Novel nonpeptide CCK-B antagonists: Design and development of quinazolinone derivatives as potent, selective, and orally active CCK-B antagonists

Article abstract of DOI:10.1021/jm970373j

We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our 'target' produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.

Full text of DOI:10.1021/jm970373j

1042
J . Med. Chem. 1998, 41, 1042-1049
Novel Non p ep tid e CCK-B An ta gon ists: Design a n d Develop m en t of
Qu in a zolin on e Der iva tives a s P oten t, Selective, a n d Or a lly Active CCK-B
An ta gon ists1
J anak K. Padia,*,† Mark Field,‡ J oanna Hinton,§ Ken Meecham,‡ J ulius Pablo,§ Rob Pinnock,‡ Bruce D. Roth,†
Lakhbir Singh,‡ Nirmala Suman-Chauhan,‡ Bharat K. Trivedi,† and Louise Webdale‡
Departments of Chemistry and of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of
Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, and Parke-Davis Neuroscience Research Centre,
Cambridge University Fotvie Site, Robinson Way, Cambridge CB2 2QB, U.K.
Received J une 6, 1997
We have designed a novel series of CCK-B receptor antagonists by combining key pharma-
cophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our
earlier studies showed that compounds with methylene linkers in our “target” produced
moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower
homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced
binding affinity and selectivity for CCK-B receptors, thus providing several compounds with
single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies
of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred
substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal
phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested
in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally
active in the elevated rat X-maze test. These compounds were also evaluated for their
pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.
In tr od u ction
antagonists which might possess even better pharma-
cokinetic properties.
Cholecystokinin (CCK), a 33-amino acid polypeptide,
is distributed in various molecular forms throughout the
peripheral and central nervous system.2 The receptors
for CCK have been classified in two subtypes, CCK-A
and CCK-B, by using various radiolabeled probes.3
CCK-A receptors exist primarily in peripheral tissues,
such as the gall bladder and pancreas, whereas CCK-B
receptors are mainly located in the central nervous
system.4,5 Discovery of potent and selective ligands for
both CCK-A and CCK-B receptors has provided further
support for the existence of two receptor subtypes.
Recently, cloning and expression of both of the CCK
receptors from rat and human have been achieved.6-8
It has been postulated that CCK-B is involved in a
variety of neurological disorders such as anxiety, pain,
and panic disorder.9,10 These findings have led to the
development of a variety of CCK-B receptor antagonists
with remarkable structural diversity for the treatment
of neurological diseases.11 Earlier, we reported CI-
988,12 a ‘peptoid’ analogue of CCK-4, as a clinical
candidate which showed poor oral bioavailability in both
preclinical and clinical studies.13-16 Further optimiza-
tion in the ‘peptoid’ series provided CI-1015 with an
improved pharmacokinetic profile;17 however, we felt the
need to develop potent and selective nonpeptide CCK-B
Asperlicin, a weak and nonselective CCK ligand,18 has
been used as a template for designing distinct series of
novel nonpeptide CCK ligands by many research groups
(Table 1).19-24 On the basis of earlier studies, we
recently outlined our approach to designing a novel
series of CCK-B antagonists (Figure 1).25 The initial
results showed that the linker between the two key
moieties was critical for CCK-B binding affinity. Com-
pound 7, with a methylene group as a linker, showed
moderate binding affinity and selectivity for CCK-B
receptors, whereas its higher and lower homologues (8
and 12) resulted in loss of binding affinity (Table 2). We
anticipated that the optimal linker between the two key
moieties, the quinazolinone ring and the arylurea
functionality, would bring the cyclic amide group of the
constrained quinazolinone and the urea moieties into a
preferred orientation, thus providing more potent and
selective CCK-B antagonists. As a part of our continued
search for the optimal linker, we decided to explore the
effect of a heteroatom as a linker. Thus, we introduced
the -NH- group as a linker and observed dramatic
improvement in CCK-B binding affinity and selectivity.
In this paper, we present the synthesis, structure-
activity relationship, functional and in vivo activities,
and pharmacokinetic profile of compounds in this new
series.
* Author to whom correspondence should be addressed. Present
address: Systems Integrated Drug Discovery Co., 9000 S. Rita Road
BLDG 40, Tucson, AZ 85747.
Ch em istr y
† Department of Chemistry, Parke-Davis Pharmaceutical Research.
‡ Parke-Davis Neuroscience Research Centre.
Compounds with methylene and ethylene linkers, 7
and 8, respectively, were prepared as shown in Scheme
1. Coupling of methyl anthranilate with protected
§ Department of Pharmacokinetics and Drug Metabolism, Parke-
Davis Pharmaceutical Research.
S0022-2623(97)00373-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/06/1998

Novel Nonpeptide CCK-B Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1043
Ta ble 1. Binding Affinities of Reference Compounds
binding affinity and selectivity of compound 13 suggest
that the -NH- group may play an important role in
interactions with the CCK-B receptor. The correspond-
ing amide analogue 14 was less active, suggesting the
requirement of the N-arylurea functionality for CCK-B
potency.
IC50 (nM)
compd
R1
3-Me
3-COOMe
3-MeO
3-MeO
3-iPrO
R2
CCK-B
CCK-A
A/B
1a
1b
2a
2b
3a
3b
8.521
8.021
8.022
2322
74021
120021
14022
87
150
18
3-Me
3-COOH
Br
92522
40
Having identified the -NH- linker as critical for
CCK-B binding affinity and selectivity, we then chose
to search for the optimal substitution on the N-3 position
of quinazolinone with -NH- as a linker. We selected
two preferred substitutions, 3-methyl and 3-carbethoxy,
on to the N-phenyl ring of the urea moiety from our
previous study.30 Compounds shown in Tables 3 and 4
were prepared simultaneously and are segregated only
for the purpose of clarity. The binding data for the
compounds shown in Table 3 suggested that the com-
pounds with one chloro substitution on the urea termi-
nus phenyl ring (18 and 19) showed no significant
improvement in binding affinities, whereas compounds
20 and 21, with dichloro substitution, showed moderate
improvement in the CCK-B binding affinity. In the case
of alkoxy group substitution at the meta position of the
phenyl ring, an increase in the size of the alkoxy side
chain at the group (methoxy 22, ethoxy 24, and isopro-
poxy 25) showed improved CCK-B binding. Thus,
compound 25, with 3-isopropoxyphenyl substitution,
showed 11 nM binding affinity for the CCK-B receptor
with 582-fold selectivity. Compound 26, with 3-amino
substitution, showed better binding affinity (107 nM)
for CCK-A receptors with 2-fold selectivity. However,
no further effort was made to improve the CCK-A
binding affinity. Interestingly, the N,N-dimethylamino
analogue 27 reverted back to CCK-B selectivity. Re-
placement of the phenyl ring with a heterocycle (pyridyl
28 and 1-naphthyl 29) proved detrimental to CCK
receptor binding affinity.
9.323
1623
3-NMe2
Br
amino acids (4a ,b) and subsequent hydrolysis provided
the corresponding acid derivatives (5a ,b). Formation
of the quinazolinone ring (6a ,b) was achieved in one pot
under the coupling condition with CDI. This one-pot
cyclization was unique since the reported procedure
involved preparation of the corresponding bisamide
derivative using CDI and then treatment with a dehy-
drating agent such as pyridinium p-toluenesulfonate or
p-toluenesulfonic acid to form the quinazolinone ring.23,24
Deprotection of compounds 6a ,b followed by treatment
with 4-bromophenyl isocyanate provided the corre-
sponding ureas 7 and 8. Attempts to prepare the
requisite amine precursor (11) of compound 12 by the
literature procedures were unsuccessful.26-28 These
methods included treatment of the thioxoquinazolinone
with ammonia or benzylamine. Amine 11 was success-
fully prepared by the treatment of the thioxoquinazoli-
none 9 with an excess of hydrazine in refluxing ethanol
to obtain the hydrazino derivative 1029 and subsequent
cleavage of the N-N bond by hydrogenolysis using 10%
palladium on carbon as a catalyst. 2-Aminoquinazoli-
none 11 was then treated with 4-bromophenyl isocyan-
ate in the presence of sodium hydride to yield compound
12 (Scheme 2). Those thioxoquinazolinones which were
not commercially available were prepared by the treat-
ment of anthranilic acid with the requisite isothiocy-
anate. The isothiocyanates which were not commer-
cially available were prepared by standard methodology
reported in the literature. The 3-(3-aminophenyl)-2-
thioxo-2,3-dihydro-1H-quinazolin-4-one was prepared by
the hydrogenolysis of the corresponding nitro derivative
using Raney nickel as a catalyst.
Binding affinities for a similar series of compounds
with the above set of substitutions on the N-3 position
of the quinazolinone ring, having 3-carbethoxy substitu-
tion on the N-phenyl ring of the urea moiety, are shown
in Table 4. It is evident from Table 4 that all the
compounds showed consistent improvement in the
CCK-B binding affinity over their corresponding 3-meth-
yl derivatives. In particular, compound 40, with 3-iso-
propoxy substitution, showed 1.5 nM binding affinity
and 2313-fold selectivity for CCK-B receptors. Thus,
analogous with earlier studies related to compound 3a ,23
we also found that 3-isopropoxyphenyl and 3-(N,N-
dimethylamino)phenyl were preferred substitutions on
to the N-3 position of the quinazolinone.
Compound 14 was prepared by the acylation of the
2-hydrazinoquinazolinone with 4-bromobenzoyl chloride.
Compounds 13, 15-51, and 53-61 were prepared by
the treatment of the 2-hydrazinoquinazolinone with the
requisite isocyanate in acetonitrile or a mixture of
acetonitrile and 1,4-dioxane (Scheme 3). The carboxylic
acid derivative 52 was prepared from its tert-butyl ester
(51) by the treatment with TFA in methylene chloride.
Having established that 3-isopropoxyphenyl substitu-
tion is a preferred substitution on the N-3 position of
quinazolinone, we then examined a structure-activity
relationship (SAR) at the urea terminus. Binding data
(Table 5) suggest that a planar hydrophobic ring was
preferred over a nonplanar lipophilic moiety (phenyl 45
vs cyclohexyl 44). Unsubstituted phenyl derivative 45
and its 3-methyl analogue 25 were equipotent. The
substitution of the electron-donating methoxy group at
any position showed no dramatic effect in binding
affinities (46-48), whereas the substitution of the
electron-withdrawing carbethoxy group showed signifi-
cant effects (49, 40, and 50). Carbethoxy substitution
at the meta position was preferred over that at the para
Resu lts a n d Discu ssion
Our initial work25 in this series suggested that the
linker between the two key moieties was critical for
CCK-B binding affinity (Table 2). Compound 7, with a
methylene group as a linker, showed moderate binding
affinity and selectivity for CCK-B receptors, whereas
its higher and lower homologues (8 and 12) resulted in
loss of CCK binding affinity. To further search for the
optimal linker, we chose to probe the effect of a het-
eroatom as a linker. Replacement of the methylene
group with nitrogen provided compound 13 with marked
improvement in binding affinity and selectivity for
CCK-B receptors. The significant improvements in

1044 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Padia et al.
F igu r e 1. Design of novel target.
Ta ble 2. Linker SARa
they exhibited excellent potency and selectivity for
CCK-B receptors.
Since compound 58, with the 3-cyano group on the
phenyl ring at the urea terminus, showed 1.2 nM
binding affinity and 4458-fold selectivity for CCK-B
receptors, we prepared compounds 59-61 (Table 6) to
probe the effect of the combination of a 3-cyanophenyl
moiety at the urea terminus with other key substitu-
tions at the N-3 position of the quinazolinone ring that
were identified earlier. Binding data suggested that
most of the compounds maintained their potency for
CCK-B receptors.
IC50 (nM)
compd
linker
CH2
CH2CH2
-
NH
A
CCK-B
CCK-A
A/B
7
7
8
12
13
14
NHCONH
NHCONH
NHCONH
NHCONH
NHCO
140
585
980
1630
2.8
>1000
>1000
3430
While the synthesis and SAR study were ongoing, we
chose to establish functional activity of this novel series
of ligands. Thus, we examined selected compounds in
in vitro functional assay which utilizes CCK-B receptors
(Table 7). Compounds 13, 40, and 33 were evaluated
in the guinea pig stomach strip assay.30 All the
compounds reversibly antagonized pentagastrin-evoked
increase in intracellular calcium levels and showed no
agonist activity.
14
245
63
NH
88
5560
a
IC50 represents the concentration (nM) producing half-
maximal inhibition of specific binding of [125I]Bolton Hunter CCK-8
to CCK receptors in the mouse cerebral cortex (CCK-B) or the rat
pancreas (CCK-A). The values given are the geometrical mean of
at least three separate experiments. Statistical errors were 15%
of the mean values.
position (40 vs 50). However, carbethoxy substitution
at the ortho position was detrimental to CCK binding
affinities. The bulky tert-butylcarbonyl group (51) was
well-tolerated at the meta position, but the correspond-
ing acid derivative (52) lost some CCK-B binding
affinity. Compounds with electron-withdrawing halo-
gen substitutions in the para position (bromo 13 and
chloro 53) showed no improvement in potency over the
unsubstituted phenyl analogue, but chlorine substitu-
tion at the meta position was preferred over that at the
para position (54 vs 53). A similar trend was also
observed for trifluoro derivatives (55 and 56). On the
basis of these observations, additional compounds with
other electron-withdrawing groups at the meta position
(nitro 57 and cyano 58) were prepared, and as expected,
To further establish the ability of these novel ligands
to antagonize CCK-induced behavioral response in an
animal model in vivo, compounds 51 and 61 were
evaluated in the elevated rat X-maze test.31 Compound
51 was selected because of its excellent CCK-B binding
affinity, whereas compound 61 was selected because of
its basic functionality. These compounds were com-
pared with the reference compound 3a . Oral adminis-
tration of 3a , 51, and 61 (0.01-1.0 mg/kg dissolved in
poly(ethylene glycol)-200) 40 min before the test in-
creased time spent by rats on the end sections of the
X-maze with respective minimum effective doses of 0.1,
1.0, and 1.0 mg/kg (Figure 3). The increase in the
percentage time spent on the end sections of the X-maze
suggests that these compounds possess anxiolytic-like

Novel Nonpeptide CCK-B Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1045
Sch em e 1a
a
(a) CDI; (b) LiOH; (c) CDI, 3-iPrO-PhNH2; (d) Pd-C/H2; (e) 4-Br-PhNCO.
Sch em e 2a
Ta ble 3. Binding Affinities of (3-Methylphenyl)urea
Derivativesa
IC50 (nM)
CCK-A
compd
R1
CCK-B
A/B
6
15b
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Ph
Ph
1244
1083
915
225
1170
73
7330
39% @ 10 µM
26% @ 10 µM
20% @ 10 µM
10% @ 10 µM
3010
10% @10 µM
5100
34% @ 10 µM
2568
6400
107
4900
12500
7% @ 10 µM
3-F-Ph
3-Cl-Ph
4-Cl-Ph
2,3-Cl2-Ph
3,4-Cl2-Ph
3-MeO-Ph
3,4-(MeO)2-Ph
3-EtO-Ph
3-iPrO
3-NH2-Ph
3-NMe2-Ph
3-pyridyl
1-naphthyl
41
26
97c
200
2110
45
11
219
63
a
(a) Hydrazine, ethanol; (b) Raney Ni, H2; (c) NaH/DMF,
R2NCO.
57
582
0.5
78
3
Sch em e 3a
4280
3562
a
b
See footnote a of Table 2. Unsubstituted phenylurea deriva-
tive. c The value from a single experiment.
in 10:40:50 dimethylacetamide/PEG400/5% dextrose
water (v/v/v) at 3.3 mL/kg. After po administration,
there were no notable clinical observations. Plasma
concentrations of compound 51 were below the limit of
quantitation (<0.25 µg/mL) for all samples from all po-
dosed animals. In addition, there was no evidence of
the corresponding carboxylic acid derivative 52 in the
samples. Estimation of best case oral bioavailability for
compound 51 was <5%. After po administration of
compound 61, maximum observed plasma concentration
(Cmax) was 0.91 mg/mL and time to reach Cmax (tmax) was
25.0 min. Estimate of absolute oral bioavailability of
compound 61, based on the ratio of normalized po AUC
to iv AUC, was 22%.
a
(a) R2NCO; (b) R1 ) 3-iPrO-Ph, 4-bromobenzoyl chloride, TEA.
action. None of the compounds altered the total number
of entries, suggesting a lack of sedative action.
Compounds 51 and 61 were also examined for their
pharmacokinetic profile (Table 8).32 Both compounds
were administered orally at 10 mg/kg, and different
vehicles were used for the administration because of
aqueous solubility limitation. Compound 51 was deliv-
ered as a solution in 25:40:35 ethanol/PEG400/5%
dextrose water (v/v/v) at a nominal concentration of 1.5
mg/mL, whereas compound 61 was dosed as a solution
Con clu sion
Our original strategy of designing a novel target by
combining key pharmacophores of two known series has

1046 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Padia et al.
Ta ble 4. Binding Affinities of (3-Carbethoxyphenyl)urea
Ta ble 6. Binding Affinities of (3-Cyanophenyl)urea
Derivativesa
Derivativesa
IC50 (nM)
IC50 (nM)
compd
R1
CCK-B
152
CCK-A
A/B
compd
R1
CCK-B
CCK-A
A/B
30
31
32
33
34
35
36
37
38
39
40
41
42
43
Ph
37% @ 10 µM
30% @ 10 µM
4980
15% @ 10 µM
1660
59
60
58
61
H
262
5.8
1.2
14
37% @ 10 µM
4450
5350
3-F-Ph
3-Cl-Ph
4-Cl-Ph
26
33
14
50
3-EtO
3-iPrO
3-NMe2
767
4458
507
151
33
7100
2,3-Cl2-Ph
3,4-Cl2-Ph
3-MeO-Ph
4-MeO-Ph
3,4-(MeO)2-Ph
3-EtO-Ph
3-iPrO
3-NMe2-Ph
3-pyridyl
1-naphthyl
a
2.4 16% @ 10 µM
15
592
611
5.0 1210
See footnote a of Table 2.
2330
20%
20% @ 10 µM
155
Ta ble 7. Functional Activity of Selected CCK-B Receptor
Antagonistsa
242
2313
530
35
1.5 3470
5.0 2650
319
35% @ 10 µM
11200
5% @10 µM
a
See footnote a of Table 2.
Ta ble 5. Binding Affinities of N-3-(3-Isopropoxyphenyl)-
compd
R1
R2
4-Br
3-COOEt
3-COOEt
IC50 (nM)
quinazolinone Derivativesa
13
40
33
3-iPrO
3-iPrO
4-Cl
54
22
33
a
Functional assays were carried out on guinea pig stomach strip
cells.
IC50 (nM)
compd
R1
CCK-B
CCK-A
A/B
44
45
25
46
47
48
49
40
50
51
52
13
53
54
55
56
57
58
cyclohexyl
Ph
3-Me-Ph
108
15
11
10
22
17300
4580
6400
4200
7470
15490
22%
3470
3160
2960
8110
3430
3590
2420
2780
2240
2560
5350
160
305
582
420
340
620
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2-COOEt-Ph
3-COOEt-Ph
4-COOEt-Ph
3-COOtBu-Ph
3-COOH-Ph
4-Br-Ph
4-Cl-Ph
3-Cl-Ph
4-CF3-Ph
3-CF3-Ph
3-NO2-Ph
3-CN-Ph
25
7670
1.5
57
1.9
29
2313
55
F igu r e 2. Summary of the SAR.
1557
280
245
256
410
73
280
2560
4458
14
14
full antagonist profiles in the in vitro assay. Com-
pounds 51 and 61 were orally active in the elevated rat
X-maze test and showed dose-dependent anxiolytic-like
action. These compounds were also evaluated for their
pharmacokinetic profile, and absolute oral bioavailabil-
ity of compound 61 in rats was estimated at 22%.
5.9
38
8.0
1.0
1.2
a
See footnote a of Table 2.
Exp er im en ta l Section
resulted in the identification of more potent series of
CCK-B receptor antagonists. The spatial arrangement
of these two moieties was critical for potency and
selectivity (Figure 2). The introduction of -NH- as a
linker significantly enhanced CCK-B binding affinity
and selectivity, thus providing compounds with single-
digit nanomolar binding affinity and excellent selectiv-
ity. Analogous to the earlier studies of the series of
quinazolinone derivatives 3, we also found 3-isopro-
poxyphenyl as a preferred substitution on to the N-3
quinazolinone. Electron-withdrawing substitutions on
the urea terminal phenyl ring enhanced CCK-B potency.
The representative compounds from this series showed
Materials used were obtained from commercial suppliers
and were used without purification, unless otherwise noted.
Melting points were determined on a Thomas-Hoover ap-
paratus and are uncorrected. The 1H NMR spectra were
determined on a Varian Unity 400 spectrometer with tetra-
methylsilane as an internal standard. Elemental analyses
were determined on a Perkin-Elmer model 240C instrument
or were determined by Robertson Labs. All new compounds
yielded spectral data consistent with the proposed structure
and microanalyses within 0.4% of the theoretical values unless
indicated otherwise. Physical data for compounds are given
in Table 9.
N-(4-Br om oph en yl)-N-[[3,4-dih ydr o-3-[3-(1-m eth yleth ox-
y)p h en yl]-4-oxo-2-q u in a zolin yl]m et h yl]u r ea (7). (a )

Novel Nonpeptide CCK-B Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1047
Ta ble 8. Summary of Pharmacokinetic Profile of Selected
CCK-B Receptor Antagonistsa
% F
compd
R1
R2
vehicle Cmax tmax CL (% RSD)
51
61
3-iPrO 3-COOtBu
3-NMe2 3-CN
A
B
<0.25 NA 18
0.91 25 29.5
<5 (10)
22 (8)
a
A, 25:40:35 ethanol/PEG400/5% dextrose water (v/v/v); B, 10:
40:50 DMA/PEG400/5% dextrose water (v/v/v); Cmax, maximum
observed plasma concentration (µg/mL); tmax, time to reach Cmax
(min); CL, systemic plasma clearance (mL/min/kg); % F, percent
absolute oral bioavailability; % RSD, percent relative standard
deviation.
2.2 mmol) in dioxane (100 mL) was added lithium hydroxide
(1.4 g, 3.3 mmol) in water (20 mL). The reaction mixture was
stirred for 24 h, concentrated, and acidified with 10% HCl.
The solid that separated was filtered and washed with water.
Drying in a vacuum at 60% C provided 7.0 g (95%) of the title
compound as a white solid, mp 155-156 °C. 1H NMR
(DMSO): δ 3.8 (d, J ) 6.0 Hz, 2H), 5.08 (s, 2H), 7.1-7-45 (m,
6H), 7.61 (dt, J ) 1.7, 7.0 Hz, 1H), 8.02 (m, 2H), 8.61 (d, J )
7.9 Hz, 1H), 11.7 (br s, 1H), 13.68 (br s, 1H). Anal.
(C17H16N2O2) C, H, N.
(c) N-[[3,4-Dih yd r o-3-[3-(m eth yleth oxy)p h en yl]-4-oxo-
2-qu in a zolin yl]m eth yl]ben zen ea ceta m id e. To a solution
of 2-[[[[(phenylmethoxy)carbonyl]amino]acetyl]amino]benzoic
acid (3.35 g, 10 mmol) in 100 mL of THF at room temperature
was added 1,1-carbonyldiimidazole (1.8 g, 11 mmol). After the
mixture stirred under nitrogen for 1 h, a solution of 3-isopro-
poxyaniline (1.51 g, 10 mmol) in 25 mL of THF was added
and the mixture was heated to reflux for 24 h. The reaction
mixture was cooled, and solvent was removed under reduced
pressure. The resulting product was dissolved in ethyl acetate
and washed with water, 1 N HCl, saturated aqueous NaHCO3,
and brine. After drying over MgSO4 and concentration, it was
chromatographed over silica gel (1:1, v/v, ethyl acetate-
hexane) to provide 3.0 g (65%) of the title compound as a white
solid, mp 155 °C. 1H NMR (CDCl3): δ 1.3 (m, 6H), 4.13 (m,
2H), 4.55 (s, 1H), 5.16 (s, 2H), 6.75 (s, 1H), 6.78 (dd, J ) 2.0,
7.7 Hz, 1H), 7.0 (dd, J ) 1.9, 6.5 Hz, 1H), 7.7 (d, J ) 8.0 Hz,
1H), 7.8 (m, 1H), 7.5-7.1 (m, 8H), 8.3 (dd, J ) 1.2, 3.4 Hz,
1H). Anal. (C26H25N3O4) C, H, N.
(d) 2-(Am in om eth yl)-3-[3-(m eth yleth oxy)ph en yl]- 4(3H)-
qu in a zolin on e. A solution of N-[[3,4-dihydro-3-[3-(methyl-
et h oxy)ph en yl]-4-oxo-2-qu in a zolin yl]m et h yl]ben zen ea ce-
tamide (1.47 g, 3.3 mmol) in 100 mL of methanol was treated
with 20% palladium on carbon (100 mg), and the resulting
suspension was subjected to 1 atm of hydrogen at 51.9 psi for
4 h with agitation at 30 °C. This mixture was then filtered
through Celite, and the solvent was removed under reduced
pressure to give 1.0 g (92%) of the title compound as a yellow
solid. 1H NMR (CDCl3): δ 1.33 (dd, J ) 2.7, 6.3 Hz, 6H), 2.15
(br s, 2H), 3.56 (s, 2H), 4.55 (m, 1H), 6.7 (m, 1H), 6.77 (m,
1H), 7.0 (m, 1H), 7.42 (t, J ) 8.0 Hz, 1H), 7.48 (dt, J ) 1.2,
5.53 Hz, 1H), 7.73-7.82 (m, 2H), 8.29 (dd, J ) 1.2, 7.5 Hz,
1H). Anal. (C18H19N3O2‚0.5CH3OH) C, H, N.
F igu r e 3. Effects of compounds 3a , 51, and 61 in the elevated
X-maze. Compounds 3a , 51, and 61 were administered po in
PEG200 40 min before the test. The percent time spent (%
TOEA) and the total number of entries (TE) were measured
for each animal during the 5-min test. Results are shown as
the mean (verticle bars represent (SEM) of 10 animals/per
group. *Significantly different from vehicle-treated controls;
P, 0.05 (ANOVA followed by Dunnett’s t-test).
2-[[[[(P h en ylm et h oxy)ca r b on yl]a m in o]a cet yl]a m in o]-
ben zoic Acid Meth yl Ester . To a solution of [(carbobenzyl)-
oxy]glycine (9.8 g, 4.7 mmol) in THF (100 mL) was added 1,1-
carbonyldiimidazole (8.1 g, 5.0 mmol) at room temperature.
After the mixture stirred under nitrogen for 1 h, methyl
anthranilate (6.3 g, 4.0 mmol) was added. The reaction
mixture was stirred for 24 h at room temperature and then
concentrated. The residue was dissolved in ethyl acetate (100
mL) and washed with water, 10% HCl, saturated aqueous
NaHCO3, and brine. The organic layer was dried over MgSO4
and concentrated. The resulting product was crystallized from
ethyl acetate to yield 7.6 g (55%) of the title compound as a
white solid, mp 121-122 °C. 1H NMR (CDCl3): δ 3.9 (s, 3H),
4.1 (d, J ) 5.8 Hz, 2H), 5.19 (s, 2H), 5.5 (br s, 1H), 7.1 (dt, J
) 1.0, 7.1 Hz, 1H), 7.15-7.45 (m, 5H), 7.55 (dt, J ) 1.5, 7.1
Hz, 1H), 8.69 (dd, J ) 1.5, 7.5 Hz, 1H), 11.52 (br s, 1H). Anal.
(C18H18N2O2) C, H, N.
(e) N-(4-Br om op h en yl)-N-[[3,4-d ih yd r o-3-[3-(1-m eth yl-
eth oxy)p h en yl]-4-oxo-2-qu in a zolin yl]m eth yl]u r ea . To a
solution of 2-(aminomethyl)-3-[3-(methylethoxy)phenyl]-4(3H)-
quinazolinone (0.1 g, 0.33 mmol) in 15 mLof ethyl acetate was
added at room temperature 4-bromophenyl isocyanate (0.047
g, 0.35 mmol). The mixture was stirred for 2 h, and the solvent
was removed under reduced pressure. The residue was
chromatographed over silica gel (1:1, v/v, ethyl acetate-
hexane) to give 70 mg (50%) of the title compound as a white
solid, mp 125-130 °C. 1H NMR (CDCl3): δ 1.33 (m, 6H), 4.16
(m, 2H), 4.53 (m, 1H), 6.35 (br t, 1H), 6.76 (t, J ) 1.1 Hz, 1H),
(b ) 2-[[[[(P h en ylm et h oxy)ca r b on yl]a m in o]a cet yl]-
a m in o]ben zoic Acid . To a solution of 2-[[[[(phenylmethoxy)-
carbonyl]amino]acetyl]amino]benzoic acid methyl ester (7.6 g,

1048 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Ta ble 9. Physical Data for Compounds of Tables 2-6
Padia et al.
was warmed to room temperature, stirred for 2 additional
hours, and concentrated under reduced pressure. The residue
was diluted with ethyl acetate, and solid triethylamine hy-
drochloride salt was removed by filtration. The filtrate was
washed with water, dried over MgSO4, and concentrated under
reduced pressure to yield 9.0 g of crude 3-isopropoxyphenyl
isothiocyanate.
The mixture of the above crude 3-isopropoxyphenyl isothio-
cyanate and anthranilic acid (6.04 g, 44 mmol) in 150 mL of
acetic acid was refluxed for 16 h. The reaction mixture then
was cooled to room temperature, and the white solid was
separated which was filtered to yield 9.0 g of the title
compound (72.1%), mp 288-290 °C. 1H NMR (DMSO): δ 1.27
(dd, J ) 1.8, 3.9 Hz, 6H), 4.58 (m, 1H), 6.8 (d, J ) 8.7 Hz, 1H),
6.87 (dd, J ) 1.9, 2.2 Hz, 1H), 6.93 (m, 1H), 7.4 (m, 2H), 7.44
(d, J ) 8.0 Hz, 1H), 7.75 (dd, J ) 1.5, 7.0 Hz, 1H), 7.92 (d, J
) 1.1, 6.75 Hz, 1H), 13.0 (br s, 1H). Anal. (C17H16N2O2S1) C,
H, N, S.
(b) 2-Hyd r a zin o-3-(3-isop r op oxyp h en yl)-3H-qu in a zo-
lin -4-on e. A mixture of the above product (3.12 g, 10 mmol)
and anhydrous hydrazine (3.2 g, 100 mmol) in 100 mL of
ethanol was refluxed for 18 h. The reaction mixture was then
cooled to room temperature, and a white solid was separated
which was filtered and washed with 10 mL of ethanol to obtain
1.2 g (38%) of the title compound as a white solid. The filtrate
was concentrated, and an additional 1.6 g (50.4%) of the title
compound was isolated by crystallization from ethyl acetate,
mp 158-160 °C. 1H NMR (DMSO-d6): δ 1.28 (d, J ) 5.55
Hz, 6H), 4.36 (br s, 2H), 4.64 (m, 1H), 6.83 (d, J ) 7.71 Hz,
1H), 6.89 (br s, 1H), 7.03 (d, J ) 8.4 Hz, 1H), 7.15 (m, 1H),
7.35-7.45 (m, 1H), 7.65 (t, J ) 7.0 Hz, 1H), 7.91 (d, J ) 7.5
Hz, 1H). Anal. (C17H18N4O2) C, H, N.
(c) 2-Am in o-3-(3-isop r op oxyp h en yl)-3H-qu in a zolin -4-
on e. A solution of 2-hydrazino-3-(3-isopropoxyphenyl)-3H-
quinazolin-4-one (2.5 g, 8.0 mmol) in 100 mL of methanol-
THF (1:1) was treated with Raney Ni (2.0), and the resulting
suspension was subjected to 1 atm of hydrogen at 52.0 psi for
30 h with agitation at a temperature of 50 °C. An additional
1.0 g of Raney Ni was added, and reaction was continued for
an additional 40 h at 50 °C. The mixture was then filtered
through Celite, and the solvent was removed under reduced
pressure to give the title compound as a reddish-yellow solid.
This crude product was then triturated with ethyl acetate and
hexane to isolate product as a light-yellow solid, mp 130-133
°C. 1H NMR (DMSO-d6): δ 1.28 (d, J ) 5.8 Hz, 6H), 4.65 (m,
1H), 6.29 (br s, 2H), 7.04 (m, 1H), 6.93 (m, 1H), 7.04 (m, 1H),
7.11 (dt, J ) 0.9, 6.0 Hz, 1H), 7.23 (d, J ) 8.0 Hz, 1H), 7.44 (t,
J ) 8.0 Hz, 1H), 7.45 (d, J ) 5.5 Hz, 1H), 7.6 (m, 1H), 7.88
(dd, J ) 1.2, 6.8 Hz, 1H). Anal. (C17H17N3O2) C, H, N.
compd
mol formula
mp (°C)
anal.
7
8
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
25H23BrN4O3‚0.1C4H8O2
26H25BrN4O3
24H21BrN4O3‚0.92H2O
24H22BrN4O3
24H21BrN4O3
21H17N5O2
125-130
191-192
230-233
212
C, H, N, Br
C, H, N, Br
C, H, N
C, H, N, Br
C, H, N, Br
C, H, N
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
120-122
>280
22H19N5O2
21H19FN5O2
277-279
>280
C, H, N
C, H, N, F
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N, F
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
22H19ClN5O2
22H19ClN5O2
22H17Cl2N5O2‚0.65H2O
22H17Cl2N5O2
23H21N5O3
24H23N5O4
24H23N5O3
25H25N5O3
22H20N6O2
>280
>280
217
>280
193-195
230-235
209-210
204
205-207
205-207
225-227
24H24N6O2
26H21N5O2
21H18N6O2‚0.1H2O
24H21N5O4‚0.2H2O
24H20FN5O4
24H20ClN5O4
24H20ClN5O4
24H19Cl2N5O4
24H19Cl2N5O4
25H23N5O5
>280
235-236
217-218
214-215
215-216
228-229
236-237
195-196
211-213
25H23N5O5
26H25N5O6
26H25N5O5
>280
186-187
190-191
207-209
212-213
258-259
205-207
197-198
209-211
204-205
190-191
194-195
194-195
185-186
207
C27H27N5O5
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
26H26N6O4
23H20N6O4‚0.34C4H8O2
28H23N5O4‚0.38H2O
24H29N5O3
24H23N5O3
25H25N5O4
25H25N5O4
25H25N5O4
27H27N5O5
27H27N5O5‚0.32C4H8O2
29H31N5O5
25H23N5O5‚0.28H2O
24H22ClN5O3
24H22ClN5O3‚3H2O
25H22F3N5O3
25H22F3N5O3
204-206
200-201
201-202
113-120
195-196
195
222-223
218-220
204-205
C, H, N, Cl
C, H, N, Cl
C, H, N, F
C, H, N, F
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
24H22N6O5‚3H2O
25H22N6O3
22H16N6O2‚0.25H2O
24H20N6O3
24H21N7O2
(d ) 1-(4-Br om op h en yl)-3-[3-(3-isop r op oxyp h en yl)-4-
oxo-3,4-d ih yd r oq u in a zolin -2-yl]u r ea . To a solution of
2-amino-3-(3-isopropoxyphenyl)-3H-quinazolin-4-one (295 mg,
1.0 mmol) in DMF (10 mL) was added 50% NaH (48 mg, 1
mmol) at room temperature, and the mixture stirred for 30
min. To this mixture was added 4-bromophenyl isocyanate
(198 mg, 1.0 mmol), and the mixture stirred for 2 h at room
temperature. The reaction was quenched with a drop of water
and concentrated. It was then diluted with ethyl acetate and
filtered. The filtrate was concentrated and chromatographed
over silica gel using 100% CH3Cl to isolate pure product as a
white solid (70 mg, 14.2%), mp 230-233 °C. 1H NMR (DMSO-
d6): δ 1.28 (d, J ) 5.0 Hz, 1H), 4.50-4.65 (m, 1H), 6.8-8.0
6.78 (m, 1H), 7.01 (d, J ) 8.6 Hz, 1H), 7.06 (br s, 1H), 7.22 (d,
J ) 8.5 Hz, 2H), 7.35 (d, J ) 8.6 Hz, 2H), 7.41 (t, J ) 8.0 Hz,
1H), 7.50 (t, J ) 7.7 Hz, 1H), 7.59 (d, J ) 8.0 Hz, 1H), 7.75
(m, 1H), 8.30 (dd, J ) 1.2, 6.7 Hz, 1H). Anal. (C25H23N4O3-
Br1‚0.1C4H8O2) C, H, N.
N-(4-Br om op h en yl)-N′-[2-[3,4-d ih yd r o-3-[3-(1-m eth yl-
eth oxy)ph en yl]-4-oxo-2-qu in azolin yl]eth yl]u r ea (8). Com-
pound 8 was synthesized according to the procedure described
for compound 7, mp 191-192 °C. 1H NMR (CDCl3): δ 1.33 (t,
J ) 5.25 Hz, 6H), 2.67 (t, J ) 5.25 Hz, 2H), 3.66 (m, 2H), 4.55
(m, 1H), 6.10 (br s, 1H), 6.50 (br s, 1H), 6.76 (m, 2H), 7.0 (m,
1H), 7.00 (m, 1H), 7.13 (d, J ) 8.7 Hz, 1H), 7.33 (m, 2H), 7.41
(m, 2H), 7.49 (m, 1H), 7.55 (t, J ) 7.7 Hz, 1H), 7.75 (dt, J )
1.44, 7.0 Hz, 1H), 8.26 (dd, J ) 2.12, 6.75 Hz, 1H). Anal.
(C26H25N4O3Br1) C, H, N.
(m, 12H), 9.17 (m, 1H), 13.0 (br s, 1H). Anal. (C24H21
-
Br1N4O3‚0.92H2O1) C, H, N, Br.
4-Br om oben zoic Acid N′-[3-(3-Isop r op oxyp h en yl)-4-
oxo-3,4-d ih yd r oqu in a zolin -2-yl]h yd r a zid e (14). To a mix-
ture of 2-hydrazino-3-(3-isopropoxyphenyl)-3H-quinazolin-4-
one (0.155 g, 0.5 mmol) and triethylamine (56 mg, 0.55 mmol)
in CH2Cl2 (10 mL) was added 4-bromobenzoyl chloride (112
mg, 0.51 mmol) at room temperature. The reaction mixture
was stirred overnight, diluted with 25 mL of CH2Cl2, and
washed with water, saturated aqueous NaHCO3, dilute HCl,
and brine. After drying over MgSO4 and concentration, it was
chromatographed over silica gel (1:4, v/v, ethyl acetate-
N-(4-Br om op h en yl)-N-[3-(3-isop r op oxyp h en yl)-4-oxo-
3,4-d ih yd r oqu in a zolin -2-yl]u r ea (12). (a ) 3-(3-Isop r o-
p o x y p h e n y l)-2-t h io x o -2,3-d ih y d r o -1H -q u in a zo lin -4-
on e. To a mixture of 3-isopropoxyaniline (6.0 g, 40 mmol) and
triethylamine (4.85 g, 48 mmol) was slowly added thiophosgene
(5.06 g, 44 mmol) at 0 °C in an ice bath. The reaction mixture

Novel Nonpeptide CCK-B Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1049
(12) Horwell, D. C.; Hughes, J .; Hunter, J . C.; Pritchard, M. C.;
Richardson, R. S.; Roberts, E.; Woodruff, G. N. Rationally
designed “dipeptoid” analogues of CCK. R-Methyltryptophan
derivatives as highly selective and orally active gastrin and
CCK-B antagonists with potent anxiolytic properties. J . Med.
Chem. 1991, 34, 404-414.
(13) Feng, R.; Hinton, J . P.; Hoffman, K.; Parker, T. D.; Wright, D.
S. Pharmacokinetics and oral bioavailability of CI-988 ester
prodrugs in Wistar rats. Pharm. Res. 1993, 10 (10), S-346.
(14) Hinton, J . P.; Rutkowski, K.; J ohnson, E. L.; Wright, D. S. Single-
dose pharmacokinetics and absolute bioavailability of the anxi-
olytic CI-988 in fasted and fed cynomolgus monkeys. Pharm. Res.
1991, 8 (10), S-330.
(15) Hinton, J . P.; Hoffman, K.; Poisson, A.; Klemisch, W.; Wright,
D. S. Mass balance and disposition of [14C]CI-988 in cynomolgus
monkeys. Pharm. Res. 1993, 10 (10), S-267.
(16) Bradwejn, J .; Koszycki, D.; Paradis, M.; Reece, P.; Hinton, J .
P.; Sedman, A. Effect of CI-988 on cholecystokinin tetrapeptide-
induced panic symptoms in healthy volunteers. Biol. Psychiat.
1995, 38, 742.
hexane) to provide 110 mg (46%) of the title compound as a
yellow solid, mp 120-122 °C. Anal. (C24H21Br1N4O3) C, H,
N, Br.
Gen er a l P r oced u r e for Syn t h esis of H yd r a zin e-
ca r boxa m id es: N-(4-Br om op h en yl)-2-[3,4-d ih yd r o-3-[3-
(1-m et h ylet h oxy)p h en yl]-4-oxo-2-q u in a zolin yl]h yd r a -
zin eca r boxa m id e (13). 2-Hydrazino-3-(3-isopropoxyphenyl)-
3H-quinazolin-4-one (0.155 g, 0.5 mmol) was dissolved in 5.0
mL of CH3CN, and 4-bromophenyl isocyanate (0.1 g, 0.5 mmol)
was added at room temperature. The resulting reaction
mixture was stirred at room temperature for 16 h. The white
solid was separated which was filtered and washed with CH3-
CN. The title compound was obtained as a white solid (0.12
g, 47.2%), mp 212 °C. 1H NMR (DMSO-d6): δ 1.30 (d, J ) 6.0
Hz, 6H), 4.6-4.7 (m, 1H), 6.8-7.5 (m, 9H), 7.67 (m, 1H), 7.85
(m, 1H), 7.97 (d, J ) 6.75 Hz, 1H), 8.26 (br s, 1H), 8.3 (br s,
1H), 10.5 (br s, 1H). Anal. (C24H22Br1N5O3) C, H, N, Br.
(17) Trivedi, B. K.; Padia, J . K.; Holmes, A.; Rose, S.; Wright, S. D.;
Hinton, J . P.; Prichard, M. C.; Eden, J . M.; Kneen, C.; Webdale,
L.; Suman-Chuhan, N.; Boden, P.; Singh, L.; Field, M. J .; Hill,
D. R. Second-generation peptoid CCKB antagonists: Identifica-
tion and development of CI-1015 with an improved pharmaco-
kinetic profile. J . Med. Chem. 1998, 41, 38-45.
(18) Chang, R. S. L.; Lotti, V. J .; Monaghan, R. L.; Birnbaum, J .;
Stapley, E. O.; Goetz, M. A.; Albers-Schonberg, G.; Patchett, A.
A.; Liesch, J . M.; Hensens, O. D.; Springer, J . P. A potent
nonpeptide cholecystokinin antagonist selective for peripheral
tissues isolated from Aspergillus alliaceus. Science 1985, 230,
177-179.
(19) Chang, R. S. L.; Lotti, V. J . Biochemical and pharmacological
characterization of an extremely potent and selective nonpeptide
cholecystokinin antagonist. Proc. Natl. Acad. Sci. U.S.A. 1986,
83, 4923-4926.
(20) Bradwejn, J .; Koszycki, D.; Couetoux du Tertre, A.; Bourin, M.;
Palmour, R.; Ervin, F. The cholecystokinin hypothesis of panic
and anxiety disorders: a review. J . Psychopharmacol. (Oxford)
1992, 6 (3), 345-51.
P h a r m a cok in etic P r otocol. The oral bioavailability and
pharmacokinetics of 51 and 61 were evaluated in fasted Wistar
rats. Groups of three male Wistar rats received either a single
oral (po) nominal dose of 10 mg/kg or a single intravenous (iv)
nominal dose of 5 mg/kg. Doses of 51 and 61 were prepared
as a solution in 25:40:35 ethanol/PEG 400/5% dextrose water
(v/v/v) and 10:40:50 dimethylacetamide/PEG 400/5% dextrose
water, respectively. Heparinized plasma samples were col-
lected from an implanted cannula in the jugular vein at serial
times out to 24 h. Plasma samples were frozen until analysis.
Plasma sample and dose solutions were assayed with validated
HPLC-fluorescence methods for each respective candidate.
Pharmacokinetic parameters were determined by standard
noncompartmental methods. Absolute oral bioavailability was
calculated as the dose-normalized ratio of the area under the
curve following po dose to the area under the curve following
iv dose.
(21) Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Whitter,
W. L.; Garsky, V. M.; Gillbert, K. F.; Leighton, J . L.; Carson, K.
L.; Veber, D. F.; Chang, S. L.; Lotti, V. J .; Freedman, S. B.;
Smith, A. J .; Patel, S.; Anderson, P. S.; Freidinger, R. M.
Development of 1,4-benzodiazepine cholecystokinin type B an-
tagonists. J . Med. Chem. 1993, 36, 4276-4292.
(22) Guyon, C.; Duboeucq, M.; Bearreau, M.; Chenot, F.; Folcke, N.
M.; Boucharinc, S.; Bertrand, P.; Bohme, G. A.; Meartin, G.;
Pendley, C. Abstract presented at XIIIth International Sympo-
sium on Medicinal Chemistry, Basel, Switzerland, September
1992; Abstracts P-184.A and P-185.A.
(23) Yu, M. J .; Thrasher, K. J .; McCowan, J . R.; Mason, N. R.;
Mendelsohn, L. G. Quinazolinone cholecystokinin-B receptor
ligands. J . Med. Chem. 1991, 34, 1508.
(24) Yu, M. J .; McCowan, J . R.; Mason, N. R.; Deeter, J . B.;
Mendelsohn, L. G. Synthesis and X-ray crystallographic analysis
of quinazolinone cholecystokinin/gastrin receptor ligands. J .
Med. Chem. 1992, 35, 2534.
(25) Padia, J . K.; Chilvers, H.; Daum, P.; Pinnock, R.; Suman-
Chauhan, N.; Webdale, L.; Trivedi, B. K. Design and synthesis
of novel nonpeptoid CCK-B receptor antagonists. Bioorg. Med.
Chem. Lett. 1997, 7, 805-810.
(26) Abdel-Megeid, F. M. E.; Elkaschef, M. A. F.; Mokhatar, K. E.
M.; Zaki, K. E. M. Reactions of 2,4(1H,3H)-quinazolinediones.
J . Chem. Soc. C 1971, 1055.
(27) Laboratorie Roger Bellon. 4-Oxo-3,4-dihydroquinazolines. British
Patent No. 1,038,729, 1966; CAN 65:15399g.
(28) Bullock, G. A.; Sheeran, P. J . 2-Amino-4(3H)-quinazolinones.
U.S. Patent No. 3,867,384, 1975; CAN 82:171037.
(29) Kottke, K.; Kuehmstedt, H. Iodine-substituted 2-hydrazino-3-
phenylquinazol-4-ones and their cyclization products. Part 6.
Synthesis of compounds with an aminoguanidine structure.
Pharmazie 1980, 35, 800-801.
(30) Bishop, L. A.; Gerskowitch, V. P.; Hull, R. A. D.; Shankley, N.
P.; Black, J . W. The use of receptor desensitization to analyze
CCKA and CCKB/gastrin receptors coupled to contraction in
guinea pig stomach muscle. Br. J . Pharmacol. 1995, 114, 339-
348.
(31) Singh, L.; Field, M. J .; Hughes, J .; Menzies, R.; Oles, R. J .; Vass,
C. A.; Woodruff, G. N. The antagonism of benzodiazepine
withdrawal effects by the selective cholecystokininB receptor
antagonist CI-988. Br. J . Pharmacol. 1991, 104, 239.
(32) Hinton, J . P.; Pablo, J .; Padia, J . P.; Wright, D. S. Bioanalytical
discovery support of novel quinazolinone CCK-B receptor an-
tagonists. Pharm. Res. 1996, 13 (9), S-36.
Ack n ow led gm en t. We thank the staff of the Ana-
lytical Department for spectral analysis.
Refer en ces
(1) (a) Preliminary accounts of this work were presented at the
211th National ACS Meeting in New Orleans, LA, 1996. (b)
Padia, J . K. Novel heterocycles as cholecystokinin (CCK) ligands.
International Patent Application No. WO 96/20178.
(2) Larsson, L. I.; Rehfeld, J . F. Localization and molecular hetero-
geneity of cholecystokinin in the central and peripheral nervous
system. Brain Res. 1979, 165, 201-218.
(3) Rehfeld, J . F.; Nielsen, F. C. Molecular forms and regional
distribution of cholecystokinin in the central nervous system.
In Cholecystokinin Anxiety: Neuron Behavior; Bradwejn, J .,
Vasar, E., Eds.; Landes: Austin, TX, 1995; pp 33-56.
(4) Innis, R. B.; Synder, S. H. Distinct cholecystokinin receptors in
brain and pancreas. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
6917-6921.
(5) Hays, S. E.; Beinfeld, M. C.; J ensen, R. T.; Goodwin, F. K.; Paul,
S. M. Demonstration of a putative receptor site for cholecysto-
kinin in rat brain. Neuropeptides (Edinburgh) 1980, 1 (1), 53-
62.
(6) Wank, S. A.; Pisegna, J . R.; DeWeerth, A. Brain and gastrointes-
tinal cholecystokinin receptor family: structure and functional
expression. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 8691-8695.
(7) Lee, Y. M.; Beinborn, M.; McBride, E. W.; Lu, M.; Kolakowski,
L. F.; Kopin, A. S. The human brain cholecystokinin-B/gastrin
receptor. Cloning and characterization. J . Biol. Chem. 1993, 268,
8164-8169.
(8) DeWeerth, A.; Pisegna, J . R.; Hupi, K.; Wank, S. A. Molecular
cloning, functional expression and chromosomal localization of
the human cholecystokinin type A receptor. Biochem. Biophys.
Res. Commun. 1993, 194, 811-818.
(9) Singh, L.; Lewis, A. S.; Field, M. J .; Hughes, J .; Woodruff, G. N.
Evidence for an involvement of the brain cholecystokinin B
receptor in anxiety. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1130.
(10) Bradwejn, J . Cholecystokinin and panic disorder. In Cholecys-
tokinin Anxiety: Neuron Behavior; Bradwejn, J ., Vasar, E., Eds.;
Landes: Austin, TX, 1995; pp 73-86.
(11) For reviews, see: (a) Trivedi, B. K. Cholecystokinin receptor
antagonists: Current status. Curr. Med. Chem. 1994, 1, 313-
327. (b) Trivedi, B. K. Ligands for cholecystokinin receptors:
Recent developments. Curr. Opin. Ther. Patents 1994, 4, 31-
44.
J M970373J