 1121, 1100, 758, 703; Anal. (C20H13-
Cl2NO2) C, H, N.
IC50
cmpd
Y-X
R
µmol/L
n
SEM
26b
27a
27b
27c
27i
27j
27k
27l
27m
27n
28d
29b
29d
30b
2
CH2EnDashsS-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
CH2sO-
OsCH2
2-NH2
0.196
0.239
3.021
>5
3
3
3
3
6
3
2
3
3
3
1
9
3
3
44
3
0.051
0.036
0.224
2,4-di-F
2,4-di-Cl
2,4-di-Br
2-NH2
4-NH2
3-NH2
2-F, 4-NH2
2-NH2, 4-F
2,4-di-NH2
2-NH2
2-NH2
4-NH2
3-(2,4-Dibromo-phenylamino)-6,11-dihydro-dibenzo[b,e]ox-
0.303
>5
0.072
1
epin-11-one (27c). Yield 8.0%; mp 157.2-159.2 °C; H NMR
1.219
1.316
0.038
>5
3.060
0.104
1.171
1.056
0.068
0.190
0.027
0.185
0.016
(CDCl3) δ 8.31-8.20 (m, 1H), 7.98-7.89 (m, 1H), 7.86-7.69 (m,
1H), 7.60-7.29 (m, 5H), 6.88-6.75 (m, 1H), 6.70-6.62 (m, 1H),
6.26 (s, 1H), 5.19 (s, 2H); 13C NMR (CDCl3) δ 188.74, 162.95,
148.36, 140.44, 137.74, 135.31 (2C), 134.13, 132.30, 131.15,
129.50, 129.14, 127.59, 120.89, 119.32, 115.47, 114.86, 111.75,
105.34, 73.60; IR (ATR, cm-1) 1634, 1602, 1586, 1561, 1463, 1329,
1301, 1276, 1252, 1121, 1049, 818, 759, 702, 686; Anal. (C20H13-
Br2NO2) C, H, N.
CH2sCH2
CH2sCH2
CHdCH
0.018
0.096
0.066
0.008
0.065
2-NH2
3
R1 ) CH3
R2 ) Cl
2-NH2
3-(2-Nitro-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-11-
one (27d). Yield 43.7%. 3-(4-Nitro-phenylamino)-6,11-dihydro-
dibenzo[b,e]oxepin-11-one (27e). Yield 95.0%. 3-(3-Nitro-
phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-11-one (27f). Yield
92.3%. 3-(2,4-Dinitro-phenylamino)-6,11-dihydro-dibenzo[b,e]-
oxepin-11-one (27g). Yield 84.0%. 3-(2-Fluoro-4-nitro-phenyl-
amino)-6,11-dihydro-dibenzo[b,e]oxepin-11-one (27h). Yield 57.5%.
2-(2-Nitro-phenylamino)-dibenzo[a,d]cyclohepten-5-one (30a).
The crude product was used in the next step without further
purification. 8-(2-Nitrophenylamino)-6H-dibenzo[b,e]oxepin-11-
one (28a). Compound 14 (0.30 g, 1.3 mmol) was given to a
suspension of 0.10 g (4.2 mmol) NaH (55%) in 10 mL of DMF in
small portions. After the gas formation was completed, 0.20 g
(1.4 mmol) 2-fluoronitrobenzene were added, and the mixture was
stirred at 0 °C for 1 h. A 10 mL portion of ice water was added,
and the deposit was filtered and washed to yield 0.30 g (65.13%)
of 28a, mp 217 °C.
4
0.089
6
0.038
Table 2. Inhibitory Activity on CYP-450 Isozymesa
2C19
2D6
3A4
2
29b
92%
53%
73%
42%
77%
70%
aAs tested by BDGentest Corp.16 Values are reported as % inhibition at
a concentration of 10 µM.
methyl-4-nitro-benzoic Acid Methyl Ester (10). Yield 75.1%.
4-Nitro-2-phenoxymethyl-benzoic Acid Methyl Ester (11). Yield
46.0%; mp 112 °C. 4-Nitro-2-phenoxymethyl-benzoic Acid (12).
Yield 67.7%; mp 180 °C. 2-Bromomethyl-benzoic Acid Methyl
Ester (16). The crude product was used in the next step without
further purification. (2-Methoxycarbonylbenzyl)-triphenylphos-
phoniumbromide (17). Yield 60.5%; mp 234 °C. 2-[(E/Z)-2-(3-
Nitro-phenyl)-vinyl]-benzoic Acid Methyl Ester (18a). Yield
78.1%; mp 66.5 °C. 2-[(E/Z)-2-(3-Fluoro-phenyl)-vinyl]-benzoic
Acid Methyl Ester (18b). Yield 79.1%. 2-[(E/Z)-2-(3-Nitro-
phenyl)-vinyl]-benzoic Acid (19a). Yield 80.0%; mp 164-166 °C.
2-[(E/Z)-2-(3-Fluoro-phenyl)-vinyl]-benzoic Acid (19b). Yield
52.9%; mp 113 °C. 2-[2-(3-Acetylamino-phenyl)-ethyl]-benzoic
Acid (21). Yield 78.9%; mp 145-148 °C. 3-Fluoro-6,11-dihydro-
dibenzo[b,e]oxepin-11-one (8a). Yield 53.2%; mp 79-81 °C.
8-Nitro-6H-dibenzo[b,e]oxepin-11-one (13). Yield 90.0%; mp 175
°C. 2-Fluoro-dibenzo[a,d]cyclohepten-5-one (24). Yield 40.7%;
mp 120 °C. 3-Amino-6,11-dihydro-dibenzo[b,e]oxepin-11-one
Hydrochloride (8b). Yield 89.0%. 3-Amino-6,11-dihydro-diben-
zo[b,e]thiepin-11-one Hydrochloride (8c). Yield 86.7%; mp 204-
206 °C. 2-Amino-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one
Hydrochloride (23). Yield 91.9%; mp 219 °C. 3-(2,4-Difluoro-
phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-11-one (27a). 2,4-
Difluoroaniline (0.46 g; 3.6 mmol) was given to a suspension of
0.30 g (6.9 mmol) NaH (55%) in 7.5 mL of DMF in small portions.
After the gas formation was completed, 0.82 g (3.60 mmol) 8a
were added, and the mixture was stirred at about 160 °C for 15 h.
After cooling down to room temperature, 50 mL of ice water was
added, and the mixture was acidified with HCl (20%). The deposit
was filtered and purified by column chromatography (SiO2 60,
DCM/MeOH 95 + 5) to yield 6.8%; mp 158.6 °C; 1H NMR
(CDCl3) δ 8.30-8.17 (m, 2H), 7.95 (d, 1H), 7.78-7.70 (m, 1H),
7.59-7.29 (m, 2H), 6.98-6.81 (m, 2H), 6.67-6.62 (m, 1H), 6.48
(s, 1H), 5.93 (s, 1H), 5.16 (s, 2H); IR 3307 cm-1 (N-H); IR (ATR,
cm-1) 1667, 1629, 1588, 1575, 1552, 1523, 1500, 1479, 1457, 1436,
1376, 1360, 1348, 1329, 1307, 1288, 1261, 1231, 1219, 1181, 1157,
1142, 1121, 1097, 1062, 1028, 965, 926, 849, 827, 761, 720, 711,
704; Anal. (C20H13F2NO2) C, H, N.
A Similar Procedure Was Used to Prepare the Following:
3-(2-Nitro-phenylamino)-6,11-dihydro-dibenzo[b,e]thiepin-11-
one (26a). Yield 43.7%; mp 186-188 °C. 8-(2-Fluoro-4-nitro-
phenylamino)-6H-dibenzo[b,e]oxepin-11-one (28b). Yield 78.8%;
mp 239 °C. 8-(4-Nitrophenylamino)-6H-dibenzo[b,e]oxepin-11-
one (28 c). Yield 51.6%; mp 280 °C. 2-(2-Nitro-phenylamino)-
10,11-dihydro-dibenzo[a,d]cyclohepten-5-one (29a). The crude
product was used in the next step without further purification. 2-(4-
Nitro-phenylamino)-10,11-dihydro-dibenzo[a,d]cyclohepten-5-
one (29c). The crude product was used in the next step without
further purification. 3-(2-Amino-phenylamino)-6,11-dihydro-di-
benzo[b,e]oxepin-11-one (27i). Compound 27d (0.75 g, 2.17 mmol)
is dissolved in 4 mL of EtOH and 2.45 g (10.9 mmol) of tin(II)-
chloride-dihydrate and stirred for 2 h at 70 °C. After cooling down
to room temperature, 20 mL of ice water was added, and the mixture
was alkalized 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) to yield 135 mg (15%) 27i; mp 122-
1
124 °C; H NMR (DMSO-d6) δ 8.16 (s, 1H), 7.96 (d, 1H), 7.79
(d, 1H), 7.60-7.46 (m, 3H), 7.01-6.93 (m, 2H), 6.78 (d, 1H),
6.62-6.49 (m, 2H), 6.08 (s, 1H), 5.15 (s, 2H), 4.86 (s, 2H); IR
(ATR, cm-1) 3335 (N-H), 1587, 1559, 1498, 1459, 1297, 1276,
1253, 1229, 1154, 1118, 746; Anal. (C20H16N2O2) C, H, N.
A Similar Procedure Was Used to Prepare the Following
Compounds: 3-(2-Amino-phenylamino)-6,11-dihydro-dibenzo-
1
[b,e]thiepin-11-one (26b). Mp 195 °C; H NMR (DMSO-δ6) δ
8.09-8.03 (d, 1H), 7.51-7.44 (m, 4H), 7.00-6.76 (m, 6H), 4.86
(br s, 2H), 4.12 (s, 2H); IR (ATR, cm-1) 2923 (N-H), 2853, 1615,
1583, 1564, 1497, 1479, 1457, 1275, 1238, 1136, 735; Anal.
(C20H16N2OS) C, H, N: calcd, 72.26, 4.85, 8.43; found, 70.75, 5.09,
7.11. C, H, N: calcd, 72.26, 4.85, 8.43; found, 70.75, 5.09, 7.11.
No satisfactory EA even after recrystallization from EtOH/toluene.
LC-MS: TSQ quantum, 92% purity; LCQDuo, 95% purity.
3-(4-Amino-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-
11-one (27j). Yield 20.3%; mp 131-133 °C; 1H NMR (CDCl3) δ
8.15 (d, 1H), 7.97-7.92 (m, 1H), 7.51-7.43 (m, 2H), 7.33-7.25
A Similar Procedure Was Used to Prepare the Following
Compounds: 3-(2,4-Dichloro-phenylamino)-6,11-dihydro-diben-
1
zo[b,e]oxepin-11-one (27b). Yield 3.1%; mp 155.6 °C; H NMR
(CDCl3) δ 8.37-8.19 (m, 1H), 8.00-7.89 (m, 1H), 7.61-7.32 (m,

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7915
(m, 1H), 7.03-7.97 (m, 2H), 6.70-6.65 (m, 2H), 6.52 (dd, 1H),
6.33 (d, 1H), 5.92 (s, 1H), 5.12 (s, 2H), 3.56 (s, 2H). IR (ATR,
cm-1) 1626, 1589, 1564, 1510, 1329, 1301, 1277, 1256, 1156, 1120,
826. Anal. (C20H16N2O2) C, H, N.
Supporting Information Available: Synthetic procedures,
purity data of test compounds, routine spectroscopic data, and IR
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
3-(3-Amino-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-
1
11-one (27k). Yield 7.8%; mp 150 °C; H NMR (CDCl3) δ 8.19
References
(d, 1H), 7.95 (dd, 1H), 7.80-7.71 (m, 1H), 7.53-7.46 (m, 2H),
7.36-7.32 (m, 1H), 7.18-7.06 (m, 1H), 6.73-6.36 (m, 4H), 6.09
(s, 2H), 5.16 (s, 2H), 4.68 (s, 1H); IR (ATR, cm-1) 1585, 1569,
1490, 1459, 1297, 1276, 1254, 1230, 1156, 1121, 759, 701; Anal.
(C20H16N2O2) C, H, N.
3-(4-Amino-2-fluoro-phenylamino)-6,11-dihydro-dibenzo[b,e]-
oxepin-11-one (27l). Yield 20.4%; mp 123-125 °C; 1H NMR
(CDCl3) δ 8.16 (d, 1H), 7.94 (d, 1H), 7.51-7.43 (m, 2H), 7.33-
7.25 (m, 1H), 7.10 (t, 2H), 6.55-6.42 (m, 2H), 6.30 (d, 1H), 5.74
(s, 1H), 5.13 (s, 2H), 3.77 (s, 2H); IR (ATR, cm-1) 1624, 1589,
1564, 1517, 1494, 1299, 1277, 1229, 1155, 1120; Anal. (C20H15-
FN2O2) C, H, N.
3-(2-Amino-4-fluoro-phenylamino)-6,11-dihydro-dibenzo[b,e]-
oxepin-11-one (27m). Yield 26.0%; mp 182.6 °C; 1H NMR
(CDCl3) δ 8.16 (d, 1H), 7.93 (d, 1H), 7.52-7.39 (m, 2H), 7.31 (d,
1H), 7.09-7.01 (m, 1H), 6.54-6.39 (m, 3H), 6.11 (s, 1H), 5.59
(s, 1H), 5.12 (s, 2H), 3.2 (ws, 2H); IR (ATR, cm-1) 1631, 1600,
1549, 1506, 1303, 1271, 1232, 1156, 1121, 825, 755; Anal. (C20H15-
FN2O2) C, H, N.
3-(2,4-Diamino-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-
11-one (27n). Yield 4.9%; mp 191.8 °C; 1H NMR (CDCl3) δ 8.15
(d, 1H), 7.94 (d, 1H), 7.57-7.40 (m, 2H), 7.36-7.23 (m, 1H), 6.87
(d, 1H), 6.44 (d, 1H), 6.20-6.05 (m, 3H), 5.50 (s, 1H), 5.12 (s,
2H), 3.68 (s, 4H); IR (ATR, cm-1) 1622, 1590, 1563, 1514, 1468,
1384, 1300, 1276, 1255, 1235, 1155, 1119, 922, 758, 700; Anal.
(C20H17N3O2) C, H, N: calcd, 72.49, 5.17, 12.68; found, 71.03,
4.35, 11.53. LC-MS: TSQ quantum, 96% purity; LCQDuo, 90%
purity.
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8-(2-Aminophenylamino)-6,11-dihydrodibenzo[b,e]oxepin-11-
one (28d). The product was purified by column chromatography
(LiChroprep RP-18, ACN/H2O 6:4) to yield 0.16 g (50.0%) 28d;
mp 231 °C; IR (ATR, cm-1) 1591, 1577, 1546, 1301, 1245, 1208,
767, 736.
2-(2-Amino-phenylamino)-10,11-dihydro-dibenzo[a,d]cyclo-
hepten-5-one (29b). Yield 10.7%; mp 153 °C; IR (ATR, cm-1
)
1599, 1581, 1566, 1499, 1290, 1279, 1258, 1111, 750, 694; Anal.
(C21H18N2O) C, H, N.
2-(4-Amino-phenylamino)-10,11-dihydro-dibenzo[a,d]cyclo-
hepten-5-one (29d). Yield 5.5%; mp 217 °C; 1H NMR (CDCl3) δ
8.15 (d, 1H), 8.02 (d, 1H), 7.31-7.41 (m, 2H), 7.19 (d, 1H), 7.04
(d, 2H), 6.69-6.75 (m, 3H), 6.55 (d, 1H), 5.81 (s, 1H), 3.66 (d,
2H), 3.06-3.16 (m, 4H); IR (ATR, cm-1) 1582, 1562, 1506, 1295,
1281, 1211, 1109, 825, 758; Anal. (C21H18N2O) C, H, N.
2-(2-Amino-phenylamino)-dibenzo[a,d]cyclohepten-5-one (30b).
1
Yield 7.2%; mp 232 °C; H NMR (DMSO-d6) δ 8.19 (d, 1H),
8.03-8.09 (m, 2H), 7.67-7.70 (m, 2H), 7.57-7.61 (m, 1H), 7.10
(d, 1H), 7.02 (d, 2H), 6.88-6.94 (m, 2H), 6.75-6.82 (m, 2H), 6.61
(t, 1H), 4.88 (s, 2H); IR (ATR, cm-1) 1596, 1571, 1558, 1497,
1370, 1304, 1257, 1226, 806, 751, 735; Anal. (C21H16N2O) C, H,
N.
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Synthesis 1988, 525-529.
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A.; Dehner, F. An immunosorbent, nonradioactive p38 MAP kinase
assay comparable to standard radioactive liquid-phase assays. Anal.
Biochem. 2005, 344, 135-137.
(16) http://www.bdbiosciences.com/discovery_labware/gentest/products//
antibodies//prod_inserts/ (accessed 2006).
Inhibitory activity on CYP-450 isozymes was determined by
BDGentest Corp.16 Values are reported as % inhibition at a
concentration of 10 µM.
Acknowledgment. We thank Dr. S. Linsenmaier, S. Luik,
and K. Bauer for biological testing and Merckle GmbH for
financial support.
JM061072P