Synthesis of 6-substituted 1-phenylbenzazepines and their dopamine D1 receptor activities

Article abstract of DOI:10.1016/j.bmc.2008.09.049

A series of racemic 6-aryl substituted 1-phenylbenzazepines 7a-e, and 17a,b were prepared. All these compounds showed binding potencies compatible to or much higher than that of the prototypic (±)-SKF-38393 ((±)-1) and (±)-SKF-83959 (3) for the D₁ receptor. Among analogs of (±)-SKF-38393, compounds 7b, 7c and 7e possess 10-, 2- and 7-fold enhancement in binding for the D₁ receptor, respectively. Lower but compatible potency to that of (±)-1 was observed for compounds 7a and 7d. The optimal 6-substituents (m-tolyl, and 2′-naphthyl) were applied to the skeleton of (±)-SKF-83959 (3). The resulting compounds 17a,b displayed high affinity at the D₁ receptor, only slightly lower than that of 3. These two compounds also showed good binding at the D₂ receptor.

Full text of DOI:10.1016/j.bmc.2008.09.049

Bioorganic & Medicinal Chemistry 16 (2008) 9425–9431
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of 6-substituted 1-phenylbenzazepines and their dopamine
D1 receptor activities
a,
Jing Zhang a, , Xuetao Chen b, , Leiping Yu b, Xuechu Zhen b, , Ao Zhang
*
*
a Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
b Neuropharmacological Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of racemic 6-aryl substituted 1-phenylbenzazepines 7a–e, and 17a,b were prepared. All these
compounds showed binding potencies compatible to or much higher than that of the prototypic ( )-
SKF-38393 (( )-1) and ( )-SKF-83959 (3) for the D1 receptor. Among analogs of ( )-SKF-38393, com-
pounds 7b, 7c and 7e possess 10-, 2- and 7-fold enhancement in binding for the D1 receptor, respectively.
Lower but compatible potency to that of ( )-1 was observed for compounds 7a and 7d. The optimal 6-
substituents (m-tolyl, and 20-naphthyl) were applied to the skeleton of ( )-SKF-83959 (3). The resulting
compounds 17a,b displayed high affinity at the D1 receptor, only slightly lower than that of 3. These two
compounds also showed good binding at the D2 receptor.
Received 13 August 2008
Accepted 17 September 2008
Available online 20 September 2008
Keywords:
Dopamine receptor
Serotonin receptor
1-Phenylbenzazepine
SKF-38393
Ó 2008 Elsevier Ltd. All rights reserved.
SKF-83959
1. Introduction
meta-tolyl, or ortho-tolyl as the 1-substituent, are optimal for the
D1 receptor activity.6 It has also been reported that a small 6-sub-
The D1 receptor is the most highly expressed subtype among
dopamine (DA) receptor family (D1–D5). It plays a crucial role in a
variety of cognitive functions and is a major target for development
of anti-parkinsonian agents.1,2 SKF-38393, (1R)-1-phenyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine-7,8-diol (R-(+)-1) (Fig. 1), is the
earliest D1 receptor agonist with high binding affinity and selectiv-
ity.3 Although it was reported more than two decades ago, SKF-
38393 still remains one of the widely used ligands for characteriza-
tion of the D1 receptor, and as the prototype for developing new D1
receptor agonists.1,4,5 Ironically, compared to the large number of
phenylbenzazepines derived from SKF-38393, clinically useful D1
receptor selective ligands are rare.5 This is mostly due to the poor
intrinsic activity, low metabolic stability and some unwanted side
effects observed from these compounds.1,4,5
stituent, such as Cl-, or Br- might further enhance the interaction
between the D1 receptor and the ligand.5,6 However, the effect of
a relatively large 6-substituent, such as ph- or substituted ph-,
on the D1 receptor binding remains largely unexplored.7 In this re-
port, we synthesized
a small series of 6-substituted phen-
ylbenzazepines, and evaluated their binding affinities at DA (D1,
D2) and 5-HT (5-HT1A, 5-HT2A) receptors.
2. Chemistry
( )-SKF-38393 (( )-1) and its 6-Cl analog (2) were prepared
from homoveratrylamine and styrene oxide by using a literature
procedure.8–10 The key intermediate 6-bromo-benzazepine 5 was
prepared from O,O-dimethyl-protected R/S( )SKF-38393 (4) in
63% yield.10,11 Suzuki coupling12,13 of bromide 5 with an appropri-
A comprehensive analysis5 of the phenylbenzazepines devel-
oped by far, reveals that the catecholic-, amino-, and the 1-phenyl-
fragments in phenylbenzazepines, such as SKF-38393, are the ma-
jor determinants of the D1 receptor agonism, but minor changes in
the N-3, C-6, as well as substitution pattern of the 1-phenyl group
also have important consequences for the D1 receptor activity.5,6 It
has been found that H, CH3, or allyl as the N-substituent, and a
Cl
Cl
HO
HO
HO
HO
NH HO
HO
N-Me
NH
* Corresponding authors. Tel./fax: +86 21 50806750 (X.Z.), +86 21 50806035
(A.Z.).
(+)-1
R/S(+)-SKF-38393
2, SKF-81297
3, R/S(+)-SKF-83959
E-mail addresses: xczhen@mail.shcnc.ac.cn (X. Zhen), aozhang@mail.shcnc.ac (A.
Zhang).
Figure 1. Representative 1-arylbenzazepines.
These authors contributed equally to this work.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.09.049

9426
J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
Br
Ar
Ar
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
HO
HO
ii
i
NH
NH
NH iii
NH
5
6a-f
7a-e
4
(a, Ph; b, 3-tolyl; c, 4-Cl-Ph; d, 4-F-Ph; e, 2-naphthyl; f, 2-furyl)
Scheme 1. Reagents and conditions: (i) Br2, Ac2O, 63%; (ii) ArB(OH)2, Pd(PPh3)4, 2 N Na2CO3, LiCl, toluene/EtOH = 4:1, 90 °C, 35–78%; (iii) BBr3, CH2Cl2, 35–75% for 7a–d.
ate arylboronic acid provided the corresponding 6-aryl-benzaze-
pines 6a–f as racemates in 35–78% yields (Scheme 1). Demethyla-
tion of 6a–e using BBr3 (1 M) in CH2Cl2 generally yielded the
expected catechols 7a–e in moderate yields.14 However, in the case
of 6f, similar demethylation procedure caused a dark complex and
no expected product could be isolated.
Treating N-trifluoroacetyl protected 5 with n-BuLi followed by
I2 in Et2O gave iodide 810 in 56% yield (Scheme 2). Sonogashira
reaction15,13 of iodide 8 with phenylacetylene initially conducted
under Pd(PPh3)4/CuI/DMF catalytic condition was found not suc-
cessful, however, simply using Pd(OAc)2 in acetone/H2O readily
led to 6-(phenylethynyl) benzazepine 9 in 46% yield. It was further
noted that a similar demethylation of 9 using BBr3 (1 M in CH2Cl2)
produced a complicated mixture and failed to give the expected
benzazepine 10. Stille coupling16 of N-Boc protected iodide 8 with
vinyltributylstannane under the catalytic condition13 of Pd2(dba)3
and CuI afforded 6-vinyl-1-phenylbenzazepine 11 in 37% yield.
Again to our surprise, treatment of 11 with BBr3 (1 M) at ꢀ78 °C
followed by quenching with MeOH did not give the expected
demethylated product. Heck reaction17 of the N-Boc protected bro-
mide 5 with methyl acrylate catalyzed by Pd(OAc)2 and (o-tolyl)3P
yielded 6-methoxycarbonylvinyl benzazepine 13 in 78% yield. The
trans-configuration of the two vinyl protons is evidenced by the
coupling constant of 16.2 Hz in the 300 M H NMR of compound
13. Treating compound 13 with BBr3 (1 M) in CH2Cl2 again did
not give the expected product. However, a careful chromatography
process provided compound 14 containing a tetrahydrochromen
moiety in 43% yield. The production of compound 14 can be ratio-
nalized by the esterification of the 6-acrylate moiety with the 7-OH
during the demethylation process of compound 13. The cis-config-
uration of the two vinyl protons is evidenced by the coupling con-
stant of 9.9 Hz in the 300 M H NMR of compound 14, other
spectroscopic data (MS, 13C NMR, HRMS) also supported the struc-
ture of 14. On the basis of this result, it is likely that the failure to
obtain compounds 10 and 12 is due to the relatively high reactivity
of the vinyl or acetylenyl moiety in these compounds.
X
H3CO
N
R
H3CO
5 (X = Br, R = H)
8 (X = I, R = H)
i,ii
vi
v
Ph
iii
COOMe
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
N-Boc
NH
N-Boc
9
11
iv
13
iv
iv
43%
Ph
O
HO
HO
O
NH
HO
HO
NH
NH
HO
14
12
10
Scheme 2. Reagents and conditions: (i) (CF3CO)2O, CH2Cl2, quantitative; (ii) n-BuLi, I2, Et2O, ꢀ78 °C to rt, 56%; (iii) phenylacetylene, Pd(OAc)2, NaOH, acetone, H2O, 46%; (iv)
BBr3, CH2Cl2; (v) a—(Boc)2O, Na2CO3, CH2Cl2; b—vinyl(tributyl)tin, Pd2(dba)3, CuI, tri-(o-tolyl)phosphine, DMF, 37%; (vi) a—(Boc)2O, Na2CO3, CH2Cl2; b—methyl acrylate,
Pd(OAc)2, tri(o-tolyl)phosphine, Et3N, DMF, 80 °C, 78%.

J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
9427
Ar
Br
HO
HO
H3CO
H3CO
H3CO
N-Me
N-Me
NH
i
ii
iii
iv
H3CO
17a, Ar = 3-tolyl; 22% overall yield
15
16
17b, Ar = 2-naphthyl; 31% overall yield
v
iv
3, (+)-SKF-83959, 34% overall yield
Scheme 3. Reagents and conditions: (i) Br2, HOAc/HCl (10:1), rt, 56%; (ii) (HCHO)n, HCOOH, 110 °C, 92%; (iii) ArB(OH)2, Pd(OAc)2, (o-tolyl)3P, K3PO4, DMF, 110 °C; (iv) BBr3,
CH2Cl2; (v) n-BuLi, C2Cl6, Et2O, ꢀ78 °C, 63%.
Two analogs of R/S( )-SKF-83959 (3), 6-aryl substituted 1-(m-
tolyl)-benzazepines 17a,b were also prepared in a similar manner
(Scheme 3). Compound 15 was prepared according to a literature
procedure in racemic form.6a,6b Bromination of 15 with Br2 in a
mixture of HOAc and concd HCl followed by N-methylation pro-
vided the key intermediate 166b in 51% yield. Suzuki coupling12,13
of bromide 16 with an appropriate arylboronic acid followed by O-
demethylation using similar procedures as described above yielded
the corresponding 6-(m-tolyl)-, and 6-(20-naphthyl)-substituted 1-
(m-tolyl)benzazepines 17a,b in 22% and 31% overall yield, respec-
tively. Treating bromide 16 with n-BuLi in C2Cl6 at ꢀ78 °C, followed
by O-demethylation afforded R/S( )-SKF-83959 (3)18 in 34% overall
yield.
Binding results were summarized in Table 1. Racemic ( )-SKF-
38393 (( )-1) and ( )-SKF-83959 (3) in our assay showed Ki values
of 393 nM and 1.93 nM, respectively, which are consistent with the
results reported in the literature (Ki: 190 nM and 1.18 nM, respec-
tively).6a,6b 6-Aryl substituted benzazepines 7a–e, which were ana-
logs of (( )-1), did not show any appreciable affinity for the D2
receptor, but good to high affinity for the D1 receptor was ob-
served. The overall good affinity for the D1 receptor further states
the fact that 1-phenylbenzazepine skeleton functions as a typical
D1 receptor scaffold,5 and a relatively larger 6-substituent is some-
what tolerated. Compared to the parent compound ( )-1, a 6-phe-
nyl substituent did not cause any effect for the D1 binding, and the
corresponding compound 7a showed a Ki value of 346 nM, statisti-
cally same as that of ( )-1 (393 nM). Compound 7b containing a
meta-tolyl group as the 6-substituent displayed a 10-fold gain in
binding affinity for the D1 receptor with a Ki value of 39 nM. Sim-
ilarly, the b-naphthyl moiety as the C-6 substituent (compound 7e)
caused a 7-fold enhancement in binding for the D1 receptor bind-
ing (Ki, 56 nM). A 6-aryl substituent with a para-electro-withdraw-
ing group, such as Cl-(7c), F-(7d), also showed good affinity for the
D1 receptor. Compound 7c was 2-fold more potent (Ki, 190 nM),
whereas compound 7d was slightly less potent (Ki, 422 nM), com-
pared to the parent compound ( )-1. It is of note that the tetra-
hydrochromenoazepinone 14 did not display appreciable binding
for any of the DA and 5-HT receptors tested, indicative of the
importance of 7-OH to the interaction between the benzazepine
compounds and the monoamine receptors.5,6 Some of these
3. Results and discussion
All the new compounds (7a–e, and 17a,b) were racemic, and
were converted to their HBr salts for the bioassay. The binding
affinity of these compounds were assayed at DA (D1, D2) and
5-HT (5-HT1A, 5-HT2A) receptors using membrane preparation
obtained from stable transfected HEK293 or CHO cells. This
procedure is similar to those reported previously14,19 by us.
[3H]SCH23390, [3H]Spiperone, [3H]8-OH-DPAT and [3H]Ketanserin
were used as the standard radioligands for DA D1, D2 and serotonin
5-HT1A, 5-HT2A receptors, respectively. Racemic R/S( )-SKF-38393
(( )-1) and R/S( )-SKF-83959 (3) were also tested in our assays
for comparison.
Table 1
Binding affinity of 1-phenylbenzazepines for DA (D1, D2) and 5-HT (5-HT1A, 5-HT2A) receptors from HEK293 or CHO cellsa
Compound
Ki (nM)
5-HT1A ([3H]8-OH-DPAT)
D1 ([3H]SCH23390)
D2 ([3H]Spiperone)
NA (720,000c)
5-HT2A ([3H]Ketanserin)
NA
( )-1 R/S( )-SKF-38393
R-(+)-1 SKF-38393
393
5
NT
NA
NT
(190b)
50b
>10,000c
NA
NA
NA
(26c)
3 R/S( )-SKF-83959
1.93 0.47
(1.18c)
7a
7b
7c
7d
7e
14
346 15
39 4.1
190 14
422 10
56 10
NA
NA
NA
NA
NA
NA
NA
775 285
736 321
NT
NT
1083 348
NA
NT
NA
NT
NT
375 107
NA
17a
17b
6.81 0.59
4.88 0.12
210 26
29 3.6
NT
NT
121 36
43 7.1
a
Values are means of three to five experiments, all compounds were tested as HBr salts in racemates,14 NA = not active (less than 80% of inhibition in radioligand binding at
10
l
M), NT = not tested.
Data from Ref. 6a.
Data from Ref. 6b.
b
c

9428
J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
compounds also showed moderate affinity for the 5-HT1A, or 5-HT2A
receptors, but good selectivity for the D1 over D2 and 5-HT receptors
were generally retained. For example, compounds 7a and 7b
showed Ki values of ꢁ800 nM for the 5-HT1A receptor, while com-
pound 7e displayed Ki value of ꢁ400 nM for the 5-HT2A receptor.
On the basis of the results from compounds derived from ( )-1,
it can be concluded that a 6-aryl substituent is generally beneficial
for the binding at the D1 receptor, especially when the 6-aryl group
contains an electron-donating substituent (m-tolyl in 7b, 20-naph-
thyl in 7e). This may indicate that there is a relatively larger lipo-
philic pocket on the D1 receptor around the 6-position of these
benzazepines.
To examine if there is a same effect of such substitution pat-
terns in other benzazepines on the D1 receptor binding, 6-(m-to-
lyl)-(17a), and 6-(20-naphthyl)-(17b) substituted analogs of 3
(( )-SKF-83959) were prepared and evaluated. Both compounds
displayed high D1 receptor binding with Ki values of 6.8 nM and
4.9 nM, respectively. Although these affinities are 3.5-, and 2.5-fold
lower than that of ( )-SKF-83959, they are statistically the same.
Much surprisingly, these two compounds also showed good to
moderate affinity at the D2 receptor with Ki values of 210 nM
and 29 nM, respectively. The 6-(20-naphthyl) analog 17b is 7-fold
more potent than the 6-(m-tolyl)-analog 17a at this receptor. The
significant D2 receptor binding cannot be explained by the single
effect of the 6-aryl substituent, however, the interaction between
the two aryl groups at C-1 and C-6 may enhance the binding of
the ligand to the D2 receptor.
Newark). Flash chromatography was used for the routine purifica-
tion of reaction products. The column output was monitored with
TLC. Yields of all the reactions were not optimized.
5.1. 6-Bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine (5)
This compound10 was prepared from homoveratrylamine in
three steps using a literature procedure. 1H NMR (300 MHz, CDCl3)
d 7.36 (m, 2H), 7.26 (m, 1H), 7.13 (d, J = 7.2 Hz, 2H), 6.40 (s, 1H),
4.30 (dd, J = 2.7, 7.2 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 3.48 (dd,
J = 7.2, 13.8 Hz, 1H), 3.38 (dd, J = 3.0, 13.8 Hz, 1H), 3.20 (m, 2H),
2.94 (m, 2H), 2.17 (br s, 1H).
5.2. General procedure for Suzuki coupling reaction
To a mixture of bromide 5 (100 mg, 0.28 mmol) and an appro-
priate arylboronic acid (0.45 mmol) in toluene and ethanol (tolu-
ene/ethanol = 4:1, 5 mL) was added Pd(PPh3)4 (52 mg,
0.045 mmol), 2 N aq Na2CO3 solution (0.5 mL) and LiClꢂH2O
(17 mg, 0.28 mmol). The resulting mixture was allowed to reflux
under nitrogen at 100 °C for 36 h. Then the dark mixture was
poured into water and extracted with EtOAc for three times, and
the combined organic phases were washed with brine and then
dried ver anhydrous Na2SO4. After filtration and removal of sol-
vents, the crude material was purified by chromatography (EtOA-
c + Et3N) to yield benzazepines 6a–f.
5.2.1. 7,8-Dimethoxy-1,6-diphenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine (6a)
4. Conclusion
Yellow liquid (35.2%). 1H NMR (300 MHz, CDCl3) d 7.40 (m, 5H),
7.26 (m, 5H), 6.47 (s, 1H), 4.33 (d, J = 5.7 Hz, 1H), 3.70 (s, 3H), 3.51
(s, 3H), 3.43 (m, 2H), 2.81 (m, 2H), 2.59 (m, 2H), 2.26 (br s, 1H); 13C
NMR (75 MHz, CDC13) d 150.1, 144.8, 142.2, 139.6, 137.9, 137.0,
132.4, 129.9, 129.8, 128.6, 128.2, 127.8, 126.7, 126.3, 113.6, 60.4,
55.6, 53.5, 52.6, 47.6, 33.9; EI-MS m/z: 359 (M+); HR-MS Calcd
for C24H25NO2 (M+) 359.1885. Found: 359.1902.
In summary, a series of racemic 6-aryl substituted 1-phen-
ylbenzazepines 7a–e, and 17a,b were prepared. All these com-
pounds showed binding potencies compatible to or much higher
than that of the prototypic ( )-SKF-38393 (( )-1) and ( )-SKF-
83959 (3) for the D1 receptor. Among analogs of ( )-SKF-38393
(( )-1), compounds 7b, 7c and 7e possess 10-, 2- and 7-fold
enhancement in binding for the D1 receptor, respectively. Lower
but comparable potency to that of ( )-1 was observed for com-
pounds 7a and 7d. Both compounds 7a and 7b showed moderate
affinity for the 5-HT1A receptor, while compound 7e exhibited rea-
sonable affinity for the 5-HT2A receptor. The optimal 6-substituents
(m-tolyl, and 20-naphthyl) were applied to the skeleton of ( )-SKF-
83959 (3). The resulting compounds 17a,b displayed high affinity
at the D1 receptor, only slightly lower than that of 3. These two
compounds also showed good binding at the D2 receptor.
Taking these findings together, the current report provides a
new medicinal chemistry strategy to enhance or retain good bind-
ing of 1-arylbenzazepine analogs at the D1 receptor, or at the D2
receptor. However, it has to be pointed out that the D1 receptor
activity of 1-arylbenzazepines has been reported mostly residing
on the R-isomer as in the case of ( )-SKF-38393 (( )-1), whose R-
isomer (R-(+)-1) is 3.8-fold more potent than the racemate ( )-1,
while the S-(ꢀ)-1 is inactive.6a,6b Therefore, our next study will fo-
cus on the resolution of the most potent analogs 7b, 7e and 17a,b,
as well as the evaluation of their intrinsic activity.
5.2.2. 7,8-Dimethoxy-1-phenyl-6-m-tolyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepine (6b)
Yellow liquid (38.7%), 1H NMR (300 MHz, CDCl3) d 7.38 (m, 2H),
7.23 (m, 5H), 7.00 (m, 2H), 6.46 (d, J = 5.7 Hz, 1H), 4.33 (d,
J = 5.7 Hz, 1H), 3.70 (d, J = 3.9 Hz, 3H), 3.52 (s, 3H), 3.41 (m, 2H),
2.80 (m, 2H), 2.56 (m, 2H), 2.40 (s, 3H), 2.29 (br s, 1H); 13C NMR
(75 MHz, CDC13) d 150.1, 144.9, 142.2, 139.5, 139.4, 137.9, 137.4,
137.1, 132.4, 130.6, 130.5, 128.7, 128.3, 128.2, 127.7, 127.5,
126.9, 126.8, 126.4, 113.6, 113.5, 60.5, 55.7, 53.5, 47.7, 33.8, 29.7,
21.5; EI-MS m/z: 373 (M+).
5.2.3. 6-(4-Chlorophenyl)-7,8-dimethoxy-1-phenyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine (6c)
39.0% yield, 1H NMR (300 MHz, CDCl3) d 7.38 (m, 4H), 7.27 (m,
1H), 7.16 (m, 4H), 6.46 (s, 1H), 4.35 (d, J = 6.6 Hz, 1H), 3.68 (s, 3H),
3.50 (s, 3H), 3.43 (m, 2H), 2.81 (m, 2H), 2.58 (m, 2H); 13C NMR
(75 MHz, CDC13) d 150.2, 144.7, 141.8, 139.7, 136.3, 135.7, 132.8,
132.0, 131.3, 131.2, 128.7, 128.1, 126.5, 113.8, 60.4, 55.6, 52.9,
52.2, 47.3, 33.4; EI-MS m/z: 393 (M+); HR-MS Calcd for
C24H24ClNO2 (M+) 393.1496. Found: 393.1487.
5. Experimental
Chemistry. Melting points were determined on a Thomas–Hoover
capillary tube apparatus and are reported uncorrected. 1H and 13C
NMR spectra were recorded on a Brucker AC300 spectrometer using
tetramethylsilane as an internal reference. Element analyses, per-
formed by the Analytic Lab, SIMM, were within 0.4% of theoretical
values. Analytical thin-layer chromatography (TLC) was carried out
on 0.2-mm Kieselgel 60F254 silica gel plastic sheets (EM Science,
5.2.4. 6-(4-Fluorophenyl)-7,8-dimethoxy-1-phenyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine (6d)
78.5% yield, 1H NMR (300 MHz, CDCl3) d 7.38 (m, 2H), 7.18 (m,
7H), 6.47 (s, 1H), 4.33 (d, J = 5.7 Hz, 1H), 3.66 (s, 3H), 3.50 (s, 3H),
3.38 (m, 2H), 2.79 (m, 2H), 2.55 (m, 2H), 2.24 (br s, 1H); 13C NMR
(75 MHz, CDC13) d 163.0, 160.5, 150.1, 144.8, 142.1, 139.7, 135.8,
133.7, 133.7, 132.4, 131.5, 131.4, 131.3, 128.6, 128.2, 126.3, 114.9,

J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
9429
114.7, 113.7, 60.3, 55.6, 53.5, 52.6, 47.6, 33.9; EI-MS m/z: 377 (M+);
3.22 (m, 1H), 2.93 (m, 2H), 2.71 (m, 1H); 13C NMR (75 MHz, CD3OD)
d 145.4, 143.5, 142.4, 138.0, 134.8, 134.6, 133.6, 133.5, 130.7,
130.0, 129.9, 129.1, 128.9, 117.2, 52.0, 48.1, 47.5, 29.0; EI-MS m/
z: 365 (M+). Anal. Calcd for C22H20ClNO2ꢂ0.85HBrꢂ0.75H2O:
C, 58.96; H, 5.03; N, 3.13. Found: C, 58.95; H, 5.07; N, 2.94.
HR-MS Calcd for C24H24FNO2 (M+) 377.1791. Found: 377.1787.
5.2.5. 8-Dimethoxy-6-(naphthalen-2-yl)-1-phenyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine (6e)
71.4% yield, 1H NMR (300 MHz, CDCl3) d 7.88 (m, 3H), 7.69 (d,
J = 6.6 Hz, 1H), 7.51 (m, 2H), 7.39 (m, 3H), 7.28 (m, 3H), 6.50 (s,
1H), 4.37 (d, J = 5.4 Hz, 1H), 3.72 (s, 3H), 3.50 (s, 3H), 2.71 (m,
6H); 13C NMR (75 MHz, CDC13) d 150.2, 145.0, 142.1, 139.7,
136.8, 135.5, 133.1, 132.4, 132.3, 128.7, 128.6, 128.5, 128.4,
128.2, 128.0, 127.7, 127.4, 126.4, 126.0, 125.8, 113.7, 60.5, 55.7,
53.4, 52.5, 47.6, 33.8, 29.6; EI-MS m/z: 409 (M+); HR-MS Calcd
for C28H27NO2 (M+) 409.2042. Found: 409.2036.
5.3.4. 6-(4-Fluorophenyl)-1-phenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-7,8-diol (7d)
56.0% yield, mp > 210 °C; 1H NMR (300 MHz, CD3OD) d 7.45 (m,
2H), 7.29 (m, 7H), 6.30 (s, 1H), 4.64 (br s, 1H), 3.68 (br s, 2H), 3.25
(m, 1H), 2.96 (m, 2H), 2.76 (m, 1H); 13C NMR (75 MHz, CD3OD) d
165.2, 162.7, 145.4, 143.6, 142.3, 135.3, 134.7, 133.8, 133.7,
133.6, 130.9, 130.7, 129.9, 129.2, 128.9, 117.1, 116.7, 116.5, 51.8,
47.8, 47.4, 28.8; EI-MS m/z: 349 (M+). Anal. Calcd for
C22H20FNO2ꢂ1.0HBrꢂ0.75H2O: C, 59.54; H, 5.11; N, 3.16. Found: C,
59.66; H, 5.19; N, 2.98.
5.2.6. 6-(Furan-2-yl)-7,8-dimethoxy-1-phenyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine (6f)
22.7% yield, 1H NMR (300 MHz, CDCl3) d 7.52 (s, 1H), 7.36 (m,
2H), 7.27 (m, 1H), 7.18 (m, 2H), 6.50 (s, 1H), 6.37 (d, J = 2.7 Hz,
1H), 4.32 (d, J = 4.5 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.46 (m,
2H), 2.91 (m, 2H), 2.66 (m, 2H), 2.46 (br s, 1H); 13C NMR
(75 MHz, CDC13) d 150.2, 149.5, 146.5, 142.0, 141.9, 139.6, 134.4,
128.7, 128.2, 126.4, 126.3, 115.4, 110.6, 110.1, 61.0, 55.8, 53.3,
52.4, 47.4, 34.1; EI-MS m/z: 349 (M+); HR-MS Calcd for
C28H27NO2 (M+) 349.1678. Found: 349.1681.
5.3.5. 6-(Naphthalen-2-yl)-1-phenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-7,8-diol (7e)
37.8% yield, mp 215–217 °C; 1H NMR (300 MHz, CD3OD) d 7.81
(m, 4H), 7.46 (m, 4H), 7.33 (m, 4H), 6.33 (s, 1H), 4.64 (t, J = 5.1 Hz,
1H), 3.64 (m, 2H), 3.23 (m, 1H), 2.86 (m, 3H); 13C NMR (75 MHz,
CD3OD) d 145.5, 143.7, 142.3, 136.8, 136.7, 135.7, 135.4, 134.6,
134.5, 133.6, 132.0, 131.2, 130.7, 130.6, 130.1, 129.9, 129.4,
129.2, 129.1, 129.0, 127.8, 127.6, 123.9, 117.1, 51.8, 47.8, 47.5,
28.8; EI-MS m/z: 381 (M+). Anal. Calcd for C26H23NO2ꢂ1.25HBrꢂ
1.0H2O: C, 62.38; H, 5.29; N, 2.80. Found: C, 62.50; H, 5.36; N, 2.48.
5.3. General procedure for demethylation of 6,7-dimethoxy-
benzazepines 6a–e
A solution of compound 6a–e (0.36 mmol) in 2 mL dry CH2Cl2
was stirred at ꢀ78 °C under N2 for 30 min, a solution of BBr3 solu-
tion (6 mL, 1 M in CH2Cl2) was added dropwise. The mixture was
allowed to stir at ꢀ78 °C for additional 30 min, and at rt overnight.
It was quenched with MeOH at ꢀ78 °C, and the mixture was
concentrated under reduced pressure. The obtained residue was
treated with MeOH and concentrated again. This procedure was
repeated for several times. Finally the crude material was recrys-
tallized from MeOH/Et2O to give the corresponding demethylated
products 7a–e.
5.4. 6-Iodo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine (8)10
Trifluoroacetic anhydride (4.9 mL, 35.23 mmol) was added to a
suspension of bromide 5 (1.4 g, 3.88 mmol) in 20 mL dry CH2Cl2,
and the mixture was stirred at rt for 2.5 h. After evaporation, the
residue was treated with CH2Cl2 and then evaporated. This proce-
dure was repeated twice to give N-trifluoroacetyl protected deriv-
ative of 5 1.90 g as a yellow liquid.
The solution of N-trifluoroacetyl protected derivative of 5
(2.47 g) in dry Et2O, was added slowly to a solution of n-butyllith-
ium (2.5 M in hexane, 7.0 mL, 17.5 mmol) in dry Et2O (20 mL) at
ꢀ78 °C. After stirring for 10 min, I2 (2.74 g, 10.79 mmol) in dry
Et2O was added. The mixture was allowed to stir at ꢀ78 °C for
0.5 h, and then at rt for another 0.5 h. The mixture was poured into
water, basified with NH3ꢂH2O, and then extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, and then evaporated. The residue was purified by
flash chromatography (EtOAc/MeOH = 40:1, 1% Et3N) to give com-
pound 8 (1.24 g, 56.5% for two steps) as a yellow solid. 1H NMR
(300 MHz, CDCl3) d 7.32 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 6.37 (s,
1H), 4.44 (dd, J = 2.7, 6.7 Hz, 1H), 3.81 (s, 3H), 3.65 (s, 3H), 3.47
(dd, J = 7.2, 13.8 Hz, 1H), 3.38 (dd, J = 3.0, 13.8 Hz, 1H), 3.23 (m,
1H), 3.15 (m, 1H), 2.74 (br s, 1H); EI-MS m/z: 409 (M+).
5.3.1. 1,6-Diphenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-
diol (7a)
Brown solid (30.6%), mp 198–205 °C; 1H NMR (300 MHz,
CD3OD) d 7.45 (m, 4H), 7.28 (m, 6H), 6.29 (s, 1H), 4.63 (t,
J = 5.4 Hz, 1H), 3.68 (m, 2H), 3.28 (m, 1H), 2.90 (m, 3H); 13C NMR
(75 MHz, CD3OD) d 145.5, 143.5, 142.2, 139.2, 134.5, 132.1,
131.9, 131.8, 130.7, 130.0, 129.9, 129.0, 128.8, 117.0, 51.8, 47.7,
47.5, 28.6; EI-MS m/z: 331 (M+). Anal. Calcd for
C22H21NO2ꢂ2HBrꢂ2H2O: C, 49.93; H, 5.14; N, 2.65. Found: C,
49.93; H, 5.30; N, 2.38.
5.3.2. 1-Phenyl-6-m-tolyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-7,8-diol (7b)
54.5% yield, mp 180–184 °C; 1H NMR (300 MHz, CD3OD) d 7.44
(m, 2H), 7.32 (m, 4H), 7.18 (m, 1H), 7.01 (m, 2H), 6.28 (d, J = 7.2 Hz,
1H), 4.61 (t, J = 5.4 Hz, 1H), 3.66 (m, 2H), 3.25 (m, 1H), 2.93 (m, 2H),
2.77 (m, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, CD3OD) d 145.5,
143.4, 142.3, 142.2, 139.7, 139.1, 134.5, 134.4, 132.5, 132.4,
132.2, 130.7, 129.9, 129.5, 129.0, 128.9, 128.8, 117.0, 116.9, 51.8,
51.7, 47.8, 47.7, 47.5, 28.6, 22.0; EI-MS m/z: 345 (M+). Anal. Calcd
for C23H23NO2ꢂ0.75HBrꢂ2.0H2O: C, 62.48; H, 6.33; N, 3.17. Found:
C, 62.77; H, 6.29; N, 2.95.
5.5. 7,8-Dimethoxy-1-phenyl-6-(phenylethynyl)-2,3,4,5-
tetrahydro-1H-benzo[d]azepine (9)
A mixture of NaOH (14 mg, 0.35 mmol), Pd(OAc)2 (0.8 mg,
0.0036 mmol) in H2O and acetone (4 mL, 1:1) was stirred at rt for
5 min, then aryl iodide 8 (70 mg, 0.17 mmol) and phenylacetylene
(60 lL, 0.53 mmol) were introduced. The mixture was stirred at
60 °C for 30 h, then concentrated. The residue was extracted with
EtOAc, and the combined organic phases were washed with brine,
dried over anhydrous Na2SO4, and concentrated. The residue was
purified by chromatography (CHCl3/MeOH = 30:1, 1% Et3N) to give
compound 9 (30 mg, 45.7%) as a yellow liquid. 1H NMR (300 MHz,
5.3.3. 6-(4-Chlorophenyl)-1-phenyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-7,8-diol (7c)
56.4% yield, mp 203–205 °C; 1H NMR (300 MHz, CD3OD) d 7.44
(m, 4H), 7.25 (m, 5H), 6.29 (s, 1H), 4.59 (br s, 1H), 3.64 (br s, 2H),

9430
J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
CDCl3) d 7.56 (m, 2H), 7.36 (m, 5H), 7.25 (m, 1H), 7.15 (d, J = 7.5 Hz,
2H), 6.47 (s, 1H), 4.27 (d, J = 6.9 Hz, 1H), 3.97 (s, 3H), 3.70 (s, 3H),
3.55 (m, 1H), 3.34 (m, 2H), 3.14 (m, 1H), 3.00 (m, 2H), 2.45 (br s,
1H); 13C NMR (75 MHz, CDC13) d 149.8, 148.4, 141.2, 139.1,
135.7, 131.1, 128.4, 128.0, 127.9, 127.8, 126.0, 123.2, 118.2,
114.9, 96.8, 84.4, 60.4, 55.6, 53.2, 52.1, 47.1, 34.9; EI-MS m/z:
383 (M+).
(s, 3H), 3.41 (m, 1H), 3.14 (m, 2H), 2.85 (m, 2H), 2.37 (s, 3H),
2.35 (s, 3H), 2.30 (m, 1H).
5.10. 3-Methyl-1,6-di-(m-tolyl)-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-7,8-diol (17a)
A solution of bromide 16 (100 mg, 0.26 mmol), m-toylboronic
acid (70 mg, 0.51 mmol), Pd(OAc)2 (12 mg, 0.53 mmol), (o-toyl)3P
(60 mg, 0.20 mmol) and K3PO4 (544 mg, 2.56 mmol) in DMF was
stirred at 110 °C overnight under N2. After removal of the solvents,
the residue was taken up in CHCl3, washed with water, brine, and
dried over anhydrous Na2SO4. After evaporation, the residue was
purified by chromatography (petroleum ether/EtOAc = 1:2) to give
the Suzuki coupling product (66 mg), which was treated with BBr3
(1.0 M in CH2Cl2) by using a similar procedure as that of prepara-
tion of 7a–e to give the title compound 17a as a white solid
(25 mg, 22% for two steps). 1H NMR (300 MHz, CDCl3 + CD3OD) d
7.35 (m, 1H), 7.23 (m, 2H), 6.95 (m, 5H), 6.13 (s, 1H), 4.46 (d,
J = 9.0 Hz, 1H), 3.38 (m, 1H), 2.99 (m, 3H), 2.72 (dd, J = 6.9,
15.6 Hz, 1H), 2.48 (s, 3H), 2.40 (m, 4H), 2.35 (s, 3H); 13C NMR
(75 MHz, CDCl3 + CD3OD) d 142.1, 141.9, 139.9, 138.1, 138.0,
136.5, 135.4, 130.7, 130.4, 129.1, 129.0, 128.9, 128.4, 128.3,
128.2, 127.9, 127.2, 127.1, 126.8, 125.2, 114.3, 62.2, 56.6, 46.6,
45.9, 29.4, 28.6, 21.1, 21.0; MS (m/z) 373 (M+). Anal. Calcd for
C24H25NO2ꢂ0.65HBrꢂ1.5H2O: C, 66.27; H, 6.82; N, 3.09. Found: C,
66.32; H, 6.90; N, 3.21.
5.6. N-tert-Butyl-7,8-dimethoxy-1-phenyl-6-vinyl-4,5-dihydro-
1H-benzo[d]azepine- 3(2H)-carboxylate (11)
A mixture of iodide 8 (239 mg, 0.58 mmol), finely ground
Na2CO3 (124 mg, 1.17 mmol) and (Boc)2O (255 mg, 1.17 mmol) in
20 mL dry CH2Cl2 was stirred at room temperature for 2 h under
N2, then the solvent was evaporated to give a yellow residue,
which was quick chromatographed (EtOAc/petroleum ether = 2:1)
to give N-Boc protected derivative of 8 (341 mg) as a yellow liquid.
Tributyl(vinyl)tin (60
lL, 0.19 mmol) was added slowly to a
mixture of N-Boc protected
8
(80 mg), Pd2(dba)3 (12.6 mg,
0.014 mmol), CuI (11 mg, 0.058 mmol) and (o-tolyl)3P (17 mg,
0.056 mmol) in dry DMF (10 mL). The mixture was allowed to react
at 50 °C for 4 days. After evaporation of the solvents, the residue
was subjected to column chromatography (EtOAc) to give a color-
less liquid 11 (24 mg, 42.9% for two steps). 1H NMR (300 MHz,
CDCl3) d 7.24 (m, 5H), 6.79 (m, 1H), 6.46 (s, 1H), 5.58 (dd, J = 2.1,
11.4 Hz, 1H), 5.42 (dd, J = 2.1, 18.0 Hz, 1H), 4.49 (m, 1H), 3.94 (m,
1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.53 (m, 2H), 2.96 (m, 2H), 1.31(m,
9H).
5.11. 3-Methyl-6-(naphthalen-2-yl)-1-m-tolyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepine-7,8-diol hydrobromide (17b)
5.7. (E)-tert-Butyl 7,8-dimethoxy-6-(3-methoxy-3-oxoprop-1-
enyl)-1-phenyl- 4,5-dihydro-1H-benzo[d]azepine-3(2H)-
carboxylate (13)
Compound 17b was prepared from 16 in 31% overall yield using
a similar procedure as preparation of compound 17a. 1H NMR
(300 MHz, CDCl3 + CD3OD) d 7.76 (m, 3H), 7.59 (s, 1H), 7.39 (dd,
J = 3.0, 6.0 Hz, 2H), 7.22 (dd, J = 1.2, 8.1 Hz, 1H), 7.12 (t, J = 7.5 Hz,
1H), 6.92 (m, 3H), 6.05 (s, 1H), 4.27 (d, J = 9.3 Hz, 1H), 3.18 (d,
J = 12.0 Hz, 1H), 2.65 (m, 4H), 2.27 (s, 3H), 2.19 (m, 4H); 13C NMR
(75 MHz, CDCl3 + CD3OD) d 142.6, 141.8, 140.0, 138.1, 136.0,
134.4, 134.2, 133.2, 132.3, 129.8, 129.0, 128.9, 128.7, 128.4,
128.1, 127.8, 127.7, 127.5, 127.4, 127.1, 126.0, 125.9, 125.8,
125.2, 114.5, 62.6, 56.7, 47.3, 46.2, 29.4, 29.2, 21.0; MS (m/z) 409
(M+). Anal. Calcd for C28H27NO2ꢂ0.25HBrꢂ1.0H2O: C,75.11; H, 6.58;
N, 3.13. Found: C, 75.08; H, 6.42; N, 2.92.
N-Boc protected bromide 5 (163 mg) prepared as above, was
added to a mixture of Pd(OAc)2 (15 mg, 0.067 mmol), (o-tolyl)3P
(80 mg, 0.263 mmol), methyl acrylate (150 lL, 1.67 mmol) and
0.2 mL Et3N in 4 mL dry DMF under N2. The reaction mixture was
allowed to stir under 80 °C overnight. After evaporation, the resi-
due was subjected to chromatography (EtOAc/petroleum
ether = 1:5) to yield compound 13 (109 mg, 74.1%) as a yellow li-
quid. 1H NMR (300 MHz, CDCl3) d 7.86 (d, J = 16.5 Hz, 1H), 7.24
(m, 2H), 6.52 (s, 1H), 6.37 (d, J = 16.2 Hz, 1H), 4.49 (m, 1H), 3.82
(s, 3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.67 (m, 4H), 2.93 (m, 2H), 1.32
(m, 9H).
5.12. Radioligand binding assays
5.8. 7-Hydroxy-5-phenyl-2,3,4,5-tetrahydrochromeno[6,5-
d]azepin-9(1H)-one (14)
The affinity of compounds to the D1 and D2 dopamine recep-
tors, and the 5-HT1A receptor was determined by competition
binding assays. Membrane homogenates of 5-HT1A-CHO cells,
D1- or D2-HEK293 cells were prepared as described previ-
ously.6a,18 Duplicated tubes were incubated at 30 °C for 50 min
with increasing concentrations of respective compound and with
0.7 nM [3H]8-OH-DPAT (for 5-HT1A receptor), [3H]SCH23390 (for
D1 dopamine receptors), or [3H]Spiperone (for dopamine D2
Compound 14 was prepared from 13 in 43.1% yield using a
similar procedure as preparation of compound 7a–e.
Mp > 220 °C; 1H NMR (300 MHz, CD3OD) d 8.32 (d, J = 10.2 Hz,
1H), 7.47 (m, 2H), 7.38 (m, 1H), 7.28 (d, J = 7.2 Hz, 2H), 6.56 (s,
1H), 6.48 (d, J = 9.6 Hz, 1H), 4.76 (t, J = 6.0 Hz, 1H), 3.76 (d,
J = 6.0 Hz, 2H), 3.49 (m, 3H), 3.22 (m, 1H); 13C NMR (75 MHz,
receptor) in a final volume of 200
50 mM Tris, 4 mM MgCl2, pH 7.4. Nonspecific binding was deter-
mined by parallel incubations with either 10 M WAY100635 for
lL binding buffer containing
DMSO-d6)
d 159.4, 142.8, 142.0, 141.4, 140.4, 138.8, 129.1,
128.4, 127.4, 126.5, 118.8, 117.9, 115.9, 48.7, 44.7, 44.4, 23.6;
EI-MS m/z: 307 (M+); HR-MS Calcd for C19H17NO3 (M+)
307.1208. Found: 307.1207.
l
5-HT1A, SCH23390 for D1 or Spiperone for D2 dopamine recep-
tors, respectively. The reaction was started by addition of mem-
branes (15 ng/tube) and stopped by rapid filtration through
Whatman GF/B glass fiber filter and subsequent washing with
cold buffer (50 mM Tris, 5 mM EDTA, pH 7.4) using a Brandel
24-well cell harvester. Scintillation cocktail was added and the
radioactivity was determined in a MicroBeta liquid scintillation
counter. The IC50 and Ki values were calculated by nonlinear
regression (PRISM, Graphpad, San Diego, CA) using a sigmoidal
function.
5.9. 6-Bromo-7,8-dimethoxy-3-methyl-1-m-tolyl-2,3,4,5-
tetrahydro-1H- benzo[d]azepine (16)
Compound 16 was prepared from compound 1518 in 51.5%
yield using
a
literature reported procedure.11 1H NMR
(300 MHz, CDCl3) d 7.26 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.98
(m, 2H), 6.24 (s, 1H), 4.34 (d, J = 8.1 Hz, 1H), 3.81 (s, 3H), 3.59

J. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 9425–9431
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Acknowledgments
This work was financially supported by grants from Chinese
National Science Foundation (30672517, to A.Z.), Shanghai Commis-
sion of Science and Technology (07pj14104, to A.Z. and X.Z.), and
grant from Ministry of Science and Technology (2007AA022163,
to X.Z.). Support from Chinese Academy of Sciences, and Shanghai
Institute of Materia Medica was also appreciated. We thank Profes-
sor John L. Neumeyer at Harvard Medical School for instructive
discussion during this work.
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Supplementary data
Supplementary data associated with this article can be found in
the online version: copies of 1H and 13C of the new compounds.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2008.09.049.
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