1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists

Article abstract of DOI:10.1021/jm990044m

A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Chemical modification of the R₁ and R₃ substitue

Full text of DOI:10.1021/jm990044m

J . Med. Chem. 1999, 42, 2621-2632
2621
1,3-Disu bstitu ted Ben za zep in es a s Novel, P oten t, Selective Neu r op ep tid e Y Y1
Recep tor An ta gon ists
Yasushi Murakami,* Hirokazu Hara, Tetsuo Okada, Hiroshi Hashizume, Makoto Kii, Yasunobu Ishihara,
Michio Ishikawa, Mayumi Shimamura, Shin-inchi Mihara, Goro Kato, Kohji Hanasaki, Sanji Hagishita, and
Masafumi Fujimoto
Shionogi Research Laboratories, Shionogi & Company, Ltd., Fukushima-ku, Osaka 553-0002, J apan
Received J anuary 26, 1999
A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists,
having benzazepine nuclei, have been designed, synthesized, and evaluated for activity.
Chemical modification of the R1 and R3 substituents in structure 1 (Chart 1) yields several
compounds that show high affinity for the Y1 receptor (Ki values of less than 10 nM). SAR
studies revealed that introduction of an isopropylurea group at R1 and a 3-(benzo-condensed-
urea) group, 3-(fluorophenylurea) group, or a 3-(N-(4-hydroxyphenyl)guanidine) group at R3
in structure 1 afforded potent and subtype-selective NPY Y1 receptor antagonists.
3-(3-(Benzothiazol-6-yl)ureido)-1-N-(3-(N′-(3-isopropylureido))benzyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepin-2-one (21), which was one of the most potent derivatives, competitively inhibited specific
[
125I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells (Ki )
5.1 nM). 21 not only inhibited the Y1 receptor-mediated increase in cytosolic free Ca2+
concentration in SK-N-MC cells but also antagonized the Y1 receptor-mediated inhibitory effect
of peptide YY on gastrin-induced histamine release in rat enterochromaffin-like cells. 21 showed
no significant affinity in 17 receptor binding assays including Y2, Y4, and Y5 receptors.
In tr od u ction
anxiolytic effects of centrally administered NPY. In
addition, NPY produces dramatic increases in food
intake via Y1-like receptors.13 The recently cloned Y5
receptor is thought to be the long-awaited Y1-like
receptor involved in feeding behavior,12 but the Y1
receptor also seems to play some role in food intake
because the orexigenic effects of NPY observed in Y5-
deficient mice were shown to be completely abolished
by the peptidic Y1 antagonist 1229U91.14 Thus blockade
of the Y1 receptor may be used in treating congestive
heart failure, angina pectoris, hypertension, digestive
function disorder, and obesity.
In the past few years, some non-peptide NPY Y1
receptor antagonists, such as BIBP3226 (Ki ) 7.2 nM),
SR120819A (Ki ) 15 nM), PD160170 (Ki ) 48 nM), and
LY-357897 (Ki ) 0.75 nM), have been reported.6,15,16 Also
in our laboratories, a benzodiazepine derivative was
found to have potent Y1 antagonist activities.17 In a
previous study,18 we synthesized compounds B (Ki ) 160
nM) and C (Ki ) 39 nM) with moderate binding affinity
from chemical modification of A (Ki ) 1.5 µM) (Chart
1), which was found to be active by blind screening. In
this paper, we report further optimization of these
compounds and the discovery of a series of novel, highly
potent, selective NPY Y1 receptor antagonists.
Neuropeptide Y (NPY), a 36-amino acid peptide, was
first isolated from porcine brain tissue in 1982 by
Tatemoto et al.1 NPY is widely distributed in the central
and peripheral nervous systems in many mammalian
species including humans and belongs to a family of
biologically active polypeptides such as peptide YY
(PYY) and pancreatic polypeptide (PP). The tertiary
structure of NPY was characterized by X-ray studies,2
molecular dynamics simulation, and spectral studies3-5
as a poly(proline) type II helix for residues 1-8, a â-turn
through positions 9-14, an amphipathic R-helix seg-
ment for residues 15-32, and a nonstructured C-
terminus for residues 33-36. NPY has been demon-
strated to be involved in numerous physiological
responses, such as cardiovascular regulation, food in-
take, energy regulation, pain, and anxiety via its specific
receptors.6,7
In human tissues, four receptor subtypes for NPY (Y1,
Y2, Y4, and Y5) have been identified and revealed to
belong to the seven-transmembrane receptor super-
family.6-8 The Y1 receptor was cloned and sequenced
in 1992,9 the Y2 receptor10 and the Y4/PP1 receptor11
in 1995, and the Y5 receptor in 1996.12 The best
characterized is the Y1 receptor, defined as having high
and equal affinity for NPY and PYY but low affinity for
PP and C-terminal fragments of NPY/PYY.6,7 In the
cardiovascular system, Y1 receptors in vascular smooth
muscle cells are suggested to mediate long-lasting
vasoconstriction. In the gastrointestinal tract, PYY is
reported to be involved in inhibition of gastric acid
secretion, pancreatic exocrine secretion, and gastrointes-
tinal motility via Y1 receptors. In the central nervous
system, the Y1 receptor appears to be involved in the
Ch em istr y
3-Aminobenzyl alcohol 2 was converted to urea and
then mesylated, followed by reaction with LiBr to give
benzyl bromide derivative 4 (Scheme 1). N-Alkylation
of 3-azidobenzazepine 519 was achieved by reaction with
3-N-(tert-butoxycarbonyl)aminobenzyl bromide which
was prepared by a literature procedure20 from 2 or
compound 4 under phase-transfer conditions (method
A), and then the azide group was reduced to amino
10.1021/jm990044m CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/29/1999

2622 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Murakami et al.
Ch a r t 1. General Formula 1 and Chemical Structures
of A, B, and C
Dimethyl isophthalate (56) was hydrolyzed to the
half-ester, which was converted to the next higher
homologue by Arndt-Aistert synthesis and then treated
with oxalyl chloride and iPrNH2 to afford amide 57
(Scheme 5). The ester group of 57 was reduced to the
alcohol, which was then brominated with triphenylphos-
phine and NBS to give the bromide 58. Compound 5
was N-alkylated with 58 by the same procedure cited
above to give 59.
3-Amino-ꢀ-caprolactam (60) was first treated with
phenyl isocyanate to give a urea compound, which was
then N-alkylated with 4 and NaH to give 61 (Scheme
6). 3-N-BOC-aminobenzoxazepine (62)22 was N-alkyl-
ated as above, and after removal of the BOC group, the
amino compound was converted to the urea derivative
63 (Scheme 7).
3-Azido-3,4,5,6-tetrahydro-1H-1-benzazocin-2-one (65),
which was prepared according to the same procedure
in the literature23 from 3,4,5,6-tetrahydro-1H-1-benz-
azocin-2-one (64),24 was treated with the same method
used for the preparation of 7 to give 66 (Scheme 8).
2-Amino-4-(hydroxymethyl)thiazole (67)25 was treated
with isopropyl isocyanate to give urea derivative 68,
which was converted to bromide 69 (Scheme 9). 3-Ami-
nobenzazepine (70) was N-alkylated with 69, and then
the product was treated by the same procedure de-
scribed in Scheme 2 to give 71.
Sch em e 1a
a
Reagents: (a) iPrNCO; (b) MsCl, Et3N, DMF; (c) LiBr, DMF.
compounds 6a ,b by the catalytic hydrogenolysis over
palladium on carbon. The amino compounds 6a ,b were
treated with isocyanates or carbonyldiimidazole followed
by amines to give urea derivatives 7 and 8-40 (methods
B, C). Amine 6b was converted to guanidine derivatives
41a -e by the reaction with isocyanate compounds,
followed by methylation at the sulfur position and then
treatment with amines (method D), as shown in Scheme
2.
The BOC group of 7 was removed with trifluoroacetic
acid to give 42, which was converted to carbamate
derivatives 43a -c by treatment with chloroformates or
to urea derivatives 44a -g or 45 by method B described
as above (Scheme 3).
The azide compound 5 was N-alkylated with 3-N-(tert-
butoxycarbonyl)aminobenzyl alcohol and then methyl-
ated at the nitrogen of a BOC-amino group. The azide
group at the C-3 position was converted to a phenylurea
group by the same method as described previously to
give 46. Compound 5 was also N-alkylated with 4, and
the azide group was reduced to an amino group, which
was converted to sulfonamide derivative 47 or carbam-
ate compound 48, as shown in Scheme 4. The hydroxyl
compound, which was easily prepared21 from the chlo-
ride 49,19 was then N-alkylated with 4, followed by
treatment with phenyl isocyanate to give 50. Replace-
ment of the chloride of 49 with a cyano group was
achieved with KCN in DMF. Next, the cyano group of
51 was hydrogenated catalytically in an acidic condition
to give an amino compound, which was treated with
phenyl isocyanate to give urea compound 52. The cyano
group of 51 was hydrolyzed with 10% HCl-MeOH to
the carboxylic acid 53, which was then reduced with
LiBH4 to the alcohol via the methyl ester. The alcohol
was treated with phenyl isocyanate to obtain 54. Also
the carboxylic acid of 53 was converted to amide
compound 55 by a coupling method with aniline.
Resu lts a n d Discu ssion
The compounds prepared in this study were evaluated
as NPY Y1 antagonists by testing their potency to
displace [125I]peptide YY ([125I]PYY) binding to human
neuroblastoma SK-N-MC cells. To find antagonists more
active than A or B,18 two positions for the R1 and R3
substituents of 1 (Chart 1) were selected for further
chemical modification.
Since aromatic substituents at urea are favorable for
the NPY Y1 binding affinity,18 the R3 position of the
benzazepine system was fixed with the phenylurea
moiety to carry out the chemical modification at position
R1 (Table 1). Urea derivatives in general were less
potent than guanidine derivatives but more suited for
chemical modifications because of greater stability
under most chemical reactions. First of all, we intro-
duced carbamate and urea residues to position R1.
Several modifications revealed that the sequences of
potency were iPr g tBu > Me, Ph (7, 43a -c) in the
case of carbamate derivatives and iPr > iBu > tBu >
cyclopropyl > Me . H, Ph (44a -g) in the case of urea
derivatives. In two series of substituents at the R1
position, carbamate derivatives were more potent in
binding affinity than urea derivatives. For example, 43b
(iPr carbamate) showed higher affinity than 44d (iPr
urea). Also, these data indicate that an alkyl group of
appropriate size is suitable as the residue introduced
to urea or carbamate at R1. iPr showed the highest
affinity. Only the size did not appear to be important,
since the phenyl group was not tolerated at all, as was
seen with 44g. The existence of π-electron may hinder
the interaction with the receptor. The replacement of
-NH- adjacent to the benzene ring with -CH2- was
detrimental to activity (44d vs 59). Since the N-
methylated BOC compound 46 lost its affinity, the

Benzazepines as NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2623
Sch em e 2a
a
Reagents: (a) 3-N-Boc-aminobenzyl alcohol or 4, KOH, nBu4N+Br-, THF (method A); (b) H2, 10% Pd-C, MeOH; (c) (method B) R3NCO;
(method C) 1. Imd2CO, CH3CN, 2. amines; or (method D) (i) R′NCS, (ii) 1. CH3I, 2. K2CO3, EtOH, (iii) amines; (d) 1. SOCl2, NaN3, 2. ∆,
toluene.
Sch em e 3a
a
Reagents: (a) TFA, CH2Cl2, anisole; (b) R′OCOCl, Et3N, THF; (c) Cl3CCONCO, toluene, NaHCO3(aq); (d) method B; (e) R′R′′NCOCl,
Et3N, CH2Cl2.
Sch em e 4a
a
Reagents: (a) method A; (b) NaH, MeI; (c) H2, 10% Pd-C, MeOH; (d) PhNCO; (e) method A; (f) ClSO2Ph; (g) PhOCOCl; (h) 1. HCOOH,
TEA, 2. HCl-MeOH; (i) NaH, 4; (j) KCN, nBuN+Br-, DMSO; (k) H2, 10% Pd-C, HCl/EtOH; (l) PhNCO, cat. (nBu3Sn)2O; (m) 1.10%
HCl-MeOH, 2. NaOH(aq); (n) CH2N2; (o) LiBH4, THF; (p) aniline, WSCD, HOBT, THF.
hydrogen of -NHCO- bound to the benzene ring at R1
may be necessary for the hydrogen bond with the
receptor.
Next, since 44d was the most potent compound in the
variations at R1, we fixed R1 as iPr urea to optimize the
position R3 of the benzazepine system again (Table 2).

2624 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Murakami et al.
Sch em e 5a
Sch em e 9a
a
a
Reagents: (a) iPrNCO; (b) NBS, PPh3, THF; (c) (2,4-F2)-
C6H3NCO; (e) nBuLi, 69, THF.
Reagents: (a) NaOH, MeOH; (b) 1. SOCl2, 2. CH2N2; (c) Ag2O,
1,4-dioxane; (d) 1. (COCl)2, 2. iPrNH2, toluene; (e) LiBH4; (f) NBS,
PPh3, THF; (g) 58, method A; (h) H2, 10% Pd-C, MeOH; (i)
PhNCO.
Ta ble 1. In Vitro NPY Y1 Receptor Binding Affinity (42,
43a -c, 44a -g, 45, 46, and 59)
Sch em e 6a
compd
R1
Ki (µM)a
a
Reagents: (a) PhNCO; (b) NaH, 4, DMF.
7
42
NHCOOtBu
1.2
>10
>10
0.69
>10
>10
7.3
0.91
0.043
0.075
0.14
>10
>10
>10
3.8
NH2
Sch em e 7a
43a
43b
43c
44a
44b
44c
44d
44e
44f
44g
45
NHCOOMe
NHCOOiPr
NHCOOPh
NHCONH2
NHCONHMe
NHCONH-cyclopropyl
NHCONHiPr
NHCONHiBu
NHCONHtBu
NHCONHPh
NHCO-morpholinyl
N(Me)COOtBu
CH2CONHiPr
a
Reagents: (a) 4, method A; (b) 4 N HCl-EtOAc; (c) PhNCO.
46
59
Sch em e 8a
a
Binding results are the means of two independent determina-
tions.
in 3-fold higher binding affinity (41a vs 44d ). These
findings imply that not only the distance between the
benzene ring and the benzazepine nucleus but also the
bond style of the position R3 is important for the
interaction with the Y1 receptor. Introduction of the
4-hydroxy group to the phenyl group enhanced the
binding affinity by about 2-fold (41c vs 41a ). This may
be related to the reported importance of Tyr1 and Tyr36
of NPY for the interaction with the Y1 receptor.26 41b
was the most potent compound of 41b and its N-
alkylated compounds (41c-e). The hydroxyethyl sub-
stituent 41d was the weakest, although it still showed
moderate affinity. The hydrophilic group may not be
profitable to the receptor-ligand interaction.
We explored and evaluated the effect of the introduc-
tion of heteroaromatic groups on urea substituents (8-
23). In these heteroaromatic series, the sequence of
potency for displacing [125I]PYY binding was as fol-
lows: 6-benzothiazolyl > 5-benzoxazolyl ) 5-indolyl g
5-indazolyl > phenyl > 6-quinolinyl g 4-pyridinyl g
3-quinolinyl ) 2-thiadiazolyl ) 2-thiazolyl g 2-pyradinyl
> 3-pyrazolyl. These results suggest that the benzene
a
Reagents: (a) Br2, PCl5; (b) NaN3; (c) 4, method A; (d) H2, 10%
Pd-C, MeOH; (e) PhNCO.
Replacement of the urea moiety (-NHCONHPh) with
a sulfonamide moiety (-NHSO2Ph) or carbamate moi-
eties (-NHCOOPh and -OCONHPh) resulted in de-
creases in binding affinity of 1-2 orders of magnitude
(44d vs 47, 48, 50). Substitution with an amide moiety
(-NHCOPh) led to the inactive compound 55. The
insertion of a methylene spacer resulted in approxi-
mately 10-fold drops in binding affinity (52 vs 44d and
54 vs 50). Introduction of a guanidine moiety resulted

Benzazepines as NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2625
Ta ble 2
Ta ble 3. In Vitro NPY Y1 Receptor Binding Affinity (61, 64,
66, and 71)
a. In Vitro NPY Y1 Receptor Binding Affinity
(44d , 47, 49, 50, 52, 54, 55, and 41a -e)
compd
Ki (nM)a
61
63
66
71
7000
470
56
>10000
a
Binding results are the means of two independent determina-
Ki (nM)a
tions.
compd
R3
44d
47
48
50
52
NHCONHiPr
NHSO2Ph
NHCOOPh
43
5500
2100
450
1400
4100
>10000
15
ring of the benzo-condensed ring is important for the
binding affinity (10 vs 22), that the benzene ring
connected directly with the ureido nitrogen would be
better than those connected indirectly (17 vs 18, 19 vs
20 and 21), and that the position of the benzene ring
connected with the ureido nitrogen is important for
binding affinity (20 vs 21).
Although introduction of substituting groups on the
ureidobenzene ring did not influence or reduce the
binding affinity in general, only 2-fluoro- and 2,4-
difluoro-substituted compounds 32 and 34, respectively,
showed higher affinities than the nonsubstituted com-
pound 44d . Not the electronic effect of the substituting
groups, such as electron-donating or -withdrawing, but
their bulkiness may be a factor influencing the binding
affinity as seen in compounds 24-31. 3,4-Cyclized
phenyl compounds 36-39, except the N-methylated
compound 40, were a little more potent than 44d .
Excessive bulkiness may not be beneficial for the
interaction with the receptor.
Other modifications were not tolerated, such as
elimination of the benzene ring of the benzazepine
yielding the lactam ring system (61) and introduction
of an oxygen atom into the lactam ring (63). Expansion
of the lactam ring size did not result in significant
change in binding affinity (66 vs 44d ). Also replacement
of the benzyl group at R1 with a 4-thiazolylmethyl group
produced the inactive compound 71.
To assess the Y1 selectivity of this series of com-
pounds, we selected 13 compounds with high affinity
for Y1 receptors from Table 2 (13-16, 21, 23, 32, 34,
37, 38, and 41a -c: Ki e 18 nM), 2 compounds from
Table 1 (44e,f), and 1 compound from Table 3 (66) and
measured their affinities for Y2 and Y5 receptors. None
of the compounds had affinity for either of them (Ki >
10 000 nM). These compounds also showed no affinity
for Y4 receptors (Ki > 10 000 nM). Although it was
reported that a peptide Y1 receptor antagonist, 1229U91
and related peptides, show Y4 receptor agonist activ-
ity,27,28 non-peptide Y1 antagonists might not able to
interact with Y4 receptors.
OCONHPh
CH2NHCONHPh
CH2OCONHPh
NHCOPh
54
55
41a
41b
41c
41d
41e
NHC(-NHMe)dNPh
NHC(-NH2)dNC6H4(4-OH)
NHC(-NHMe)dNC6H4(4-OH)
NHC(-NH(CH2CH2OH))dNC6H4(4-OH)
NHC(-NHiPr)dNC6H4(4-OH)
2.9
7.3
65
36
b. In Vitro NPY Y1 Receptor Binding Affinity (8-23)
compd
R3′
4-pyridinyl
2-pyradinyl
3-pyrazolyl
2-thiazolyl
1,3,4-thiadiazolyl
5-indolyl
6-benzofuryl
5-benzothienyl
6-benzothienyl
3-quinolinyl
Ki (nM)a
8
9
83
240
>10000
10
11
12
13
14
15
16
17
18
19
20
21
22
23
160
150
18
7.8
13
7.8
140
56
690
24
5.1
6-quinolinyl
2-benzothiazolyl
5-benzothiazolyl
6-benzothiazolyl
5-indazolyl
26
17
5-benzoxazolyl
c. In Vitro NPY Y1 Receptor Binding Affinity (44d and 24-40)
compd
R3′′
Ki (nM)a
44d
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
H
4-OH
4-F
43
82
29
71
88
66
610
80
Further characterization of this series of compounds
was performed with 21. The affinity of 21 was close to
that of NPY or BIBP3226, a well-known Y1 antagonist,
as shown in Figure 1A. Scatchard plot analysis revealed
that the presence of 21 changed only the Kd value of
4-Cl
4-NO2
4-NMe2
4-Ph
4-OMe
4-NH2
2-F
2,3-F2
2,4-F2
3,5-F2
200
7.6
100
7.8
86
[
125I]PYY binding without alteration of the maximal
binding (Figure 1B), suggesting apparently competitive
antagonism. The NPY Y1 receptor, as well as other NPY
receptor subtypes, belongs to the seven-transmembrane
G-protein-coupled receptor superfamily. 21 did not show
any effects on Y2, Y4, and Y5 receptor bindings or on
those of other members of the seven-transmembrane
G-protein-coupled receptor family, for example, endo-
thelins ET-A and ET-B, bombesin, angiotensins AT1
3,4-(OCH2O)-
28
18
17
25
3,4-(OCH2CH2O)-
3,4-(CH2CH2CH2)-
3,4-(CONHCO)-
3,4-(CON(Me)CO)-
780
a
Binding results are the means of two independent determina-
tions.

2626 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Murakami et al.
F igu r e 3. Effect of 21 on the inhibition by PYY of gastrin-
17-stimulated histamine release from the ECL cell-enriched
fraction. Cells were stimulated by 5 × 10-9 M gastrin-17 (G)
with or without 1 × 10-8 M PYY (P). 21 (A; 2 × 10-6 M) was
added 30 min before the stimulation. Data represent the
released histamine content and are presented as the mean (
SE from four experiments.
property of 21 as a Y1 antagonist was confirmed by
another study with ECL cells. PYY partially, but not
completely, inhibited the gastrin-evoked histamine re-
lease from ECL cells. 21 antagonized this inhibitory
effect of PYY on the histamine release (Figure 3). These
results of the functional experiments suggested that this
series of compounds including 21 are Y1 receptor-
specific antagonists.
F igu r e 1. (A) Effect of NPY (O), 21 (0), and BIBP3226 (4)
on the [125I]PYY binding to SK-N-MC cells. Symbols represent
the mean values of duplicate determinations and are repre-
sentative of those from three separate experiments. (B) Scat-
chard plot analysis of the [125I]PYY binding to SK-N-MC cells
in the absence (b) or presence (O) of 100 nM 21. The plot was
transformed from the saturation curve of the specific binding.
Con clu sion
We have discovered novel 1,3-disubstituted 2,3,4,5-
tetrahydro-1H-1-benzazepin-2-ones to be potent and
selective NPY Y1 receptor antagonists. SAR studies
revealed that introduction of an isopropylurea group at
R1 and a 3-(benzo-condensed-urea) group, 3-(fluoro-
phenylurea) group, or 3-(N-(4-hydroxyphenyl)guanidine)
group at R3 in structure 1 (Chart 1) afforded potent and
subtype-selective NPY Y1 receptor antagonists, seven
compounds of which showed Ki values of less than 10
nM. Unfortunately, there still remain some unsolved
issues with regard to the solubility of these compounds
in aqueous solution and oral bioavailability; further in
vivo evaluation of this antagonist has not been per-
formed. However, their novel and unique structure
should offer much information useful for not only the
analysis of the binding pocket of the NPY Y1 receptor
but also the exploration of clinically effective NPY Y1
receptor antagonists.
F igu r e 2. Effect of 21 on antagonist-induced increases in
cytosolic free Ca2+ concentration ([Ca2+]i) in SK-N-MC cells.
Cells were stimulated by 10-7 M NPY or 10-7 M endothelin-1
(ET-1). 21 (A) and dimethyl sulfoxide (V) were added 2 min
before the stimulation. The traces were obtained from one
experiment but are representative of three separate experi-
ments.
and AT2, bradykinins B1 and B2, cholecystokinins A
and B, calcitonin-gene-related peptide, tachykinin NK1,
and opiate-δ, -κ, and -µ receptors. In addition to the
binding profile, functional activities of 21 were exam-
ined using two types of living cells, SK-N-MC cells and
rat enterochromaffin-like (ECL) cells, both of which
have functional Y1 receptors.17,29 First, 21 dose-depend-
ently inhibited the NPY-induced, but not the endothelin-
1-induced, increase in cytosolic free Ca2+ concentration
in SK-N-MC cells (Figure 2). 21 had no effect on basal
cytosolic free Ca2+ levels, indicating it has no agonist
activity. Eight other selected compounds (15, 21, 32, 38,
41b, 44e,f, and 66) also scarcely affected the basal Ca2+
level but inhibited NPY-induced Ca2+ mobilization. The
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are not corrected. 1H
NMR spectra were recorded on Varian VXR-200 and VXR-300
FT 1H NMR spectrometers with tetramethylsilane (TMS) as
an internal reference. Fast atom bombardment mass spectra
(FABMS) and high-resolution (HR)-FABMS were determined
using m-nitrobenzyl alcohol as a matrix. Silica gel used for
column chromatography was Kiesegel 60 (Merck). Preparative
thin-layer chromatography (PLC) was carried out on E. Merck
60F-254 precoated plates (0.5-mm thickness). All reactions
were carried out under nitrogen atmosphere with anhydrous
solvents that had been dried over 4-Å molecular sieves.
The following compounds were prepared by the literature
methods: 5-benzothiazolamine,30 6-benzothiazolamine,31 5-benz-
oxazolamine,32 benzo[b]thiophen-5-amine,33 benzo[b]thiophen-

Benzazepines as NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2627
6-amine,34 6-nitrobenzofuran,35 benzo[b]thiophene-5-carboxylic
acid,36 and benzo[b]thiophene-6-carboxylic acid.36
15.6 Hz), 6.54 (1H, brs), 6.80-7.03 (8H, m), 7.35 (1H, brs),
7.62 (1H, brd, J ) 7.8 Hz). Anal. (C29H32N4O4‚1/10H2O) C, H,
N.
3-(N-(Isop r op ylu r eid o))ben zyl Alcoh ol (3). To a solution
of 3-aminobenzyl alcohol (25 g, 203 mmol) in CH3CN (45 mL)
was added a solution of isopropyl isocyanate (23 mL, 201
mmol) in CH3CN (60 mL) at 0 °C. The mixture was stirred at
room temperature for 30 min and at 50 °C for 2.5 h. EtOAc
(300 mL) was added, the reaction mixture was allowed to stand
for 30 min, and the deposited solid was collected. Trituration
with ether afforded 3 (35.3 g, 84%) as crystals, which were
used directly in the next step: mp 144-145 °C; 1H NMR
(CD3OD) δ 1.17 (6H, d, J ) 6.6 Hz), 3.88 (1H, m, J ) 6.6 Hz),
4.55 (2H, s), 6.96 (1H, d, J ) 6.9 Hz), 7.24 (2H, m), 7.32 (1H,
s). Anal. (C11H16N2O2) C, H, N.
Compounds 26, 29 (from 6b), and 44b-g (from 42) were
prepared according to a similar procedure.
Method C. P reparation of 1-N-(3-(N′-(3-Isopropylureido)-
ben zyl)-3-(3-(p yr id in -4-yl)u r eid o)-2,3,4,5-tetr a h yd r o-1H-
1-ben zazepin -2-on e (8). 3-((Im idazol-1-yl)car bon ylam in o)-
1-N-(3-(N′-(3-isop r op ylu r eid o))ben zyl)-2,3,4,5-tetr a h yd r o-
1H-1-ben za zep in -2-on e. To a solution of compound 6b (5.02
g, 13.7 mmol) in CH3CN (55 mL) was added carbonyldiimid-
azole (2.67 g 16.5 mmol) at 0 °C. After the mixture was stirred
at room temperature for 1.5 h, it was poured into water and
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
residue was triturated with Et2O to give 6.86 g (quantitative)
of the title compound: 1H NMR (CD3OD) δ 1.15 (6H, d, J )
6.6 Hz), 2.42 (2H, m), 2.53-2.77 (2H, m), 3.85 (1H, m), 4.45
(1H, dd, J ) 8.0 Hz, 11.5 Hz), 4.87 (1H, d, J ) 14.7 Hz), 5.24
(1H, d, J ) 14.7 Hz), 6.85 (1H, d, J ) 7.5 Hz), 7.04 (1H, m),
7.13 (1H, t, J ) 8.0 Hz), 7.19-7.42 (6H, m), 7.68 (1H, s), 8.30
(1H, s).
1-N-(3-(N′-(3-Isop r op ylu r eid o)ben zyl)-3-(3-(p yr id in -4-
yl)u r eid o)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (8).
To a suspension of 3-((imidazol-1-yl)carbonylamino)-1-N-(3-(N′-
(3-isopropylureido))benzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-
2-one (200 mg, 0.419 mmol) in CH3CN (1 mL) was added
4-aminopyridine (160 mg, 0.838 mmol) at 0 °C, and the
mixture stirred at room temperature for 1.5 h and was heated
to reflux for 1.5 h. After cooling, the reaction mixture was
poured into water. Extractive workup with EtOAc and PLC
(EtOAc/MeOH ) 5/1) afforded 8 (47 mg, 23%) as a powder:
1H NMR (CD3OD) δ 1.14 (6H, d, J ) 6.6 Hz), 2.00 (1H, m),
2.35-2.74 (3H, m), 3.85 (1H, m), 4.35 (1H, dd, J ) 7.8, 11.4
Hz), 4.81 (1H, d, J ) 14.7 Hz), 5.29 (1H, d, J ) 14.7 Hz), 6.84
(1H, d, J ) 7.5 Hz), 7.12 (1H, t, J ) 7.8 Hz), 7.16-7.42 (8H,
m), 8.24 (2H, d, J ) 6.6 Hz). Anal. (C27H30N6O3‚3/10MeOH‚1/
10H2O) C, H, N.
3-(N-(Isop r op ylu r eid o))ben zyl Br om id e (4). To a solu-
tion of compound 3 (2.34 g, 11.2 mmol) in DMF (23 mL) were
added triethylamine (Et3N) (2.04 mL, 14.6 mmol) and meth-
anesulfonyl chloride (1.13 mL 14.6 mmol) at 0 °C. After the
mixture was stirred at room temperature for 1 h, it was
partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc, and combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was crystallized from ether to give the
mesylate compound (2.66 g, 93%). To a solution of the mesylate
compound (2.60 g, 9.1 mmol) in DMF (20 mL) was added
lithium bromide (1.21 g, 13.9 mmol) at 0 °C. The mixture was
stirred at same temperature for 1.3 h. The same workup and
purification was done to give 5 (2.38 g, 80% from 3) as
1
crystals: mp 162-165 °C; H NMR (CD3OD) δ 1.17 (6H, d, J
) 6.6 Hz), 3.88 (1H, m, J ) 6.6 Hz), 4.50 (2H, s), 7.01 (1H, m),
7.23 (2H, m), 7.45 (1H, m). Anal. (C11H15N2OBr) C, H, N, Br.
Meth od A. P r ep a r a tion of 3-Azid o-1-N-(3-N′-(ter t-bu -
toxycar bon yl)am in oben zyl)-2,3,4,5-tetr ah ydr o-1H-1-ben z-
a zep in -2-on e. A suspension of 3-N-(tert-butoxycarbonyl)-
aminobenzyl bromide25 (3.26 g, 11.4 mmol), 5 (2.0 g, 9.89
mmol), and tetra-n-butylammonium bromide (0.33 g, 0.99
mmol) in THF (125 mL) was added to powdered KOH (742
mg, 11.4 mmol) at 0 °C and stirred at room temperature for 2
h. The reaction mixture was neutralized by 0.5 N HCl and
extracted with EtOAc. The organic extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (Et2O/n-
hexane ) 1/2) to afford 3.80 g (96%) of the title compound as
a powder: 1H NMR(CDCl3) δ 1.50 (9H, s), 2.24-2.70 (4H, m),
3.76 (1H, t, J ) 9.0 Hz), 4.85 (1H, d, J ) 14.7 Hz), 5.17 (1H,
d, J ) 14.7 Hz), 6.43 (1H, s), 6.86 (1H, d, J ) 7.5 Hz), 7.16-
7.41 (7H, m).
Compounds 9-25, 28, and 30-40 were prepared from 6b
according to a similar procedure.
Ben zo[b]th iop h en e-5-isocya n a te. To a suspention of
benzo[b]thiophene-5-carboxylic acid (573 mg, 3.22 mmol) in
toluene (5 mL) were added DMF (1 drop) and SOCl2 (0.7 mL,
9.64 mmol). After the mixture was heated to reflux for 3 h, it
was concentrated by distillation and the residue was dissolved
in THF (6 mL). Sodium azide (230 mg, 3.54 mmol) was added,
the mixture was stirred for 15 h and then filtered, and the
filtrate was evaporated to dryness. The residue was dissolved
in EtOAc and filtered and the filtrate was evaporated to
dryness to afford benzothiophene-5-carbonyl azide (657 mg,
quantitative) as crystals. Then a suspension of the carbonyl
azide compound was dissolved in toluene (6 mL) and refluxed
for 1 h. The filtrate was evaporated to dryness to give 563 mg
(quantitative) of the title compound as crystals, which were
used directly in the next step: benzothiophene-6-isocyanate
was prepared in a similar manner.
Ben zo[b]fu r a n -6-a m in e. 6-Nitrobenzofuran (100 mg, 0.613
mmol) was hydrogenated in EtOH (5 mL) with 10% Pd-C (24
mg) under hydrogen atmosphere at room temperature for 15
min. After removal of the catalyst by filtration, the filtrate was
evaporated to dryness. PLC (toluene/EtOAc ) 7/1) afforded
50 mg (61%) of the title compound as an oil: 1H NMR (DMSO-
d6) δ 1.07 (6H, d, J ) 6.6 Hz), 6.61 (1H, dd, J ) 1.2, 2.4 Hz),
6.68 (1H, dd, J ) 2.4, 8.7 Hz), 6.87 (1H, d, J ) 2.4 Hz), 8.29
(1H, d, J ) 8.7 Hz), 7.53 (1H, d, J ) 2.1 Hz).
3-Am in o-1-N-(3-N′-(ter t-bu toxyca r bon yl)a m in oben zyl)-
2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (6a ). The above
3-azide compound (3.79 g, 9.49 mmol) was hydrogenated in
MeOH (35 mL) with 10% Pd-C (370 mg) under hydrogen
atmosphere at room temperature overnight. After removal of
the catalyst by filtration, the filtrate was evaporated to dryness
to give 6a (4.09 g, quantitative) as a powder: 1H NMR (CDCl3)
δ 1.46 (9H, s), 2.21-2.66 (4H, m), 3.83 (1H, m), 4.72 (1H, d, J
) 15.3 Hz), 5.00 (1H, d, J ) 15.6 Hz), 6.76 (1H, d, J ) 7.2 Hz),
7.00-7.19 (5H, m), 7.43-7.55 (2H, m). Anal. (C22H27N3O3‚9/
10H2O) C, H, N.
Compound 6b was prepared from 5 according to a similar
procedure.
Meth od B. P r ep a r a tion of 1-N-(3-N′-(ter t-Bu toxyca r -
bon yl)a m in oben zyl)-3-(3-p h en ylu r eid o)-2,3,4,5-tetr a h y-
d r o-1H-1-ben za zep in -2-on e (7). A solution of phenyl isocy-
anate (45 µL, 0.412 mmol) in DMF (0.5 mL) was added to a
solution of compound 6a (150 mg, 0.393 mmol) in DMF (3 mL)
at 0 °C and was stirred at room temperature overnight. The
reaction mixture was diluted with water and extracted with
EtOAc. The organic extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (Et2O/n-hexane ) 3/2) to
afford 7 (137 mg, 70%) as a powder: mp 139 °C dec; 1H NMR
(CDCl3) δ 1.50 (9H, s), 1.99 (1H, m), 2.59 (2H, m), 2.80 (1H,
m), 4.65 (1H, m), 4.79 (1H, d, J ) 15.6 Hz), 5.35 (1H, d, J )
Meth od D1. P r ep a r a tion of 1-N-(3-(3-Isop r op ylu r eid o)-
ben zyl)-3-(N-m eth yl-N′-ph en ylgu an idin o)-2,3,4,5-tetr ah y-
d r o-1H-1-ben za zep in -2-on e (41a ). 1-N-(3-(3-Isop r op ylu r e-
i d o )a m i n o b e n z y l)-3-(3-p h e n y lt h i o u r e i d o )-2,3,4,5-
tetr ah ydr o-1H-1-ben zazepin -2-on e.Toa solution ofcompound
6b (300 mg, 0.819 mmol) in CH3CN (1 mL) was added
phenylthioisocynate (135 mg, 1.0 mmol) at 0 °C. After the
mixture was stirred at room temperature for 1 h, the deposited
crystals were collected by filtration to give 360 mg (85%) of

2628 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Murakami et al.
the title compound: mp 195-197 °C; 1H NMR (CD3OD) δ 1.15
(6H, d, J ) 6.3 Hz), 1.95 (1H, m), 2.50-2.70 (3H, m), 3.86 (1H,
m), 4.88 (1H, d, J ) 15.0 Hz), 5.03 (1H, dd, J ) 7.2, 10.1 Hz),
5.17 (1H, d, J ) 15.0 Hz), 6.86 (1H, d, J ) 7.5 Hz), 7.13 (1H,
t, J ) 8.1 Hz), 7.20-7.40 (11H, m). Anal. (C28H31N5O2S) C, H,
N, S.
1-N -(3-(3-I s o p r o p y lu r e id o )b e n zy l)-3-(3-S -m e t h y l-
ph en ylisoth iou r eido)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -
2-on e. A suspension of the above thiourea compound (300 mg,
0.58 mmol) and MeI (0.3 mL, 4.8 mmol) in CH3CN (1 mL) was
heated to 40 °C with stirring for 1 h. After removal of the
solvent, the residue was dissolved in water. The solution was
basified to pH 10 with 20% aqueous Na2CO3 and was extracted
with EtOAc. The extract was dried over K2CO3 and concen-
trated to afford 290 mg (94%) of the title compound as a foam,
which was used directly in the next step: 1H NMR (CD3OD)
δ 1.15 (6H, d, J ) 6.6 Hz), 2.13 (1H, m), 2.30 (3H, s), 2.40-
2.70 (3H, m), 3.85 (1H, m), 4.51 (1H, dd, J ) 7.0, 10.2 Hz),
4.97 (1H, d, J ) 15.0 Hz), 5.08 (1H, d, J ) 15.0 Hz), 6.73 (2H,
d, J ) 7.5 Hz), 5.90-7.00 (3H, m), 7.10-7.30 (8H, m).
1-N -(3-(3-Isop r op ylu r e id o)b e n zyl)-3-(N -m e t h yl-N ′-
p h en ylgu a n id in o)-2,3,4,5-t et r a h yd r o-1H -1-b en za zep in -
2-on e (41a ). To 1-N-(3-(N′-(3-isopropylureido)benzyl)-3-(3-
phenylthiomethylureido)-2,3,4,5-tetrahydro-1H-1-benzazepin-
2-one (230 mg, 0.433 mmol) was added 40% methylamine in
MeOH solution (1 mL). The mixture was heated to 80 °C with
stirring in a sealed tube for 4 h. After removal of the solvent,
the residue was purified by PLC (CH3CN/MeOH/AcOH ) 3/1/
0.2) to afford 41a (140 mg, 38%) as a powder: 1H NMR
(CD3OD) δ 1.14 (6H, d, J ) 6.3 Hz), 1.98 (1H, m), 2.40-2.70
(3H, m), 2.73 (3H, s), 3.83 (1H, m), 4.30 (1H, dd, J ) 7.2, 10.4
Hz), 4.88 (1H, d, J ) 15.3 Hz), 5.14 (1H, d, J ) 15.0 Hz), 6.83
(3H, m), 6.91 (1H, t, J ) 7.5 Hz), 7.03 (1H, t, J ) 7.5 Hz),
7.10-7.40 (8H, m). Anal. (C28H32N6O2‚0.3H2O) C, H, N.
Meth od D2. P r ep a r a tion of 3-(N-(4-Hyd r oxyp h en yl)-
N ′-m e t h y lg u a n i d i n o )-1-N -(3-(3-i s o p r o p y lu r e i d o )-
ben zyl)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (41c).
1-N -(3-(3-Isop r op ylu r e id o)b e n zyl)-3-(3-(4-(m e t h oxy-
m eth yloxy)p h en yl)th iou r eid o)-2,3,4,5-tetr a h yd r o-1H-1-
ben za zep in -2-on e. Compound 6b (1.22 g, 3.33 mmol) was
dissolved in CH3CN (12 mL) and cooled to -50 °C, and it was
added thiocarbonyldiimidazole (1.40 g, 7.86 mmol). The mix-
ture was stirred at the same temperature for 10 min and at
room temperature for 10 min. 4-(Methoxymethyloxy)aniline
(2.60 g, 17.0 mmol) was added. After 1 h the reaction mixture
was partitioned between EtOAc and water. The aqueous phase
was extracted with EtOAc, and combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by column chromatography
(toluene/EtOAc ) 1/1) to afford 3.50 g (88%) of the title
compound as a powder: 1H NMR (CD3OD) δ 1.14 (6H, d, J )
6.3 Hz), 1.95 (1H, m), 2.50-2.70 (3H, m), 3.43 (3H, s), 3.85
(1H, m), 4.83 (1H, d, 15.2 Hz), 5.00 (1H, dd, J ) 6.0, 10.0 Hz),
5.17 (2H, s), 5.21 (1H, d, J ) 15.2 Hz), 6.86 (1H, d, J ) 7.0
Hz), 7.00-7.40 (11H, m).
Na2CO3 and was extracted with EtOAc. The extract was dried
over K2CO3 and concentrated to afford 1.56 g (79%) of the title
compound as a foam, which was used directly in the next
step: 1H NMR (CD3OD) δ 1.14 (6H, J ) 6.3 Hz), 2.1 (1H, m),
2.31 (3H, s), 2.50-2.70 (3H, m), 3.86 (1H, m), 4.97 (1H, d, J )
15.0 Hz), 5.11 (1H, d, J ) 15.0 Hz), 6.50-6.70 (4H, m), 6.89
(1H, d, J ) 7.2 Hz), 7.01 (1H, t, J ) 7.8 Hz), 7.10-7.30 (6H,
m).
3-(N-(4-Hyd r oxyp h en yl)-N′-m et h ylgu a n id in o)-1-N-(3-
(3-isop r op ylu r eid o)ben zyl)-2,3,4,5-tetr a h yd r o-1H-1-ben z-
a zep in -2-on e (41c). The mixture of the above S-methyl-
phenylisothioureido compound (200 mg, 0.376 mmol) and 20%
methylamine in EtOH solution (2 mL) was heated to 70 °C
with stirring in a sealed tube for 6 h. After removal of the
solvent, the residue was purified by PLC (n-butanol/AcOH/
H2O ) 5/1/1) to afford 41c (52 mg, 27%) as a powder: 1H NMR
(CD3OD) δ 1.13 (6H, dd, J ) 1.8, 6.3 Hz), 2.05 (1H, m), 2.50-
2.70 (3H, m), 2.82 (3H, s), 3.83 (1H, m), 4.30 (1H, dd, J ) 7.2,
10.0 Hz), 4.85 (1H, d, J ) 15.0 Hz), 5.20 (1H, d, J ) 15.0 Hz),
6.63 (2H, d, J ) 8.7 Hz), 6.75 (2H, d, J ) 8.7 Hz), 6.80 (1H, t,
J ) 7.5 Hz), 7.07 (1H, t, J ) 7.5 Hz), 7.20-7.40 (6H, m). Anal.
(C29H34N6O3‚5/10H2O) C, H, N.
Compounds 41b,d ,e were prepared from 6b according to a
similar procedure.
1-N-(3-Am in oben zyl)-3-(3-ph en ylu r eido)-2,3,4,5-tetr ah y-
d r o-1H-1-ben za zep in -2-on e (42). A solution of compound 7
(1.61 g, 3.21 mmol) in CH2Cl2 (16 mL), anisole (5 mL), and
trifluoroacetic acid (5 mL) was stirred at 0 °C for 10 min and
at room temperature for an additional 3 h. After removal of
the solvent, n-hexane (80 mL) was added, and the deposited
precipitate was collected; 5% aqueous NaHCO3 was added, and
the mixture was extracted twice with ethyl acetate, washed
with 5% aqueous NaHCO3, H2O, and brine, dried over Na2SO4,
and concentrated to afford 1.36 g (quantitative) of the title
compound as a foam: 1H NMR (CD3OD) δ 1.93-2.04 (1H, m),
2.36-2.71 (3H, m), 4.72-4.40 (1H, m), 4.79 (1H, d, J ) 14.4
Hz), 5.17 (1H, d, J ) 14.7 Hz), 6.53-6.65 (3H, m), 6.94-6.99
(2H, m), 7.19-7.34 (7H, m).
1-N-(3-N′-(Meth oxycar bon yl)am in oben zyl)-3-(3-ph en yl-
u r eid o)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (43a ).
To a solution of compound 42 (158 mg, 0.375 mmol) in THF (4
mL) were added Et3N (65 µL, 0.468 mmol) and methyl
chloroformate (34 µL, 0.468 mmol) at 0 °C. The mixture was
stirred at the same temperature for 1 h and at room temper-
ature for an additional 1.4 h. The reaction mixture was
partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc, and combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by PLC (toluene/EtOAc ) 1/1)
to afford 43a (85 mg, 49%) as a powder: 1H NMR (CD3OD) δ
2.00 (1H, m), 2.36-2.73 (3H, m), 3.70 (3H, s), 4.36 (1H, dd, J
) 7.5, 11.4 Hz), 4.83 (1H, d, J ) 15.0 Hz), 5.29 (1H, d, J )
15.0 Hz), 6.92 (1H, m), 7.12-7.37 (11H, m). Anal. (C26H26N4O4‚
4/5H2O) C, H, N.
Compounds 43b,c were prepared from 42 according to a
similar procedure. Compounds 47 and 48 were prepared
according to a similar procedure from compound 6a and
benzenesulfonyl chloride or phenyl chloroformate, respectively.
3-(3-(4-Hydr oxyph en yl)th iou r eido)-1-N-(3-(3-isopr opyl-
u r eido)ben zyl)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -2-on e.
A solution of the above 4-(methoxymethyloxy)phenyl compound
(2.50 g, 4.45 mmol) in CH2Cl2 (10 mL) and trifluoroacetic acid
(5 mL) was stirred at 0 °C for 1 h. After toluene (5 mL) was
added, the mixture was concentrated to give 1.90 g (85%) of
the title compound as a foam, which was used directly in the
next step: 1H NMR (CD3OD) δ 1.13 (6H, J ) 6.3 Hz), 1.95
(1H, m), 2.50-2.70 (3H, m), 3.85 (1H, m), 4.81 (1H, d, J )
14.7 Hz), 4.99 (1H, dd, 6.9, 10.8 Hz), 5.22 (1H, J ) 14.7 Hz),
6.81 (2H, d, J ) 8.7 Hz), 6.83 (1H, d, J ) 7.0 Hz), 7.10 (1H,
m), 7.11 (2H, d, J ) 8.7 Hz), 7.20-7.40 (6H, m).
3-(3-(4-Hydr oxyph en yl)-S-m eth ylph en ylisoth iou r eido)-
1-N-(3-(3-isop r op ylu r eid o)ben zyl)-2,3,4,5-tetr a h yd r o-1H-
1-ben za zep in -2-on e. A suspension of the above thiourea
compound (1.80 g, 3.48 mmol) and MeI (3.0 mL, 46.5 mmol)
in CH3CN (30 mL) was stirred at room temperature for 3 h.
After removal of the solvent, the residue was dissolved in
water. The solution was basified to pH 10 with 20% aqueous
3-(3-P h en ylu r eido)-1-N-(3-u r eidoben zyl)-2,3,4,5-tetr ah y-
d r o-1H-1-ben za zep in -2-on e (44a ). To a solution of compound
42 (200 mg, 0.475 mmol) in toluene (3 mL) and CH3CN (0.5
mL) was added trichloroacetyl isocyanate (0.2 mL, 0.168 mmol)
at 0 °C. The mixture was stirred at room temperature for 1 h.
The deposited solid was filtered, to which EtOAc (5 mL),
MeOH (1 mL), and saturated NaHCO3 aq. (3 mL) were added
and stirred vigorously at room temperature overnight. After
removal of MeOH, EtOAc was added and treated with silica
gel. Then the silica gel was filtered off, and the filtrate was
concentrated in vacuo. The residue was recrystallized from
EtOAc to afford 44a (145 mg, 63%): mp 210-215 °C; 1H NMR
(CD3OD) δ 2.01 (1H, m), 2.4-2.6 (2H, m), 2.65 (1H, m), 4.36
(1H, dd, J ) 7.4, 11.7 Hz), 4.83 (1H, d, J ) 14.7 Hz), 5.28 (1H,
d, J ) 14.7 Hz), 6.87 (1H, d, J ) 6.3 Hz), 6.96 (1H, t, J ) 6.6

Benzazepines as NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2629
Hz), 7.14 (1H, t, J ) 7.0 Hz), 7.10-7.40 (10H, m). Anal.
P r ep a r a tion of 1-N-(3-(N′-(3-Isop r op ylu r eid o))ben z-
yl)-3-((3-p h en ylu r eid o)m et h yl)-2,3,4,5-t et r a h yd r o-1H-1-
ben za zep in -2-on e (52). 3-(Am in om eth yl)-1-N-(3-(N′-(3-iso-
pr opylu r eido))ben zyl)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -
2-on e. A solution of compound 51 (500 mg, 1.33 mmol) in
EtOH (10 mL) and 12 N HCl (0.33 mL) was hydrogenated over
10% Pd-C (300 mg) at 4.0 kg/cm2 overnight. After removal of
the catalyst by filtration, the filtrate was evaporated to
dryness. The residue was partitioned between EtOAc and 1
N HCl. The aqueous phase was basified with saturated
aqueous NaHCO3 and extracted with EtOAc. The organic
phase was washed with water and brine, dried over MgSO4,
and concentrated to give 340 mg (67%) of the title compound,
which was used directly in the next step: 1H NMR (DMSO-
d6) δ 1.07 (6H, d, J ) 6.6 Hz), 1.88-1.91 (1H, m), 2.03-2.14
(1H, m), 2.63-2.69 (1H, m), 2.99-3.06 (1H, m), 4.75 (1H, d, J
) 15.3 Hz), 5.22 (1H, d, J ) 14.7 Hz), 6.04 (1H, d, J ) 7.8 Hz),
6.70 (1H, d, J ) 7.5 Hz), 7.04-7.39 (7H, m), 8.43 (1H, s); HR-
FABMS m/z (M + H)+ 381.2291 (calcd for C22H29N4O2 m/z
381.2289).
(C25H25N5O3) C, H, N.
1-N-(3-N′-(Mor ph olin ocar bon yl)am in oben zyl)-3-(3-ph en -
ylu r eid o)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (45).
To a solution of compound 42 (200 mg, 0.499 mmol) in CH2Cl2
(2 mL) were added Et3N (77 µL, 0.55 mmol) and 4-morpho-
linecarbonyl chloride (64 µL, 0.55 mmol) at -50 °C. The
mixture was stirred at the same temperature for 1.3 h and at
room temperature for 1.3 h; 5% aqueous NaHCO3 was added,
and the mixture was extracted twice with ethyl acetate,
washed twice with H2O and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by PLC
(toluene/EtOAc/AcOH ) 50/30/0.5) to afford 45 (85 mg, 33%)
as a powder: 1H NMR (CD3OD) δ 2.00 (1H, m), 2.38-2.74 (3H,
m), 3.44 (4H, m), 3.66 (4H, m), 4.36 (1H, dd, J ) 7.5, 11.4 Hz),
4.90 (1H, d, J ) 15.0 Hz), 5.21 (1H, d, J ) 15.0 Hz), 6.90 (2H,
m), 7.15-7.36 (11H, m). Anal. (C29H31N5O4‚2/5Et2O‚5/10H2O)
C, H, N.
P r ep a r a tion of 1-N-(3-(N′-(3-Isop r op ylu r eid o))ben z-
yl)-3-(ph en ylcar bam oyloxy)-2,3,4,5-tetr ah ydr o-1H-1-ben z-
a zep in -2-on e (50). 3-(P h en ylca r ba m oyloxy)-2,3,4,5-tet-
r a h yd r o-1H-1-ben za zep in -2-on e. To a solution of 3-(hy-
droxyoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (42.8 mg,
0.241 mmol) in CH3CN (1.0 mL) and THF (0.5 mL) were added
phenyl isocyanate (27.5 µL, 0.253 mmol) and (nBu3Sn)2O (12
µL, 0.253 mmol) at 0 °C. The reaction mixture was stirred at
0 °C for 50 min and at room temperature for 30 min. After
removal of the solvent, the residue was triturated with Et2O
to give 56.6 mg (80%) of the title compound as crystals, which
were used directly in the next step: 1H NMR (DMSO-d6) δ
2.17-2.28 (1H, m), 2.45-2.59 (1H, m), 2.71-2.87 (2H, m), 4.83
(1H, dd, J ) 7.8, 11.4 Hz), 6.95-7.44 (9H, m).
1-N-(3-(N′-(3-Isop r op ylu r eid o))b en zyl)-3-(p h en ylca r -
bam oyloxy)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -2-on e (50).
The above 3-phenylcarbamoyloxy compound (50 mg, 0.168
mmol) was added to a cooled mixture of 60% NaH (6.6 mg,
0.164 mmol) in DMF (1 mL) at 0 °C. The mixture was stirred
for 30 min. Compound 4 (46 mg, 0.164 mmol) was added at 0
°C. After 30 min, it was partitioned between EtOAc and water.
The aqueous phase was extracted with EtOAc, and combined
organic extracts were washed four times with water and brine,
dried over MgSO4, and concentrated. PLC (toluene/EtOAc )
1/1) afforded 50 (72 mg, 89%) as a powder: 1H NMR (CDCl3)
δ 1.12 (6H, d, J ) 6.6 Hz), 2.20-2.76 (4H, m), 3.94 (1H, m),
4.61 (1H, d, J ) 7.2 Hz), 4.91 (1H, d, J ) 15.0 Hz), 5.09 (1H,
d, J ) 15.0 Hz), 5.09 (1H, dd, J ) 7.8, 10.8 Hz), 6.72 (1H, s),
7.00-7.40 (12H, m), 7.61 (1H, d, J ) 8.7 Hz). Anal. (C28H30N4O4‚
9/10H2O) C, H, N.
1-N-(3-(N′-(3-Isopr opylu r eido))ben zyl)-3-((3-ph en ylu r e-
ido)m eth yl)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -2-on e (52)
was prepared according to method B using the 3-aminomethyl
1
compound in 26% yield: mp 223-226 °C; H NMR (DMSO-
d6) δ 1.07 (6H, d, J ) 6.6 Hz), 1.80-2.10 (2H, m), 2.39-2.55
(3H, m), 3.25 (2H, dd, J ) 6.0, 6.0 Hz), 3.72 (1H, m), 4.70 (1H,
d, J ) 15.0 Hz), 5.31 (1H, d, J ) 15.0 Hz), 5.91 (1H, d, J ) 7.8
Hz), 6.30 (1H, t, J ) 6.0 Hz), 6.69 (1H, d, J ) 7.5 Hz), 6.85
(1H, t, J ) 7.5 Hz), 7.00-7.40 (11H, m), 8.26 (1H, s), 8.52 (1H,
s). Anal. (C29H33N5O3) C, H, N.
P r ep a r a tion of 3-Ca r boxy-1-N-(3-(N′-(3-isop r op ylu r e-
ido))ben zyl)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin -2-on e (53).
1-N-(3-(N′-(3-Isop r op ylu r eid o))b en zyl)-3-(m et h oxyca r -
bon yl)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e. A sus-
pension of compound 51 (300 mg, 0.797 mmol) in 10% HCl in
MeOH solution (4.5 mL) and a small amount of THF were
heated in a sealed tube at 70 °C for 3 h and at 50 °C for 14 h.
After concentration, 10% HCl in MeOH solution (7 mL) was
added to the residue; the solution was heated in a sealed tube
at 80 °C for 32 h. It was poured into water and extracted with
EtOAc. The organic phase was washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, and concentrated. PLC
(toluene/EtOAc ) 1/1) afforded 150 mg (46%) of the title
compound as a foam, which was used directly in the next
step: 1H NMR (DMSO-d6) δ 1.07 (6H, d, J ) 6.6 Hz), 2.15
(1H, m), 2.44-2.58 (3H, m), 3.30 (1H, m), 3.58 (3H, m), 3.72
(1H, m), 4.66 (1H, brs), 5.27 (1H, brs), 5.71 (1H, d, J ) 7.5
Hz), 6.67 (1H, d, J ) 7.5 Hz), 7.06 (1H, t, J ) 7.8 Hz), 7.10-
7.50 (6H, m), 8.27 (1H, m); HR-FABMS m/z (M + H)+ 410.2081
(calcd for C23H28N3O4 m/z 410.2079).
3-Car boxy-1-N-(3-(N′-(3-isopr opylu r eido))ben zyl)-2,3,4,5-
tetr a h yd r o-1H-1-ben za zep in -2-on e (53). To the above 3-
methyl ester compound (125 mg, 0.305 mmol) was added 4 N
aqueous NaOH (0.14 mL) at 0 °C. The mixture was stirred at
room temperature for 3 h 20 min. After removal of the solvent,
1 N HCl was added and the mixture extracted with EtOAc.
The organic phase was washed with brine, dried over MgSO4,
and concentrated to afforded 125 mg (quantitative) of the title
compound as a foam, which was used directly in the next
step: 1H NMR (DMSO-d6) δ 1.07 (6H, d, J ) 6.6 Hz), 2.15
(1H, m), 2.44-2.51 (1H, m), 3.72 (1H, m), 4.71 (2H, m), 5.23
(2H, m), 5.90 (1H, d, J ) 7.2 Hz), 6.69 (1H, d, J ) 7.8 Hz),
7.42-7.83 (7H, m), 8.25 (1H, s), 12.37 (1H, s).
P r epar ation of 3-Cyan o-1-N-(3-(N′-(3-isopr opylu r eido))-
b en zyl)-2,3,4,5-t et r a h yd r o-1H -1-b en za zep in -2-on e (51).
3-Ch lor o-1-N-(3-(N′-(3-isop r op ylu r eid o))b en zyl)-2,3,4,5-
tetr a h yd r o-1H-1-ben za zep in -2-on e was prepared according
to method A using 3-chloro-2,3,4,5-tetrahydro-1H-1-benz-
azepin-2-one in 97% yield: 1H NMR (CDCl3) δ 1.15 (6H, d, J
) 6.3 Hz), 2.35-2.63 (4H, m), 3.97 (1H, m), 4.44-4.50 (1H,
m), 4.94 (1H, d, J ) 14.7 Hz), 5.09 (1H, d, J ) 14.7 Hz), 6.77
(2H, d, J ) 6.3 Hz), 7.11-7.31 (6H, m), 7.42-7.45 (1H, m).
3-Cya n o-1-N-(3-(N′-(3-isop r op ylu r eid o))ben zyl)-2,3,4,5-
tetr a h yd r o-1H-1-ben za zep in -2-on e (51). A mixture of the
above 3-chloro compound (5.0 g, 13.0 mmol), KCN (1.953 g,
34.9 mmol), and nBu4NBr (388 mg, 3.49 mmol) in DMSO (20
mL) was heated to 115 °C with stirring for 9 h and stirred at
room temperature overnight. The reaction mixture was par-
titioned between EtOAc and water. The aqueous phase was
extracted with EtOAc, and combined organic extracts were
washed four times with water and brine, dried over MgSO4,
and concentrated to give a foam. Trituration with EtOAc gave
51 (2.99 g, 59%) as crystals: mp 216-217 °C; 1H NMR (DMSO-
d6) δ 1.07 (6H, d, J ) 6.3 Hz), 2.39-2.61 (4H, m), 3.72 (1H,
m), 3.84 (1H, t, J ) 9.6 Hz), 4.73 (1H, d, J ) 14.7 Hz), 5.21
(1H, d, J ) 14.7 Hz), 5.91 (1H, d, J ) 7.5 Hz), 6.69 (1H, d, J
) 7.8 Hz), 7.07-7.44 (7H, m), 8.27 (1H, s); HR-FABMS m/z
(M + H)+ 377.1975 (calcd for C22H25N4O2 m/z 377.1976).
P r ep a r a tion of 1-N-(3-(N′-(3-Isop r op ylu r eid o))ben zyl)-
3-(p h en ylca r ba m oyloxym eth yl)-2,3,4,5-tetr a h yd r o-1H-1-
b en za zep in -2-on e (54). 3-(H yd r oxym et h yl)-1-N-(3-(N′-
(3-isopr opylu r eido))ben zyl)-2,3,4,5-tetr ah ydr o-1H-1-ben z-
a zep in -2-on e. Compound 53 (753 mg, 0.19 mmol) was esteri-
fied by diazomethane. To a solution of the resulting 3-meth-
oxycarbonyl compound in THF (2 mL) was added LiBH4 (42
mg, 1.93 mmol) at 0 °C, and the mixture was stirred at room
temperature for 1 h 15 min. The reaction mixture was
quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The organic extracts were washed with H2O and brine,

2630 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Murakami et al.
dried over MgSO4, and concentrated in vacuo. Trituration with
EtOAc gave 247 mg (34%) of the title compound as crystals:
mp 87-91 °C; H NMR (CDCl3 + CD3OD) δ 1.15 (6H, d, J )
6.3 Hz), 1.99-2.11 (2H, m), 2.51-2.68 (3H, m), 3.63 (1H, dd,
J ) 3.9, 12.6 Hz), 3.79-3.95 (2H, m), 4.92 (1H, d, J ) 15.0
Hz), 5.02 (1H, d, J ) 15.3 Hz), 6.77 (1H, d, J ) 7.5 Hz), 7.05
(1H, m), 7.14-7.26 (5H, m), 7.49 (1H, dd, J ) 2.1, 8.4 Hz).
Anal. (C22H27N3O3‚1/5H2O) C, H, N.
stirred for 20 min. The mixture was filtered, and the residue
was partitioned between EtOAc and 1 N HCl. The aqueous
phase was extracted with EtOAc. The organic extract was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated to give 57 (302 mg, 50%) as a
powder: 1H NMR (CDCl3) δ 1.05 (6H, d, J ) 6.6 Hz), 3.44 (2H,
s), 3.80 (1H, s), 3.85 (3H, s), 7.42-7.54 (2H, m), 7.80-7.88 (2H,
m), 7.90 (1H, d, J ) 7.2 Hz). Anal. (C13H17NO3) C, H, N.
1
1-N-(3-(N′-(3-Isop r op ylu r eid o))b en zyl)-3-(p h en ylca r -
ba m oyloxym eth yl)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -
2-on e (54) was prepared in a similar to that described in the
preparation of compound 52 using the 3-hydroxymethyl com-
pound: 73% yield; 1H NMR (CDCl3) δ 1.11 (6H, d, J ) 6.6
Hz), 1.94 (4H, m), 2.12 (1H, m), 2.50-2.72 (2H, m), 2.84 (1H,
m), 3.92 (1H, m), 4.25 (1H, m), 4.50 (1H, m), 4.66 (1H, d, J )
8.1 Hz), 4.81 (1H, d, J ) 15.0 Hz), 5.16 (1H, d, J ) 15.0 Hz),
6.63 (1H, s), 6.85 (1H, d, J ) 7.2 Hz), 6.72 (1H, s), 7.00-7.36
(13H, m). Anal. (C29H31N4O4‚3/10H2O) C, H, N.
3-(An ilin oca r b on yl)-1-N-(3-(N′-(3-isop r op ylu r eid o))-
ben zyl)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (55). To
a solution of compound 53 (110 mg, 0.278 mmol), HOBT (3.8
mg, 0.028 mmol), and aniline (25 mL, 0.278 mmol) in THF (1
mL) was added 1-(3-(dimethylamino)propyl)-3-ethoxycarbon-
yldiimide hydrochloride (43 mg, 0.278 mmol) at 0 °C, and the
mixture was stirred at room temperature for 3 h. The reaction
mixture was partitioned between EtOAc and water. The
aqueous phase was extracted with EtOAc, combined organic
extracts were washed with H2O and brine, dried over MgSO4,
and concentrated, and the deposited solid was collected.
Trituration with Et2O gave 55 (61 mg, 47%) as a powder: 1H
NMR (DMSO-d6) δ 1.07 (6H, d, J ) 6.6 Hz), 2.05 (4H, m),
2.50-2.70 (3H, m), 3.40 (1H, m), 3.72 (1H, m), 4.70 (1H, d, J
) 15.0 Hz), 5.30 (1H, d, J ) 15.0 Hz), 5.90 (1H, d, J ) 7.5 Hz),
6.73 (1H, d, J ) 7.5 Hz), 7.00-7.40 (9H, m), 7.49 (1H, d, J )
7.8 Hz), 7.55 (2H, d, J ) 7.5 Hz), 8.26 (1H, s), 9.84 (1H, s).
Anal. (C28H30N4O3‚3/10H2O) C, H, N.
P r ep a r a t ion of Met h yl 3-(Isop r op yla m in oca r b on yl-
m et h yl)b en zoa t e (57). (i) A suspension of dimethyl iso-
phthalate (7.02 g, 36.2 mmol) in 1 M NaOH in MeOH solution
was stirred overnight. The mixture was neutralized with HCl
and evaporated to dryness. The residue was partitioned
between toluene and saturated aqueous NaHCO3. The aqueous
phase was acidified with concentrated aqueous HCl and
extracted with EtOAc. The organic extract was washed with
saturated aqueous NaHCO3, dried over MgSO4, and concen-
trated. Trituration with EtOAc gave the monocarboxylic acid
(4.0 g, 61%) as crystals: 1H NMR (DMSO-d6) δ 3.90 (3H, s),
7.68 (1H, t, J ) 7.5 Hz), 8.18-8.22 (2H, m), 8.49 (1H, s), 13.31
(1H, brs).
(ii) To thionyl chloride (3.40 mL, 46.9 mmol) in toluene (20
mL) was added the above monocarboxylic acid compound (4.02
g, 23.3 mmol) and DMF (3 drops). The mixture was heated to
92 °C with stirring for 50 min and then concentrated in vacuo
to give an oil. A solution of diazomethane in Et2O was added
dropwise to the oil at 0 °C and evaporated to dryness to give
the diazo compound (4.77 g, quantitative): 1H NMR (CDCl3)
δ 3.95 (3H, s), 5.99 (1H, s), 7.55 (1H, t, J ) 7.5 Hz), 8.02 (1H,
dt, J ) 1.5, 7.8 Hz), 8.21 (1H, dt, J ) 1.5, 7.5 Hz), 7.36 (1H, t,
J ) 7.8 Hz).
3-(Isopr opylam in ocar bon ylm eth yl)ben zyl Br om ide (58).
To a solution of compound 57 (457 mg, 1.94 mmol) in THF
(9.5 mL) was added 0.878 M LiBH4 in THF solution (3.93 mL)
at -65 °C. The mixture was warmed to 0 °C with stirring for
30 min. It was cooled to -55 °C, then H2O was added, and it
was warmed to room temperature. After filtration, the filtrate
was concentrated in vacuo to give the alcohol compound (400
mg). To the alcohol compound (100 mg, 0.482 mmol) in THF
(1 mL) were added PPh3 (140 g, 0.53 mmol) and NBS (82 mg,
0.458 mmol). The mixture was stirred for 30 min, and n-hexane
was added. The resulting precipitate was filtered off, and the
filtrate was concentrated. The residue was purified by PLC
(EtOAc/toluene ) 1/1) to afford 58 (87 mg, 67%) as crystals:
mp 94-97 °C; 1H NMR (CDCl3) δ 1.09 (6H, d, J ) 6.6 Hz),
3.52 (2H, s), 4.07 (1H, m), 4.49 (2H, s), 5.18 (1H, brs), 7.18-
7.34 (4H, m). Anal. (C12H16NOBr) C, H, N, Br.
1-N-(3-Isopr opylam in ocar bon ylm eth yl)-3-(3-ph en ylu r e-
id o)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in -2-on e (59) was
prepared according to the same procedure from 5 to 7 using
compound 58 in 77% yield: mp 178-179 °C; 1H NMR (200
MHz, CDCl3) δ 0.82 (3H, d, J ) 6.6 Hz), 0.99 (3H, d, J ) 6.6
Hz), 2.00 (1H, m), 2.45-2.90 (3H, m), 3.29 (1H, d, J ) 14.0
Hz), 3.37 (1H, d, J ) 14.0 Hz), 3.93 (1H, m), 4.60 (1H, m),
4.74 (1H, d, J ) 15.6 Hz), 5.46 (1H, d, J ) 15.6 Hz), 6.33 (1H,
d, J ) 7.8 Hz), 6.47 (1H, d, J ) 8.2 Hz), 6.80-7.40 (14H, m).
Anal. (C29H32N4O3) C, H, N.
P r ep a r a tion of 5-N-(3-(3-Isop r op ylu r eid o)ben zyl)-3-(3-
p h en ylu r eid o)-2,3-d ih yd r o-5H -1,5-b en zoxa zep in -4-on e
(63). 3-(ter t-Bu toxyca r bon yla m in o)-5-N-(3-(3-isop r op yl-
u r eido)ben zyl)-2,3-dih ydr o-5H-1,5-ben zoxazepin -4-on e was
prepared according to method A using 3-(tert-butoxycarbonyl-
amino)-2,3-dihydro-5H-1,5-benzoxazepin-4-one in 70% yield:
mp 197-205 °C; 1H NMR (CD3OD) δ 1.15 (6H, d, J ) 6.6 Hz),
1.41 (9H, s), 3.85 (1H, m), 4.28-4.45 (2H, m), 4.59-4.66 (1H,
m), 4.63 (1H, dd, J ) 7.8, 11.4 Hz), 4.90 (1H, d, J ) 15.6 Hz),
5.26 (1H, d, J ) 15.9 Hz), 6.85 (1H, d, J ) 7.2 Hz), 6.83-7.40
(8H, m).
3-Am in o-5-N-(3-(3-isopr opylu r eido)ben zyl)-2,3-dih ydr o-
5H-1,5-ben zoxa zep in -4-on e. To the 3-BOC compound (240
mg, 0.512 mmol) was added 4 N HCl in EtOAc solution at 0
°C. The mixture was stirred at room temperature for 0.5 h.
The reaction mixture was evaporated to dryness, and the
residue was washed with Et2O; 5% aqueous NaHCO3 was
added, and the mixture was extracted twice with ethyl acetate,
washed twice with H2O and brine, dried over MgSO4, and
concentrated to afford 150 mg (80%) of the title compound as
a powder, which was used directly in the next step: 1H NMR
(CD3OD) δ 1.15 (6H, d, J ) 6.3 Hz), 3.81-3.89 (2H, m), 4.15-
4.22 (1H, m), 4.39-4.45 (1H, m), 4.96 (1H, d, J ) 15.9 Hz),
5.20 (1H, d, J ) 15.0 Hz), 6.87 (1H, d, J ) 7.5 Hz), 7.11-7.37
(7H, m).
(iii) A solution of the above diazo compound in 1,4-dioxane
(64 mL) was added to a suspension of Ag2O (680 mg, 2.94
mmol) in H2O and heated to 55 °C. After 15 min, Ag2O (680
mg, 2.94 mmol) was added, continued to stir at 55 °C for 10
min, and concentrated. Workup was done the same as in (i) to
give the monocarboxylic acid 1.137 g (60%) as an oil: 1H NMR
(DMSO-d6) δ 3.48 (2H, s), 3.84 (3H, s), 7.39 (1H, t, J ) 7.5
Hz), 7.50 (1H, d, J ) 7.8 Hz), 8.21 (1H, d, J ) 7.8 Hz), 7.76
(1H, t, J ) 7.5 Hz), 7.86 (1H, s).
(iv) To the above carboxylic acid compound (500 mg, 2.58
mmol) in toluene (2 mL) were added oxalyl chloride (0.675 mL,
7.73 mmol) in toluene (2 mL) and DMF (3 drops). The reaction
mixture was heated to 50 °C and stirred for 15 min. After
concentrated, the resulting oil was dissolved in toluene (1 mL).
Isopropylamide (0.88 mL, 10.3 mmol) was added at 0 °C and
5-N-(3-(3-Isop r op ylu r eid o)ben zyl)-3-(3-p h en ylu r eid o)-
2,3-d ih yd r o-5H-1,5-ben zoxa zep in -4-on e (63) was prepared
according to method B in 81% yield: mp 237-239.5 °C; 1H
NMR (CD3OD + DMSO-d6) δ 1.13 (6H, d, J ) 6.6 Hz), 3.82
(1H, m), 4.30 (1H, m), 4.55 (1H, m), 4.84 (1H, dd, J ) 7.8, 11.4
Hz), 4.93 (1H, d, J ) 15.9 Hz), 5.29 (1H, d, J ) 15.9 Hz), 6.85
(1H, d, J ) 7.8 Hz), 6.97 (1H, t, J ) 7.2 Hz), 7.10-7.50 (11H,
m). Anal. (C28H32N6O3‚3/10H2O) C, H, N.
1-N-(3-(N′-(3-Isop r op ylu r eid o))ben zyl)-3-(3-p h en ylu r e-
id o)-3,4,5,6-tetr a h yd r o-1H-1-ben za zocin -2-on e (66) was
prepared according to the same procedure from 5 to 7 using
compound 65 in 44% yield: mp 241-244 °C; 1H NMR (DMSO-
d6) δ 1.06 (6H, d, J ) 6.6 Hz), 1.30 (1H, m), 1.75 (2H, brs.),
2.00 (2H, m), 2.50 (2H, m), 3.70 (1H, m), 3.80 (1H, m), 4.55
(1H, d, J ) 14.4 Hz), 5.19 (1H, d, J ) 14.4 Hz), 5.91 (1H, d, J

Benzazepines as NPY Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2631
) 7.5 Hz), 6.58 (2H, d, J ) 8.1 Hz), 6.66 (1H, d, J ) 7.2 Hz),
6.87 (1H, t, J ) 7.2 Hz), 7.05-7.35 (11H, m), 8.24 (1H, s), 8.71
(1H, s). Anal. (C29H33N5O3‚4/5H2O) C, H, N.
4-(Hydr oxym eth yl)-2-(isopr opylu r eido)th iazole (68) was
prepared in a similar manner to that described in the prepara-
tion of compound 5 in 44% yield: mp 163-165 °C; 1H NMR
(DMSO-d6) δ 1.11 (6H, d, J ) 6.3 Hz), 3.37 (1H, m), 4.37 (2H,
d, J ) 6.0 Hz), 5.11 (1H, t, J ) 6.0 Hz), 6.41 (1H, d, J ) 7.5
Hz), 6.70 (1H, s). Anal. (C8H13N3O2S) C, H, N, S.
20 mM HEPES-buffered Hank’s solution (pH 7.4) at a con-
centration of 0.5 × 106 cells/mL in a cuvette (50-mm × 7-mm
diameter) and continuously stirred. Antagonists were added
1 min before the addition of NPY or endothelin-1. Fluorescence
measurements were done with a spectrofluorometer (CAF-100,
J apan Spectroscopy Inc., Tokyo, J apan) as described previ-
ously.7
Hista m in e Exp er im en ts.41 Histamine release was deter-
mined after 48-h short-term culture by incubating isolated
ECL cells in a six-well plate containing 1 mL of HBSS. Cells
(2 × 105/well plate) were stimulated by 5 × 10-9 M gastrin-17
with or without 1 × 10-8 M PYY at 37 °C for 60 min. 21 (2 ×
10-6 M) was added 30 min before the stimulation. Dimethyl
sulfoxide was used as a vehicle for 21 at a final concentration
of less than 0.5%, which did not alter histamine release.
Histamine content was determined by the HPLC method.
4-(Br om om eth yl)-2-(isop r op ylu r eid o)th ia zole (69) was
prepared in a similar manner to that described in the prepara-
1
tion of compound 58 using 68 in 25% yield: mp 94-97 °C; H
NMR (CDCl3) δ 1.26 (6H, d, J ) 6.6 Hz), 4.03 (1H, m), 4.45
(2H, s), 6.78 (1H, s). Anal. (C12H16NOBr) C, H, N.
P r ep a r a tion of 3-((3-(2,4-Diflu or op h en yl)u r eid o)m eth -
yl)-1-N-(2-(isop r op ylu r eid o)t h ia zol-4-ylm et h yl)-2,3,4,5-
t et r a h yd r o-1H -1-b en za zep in -2-on e (71). 3-((3-(2,4-Di-
flu or oph en yl)u r eido)m eth yl)-2,3,4,5-tetr ah ydr o-1H-1-ben z-
a zep in -2-on e was prepared according to method B using
3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, 70,24 and
2,4-difluorophenyl isocyanate: 91% yield; mp 193-195 °C; 1H
NMR (DMSO-d6) δ 1.87-1.97 (1H, m), 2.37-2.48 (1H, m),
2.66-2.82 (2H, m), 4.14 (1H, dd, J ) 7.5, 9.0 Hz), 6.91-7.33
(6H, m), 7.91-7.99 (1H, m).
Su p p or tin g In for m a tion Ava ila ble: Characteristic data
for part of the synthetic intermediates and final products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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