Preparation of highly potent and selective non-peptide antagonists of the arginine vasopressin V1A receptor by introduction of a 2-ethyl-1H-1-imidazolyl group

Article abstract of DOI:10.1248/cpb.53.764

To find a new series of arginine vasopressin (AVP) V_1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4′-[(2,3,4,5- tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V_1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4′-({4,4-difluoro-5-[(N-cyclo-propylcarbamoyl) methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1- imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V_1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper

Full text of DOI:10.1248/cpb.53.764

764
Chem. Pharm. Bull. 53(7) 764—769 (2005)
Vol. 53, No. 7
Preparation of Highly Potent and Selective Non-Peptide Antagonists of the
Arginine Vasopressin V1A Receptor by Introduction of a 2-Ethyl-1H-1-
imidazolyl Group
Yoshiaki SHIMADA,*,a Hiroaki AKANE,b Nobuaki TANIGUCHI,a Akira MATSUHISA,a Noriyuki KAWANO,a
Kazumi KIKUCHI,a Takeyuki YATSU,a Atsuo TAHARA,a Yuichi TOMURA,a Toshiyuki KUSAYAMA,a
d
Koh-ichi WADA,a Junko TSUKADA,b Takashi TSUNODA,c and Akihiro TANAKA
a Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; 21 Miyukigaoka, Tsukuba, Ibaraki
305–8585, Japan: b Clinical Development Department, Yamanouchi Pharmaceutical Co., Ltd.; 3–17–1 Hasune, Itabashi-
c
ku, Tokyo 174–8612, Japan: Chemical Technology Laboratory, Yamanouchi Pharmaceutical Co., Ltd.; 160–2 Akahama,
Takahagi, Ibaraki 318–0001, Japan: and d Corporate Communications Department, Yamanouchi Pharmaceutical Co., Ltd.;
2–3–11 Nihonbashi-honcho, Chuo-ku, Tokyo 103–8411, Japan. Received January 5, 2005; accepted April 5, 2005
To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl
group of 2-phenyl-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated.
Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective
compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further
studies of these compounds were performed. Consequently, we found that the (Z)-4ꢀ-({4,4-difluoro-5-[(N-cyclo-
propylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A
receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are
described in this paper
Key words arginine vasopressin; V1A receptor selective antagonist; 2-ethyl-1H-1-imidazole
Arginine vasopressin (AVP) is a cyclic nonapeptide hor- (shown in box B) of compound 7 resulted in changes in
mone secreted from the posterior pituitary gland. AVP has a selectivity between the V1A and V2 receptors. That is to say,
variety of physiological functions, such as regulation of the replacement of B with either 2-(4-NHAc)Ph or 2-(4-
blood pressure, secretion of ACTH and control of water in OMe)Ph resulted in V1A receptor selectivity versus the V2
the kidney. These physiological functions are regulated receptor. On the other hand, replacement of B by 2-(3-
through three receptors (V1A, V1B and V2). Among these re- Me)Ph, 2-(4-Et)Ph, 2-(4-NH2)Ph or 2-(4-OH)Ph gave V2 se-
ceptors, the V1A receptor mediates the vasoconstrictive action lectivity. For all these compounds, selectivity between the
of AVP. The receptor is found in vascular smooth muscle, the two receptors was insufficient, but we concluded that the R2
liver, platelets, and renal mesangial cells.1—4)
group plays an important role in changing receptor selectiv-
Due to the physiological properties of AVP and the distrib- ity. Therefore, we tried to convert the 2-phenyl group into
ution of the V1A receptor, abnormal secretion of AVP causes other aryl groups, such as azole groups (8a—g). The most
high blood pressure, cardiac disease, and kidney disease effective compound with an azole group introduced into the
through the V1A receptor.5) Therefore, V1A receptor antago- skeleton of (Z)-4ꢀ-{[(4,4-difluoro-5-carbamoylmethylene-
nists are expected to be important new curative drugs for 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl}-
these diseases. OPC-21268 (1) and SR49059 (2) have been benzanilide underwent further optimization of the R3
reported as non-peptide V1A receptor antagonists,6,7) and we group (9a—k), and this led to a series of compounds pos-
have discovered and reported the 4,4-difluoro-5-methylidene-
2,3,4,5-tetrahydro-1H-1-benzazepine derivatives as V1A re-
ceptor antagonists, and introduced a 2-ethoxybenzoyl group
into these derivatives (3, 4) (Fig. 1).8)
In preceding papers,9,10) we reported the discovery of two
AVP dual antagonists (YM087 (conivaptan), 5; and YM-
35471, 6) which possess strong binding affinities for both
V1A and V2 receptors, through optimization of the ben-
zazepine moiety (shown in box A) of compound 7 (Fig. 2).11)
The introduction of various groups in the 2-phenyl position
Fig. 1
Fig. 2
∗ To whom correspondence should be addressed. e-mail: shimada@yamanouchi.co.jp
© 2005 Pharmaceutical Society of Japan

July 2005
765
Chart 1
Chart 3
1 M NaOH afforded the acetic acid derivative 19. The target
compounds (9a—k) were synthesized by condensation of 19
and various amines in the presence of WSC·HCl and 1-hy-
droxybenzotriazole (HOBt).
Chart 2
Results and Discussion
sessing highly potent affinity and selectivity for the V1A
Binding Affinities Methods for determining the in vitro
receptor. Here, we describe the synthesis, structure–activity AVP receptor binding affinities have been described in a pre-
relationships, and pharmacological properties of these vious paper.8) The results of binding assay of the compounds
novel compounds.
are shown in Tables 1—3. Initially, we investigated the role
of the R2 position in V1A selectivity in 2,3,4,5-tetrahydro-1H-
1-benzazepine derivatives, as shown in Table 1. When the
Chemistry
The synthetic pathways of the compounds listed in Tables 1H-imidazol-1-yl group (8a) was introduced at the R2 posi-
1—3 are shown in Charts 1—3. Intermediates of 2,3,4,5- tion, selectivity for the V1A receptor versus the V2 receptor
tetrahydro-1H-1-benzazepine derivatives (11a—f, 12) were was greater than that of 7. Additionally, the 1H-1,2,4-triazol-
synthesized as outlined in Chart 1. The 2-(2-substituted- 1-yl (8f) and 1H-tetrazol-1-yl (8g) derivatives showed slight
1H-imidazol-1-yl) or 2-(1H-1,2,4-triazol-1-yl) benzoic acid V1A selectivity, but the V1A binding affinity of these deriva-
derivatives (11a—f) were obtained by condensation of 2-flu- tives (8f, g) decreased compared to 7. It was concluded that
orobenzonitrile (10) and 2-substituted imidazole or a tria- the nitrogen atom of the azole group contributed to the
zole,12) followed by hydrolysis of the nitrile group under increase in V1A receptor selectivity.
basic conditions. The methyl 2-cyanobenzoate (12) was syn-
Among compounds 8a, 8f and 8g, the imidazole derivative
thesized as described below. The phthalic anhydride (13) was (8a) tended to possess higher V1A binding affinity and selec-
hydrolyzed by 28% NH4OH to give 2-(aminocarbonyl)ben- tivity than 8f or 8g, and the imidazolyl moiety was therefore
zoic acid (14),13) and compound 12 was obtained by treat- studied further. The methyl (8b) and ethyl (8c) derivatives at
ment of 14 with methyl chloroformate.14)
the 2-position of imidazole (R4) exhibited highly potent bind-
The 2,3,4,5-tetrahydro-1H-1-benzazepine derivatives (8a— ing affinity and selectivity for the V1A receptor, but the intro-
g) were synthesized according to the route shown in Chart 2. duction of a bulky substituent such as an n-propyl or phenyl
The imidazole and triazole derivatives (8a—f) were prepared group (8d, e) decreased the affinity and selectivity. Conse-
by condensation of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro- quently, the introduction of a 2-ethyl-1H-imidazol-1-yl group
1H-1-benzazepine (15)11) and 11a—f in the presence of 1- was effective in increasing V1A receptor selectivity versus the
ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride V2 receptor, while maintaining the V1A binding affinity.
(WSC·HCl). Compound 12 was hydrolyzed with 1 M NaOH These observations suggested that V1A binding affinity and
to give the corresponding carboxylic acid derivative, fol- selectivity were influenced by both the electronic effect of
lowed by the addition of oxalyl chloride to give the acyl chlo- the azole group and the steric effect of the substituent at the
ride derivative. This acyl chloride was condensed with 15 to R4 position.
give the 2-cyanobenzanilide derivative 16. The tetrazole de-
rivative (8g) was synthesized by treating 16 with n- group of compound 6 (YM-35471 skeleton) into a 2-ethyl-
Bu3SnN3.15,16)
1H-imidazol-1-yl group, and further modifications of various
The 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1- amide groups at the R3 position were performed.
benzazepine derivatives (9a—k) were prepared according to Because the YM-35471 skeleton possesses high binding
Based on these results, we tried to convert the 2-phenyl
the methods shown in Chart 3. The methyl ester derivative 18 affinities for the V1A and V2 receptors, we thought that intro-
was obtained by acylation of 1710) with the acyl chloride duction of a 2-ethyl-1H-imidazol-1-yl group might give com-
derivative of 11c. Hydrolysis of the methyl ester in 18 with pounds with both highly potent binding affinity and selectiv-

766
Vol. 53, No. 7
Table 1. Receptor-Binding Affinities of 2,3,4,5-Tetrahydro-1H-1-benz- ity for the V1A receptor. The binding affinities of 4,4-diflu-
azepine Derivatives
oro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzazepine de-
rivatives are shown in Table 2. All these derivatives (9a—k)
showed an increase in V1A receptor selectivity versus the V2
receptor, compared to 6 and 8c, and exhibited more potent
binding affinity for the V1A receptor, compared to 8c. The
alkyl-substituted derivatives (9b—i) possessed highly potent
Binding affinity (pKi)
binding affinity compared with the carbamoyl derivative 9a,
c)
No.
R2
Ph
R4
V1A/V2
but the introduction of a bulky substituent group, such as in
compounds 9h and 9i, was found to decrease selectivity for
the V1A receptor. The cyclopropyl-substituted derivative (9f)
exhibited the most potent affinity among these derivatives
and showed a 457-fold selectivity for the V1A versus the V2
receptor. In the derivatives containing oxygen atoms (9j, k),
the V1A selectivity of 9j was insufficient, but compound 9k
showed a more potent affinity for the V1A receptor, compared
with corresponding hydrocarbon derivative (9i). Therefore,
the influence of the oxygen atom in V1A selectivity was un-
clear. These results suggested that V1A binding affinity and
selectivity are influenced by a steric effect at the R3 position,
making substitution with a cyclopropyl group suitable for ob-
taining the desired compound.
a)
b)
V1A
V2
7d)
8a
8b
8c
8d
8e
—
H
Me
Et
n-Pr
Ph
7.85
7.33
8.20
8.58
7.40
6.31
8.12
6.43
6.79
7.21
6.97
5.71
0.54
8
26
23
3
4
8f
—
7.16
6.42
5
8g
—
6.63
6.22
3
a) pKi of [3H]-vasopressin binding to rat liver membranes. b) pKi of [3H]-vaso-
pressin binding to rat kidney membranes. c) V1A/V2 shows the selectivity for binding
with the V1A receptor versus the V2 receptor. d) See ref. 8.
Subsequently, we investigated the binding affinities of
compound 9f for cloned human V1A (hV1A) and V2 (hV2) re-
ceptors (Table 3).8) Compound 9f exhibited potent binding
affinity for the V1A receptor and 140-fold selectivity for the
V1A versus the V2 receptor. Additionally, 9f showed 70-fold
V1A selectivity compared to 6. Therefore, conversion of the
2-phenyl group into a 2-ethyl-1H-imidazol-1-yl group also
contributed to increased V1A selectivity in cloned human
AVP receptors.
Table 2. Receptor-Binding Affinities of 4,4-Difluoro-5-methylidene-2,3,4,5-
tetrahydro-1H-1-benzazepine Derivatives
Antagonist Activity The V1A receptor antagonist activ-
ity was determined by measuring inhibition of the AVP-in-
duced diastolic blood pressure (DBP) response in pithed rats
after intravenous (i.v.) administration. The dose of the com-
pound causing a 50% inhibition of the pressor response to
AVP (ID50) was calculated. The experimental method used to
determine AVP antagonist activity has been described in a
previous paper.8)
Compound 9f was selected and the above in vivo experi-
ment was performed. Results showed that 9f exhibited potent
antagonist activity (ID50: 0.0010 mg/kg i.v.) for the V1A re-
ceptor. Furthermore, the antagonist activity of 9f was more
effective than that of 6 (ID50: 0.0027 mg/kg i.v.). Therefore,
introduction of a 2-ethyl-1H-imidazol-1-yl group at the R2
position and a cyclopropylamino group at the R4 position
provided the most potent V1A receptor antagonist activity.
Binding affinity (pKi)
c)
No.
R3
V1A/V2
a)
b)
V1A
10.10
V2
6d)
8c
9a
9b
9c
9d
9e
9f
—
—
–NH2
–NHMe
–NHEt
–NH(n-Pr)
–NH(i-Pr)
–NH(c-Pr)
–NMe2
–NEt2
9.58
7.21
6.35
6.68
6.92
6.38
6.42
6.81
6.65
7.41
3
23
224
214
123
219
269
457
155
28
8.58
8.70
9.01
9.01
8.72
8.85
9.47
8.84
8.86
9g
9h
9i
8.79
8.92
9.27
7.06
7.06
6.96
54
72
9j
9k
204
a—c) See footnotes in Table 1. d) Compound 6 has a phenyl group at the same Conclusion
position as the 2-ethyl-1H-imidazol-1-yl group.
In this paper, we have described the synthesis of 2-substi-
tuted 4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]
benzanilide derivatives and (Z)-2-substituted 4ꢀ-[(4,4-diflu-
oro-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benz-
anilide derivatives, and evaluated their AVP receptor binding
affinities and antagonist activities. It was found that the intro-
duction of a 2-ethyl-1H-imidazol-1-yl group at the 2-po-
sition increased V1A selectivity versus the V2 receptor. In
particular, (Z)-4ꢀ-({4,4-difluoro-5-[(N-cyclopropylcarbamoyl)-
methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}car-
bonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhib-
ited potent binding affinity for the V1A receptor and high
Table 3. Binding Affinities of Compounds 9f and 6 for Cloned Human
V1A (hV1A) and V2 (hV2) Receptors and AVP-Antagonist Activities
Binding affinity (pKi)
c)
No.
V1A/V2
a)
b)
hV1A
hV2
9f
6
9.00
9.21
6.85
8.92
140
2
a, b) See ref. 8. c) See footnote in Table 1.

July 2005
767
Table 4. Physical and Spectral Data for the 2-Substituted Benzoic Acid Derivatives
No.
R2
R4
Yield (%)
1H-NMR (DMSO-d6) d
EI-MS m/z (Mꢂ)
11a
11b
11c
H
64
74
7.65—7.89 (4H, m), 7.95—8.01 (1H, m), 8.08—8.19 (1H, m), 9.05 (1H, m)
2.19 (3H, s), 7.52—7.93 (4H, m), 7.95—8.11 (1H, m), 8.21—8.25 (1H, m)
1.13 (3H, t, Jꢃ7 Hz), 3.55 (2H, q, Jꢃ7 Hz), 7.61—7.90 (4H, m), 7.99—8.07
(1H, m), 8.10—8.19 (1H, m)
188
202
Me
Et
60
52
216
230
11d
0.76 (3H, t, Jꢃ7 Hz), 2.03 (2H, m), 2.47 (2H, m), 7.34—7.80 (4H, m), 7.91—
8.03 (1H, m), 8.09—8.21 (1H, m)
n-Pr
11e
11f
Ph
—
19
38
7.14—7.45 (6H, m), 7.51—7.70 (3H, m), 7.89—8.01 (2H, m)
264
189
7.47—7.72 (4H, m), 7.85—8.05 (1H, m), 8.64 (1H, m)
carbonyl]benzanilide Monohydrochloride (8a) To a cooled mixture of
11a (170 mg, 0.90 mmol) in CH2Cl2 (3 ml) and N-methylmorpholine
(0.12 ml) was added 1-ethyl-3-(dimethylaminopropyl)carbodiimide hy-
drochloride (WSC·HCl; 190 mg, 0.90 mmol). After the mixture was stirred
for 1 h, a solution of 1511) (200 mg, 0.751 mmol) in CH2Cl2 (3 ml) was
antagonist activity following i.v. administration. Further
efforts to develop AVP antagonists are ongoing.
Experimental
1H- and 13C-NMR spectra were obtained on a JNM-400 spectrometer. The
chemical shifts are expressed in d (ppm) values with tetramethylsilane as an added. The whole mixture was stirred at room temperature overnight. To the
1
internal standard. Abbreviations of H-NMR signal patterns are as follows: mixture was added a saturated aqueous solution of NaHCO3, and it was ex-
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. Mass
spectra were obtained using a JEOL JMS-DX300 spectrometer. Elemental
analysis was performed with a Yanaco MT-5. Melting points were deter-
mined on a Yanaco MP-500D micro melting point apparatus without correc-
tion. Column chromatography on silica gel was performed using Merck
KGaA Silica gel 60 (0.040—0.063 mm).
tracted with CHCl3. The organic layer was dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified by column chro-
matography (eluent, CHCl3 : MeOHꢃ19 : 1), yielding 286 mg (0.655 mmol,
87% yield) of 8a as a free amine. The resulting amine (236 mg, 0.602 mmol)
was diluted with ethyl acetate (AcOEt; 10 ml), and the solution was cooled
at 0 °C. To this solution, 4 M solution of HCl in AcOEt (4 M HCl/AcOEt;
General Procedure for Synthesis of 2-Substituted Benzoic Acid Deriv- 10 ml) was added. The mixture was subsequently concentrated in vacuo and
atives (11a—f)12) A mixture of 2-fluorocyanobenzene (10, 5.00 g, 41.3
recrystallized from MeOH–diethyl ether (Et2O) to give 200 mg (0.422 mmol,
mmol), imidazole derivatives or 1H-1,2,4-triazole (41.3 mmol) and K2CO3 56% from 11a) of 8a as a colorless amorphous substance. 1H-NMR
(6.39 g, 45.4 mmol) in dimethyl sulfoxide (DMSO, 25 ml) was stirred at (DMSO-d6) d: 1.40 (1H, m), 1.84 (2H, m), 1.99 (1H, m), 2.65 (1H, m), 2.88
100 °C for 3 h. After cooling, the reaction mixture was poured into H2O (1H, m), 2.94 (1H, m), 4.82 (1H, m), 6.69 (1H, d, Jꢃ7 Hz), 6.96 (1H, m),
(50 ml) and the product was precipitated readily and separated out. The pre-
cipitate was washed with H2O (50 mlꢁ2) and dried to give 2-substituted
cyanobenzene derivatives. Then, these derivatives were hydrolyzed with
7.10 (3H, m), 7.29 (1H, d, Jꢃ7 Hz), 7.41 (2H, d, Jꢃ7 Hz), 7.65 (4H, m),
7.88 (2H, m), 9.45 (1H, s), 10.72 (1H, s). FAB-MS m/z: 465 (Mꢂꢂ1).
The compounds 8b—f were prepared from 15 and 11b—f in the same
KOH (14.5 g, 258 mmol), H2O (3.0 ml), and 2-ethoxyethanol (30 ml). After manner as described in the synthesis of 8a.
refluxing for 3 h, the reaction mixture was diluted with H2O and acidified
with 12 M HCl (20 ml) under cooling at 0 °C. The mixture was extracted with
CHCl3 (50 mlꢁ2). The organic layer was concentrated in vacuo and the
2-(2-Methyl-1H-imidazol-1-yl)-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benz-
azepin-1-yl)carbonyl]benzanilide Monohydrochloride (8b) Colorless
amorphous substance. Yield: 71%. 1H-NMR (DMSO-d6) d: 1.55 (1H, m),
residual solvent was separated as the ethanol (EtOH) azeotrope. The residue 2.05 (3H, m), 2.19 (3H, s), 2.76 (1H, m), 2.87 (1H, m), 3.05 (1H, m), 5.02
was diluted with brine and extracted with CHCl3 (50 mlꢁ2). The organic (1H, m), 6.58 (1H, d, Jꢃ7 Hz), 6.73 (1H, s), 6.90 (1H, m), 7.12 (6H, m),
extract was dried over anhydrous MgSO4 and concentrated in vacuo. The
2-substituted benzoic acid derivatives (11a—f) were obtained as a colorless
crystal by recrystallization from 2-propanol-methanol (MeOH). All physical
7.32—7.42 (3H, m), 7.65 (2H, m), 8.05 (1H, m). FAB-MS m/z: 451
(Mꢂꢂ1).
2-(2-Ethyl-1H-imidazol-1-yl)-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benz-
and spectral data for the 2-substituted benzoic acid derivatives are shown in azepin-1-yl)carbonyl]benzanilide Monohydrochloride (8c) Colorless
1
Table 4.
amorphous substance. Yield: 30%. H-NMR (DMSO-d6) d: 1.13 (3H, t, Jꢃ
Phthalamic Acid (14)13) A suspension of phthalic anhydride (13, 7 Hz), 1.57 (1H, m), 1.99 (2H, m), 2.04 (1H, m), 2.48 (2H, q, Jꢃ7 Hz), 2.74
10.0 g, 67.5 mmol) in 28% NH4OH (50 ml) was stirred at 70 °C for 10 min,
and the reagent was dissolved. After cooling to 0 °C, the product precipi-
(1H, m), 2.87 (1H, m), 3.00 (1H, m), 4.99 (1H, m), 6.61 (1H, d, Jꢃ7 Hz),
6.74 (1H, s), 6.90 (1H, m), 7.07 (6H, m), 7.22—7.32 (3H, m), 7.63 (2H, m),
tated readily and was separated out. To the filtrate, tetrahydrofuran (THF, 8.09 (1H, d, Jꢃ7 Hz). FAB-MS m/z: 465 (Mꢂꢂ1).
50 ml) was added and the precipitate was obtained again. The combined pre-
cipitates were dissolved in H2O (25 ml) and a reprecipitation was performed
with the addition of 12 M HCl (10 ml, dropwise) while cooling. The precipi-
tate was filtered and dried. The compound 14 (4.69 g, 28.4 mmol, 42%) was
obtained as a colorless crystal. 1H-NMR (DMSO-d6) d: 7.29 (1H, br), 7.35—
7.58 (3H, m), 7.65—7.76 (2H, m), 12.8 (1H, br). FAB-MS m/z: 166 (Mꢂꢂ1).
Methyl 2-Cyanobenzoate (12)14) To a stirred suspension of compound
14 (3.52 g, 21.3 mmol) in CH2Cl2 (50 ml) at 0 °C were added triethylamine
(Et3N; 6.23 ml, 44.7 mmol) and methyl chloroformate (3.62 ml, 46.8 mmol).
After stirring at room temperature for 8 h, the reaction mixture was extracted
with CHCl3, washed with H2O, dried over anhydrous MgSO4, and concen-
trated in vacuo. The product was washed with hexane and dried. The title
2-(2-Propyl-1H-imidazol-1-yl)-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benz-
azepin-1-yl)carbonyl]benzanilide Monohydrochloride (8d) Colorless
amorphous substance. Yield: 72%. 1H-NMR (DMSO-d6) d: 0.75 (3H, t,
Jꢃ7 Hz), 1.62 (4H, m), 2.04 (2H, m), 2.48 (2H, m), 2.74 (1H, m), 2.83 (1H,
m), 2.98 (1H, m), 4.99 (1H, m), 6.58 (1H, d, Jꢃ7 Hz), 6.78 (1H, s), 6.90
(1H, m), 7.10 (6H, m), 7.15—7.35 (3H, m), 7.70 (2H, m), 8.11 (1H, d,
Jꢃ7 Hz). FAB-MS m/z: 479 (Mꢂꢂ1).
2-(2-Phenyl-1H-imidazol-1-yl)-4ꢀ-(2,3,4,5-tetrahydro-1H-1-benz-
azepin-1-yl)carbonyl]benzanilide Monohydrochloride (8e) Colorless
amorphous substance. Yield: 68%. 1H-NMR (DMSO-d6) d: 1.82 (3H, m),
2.91 (4H, m), 4.82 (1H, m), 6.72 (2H, m), 7.12 (4H, m), 7.39 (8H, m), 7.72
(3H, m), 7.90 (2H, d, Jꢃ7 Hz), 10.39 (1H, s). FAB-MS m/z: 513 (Mꢂꢂ1).
2-(1H-1,2,4-Triazol-1-yl)-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-
compound 12 (3.34 g, 20.7 mmol, 97% yield) was obtained as a colorless
1
crystal. H-NMR (CDCl3) d: 3.98 (3H, s), 7.62—7.88 (3H, m), 8.06—8.21 yl)carbonyl]benzanilide Monohydrochloride (8f) Colorless amorphous
(1H, m). GC-MS m/z: 161 (Mꢂ).
substance. Yield: 33%. 1H-NMR (DMSO-d6) d: 1.93 (3H, m), 2.90 (4H, m),
5.00 (1H, m), 6.67 (1H, d, Jꢃ7 Hz), 6.80—7.10 (3H, m), 7.20 (5H, m),
2-(1H-Imidazol-1-yl)-4ꢀ-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-

768
Vol. 53, No. 7
7.41—7.75 (3H, m), 8.07 (1H, s), 8.16 (1H, br), 8.36 (1H, s). FAB-MS m/z:
438 (Mꢂꢂ1).
(2H, d, Jꢃ7 Hz), 7.08 (1H, s), 7.17 (1H, t, Jꢃ8 Hz), 7.29 (1H, t, Jꢃ8 Hz),
7.35—7.45 (4H, m), 7.60—7.71 (3H, m), 10.41 (1H, s). FAB-MS m/z: 557
(Mꢂꢂ1).
4ꢀ-[(2,3,4,5-Tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-cyanobenz-
anilide (16) The mixture of compound 12 (3.29 g, 20.4 mmol), MeOH
(60 ml) and 1 M NaOH (22 ml) were stirred at room temperature for 8 h, and
then concentrated in vacuo. The residue was diluted with H2O and CHCl3,
and then acidified with 1 M HCl (22 ml) under cooling. The resulting precipi-
tate was collected, washed with H2O and hexane, and dried in vacuo. The
corresponding benzoic acid derivative (2.21 g, 15.0 mmol, 74%) was ob-
(Z)-4ꢀ-[(5-Carbamoylmethylene-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-
benzazepin-1-yl)carbonyl]-2-(2-ethyl-1H-imidazol-1-yl)benzanilide
(9a) A mixture of compound 19 (1.0 g, 1.80 mmol), HOBt (292 mg,
2.16 mmol) and WSC·HCl (414 mg, 2.16 mmol) in DMF (20 ml) was stirred
at room temperature for 1 h. After being cooled at 0 °C, 28% NH4OH (3 ml)
was added, and the mixture was stirred at room temperature for 8 h. To the
mixture was added saturated aqueous solution of NaHCO3 and extracted
with AcOEt. The organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was chromatographed on a
silica gel column using CHCl3–MeOH (95 : 5) as the eluent, then recrystal-
lized from 2-propanol to give 583 mg (1.05 mmol, 58%) of 9a as a colorless
powder. mp 292—293 °C. 1H-NMR (DMSO-d6) d: 1.04 (3H, t, Jꢃ8 Hz),
2.39 (2H, q, Jꢃ8 Hz), 2.50 (1H, s), 2.65 (1H, br), 3.32 (1H, s), 4.87 (1H, br),
6.48 (1H, s), 6.75 (1H, d, Jꢃ7 Hz), 6.79 (1H, s), 7.06 (3H, m), 7.13 (1H, t,
Jꢃ8 Hz), 7.25—7.37 (5H, m), 7.43 (1H, d, Jꢃ7 Hz), 7.59—7.77 (3H, m),
7.95 (1H, s), 10.39 (1H, s). FAB-MS m/z: 556 (Mꢂꢂ1). Anal. Calcd for
C31H27N5O3F2·0.1H2O: C, 66.78; H, 4.24; N, 12.56; F, 6.81. Found: C,
66.35; H, 4.97; N, 12.56; F, 6.84.
tained as
a colorless crystal. The benzoic acid derivatives (663 mg,
4.51 mmol) and a drop of N,N-dimethylformamide (DMF) in CH2Cl2 (30 ml)
was added oxalyl chloride (0.59 ml, 6.76 mmol). The mixture was stirred at
room temperature for 2 h and concentrated in vacuo to give colorless oil. To
an ice-cooled mixture of 1511) (1.00 g, 3.76 mmol), pyridine (20 ml) and a
catalytic amount of 4-dimethylaminopyridine (DMAP) was added a solution
of above colorless oil in CH2Cl2 (20 ml). The mixture was stirred at room
temperature for 8 h, and then concentrated in vacuo. The residue was diluted
with CHCl3, and the organic layer was washed with 1 M NaOH, 1 M HCl, and
brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (eluent,
CHCl3/AcOEtꢃ20/1) and recrystallized from CHCl3–Et2O to give 932 mg
of 16 (2.36 mmol, 63%) as a yellow crystal. 1H-NMR (CDCl3) d: 1.80—
2.35 (3H, m), 2.70—3.15 (4H, m), 5.05 (1H, m), 6.70 (1H, d, Jꢃ7 Hz),
6.95—7.50 (7H, m), 7.70—8.15 (4H, m). FAB-MS m/z: 396 (Mꢂꢂ1).
4ꢀ-[(2,3,4,5-Tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-(1H-tetra-
Compounds 9b—k were synthesized in the same manner.
(Z)-4ꢀ-({4,4-Difluoro-5-[(N-methylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
1
yl)benzanilide (9b) Colorless powder. Yield: 37%. mp 280—281 °C. H-
zol-5-yl)benzanilide (8g)15,16)
A mixture of compound 16 (932 mg,
NMR (DMSO-d6) d: 1.04 (3H, t, Jꢃ8 Hz), 2.37 (1H, br), 2.40 (2H, q,
Jꢃ8 Hz), 2.50 (3H, d, Jꢃ7 Hz), 3.04 (1H, br), 3.33 (1H, s), 4.88 (1H, br),
6.50 (1H, s), 6.70 (1H, d, Jꢃ7 Hz), 6.79 (1H, s), 7.06 (3H, m), 7.14 (1H, t,
Jꢃ8 Hz), 7.25—7.37 (4H, m), 7.42 (1H, d, Jꢃ7 Hz), 7.59—7.70 (3H, m),
8.21 (1H, m), 10.38 (1H, s). FAB-MS m/z: 570 (Mꢂꢂ1). Anal. Calcd for
C32H29N5O3F2: C, 67.48; H, 5.13; N, 12.30; F, 6.67. Found: C, 67.19; H,
5.30; N, 12.32; F, 6.61.
2.36 mmol) and azidotributyltin (1.17 g, 3.54 mmol) in toluene (20 ml) was
refluxed for 24 h. An additional amount of azidotributyltin (2.73 g, 8.25
mmol) was added and the mixture was refluxed for 48 h. After cooling at
room temperature, to the stirred mixture was added Et2O (20 ml) and 1 M
NaOH (20 ml). After 30 min, the reaction mixture was extracted with 1 M
NaOH (20 mlꢁ2), and the combined extracts were acidified with 12 M HCl
(30 ml) under cooling. The solution was extracted with CHCl3 and the
organic layer was dried over anhydrous MgSO4 and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel
(eluent, CHCl3/MeOHꢃ30/1) and recrystallized from a mixture of CHCl3
and Et2O to give 351 mg (0.80 mmol, 34%) of 8g as a yellow amorphous
substance. 1H-NMR (DMSO-d6) d: 1.60—2.15 (3H, m), 2.53—3.17 (4H,
m), 4.85 (1H, m), 6.75 (1H, m), 6.97—7.25 (4H, m), 7.33—7.50 (3H, m),
7.70—7.82 (4H, m), 10.50 (1H, s). FAB-MS m/z: 439 (Mꢂꢂ1).
Methyl (Z)-(1-{4-[2-(2-ethyl-1H-imidazol-1-yl)benzoylamino]benzoyl}-
4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetate (18)
To an ice-cooled mixture of 2-(2-ethyl-1H-imidazol-1-yl)benzoic acid (11c,
3.00 g, 13.9 mmol) and a drop of DMF in CH2Cl2 (60 ml) was added oxalyl
chloride (1.82 ml, 20.9 mmol). The mixture was stirred at room temperature
for 3 h, diluted with CHCl3, and concentrated in vacuo to give a colorless
powder. The colorless powder (acyl chloride derivatives) was used after the
reaction without further purification. To an ice-cooled mixture of methyl
(Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-
5-ylidene]acetate (17)10) (4.31 g, 11.6 mmol) and Et3N (1.94 ml) in CH2Cl2
(40 ml) was added a solution of this colorless powder in CH2Cl2 (30 ml). The
mixture was stirred at room temperature for 8 h, and then concentrated in
vacuo. The residue was diluted with chloroform and the organic layer was
washed with saturated aqueous solution of Na2CO3, 1 M HCl and brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude product was
chromatographed on a silica gel column using CHCl3–MeOH (95 : 5), and
recrystallized from MeOH–toluene to give 4.96 g of 18 (8.70 mmol, 75%
yield) as a colorless amorphous substance. 1H-NMR (DMSO-d6) d: 1.04
(3H, t, Jꢃ7 Hz), 2.39 (2H, q, Jꢃ7 Hz), 2.50 (1H, m), 3.11 (1H, br), 3.32
(1H, s), 3.74 (3H, s), 4.86 (1H, br), 6.77 (1H, d, Jꢃ7 Hz), 6.80 (2H, d,
Jꢃ7 Hz), 7.01 (2H, d, Jꢃ7 Hz), 7.06 (1H, s), 7.20 (1H, t, Jꢃ8 Hz), 7.29 (1H,
t, Jꢃ8 Hz), 7.37—7.44 (4H, m), 7.60—7.70 (3H, m), 10.40 (1H, s). FAB-
MS m/z: 571 (Mꢂꢂ1).
(Z)-4ꢀ-({4,4-Difluoro-5-[(N-ethylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
1
yl)benzanilide (9c) Colorless powder. Yield: 63%. mp 272—274 °C. H-
NMR (DMSO-d6) d: 1.04 (3H, t, Jꢃ8 Hz), 1.06 (3H, t, Jꢃ8 Hz), 2.40 (4H,
q, Jꢃ8 Hz), 3.15 (2H, br), 3.32 (1H, s), 4.88 (1H, br), 6.49 (1H, s), 6.74 (1H,
d, Jꢃ7 Hz), 6.79 (1H, s), 7.03—7.07 (2H, m), 7.13 (1H, t, Jꢃ8 Hz), 7.27
(1H, t, Jꢃ8 Hz), 7.34 (4H, m), 7.43 (1H, d, Jꢃ7 Hz), 7.59—7.70 (3H, m),
8.27 (1H, t, Jꢃ8 Hz), 10.38 (1H, s). FAB-MS m/z: 584 (Mꢂꢂ1). Anal. Calcd
for C33H31N5O3F2: C, 67.91; H, 5.35; N, 12.00; F, 6.51. Found: C, 67.64; H,
5.45; N, 11.79; F, 6.46.
(Z)-4ꢀ-({4,4-Difluoro-5-[(N-1-propylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide Monohydrochloride (9d) The free amine of 9d was dis-
solved in 2-propanol (6 ml), and to this ice-cooled solution was added 4 M
HCl/AcOEt (0.2 ml). The resulting precipitate was filtered and dried to give
1
9d (70%) as a colorless powder. mp 252—254 °C. H-NMR (DMSO-d6) d:
0.88 (3H, m), 1.14 (3H, m), 1.45 (2H, m), 2.34 (1H, br), 2.71 (3H, br), 3.07
(2H, br), 3.43 (1H, br), 4.88 (1H, br), 6.52 (1H, s), 6.75 (1H, d, Jꢃ7 Hz),
7.06—7.15 (3H, m), 7.26 (1H, t, Jꢃ8 Hz), 7.36 (1H, d, Jꢃ7 Hz), 7.43 (2H,
d, Jꢃ7 Hz), 7.59—7.96 (6H, m), 8.32 (1H, m), 10.81 (1H, s). FAB-MS m/z:
598 (Mꢂꢂ1). Anal. Calcd for C34H33N5O3F2·HCl·0.5H2O: C, 63.50; H,
5.49; N, 10.89; F, 5.91; Cl, 5.51. Found: C, 63.30; H, 5.33; N, 10.81; F, 5.60;
Cl, 5.54.
(Z)-4ꢀ-({4,4-Difluoro-5-[(N-2-propylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide Monohydrochloride (9e) The free amine of 9e was dis-
solved in 2-propanol (10 ml), and to this ice-cooled solution was added 4 M
HCl/AcOEt (0.2 ml). After removing the volatiles, the residue was recrystal-
ized from CH3CN and dried to give 9e (89%) as a colorless powder. mp
1
182—184 °C. H-NMR (DMSO-d6) d: 1.10 (3H, s), 1.12 (3H, s), 1.15 (3H,
t, Jꢃ8 Hz), 2.07 (2H, s), 2.70 (2H, br), 3.07 (1H, br), 3.94 (1H, m), 4.88
(1H, br), 6.50 (1H, s), 6.75 (1H, d, Jꢃ7 Hz), 7.06 (2H, d, Jꢃ7 Hz), 7.13 (2H,
t, Jꢃ8 Hz), 7.27 (1H, t, Jꢃ8 Hz), 7.34 (1H, d, Jꢃ7 Hz), 7.44 (2H, d,
Jꢃ7 Hz), 7.70—7.81 (4H, m), 7.93 (1H, m), 8.15 (1H, d, Jꢃ7 Hz), 10.80
(1H, s). FAB-MS m/z: 598 (Mꢂꢂ1). Anal. Calcd for C34H33N5O3F2·HCl·
2.5H2O: C, 60.13; H, 5.79; N, 10.31; F, 5.59; Cl, 5.22. Found: C, 59.66; H,
5.31; N, 10.20; F, 5.54; Cl, 5.19.
(Z)-(1-{4-[2-(2-Ethyl-1H-imidazol-1-yl)benzoylamino]benzoyl}-4,4-di-
fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetic Acid (19)
The mixture of compound 18 (4.50 g, 7.89 mmol) in MeOH (30 ml) and 1 M
NaOH (12 ml) was stirred at room temperature for 8 h, and then concen-
trated in vacuo. The residue was diluted with H2O and CHCl3, and then
acidified with 1 M HCl (20 ml) under cooling. The mixture was extracted
with CHCl3 and the organic layer was dried over anhydrous MgSO4 and con-
centrated in vacuo. The crude product was recrystallized from 2-propanol to
give 4.50 g of 19 (quant.) as a colorless amorphous substance. 1H-NMR
(DMSO-d6) d: 1.04 (3H, t, Jꢃ7 Hz), 2.40 (2H, q, Jꢃ7 Hz), 2.50 (1H, m),
3.08 (1H, br), 3.17 (1H, s), 4.86 (1H, br), 6.60 (1H, s), 6.80 (1H, s), 7.01
(Z)-4ꢀ-({4,4-Difluoro-5-[(N-cyclopropylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide (9f) Colorless powder. Yield: 27%. mp 265—267 °C. 1H-
NMR (DMSO-d6) d: 0.45 (2H, m), 0.66 (2H, m), 1.04 (3H, t, Jꢃ8 Hz), 2.41
(2H, q, Jꢃ8 Hz), 2.35 (1H, br), 2.50 (1H, s), 3.04 (1H, br), 3.32 (1H, s), 4.87

July 2005
769
60.31; H, 5.51; N, 10.34; F, 5.61; Cl, 5.24. Found: C, 60.19; H, 5.62; N,
10.42; F, 5.36; Cl, 5.57.
(1H, br), 6.48 (1H, s), 6.73 (1H, d, Jꢃ7 Hz), 6.79 (1H, s), 7.03—7.07 (3H,
m), 7.14 (1H, t, Jꢃ8 Hz), 7.24—7.40 (4H, m), 7.44 (1H, d, Jꢃ7 Hz), 7.60—
7.70 (3H, m), 8.34 (1H, d, Jꢃ7 Hz), 10.41 (1H, s). 13C-NMR (DMSO-d6) d:
5.40 (s), 11.9 (s), 19.5 (s), 22.0 (s), 37.0 (t), 41.4 (s), 118.3 (s), 120.6 (s),
121.3 (t), 126.7 (s), 127.8 (s), 128.3 (s), 128.4 (s), 128.8 (s), 128.9 (s), 129.3
(s), 129.8 (s), 130.6 (s), 130.8 (s), 134.1 (s), 134.6 (s), 138.0 (t), 139.7 (s),
140.8 (s), 149.1 (s), 164.7 (s), 166.0 (s), 168.0 (s). FAB-MS m/z: 596
(Mꢂꢂ1). Anal. Calcd for C34H31N5O3F2: C, 68.56; H, 5.25; N, 11.76; F,
6.38. Found: C, 68.48; H, 5.35; N, 11.80; F, 6.42.
(Z)-4ꢀ-{[4,4-Difluoro-5-(2-morpholino-2-oxoethylidene)-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-2-(2-ethyl-1H-imidazol-1-
yl)benzanilide Monohydrochloride (9k) The free amine of 9k was dis-
solved in EtOH (10 ml), and to the ice-cooled solution was added 4 M
HCl/AcOEt (0.2 ml). After removing the volatiles, the residue was recrystal-
lized from EtOH–Et2O and dried to give 9k (54%) as a colorless powder. mp
1
220—222 °C. H-NMR (DMSO-d6) d: 1.15 (3H, t, Jꢃ8 Hz), 2.42 (1H, br),
2.70 (2H, br), 3.09 (2H, br), 3.51—3.61 (8H, m), 4.85 (1H, br), 6.79 (1H, s),
6.82 (1H, d, Jꢃ7 Hz), 7.05 (2H, d, Jꢃ7 Hz), 7.17 (1H, t, Jꢃ8 Hz), 7.27 (1H,
t, Jꢃ8 Hz), 7.45—7.50 (3H, m), 7.70—7.80 (5H, m), 7.95 (1H, m), 10.82
(1H, s). FAB-MS m/z: 626 (Mꢂꢂ1). Anal. Calcd for C35H33N5O4F2·HCl·
0.5H2O: C, 62.64; H, 5.26; N, 10.44; F, 5.66; Cl, 5.28. Found: C, 62.75; H,
5.26; N, 10.45; F, 5.35; Cl, 5.22.
(Z)-4ꢀ-({4,4-Difluoro-5-[(N,N-dimethylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide Monohydrochloride (9g) The free amine of 9g was dis-
solved in EtOH (10 ml), and to this ice-cooled solution was added 4 M
HCl/AcOEt (0.2 ml). After removing the volatiles, the residue was recrystal-
lized from MeOH–AcOEt and dried to give 9g (81%) as a colorless powder.
1
mp 189—191 °C. H-NMR (DMSO-d6) d: 1.16 (3H, t, Jꢃ8 Hz), 2.40 (1H,
Acknowledgements The authors are grateful to Dr. Chikashi Saitoh and
Ms. Chika Kitada for performing the cloned human receptors binding assay,
and to the staff of the Division of Analysis Research Laboratories for the
spectral measurements.
br), 2.70 (2H, br), 2.88 (3H, s), 3.03 (3H, s), 3.09 (1H, br), 3.40 (1H, br),
4.83 (1H, br), 6.79 (1H, s), 6.81 (1H, s), 7.06 (2H, d, Jꢃ7 Hz), 7.17 (2H, t,
Jꢃ8 Hz), 7.30 (1H, t, Jꢃ8 Hz), 7.45 (2H, d, Jꢃ7 Hz), 7.70—7.81 (5H, m),
7.93 (1H, m), 10.82 (1H, s). FAB-MS m/z: 584 (Mꢂꢂ1). Anal. Calcd for
C33H31N5O3F2·HCl·0.5H2O: C, 63.00; H, 5.29; N, 11.13; F, 6.04; Cl, 5.64.
Found: C, 63.06; H, 5.24; N, 11.11; F, 5.74; Cl, 5.98.
References
1) Hardman J. G., Limbird L. E., “Goodman & Gilman’s The Pharmaco-
logical Basis of Therapeutics,” 10th ed., Chap. 30, McGraw-Hill, New
York, 2001, pp. 789—808.
(Z)-4ꢀ-({4,4-Difluoro-5-[(N,N-diethylcarbamoyl)methylene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-
yl)benzanilide (9h) Colorless powder. Yield: 76%. mp 245—247 °C. H-
1
2) Michel R. H., Kirk C. J., Billah M. M., Biochem. Soc. Trans., 7, 861—
865 (1979).
3) Jard S., Kidney Int., Supp., 26, 38—42 (1988).
NMR (DMSO-d6) d: 1.13 (3H, t, Jꢃ8 Hz), 1.19 (3H, t, Jꢃ8 Hz), 1.22 (3H, t,
Jꢃ8 Hz), 2.48 (4H, q, Jꢃ8 Hz), 2.60 (1H, br), 3.22 (1H, br), 3.47 (3H, m),
5.00 (1H, br), 6.38 (1H, s), 6.66 (1H, d, Jꢃ7 Hz), 6.83 (1H, s), 7.05—7.12
(5H, m), 7.20—7.23 (2H, m), 7.26 (1H, s), 7.31—7.35 (2H, m), 7.62 (2H,
m), 8.10 (1H, m). FAB-MS m/z: 612 (Mꢂꢂ1). Anal. Calcd for C34H31-
N5O3F2·0.75H2O: C, 67.24; H, 5.88; N, 11.20; F, 6.08. Found: C, 67.15; H,
5.76; N, 11.23; F, 6.04.
4) Sugimoto T., Saito M., Mochizuki S., Watanabe Y., Hashimoto S.,
Kawashima H., J. Biol. Chem., 269, 27088—27092 (1994).
5) Yatsu T., Tomura T., Tahara A., Wada K., Tsukada J., Uchida W.,
Tanaka A., Takenaka T., Eur. J. Pharmacol., 321, 225—230 (1997).
6) Ogawa H., Yamamura Y., Miyamoto H., Kondo K., Yamashita H.,
Nakaya K., Chihara T., Mori T., Tominaga M., Yabuuchi Y., J. Med.
Chem., 36, 2011—2017 (1993).
7) Serradeil-Li Gal C., Wagnon J., Garcia C., Lacour C., Guiraudou P.,
Christophe B., Villanova G., Nisato D., Maffrand J. P., Le Fur G., Guil-
lon G., Cantau B., Barberis C., Trueba M., Ala Y., Jard S., J. Clin. In-
vest., 92, 224—231 (1993).
(Z)-4ꢀ-({4,4-Difluoro-5-[2-oxo-2-(1-piperidinyl)ethylidene]-2,3,4,5-
tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-imidazol-1-
yl)benzanilide Monohydrochloride (9i) Colorless powder. Yield: 88%.
1
mp 232—235 °C. H-NMR (DMSO-d6) d: 1.16 (3H, t, Jꢃ8 Hz), 1.47 (2H,
br), 1.52 (1H, br), 1.60 (2H, d, Jꢃ8 Hz), 2.40 (1H, br), 2.70 (2H, d, Jꢃ8 Hz),
3.09 (1H, br), 3.47 (6H, br), 4.84 (1H, br), 6.79 (2H, s), 7.06 (2H, d,
Jꢃ7 Hz), 7.16 (1H, t, Jꢃ8 Hz), 7.29 (1H, t, Jꢃ8 Hz), 7.45—7.48 (3H, m),
7.70—7.80 (5H, m), 7.95 (1H, m), 10.83 (1H, s). FAB-MS m/z: 624 (Mꢂꢂ
1). Anal. Calcd for C36H35N5O3F2·HCl·0.3H2O: C, 64.97; H, 5.54; N, 10.52;
F, 5.71; Cl, 5.33. Found: C, 64.78; H, 5.66; N, 10.47; F, 5.98; Cl, 5.36.
(Z)-4ꢀ-[(4,4-Difluoro-5-{[N-(2-methoxyethyl)carbamoyl]methylene}-
2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-(2-ethyl-1H-1-imi-
dazol-1-yl)benzanilide Monohydrochloride (9j) The free amine of 9j
was dissolved in EtOH (10 ml), and to this ice-cooled solution was added
4 M HCl/AcOEt (0.2 ml). After removing the volatiles, the residue was re-
crystallized from 2-propanol–Et2O and dried to give 9j (48%) as a colorless
powder. mp 203—205 °C. 1H-NMR (DMSO-d6) d: 1.13 (3H, t, Jꢃ8 Hz),
2.35 (1H, br), 2.72 (2H, br), 3.05 (2H, br), 3.27 (3H, s), 3.38 (4H, br), 4.89
(1H, br), 6.52 (1H, s), 6.74 (1H, d, Jꢃ7 Hz), 7.08 (2H, d, Jꢃ7 Hz), 7.12 (1H,
t, Jꢃ8 Hz), 7.26 (1H, t, Jꢃ8 Hz), 7.34 (1H, d, Jꢃ7 Hz), 7.43 (2H, d, Jꢃ
7 Hz), 7.70—7.79 (5H, m), 7.94 (1H, m), 8.47 (1H, s), 10.82 (1H, s). FAB-
MS m/z: 614 (Mꢂꢂ1). Anal. Calcd for C34H33N5O4F2·HCl·1.5H2O: C,
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