An efficient preparation of N-alkyl-2-benzazepine derivatives and investigation of their biological activity

Article abstract of DOI:10.1016/j.bmcl.2009.04.117

N-Alkyl-2-benzazepine derivatives are readily prepared through N-alkylation of secondary 2-benzazepines that are constructed via 7-endo selective cyclization of radical cyclization of N-boc-N-(2-bromo-5-methoxyphenylmethyl) methacrylamides. The structure

Full text of DOI:10.1016/j.bmcl.2009.04.117

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3193–3195
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An efficient preparation of N-alkyl-2-benzazepine derivatives
and investigation of their biological activity
a
a
b
b,
*
Akio Kamimura a, , Masahiro So , Tomohiro Kuratani , Kenji Matsuura , Makoto Inui
*
a Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan
b Department of Pharmacology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 December 2008
Revised 6 April 2009
Accepted 24 April 2009
Available online 3 May 2009
N-Alkyl-2-benzazepine derivatives are readily prepared through N-alkylation of secondary 2-benzaze-
pines that are constructed via 7-endo selective cyclization of radical cyclization of N-boc-N-(2-bromo-
5-methoxyphenylmethyl) methacrylamides. The structure and activity relationship of these derivatives
are examined.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Benzazepines
SAR studies
HaCat cell
Epithelial cell migration
Promotion of skin wound
Radical cyclization
N-Alkylation
Benzazepines, containing seven-membered aza-heterocyclic
ring fusing aromatic unit, are of interest due to their biological
activity that would be expected as a potential drug candidate.1
For example, this heterocyclic nucleus was applied in a part of pep-
tide mimic of RGD motif, which was a well-known antagonist of
integrin that engaged cell adhesion and signal transduction.2 Re-
cently, we found that 2-benzazepines structure showed an activity
that promoted not only the epithelial cell migration in vitro but
also the skin wound healing in vivo. This is a remarkable activity
of 2-benzazepines promising new potential drug candidate.3 Prep-
aration of this structure used to require long steps.2 2-Benazepines
are readily prepared through a unique 7-endo selective cyclization
of aryl radical.4 To investigate structure and activity relationship of
these compounds, we need to develop a quick method to derivatize
2-benzazepines. In this Letter, we disclose a convenient derivatiza-
tion of benzazepines through the preparation of secondary 2-ben-
zaepienes and subsequent N-alkylation. The biological activity of
these compounds is also reported.
conformation of the amide unit. The dummy substituent should
be readily introduced and removed in good yield under mild con-
ditions. We chose N-carbamate derivatives such as N-boc as the
suitable dummy substituents for this preparation.
Preparation of 1 was carried out straightly from commercial
available 2-bromo-5-methoxybenzoic acid 2. The acid was re-
duced to corresponding benzyl alcohol then converted into azide
3 in 89% yield through chloride. Reductive treatment of azide 3
with Raney-Ni gave primary benzyl amine which underwent acyl-
ation reaction with methacroyl chloride to give unsaturated
amide 4 in 59% yield. N-protection of 4 with (boc)2O or ClCO2Me
under standard conditions smoothly afforded precursor 5a and 5b
in good yield (Scheme 1).
The radical cyclization of 5 was carried out under standard rad-
ical reaction conditions. Treatment of 5a and 5b with Bu3SnH with
syringe pump technique resulted in the smooth conversion to de-
sired 6a and 6b in 29% and 44%, respectively. Although the yield
was moderate, the cyclization took place very selective because
no regioisomeric product of 6 was observed in the reaction pot.
This is a great advantage in the preparation because the radical
cyclization from N-alkyl amides always contained small amounts
of side products such as 6-exo products which was hard to be re-
moved through usual chromatographic treatment.4 The 7-endo
selectivity might be enhanced by the presence of carbamate group
such as N-boc. Compound 6 was readily purified by recrystalliza-
tion so the present method was much advantageous to prepare
Our strategy for the derivatization is based on the preparation
of secondary 2-benzazepines 1 and following N-alkylation. To pre-
pare compound 1, a dummy substituent should be introduced be-
fore cyclization because any kind of cyclization from secondary
amides should be reluctant to undergo due to dominant s-trans
* Corresponding authors.
E-mail address: ak10@yamaguchi-u.ac.jp (A. Kamimura).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.117

3194
A. Kamimura et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3193–3195
MeO
MeO
CO2H
1) (CH3)2S BH
2) MsCl/Et N/CH
3) NaN3/NaI/acetone/H2O/0 ºC to rt
R
MeO
3
/THF/-10 ºC to rt
N
MeO
NH
R-I
KHMDS/
3
2
Cl2/0 ºC to rt
O
O
Br
2
18-crown-6/THF
7
1
N3
1) Raney-Ni/MeOH/60 ºC
2) Et N/DMAP/CH Cl /-50 ºC
Scheme 3. N-Alkylation and derivatization of 1.
3
2
2
Br
CH2=C(CH3)COCl
3; 89% (3 steps)
Table 1
Alkylation of amide 1
CO2R
O
MeO
MeO
NH
N
(Boc)2O
or ClCO2Me
Entry
R–I
7
Yielda (%)
Mp (°C)
O
Br
Br
4; 2steps 59%
1
2
3
4
5
6
7
8
9
Me
Et
Pr
7a
7b
7c
7d
7e
7f
7g
7h
7i
81
87
72
71
79
58
Trace
8
75.5–76.0
105.8–106.2
63.5–64.5
61.8–62.3
68.8–69.3
36.8–37.4
n.d.
5a
5b
; R = tBu, 99%
; R = Me, 66%
Bu
C5H11
C6H13
iPr
Scheme 1. Preparation of precursor 5 of 7-endo selective radical cyclization.
iBu
n.d.
104.9–105.4
Bnb
84
2-benzazepines in pure form. The N-boc group in 6a was then re-
moved by treatment with acidic media to give secondary benzaze-
pine 1 in 63% yield. Basic treatment of 6b followed by acidic
treatment resulted in the removal of methoxycarbonyl group, giv-
ing 1 in 52% yield. The present preparation could be carried out in
multi-gram scale so the present method was useful for quick deriv-
atization of 2-benzazepine derivatives (Scheme 2).
a
Isolated yields.
Benzyl bromide was used.
b
N-Alkylation of 1 was examined under various conditions. Final-
ly we found that use of KHMDS in the presence of 18-crown-6
achieved efficient alkylation and desired N-alkyl-2-benzazepines
7 were prepared in good yield (Scheme 3). Use of wet 18-crown-6
spoiled the yield of 7 in a moderate level. Use of primary iodide pro-
gressed the reaction smoothly to give 7 in good yield. For example,
MeI and EtI served as a good alkylating agent for 1 to give 7a and 7b
in 81% and 87% yield, respectively (entries 1 and 2). Use of benzyl
bromide was also good result (entry 9). On the other hand, use of
secondary iodide, isopropyl iodide, gave 7g in trace amounts (entry
7). Sterically demanding primary alkyl iodide also gave sluggish re-
sults (entry 8). The results are summarized in Table 1.5
With 2-benzazepine derivatives in hand, a biological activity of
2-benzazepine derivatives was evaluated using in vitro wound
healing assay (scratch assay) with human skin epithelial HaCat
cells.3 The results were shown in Figure 1. Compounds 1, 7a and
7b significantly promoted the migration of HaCat cells as fibronec-
tin (positive control), whereas 7c, 7d, 7e, 7g and 7i had no effect on
it. A side chain at N-2 position was thus important for this biolog-
ical activity of 2-benzazepine derivatives. The steric size between
methyl and ethyl seems optimal at this side chain position, and
longer alkyl chain than propyl group at N-2 position spoiled the
biological activity.
Figure 1. A biological activity of 2-benzazepine derivatives. The effects of the
compounds on the migration of human skin epithelial HaCat cells were examined at
30 lM using in vitro wound healing assay (scratch assay). Fibronectin (100 nM) was
used as positive control. Data were means S.E.M. of six independent determina-
** ***
tions. <0.01,
<0.001 versus DMSO (Student’s t-test).
is suitable for quick derivatization at N-2 side chain. Prepared
derivatives were examined for SAR studies of their biological activ-
ity and N-side chain significantly affected the promotion activity
for cell migration, in which methyl substituent at N-2 position
showed the best activity. Further investigation on this system is
now underway in our group.
In conclusion, we have developed a new preparation of 2-ben-
zazepine derivatives from N-boc acrylamide. The present method
References and notes
CO2R
CO2R
O
MeO
MeO
N
N
1. Recent examples: Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.; Fisher, M. H.;
Abbadie, C.; Felix, J. P.; Garcia, M. L.; Li, X.; Lyons, K. A.; McGowan, E.; MacIntyre,
D. E.; Martin, W. J.; Priest, B. T.; Ritter, A.; Smith, M. M.; Warren, V. A.; Williams,
B. S.; Kaczorowski, G. J.; Parsons, W. H. Bioorg. Med. Chem. Lett. 2007, 17, 4630;
Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.;
Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Thomsen, W. J.;
Saldana, H. R.; Whelan, K. T.; Menzaghi, F.; Webb, R. R.; Beeley, N. R. A. Bioorg.
Med. Chem. Lett. 2005, 15, 1467; Seto, M.; Miyamoto, N.; Aikawa, K.; Aramaki, Y.;
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Seto, M.; Aramaki, Y.; Okawa, T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.-
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Kan, K.; Tanada, Y.; Bando, M.; Shinohara, T.; Kurimura, M.; Ogawa, H.;
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Agents 2000, 14, 193.
Bu3SnH, AIBN
O
Br
Benzene reflux
t
6a
; R = Bu, 29%
; R = Me, 49%
5
6b
MeO
NH
O
i, AcCl, MeOH for 6a.
i or ii
ii,KOH/MeOH reflux
6b.
then HCl reflux for
1; 63% (from 6a), 52% (from 6b)
mp 157.1-157.8 ºC
Scheme 2. 7-Endo selective radical cyclization of 5 and preparation of 1.

A. Kamimura et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3193–3195
3195
2. Miller, W. H.; Alberts, D. P.; Bhatnagar, P. K.; Bondinell, W. E.; Callahan, J. F.;
Calvo, R. R.; Cousins, R. D.; Erhard, K. F.; Heerding, D. A.; Keenan, R. M.; Kwon, C.;
Manley, P. J.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas, I. N.;
Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.; Hwang, S.-M.;
James, I. E.; Lark, M. W.; Rieman, D. J.; Stroup, G. B.; Azzarano, L. M.; Salyers, K.
L.; Smith, B. R.; Ward, K. W.; Johanson, K. O.; Huffman, W. F. J. Med. Chem. 2000,
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1H), 3.79 (s, 3H), 3.48 (m, 1H), 3.43 – 3.25 (m, 1H), 3.00 – 2.73 (m, 2H), 1.48 (dd,
J = 7.5, 15.0 Hz, 2H), 1.24 (d, J = 6.5 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR
(68 MHz, CDCl3) d 175.5, 157.5, 135.9, 131.6, 129.5, 114.0, 113.0, 55.2, 52.4, 49.5,
37.2, 34.8, 21.4, 17.4, 11.0. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.71; H, 8.71; N, 5.66. Compound 7d; H NMR (270 MHz, CDCl3) d 7.00
(d, J = 8.4 Hz, 1H), 6.75 (dd, J = 2.7, 8.4 Hz, 1H), 6.61 (s, 1H), 5.09 (d, J = 16.4 Hz,
1H), 3.80 (d, J = 16.3 Hz, 1H), 3.77 (s, 3H), 3.43 (m, 3H), 3.03–2.70 (m, 2H), 1.42
(dd, J = 7.1, 14.4 Hz, 2H), 1.29–1.15 (m, 5H), 0.84 (t, J = 6.8 Hz, 3H). 13C NMR
(68 MHz, CDCl3) d 175.5, 157.6, 136.0, 131.7, 129.7, 114.1, 113.0, 55.3, 52.4, 47.7,
37.3, 35.0, 30.4, 19.9, 17.5, 13.7. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.14; H, 8.88; N, 5.33. Compound 7e; 1H NMR (270 MHz, CDCl3)
d 7.02 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 5.11 (d,
J = 16.4 Hz, 1H), 3.80 (d, J = 9.6 Hz, 1H), 3.78 (s, 3H), 3.60–3.24 (m, 3H), 3.03–
2.74 (m, 2H), 1.52–1.39 (m, 3H), 1.24 (d, J = 6.5 Hz, 7H), 0.80 (t, J = 7.0 Hz, 3H).
13C NMR (68 MHz, CDCl3) d 175.3, 157.5, 135.9, 131.5, 129.5, 113.9, 113.0, 55.2,
52.3, 47.8, 37.1, 34.8, 28.7, 27.8, 22.1, 17.4, 13.7. Anal. Calcd for C17H25NO2: C,
74.14; H, 9.15; N, 5.09. Found: C, 73.01; H, 9.18; N, 4.94. Compound 7f; 1H NMR
(270 MHz, CDCl3) d 7.01 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 6.61 (d,
J = 2.6 Hz, 2H), 5.11 (d, J = 16.3 Hz, 1H), 3.80 (d, J = 16.3 Hz, 1H), 3.78 (s, 3H), 3.41
(m, 3H), 2.86 (m, 2H), 1.45 (m, 2H), 1.35–1.08 (m, 9H), 0.81 (t, 3H). 13C NMR
(68 MHz, CDCl3) d 175.5, 157.5, 136.0, 131.6, 129.6, 114.0, 113.0, 55.3, 52.4, 47.9,
37.2, 34.9, 31.4, 28.2, 26.3, 22.3, 17.5, 13.8. Anal. Calcd for C18H27NO2: C, 74.70;
H, 9.40; N, 4.84. Found: C, 74.34; H, 9.72; N, 4.69. Compound 7i; 1H NMR
(270 MHz, CDCl3) d 7.41 – 7.14 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 2.6,
8.4 Hz, 1H), 6.37 (d, J = 2.7 Hz, 1H), 4.99 (d, J = 14.9 Hz, 2H), 4.33 (d, J = 14.8 Hz,
1H), 3.77 (d, J = 16.5 Hz, 1H), 3.72 (s, 3H), 3.42 – 3.34 (m, 1H), 2.95 (m, 2H), 1.31
(d, J = 6.5 Hz, 3H). 13C NMR (68 MHz, CDCl3) d 175.7, 157.3, 137.6, 135.3, 131.4,
129.3, 128.4, 128.4, 128.1, 128.1, 127.3, 113.9, 113.2, 55.1, 51.1, 50.3, 37.1, 34.9,
17.5. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.11; H,
7.32; N, 4.63.
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5. Physical data for 2-benzazepines; 1; 1H NMR (270 MHz, CDCl3)
d 7.08 (d,
J = 8.4 Hz, 1H), 6.79 (dd, J = 2.6, 8.3 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 3.99 (dd,
J = 6.7, 16.0 Hz, 1H), 3.79 (s, 3H), 3.13 (ddd, J = 4.4, 6.8, 11.1 Hz, 1H), 2.97–2.88
(m, 2H), 1.26 (d, J = 6.7 Hz, 5H). 13C NMR (68 MHz, CDCl3) d 178.7, 157.8, 136.9,
131.4, 129.9, 113.7, 113.1, 55.3, 45.8, 36.4, 36.2, 17.5. HRMS (EI+ M) m/z
205.1102. Calcd for C12H15NO2 205.1103.7a; 1H NMR (270 MHz, CDCl3) d 7.04 (d,
J = 8.4 Hz, 1H), 6.78 (dd, J = 2.7, 8.5 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 5.18 (d,
J = 16.0 Hz, 1H), 3.80 (s, 3H), 3.76 (d, J = 13.8 Hz, 1H), 3.45–3.30 (m, 1H), 3.05 (s,
3H), 2.90 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). 13C NMR (68 MHz, CDCl3) d 175.9,
157.5, 135.2, 131.8, 129.6, 114.3, 113.2, 55.3, 54.1, 37.1, 35.2, 34.8, 17.6. Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 70.95; H, 7.69; N, 6.39.
Compound 7b; 1H NMR (270 MHz, CDCl3) d 7.02 (d, J = 8.4 Hz, 1H), 6.82 – 6.70
(m, 1H), 6.62 (d, J = 2.8 Hz, 1H), 5.10 (d, J = 16.4 Hz, 1H), 3.81 (d, J = 16.4 Hz, 1H),
3.79 (s, 3H), 3.52 (q, J = 7.2 Hz, 2H), 3.41–3.24 (m, 1H), 2.86 (d, J = 12.5 Hz, 2H),
1.24 (d, J = 6.5 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H). 13C NMR (68 MHz, CDCl3) d 175.3,
157.5, 136.0, 131.8, 129.7, 114.0, 113.0, 55.3, 52.0, 42.7, 37.2, 34.9, 17.5, 13.5.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.99; H, 8.32; N,
5.99. Compound 7c; 1H NMR (270 MHz, CDCl3) d 7.02 (d, J = 8.4 Hz, 1H), 6.83–
6.68 (m, 1H), 6.61 (d, J = 2.7 Hz, 1H), 5.12 (d, J = 16.6 Hz, 1H), 3.80 (d, J = 16.6 Hz,