Structure-activity study of novel tricyclic benzazepine arginine vasopressin antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00388-3

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V_1a and V₂. Derivatives containing pyrrolo-tricy

Full text of DOI:10.1016/S0960-894X(03)00388-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2195–2198
Structure–Activity Study of Novel Tricyclic Benzazepine Arginine
Vasopressin Antagonists
Fuk-Wah Sum,a,* John Dusza,a Efren Delos Santos,a George Grosu,a Marvin Reich,a
a
Xumei Du,a J.Donald Albright, Peter Chan,b Joseph Coupet,b Xun Ru,b
Hossein Mazandaranib and Trina Saundersb
aChemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
bCardiovascular and Metabolic Diseases Research, Wyeth Research, Princeton, NJ 08543, USA
Received 7 November 2002; accepted 24 March 2003
Abstract—Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists.Several tricyclic
compounds showed potent antagonistic activity in rat AVP receptors V1a and V2.Derivatives containing pyrrolo-tricyclic amines,
13i–k, 30, and 31 also showed selectivity for the V2 receptor.
# 2003 Elsevier Science Ltd.All rights reserved.
Arginine vasopressin (AVP) is a cyclic nonapeptide
hormone released from the posterior pituitary in
response to either increased plasma osmolality, or
decreased blood volume and blood pressure.AVP binds
to three known receptor subtypes: vascular V1a, hor-
mone releasing V1b, and renal V2 receptors, and reg-
ulates osmotic water permeability of water channels in
the kidney through the V2 receptor.1À3 Antagonists of
the V2 receptor are potentially useful for treating dis-
eases characterized by excess renal reabsorption of free
water, such as congestive heart failure, liver cirrhosis,
nephrotic syndrome, and hyponatremia.4
We have selected eleven tricyclic amines (Fig.2 ) to
study the effect of various head-pieces on AVP antag-
onistic activity.5,6-Dihydro-phenanthridine ( 1a) was
prepared by reduction of the commercially available
6(5H)-phenanthridinone (Scheme 1).The 4-nitro-
benzoyl derivative of 1b was synthesized according to
Scheme 2.The acid chloride of 2-iodophenylacetic acid
was reacted with 2-iodoaniline to give amide 2, which
was reduced to amine 3 with borane-methyl sulfide.The
cyclization of 3 through aryl–aryl coupling to form 1b
proved to be problematic.However, the 4-nitrobenz-
amide 4 cyclized smoothly to 5 under copper catalyzed
coupling conditions.Compound 5 was used directly to
prepare the final product 13b through reduction of the
nitro group, followed by acylation of the resulting
amine with o-toluoyl chloride.The synthesis of 1h is
VPA-985 (Fig.1 ), discovered in our laboratories,5 is an
orally active AVP antagonist with selectivity for the V2
receptor.It is currently in clinical trials for the treat-
ment of congestive heart failure.During the course of
developing VPA-985, we have investigated a large
number of tricyclic benzazepine derivatives.Herein we
report the synthesis and structure–activity relationship
of a series of compounds containing different tricyclic
‘head-pieces’, as well as a series of 10,11-dihydro-5H-pyr-
rolo[2,1-c][1,4]benzdiazepine analogues with modifications
at the benzoylamino ‘tail-piece’.
*Corresponding author.Fax: +1-845-602-5561; e-mail: sum@wyeth.
com
Figure 1.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd.All rights reserved.
doi:10.1016/S0960-894X(03)00388-3

2196
F.-W. Sum et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2195–2198
Scheme 3. (a) Cu, K2CO3, neat, 200 ꢀC; (b) H2, 10% Pd/C, MeOH; (c)
xylene, reflux; (d) BH3–Me2S, THF, reflux.
Figure 2.
Scheme 1. (a) BH3–Me2S, THF, reflux.
Scheme 4. (a) POCl3, DMF; (b) H2, 10% Pd/C, MeOH; (c) ethyl oxalyl
chloride, BF3–Et2O, CH2Cl2; (d) ZnI2, NaCNBH3, 1,2-dichloroethane,
reflux; (e) SnCl2, EtOH, reflux; (f) BH3–Me2S, THF, reflux.
Similarly, 1-(4-nitrophenyl)-1H-pyrrole was first acy-
lated with ethyl oxalyl chloride to give compound 10,
which was selectively reduced to the ester 11 with zinc
iodide and sodium cyanoborohydride.Reduction of the
nitro group and cyclization to the lactam was accom-
plished by treatment with stannous chloride in refluxing
ethanol.Subsequent reduction with borane-methyl
sulfide led to the pyrrolobenzodiazepine 1j.
5,6-Dihydro-11H-dibenz[b,e]azepine
(1c),6
10,11-
dihydrodibenz[b,f][1,4]oxazepine (1f),7 10,11-dihydrodi-
benz[b,f][1,4]thiazepine (1g),7 and 10,11-dihydro-5H-
pyrrolo[2,1-c][1,4]-benzodiazepine (1k)8 were prepared
according to procedures reported in the literature.Com-
mercially available 5,6,11,12-tetrahydrodibenz[b,f]azo-
cine (1d) and 10,11-dihydro-5H-dibenz[b,f]azepine (1e)
were used directly.
Scheme 2. (a) SOCl2; (b) 2-iodoaniline, Et3N, CH2Cl2; (c) BH3–Me2S,
THF, reflux; (d) 4-nitrobenzoyl chloride, Et3N, CH2Cl2; (e) Cu, DMF,
reflux; (f) H2, 10% Pd/C, MeOH; (g) o-toluoyl chloride, Et3N,
CH2Cl2.
In order to study the structure–activity relationship of
various tricyclic derivatives, the o-toluoyl group was
chosen as the common tail-piece.These compounds
were prepared in a convergent manner as shown in
Scheme 5.Thus, the common acid chloride intermediate
12, prepared in three steps from methyl 4-aminobenzo-
ate, was treated with the aforementioned tricyclic
amines (except 1b) to give products 13a, c–k.The
antagonistic activities of these compounds for the rat
V1a and V2 receptors5c are summarized in Table 1.
shown in Scheme 3.A mixture of 1-bromo-2-nitro-
benzene and anthranilic acid was heated neat in the
presence of copper and potassium carbonate to give the
diarylamine 6.Hydrogenation of 6, and subsequent
cyclization of the resulting amine 7 gave the lactam 8,
which upon reduction with borane-methyl sulfide yiel-
ded the dibenzdiazepine 1h. Scheme 4 illustrates the
synthetic routes to amines 1i and 1j.Formylation of
1-(4-nitrophenyl)-1H-pyrrole, followed by hydrogena-
tion of the product 9 gave the pyrroloquinoxaline 1i.
To investigate the effect of modifications of the tail-
piece, we synthesized a series of analogues containing

F.-W. Sum et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2195–2198
2197
Table 2. Activity of derivatives containing 1k in V1a and V2 receptors
Compd
X
V1a IC50, mMa
V2 IC50, mMa
13k
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-Methyl
2-Trifluoromethyl
2-Methoxy
2-Methylthio
2-Ethoxy
2-Hydroxy
0.038
0.026
0.031
0.009
0.045
0.085
0.056
0.01
0.002
0.24
0.027
0.023
0.12
0.004
0.022
0.014
0.013
0.077
0.54
0.035
0.005
0.007
0.013
0.029
0.003
0.014
0.015
0.004
0.004
0.0015
0.0023
2-Fluoro
2-Chloro
2-Bromo
2,3-Dimethyl
2,3-Dichloro
2,4-Dichloro
2,5-Dichloro
2,6-Dichloro
2-Chloro-4-fluoro
2-Methyl-3-fluoro
2-Methyl-5-fluoro
Scheme 5. (a) o-Toluoyl chloride, Et3N, CH2Cl2; (b) 1 N NaOH,
MeOH; (c) SOCl2; (d) R-H, Et3N, CH2Cl2.
Table 1. Activity of tricyclic derivatives in V1a and V2 receptors
0.094
0.007
0.026
0.02
Compd
R-H
V1a IC50, mMa
V2 IC50, mMa
31
VPA-985
13a
13b
13c
13d
13e
13f
13g
13h
13i
1a
1b
1c
1d
1e
1f
1g
1h
1i
0.056
0.098
0.15
0.029
0.025
0.068
0.41
aBinding assays were determined by measuring the inhibition of 3H-AVP
binding to rat hepatic V1a receptors or rat kidney medullary V2 receptors.
60% (50 mM)
2.5
1.5
80% (50 mM)
0.86
1.7
0.40
0.86
0.042
0.066
0.033
0.004
Majority of these compounds exhibited aquaresis activity
in agreement their V2 antagonistic activity.
0.019
0.17
0.27
13j
13k
1j
1k
0.038
It is apparent from the data in Table 1 that the tricyclic
head-piece of the examples prepared has a substantial
effect on their antagonistic activity for the V1a and V2
receptors.A few trends are also notable.Within the
dibenz-tricyclic amine series of compounds (13a–13e)
the 6,7-dihydro-5H-dibenz[b,d]azepine derivative 13b
exhibited the best V2 activity as well as selectivity over
V1a.Azepine head-pieces containing another heteroa-
tom (examples 13f–13h) tend to diminish both activity
and selectivity.The pyrrolo-tricyclic compounds ( 13I–
13k) showed higher selectivity for the V2 receptor.
Compound 13k, with the 10,11-dihydro-5H-pyrrolo[2,1-
c][1,4]benzdiazepine head-piece 1k, also showed potent
V2 activity.
aBinding assays were determined by measuring the inhibition of 3H-
AVP binding to rat hepatic V1a receptors or rat kidney medullary V2
receptors.
the head-piece 1k and different substituted benzoyl
groups according to Scheme 6.Acylation of 1k with 4-
nitrobenzoyl chloride gave the amide 14, which was
reduced by either catalytic hydrogenation or stannous
chloride to the amine 15.The common intermediate 15
was then coupled with various aroyl chlorides to give
the final products.Examples of these analogues and
their V1a and V2 activities are listed in Table 2.
In vivo studies were conducted on a number of the
derivatives in Tables 1 and 2 using water loaded (30
mL/kg) Sprague–Dawley rats treated (ip) with AVP (0.4
mg/kg).The aquaretic effect of these compounds was
measured by the amount of urine collected after 4 h
compared with control, and results are shown in Table 3.
Substitutions on the phenyl ring of the benzoyl tail-
piece appear to influence selectivity for the V2 receptor,
Table 3. Aquaretic effect in normal Sprague–Dawley rats
Compd
Dose (ip)
(mg/kg)
No.of
rats
Urine volume
(mL/4 h)
Control (10%DMSO)
AVP control
6
6
2
6
2
2
2
2
7
2
2
2
2
8
2
2
2
2
2
12.1Æ1
2Æ0.2
13.5
13b
13c
13g
13h
13i
13j
13k
16
17
22
24
26
10
10
10
30
10
10
10
10
10
10
10
10
10
10
10
10
10
15.2Æ2.4
7.7
7.4
5.2
7
15.8Æ1
12.5
9.3
12.4
18.0
20.4Æ1
27
28
30
31
16.9
11.3
14.1
21.8
22
Scheme 6. (a) 4-Nitrobenzoyl chloride, Et3N, CH2Cl2; (b) H2, 10%
Pd/C, MeOH; or SnCl2, EtOH, reflux; (d) ArCOCl, Et3N, CH2Cl2.
VPA-985

2198
F.-W. Sum et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2195–2198
as data on examples containing the common head-piece
1k in Table 2 indicate.In general, a methyl group at the
2-position (13k, 30, and 31) enhances V2 over V1a selec-
tivity significantly.Surprisingly, a 2-hydroxy substitu-
tion (20) reverses the selectivity.Among other 2-
substituted analogues, the 2-chloro derivative showed
better V2 activity.However, most of them lost selectiv-
ity.The 2,4-dichloro compound 26 seems to be superior
to the other dichloro-substituted positional isomers.A
3-fold increase in V2 activity was achieved with the 5-
fluoro substituted compound 31 in comparison with
compound 13k, while V1a activity was relatively
unchanged.
bulski for their support, Drs.Tarek Mansour, and
Dennis Powell for proofreading and providing valuable
suggestions, and the Wyeth Discovery Analytical
Chemistry group for analytical and spectral determina-
tions.
References and Notes
1. Laszlo, F. A.; Laszlo, F., Jr.; De Wied, D. Pharmacol. Rev.
1991, 43, 73.
2.Thibonnier, M. Regul. Pep. 1992, 38, 1.
3. Laszlo, F. A.; Laszlo, F., Jr. Drug News Perspect. 1993, 6,
In summary, we have discovered a number of novel,
potent, as well as selective, AVP antagonists of the V2
receptor by incorporating tricyclic benzazepines as
head-pieces in our designed targets.Further structure–
activity study of a series of derivatives containing the
most promising head-piece 1k and modifications at the
tail-piece led to the discovery of compound 31, which
showed potent V2 receptor activity (IC50=1.5 nM) and
greater than 10-fold selectivity over the V1a receptor.
Results from this investigation provided potential lead
candidates in our effort to develop AVP antagonists for
the treatment of diseases associated with excess renal
reabsorption of free water.
591.
4.(a) Wong, L.L;.Verbalis, J.G.
Cardiovasc. Res. 2001, 51,
391. (b) Palm, C.; Reimann, D.; Gross, P. Cardiovasc. Res.
2001, 51, 403.(c) Paranjape, S.B;. Thibonnier, M. Exp. Opin.
Invest. Drugs 2001, 10, 825.(d) Trybulski, E.J. Ann. Rep.
Med. Chem. 2001, 36, 159.(e) Albright, J.D;. Chan, P.S.
Curr. Pharm. Des 1997, 3, 615.
5.(a) Matinez-Castelao, A. Curr. Opin. Invest. Drugs 2001, 2,
525. (b) Albright, J. D.; Delos Santos, E. G.; Dusza, J. P.;
Chan, P. S.; Coupet, J.; Ru, X.; Mazandarani, H. Bioorg.
Med. Chem. Lett. 2000, 10, 695.(c) Albright, J.D;. Reich,
M. F.; Delos Santos, E. G.; Dusza, J. P.; Sum, F. W.; Venka-
tesan, A. M.; Coupet, J.; Chan, P. S.; Ru, X.; Mazandarani,
H.; Bailey, T. J. Med. Chem. 1998, 41, 2442.
6. Werner, L. H.; Ricca, S.; Mochacsi, E.; Rossi, A.; Arya,
V.P. J. Med. Chem. 1965, 8, 74.
7. Wardrop, A. W. H.; Sainsbury, F. L.; Harrison, J. M.;
Inch, T.D. J. Chem. Soc., Perkins Trans. 1 1976, 1279.
8. Wright, W. B.; Greenblatt, E. N.; Day, I. P.; Quinones,
N.Q;. Hardy, R.A. J. Med. Chem. 1980, 23, 462.
Acknowledgements
We thank Dr.Charles Homcy for initiating this pro-
gram, Drs.Magid Abou-Gharbia, and Eugene Try-