Novel design of nonpeptide AVP V2 receptor agonists: Structural requirements for an agonist having 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a template

Article abstract of DOI:10.1021/jm000108p

The discovery of a series of nonpeptide arginine vasopressin V₂ receptor agonists is described. After identifying the aniline derivative 8 as our lead compound from the metabolites of compound 7 that showed antidiuretic activity by po administr

Full text of DOI:10.1021/jm000108p

4388
J . Med. Chem. 2000, 43, 4388-4397
Articles
Novel Design of Non p ep tid e AVP V2 Recep tor Agon ists: Str u ctu r a l
Requ ir em en ts for a n Agon ist Ha vin g
1-(4-Am in oben zoyl)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in e a s a Tem p la te
Kazumi Kondo,* Hidenori Ogawa, Tomoichi Shinohara, Muneaki Kurimura, Yoshihisa Tanada, Keizo Kan,
Hiroshi Yamashita, Shigeki Nakamura, Takahiro Hirano, Yoshitaka Yamamura, Toyoki Mori,
Michiaki Tominaga, and Akiko Itai†
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Company, 463-10 Kagasuno Kawauchi-cho,
Tokushima 771-0192, J apan, and Institute of Medicinal Molecular Design, 5-24-5 Hongo, Kadokawa Bldg 4F, Bunkyo-ku,
Tokyo 113-0033, J apan
Received March 6, 2000
The discovery of a series of nonpeptide arginine vasopressin V2 receptor agonists is described.
After identifying the aniline derivative 8 as our lead compound from the metabolites of
compound 7 that showed antidiuretic activity by po administration to Brattleboro rats,
improvements in the in vitro potency involving evaluations of the structural requirements for
agonist action and optimizing the structure of the benzoyl moiety have been intensively
undertaken. These studies led to compounds 16g, 19a , and 23b,h ,i that show potent agonist
activity for the V2 receptor.
In tr od u ction
tempts to discover some structurally diverse nonpep-
tides having an affinity for the AVP receptors, to
overcome this problem.
Arginine vasopressin (AVP) is a well-known hormone
that exerts its major actions through two well-defined
receptor subtypes in the periphery: the V1a and V2
receptors.1 The V1a receptor subtype exists mainly in
vascular smooth muscle cells, platelets, liver, adrenal,
and uterus, and the V2 receptor is present in the kidney.
Vasopressin-induced antidiuresis, mediated by renal
epithelial V2 receptors, helps to maintain normal plasma
osmolality, blood volume, and blood pressure. Another
subtype of the AVP receptor was found in the pituitary
as a V1b receptor that is involved in the corticotropic
response to stress through regulation of ACTH secretion
and the potentiating effect on the corticotropin-releasing
hormone (CRH). Although many attempts to develop a
V2 antagonist for treating diseases characterized by
excess renal reabsorption of free water have been
reported, because V2 antagonists may correct the fluid
retention and hyponatremia observed in congestive
heart failure, liver cirrhosis, and nephrotic syndrome,
marked species differences and inconsistencies have
been revealed between the in vivo and in vitro assay
systems as reported in the case of 1 (Figure 1).2 This
compound showed antagonist activity in an in vitro
study and in animal models including the rhesus
monkey but showed full antidiuretic response in hu-
mans. We assumed that such species differences origi-
nated from the structural resemblance of the peptide
derivatives to AVP itself; therefore, we initiated at-
After our reports of the nonpeptide V1a antagonist (2),3
some studies4 pointed out the possibility of species
differences with respect to the binding affinity even with
a nonpeptide ligand having a structure different from
that of AVP using human tissues (Ki rat liver ) 32 (
5.2 nM, human liver ) 14 000 nM).4g Though the same
issue for the peptide ligands was apparently found with
the nonpeptide, compound 3 was found to be an orally
active nonpeptide V2 antagonist as the result of our
continuous efforts5 and was able to demonstrate its
aquaretic effect in clinical tests.6
The definitive characterization of vasopressin recep-
tors and their function has become possible since the
successive cloning studies of the V1a, V2, and V1b
receptors.7 These receptors were confirmed to be a
superfamily of the G-protein-coupled receptors (GPCRs).
From our efforts to find more potent V2 receptor
antagonists, 4 (Tolvaptan) inhibited the [3H]AVP bind-
ing to human V2 receptors (Ki ) 0.43 ( 0.06 nM) more
potently than AVP (Ki ) 0.79 ( 0.08 nM) or 3 (Ki )
9.42 ( 0.90 nM). The antagonistic action of 4 was
confirmed by the inhibition of cAMP production induced
by AVP using the human receptor expressed HeLa cells8
and also by clinical tests.
Although the V2 agonist may be beneficial for the
treatment of central diabetes insipidus, urinary incon-
tinence, and nocturnal enuresis, no report was found
for agonists having a nonpeptide structure that may be
beneficial for oral bioavailability. In central diabetes
insipidus, excessive diuresis occurs due to lack of
* To whom correspondence should be addressed. Tel: 81 88
665 2126, ext. 2300. Fax: 81 88 665 6031. E-mail: k_kondo@
research.otsuka.co.jp.
† Institute of Medicinal Molecular Design.
10.1021/jm000108p CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/19/2000

Design of Nonpeptide AVP V2 Receptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4389
F igu r e 1. Structures of AVP and compounds 1-6.
po administration, we found that this phenoxyacetyl
moiety of 7 was labile and easily transformed into
aniline 8, because the resulting aniline 8 and a trace
amount of the parent compound were found in the blood
serum. Though both compounds 7 and 8 showed a
nanomolar magnitude of binding affinity to the human
V2 receptor (IC50 7 ) 0.95 nM, 8 ) 4.1 nM), compound
7 did not show accumulation of cAMP while compound
8 showed a small amount of cAMP accumulation (9%
at 10 µM). Compound 8 also showed an antidiuretic
effect by po administration (U.V. ) 3 mL, 1 mg/kg). As
we have described in the finding for the potent V2
receptor antagonist, the key to enhancing the binding
affinity and selectivity is the position and nature of the
functional groups at X and Y shown in Figure 2.8b After
optimizing and evaluating the functional groups at X
and Y, the requirement of an amino group on the phenyl
ring using structure-activity relationships (SARs) led
us to the discovery of novel nonpeptide V2 receptor
agonists. We also found an enhancement of agonist
activity by adding functional groups to the lead com-
pound 8, but a narrow structural allowance was found
for agonist activity on this series of compounds.
F igu r e 2. Preliminary design of AVP V2 receptor agonists.
vasopressin release from the pituitary. 1-Desamino-8-
D-arginine vasopressin (DDAVP), a peptide derivative
of AVP, and AVP itself are clinically used for the
treatment of such diseases. Recently, nonpeptide ago-
nists for the seven transmembraine G-protein-coupled
receptors have been reported in the angiotensin
system9a-h and the cholecystokinin system.9i,j We were
very interested to learn that two nonpeptide ligands
that differ by only a single methyl group but have
agonist (compound 5 Figure 1) and antagonist (com-
pound 6) properties in vivo were characterized on the
cloned angiotensin AT1 receptor. This may be the first
report that the additional functional group contributes
to producing the agonist action.
On the basis of the discovery of nonpeptide antago-
nists, we started to design a V2 agonist by monitoring
the accumulation of the cAMP production using human
receptor expressed HeLa cells. During the early stage
of our research to find the nonpeptide V2 receptor
antagonists, the phenoxyacetyl derivative 7 (Figure 2)
showed an antidiuretic effect using Brattleboro rats by
po administration (IC50 rat V1a ) 5.1 µM, V2 ) 0.038
µM; U.V. ) 0 mL, 1 mg/kg, po).10 As a result of the
pharmacokinetic study for this series of compounds by
Ch em istr y
The syntheses of compound 8 and 16a -j (Table 1) are
shown in Scheme 1. 2,3,4,5-Tetrahydro-1H-1-benz-
azepine (10) was obtained by the Wolff-Kishner reduc-
tion of the 5-oxo derivative 9. The 1-tosyl group was
easily removed by the reaction with Mg in methanol to
afford 11. After the condensation of benzazepine 11 or
12 with 2-chloro-4-nitrobenzoyl chloride (13a) or 2-meth-
yl-4-nitrobenzoyl chloride (13b), the nitro group of
14a-c was reduced with SnCl2‚2H2O to give the anilines
15a ,b and 8, respectively. Target compounds (16a -j)
were obtained by the alkylation of the aniline 15a ,b
with the corresponding alkyl iodides in the presence of
K2CO3 in DMF.
The synthesis of the heterocyclic ring-substituted
derivatives (19a ,b, 23a -i) is shown in Scheme 2. The

4390 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Kondo et al.
Sch em e 1a
a
Reagents: (a) hydrazine monohydrate, KOH, diethylene glycol; (b) Mg, MeOH; (c) pyridine, CH2Cl2; (d) SnCl2‚2H2O, EtOH; (e) R-I,
K2CO3, DMF.
Sch em e 2a
(18) in acetic acid. The other heterocyclic ring-substi-
tuted benzoic acids were obtained by nucleophilic sub-
stitution of 4-F by the heterocyclic rings followed by
hydrolysis of the ester groups. These benzoic acid
derivatives thus obtained were condensed with the
benzazepine derivatives 11 and 12 to afford the target
compounds 23a -i.
Resu lts a n d Discu ssion
The SARs of R1, R2, and R3 are shown in Table 1. The
introduction of R1 ) Cl and R2 ) CH3 (8) enhanced the
binding affinity compared with the unsubstituted com-
pound 17. As we reported with the finding of compound
4 (Tolvaptan), the binding affinity of derivatives having
R2 ) CH3 was identical with R2 ) Cl; therefore, we have
prepared the derivatives having R2 ) Cl by the com-
mercial availability of the benzoyl chloride (13a ). We
were fortunate that only weak agonist activity of 8 and
16a was observed as the accumulation of cAMP produc-
tion, while unsubstituted compound 17 showed no cAMP
accumulation. Agonist activity was enhanced when R4
) CH3 (16b), but the binding affinity was not affected.
The diethylamino moiety (16c) or the introduction of a
Cl group on R1 (16d ) did not enhance agonist activity.
The monosubstituted amino derivatives are shown in
16e-j. In this series of compounds, the n-propylamino
derivative (16g) show the highest agonist activity. The
ethylamino (16e), n-butylamino (16h ), and n-pentyl-
amino (16i) derivatives showed poor agonist activity
compared with 16g.
Molecular modeling was carried out to analyze the
structural requirements of the amino moiety (P-1 region,
Figure 3).12 In comparison with the structures of
16b,c,g, the P-1 region must be occupied with lipophilic
substituents for the agonist activity. However, the steric
requirements were rigorous at P-1, because the chain
length and the size of the substituent were limited for
the potency of agonist activity. Therefore, we designed
a
Reagents: (a) AcOH; (b) R6-H, K2CO3, NMP; (c) NaOH, MeOH;
(d) (i) SOCl2, NMP, CH2Cl2, (ii) pyridine, CH2Cl2.
pyrrole derivatives 19a ,b were easily obtained from the
anilines 17 and 15a according to the Clauson-Kaas
method11 by heating with 2,5-dimethoxytetrahydrofuran

Design of Nonpeptide AVP V2 Receptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4391
Ta ble 1. Binding Affinity and Percentage of Maximal cAMP
Accumulation for Aniline Derivatives
F igu r e 3. Schematic representations for P-1 regions shown
as 3D models. Liquorice models are drawn using QUANTA97.
very happy to learn that the 3-methyl derivative 23i
possessed good affinity for the V2 receptor and had
potent agonist activity, as we had expected using
molecular modeling.
a
Inhibition of [3H]AVP binding to human V2 receptor coded
HeLa cells. IC50 values are the concentration of compound which
inhibits [3H]AVP binding by 50%. All assays were performed in
b
duplicate. CI denotes confidence interval. Percentage of maximal
Figure 4 shows the concentration-dependent percent-
age of maximal cAMP accumulation for 16g, 19a , and
23b,i. 19a was shown to have high agonist activity at a
concentration of 10-5 M. Other compounds seemed to
be partial agonists. 23b did not reach a maximum
response at higher concentrations, but the binding
affinity of 23b is 9 nM (IC50). There are also some gaps
between the binding affinities (IC50) and agonist activi-
ties at a concentration of 10-6 M for the other com-
pounds, but the cAMP accumulation was observed at a
low concentration when the compound showed high
binding affinity like 23i.
AVP V2-receptor mediated cAMP accumulation of
nonpeptide compound 23b was confirmed by treating
with V2 receptor antagonist 3 (Figure 5), because the
dose-response curve for cAMP accumulation of 23b was
shifted to the right by treating with the V2 antagonist.
And compound 23b was not confirmed as a partial
agonist by the interaction study with AVP (1 nM),
because only a weak suppression was observed to the
maximal cAMP accumulation. The antidiuretic effect of
compound 23b was also confirmed by po administration
using Brattleboro rats (U.V. ) 1.3 mL, 1 mg/kg),
although the binding affinity of 23b for the rat V2
receptor was less potent than for the human receptor
(IC50 rat V2 ) 0.15 µM).
cAMP accumulation (PMA) at a concentration of 10-6 M. Values
are means (%) ( SEM. c Reported in ref 5b.
the pyrrolidinyl derivative 23b to fill the P-1 region.
Also, 23i was designed by the superimposition of 16g
and 23b in order to show a more potent agonist ac-
tivity.
Some heterocycle-substituted derivatives are shown
in Table 2. As expected, 23b showed potent agonist
activity having the same order of binding affinity as
16b. The substituent effects of the Cl atom at R1 and
R5 are clearly understood by 23a -d . The presence of
the Cl atom at R1 or the absence of the Cl atom at R5 is
obstructive for agonist activity. Interestingly, the bind-
ing affinity was strongly enhanced by introducing a Cl
atom at R5. This enhancement seems specific to the
human receptor, because we have never observed this
effect in the rat V2 receptor in SAR of antagonists.5,8
Six-membered rings at R6 lower agonist activities more
than the five-membered rings. More potent agonist
activity was seen when a pyrrole ring was substituted
at R6 (19a ) instead of pyrrolidine (23a ), though the
binding affinity was not satisfactory. Although the
introduction of a Cl atom at R5 (19b) enhances binding
affinity, the accumulation of cAMP was moderate when
compared with 19a . The pyrazole derivative 23g showed
similar activities to 19b, and the introduction of a
3-methyl group (23h ) enhanced the activity. We were
The structural requirements responsible for binding
affinity to the V2 receptor and agonist activity are

4392 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Kondo et al.
Ta ble 2. Binding Affinity and Percentage of Maximal cAMP
Accumulation of Heterocyclic Derivatives
F igu r e 5. cAMP accumulation in response to nonpeptide
compounds (23b) treated alone or with AVP (1 nM) or V2
antagonist 3 (1 µM) in human V2 receptor transfected HeLa
cells. The cAMP accumulation is expressed as percentage with
standard error of the maximal response obtained by stimula-
tion with AVP (1 nM).
ties in the case of the nonpeptide angiotensin AT1
ligands.9a-h A very strict limitation was similarly found
for the presence of agonist action using our ligands for
the V2 receptor in the P-1 region. We also found that
the intensities of agonist action sharply fluctuated due
to the difference of a single methylene group as shown
in the case of 16g,h or 23b,e. These phenomena were
easily understood by hypothesizing the presence of an
activation cavity in the P-1 region. When this cavity is
satisfied with a ligand, the maximam response of
agonist action may be expected. The size of this cavity
may be easily estimated using the superimposition of
agonists shown in Figure 3.
We believe that our evaluation of the structural
requirements for the P-1, P-2, and P-3 regions may be
useful for understanding the signal transduction mech-
anisms inside the receptor.
a,b
See corresponding footnotes in Table 1.
Exp er im en ta l Section
Melting points were determined using a Yanagimoto micro
point apparatus and are uncorrected. 1H NMR spectra were
recorded on Bruker AC-200 (200 MHz) or DPX-300 (300 MHz)
spectrometers using tetramethylsilane (TMS) or 3-(trimeth-
ylsilyl)propionic acid-d5 (TSP) as the internal standard. Some
of the integral values and peaks were not well determined due
to the broadening of the peaks by the slow exchange of
rotamers. Elemental analyses were determined with a Yanaco
MT-5 CHN recorder. Mass spectra were measured on a Varian
MAT-312 instrument. All compounds were routinely checked
by TLC on Merck silica gel 60 F254 precoated plates. Chroma-
tography refers to flash chromatography using a E. Merck
Kieselgel 60, 230-400 mesh silica gel. All materials were
commercially available unless otherwise noted.
7-Ch lor o-1-tolu en esu lfon yl-1,2,3,4-tetr ah ydr o-1H-1-ben z-
a zep in e (10). A mixture of ketone 9 (50 g, 0.143 mol),
hydrazine monohydrate (29 mL, 0.60 mol) and KOH (37.8 g,
0.95 mol) in diethylene glycol (500 mL) was heated at reflux
for 6 h. After cooling, the reaction mixture was poured into
ice-water and the pH was adjusted to 7 by adding 1 N HCl,
then extracted with AcOEt. The organic layers were separated,
washed with water, dried over MgSO4, and concentrated under
reduced pressure. The resulting precipitates were crystallized
with Et2O to give 10 (44.6 g, 93%) as a white powder: 1H NMR
(200 MHz, CDCl3) δ 1.43-1.91 (4H, m), 2.22-2.47 (2H, m),
2.42 (3H, s), 3.41-3.93 (2H, m), 7.05-7.35 (5H, m), 7.52-7.67
(2H, m).
F igu r e 4. cAMP accumulation in response to nonpeptide
compounds at the given concentration expressed as percent
with standard error of the response obtained by stimulation
with AVP (1 nM).
summarized in Figure 6. The steric size in the P-1 region
is rigorously limited for revealing agonist activity. The
P-2 region is important for enhancing binding affinity
for the V2 receptor. A substituent in the P-3 region
lowers agonist activity.
Con clu sion
The difference of only a single methyl group was
shown to distinguish the agonist or antagonistic proper-
7-Ch lor o-1,2,3,4-tetr a h yd r o-1H-1-ben za zep in e (11). To
a solution of tosylate 10 (30 g, mmol) in MeOH (300 mL) was

Design of Nonpeptide AVP V2 Receptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4393
F igu r e 6. Stereo 3D plot of 23i. Solvent-accessible surface areas of P-1, P-2, and P-3 regions are shown as dotted spheres.
slowly added Mg (7.2 g, mmol) to maintain a gentle reflux and
H2 evolution. After stirring for 4 h at ambient temperature,
the mixture was concentrated under reduced pressure. The
resulting precipitates were dispersed with CH2Cl2, then dilute
aqueous NaOH was slowly added to dissolve the precipitates
with ice cooling. The organic layer was separated, washed with
water, dried over MgSO4, and concentrated to afford 11 (11.1
g, quant.) as a pale yellow oil: 1H NMR (200 MHz, CDCl3) δ
1.47-1.93 (4H, m), 2.62-4.03 (5H, m), 6.63 (1H, d, J ) 8.3
Hz), 6.97 (1H, dd, J ) 8.3, 2.4 Hz), 7.07 (1H, d, J ) 2.4 Hz).
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
n itr oben za m id e (14a ). To a mixture of 12 (5 g, 34 mmol),
pyridine (13.7 mL, 170 mmol) in CH2Cl2 (500 mL) was added
dropwise a solution of 2-chloro-4-nitrobenzoyl chloride (13a ;
9 g, 40.8 mmol) in CH2Cl2 (10 mL) at 0-5 °C. After stirring
for 1 h, the mixture was poured into water, and extracted with
CH2Cl2. The organic layers were separated, washed with dilute
HCl, water, dried over Na2CO3 and concentrated. The residue
was purified by silica gel column chromatography (n-hexane:
AcOEt, 5:1), and crystallized with i-Pr2O to give 14a (7.72 g,
69%) as a white powder: mp 114-115 °C; 1H NMR (300 MHz,
CDCl3) δ 1.38-2.21 (4H, m), 2.83-3.72 (3.1H, m), 4.82-4.95
(0.9H, m), 6.83-7.43 (5.2H, m), 7.86-7.94 (0.9H, m), 8.08-
8.18 (0.9H, m).
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-2-
ch lor o-4-n itr oben za m id e (14b). Using the same procedure
as 14a , 14b (7.69 g, 77%) was obtained as a white powder from
11 (5 g, 27.5 mmol): mp 129-130 °C; 1H NMR (300 MHz,
CDCl3) δ 1.33-2.28 (4H, m), 2.58-3.63 (3.1H, m), 4.78-4.98
(0.9H, m), 6.75-7.36 (4.2H, m), 7.93 (0.9H, d, J ) 7.7 Hz),
8.16 (0.9H, s).
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-2-
m eth yl-4-n itr oben za m id e (14c). Using the same procedure
as 14a , 14c (1.73 g, 91%) was obtained as a white powder from
11 (1 g, 5.5 mmol) and 2-methyl-4-nitrobenzoyl chloride (13b;
1.2 g, 6.6 mmol):8b 1H NMR (300 MHz, CDCl3) δ 1.38-2.28
(4H, m), 2.53, 2.59 (total 3H, each s), 2.63-3.55 (3.1H, m),
4.33-5.06 (0.9H, m), 6.55 (1H, d, J ) 8.3 Hz), 6.85 (1H, dd, J
) 8.3, 2.4 Hz), 6.93 (0.9H, d, J ) 8.4 Hz), 7.17 (1H, d, J ) 2.4
Hz), 7.49-7.62 (0.1H, m), 7.77 (0.9H, dd, J ) 8.4, 2.2 Hz), 8.00
(0.9H, d, J ) 2.2 Hz), 8.07-8.25 (0.2H, m).
2.65-4.08 (5.2H, m), 4.83-5.03 (0.8H, m), 6.23 (0.8H, dd, J )
8.3, 2.2 Hz), 6.54 (0.8H, d, J ) 2.2 Hz), 6.56-7.43 (5.4H, m).
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-4-
a m in o-2-ch lor oben za m id e (15b). Using the same procedure
as 15a , 15b (5.3 g, 84%) was obtained as a white powder from
14b (7.69 g, 21.1 mmol): mp 196-198 °C; 1H NMR (300 MHz,
CDCl3) δ 1.33-2.17 (4H, m), 2.45-4.02 (5.15H, m), 4.79-4.98
(0.85H, m), 6.27 (0.85H, dd, J ) 8.3, 2.2 Hz), 6.54 (0.85H, d, J
) 2.2 Hz), 6.68-6.85 (1.1H, m), 6.81 (0.85H, dd, J ) 8.4, 2.3
Hz), 7.12 (0.85H, d, J ) 2.3 Hz, 7.15-7.33 (0.65H, m).
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-4-
a m in o-2-m eth ylben za m id e (8). Using the same procedure
as 15a , 8 (1.52 g, 97%) was obtained as a white powder from
1
14c (1.71 g, 5.0 mmol): mp 199-200 °C; H NMR (300 MHz,
CDCl3) δ 1.30-2.18 (4H, m), 2.34 (3H, s), 2.45-3.93 (5.1H, m),
4.75-5.13 (0.9H, m), 6.07-6.23 (0.9H, m), 6.33-6.67 (3.1H,
m), 6.77-6.93 (1H, m), 7.06-7.27 (1H, m). Anal. (C18H19ClN2O)
C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N-m eth yla m in o)ben za m id e (14a ) a n d (1,2,3,4-Tetr a h y-
dro-1H-1-benzazepin-1-yl)-2-chloro-4-(N,N-dimethylamino)-
ben za m id e (16b). A mixture of 15a (1 g, 3.3 mmol), MeI (0.41
mL, 6.6 mmol), K2CO3 (0.68 g, 5 mmol) in DMF (50 mL) was
heated at 70 °C for 1 day. The reaction mixture was poured
into water, extracted with AcOEt-toluene, washed three times
with water, dried over Na2CO3 and concentrated. The resulting
precipitates were purified by silica gel column chromatography
(n-hexane:AcOEt, 4:1) followed by recrystallization from
MeOH-CH2Cl2 to give 16a (TLC Rf ca. 0.3, n-hexane:AcOEt
2:1, 0.2 g, 19%) as a white powder: mp 203-204 °C; 1H NMR
(300 MHz, CDCl3) δ 1.32-2.18 (4H, m), 2.61-4.12 (7.15H, m),
4.83-5.03 (0.85H, m), 6.14 (0.85H, dd, J ) 8.4, 2.3 Hz), 6.43
(0.85H, d, J ) 2.3 Hz), 6.48-6.65 (0.3H, m), 6.70 (0.85H, d, J
) 8.4 Hz), 6.82-7.43 (4.15H, m). Anal. (C18H19N2OCl) C, H,
N. 16b (TLC Rf ca. 0.7, n-hexane:AcOEt 2:1, 0.55 g, 51%) as
colorless prisms: mp 173-174 °C; 1H NMR (300 MHz, CDCl3)
δ 1.32-2.26 (4H, m), 2.52-3.87 (9.15H, m), 4.83-5.05 (0.85H,
m), 6.24 (0.85H, dd, J ) 8.7, 2.5 Hz), 6.51 (0.85H, d, J ) 2.5
Hz), 6.59-6.83 (1.1H, m), 6.85-7.44 (4.2H, m). Anal. (C19H21N2-
OCl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N,N-dieth ylam in o)ben zam ide (16c) an d (1,2,3,4-Tetr ah y-
dr o-1H-1-ben zazepin -1-yl)-2-ch lor o-4-(N-eth ylam in o)ben z-
a m id e (16e).Usingthe same procedure as 16b, the diethylamino
derivative (16c, TLC Rf ca. 0.7, n-hexane:AcOEt, 2:1, 0.3 g,
26%) was obtained as colorless prisms from 15a (1 g, 3.3 mmol)
using EtI (0.8 mL, 10 mmol) instead of MeI in N-methyl-2-
pyrrolidone (NMP): mp 162-163.5 °C; 1H NMR (200 MHz,
CDCl3) δ 0.88-2.24 (0.3H, m), 2.52-3.55 (7.2H, m), 4.80-5.13
(0.8H, m), 6.20 (0.8H, dd, J ) 8.7, 2.5 Hz), 6.30-7.44 (6.2H,
m). Anal. (C21H25N2OCl) C, H, N. Monoethylamino derivative
16e (TLC Rf ca. 0.4, n-hexane:AcOEt, 2:1, 0.55 g, 52%) was
(1,2,3,4-Tet r a h yd r o-1H-1-b en za zep in -1-yl)-4-a m in o-2-
ch lor oben za m id e (15a ). A mixture of 14a (7.72 g, 23.3 mmol)
and SnCl2‚2H2O (26.3 g, 117 mmol) in EtOH (200 mL) was
heated under reflux for 3 h. After cooling to ambient temper-
ature, the mixture was concentrated under reduced pressure.
The residue thus obtained was dispersed in CH2Cl2 and
aqueous 6 N NaOH was slowly added to dissolve some
precipitated materials. After the extraction with CH2Cl2, the
organic layers were separated, washed with water, dried over
Na2CO3, and concentrated. The resulting crystals were washed
with Et2O to yield 15a (6.7 g, 86%) as a white powder: mp
187-189 °C; 1H NMR (300 MHz, CDCl3) δ 1.32-2.28 (4H, m),
1
obtained as colorless prisms: mp 180-182 °C; H NMR (200

4394 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Kondo et al.
MHz, CDCl3) δ 1.17, 1.27 (total 3H, each t, J ) 7.2 Hz), 1.33-
2.23 (4H, m), 2.55-4.45 (6.2H, m), 4.83-5.04 (0.8H, m), 6.14
(0.8H, dd, J ) 8.4, 2.3 Hz), 6.23-7.43 (6.2H, m). Anal.
(C19H21N2OCl‚0.2H2O) C, H, N.
cedure as 16a , the n-pentylamino derivative 16i (TLC Rf ca.
0.4, n-hexane:AcOEt, 2:1, 0.6 g, 49%) was obtained as a white
powder from 15a (1 g, 3.3 mmol) using n-butyl iodide instead
of MeI: mp 124-125 °C; 1H NMR (300 MHz, CDCl3) δ 0.78-
1.00 (3H, m), 1.21-2.27 (0.3H, m), 2.62-4.06 (6.15H, m), 4.82-
5.08 (0.85H, m), 6.13 (0.85H, dd, J ) 8.4, 2.3 Hz), 6.42 (0.85H,
d, J ) 2.3 Hz), 6.48-6.73 (1.15H, m), 6.86-7.42 (4.15H, m).
Anal. (C22H27N2OCl) C, H, N.
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-2-
ch lor o-4-(N,N-d im eth yla m in o)ben za m id e (16d ). Using the
same procedure as 16b, the dimethylamino derivative 16d
(TLC Rf ca. 0.7, n-hexane:AcOEt, 2:1, 0.35 g, 32%) was
obtained as a white powder from 15b (1 g, 3 mmol): mp 172-
173 °C; 1H NMR (300 MHz, CDCl3) δ 1.30-2.18 (4H, m), 2.43-
3.83 (9.15H, m), 4.80-5.03 (0.85H, m), 6.28 (0.85H, dd,
J ) 8.6, 2.4 Hz), 6.51 (0.85 H, d, J ) 2.4 Hz), 6.56-7.43 (4.3
H, m). Anal. (C19H20N2OCl2) C, H, N. (7-Chloro-1,2,3,4-tetra-
hydro-1H-1-benzazepin-1-yl)-2-chloro-4-(N-methylamino)benz-
amide (TCL Rf ca. 0.4, n-hexane:AcOEt, 2:1, 0.21 g, 20%) was
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N-a llyla m in o)ben za m id e (16j). Using the same procedure
as 16a , the n-allylamino derivative 16j (TLC Rf ca. 0.4,
n-hexane:AcOEt, 2:1, 0.49 g, 62%) was obtained as a white
powder from 15a (0.7 g, 2.3 mmol) using the allyl bromide
1
instead of MeI: mp 130-133 °C; H NMR (300 MHz, CDCl3)
δ 1.34-2.28 (4H, m), 2.60-4.22 (6.15H, m), 4.82-5.05 (0.85H,
m), 5.05-5.39 (2H, m), 5.63-6.00 (1H, m), 6.16 (0.85H, dd, J
) 8.4, 2.2 Hz), 6.45 (0.85H, d, J ) 2.2 Hz), 6.52-6.59 (0.15H,
m), 6.60-6.75 (1H, m), 6.84-6.97 (1.7H, m), 7.02 (0.85H, dt,
J ) 1.7, 7.1 Hz), 7.12 (0.85H, d, J ) 7.2 Hz), 7.16-7.33 (0.6H,
m), 7.34-7.45 (0.15H, m). Anal. (C20H21N2OCl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-4-(p yr r ol-1-
yl)ben za m id e (19a ). A mixture of 17 (2 g, 5.5 mmol) and 2,5-
dimethoxytetrahydrofuran (18) (1.02 mL, 7.9 mmol) in AcOH
(10 mL) was heated at reflux for 15 min. After the reaction
was completed, the mixture was concentrated under reduced
pressure. The residue was dissolved in AcOEt, washed with
dilute aqueous NaOH, water, dried over Na2CO3, and concen-
trated. The residue was purified by silica gel column chroma-
tography (n-hexane:AcOEt 4:1) and recrystallized with AcOEt:
n-hexane to give 19a (1.2 g, 50%) as colorless columns: mp
159-160 °C; 1H NMR (300 MHz, CDCl3) δ 1.85-2.23 (3H, m),
2.67-3.18 (3H, m), 4.94-5.12 (1H, m), 6.27-6.33 (2H, m), 6.66
(1H, d, J ) 8.0 Hz), 6.88-7.28 (9H, m). Anal. (C21H20N2O) C,
H, N.
1
obtained as a white powder: mp 150-151 °C; H NMR (300
MHz, CDCl3) δ 1.29-2.18 (4H, m), 2.47-4.13 (7.1H, m), 4.80-
5.03 (0.9H, m), 6.18 (0.9H, dd, J ) 8.4, 2.0 Hz), 6.43 (0.9H, d,
J ) 2.0 Hz), 6.47-6.97 (2.9H, m), 7.05-7.37 (1.3H, m).
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-2-
ch lor o-4-(N-eth yla m in o)ben za m id e (16f). Using the same
procedure as 16a , the ethylamino derivative 16f (TLC Rf ca.
0.4, n-hexane:AcOEt, 2:1, 0.77 g, 74%) was obtained as
colorless prisms from 15b (1 g, 2.88 mmol) using EtI (0.7 mL,
8.6 mmol) instead of MeI: mp 160-162 °C; 1H NMR (300 MHz,
CDCl3) δ 1.20, 1.28 (total 3H, each t, J ) 7.1 Hz), 1.33-2.18
(4H, m), 2.60-4.03 (6.15H, m), 4.82-5.03 (0.85H, m), 6.18
(0.85H, dd, J ) 8.4, 2.2 Hz), 6.43 (0.85H, d, J ) 2.2 Hz), 6.56-
6.63 (0.3H, m), 6.69 (0.85H, d, J ) 8.4 Hz), 6.81 (0.85H, d, J
) 8.4 Hz), 6.89 (0.85H, dd, J ) 8.4, 2.3 Hz), 7.12 (0.85H, d, J
) 2.3 Hz), 7.15-7.36 (0.6H, m). Anal. (C19H20N2OCl2) C, H,
N. Diethylamino derivative (TLC Rf ca. 0.7, n-hexane:AcOEt,
2:1, 0.12 g, 10%) was obtained as a white powder: 1H NMR
(300 MHz, CDCl3) δ 0.97-2.23 (10H, m), 2.53-3.78 (7.15H,
m), 4.83-5.07 (0.85H, m), 6.23 (0.85H, dd, J ) 8.7, 2.4 Hz)
6.47 (0.85H, d, J ) 2.4 Hz), 6.53-6.75 (1.15H, m), 6.82 (0.85H,
d, J ) 8.4 Hz), 6.90 (0.85H, dd, J ) 8.4, 2.3 Hz), 7.06-7.38
(1.45H, m).
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(p yr r ol-1-yl)ben za m id e (19b). Using the same procedure as
19a , 19b (0.69 g, 84%) was obtained as a white powder from
1
15a (0.7 g, 2.3 mmol): mp 155-156 °C; H NMR (200 MHz,
CDCl3) δ 1.31-2.25 (4H, m), 2.67-3.73 (3.1H, m), 4.83-5.02
(0.9H, m), 6.21-6.43 (2H, m), 6.83-7.57 (9H, m). Anal.
(C21H19N2OCl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N-n -p r op yla m in o)ben za m id e (16g). Using the same pro-
cedure as 16a , the n-propylamino derivative 16g (TLC Rf ca.
0.4, n-hexane:AcOEt, 2:1, 0.9 g, 80%) was obtained as a white
powder from 15a (1 g, 3.3 mmol) using n-propyl iodide instead
2-Ch lor o-4-(p yr r olid in -1-yl)ben zoic Acid Meth yl Ester
(21b). A mixture of 2-chloro-4-fluorobenzoic acid methyl ester
(20) (2 g, 10.6 mmol), pyrrolidine (0.91 g, 12.8 mmol),and K2-
CO3 (2.9 g, 21 mmol) in N-methyl-2-pyrrolidone (10 mL) was
heated at 120 °C for 5 h. After cooling to ambient temperature,
the mixture was poured into water, extracted with AcOEt,
washed with water, dried over MgSO4, and concentrated. The
resulting precipitates were washed with Et2O to give 21b (1.9
g, 76%) as yellow prisms: 1H NMR (200 MHz, CDCl3) δ 1.90-
2.16 (4H, m), 3.21-3.45 (4H, m), 3.85 (3H, s), 6.38 (1H, dd, J )
8.9, 2.5 Hz), 6.52 (1H, d, J ) 2.5 Hz), 7.83 (1H, d, J ) 8.9 Hz).
2-Ch lor o-4-(p ip er id in -1-yl)ben zoic Acid Meth yl Ester
(21e). Using the same procedure as 21b, 21e (1.3 g, 88%) was
obtained as a white powder from 20 (1.1 g, 5.8 mmol) using
piperidine instead of pyrrolidine: 1H NMR (200 MHz, CDCl3)
δ 1.54-1.80 (6H, m), 3.20-3.41 (4H, m), 3.86 (3H, s), 6.71 (1H,
dd, J ) 8.9, 2.6 Hz), 6.84 (1H, d, J ) 2.6 Hz), 7.82 (1H, d, J )
8.9 Hz).
2-Ch lor o-4-(m or p h olin -4-yl)ben zoic Acid Meth yl Ester
(21f). Using the same procedure as 21b, 21f (6.6 g, 78%) was
obtained as colorless needles from 20 (6.2 g, 32.9 mmol) using
morpholine instead of pyrrolidine: 1H NMR (200 MHz, CDCl3)
δ 3.19-3.38 (4H, m), 3.77-3.97 (4H, m), 3.87 (3H, s), 6.73 (1H,
dd, J ) 8.9, 2.6 Hz), 6.86 (1H, d, J ) 2.6 Hz), 7.86 (1H, d, J )
8.9 Hz).
2-Ch lor o-4-(p yr a zol-1-yl)ben zoic Acid Meth yl Ester
(21g). Using the same procedure as 21b, 21g (16 g, 85%) was
obtained as a white powder from 20 (15 g, 79.5 mmol) using
pyrazole instead of pyrrolidine: 1H NMR (200 MHz, CDCl3) δ
3.95 (3H, s), 6.48-6.58 (1H, m), 7.66 (1H, dd, J ) 8.6, 2.2 Hz),
7.73-7.79 (1H, m), 7.93-8.03 (2H, m).
1
of MeI: mp 139-141 °C; H NMR (300 MHz, CDCl3) δ 0.93,
1.01 (total 3H, each t, J ) 7.4 Hz), 1.32-2.20 (6H, m), 3.66-
4.08 (6.15H, m), 4.85-5.03 (0.85H, m), 6.14 (0.85H, dd, J )
8.4, 2.3 Hz), 6.43 (0.85H, d, J ) 2.3 Hz), 6.45-7.44 (5.3H, m).
Anal. (C20H23N2OCl) C, H, N. (1,2,3,4-Tetrahydro-1H-1-benz-
azepin-1-yl)-2-chloro-4-(N,N-di-n-propylamino)benzamide (TLC
Rf ca. 0.7, n-hexane:AcOEt, 2:1, 0.1 g, 8%) was obtained as a
white powder: 1H NMR (300 MHz, CDCl3) δ 0.86, 0.95 (total
6H, each t, J ) 7.4 Hz), 1.33-2.21 (8H, m), 2.48-3.77 (7.2H,
m), 4.85-5.06 (0.8H, m), 6.16 (0.8H, dd, J ) 8.7, 2.4 Hz), 6.24
(0.8H, d, J ) 2.4 Hz), 6.48-6.75 (1.2H, m), 6.84-7.43 (4.2H,
m).
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N-n -bu tyla m in o)ben za m id e (16h ). Using the same proce-
dure as 16a , the n-butylamino derivative 16h (TLC Rf ca. 0.4,
n-hexane:AcOEt, 2:1, 0.8 g, 68%) was obtained as a white
powder from 15a (1 g, 3.3 mmol) using n-butyl iodide instead
1
of MeI: mp 137-139 °C; H NMR (300 MHz, CDCl3) δ 0.92,
0.97 (total 3H, each t, J ) 7.2 Hz), 1.25-2.16 (8H, m), 2.67-
3.94 (6.1H, m), 4.86-5.02 (0.9H, m), 6.13 (0.9H, dd, J ) 8.4,
2.3 Hz), 6.43 (0.9H, d, J ) 2.3 Hz), 6.50-7.42 (5.2H, m). Anal.
(C21H25N2OCl) C, H, N. (1,2,3,4-Tetrahydro-1H-1-benzazepin-
1-yl)-2-chloro-4-(N,N-di-n-butylamino)benzamide (TLC Rf ca.
0.7, n-hexane:AcOEt, 2:1, 0.1 g, 7%) was obtained as a white
powder: 1H NMR (300 MHz, CDCl3) δ 0.91, 0.97 (total 6H,
each t, J ) 7.2 Hz), 1.03-2.16 (12H, m), 2.55-3.85 (7.2H, m),
4.85-5.07 (0.8H, m), 6.16 (0.8H, dd, J ) 8.7, 2.4 Hz), 6.43
(0.8H, d, J ) 2.4 Hz), 6.48-6.74 (1.1H, m), 6.82-7.43 (4.3H,
m).
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(N-n -p en tyla m in o)ben za m id e (16i). Using the same pro-
2-Ch lor o-4-(3-m eth ylp yr a zol-1-yl)ben zoic Acid Meth yl
Ester (21h ). Using the same procedure as 21b, 21h (12.1 g,

Design of Nonpeptide AVP V2 Receptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4395
61%, as less polar product) was obtained as a white powder
from 20 (15 g, 79.5 mmol) using 3-methylpyrazole instead of
pyrrolidine: 1H NMR (200 MHz, CDCl3) δ 2.38 (3H, s), 3.94
(3H, s), 6.30 (1H, d, J ) 2.5 Hz), 7.59 (1H, dd, J ) 8.6, 2.2
Hz), 7.82 (1H, d, J ) 2.2 Hz), 7.86 (1H, d, J ) 2.5 Hz), 7.96
(1H, d, J ) 8.6 Hz). 2-Chloro-4-(5-methylpyrazol-1-yl)benzoic
acid methyl ester (2.1 g, 11%, as polar product) was obtained
as a white powder: 1H NMR (200 MHz, CDCl3) δ 2.44 (3H, s),
3.96 (3H, s), 6.22-6.25 (1H, m), 7.47 (1H, dd, J ) 8.4, 2.1 Hz),
7.68-7.62 (1H, m), 7.66 (1H, d, J ) 2.1 Hz), 7.97 (1H, d, J )
8.4 Hz).
2-Ch lor o-4-(p yr r olid in -1-yl)ben zoic Acid (22b). A mix-
ture of 21b (1 g, 4.2 mmol), 5 N NaOH (2 mL) in MeOH (5
mL) was heated at reflux for 15 h. After the reaction was
completed, 2 N HCl was added to adjust the pH to ca. 5, then
concentrated under reduced pressure. The resulting precipi-
tates were dispersed in MeOH-CH2Cl2, and any undissolved
materials were removed by filtration. The filtrates were
concentrated, washed with MeOH, then dried to afford 22b
(0.5 g, 53%) as a white powder: 1H NMR (200 MHz, DMSO-
d6) δ 1.76-2.02 (4H, m), 3.11-3.46 (4H, m), 6.34-6.63 (2H,
m), 7.75 (1H, d, J ) 8.6 Hz), 12.35 (1H, brs).
2-Ch lor o-4-(p ip er id in -1-yl)ben zoic Acid (22e). Using the
same procedure as 22b, 22e (0.74 g, 60%) was obtained as a
white powder from 15e (1.3 g, 5.1 mmol): 1H NMR (200 MHz,
DMSO-d6) δ 1.45-1.73 (6H, m), 3.21-3.48 (4H, m), 6.88-7.12
(2H, m), 7.74 (1H, d, J ) 8.7 Hz), 8.60 (1H, brs).
2-Ch lor o-4-(m or p h olin -4-yl)ben zoic Acid (22f). Using
the same procedure as 22b, 22f (0.92 g, 98%) was obtained as
a white powder from 21f (1 g, 3.9 mmol): 1H NMR (200 MHz,
DMSO-d6) δ 3.15-3.37 (4H, m), 3.60-3.80 (4H, m), 6.79-7.05
(2H, m), 7.75 (1H, d, J ) 8.7 Hz). The corresponding COOH
proton was not observed under this condition.
(1,2,3,4-Tetr ah ydr o-1H-1-ben zazepin -1-yl)-4-(pyr r olidin -
1-yl)ben za m id e (23a ). A mixture of 4-pyrrolidin-1-ylbenzoic
acid (22a )13 (2.85 g, 14.9 mmol), SOCl2 (1.2 mL, 16.3 mmol),
and NMP (2 drops) in CH2Cl2 (50 mL) was stirred overnight
at room temperature to prepare the acid chloride solution. To
a mixture of 12 (2 g, 13.6 mmol) and pyridine (5.5 mL, 68
mmol) in CH2Cl2 (100 mL) was added dropwise a solution of
the acid chloride at 0-5 °C. After stirring for 3 h at room
temperature, the mixture was poured into water, extracted
with CH2Cl2, washed with water, dried over Na2CO3, and
concentrated. The resulting residue was purified by silica gel
column chromatography (n-hexane:AcOEt, 4:1) to give 23a (2.3
g, 52%) as colorless prisms: mp 182-183 °C; 1H NMR (200
MHz, CDCl3) δ 1.30-2.15 (6H, m), 2.50-3.45 (5H, m), 4.82-
5.31 (1H, m), 6.15-6.30 (2H, m), 6.65-6.77 (1H, m), 6.85-
7.28 (5H, m). Anal. (C21H24N2O) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(p yr r olid in -1-yl)ben za m id e (23b). Using the same proce-
dure as 23a , 23b (0.3 g, 39%) was obtained as a white powder
from 12 (0.32 g, 2.2 mmol) and 22b (0.5 g, 2.2 mmol): mp 160-
162 °C; 1H NMR (200 MHz, CDCl3) δ 1.27-2.20 (8H, m), 2.60-
3.58 (7.1H, m), 4.83-5.12 (0.9H, m), 6.08 (0.9H, dd, J ) 8.5,
2.2 Hz), 6.31-6.63 (1.3H, m), 6.72 (0.9H, d, J ) 8.5 Hz), 6.82-
7.45 (3.9H, m). Anal. (C21H23N2OCl) C, H, N.
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-4-
(p yr r olid in -1-yl)ben za m id e (23c). Using the same proce-
dure as 23a , 23c (1.8 g, 46%) was obtained as colorless needles
from 11 (2 g, 11 mmol) and 22a (2.3 g, 12 mmol): mp 147-
148 °C; 1H NMR (200 MHz, CDCl3) δ 1.32-2.17 (6H, m), 2.47-
3.34 (5H, m), 4.70-5.33 (1H, m), 6.20-6.32 (2H, m), 6.63 (1H,
d, J ) 8.4 Hz), 6.92 (1H, dd, J ) 8.4, 2.4 Hz), 7.03-7.14 (2H,
m), 7.22 (1H, d, J ) 2.4 Hz). Anal. (C21H23N2OCl‚0.1H2O) C,
H, N.
(7-Ch lor o-1,2,3,4-t et r a h yd r o-1H-1-b en za zep in -1-yl)-2-
ch lor o-4-(p yr r olid in -1-yl)ben za m id e (23d ). Using the same
procedure as 23a , 23d (0.78 g, 83%) was obtained as a white
powder from 11 (0.44 g, 2.4 mmol) and 22b (0.55 g, 2.4
2-Ch lor o-4-(p yr a zol-1-yl)ben zoic Acid (22g). A mixture
of 22g (10 g, 42.3 mmol), 6 N HCl (10 mL) and AcOH (10 mL)
was heated at reflux for 4 h. After the reaction was completed,
the mixture was poured into ice-water, and the resulting
crystals were collected by filtration to provide 22g (9.6 g, 100%)
as a white powder.
2-Ch lor o-4-(3-m eth ylp yr a zol-1-yl)ben zoic Acid (22h ).
Using the same procedure as 22g, 22h (11 g, 97%) was
obtained as a white powder from 21h (12 g, 48 mmol): 1H
NMR (200 MHz, DMSO-d6) δ 2.28 (3H, s), 6.41 (1H, d, J ) 2.4
Hz), 7.80-8.06 (3H, m), 8.55 (1H, d, J ) 2.6 Hz), 13.3 (1H,
brs).
3-Meth ylp yr r olid in e. To a dispersion of LiAlH4 (9.6 g,
0.252 mol) in Et2O (200 mL) was added dropwise a solution of
3-methyl-2-pyrrolidone (25 g, 0.252 mol) in Et2O (100 mL) at
0-5 °C. After completing the additions, the mixture was
heated at reflux for 1h. The mixture was then cooled to 0-5
°C, and saturated aqueous Na2SO4 was added dropwise until
the generation of H2 gas had ceased. After additional stirring
for 30 min at 0-5 °C, the resulting precipitates were removed
by filtration. The filtrates were concentrated to give 3-meth-
ylpyrrolidine (18 g, 84%) as a yellow oil: 1H NMR (200 MHz,
CDCl3) δ 0.91 (3H, d, J ) 6.6 Hz), 1.04-1.28 (1H, m), 1.68-
2.11 (2H, m), 2.27 (1H, dd, J ) 10.6, 7.1 Hz), 2.68-3.02 (3H,
m), 4.71 (1H, brs).
2-Ch lor o-4-(3-m eth ylp yr r olid in -1-yl)ben zoic Acid (22i).
A mixture of 20 (10 g, 53 mmol), 3-methylpyrrolidine (5.4 g,
63 mmol), and K2CO3 (63 mmol) in NMP (20 mL) was heated
at 120 °C for 4 h. After cooling, the mixture was poured into
water, extracted with AcOEt, washed with water, dried over
MgSO4, and concentrated. The residue thus obtained was
diluted with MeOH (50 mL), and 6 N NaOH (21 mL) was then
added to the mixture. After refluxing for 1 h, yellow cakes
resulted. The cakes were dissolved in water, the pH was
adjusted to ca. 4 by adding concentrated HCl, extracted with
AcOEt, dried over MgSO4, and concentrated. The precipitates
were washed with i-Pr2O to afford 22i (9 g, 71%) as a pale
brown powder: 1H NMR (200 MHz, CDCl3) δ 1.14 (3H, d, J )
6.6 Hz), 1.51-1.77 (1H, m), 1.96-2.54 (2H, m), 2.80-2.98 (1H,
m), 3.18-3.58 (3H, m), 6.38 (1H, dd, J ) 8.9, 2.4 Hz), 6.52
(1H, d, J ) 2.4 Hz), 7.97 (1H, d, J ) 8.7 Hz), 8.90 (1H, brs).
1
mmol): mp 137-138 °C; H NMR (300 MHz, CDCl3) δ 1.32-
2.28 (8H, m), 2.49-3.77 (7.16H, m), 4.78-5.10 (0.84H, m), 6.12
(0.84H, dd, J ) 8.5, 2.2 Hz), 6.37 (0.84H, d, J ) 2.2 Hz), 6.42-
6.59 (0.32H, m), 6.72 (0.84H, d, J ) 8.5 Hz), 6.81 (0.84H, d, J
) 8.4 Hz), 6.89 (0.84H, dd, J ) 8.4, 2.3 Hz), 7.12 (0.84H, d, J
) 2.3 Hz), 7.17-7.39 (0.64H, m). Anal. (C21H22N2OCl2) C, H,
N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(p ip er id in -1-yl)ben za m id e (23e). Using the same procedure
as 23a , 23e (0.42 g, 40%) was obtained as a white powder from
12 (0.42 g, 2.8 mmol) and 22e (0.5 g, 1.8 mmol): mp 150-152
1
°C; H NMR (200 MHz, CDCl3) δ 1.34-2.18 (10H, m), 2.57-
3.86 (7.2H, m), 4.83-5.03 (0.8H, m), 6.47 (0.8H, dd, J ) 8.6,
2.4 Hz), 6.65-7.44 (6.2H, m). Anal. (C22H25N2OCl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-4-(m or p h o-
lin -1-yl)ben za m id e (23f). Using the same procedure as 23a ,
23f (0.45 g, 69%) was obtained as a white powder from 12 (0.26
1
g, 1.7 mmol) and 22f (0.74 g, 3.1 mmol): mp 124-126 °C; H
NMR (300 MHz, CDCl3) δ 1.31-2.21 (4H, m), 2.61-4.40
(11.2H, m), 4.80-5.09 (0.8H, m), 6.46 (0.8H, dd, J ) 8.5, 2.1
Hz), 6.63-7.46 (6.2H, m). Anal. (C21H23N2O2Cl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(p yr a zol-1-yl)ben za m id e (23g). Using the same procedure
as 23a , 23g (0.48 g, 51%) was obtained as a white powder from
12 (0.4 g, 2.7 mmol) and 22g (0.6 g, 2.7 mmol): mp 156-157
°C; 1H NMR (200 MHz, CDCl3) δ 1.30-2.23 (4H, m), 2.68-
3.75 (3.1H, m), 4.85-5.03 (0.9H, m), 6.37-6.55 (1H, m), 6.83-
8.00 (8.1H, m). Anal. (C20H18N3OCl) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(3-m eth ylp yr a zol-1-yl)ben za m id e (23h ). Using the same
procedure as 23a , 23h (0.56 g, 60%) was obtained as a white
powder from 12 (0.37 g, 2.5 mmol) and 22h (0.6 g, 2.5 mmol):
mp 117-120 °C; 1H NMR (200 MHz, CDCl3) d 1.18-2.48 (7H,
m), 2.67-3.82 (3.1H, m), 4.83-5.00 (0.9H, m), 6.15-6.32 (1H,
m), 6.80-7.86 (8H, m). Anal. (C21H20N3OCl‚0.1H2O) C, H, N.
(1,2,3,4-Tetr a h yd r o-1H-1-ben za zep in -1-yl)-2-ch lor o-4-
(3-m eth ylp yr r olid in -1-yl)ben za m id e (23i). Using the same

4396 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Kondo et al.
procedure as 23a , 23i (0.25 g, 32%) was obtained as a white
powder from 12 (0.3 g, 2.1 mmol) and 22i (0.5 g, 2.1 mmol):
mp 130.5-131.5 °C; H NMR (200 MHz, CDCl3) δ 1.07, 1.15
Su p p or tin g In for m a tion Ava ila ble: Tables 1 and 2
containing elemental analyses. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
(total 3H, each d, J ) 6.6 Hz), 1.31-2.52 (8H, m), 2.57-3.68
(8.1H, m), 4.83-5.14 (0.9 H, m), 6.05 (0.9H, dd, J ) 8.5, 2.3
Hz), 6.26-6.58 (1.3H, m), 6.71 (0.9H, d, J ) 8.5 Hz), 6.80-
7.46 (3.9H, m). Anal. (C22H25N2OCl) C, H, N.
Refer en ces
(1) (a) Altura, B. M.; Altura, B. T. Vascular smooth muscle and
neurohypophyseal hormones. Fed. Proc. 1977, 36, 1853-1860.
(b) Howl, J .; Ismail, T.; Strain, A. J .; Kirk, C. J .; Anderson, D.;
Wheatley, M. Characterization of human liver vasopressin
receptor. Profound differences between human and rat vaso-
pressin-receptor-mediated responses suggest only a minor role
for vasopressin in regulating human hepatic function. Biochem.
J . 1991, 276, 189-195. (c) J ard, S.; Lombard, C.; Marie, J .;
Devilliers, G. Vasopressin receptors from cultured mesangial
cells resemble V1a type. Am. J . Physiol. 1987, 253, F41-F49.
(d) Penit, J .; Faure, M.; J ard, S. Vasopressin and angiotensin II
receptors in rat aortic smooth muscle cells in culture. Am. J .
Physiol. 1983, 244, E72-82. (e) Thibonnier, M.; Roberts, J . M.
Characterization of human platelet vasopressin receptors. J .
Clin. Invest. 1985, 76, 1857-1864. (f) Dorsa, D. M.; Majumdar,
L. A.; Petracca, F. M.; Baskin, D. G.; Cornett, L. E. Character-
ization and localization of 3H-arginine8-vasopressin binding to
rat kidney and brain tissue. Peptides 1983, 4, 699-706.
(2) (a) Brooks, D. P.; Koster, P. F.; Albrightson-Winslow, C. R.;
Stassen, F. L.; Huffman, W, F.; Kinter, L. B. SK&F 105494 is a
potent antidiuretic hormone antagonist in the rhesus monkey
(Macaca mulatto). J . Pharmacol. Exp. Ther. 1988, 245, 211-
215. (b) Caldwell, N.; Brickson, B.; Kinter, L. B.; Brooks, D. P.;
Huffman. W. F.; Stassen, F. L.; Albrightson-Winslow, C. SK&F
105494: a potent antidiuretic hormone antagonist devoid of
partial agonist activity in dogs. J . Pharmacol. Exp. Ther. 1988,
247, 897-901. (c) Brooks, D. P.; Koster, P. F.; Albrightson, C.
R.; Huffman, W. F.; Moore, M. L.; Stassen, F. L.; Schmidt, D.
B.; Kinter, L. B. Vasopressin receptor antagonism in rhesus
monkey and man: stereochemical requirements. Eur. J . Phar-
macol. 1989, 160, 159-162. (d) Ruffolo, R. R., J r.; Brooks, D.
P.; Huffman, W. F.; Poste, G. From vasopressin antagonist to
agonist: a saga of surprise! Drug News Perspect. 1991, 4, 217-
222.
Ra d ioliga n d Bin d in g Assa y to HeLa Cells Exp r essin g
Hu m a n AVP Recep tor s. The procedures for the radioligand
binding assay and the preparation of HeLa cells expressing
the human V2 receptor have been reported in detail.8a,14 The
experiments were performed after each cell reached confluence
in 24-well dishes. After washing three times with ice-cold
phosphate-buffered saline (PBS), the cells were incubated with
[3H]AVP with or without unlabeled AVP (final concentration
of 1 µM) to determine the total binding or the nonspecific
binding, respectively, in DMEM containing 0.3% BSA brought
to a pH of 7.4 with 10 mM HEPES-NaOH. For the competi-
tion experiments, the test compounds dissolved in dimethyl
sulfoxide (DMSO) and AVP dissolved in saline were diluted
with the DMEM medium and added to each well at several
appropriate concentrations. After incubation at 4 °C for 2 h,
the reaction was stopped by removing the buffer, and the cells
were rinsed three times with ice-cold PBS. The cells were lysed
with 250 µL of 0.1 N NaOH containing 0.1% sodium dodecyl
sulfate (SDS), transferred into scintillation vials, and mixed
with 5 mL of Aquazol II (Packard, Tokyo, J apan). Radioactivity
was detected using a liquid scintillation counter (LSC-1050;
Aloka, Tokyo, J apan). The cells in some wells were lysed in
0.1 N NaOH and then protein contents were determined by
the dye method (Bradford, 1976). IC50 values are the concen-
trations of compounds which inhibit [3H]AVP binding by 50%.
All assays were performed in duplicate. The intraassay and
interassay IC50 values for the given compounds varied by less
than 3% and less than 20%, respectively.
(3) (a) Yamamura, Y.; Ogawa, H.; Chihara, T.; Kondo, K.; Onogawa,
T.; Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y. OPC-
21268, an orally effective, nonpeptide vasopressin V1 receptor
antagonist. Science 1991, 252, 572-574. (b) Ogawa, H.; Yama-
mura, Y.; Miyamoto, H.; Kondo, K.; Yamashita, H.; Nakaya, K.;
Chihara, T.; Mori, T.; Tominaga, M.; Yabuuchi, Y. Orally active,
nonpeptide vasopressin V1 antagonists. A novel series of 1-(1-
substituted 4-piperidyl)-3,4-dihydro-2(1H)-quinolinone. J . Med.
Chem. 1993, 36, 2011-2017. (c) Kondo, K.; Ogawa, H.; Nakaya,
K.; Tominaga, M.; Yabuuchi, Y. Structure-activity relationships
of non-peptide vasopressin V1a antagonists: 1-(1-multi-substi-
tuted benzoyl 4-piperidyl)-3,4-dihydro-2(1H)-quinolinones. Chem.
Pharm. Bull. 1996, 44, 725-733.
Cyclic AMP P r od u ction in HeLa Cells Exp r essin g V2
Recep tor s. After reaching confluence in 24-well dishes, the
cells were washed twice with ice-cold PBS, incubated with the
DMEM containing 0.3% BSA and 1 mM IBMX, and brought
to a pH of 7.4 with 10 mM HEPES-NaOH. After the addition
of certain concentrations of test compounds or AVP, the
incubation was carried out at 37 °C for 10 min. The reaction
was stopped by aspiration of the medium then the cells were
rinsed twice with ice-cold PBS. Cyclic AMP was extracted from
the cells by adding 250 µL of 0.1 N HCl and stored at -20 °C
until the cAMP determination using a radioimmunoassay kit
(Yamasa, Tokyo, J apan). All assays were performed in tripli-
cate.
(4) (a) Pettibone, D. J .; Kishel, M. T.; Woyden, C, J .; Clineschmidt,
B. V.; Bock, M. G.; Freidinger, R. M.; Veber, D. F.; Williams, P.
D. Radioligand binding studies reveal marked species differences
in the vasopressin V1 receptor of rat, rhesus and human tissues.
Life Sci. 1992, 50, 1953-1958. (b) Serradeil-Le Gal, C.; Wagnon,
J .; Lacour, C.; Christophe, B.; Barthe´le´my, G.; Guiraudou, P.;
Nisato, D.; Le Fur, G.; Maffrand, J .-P.; Cantau, B.; Barberis,
C.; Guillon, G.; J ard, S. Pharmacological profile of SR 49059, a
potent non-peptide antagonist of V1 vasopressin receptors. In
Vasopressin; Gross, P., Richter, D., Robertson, G. L., Eds.; J ohn
Libbey Eurotext: London, 1993; pp 529-537. (c) Serradeil-Le
Gal, C.; Wagnon, J .; Garcia, C.; Lacour, C.; Guiraudou, P.;
Christophe, B.; Villanova, G.; Nisato, D.; Maffrand, J .-P.; Le Fur,
G. Biochemical and pharmacological properties of SR 49059, a
new, potent, nonpeptide antagonist of rat and human vaso-
pressin V1a receptors. J . Clin. Invest. 1993, 92, 224-231. (d)
Serradeil-Le Gal, C.; Raufaste, D.; Marty, E.; Garcia, C.;
Maffrand, J .-P.; Le Fur, G. Binding of [3H]SR 49059, a potent
nonpeptide vasopressin V1a antagonist, to rat and human liver
membranes. Biochem. Biophys. Res. Commun. 1994, 199, 353-
360. (e) Tahara, A.; Tsukada, J .; Ishii, N.; Tomura, Y.; Wada,
K.; Kusayama, T.; Yatsu, T.; Uchida, W.; Tanaka, A. Charac-
terization of rodent liver and kidney AVP receptors: pharma-
cologic evidence for species differences. Regul. Pept. 1999, 84,
13-19. (f) Hirasawa, A.; Shibata, K.; Kotosai, K.; Tsujimoto, G.
Cloning, functional expression and tissue distribution of human
cDNA for the vascular-type vasopressin receptor. Biochem.
Biophys. Res. Commun. 1994, 203, 72-79. (g) Williams, P. D.;
Clineschmidt, B. V.; Erb, J . M.; Freidinger, R. M.; Guidotti, M.
T.; Lis, E. V.; Pawluczyk, J . M.; Pettibone, D. J .; Reiss, D. R.;
Veber, D. F.; Woyden, C. J . 1-(1-[4-[(N-acetyl-4-piperidinyl)oxy]-
2-methoxybenzoyl]piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-
one (L-371,257): a new, orally bioavailable, non-peptide oxytocin
antagonist. J . Med. Chem. 1995, 38, 4634-4636.
Da ta An a lysis. The percentage of maximal cAMP ac-
cumulation (PMA) of each compound at 10-6 M was deter-
mined as the percent to the response with AVP (10-9 M). It
was calculated using the equation: PMA (%) ) (cAMPA
-
cAMPB) × 100/(cAMPV - cAMPB), where cAMPA is the cAMP
count using a compound at the given concentration, cAMPB is
the cAMP count without a compound, and cAMPV is the cAMP
count using AVP (10-9 M).
Con for m a tion a l En er gy Ca lcu la tion s. All calculations
were performed using the CHARMM force field. Conforma-
tional searches were performed using QUANTA97 (MSI, 9685
Scranton Rd., San Diego, CA 92121-3752) to obtain stable
conformers. Powell minimization with a maximum of 5000
iterations was used in the conformational search with the
default convergence set at a value of 0.001 (kJ /mol)/Å. All
superimpositions and calculations of solvent-accessible surface
areas were performed using QUANTA97 with default param-
eters.
Ack n ow led gm en t. The authors thank Dr. Y. Yab-
uuchi and Dr. T. Sumida for their valuable comments
and continuing encouragement and Dr. Y. Kurogi for
his comments on this manuscript. We also thank Ms.
M. Murakami for her technical support with the in vitro
assay.

Design of Nonpeptide AVP V2 Receptor Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4397
(5) (a) Yamamura, Y.; Ogawa, H.; Yamashita, H.; Chihara, T.;
Miyamoto, H.; Nakamura, S.; Onogawa, T.; Yamashita, T.;
Hosokawa, T.; Mori, T.; Tominaga, M.; Yabuuchi, Y. Character-
ization of a novel aquaretic agent, OPC-31260, as an orally
effective, nonpeptide vasopressin V2 receptor antagonist. Br. J .
Pharmacol. 1992, 105, 787-791. (b) Ogawa, H.; Yamashita, H.;
Kondo, K.; Yamamura, Y.; Miyamoto, H.; Kan, K.; Kitano, K.;
Tanaka, M.; Nakaya, K.; Nakamura, S.; Mori, T.; Tominaga M.;
Yabuuchi, Y. Orally active, nonpeptide vasopressin V2 receptor
Greenlee, W. J .; Schwartz, T. W. Identification of peptide binding
residues in the extracellular domains of the AT1 receptor. J . Biol
Chem. 1994, 269, 30953-30959. (c) Underwood, D. J .; Strader,
C. D.; Rivero, R.; Patchett, A. A.; Greenlee, W.; Prendergast, K.
Structural model of antagonist and agonist binding to the
angiotensin II, AT1 subtype, G protein coupled receptor. Chem.
Biol. 1994, 1, 211-221. (d) J i, H.; Leung, M.; Zhang, Y.; Catt,
K. J .; Sandberg, K. Differential structural requirments for
specific binding of nonpeptide and peptide antagonists to the
AT1 angiotensin receptor. Identification of amino acid residues
that determine binding of the antihypertensive drug Iosartan.
J . Biol. Chem. 1994, 269, 16533-16536. (e) Almansa, C.; Gomez,
L. A.; Cavalcanti, F. L.; de Arriba, A. F.; Garcia-Rafanell, J .;
Forn, J . Synthesis and structure-activity relationship of a new
series of potent AT1 selective angiotensin II receptor antago-
nists: 5-(biphenyl-4-ylmethyl)pyrazoles. J . Med. Chem. 1977, 40,
547-558. (f) Perlman, S.; Costa-Neto, C. M.; Miyakawa, A. A.;
Schambye, H. T.; Hjorth, S. A.; Paiva, A. C.; Rivero, R. A.;
Greenlee, W. J .; Schwartz, T. W. Dual agonistic and antagonistic
property of nonpeptide angiotensin AT1 ligands: susceptibility
to receptor mutations. Mol. Pharmacol. 1997, 51, 301-311. (g)
Robertson, M. J .; Dougall, I. G.; Harper, D.; McKechnie, K. C.;
Leff, P. Agonist-antagonist interactions at angiotensin recep-
tors: application of a two-state receptor model. Trends Phar-
macol. Sci. 1994, 15, 364-369. (h) Perlman, S.; Schambye, H.
T.; Rivero, R. A.; Greenlee, W. J .; Hjorth, S. A.; Schwartz, T. W.
Non-peptide angiotensin agonist. Functional and molecular
interaction with the AT1 receptor. J . Biol. Chem. 1995, 270,
1493-1496. (i) Aquino, C. J .; Armour, D. R.; Berman, J . M.;
Birkemo, L. S.; Carr, R. A.; Croom, D. K.; Dezube, M.; Dougherty,
R. W. J r.; Ervin, G. N.; Grizzle, M. K.; Head, J . E.; Hirst, G. C.;
J ames, M. K.; J ohnson, M. F.; Miller, L. J .; Queen, K. L.; Rimele,
T. J .; Smith, D. N.; Sugg, E. E. Discovery of 1,5-benzodiazepines
with peripheral cholecystokinin (CCK-A) receptor agonist activ-
ity. 1. Optimization of the agonist ‘trigger’. J . Med. Chem. 1996,
39, 562-569. (j) Willson, T. M.; Henke, B. R.; Momtahen, T. M.;
Myers, P. L.; Sugg, E. E.; Unwalla, R. J .; Croom, D. K.;
Dougherty, R. W.; Grizzle, M. K.; J ohnson, M. F.; Queen, K. L.;
Rimele, T. J .; Yingling, J . D.; J ames, M. K. 3-[2-(N-Phenyl-
acetamide)]-1,5-benzodiazepines: orally active, binding selective
CCK-A agonists. J . Med. Chem. 1996, 39, 3030-3034.
antagonists:
a novel series of 1-[4-(benzoylamino)benzoyl]-
2,3,4,5-tetrahydro-1H-benzazepines and related compounds. J .
Med. Chem. 1996, 39, 3547-3555.
(6) (a) Ohnishi, A.; Orita, Y.; Okahara, R.; Fujihara, H.; Inoue, T.;
Yamamura, Y.; Yabuuchi, Y.; Tanaka, T. Potent aquaretic agent.
A novel nonpeptide selective vasopressin 2 antagonist (OPC-
3260) in men. J . Clin. Invest. 1993, 92, 2653-2659. (b) Ohnishi,
A.; Orita, Y.; Takagi, N.; Fujita, T.; Toyoki, T.; Ihara, Y.;
Yamamura, Y.; Inoue, T.; Tanaka, T. Aquaretic effect of a potent,
orally active, nonpeptide V2 antagonist in men. J . Pharmacol.
Exp. Ther. 1995, 272, 546-551; published erratum: J . Pharma-
col. Exp. Ther. 1995, 274, 1573.
(7) (a) Thibonnier, M.; Auzan, C.; Madhum, Z.; Wilkins, P.; Berti-
Mattera, L.; Clauser, E. Molecular cloning, sequencing, and
functional expression of a cDNA encoding the human V1a
vasopressin receptor. J . Biol. Chem. 1994, 269, 3304-3310. (b)
Hirasawa, A.; Shibata, K.; Kotosai, K.; Tsujimoto, G. Cloning,
functional expression and tissue distribution of human cDNA
for the vascular-type vasopressin receptor. Biochem. Biophys.
Res. Commun. 1994, 203, 72-79. (c) Birnbaumer, M.; Seibold,
A.; Gilert, S.; Ishido, M.; Barberis, C.; Antaramian, A.; Brabet,
P.; Rosenthal, W. Molecular cloning of the receptor for human
antidiuretic hormone. Nature 1992, 357, 333-335. (d) Sugimoto,
T.; Saito, M.; Mochizuki, S.; Watanabe, Y.; Hashimoto, S.;
Kawashima, H. Molecular cloning and functional expression of
cDNA encoding the human V1b vasopressin receptor. J . Biol.
Chem. 1994, 269, 27088-27092. (e) Kimura, T.; Tanizawa, O.;
Mori, K.; Brownstein, M. J .; Okayama, H. Structure and
expression of a human oxytocin receptor. Nature 1992, 356, 526-
529; published erratum: Nature 1992, 357, 176. (f) Mouillac,
B.; Chini, B.; Balestre, M. N.; J ard, S.; Barberis, C.; Manning,
M.; Tribollet, E.; Trumpp-Kallmeyer, S.; Hoflack, J .; Elands, J .;
Hibert, M. Identification of agonist binding sites of vasopressin
and oxytocin receptors. Adv. Exp. Med. Biol. 1995, 395, 301-
310. (g) Peter, J .; Burbach, H.; Adan, R. A.; Lolait, S. J .; van
Leeuwen, F. W.; Mezey, E.; Palkovits, M.; Barberis, C. Molecular
neurobiology and pharmacology of the vasopressin/oxytocin
receptor family. Cell. Mol. Neurobiol. 1995, 15, 575-595.
(8) (a) Yamamura, Y.; Nakamura, S.; Itoh, S.; Hirano, T.; Onogawa,
T.; Yamashita, T.; Yamada, Y.; Tsujimae, K.; Aoyama, M.;
Kotosai, K.; Ogawa, H.; Yamashita, H.; Kondo, K.; Tominaga,
M.; Tsujimoto, G.; Mori, T. OPC-41061, a highly potent human
vasopressin V2-receptor antagonist: pharmacological profile and
aquaretic effect by single and multiple oral dosing in rats. J .
Pharmacol. Exp. Ther. 1998, 287, 860-867. (b) Kondo, K.;
Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya,
K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; Mori,
T.; Tominaga, M. 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-
41061): a potent, orally active nonpeptide arginine vasopressin
V2 receptor antagonist. Bioorg. Med. Chem. 1999, 7, 1743-1754.
(9) (a) Norman, M. H.; Smith, H. D.; Andrews, C. W.; Tang, F. L.;
Cowan, C. L.; Steffen, R. P. 4-(Heteroarylthio)-2-biphenyltetra-
zoles as nonpeptide angiotensin II antagonists. J . Med. Chem.
1995, 38, 4670-4678. (b) Hjorth, S. A.; Schambye, H. T.;
(10) Urine volume values (U.V.) mean urine volume (mL) ac-
cumulated for 2 h when the test compound was orally admin-
istered using female Brattleboro rats. The controle value for
urine volume is ca. 10 mL.
(11) (a) Clauson-Kaas, N.; Tyle, Z. Preparation of cis- and trans-2,5-
dimethoxy-2-(acetamidomethyl)-2,5-dihydrofuran, of cis- and
trans-dimethoxy-2-(acetamidomethoxy)-tetrahydrofuran, and
1-phenyl-2-(acetamidomethyl)pyrrole. Acta Chem. Scand. 1952,
6, 667-670. (b) Elming, N.; Clauson-Kaas, N. The preparation
of pyrroles from furans. Acta Chem. Scand. 1952, 6, 867-874.
(12) See Experimental Section for conformational energy calculations.
(13) Weringa, W. D.; J anssen, M. J . Substituent effect of pyrrolidino
and piperidino groups in benzoic acids and nitrobenzenes. Recl.
Trav. Chim. Pays-Bas. 1968, 87, 1372-1380.
(14) Nakamura, S.; Yamamura, Y.; Itoh, S.; Hirano, T.; Tsujimae,
K.; Aoyama, M.; Kondo, K.; Ogawa, H.; Shinohara, T.; Kan, K.;
Tanada, Y.; Teramoto, S.; Sumida, T.; Nakayama, S.; Sekiguchi,
K.; Kambe, T.; Tsujimoto, G.; Mori, T.; Tominaga, M. Charac-
terization of a novel nonpeptide vasopressin V2-agonist, OPC-
51803, in cells transfected human vasopressin receptor subtypes.
Br. J . Pharmacol. 2000, 129, 1700-1706.
J M000108P