(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2005.08.007

Synthesis and structure-activity relationships (SAR) of arginine vasopressin (AVP) receptor modulators are described. Potent and selective compounds are prepared when the amide linkage connecting rings A and B of VPA-985 is replaced with a bond, CO, -O-,

Full text of DOI:10.1016/j.bmcl.2005.08.007

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5003–5006
(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4]
benzodiazepin-10-yl)-methanone derivatives as vasopressin
receptor modulators
Aranapakam M. Venkatesan,a,* George T. Grosu,a Amedeo A. Failli,b Peter S. Chan,c
Joseph Coupet,c Trina Saunders,c Hussain Mazandaranic and Xun Ruc
aChemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA
bChemical and Screening Sciences, Wyeth Research, 567 Ridge Road, Princeton, NJ 08543-8000, USA
cCardiovascular and Metabolic Diseases, Wyeth Research, 567 Ridge Road, Princeton, NJ 08543-8000, USA
Received 23 June 2005; revised 1 August 2005; accepted 2 August 2005
Available online 8 September 2005
Abstract—Synthesis and structure–activity relationships (SAR) of arginine vasopressin (AVP) receptor modulators are described.
Potent and selective compounds are prepared when the amide linkage connecting rings A and B of VPA-985 is replaced with a bond,
C@O, –O–, –S–, or –SO2– bond.
Ó 2005 Elsevier Ltd. All rights reserved.
The cyclic peptide hormone, arginine vasopressin
(AVP), an anti-diuretic hormone released from the pos-
terior pituitary gland, plays an important role in water
balance in the body.1–4 This hormone is released in
response to increased plasma osmolality detected by
the brain osmoreceptor, decreased blood volume or de-
crease in blood pressure sensed by low-pressure volume
receptors and arterial baroreceptors. The hormone
exerts its action through well-defined receptor subtypes:
vascular V1a and renal epithelial V2 receptors. One of
the key roles of AVP is the control of salt (NaCl) bal-
ance. The blockade of V2 receptors may correct the fluid
retention in congestive heart failure, liver cirrhosis,
nephritic syndrome, CNS injuries, lung disease and
hyponatremia. Thus, antagonizing AVP action at the
V2 receptor level with an orally active, non-peptide
agent may be the treatment of choice for the above-
mentioned disease states.
V2 antagonist VPA-985 1 and closely related analogues,
such as 2a.7–11 In all these compounds, an amide bond
connected rings A and B (Fig. 1). We have shown in
the past4 that a compound such as 2b, where the rings
A and B are directly connected, exhibits excellent V2
agonist activity. The therapeutic utilities of vasopressin
V2 receptor agonists include diabetes insipidus, noctur-
nal enuresis, nocturia and urinary incontinence. Hence,
it is the objective of this paper to investigate the SAR
of compounds, where the amide linkage between these
two rings has been replaced with a bond, C@O, –O–,
–S–, or –SO2– bond.
Compounds 3a–3p (Table 1) required for the present
investigation were prepared, as indicated in Scheme 1.
The tricyclic 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzo-
diazepine 4 was synthesized, according to the literature
procedures.12,13 Derivatives 3a, 3f–g and 3i–3m were
prepared by reacting their respective acid chlorides with
4 in the presence of triethylamine in methylene chloride
solution (Scheme 1).14 The acetylene derivative, 3h, was
synthesized by reacting 7 with phenyl acetylene in the
presence of Pd(II)chloride in refluxing acetonitrile.
Intermediate 7 was used to prepare compounds 3b–3e
by a two-step process. Compound 7 was reacted with
bis(tributyl)tin, lithium chloride and tetrakis(triphenyl-
phosphine)palladium(0) in refluxing dioxane to yield
the stannyl derivative 8, which was coupled with the
In the past, several benzazepine derivatives have been
reported by Otsuka chemists as V1a and V2 receptor
AVP antagonists.5,6 As part of the efforts to develop
non-peptide vasopressin antagonists, we previously
reported on the design and synthesis of the selective
Keywords: Vasopressin receptor modulators.
*
Corresponding author. Tel.: +84 56 02 40 23; fax: +84 56 02 55 61;
e-mail: venkata@wyeth.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.007

5004
A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5003–5006
N
N
N
Ring A
N
N
N
O
O
O
O
O
N
Cl
N
H
N
N
N
Ring B
H
F
F
1- (VPA-985)
Figure 1. Previously reported AVP modulators.
2b- (VNA-932)
2a- (CL-385004)
Table 1. In vitro and in vivo data for compounds 3a–3p
1
R
N
N
O
R
Compound
R
R1
IC50 human nM (% inhibition)
Urine volumed (mL)
a
b
V1
V2
AVP treated control
5.0
37
3.5
7.8
5.5
5.9
NA
4
VPA-985
Phenyl
180
3
1.0
3a
3b
3c
3d
3e
3f
H
390
2000
96
2-Methylphenyl
2-Nitrophenyl
3,5-Difluorophenyl
4-CH3-phenyl
4-Allyloxyphenyl
4-Propyl phenyl
Phenyl-acetynyl-
-O-4-Methylphenyl
-S-Phenyl
H
88
64
85
2
H
H
2500
300
NAc
H
H
(9% at 10 lM)
12
3g
3h
3i
H
58
4.5
6.3
5.3
4
H
(35% at 1 lM)
280
(63% at 1 lM)
(50% at 1 lM)
(42% at 1 lM)
(32% at 1 lM)
NAc
H
3j
H
(47% at 1 lM)
(15% at 1 lM)
21
3k
3l
-S-4-Methylphenyl
-SO2-4-Methylphenyl
-CO-Phenyl
H
11
5.5
6
H
3m
3n
3o
3p
H
(82% at 10 lM)
(42% at 1 lM)
510
2-Thienyl
Phenyl
2-Thienyl
H
13
13
63
5
-CH2N(Me)2
-CH2N(Me)2
(78% at 10 lM)
15,000
3.5
3
a V1 receptor binding in human platelets.
b Binding to murine fibroblast LV2 cell line membranes transfected with the human V2 receptor; urine volume in water-loaded control ani-
mals = 13 mL/4 h.
c NA = examples 3f and 3l have only the rat data for V2 binding affinity and they show 63% and 51% inhibition at 1 lM concentration.
d Urine volume in AVP treated animals = 5 mL/4h.
appropriately substituted aryl bromides in the presence
of (PPh3)4Pd(0) in boiling toluene to yield 3b–3e. Simi-
larly, compound 3n was synthesized starting from the
iodo intermediate 7. Stille coupling of 7 with 2-stannyl
substituted thiophene yielded 3n in good yield. To
improve water solubility, compounds 3o and 3p were
prepared with an appended polar functionality.
Incorporation of –CH2N(CH3)2 functionality was
achieved by treating 3a and 3n with formaline and dim-
ethylamine in the presence of acetic acid at room
temperature.
inhibition of binding of 3H-AVP to isolated kidney
medullary V2 receptors. However, the possibility of
species differences with respect to the binding affinities
at the V1a receptors16 prompted us to consider binding
studies with human receptors. Thus, the newly synthe-
sized compounds were evaluated for inhibition of
binding to membrane preparations from a murine
fibroblast cell line (LV2) expressing human V2 receptors
and to V1a receptors from human platelet mem-
3
3
branes measuring the displacement of H-AVP or H-
1
[d(CH2)5 , Tyr(Me),2Arg8]-AVP by the test compound.
The in vitro binding affinities for a series of 10,11-dihy-
dro-10-[(biaryl and aryl-heteroaryl)carbonyl]-5H-pyr-
rolo[2,1-c][1,4]benzodiazepine derivatives 3a–3p are
shown in Table 1. VPA-985 was used as comparator.
It is interesting to note that, when the amide linkage
The initial in vitro radio ligand binding studies were car-
ried out with rat receptors. Binding affinities were deter-
mined by measuring the inhibition of (Phe-3,4,53H)
AVP binding to isolated rat hepatic V1a receptors or

A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5003–5006
5005
N
O
Cl
N
N
N
f
a
+
N
H
N
N
R
O
O
4
5 = R = Ph
5a = R = 4-n-propyl phenyl
6 = R = I
R
R
e
3a,3f-g,3i-3m
7 R = I
3o, 3p
N
d
b
N
O
N
N
N
O
N
O
3h
R
Sn(Bu)3
3n = R = 2-Thienyl
8
c
N
3b = R = 2-Methylphenyl
3c = R = 2-Nitrophenyl
3d = R = 3,5-Difluorophenyl
3e = R = 4- Methylphenyl
N
O
R
Scheme 1. Reagents and conditions: (a) CH2Cl2/Et3N; (b) 7/LiCl/Sn2 (n-Bu3)2/Pd(PPh3)4/dioxane/reflux; (c) arylbromide/Pd(PPh3)4/toluene/reflux;
(d) 7/2-stannyl derivatives of thiophene/Pd(PPh3)4/toluene/reflux; (e) 7/phenyl acetylene/PdCl2/CH3CN/reflux; (f) 3a or 3o/formaline/(CH3)2NH/H+/
THF/rt.
in VPA-985 is replaced with a direct C–C bond, it
appears as though the affinity for the human V2 receptor
decreases and the V1a human receptor affinity increases
compared to VPA-985. Thus, when compared to VPA-
985, the unsubstituted compound 3a exhibits very
potent affinity for V1a receptor and poor V2 affinity.
Among the newly synthesized molecules, introduction
of a methyl substituent at the 2 position of ring B, (com-
pound 3b) led to decrease in the affinity of both V1a and
V2 receptors. However, switching the methyl group to
the 4 position (compound 3e) restored the potency. Sim-
ilarly, a n-propyl substituent at the 4 position of ring B
(compound 3g) also showed good affinity for both V1a
and V2 receptors. When ring A is linked to ring B via
an acetylene (e.g., 3h), V1a and V2 affinities decrease
drastically. However, when connecting rings A and B
via an ether linkage (3i), both V1a and V2 affinities are
retained, albeit reduced. The presence of a thioether
linkage (3j and 3k), between ring A and ring B or
C@O (3m), leads to decreased affinity towards both
receptors. The fully oxidized sulfone derivative 3l exhib-
ited good V1a affinity. Replacement of ring B in 3a with
a heterocycle, such as 2-thienyl (3n), leads to retention of
affinity at both V1a and V2 receptors. Introduction of
basic groups, such as –CH2N(Me)2 (3o and 3p), leads
to a decrease in affinities for both V1a and V2 receptors,
when compared to their respective unsubstituted ana-
logues 3a and 3n.
In vivo studies were conducted in conscious AVP-treat-
ed (0.4 lg/kg, ip), water-loaded (30 mL/kg, po) rats. The
synthesized compounds 3a–3p were given orally at
10 mg/kg (mixed with starch and DMSO). The urine
volume was measured during the period of 4 h and com-
pared with AVP-treated controls,which is shown in
Table 1. Simultaneously, osmolality was analyzed.15 It
is evident from Table 1 that most of the compounds
reported here, when given orally, did not show diuretic
effect when compared to water-loaded control animals
and AVP-treated controls. In control animals, the urine
output was found to be 13 mL/4h and in the AVP-treat-
ed animals it was found to be 5 mL/4h. Among the new-
ly synthesized molecules, the unsubstituted derivative 3a
and other derivatives, such as 3f, 3j, 3o and 3p, exhibit a
slight anti-diuretic activity. Compound 3b in vitro is
about 20 times less active than compound 3c against
V2 receptor, yet slightly more active in vivo. Surprising-
ly, compound 3k, which exhibits a poor affinity for the
human V2 receptor, has the most diuretic effect among
the newly synthesized derivatives. It almost reversed
the effect of AVP on the water-loaded control. This
may be due to several factors, such as species differenc-
es16 or a higher blood level concentration of 3k,
although we have no data to put forward to support this
aspect. However, none of the other newly synthesized
compounds completely reversed the effect of AVP on
the water-loaded control (13 mL/4h).

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A. M. Venkatesan et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5003–5006
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As mentioned earlier, a direct linking of ring A and ring
B in VPA-985 through a C–C or a C–N bond can lead to
molecules, such as VNA-932 2b, which has been shown
to exhibit AVP-mimetic properties.17 To be consistent
with these latter findings, the compounds reported here
could potentially be partial agonists that cannot be dis-
tinguished from weak antagonists using the reported
in vivo protocol. Further work is in progress to fully elu-
cidate the structural requirements leading from antago-
nism to agonism, which will be reported separately.
6. Ohinishi, A.; Orita, Y.; Okahara, R.; Fujihara, R.; Inoue,
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Santos, E. G.; Chan, P. S.; Coupet, J.; Saunders, T.; Ru,
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In summary, this paper describes a series of compounds,
where ring A and ring B in VPA-985 have been replaced
by a bond, C@O, –O–, –S– or –SO2–. This modification
in VPA-985 gave derivatives 3a–3p with binding affinity
for the AVP V1a and V2 receptors.
10. Albright, J. D.; Reich, M. F.; Delos santos, E. G.; Dusza,
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Acknowledgments
11. Ashwell, M. A.; Bagli, J. F.; Caggiano, T. J.; Chan, P. S.;
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The authors thank Drs. Tarek S. Mansour for his
support and helpful suggestions, and J. D. Albright,
Semiramis Ayral-Kaloustian and Eugene Trybulski for
useful discussions. The authors thank the members of
the Wyeth Chemical Technologies group for analytical
and spectral determination.
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