2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine as a new template for the design of CCK2 receptor antagonists

Article abstract of DOI:10.1021/jm000960w

A novel series of nonpeptide CCK₂ receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted for

Full text of DOI:10.1021/jm000960w

3518
J . Med. Chem. 2000, 43, 3518-3529
2,7-Dioxo-2,3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e a s a New Tem p la te for
th e Design of CCK2 Recep tor An ta gon ists
Iain M. McDonald,* David J . Dunstone, S. Barret Kalindjian, Ian D. Linney, Caroline M. R. Low,
Michael J . Pether, Katherine I. M. Steel, Matthew J . Tozer, and J . G. Vinter
J ames Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9J E, U.K.
Received April 3, 2000
A novel series of nonpeptide CCK2 receptor antagonists has been prepared, in which 2,7-dioxo-
2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine (5) was used as a chemical template. This
uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis
of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole derivatives (4), in which the
configuration of the substituents was established stereoselectively via the Pictet-Spengler
reaction. Further structural manipulation was guided by molecular modeling through
comparison of fieldpoint-based structures of candidate compounds with a selected low-energy
conformation of the representative CCK2 receptor antagonist 5-[[[(1S)-[[(3,5-dicarboxyphenyl)-
amino]carbonyl]-2-phenylethyl]amino]carbonyl]-6-[[(1-adamantylmethyl)amino]carbonyl]-
indole (J B93182 (3)). By this approach compounds such as (3R,5S)-4-acetyl-3-(1-adamantyl)-
methyl-1-(2-chlorobenzyl)-5-carboxymethylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-
benzo[h][1,4]diazonine (32) were prepared. Compound 32 behaved as a competitive CCK2
receptor antagonist in vitro as judged by its inhibition of pentagastrin-stimulated acid secretion
in an isolated, lumen-perfused, immature rat stomach assay (pKB ) 6.74 ( 0.27) and by its
displacement of [125I]CCK-8S from CCK2 sites in mouse cortical homogenates (pKi ) 6.99 (
0.05). Compound 32 was 100-fold selective for CCK2 over CCK1 receptors based on the affinity
estimate obtained in a guinea pig pancreas radioligand binding assay (pKi ) 5.0).
In tr od u ction
such compounds; however, none of the CCK2 receptor
antagonists available so far have fulfilled their expected
therapeutic role.8
Blocking the action of the polypeptide hormones
cholecystokinin and gastrin has attracted interest be-
cause of their roles in both the CNS and peripheral
tissues.1 In the periphery, cholecystokinin mediates gall
bladder contraction and pancreatic secretion via CCK1
receptors, stimulation of which, to full effect, requires
at least the C-terminal octapeptide fragment of the
hormone in its tyrosine-sulfated form (Asp-Tyr(SO3H)-
Met-Gly-Trp-Met-Asp-PheNH2 or CCK-8S).2 CCK1 re-
ceptors are also found in the CNS where they are
associated with the regulation of food intake. In addition
there also exist receptors which, depending on where
they are located, can be stimulated by either or both
gastrin and cholecystokinin and which require only the
C-terminal tetrapeptide (Trp-Met-Asp-Phe-NH2), which
is common to both hormones, to elicit a full response.3
In the CNS these receptors have been associated with
panic, anxiety, and pain, whereas in peripheral tissues,
where they are mainly activated by gastrin, they
stimulate gastric acid secretion4 and gastrointestinal
cell growth.5 Their similarity in responsiveness to the
hormone fragments and their subsequent cloning has
confirmed that, whether located in the periphery or in
the CNS, these receptors are identical, and they are now
designated CCK2 receptors.6 Our interest in the physi-
ological effects of gastrin prompted our efforts to obtain
CCK2 receptor antagonists which are postulated to have
benefit in antisecretory therapy as well as in CNS
disorders.7 Much effort has been devoted to obtaining
CCK2 receptor antagonists have been devised by one
of two main approaches and span a diverse range of
chemical structures.9 Optimization of the natural prod-
uct lead asperlicin has yielded compounds such as
L-365,260 (1) (Chart 1) and other 1,4-benzodiazepines,
and subsequently 1,5-benzodiazepine-2,4-diones, and
ureido acetamides, in addition to quinazolinone-based
compounds. Alternatively, the peptoid-based compound
CI 988 (2) (Chart 1) was derived by rational design from
the native hormone.10 By adopting this latter approach
we obtained competitive CCK2 receptor antagonists
based on bicyclic heteroaromatic skeletons.11 These
compounds exhibited comparable affinity estimates
between species as judged by in vitro bioassays, selec-
tivity with respect to CCK1 receptors, and potent in vivo
behavior. This strategy involved identification of novel
chemical structures potentially capable of replacing or
mimicking the tertiary structure of the native hormone.
Molecular modeling, through the use of fieldpoint-based
comparison rather than structure-based comparison,12
was used to help choose the most suitable chemical
structures. Having successfully derived novel CCK2
receptor antagonists from the native hormone agonist
using this approach, culminating in the discovery of the
highly potent J B93182 (3), we now sought to devise new
structures with similar in vitro behavior to 3 (Chart 1)
but with improved in vivo properties.13 We envisaged
that comparison of fieldpoint distribution patterns of the
new compounds with 3 would be a suitable means of
* To whom correspondence should be addressed. Phone: 020-7737-
8282. Fax: 020-7274-9687. E-mail: iain.mcdonald@kcl.ac.uk.
10.1021/jm000960w CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/01/2000

Design of CCK2 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3519
Ch a r t 1. Structures of CCK2 Receptor Antagonists
Sch em e 1. Oxidative Fragmentation of
1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indole (4)
predicting their in vitro behavior. In this paper we
describe the implementation of this strategy through
the discovery of a novel series of nonpeptide CCK2
receptor antagonists, in which a 2,7-dioxo-2,3,4,5,6,7-
hexahydro-1H-benzo[h][1,4]diazonine ring (5) is used as
a structural template.
Substitution of the conformationally flexible second-
ary structure of peptides by nonpeptide frameworks and
replacement of individual amino acid residues or dipep-
tide fragments by constrained derivatives are adopted
frequently as tactics in peptido-mimetic design.14 These
techniques have been employed principally with the aim
of attaining a more favorable entropic component on
receptor binding by limiting the accessible conforma-
tions, through substitution of intramolecular hydrogen
bonding by covalent bonds or by restriction of available
conformational space.15 In addition these changes have
at times conferred improved pharmacokinetic proper-
ties, such as increased metabolic stability and prolonged
half-life, on the new ligands.16 3 and its analogues
largely evolved from this strategy but with an additional
aim being the abolition of the efficacy of the native
hormone from which it evolved. It is evident by the
biological behavior of 3 that this latter objective has
clearly been met. However, the high potency of 3 was
achieved at a cost of relatively high molecular weight,
and the calculated low-energy conformations relied on
intramolecular H-bonding for stabilization. Nonetheless,
the combination of high affinity, lack of efficacy, and
selectivity over CCK1 receptors identified 3 as a suitable
candidate for use in the design of new ligands. Com-
pared to the bicyclic heteroaromatic-based series of
CCK2 receptor antagonists, of which 3 is an example,
benzodiazepines are relatively conformationally con-
strained. Due to their varied syntheses and ease of
substitution, they have been used widely as dipeptide
mimics and as templates for mimetics of larger pep-
tides,17 as well as occupying a pivotal position in the
area of CCK research.18 We considered that higher
homologues of benzodiazepines might fulfill a similar
role in our aim to design novel CCK2 receptor antago-
nists, using 3 as a guide.
appropriately substituted 1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indole 4 were oxidized, the resultant keto-lactam
product 5 could serve as a framework suitable for
further elaboration (Scheme 1). Rare examples of the
desired 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h]-
[1,4]diazonine ring system 5 are known. For instance,
a ring system of this type was the principal product
obtained on singlet oxygenation of the alkaloid vincam-
ine,20 as an unexpected byproduct from the attempted
m-chloroperoxybenzoic acid-promoted Meisenheimer re-
arrangement of 1,2,4,5,10,10b-hexahydroazeto[1′,2′:1,2]-
pyrido[3,4-b]indoles,21 and prepared as an intermediate
in the biomimetic synthesis of the alkaloid camptoth-
ecin.22 However, the conditions employed in the oxida-
tion of 1,2,3,4-tetrahydro-â-carbolines 4 has more often
led to the formation of the tricyclic 1,2,3,4-pyrrolo[3,4-
b]quinolin-9-ones 6a via 5 by transannular ketone
enolate addition to the amide, followed by dehydration.23
The presence of an ester group at C-1 of 4 was found to
influence this reaction in favor of the isomeric 1,2,3,4-
pyrrolo[2,3-c]quinolin-4-ones 6b.24 We sought to obtain
a practical and general route to the uncommon 2,7-
dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine
ring system 5.25
Ch em istr y
The compounds listed in Table 1 were prepared by
the general routes outlined in Schemes 2-5. L-Tryp-
tophan benzyl esters 7, unsubstituted on the indole
nitrogen, were condensed with the appropriate acetal-
dehyde in a Pictet-Spengler reaction to form the 1,2,3,4-
tetrahydropyrido[3,4-b]indole ring system 8 (Scheme 2,
method A).26 This product was generally obtained as a
mixture of cis-(1S,3S) and trans-(1R,3S) diastereoiso-
mers, from which the predominant trans isomer was
isolated by column chromatography. This product was
first acylated on the pyrido nitrogen then alkylated on
the indole nitrogen to afford the protected trans-(1R,3S)-
While medium-sized rings have been utilized with
some success in other areas of peptide mimetics, their
application has been hampered by the difficulty in
preparing them in highly functionalized form.19 On the
other hand, bicyclic ring fragmentation offers an ef-
ficient alternative means of accessing medium-sized
rings. To satisfy our requirements it was necessary that
the synthesis of the bicyclic precursor allowed a high
degree of functionality and was stereoselective. To this
end we considered that if the enamine bond of an

3520 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
McDonald et al.
Sch em e 2. Synthesis of 1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indoles 11a -p a,b
a
b
(a) XCH2CHO, CF3CO2H, 3A molecular sieves, CH2Cl2; (b) YCOCl, NEt3, CH2Cl2; (c) NaH, R1CH2Br, DMF. Only the preparation of
the (3R,5S) diastereoisomers is shown; (3S,5R) diastereoisomer 11b was prepared by using the D-tryptophan benzyl ester, and 11k -m
were obtained as racemic mixtures of trans-(3R,5S/3S,5R) diastereoisomers starting from the appropriate 5-substituted D/L-tryptophan
esters 7.
1,2,3,4-tetrahydro-â-carbolines (11a,c-h ,k-p). Although
the minor cis-(1S,3S) diastereoisomer of 8 was isolated
and acetylation achieved using harsher conditions than
those used to effect acylation of the trans adduct,
subsequent base-mediated alkylation on the pyrrole
nitrogen resulted in concomitant epimerization at the

Design of CCK2 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3521
Sch em e 3. Synthesis of 2,7-Dioxo-2,3,4,5,6,7-hexahydro-
1H-benzo[h][1,4]diazonines 20-37 and 41-44a,b
obtained which was readily acylated on the pyrido
nitrogen to afford 11i,j,n ,o. Comparison of the outcome
of attempted oxidation of the 1,2,3,4-tetrahydro-9H-
pyrido[3,4-b]indoles 11 under various conditions estab-
lished that while most methods yielded mixtures of
products, the 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo-
[h][1,4]diazonine ring system (12) was the principal
product formed using either singlet oxygen or ozone
(Scheme 3). Ozonolysis followed by reductive workup
was the preferred method, since it was less limited by
scale and avoided the long reaction times necessary to
effect the transformation using singlet oxygen. Removal
of the benzyl ester protecting group of intermediates 12
by hydrogenolysis enabled coupling of the appropriate
amino acid derivatives to the acids 13 under standard
active ester coupling conditions. Where the terminal
substituent was a carboxylic acid group this component
was most conveniently incorporated as its benzyl ester
derivative (examples 20-23, 25-37). However, in some
instances hydrogenolysis resulted in concomitant reduc-
tion of the aryl ketone group, thus requiring use of an
allyl ester protected amino acid (41). Using the same
route the (3R,5S) enantiomer 24 was also prepared
staring from D-tryptophan. Compound 42 was obtained
by coupling of 13a with glycine methyl ester. The
tetrazole analogue 43 was prepared by coupling of
intermediate 13j with SEM-protected C-(tetrazol-5-yl)-
methylamine, followed by removal of the SEM protect-
ing group by Lewis acid-promoted cleavage. The acyl-
sulfonamide derivative 44 was prepared from 31 by
treatment with methanesulfonamide using EDCI acti-
vation of the terminal acid group.
a
(d) O3, Me2S, MeOH, CH2Cl2; (e) Pd-C, H2, MeOH, THF; (f)
amino acid ester (H2NCH2CN4(SEM) for 43), PyBroP, i-PrNEt2,
CH2Cl2, or EDCI, HOBt, DMAP, CH2Cl2; (g) (Ph3P)4Pd, HNEt2,
THF; (h) MgBr2‚Et2O, CH2Cl2; (i) EDCI, MeSO2NH2, CH2Cl2.
b
Same as for Scheme 2.
Sch em e 4. Synthesis of 2,4,7,9-Tetraoxo-
2,3,4,5,7,7a,8,9-octahydro-1H-pyrazino[1,6-a]benzo[h]-
[1,4]diazonine 38a
Synthesis of the tricyclic pyrazino[1,6-a]benzo[h][1,4]-
diazonine 38 is shown in Scheme 4. The benzyl ester
protecting group of 11p was removed by hydrogenation
and the carboxylic acid obtained coupled with glycine
benzyl ester 14. The tert-butyloxycarbonyl protecting
group of 14 was removed and replaced by a bromoacetyl
group to give 15. Base promoted ring closure afforded
the pyrazino[1′,2′:1,6]pyrido[3,4-b]indole 16 which was
ozonized and deprotected to obtain 38.
a
(d-f) Same as for Scheme 3; (j) CF3CO2H, CH2Cl2; (k)
BrCH2COCl, NEt3, CH2Cl2; (l) Cs2CO3, DMF.
Sch em e 5. Synthesis of 2,7-Dioxo-2,3,4,5,6,7-
hexahydro-1H-benzo[h][1,4]diazonines 39 and 40a
The ketomethylene derivatives 39 and 40 were pre-
pared starting from 11i (Scheme 5). Following removal
of the benzyl ester protecting group and treatment with
1,1′-carbonyldiimidazole, the imidazolide obtained was
reacted with tert-butyl lithioacetate.27 The â-keto ester
17 obtained was alkylated directly with benzyl bromo-
acetate to afford 18 followed by decarboxylation of the
tert-butyl-protected acid with trifluoroacetic acid to give
a γ-keto ester 19. Oxidation of the â-keto tert-butyl ester
derivative 17 and treatment with trifluoroacetic acid
using standard conditions afforded 40. Ozonolysis of 19
gave the protected 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-
benzo[h][1,4]diazonine from which the carboxylic acid
group of the γ-keto benzyl ester group was unmasked
by hydrogenolysis. This was accompanied by reduction
of the aryl ketone group, thus requiring reoxidation with
TPAP to obtain 39.
a
(d,e,j) Same as for Schemes 3 and 4; (m) CDI, CH2Cl2,
CH3CO2t-Bu, LiN(i-Pr)2, THF; (n) NaH, BrCH2CO2Bn, DMF; (o)
Pd-C, H2, MeOH, THF, TPAP, NMO, MeCN, CH2Cl2.
Molecu la r Mod elin g
C-3 position to afford the thermodynamically more
stable trans-(1S,3R) diastereoisomer. Alternatively when
N ′-benzyl-substituted L-tryptophan benzyl esters 9 were
used in the Pictet-Spengler reaction (Scheme 2, method
B) a single trans-(1R,3S) diastereoisomer (10) was
By consideration of the most amenable sites for
substitution on the 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-
benzo[h][1,4]diazonine ring system, potential target
compounds were examined using the method of field-

3522 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
McDonald et al.
point-based analysis described previously.11,12 New
ligands were chosen through an iterative process, based
on the overlay energy of each conformation within 15
kcal mol-1 of the global minimum with a selected low-
energy conformation of 3. The outcome of this process,
when applied to the representative ligand 32, is il-
lustrated in Figure 1.
Discu ssion
The compounds were assessed as CCK2 receptor
antagonists by their ability to inhibit pentagastrin-
stimulated acid secretion in an isolated perfused rat
stomach assay28 and to displace the binding of [125I]-
CCK-8S to CCK2 sites in mouse cerebral cortex homo-
genates29 (Table 1). While not considered an optimum
structure in terms of its comparison with 3, our initial
compound 13a did at least display weak affinity for
CCK2 receptors, with a higher affinity estimate being
obtained in the radioligand binding assay. Differences
of this type in cross-tissue affinity estimates at CCK2
receptors have also been observed for other more fully
characterized antagonists such as 1. This behavior has
been ascribed to the existence of CCK2 receptor subtypes
which are considered to be differentially expressed
within these tissues.29 It was therefore a further objec-
tive to obtain compounds that did not discriminate
between CCK2 receptor subtypes. Thus, compound 13a
was deficient in this regard, being at least 10-fold less
potent in the isolated rat stomach assay than in the
mouse cortex assay. However, both increased receptor
affinity, and parity in the estimates between the two
assays was achieved by attachment of amino acids to
the carboxylate of 13a to generate analogues 20-23.
From molecular modeling analysis it appeared that the
terminal carboxylic acid group was positioned in a
location more like that of 3 (see Figure 1c). This increase
in receptor affinity was greatest for the glycine deriva-
tive 20 and diminished on further chain lengthening in
the form of the â-alanine homologue 21. The affinity was
also subject to conformational influence since the L- and
D-alanine derivatives 22 and 23, respectively, exhibited
different behavior. Compound 24, the (3S,5R) enanti-
omer of 20, was significantly less potent, indicating that
the (3R,5S) configuration, and more particularly the
disposition of the 1-adamantylmethyl and glycine sub-
stituents that this stereochemistry confers, is the pre-
ferred configuration for the trans diastereoisomers of
this series. The two additional possible cis diastereo-
isomers were not accessible using the existing synthetic
route due to the ready epimerization at C-3 to the
thermodynamically more stable trans diastereoisomers
(vide supra).
F igu r e 1. Composite molecular fields of 32 and 3 (J B93182):
(a) conformation of compound 32 which achieved the greatest
overlay energy with 3; (b) conformation of 3 used for the
comparison, with its related composite fields; (c) depiction of
steric overlay of 32 and 3 arising from the fieldpoint-based
superimposition of panels a and b, in which the hydrogen
atoms have been omitted for clarity (3 is shown in yellow and
32 is shown in white). Green spheres represent negative
electrostatic fieldpoints, red spheres represent electropositive
fieldpoints, and yellow spheres depict the hydrophobic or
‘sticky points’. The size of the each sphere is directly related
to the magnitude of the fieldpoint.
As with the bicyclic heteroaromatic series, exemplified
by 3, a 1-adamantylmethyl group appeared to be the
optimum hydrophobic substituent at C-3, since its
substitution in 20 with other less bulky groups, 25-
27, resulted in a reduction in receptor affinity. The
cycloheptylmethyl analogue 27 was closest to 20 in
receptor affinity but only in the functional bioassay. This
trend was also observed for analogues of 3 and increases
the likelihood that these structurally distinct classes of
ligands interact with same domain of the CCK2 receptor.
This assertion is reinforced by the apparent requirement
for an aromatic substituent at the N-1 position of the
benzodiazonine ring. The molecular modeling-derived
superposition overlays the indole group of 3 with the
1-benzyl group of the benzodiazonine ring (Figure 1c).

Design of CCK2 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3523
Ta ble 1. In Vitro CCK2 Receptor Affinity Estimates for 2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonines
no.a
W
R1
X
R2
Y
CCK2
CCK2
b
c
13a
20
21
22
23
24d
25
26
27
28
29
30
31
32
33f
34f
35f
36
37
38
39
40
41
42
43
44
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
4-F-C6H4
3-F-C6H4
2-F-C6H4
2-Cl-C6H4
Ph
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
t-Bu
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OMe
Et
4.88 ( 0.19
6.79 ( 0.25
6.10 ( 0.33
6.84 ( 0.32
6.27 ( 0.34
iae
5.76 ( 0.35
6.30 ( 0.38
6.78 ( 0.32
iae
6.03 ( 0.01
6.76 ( 0.08
6.05 ( 0.09
6.73 ( 0.08
6.29 ( 0.09
5.29 ( 0.04
5.31 ( 0.03
5.37 ( 0.03
5.57 ( 0.04
<5
5.68 ( 0.03
6.66 ( 0.05
7.01 ( 0.04
6.99 ( 0.05
6.93 ( 0.05
6.92 ( 0.05
6.39 ( 0.10
6.23 ( 0.03
5.79 ( 0.02
5.52 ( 0.04
5.58 ( 0.01
6.48 ( 0.10
7.33 ( 0.11
5.66 ( 0.06
7.01 ( 0.19
6.43 ( 0.01
8.40 ( 0.01
8.95 ( 0.24
H
NHCH2CO2H
NH(CH2)2CO2H
(S)-NHCH(Me)CO2H
(R)-NHCH(Me)CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
NHCH2CO2H
H
H
H
H
H
H
c-C6H11
c-C7H13
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
H
H
H
5.54 ( 0.41
6.42 ( 0.31
6.93 ( 0.29
6.74 ( 0.27
6.86 ( 0.21
7.11 ( 0.15
7.66 ( 0.63
6.02 ( 0.32
6.48 ( 0.28
iae
H
H
H
OMe
Me
F
Ph
Ph
H
2-Cl-C6H4
2-Cl-C6H4
Ph
2-F-C6H4
2-F-C6H4
2-Cl-C6H4
Ph
H
H
-N(CH2CO2H)CH2-
H
(CH2)2CO2H
CH2CO2H
Me
Me
Me
Me
Me
Me
iae
H
6.75 ( 0.32
7.47 ( 0.19
7.24 ( 0.31
7.49 ( 0.38
6.61 ( 0.49
7.54 ( 0.03
9.90 ( 0.18
H
(S)-NHCH(Me)CO2H
NHCH2CO2Me
NHCH2CN4H
H
H
2-Cl-C6H4
2-F-C6H4
H
NHCH2CONHSO2Me
1, L-365,260
3, J B93182
a
f
b
All compounds have (3R,5S) configuration except: d(3S,5R) and (3S,5R/3R,5S). pKB ( SEM values, estimated from single shifts of
pentagastrin concentration-effect curves in the isolated, lumen-perfused immature rat stomach. c pKiI ( SEM values obtained from
competition with 20 pM [125I]BH-CCK-8S for CCK2 binding sites in mouse cortex homogenates from at least three separate experiments.
e Inactive at concentration tested (between 10-4 and 3 × 10-5 M).
While removal of the aromatic ring of this substituent,
as in compound 28, leads to a marked reduction in
receptor affinity with respect to 20, the variation in
affinity observed on introduction of substituents into
this ring is consistent with it occupying the same region
of the indole of 3: for instance, the 4-fluoro derivative
29 in which the location of an electronegative substitu-
ent, presumably in a region of the receptor more suited
to the electropositive pyrrolo nitrogen group, is reflected
in the reduced affinity of 29 and to a lesser extent in
the 3-fluoro derivative 30. In contrast, receptor affinity
is maintained in the 2-substituted derivatives 31 and
32, in which the inductive effect of the fluoro and chloro
substituents, respectively, generates a net positive
charge, albeit smaller in density than that generated
by the pyrrole in 3, on the opposite edge of the aromatic
ring to the 2-halo substituent (Figure 1a). The CCK2
receptor affinity in the bicyclic heteroaromatic series
was shown to be sensitive to the fieldpoint distribution
around the pyrrolo ring of the indole substituent, with
the 10-fold lower potency of the indole regioisomer of 3
being ascribed to the reversal of polarity around this
ring. Moreover the magnitude of the positive fieldpoints
in this region of 3 is strengthened by electron delocal-
ization through the 5,6-dicarbonyl substituents of the
fused aromatic ring. Although it may be envisaged that
introduction of a 1-(6-indolomethyl) group in place of
the 1-benzyl substituent of the benzodiazonine ring
would generate an electropositive fieldpoint of greater
magnitude than that arising from the 2-halo-substituted
benzyl substituent in the benzodiazonines, the absence
of additional delocalization derived from conjugation
with the 5,6-dicarbonyl moiety, which occurs in the
indole of 3, would not be reproduced and would therefore
be unlikely to have such a significant influence on the
receptor affinity. In addition, introduction of an indole
substituent in this position is incompatible with the
existing synthetic route. On the other hand, the appar-
ent insensitivity of the affinity to the presence or nature
of substituents on the fused aromatic ring in examples
33-35 was mirrored in the high degree of tolerance of
substituents in the phenylalanine-derived aromatic ring
of 3 and its analogues, which corresponds to the benzo-
fused aromatic ring of 32 in the superposition (Figure
1c).
The structure-activity relationships (SAR) of the
fused bicyclic heteroaromatic-based and benzodiazonine-
based series were consistent with the superposition
predicted by a fieldpoint-generated molecular modeling
comparison, and as such the opportunity for achieving
a further increase in the receptor affinity of the benzo-
diazonines, by consideration of 3, was limited. Alterna-
tively constraint of those substituents already present
was considered to achieve more favorable entropy on
receptor binding.
Within the family of low-energy conformations of
benzodiazonines, there occurred conformations in which
the N-acetyl carbonyl group appeared to act as a

3524 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
McDonald et al.
Ta ble 2. Inhibition of Pentagastrin-Stimulated Acid Secretion
in Anesthetized Rats
hydrogen bond acceptor for the amide NH on the C-3
side chain (data not shown). These conformations were
generally not the global minimum conformation but
were sufficiently energetically low lying to likely exist
at body temperature. To ascertain whether such con-
formations were biologically relevant, the tricyclic com-
pound 38 was prepared as an unrefined probe of their
significance. This change significantly reduced the
receptor affinity, although the difference in ring size
between this compound and that resulting from forma-
tion of a putative hydrogen bond in 20, as well as the
realignment of the carbonyl group, makes this an
imperfect analogue. Substitution of the acetyl group of
32 by bulkier substituents, as in examples 36 and 37,
which might be expected to influence their ability to
participate in intramolecular hydrogen bonding, results
in a reduction in affinity with respect to the acetyl
derivative. However, these more subtle changes resulted
in a less pronounced reduction in affinity with respect
to 32 than that resulting from the preparation of
tricyclic compound 38. Furthermore in the γ-keto acid
derivative 39, in which the amide of the side chain is
replaced with a ketomethylene moiety, which is unable
to act as a hydrogen bond donor, it was found that the
receptor affinity was similarly diminished with respect
to 31. This effect can be attributed to the increased
entropy arising from having a methylene substituent
in place of an amide nitrogen. The â-keto acid derivative
40, in which the entropic component to receptor binding
would be expected to less, has comparable affinity to
31, at least in the functional assay. That this is so may
be considered surprising in view of the different lengths
of the respective side chains of 40 and 31, but it is
consistent with ionic interactions, in which the carboxy-
lic acid would be expected to partake, being influenced
by spatial as well as directional relationships. At first
glance the requirement for a carboxylic acid in this
position would appear to be unnecessary since the
methyl ester derivative 42 is as potent in the isolated
rat stomach assay as the corresponding acid containing
compound 20. However, this compound was approxi-
mately 10-fold less potent in the radioligand binding
assay and as such fell short of our requirements. The
carboxylic acid group could be replaced by other acid
mimics such as tetrazole (43) and acylsulfonamide (44)
without a substantial loss of affinity in both assays.
no.
dosea
inhibitionb
1 (L-365,260)
3 (J B93182)
32
1.0
0.025
0.1
46 ( 10 (3)
97 ( 11 (4)
35 ( 5 (4)
67 ( 10 (4)
0.3
a
Compound dose in µmol/kg. N-Methyl-D-glucamine salts of 3
and 32 were administered in 0.9% saline solution and 1 in aqueous
2-hydroxypropyl-â-cyclodextrin solution (45% w/v). b Peak percent-
age inhibition ( SEM (number of replicates) relative to submaxi-
mal acid secretory infusion dose of pentagastrin (0.1 µg/kg/min).
Values obtained by comparison with the acid output of the
stimulated preparation prior to dosing with the test compounds.
Con clu sion
A practical route to 2,7-dioxo-2,3,4,5,6,7-hexahydro-
1H-benzo[h][1,4]diazonines has been developed. Field-
point-based comparison with the prototypical CCK2
receptor antagonist 3 identified this uncommon ring
system as a potential chemical template, and through
further structural manipulation it has been possible to
reproduce, in part, some of the properties of 3 in a novel
series of benzodiazonines. There remains a variance of
approximately 100-fold in CCK2 receptor affinity be-
tween the most potent examples of the benzodiazonine
series and 3, which can at least, in part, be attributed
to differences in magnitude and distribution of the
respective fieldpoint patterns. Selectivity over CCK1
receptors has been retained, and examples of this series
inhibited gastric acid secretion in an in vivo assay.
Although the benzodiazonines do not display substan-
tially greater potency in vivo than 3 even when allowing
for their inferior receptor affinity, this work has en-
hanced further the value of fieldpoints as a method of
comparing conformations of different molecules and by
a rational sequence has enabled us, in this instance, to
devise a novel and effective chemical template, structur-
ally much removed from the starting hormone and
distinct from other CCK2 receptor antagonists.
Exp er im en ta l Section
Gen er a l. All the compounds, except for compounds 1 and
42, were tested as either N-methyl-D-glucamine or sodium
salts. The salts were prepared by stirring an aqueous mixture
of the compound with 1 equiv of N-methyl-D-glucamine or 0.1
M sodium hydroxide, until a solution was obtained (a mini-
mum amount of 1,4-dioxan was added if necessary to complete
dissolution) and the solutions freeze-dried. The isolated per-
fused rat stomach assay and the method of analysis were
conducted as previously described.28 For testing, the com-
pounds were dissolved in dimethyl sulfoxide at a single
concentration between 10-4 and 3 × 10-5 M, and at least six
separate experiments were used to obtain pKB estimates for
each compound. The mouse cerebral cortex29 and guinea pig
pancreas30 assays were used as previously described, in which
each of the compounds were dissolved in dimethylformamide
to give stock concentrations of 10 mM and further dilutions
made in HEPES-NaOH buffer. Details of the anesthetized
rat preparation used have been described previously.11
NMR spectra were recorded on a Bruker DRX 300 spec-
trometer with chemical shifts reported in ppm relative to
tetramethylsilane used as internal standard. Elemental analy-
ses were determined at the London School of Pharmacy and
are within 0.4% of the theoretical values. Optical rotations
were measured using an Optical Activity Ltd., AA-10 pola-
rimeter. Merck silica gel 60 (40-63 µm) was used for column
chromatography.
Consideration of the foregoing results and their
interpretations prompted preparation of 41, which is the
most potent example of this class of compounds and has
matching affinity estimates in both of the CCK2 assays.
Compound 41 was at least 100-fold selective for CCK2
over CCK1 receptors as judged by its displacement of
20 pM [125I]BH-CCK-8S to CCK1 binding sites on guinea
pig pancreatic cells,30 in which 41 and all other benzo-
diazonines examined, were ineffective (pKi e 5). In
addition, several of the benzodiazonines were effective
in vivo by intravenous administration in a Ghosh and
Schild rat model of pentagastrin-stimulated gastric acid
secretion.11 For instance, although apparently of lower
receptor affinity than compounds 1 and 3, 32 was
effective in this assay at intermediate doses compared
to that required to achieve inhibition by the reference
compounds and, moreover, displayed dose-dependent
behavior (Table 2).

Design of CCK2 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3525
Abbr evia tion s: 1-Ad (adamantan-1-yl), PyBroP (bromo-
trispyrrolidinophosphonium hexafluorophosphate), CDI (1,1′-
carbonyldiimidazole), DCM (dichloromethane), EDCI (1-(3-
(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride),
DMAP (4-(dimethylamino)pyridine), HOBt (1-hydroxybenzo-
triazole), NMO (4-methylmorpholine N-oxide), PCC (pyri-
dinium chlorochromate), SEM (2-(trimethylsilyl)ethoxymeth-
yl), TPAP (tetrapropylammonium perruthenate), pTSA (p-
toluenesulfonic acid monohydrate).
4.22 (m, 1H, H-3), 3.37 (m, 1H, H-4), 3.07 (m, 1H, H-4), 1.90
(br s, 3H, 3 × CH), 1.71-1.42 (m, 17H, 6 × CH2, COCH3 and
CH2Ad).
Meth od B: Ben zyl (1R,3S)-1-[(1-Ad a m a n tyl)m eth yl]-
2-a cetyl-9-(2-flu or oben zyl)-1,2,3,4-tetr a h yd r o-9H-p yr id o-
[3,4-b]in d ole-3-ca r boxyla t e (11i). N ′-(2-Fluorobenzyl)-L-
tryptophan was prepared by reacting L-tryptophan with
sodamide and 2-fluorobenzyl bromide in liquid ammonia
according to a literature method.33 The product was esterified
using benzyl alcohol and pTSA in toluene, to afford N ′-(2-
fluorobenzyl)-L-tryptophan benzyl ester as the p-toluene-
sulfonate salt.
N ′-(2-Fluorobenzyl)-L-tryptophan benzyl ester (23.06 g, 57.3
mmol) was reacted with adamantan-1-ylacetaldehyde accord-
ing to step a to give benzyl (1R,3S)-1-[(1-adamantyl)methyl]-
9-(2-fluorobenzyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-
carboxylate as a red fluffy solid (30.01 g, 93%): 1H NMR
(CDCl3) δ 7.53 (m, 1H, Ar H), 7.41-7.08 (m, 10H, Ar H), 6.89
(m, 1H, Ar H), 6.38 (m, 1H, Ar H), 5.32-5.21 (m, 4H, CH2Ar),
4.35 (d, J ) 9.9 Hz, 1H, H-1), 4.07 (dd, J ) 10.5 and 4.5 Hz,
1H, H-3), 3.18 (dd, J ) 15.3 and 4.5 Hz, H-4), 2.91 (dd, J )
15.3 and 10.5 Hz, H-4), 2.20-2.00 (br s, 1H, NH), 1.94 (br s,
3H, 3 × CH), 1.72-1.57 (m, 13H, 6 × CH2 and CHCHHAd),
1.23 (d, J ) 15 Hz, 1H, CHCHHAd).
Benzyl (1R,3S)-1-[(1-adamantyl)methyl]-9-(2-fluorobenzyl)-
1,2, 3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (18.81
g, 33.4 mmol) was reacted according to step b to give 11i as
a white amorphous solid (16.65 g, 84%): 1H NMR (CDCl3) δ
7.56 (m, 1H, Ar H), 7.35-7.11 (m, 10H, Ar H), 6.93 (m, 1H,
Ar H), 6.27 (m, 1H, Ar H), 5.32 (m, 3H, CH2Ar and CHHAr),
5.12 (d, J ) 12.3 Hz, 1H, CHHAr), 4.93 (d, J ) 10.5 Hz, 1H,
H-1), 4.24 (dd, J ) 11.7 and 4.5 Hz, 1H, H-3), 3.40 (dd, J )
11.7 Hz, 1H, H-4), 3.05 (dd, J ) 15.9 and 4.5 Hz, H-4), 1.86
(br s, 6H, 3 × CH and COCH3), 1.81-1.50 (m, 13H, 6 × CH2
and CHCHHAd), 1.41 (d, J ) 15.0 Hz, 1H, CHCHHAd).
Ben zyl (3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-
ben zyl-2,7-d ioxo-2,3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]-
d ia zon in e-5-ca r boxyla te (12a ). Step d : Ozone was bubbled
through a solution of 11a (7.45 g, 12.7 mmol) in MeOH (200
mL) at -78 °C until a blue color persisted. Nitrogen was then
bubbled through the solution until it turned clear, followed
by the addition of Me2S (6.0 mL, 81.7 mmol). The solution was
allowed to warm to room temperature stirred for a further 2
h, and evaporated to dryness. The crude product was purified
by chromatography on silica gel using EtOAc-CH2Cl2 (1:19)
as eluant, affording 12a as a colorless oil (5.8 g, 72%): 1H NMR
(CDCl3) δ 7.43-7.22 (m, 13H, Ar H), 6.75 (m, 1H, Ar H), 5.63
(d, J ) 14.1 Hz, 1H, CHHAr), 5.16 (d, J ) 12.3 Hz, 1H,
CHHAr′), 5.05 (d, J ) 12.3 Hz, 1H, CHHAr′), 4.03-3.99 (m,
3H, H-3, H-5 and H-6), 3.90 (d, J ) 14.1 Hz, 1H, CHHAr),
3.05 (dd, J ) 6.6 and 2.1 Hz, 1H, H-6), 2.46 (dd, J ) 14.4 and
11.7 Hz, 1H, CHHAd), 1.91 (br s, 3H, 3 × CH), 1.71-1.55 (m,
6H, 3 × CH2), 1.48-1.28 (m, 6H, 3 × CH2), 1.16 (s, 3H,
COCH3), 1.08 (d, J ) 14.4 Hz, 1H, CHHAd).
Adamantan-1-ylacetaldehyde, cyclohexylacetaldehyde, and
3,3-dimethylbutyraldehyde were prepared by PCC oxidation31
of the corresponding commercially available alcohols. Cyclo-
heptylacetaldehyde was similarly prepared from 2-cyclohep-
tylethanol.32 The 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole in-
termediates 11a -p were prepared by either of the two
methods described below (Scheme 2).
Meth od A: Ben zyl (1R,3S)-1-[(1-Ad a m a n tyl)m eth yl]-
2-a cetyl-9-ben zyl-1,2,3,4-tetr a h yd r o-9H-p yr id o[3,4-b]in -
d ole-3-ca r boxyla te (11a ). Step a : Trifluoroacetic acid (0.27
mL, 3.5 mmol) was added to a solution of L-tryptophan benzyl
ester (10.23 g, 34.8 mmol) and adamantan-1-ylacetaldehyde
(6.2 g, 34.8 mmol) in dry CH2Cl2 (300 mL) with 3A molecular
sieves (46.5 g) at -10 °C. The reaction mixture was allowed
to warm to room temperature and stirred for 7 h. The mixture
was cooled to 0 °C, trifluoroacetic acid (5.6 mL, 72.7 mmol)
added, and stirring continued at room temperature for 16 h.
The reaction mixture was filtered, washed with saturated
NaHCO3 (200 mL), brine (2 × 200 mL) and dried (MgSO4).
Filtration and evaporation of the solvent gave the crude
product as a mixture of diastereoisomers. Benzyl (1R,3S)-1-
[(1-adamantyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]in-
dole-3-carboxylate was obtained by isolation of the more polar
component by chromatography using EtOAc-CH2Cl2 (1:40) as
eluant (6.2 g, 39%): 1H NMR (CDCl3) δ 7.60 (s, 1H, NH), 7.48
(m, 1H, Ar H), 7.33-7.27 (m, 5H, Ar H), 7.17-7.07 (m, 3H, Ar
H), 5.20 (s, 2H, CH2Ar), 4.41 (d, J ) 6.9 Hz, 1H, H-1), 4.01
(dd, J ) 7.2 and 5.1 Hz, 1H, H-3), 3.13 (dd, J ) 15.6 and 5.1
Hz, 1H, H-4), 3.01 (dd, J ) 15.6 and 7.2 Hz, 1H, H-4), 2.01 (br
s, 3H, 3 × CH), 1.78-1.59 (m, 13H, 6 × CH2 and CHCHHAd),
1.48 (m, 1H, CHCHHAd).
Step b: Acetyl chloride (1.2 mL, 16.9 mmol) was added to a
solution of benzyl (1R,3S)-1-[(1-adamantyl)methyl]-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (6.24 g, 13.7
mmol) and NEt3 (1.9 mL, 13.6 mmol) with DMAP (30 mg) in
dry CH2Cl2 (120 mL) at -20 °C under nitrogen. The solution
was allowed to warm to room temperature and after stirring
for a further 2 h was washed with 10% citric acid solution (100
mL), brine (2 × 100 mL) and dried (MgSO4). Filtration and
evaporation of the solvent gave an oil which on trituration with
EtOAc afforded benzyl (1R,3S)-1-[(1-adamantyl)methyl]-2-
acetyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxy-
late as a white amorphous solid (6.3 g, 93%): 1H NMR (CDCl3)
δ 7.75 (s, 1H, NH), 7.51 (m, 1H, Ar H), 7.36-7.27 (m, 5H, Ar
H), 7.21-7.09 (m, 3H, Ar H), 5.29 (d, J ) 11.1 Hz, 1H, CHHAr),
5.12 (m, 2H, CHHAr and H-1), 4.16 (m, 1H, H-3), 3.38 (dd, J
) 15.9 and 10.5 Hz, 1H, H-4), 3.03 (dd, J ) 15.9 and 4.2 Hz,
1H, H-4), 2.22 (s, 3H, COCH3), 1.92 (br s, 3H, 3 × CH), 1.74-
1.51 (m, 14H, 6 × CH2 and CH2Ad).
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-ben zyl-2,7-
d ioxo-2,3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e-
5-ca r boxyla te (13a ). Step e: 12a (5.8 g, 9.2 mmol) was stirred
under an hydrogen atmosphere with 10% palladium on
charcoal (500 mg) in MeOH-THF (100 mL/1:1) at room
temperature for 1 h. The reaction mixture was filtered through
a pad of Celite and evaporated to dryness, affording 13a as a
white amorphous solid (4.75 g, 96%): 1H NMR (DMSO-d6) δ
7.50 (s, 3H, Ar H), 7.32-7.20 (m, 5H, Ar H), 7.00 (m, 1H, Ar
H), 5.34 (d, J ) 14.4 Hz, 1H, CHHAr), 4.00-3.71 (m, 4H, H-3,
H-5, H-6 and CHHAr), 2.74 (m, 1H, H-6), 2.40 (m, 1H,
CHHAd), 1.86 (br s, 3H, 3 × CH), 1.59 (m, 6H, 3 × CH2), 1.49-
1.26 (m, 6H, 3 × CH2), 1.10 (m, 2H, CHHAd and COCH3);
Step c: A solution of benzyl (1R,3S)-1-[(1-adamantyl)-
methyl]-2-acetyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-
carboxylate (6.3 g, 12.7 mmol) in dry DMF (50 mL) was added
to a suspension of NaH (60% dispersion in oil/0.56 g, 14 mmol)
in dry DMF (20 mL) under nitrogen at room temperature. The
reaction mixture was stirred for 15 min at room temperature
whereupon a solution of benzyl bromide (1.6 mL, 13.5 mmol)
in DMF (10 mL) was added. The reaction was stirred for a
further 1 h, diluted with EtOAc (150 mL), washed with 2 N
HCl (150 mL), brine (3 × 150 mL) and dried (MgSO4).
Filtration and evaporation of the solvent gave (11a ) as a yellow
foam (7.45 g, 100%): 1H NMR (CDCl3) δ 7.56 (m, 1H, Ar H),
7.39-7.14 (m, 12H, Ar H), 6.83 (m, 1H, Ar H), 5.48 (d, J )
17.1 Hz, 1H, CHHAr), 5.30 (d, J ) 12.3 Hz, 1H, CHHAr′), 5.10
(m, 2H, CHHAr and CHHAr′), 4.84 (d, J ) 10.5 Hz, 1H, H-1),
[R]20 -82.0° (c 1.00, MeOH); further characterized as the
D
N-methyl-D-glucamine salt. Anal. (C32H36N2O5‚C7H17NO5‚
2.0H2O) C, H, N.
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
ca r boxym eth yla m in oca r bon yl-2,7-d ioxo-2,3,4,5,6,7-h exa -
h yd r o-1H-ben zo[h ][1,4]d ia zon in e (20). Step f: PyBroP (233
mg, 0.5 mmol) was added to a solution of 13a (264 mg, 0.5

3526 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
McDonald et al.
mmol), glycine benzyl ester p-toluenesulfonate (170 mg, 0.5
mmol) and i-Pr2NEt (260 µL, 1.5 mmol) in dry CH2Cl2 (5 mL).
The reaction mixture was stirred at room temperature for 18
h, diluted with CH2Cl2 (20 mL), washed with 2 N HCl (25 mL),
brine (25 mL) and dried (MgSO4). Filtration and evaporation
of the solvent gave the crude product, which was purified by
chromatography with EtOAc-CH2Cl2 (3:7) as eluant. (3R,5S)-
4-Acetyl-3-[(1-adamantyl)methyl]-1-benzyl-5-benzyloxycarbo-
nylmethylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-
benzo[h][1,4]diazonine was obtained as a colorless oil (190 mg,
55%): 1H NMR (CDCl3) δ 7.45-7.23 (m, 13H, Ar H), 6.76 (m,
1H, Ar H), 6.38 (br s, 1H, CONH), 5.63 (d, J ) 14.1 Hz, 1H,
CHHAr), 5.18 (s, 2H, CH2Ar′), 4.14-3.98 (m, 5H, H-3, H-5,
H-6 and CONHCH2), 3.92 (d, J ) 14.1 Hz, 1H, CHHAr), 3.07
(dd, J ) 11.7 and 3.3 Hz, 1H, H-6), 2.73 (m, 1H, CHHAd), 1.95
(br s, 3H, 3 × CH), 1.74-1.38 (m, 12H, 6 × CH2), 1.24 (m, 4H,
COCH3 and CHHAd).
25-27 were prepared by a similar sequence used to prepare
20 except that the appropriate acetaldehyde was used in place
of adamantan-1-ylacetaldehyde in step a .
(3R,5S)-4-Acetyl-1-ben zyl-5-ca r boxym eth yla m in oca r -
bon yl-3-(2,2-dim eth ylpr opyl)-2,7-dioxo-2,3,4,5,6,7-h exah y-
d r o-1H-ben zo[h ][1,4]d ia zon in e (25): 1H NMR (DMSO-d6)
δ 7.47-7.12 (m, 9H), 6.97 (m, 1H), 5.43 (m, 1H), 3.96 (m, 3H),
3.61 (m, 3H), 2.90 (m, 1H), 2.48 (m, 1H), 1.56 (m, 1H), 1.05 (s,
3H), 0.84 (s, 9H); further characterized as the N-methyl-D-
glucamine salt. Anal. (C28H33N3O6‚C7H17NO5‚4.5H2O) C, H, N.
(3R,5S)-4-Acetyl-1-ben zyl-5-ca r boxym eth yla m in oca r -
bon yl-3-cycloh exylm eth yl-2,7-dioxo-2,3,4,5,6,7-h exah ydr o-
1H-ben zo[h ][1,4]d ia zon in e (26): 1H NMR (DMSO-d6) δ
7.43-7.20 (m, 8H), 6.73 (m, 1H), 6.62 (m, 1H), 5.66 (m, 1H),
4.15-3.93 (m, 6H), 3.07 (m, 1H), 2.45 (m, 1H), 1.74-0.90 (m,
15H); further characterized as the N-methyl-D-glucamine salt.
Anal. (C30H35N3O6‚C7H17NO5‚6.0H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-adamantyl)methyl]-1-benzyl-5-benzyl-
oxycarbonylmethylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahy-
dro-1H-benzo[h][1,4]diazonine (190 mg, 0.28 mmol) was re-
acted according to step e affording 20 as a white amorphous
solid (154 mg, 92%): 1H NMR (DMSO-d6) δ 12.54 (br s, 1H,
CO2H) 7.47 (s, 4H, Ar H), 7.27 (m, 5H, Ar H), 7.00 (s, 1H,
CONH), 5.35 (d, J ) 15.0 Hz, 1H, CHHAr), 3.99-3.76 (m, 3H,
H-3, H-5 and H-6) 3.70-3.65 (m, 3H, CHHAr and CONHCH2),
2.92 (m, 1H, H-6), 2.30 (m, 1H, CHHAd), 1.86 (br s, 3H, 3 ×
CH), 1.65-1.25 (m, 13H, 6 × CH2 and CHHAd) 1.04 (s, 3H,
COCH3); further characterized as the N-methyl-D-glucamine
salt. Anal. (C34H39N3O6‚C7H17NO5‚2.0H2O) C, H, N.
(3R,5S)-4-Acetyl-1-ben zyl-5-ca r boxym eth yla m in oca r -
bon yl-3-cycloh ep tylm eth yl-2,7-d ioxo-2,3,4,5,6,7-h exa h y-
d r o-1H-ben zo[h ][1,4]d ia zon in e (27): 1H NMR (DMSO-d6)
δ 7.43-7.20 (m, 8H), 6.73 (m, 1H), 6.62 (m, 1H), 5.66 (m, 1H),
4.16-3.92 (m, 6H), 3.07 (m, 1H), 2.45 (m, 1H), 1.62-1.26 (m,
13H), 1.10 (s, 3H); further characterized as the N-methyl-D-
glucamine salt. Anal. (C31H37N3O6‚C7H17NO5‚6.0H2O) C, H, N.
28-30 were prepared by a similar sequence used to prepare
20 except that either methyl iodide or the appropriate fluoro-
substituted benzyl bromides were used in place of benzyl
bromide in step c.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-m eth yl-5-
ca r boxym eth yla m in oca r bon yl-2,7-d ioxo-2,3,4,5,6,7-h exa -
h yd r o-1H-ben zo[h ][1,4]d ia zon in e (28): 1H NMR (DMSO-
d6) δ 7.65 (m, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H),
4.01-3.91 (m, 2H), 3.67-3.53 (m, 3H), 3.07 (s, 3H), 2.89 (m,
1H), 2.40 (m, 1H), 1.90 (s, 3H), 1.62 (s, 6H), 1.57-1.48 (m, 3H),
1.38-1.30 (m, 4H), 1.07 (s, 3H); further characterized as the
N-methyl-D-glucamine salt. Anal. (C28H35N3O6‚C7H17NO5‚
3.0H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(4-flu or o-
b en zyl)-5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exah ydr o-1H-ben zo[h ][1,4]diazon in e (29): 1H NMR
(CDCl3) δ 7.2 (m, 5H), 6.95 (m, 2H), 6.72 (m, 1H), 5.73 (m,
1H), 5.26 (s, 1H), 4.26 (m, 1H), 4.05 (m, 4H), 3.31 (m, 1H),
2.63 (m, 1H), 2.35 (m, 1H), 1.88(s, 3H), 1.73-1.24 (m, 12H),
1.23 (s, 3H), 1.08 (m, 1H); further characterized as the
N-methyl-D-glucamine salt. Anal. (C34H38FN3O6‚C7H17NO5‚
1.4H2O) C, H, N.
21-23 were prepared by a similar sequence used to prepare
20 except that the appropriate amino acid benzyl esters were
used in place of glycine benzyl ester p-toluenesulfonate in step
f.
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
(2-car boxyeth yl)am in ocar bon yl-2,7-dioxo-2,3,4,5,6,7-h exa-
h yd r o-1H-ben zo[h ][1,4]d ia zon in e (21): 1H NMR (DMSO-
d6) δ 7.49 (s, 3H), 7.28-7.23 (m, 5H), 7.06 (m, 1H), 7.00 (m,
1H), 5.35 (m, 1H), 3.98-3.88 (m, 3H), 3.61 (m, 1H), 3.21-3.16
(m, 3H), 2.89 (m,1H), 2.31 (m, 3H), 1.86 (s, 3H), 1.57-1.45
(m, 8H), 1.27 (m, 4H), 1.04 (s, 3H); [R]20 -56.0° (c 1.00,
D
MeOH); further characterized as the N-methyl-D-glucamine
salt. Anal. (C35H41N3O6‚C7H17NO5‚3.0H2O) C, H, N.
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
[(1S)-ca r boxyeth yl]a m in oca r bon yl-2,7-d ioxo-2,3,4,5,6,7-
h exah ydr o-1H-ben zo[h ][1,4]diazon in e (22): 1H NMR (DM-
SO-d6) δ 7.49 (m, 3H), 7.30-7.21 (m, 5H), 7.11 (m, 1H), 7.00
(m, 1H), 5.38 (m, 1H), 4.20 (m, 1H), 4.01-3.87 (m, 3H), 3.65
(m, 1H), 2.89 (m, 1H), 2.40 (m, 1H), 1.87 (s, 3H), 1.62-1.31
(m, 9H), 1.27 (m, 4H), 1.19 (m, 3H), 1.06 (s, 3H); further
characterized as the N-methyl-D-glucamine salt. Anal.
(C35H41N3O6‚C7H17NO5‚2.0H2O) C, H, N.
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
[(1R)-ca r boxyeth yl]a m in oca r bon yl-2,7-d ioxo-2,3,4,5,6,7-
h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (23): 1H NMR (DM-
SO-d6) δ 7.49 (m, 3H), 7.41 (m, 1H), 7.30-7.22 (m, 5H), 7.00
(m, 1H), 5.38 (m, 1H), 4.06 (m, 1H), 3.99-3.86 (m, 3H), 3.62
(m, 1H), 3.00 (m, 1H), 2.40 (m, 1H), 1.86 (s, 3H), 1.62-1.31
(m, 9H), 1.27-1.24 (m, 7H), 1.06 (s, 3H); further characterized
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(3-flu or o-
b en zyl)-5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exah ydr o-1H-ben zo[h ][1,4]diazon in e (30): 1H NMR
(CDCl3) δ 7.35-7.20 (m, 5H), 7.03 (m, 3H), 6.76 (m, 1H), 5.77
(m, 1H), 4.02 (m, 4H), 3.63 (m, 1H), 2.64 (m, 1H), 2.37 (m,
1H), 1.90 (s, 3H), 1.90-1.20 (m, 12H), 1.24 (s, 3H), 1.10 (m,
1H); further characterized as the N-methyl-D-glucamine salt.
Anal. (C34H38FN3O6‚C7H17NO5‚1.3H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-flu or o-
b en zyl)-5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (31): pre-
pared from 11i by the same sequence used to obtain 20 from
11a ; 1H NMR (CDCl3) δ 7.47-7.24 (m, 5H), 7.04 (m, 3H), 6.37
(m, 1H), 5.40 (m, 1H), 4.10 (m, 1H), 4.35 (m, 2H), 4.03 (m,
2H), 3.07 (m, 1H), 2.64 (m, 1H), 2.35 (m, 1H), 1.88 (s, 3H),
1.73-1.24 (m, 12H) 1.22 (s, 3H), 1.15 (m, 1H); further
as the N-methyl-D-glucamine salt. Anal. (C35H41N3O6‚C7H17
NO5‚3.0H2O) C, H, N.
-
(3S,5R)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
ca r boxym eth yla m in oca r bon yl-2,7-d ioxo-2,3,4,5,6,7-h exa -
h yd r o-1H-ben zo[h ][1,4]d ia zon in e (24): prepared by a simi-
lar sequence used to prepare 20 except that D-tryptophan
benzyl ester was used in place of L-tryptophan benzyl ester in
step a ; 1H NMR (DMSO-d6) δ 12.54 (br s, 1H, CO2H) 7.47 (s,
4H, Ar H), 7.27 (m, 5H, Ar H), 7.00 (s, 1H, CONH), 5.35 (d, J
) 15.0 Hz, 1H, CHHAr), 3.99-3.76 (m, 3H, H-3, H-5 and H-6)
3.70-3.65 (m, 3H, CHHAr and CONHCH2), 2.92 (m, 1H, H-6),
2.30 (m, 1H, CHHAd), 1.86 (br s, 3H, 3 × CH), 1.65-1.25 (m,
13H, 6 × CH2 and CHHAd) 1.04 (s, 3H, COCH3); further
characterized as the N-methyl-D-glucamine salt. Anal.
(C34H39N3O6‚C7H17NO5‚2.0H2O) C, H, N.
characterized as the N-methyl-D-glucamine salt. Anal. (C34H38
FN3O6‚C7H17NO5‚1.2H2O) C, H, N.
-
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-ch lor o-
b en zyl)-5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (32): pre-
pared by the same route used to prepare 31 except that N ′-
(2-chlorobenzyl)-L-tryptophan benzyl ester was used in place
of N ′-(2-fluorobenzyl)-L-tryptophan benzyl ester in step a ; 1H
NMR (CDCl3) δ 7.42-7.12 (m, 6H), 7.10 (m, 1H), 6.86 (m, 1H),
6.46 (br s, 1H), 5.64 (m, 1H), 4.25-4.10 (m, 5H), 3.10 (m, 1H),
2.69 (m, 1H), 1.95 (s, 3H), 1.74-1.40 (m, 12H), 1.25 (m, 6H);

Design of CCK2 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3527
further characterized as the N-methyl-D-glucamine salt. Anal.
(C34H38ClN3O6‚C7H17NO5) C, H, N.
33-35 were prepared by a similar sequence used to prepare
20 except that the appropriate 5-substituted D/L-tryptophan
benzyl ester was used in place of L-tryptophan benzyl ester in
step a .
(()-tr a n s-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-ben zyl-
5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-9-m et h oxy-
2,3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (33): 1H
NMR (CDCl3) δ 7.30-7.20 (m, 6H), 6.88 (m, 2H), 6.65 (m, 1H),
6.45 (br s, 1H), 5.60 (m, 1H), 4.15 (m, 1H), 4.00 (m 3H), 3.92
(m, 1H), 3.85 (s, 3H), 3.04 (m, 1H), 2.72 (m, 1H), 1.94 (s, 3H),
1.73-1.54 (m, 9H), 1.38 (m, 3H), 1.34 (s, 3H,), 1.18 (m, 1H);
further characterized as the N-methyl-D-glucamine salt. Anal.
(C35H41N3O7‚C7H17NO5‚2.0H2O) C, H, N.
(m, 7H), 7.00 (m, 1H), 5.45 (m, 1H), 4.19-3.95 (m, 4H), 3.60
(m, 1H), 3.00 (m, 1H), 2.29 (m, 1H), 1.88 (s, 3H), 1.63-1.28
(m, 13H), 1.19 (m, 3H), 1.08 (s, 3H); further characterized as
the N-methyl-D-glucamine salt. Anal. (C35H40ClN3O6‚C7H17
NO5‚3.0H2O) C, H, N.
-
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
m et h oxyca r b on ylm et h yla m in oca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (42): pre-
pared by a similar sequence used to prepare 20 except that
glycine methyl ester was used in place of glycine benzyl ester
p-toluenesulfonate in step f, and the final deprotection step
e was omitted; 1H NMR (CDCl3) δ 7.45-7.23 (m, 8H), 6.77
(m, 1H), 6.30 (m, 1H), 5.60 (m, 1H), 4.10-4.00 (m, 4H), 3.90
(m, 1H), 3.76 (m, 3H), 3.09 (m, 1H), 2.70 (m, 1H), 1.74 (s, 3H),
1.73-1.40 (m, 13H), 1.15 (s, 3H). Anal. (C35H41N3O6‚0.5H2O)
C, H, N.
(()-tr a n s-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-ben zyl-
5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-9-m et h yl-2,
3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (34): 1H
NMR (CDCl3) δ 7.27-7.18 (m, 7H), 6.65 (m, 1H), 6.50 (br s,
1H), 5.60 (m, 1H), 4.11-3.89 (m, 5H), 3.04 (m, 1H), 2.70 (m,
1H), 2.37 (s, 3H), 1.93 (s, 3H), 1.78-1.53 (m, 12H), 1.38 (m,
3H), 1.24 (s, 3H); further characterized as the N-methyl-D-
glucamine salt. Anal. (C35H41N3O6‚C7H17NO5‚3.0H2O) C, H, N.
(()-tr a n s-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-ben zyl-
5-ca r b oxym et h yla m in oca r b on yl-2,7-d ioxo-9-flu or o-2,3,
4,5,6,7-h exah ydr o-1H-ben zo[h ][1,4]diazon in e (35): 1H NMR
(CDCl3) δ 7.30 (m, 3H), 7.27 (m, 2H), 7.20 (m, 1H), 6.70 (m,
1H), 6.42 (m, 1H), 5.60 (m, 1H), 4.08 (m, 1H), 4.04 (m, 4H),
3.86 (m, 1H), 3.05 (m, 1H), 2.72 (m, 1H), 2.10 (s, 3H), 1.58 (m,
6H), 1.38 (m, 6H), 1.32 (s, 3H), 1.20 (m 1H); further character-
ized as the N-methyl-D-glucamine salt. Anal. (C34H38FN3O6‚
C7H17NO5‚1.5H2O) C, H, N.
36 and 37 were prepared by a similar sequence used to
obtain 32 except that methyl chloroformate and propionyl
chloride, respectively, were used in place of acetyl chloride in
step b.
(3R,5S)-4-Meth oxyca r bon yl-3-[(1-a d a m a n tyl)m eth yl]-
1-(2-ch lor oben zyl)-5-ca r boxym eth ylca r bon yl-2,7-d ioxo-
2,3,4,5,6,7-h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (36): 1H
NMR (DMSO-d6) δ 7.56 (m, 1H), 7.45-7.20 (m, 7H), 6.84 (m,
1H), 5.43 (m, 1H), 4.40 (m, 1H), 4.07 (m, 1H), 3.75 (m, 1H),
3.61 (m, 2H), 3.01 (m, 1H), 2.20 (m, 1H), 1.86 (s, 3H), 1.57-
1.30 (m, 11H), 1.22 (m, 5H); further characterized as the
N-methyl-D-glucamine salt. Anal. (C34H38ClN3O7‚C7H17NO5‚
1.0H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-ch lor o-
ben zyl)-5-(tetr a zol-5-yl)m eth yla m in oca r bon yl-2,7-d ioxo-
2,3,4,5,6,7-h exa h yd r o-1H -b en zo[h ][1,4]d ia zon in e (43).
N-Benzyloxycarbonyl-C-(2H-tetrazol-5-yl)methylamine (ob-
tained from N-benzyloxycarbonylaminoacetonitrile by modi-
fication of a literature method)34 (7.81 g, 34 mmol) and Cs2CO3
(16.55 g, 51 mmol) in MeOH-H2O (4:1/175 mL) was stirred
at room temperature for 2 h. The mixture was evaporated to
dryness, re-evaporated from EtOH (2 × 150 mL) and the
residual oil suspended in dry DMF (180 mL). SEM-chloride
(7.0 mL, 38 mmol) was added, and the mixture stirred at room
temperature for 18 h. The reaction mixture was poured into
EtOAc-H2O (2:1/450 mL), the organic layer separated, washed
with 5% KHSO4 (150 mL), 10% Na2CO3 (150 mL), brine (2 ×
100 mL) and dried (Na2SO4). Filtration and evaporation of the
solvent gave N-benzyloxycarbonyl-C-(SEM-2H-tetrazol-5-yl)-
methylamine as a colorless oil (12.18 g, 100%).
A mixture of N-benzyloxycarbonyl-C-(SEM-2H-tetrazol-5-
yl)methylamine (12.18 g, 34 mmol) and 10% palladium on
charcoal (0.93 g) in MeOH-THF (40:1/205 mL) was stirred
under hydrogen at room temperature for 18 h. The reaction
mixture was filtered through a pad of Celite and evaporated
to dryness to give the crude product as a colorless oil. The oil
was dissolved in a saturated solution of HCl in MeOH and
evaporated to dryness. The crude product was dissolved in
H2O, washed with Et2O and the aqueous solution freeze-dried
to give C-(SEM-2H-tetrazol-5-yl)methylamine hydrochloride as
a white fluffy solid (5.79 g, 65%).
Compound 13j was reacted according to step f except that
C-(SEM-2H-tetrazol-5-yl)methylamine hydrochloride was used
in place of glycine benzyl ester p-toluenesulfonate to give
(3R,5S)-4-acetyl-3-[(1-adamantyl)methyl]-1-(2-chlorobenzyl)-5-
[2-(2-trimethylsilylethoxy)methyl-2H-tetrazol-5-yl]methylami-
nocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]-
diazonine.
(3R,5S)-4-Eth ylca r bon yl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-
ch lor ob en zyl)-5-ca r b oxym et h ylca r b on yl-2,7-d ioxo-2,3,
4,5,6,7-h exah ydr o-1H-ben zo[h ][1,4]diazon in e (37): 1H NMR
(DMSO-d6) δ 7.62-7.19 (m, 7H), 6.98 (m, 1H), 5.45 (m, 1H),
4.06 (m, 5H), 3.68 (m, 3H), 3.01 (m, 1H), 2.25 (m, 1H) 1.88 (s,
3H), 1.67-1.14 (m, 13H), 0.55 (m, 3H); [R]20 -83.3° (c 0.66,
D
MeOH); further characterized as the N-methyl-D-glucamine
salt. Anal. (C35H40ClN3O6‚C7H17NO5‚2.0H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-ch lor o-
ben zyl)-5-[(1S)-ca r b oxyet h yl]a m in oca r bon yl-2,7-d ioxo-
2,3,4,5,6,7-h exah ydr o-1H-ben zo[h ][1,4]diazon in e (41). Com-
pound 13j was reacted according to step f except that
L-alanine allyl ester was used in place of glycine benzyl ester
p-toluenesulfonate to give (3R,5S)-4-acetyl-3-[(1-adamantyl)-
methyl]-1-(2-chlorobenzyl)-5-[(1S)-allyloxycarbonylethyl]ami-
nocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]-
diazonine.
Step g: Et2NH (0.9 mL, 8.7 mmol) was added to a solution
of (3R,5S)-4-acetyl-3-[(1-adamantyl)methyl]-1-(2-chlorobenzyl)-
5-[(1S)-allyloxycarbonylethyl]aminocarbonyl-2,7-dioxo-2,3,4,5,6,7-
hexahydro-1H-benzo[h][1,4]diazonine (1.06 g, 1.6 mmol) and
(Ph3P)4Pd (200 mg, 0.17 mmol) in dry THF (60 mL) and the
mixture stirred under argon for 17 h. The reaction mixture
was diluted with EtOAc (40 mL), washed with 5% KHSO4 (80
mL), brine (60 mL) and dried (Na2SO4). Filtration and evapo-
ration of the solvent gave the crude product, which was
purified by chromatography with HOAc-MeOH-CH2Cl2 (1:
3:40) as eluant. 41was obtained as a pale yellow solid (971
mg, 96%): 1H NMR (DMSO-d6) δ 12.60 (br s, 1H), 7.46-7.13
Step h : (3R,5S)-4-Acetyl-3-[(1-adamantyl)methyl]-1-(2-chlo-
robenzyl)-5-[2-(2-trimethylsilylethoxy)methyl-2H-tetrazol-5-yl]-
methylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo-
[h][1,4]diazonine (977 mg, 1.3 mmol) and MgBr2‚Et2O (2.33 g,
9.1 mmol) in dry CH2Cl2 (50 mL) were stirred at room
temperature for 24 h. The mixture was diluted with CH2Cl2
(50 mL), washed with 5% KHSO4 (100 mL), brine (2 × 100
mL) and dried (Na2SO4). Filtration and evaporation of the
solvent gave the crude product, which was purified by chro-
matography using MeOH-CH2Cl2 (1:5) as eluant. 43 was
obtained as a white amorphous solid (725 mg, 89%): 1H NMR
(DMSO-d6) δ 7.63 (m, 1H), 7.47-7.12 (m, 7H), 7.00 (m, 1H),
5.46 (m, 1H), 4.41 (m, 2H), 4.14-3.93 (m, 3H), 3.80 (m, 1H),
3.00 (m, 1H) 2.69 (m, 1H), 2.40 (m, 1H) 1.88 (s, 3H), 1.70-
1.32 (m, 13H), 1.04 (s, 3H); further characterized as the sodium
salt. Anal. (C34H37ClN7O4‚Na‚2.5H2O) C, H, N.
(3R,5S)-4-Acet yl-3-[(1-a d a m a n t yl)m et h yl]-1-b en zyl-5-
m eth a n esu lfon a m id oca r boxym eth yla m in oca r bon yl-2,7-
d ioxo-2,3,4,5,6,7-h exa h yd r o-1H -b en zo[h ][1,4]d ia zon in e
(44). Step i: Methanesulfonamide (40 mg, 0.4 mmol) was
added to a solution of 31 (194 mg, 0.32 mmol), EDCI (77 mg,
0.40 mmol), and DMAP (50 mg, 0.4 mmol) in dry CH2Cl2 (20
mL), and the reaction mixture stirred at room temperature

3528 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
McDonald et al.
for 18 h. The solution was diluted with CH2Cl2 (10 mL),
washed with 5% KHSO4 (2 × 20 mL), brine (2 × 20 mL) and
dried (MgSO4). Filtration and evaporation of the solvent gave
the crude product, which was purified by chromatography
using HOAc-MeOH-CH2Cl2 (1:20:200) as eluant. 44 was
obtained as a yellow fluffy solid (102 mg, 47%): 1H NMR
(DMSO-d6) δ 11.48 (s, 1H), 7.53-7.42 (m, 4H), 7.30-7.21 (m,
5H), 7.00 (m, 1H), 5.34 (m, 1H), 4.00-3.87 (m, 4H), 3.74 (m,
2H), 3.21 (s, 3H), 2.90 (m, 1H), 2.40 (m, 1H), 1.87 (s, 3H), 1.64-
1.27 (m, 13H), 1.06 (s, 3H); further characterized as the sodium
salt. Anal. (C35H40FN4O7S‚Na‚H2O) C, H, N.
(3R,7a S)-3-[(1-Ad a m a n tyl)m eth yl]-1-ben zyl-6-ca r boxy-
m eth yl-2,4,7,9-tetr aoxo-2,3,4,5,7,7a,8,9-octah ydr o-1H-pyr a-
zin o[1,6-a ]ben zo[h ][1,4]d ia zon in e (38). Benzyl (1R,3S)-1-
[(1-adamantyl)methyl]-9-benzyl-2-tert-butyloxycarbonyl-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (11p ) was
obtained by a similar sequence used to prepare 11a except that
di-tert-butyl dicarbonate was used in place of acetyl chloride
in step b. (1R,3S)-1-[(1-Adamantyl)methyl]-9-benzyl-3-ben-
zyloxycarbonylmethylaminocarbonyl-2-tert-butyloxycarbonyl-
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (14) was obtained by
treatment of 11p according to step s e and f: 1H NMR (CDCl3)
δ 7.58 (m, 1H, Ar H), 7.39-7.15 (m, 12H, Ar H), 7.00 (m, 1H,
Ar H), 5.60 (m, 1H, CHHAr), 5.36-5.09 (m, 5H, H-1, CHHAr
and CH2Ar′), 4.30-4.15 (m, 3H, H-3 and CONHCH2CO), 3.60
(m, 1H, H-4), 3.33 (m, 1H, H-4), 1.94 (br s, 3H, 3 × CH), 1.74-
1.30 (m, 23H, 6 × CH2, CH2Ad and C(CH3)3).
Reaction of 16 according to step d gave (3R,7aS)-3-[(1-
adamantyl)methyl]-1-benzyl-6-benzyloxycarbonylmethyl-2,4,7,9-
tetraoxo-2,3,4,5,7,7a,8,9-octahydro-1H-pyrazino[1,6-a]benzo-
[h][1,4]diazonine: 1H NMR (CDCl3) δ 7.85 (m, 1H, Ar H), 7.58
(m, 1H, Ar H), 7.38 (m, 6H, Ar H), 7.27 (m, 3H, Ar H), 7.10
(m, 2H, Ar H), 6.98 (m, 1H, Ar H), 5.21-5.09 (m, 4H, CHHAr,
H-3 and CH2Ar′), 4.44 (m × 2, 2H, CHHAr and H-5), 4.32 (m,
1H, COCHHN), 3.77 (m, 1H, COCHHN), 3.67 (m, 1H,
NCHHCO2Bn), 3.43 (m × 2, 2H, NCHHCO2Bn and H-6), 4.97
(m, 1H, CONH), 4.17 (m, 1H, H-3), 4.03 (m, 2H, CONHCH2-
CO), 2.99 (m, 1H, CHHAd), 2.50 (m, 1H, H-6), 1.93 (br s, 3H,
3 × CH), 1.70-1.34 (m, 12H, 6 × CH2), 0.93 (m, 1H, CHHAd).
38 was obtained as a white amorphous solid by deprotection
of (3R,7aS)-3-[(1-adamantyl)methyl]-1-benzyl-6-benzyloxycar-
bonylmethyl-2,4,7,9-tetraoxo-2,3,4,5,7,7a,8,9-octahydro-1H-
pyrazino[1,6-a]benzo[h][1,4]diazonine according to step e: 1H
NMR (DMSO-d6) δ 7.70-7.03 (m, 9H), 5.06 (m, 1H), 4.95 (m,
1H), 4.34 (m, 1H), 4.24 (m, 1H), 3.90 (m, 2H), 3.55 (m, 2H),
2.95 (m, 1H), 2.30 (m, 1H), 1.85 (s, 3H), 1.63-1.24 (m, 12H),
0.99 (m, 1H); [R]20 +67.4° (c 0.89, MeOH); further character-
D
ized as the N-methyl-D-glucamine salt. Anal. (C34H37N3O6‚C7H17
NO5‚2.0H2O) C, H, N.
-
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-flu or o-
ben zyl)-5-car boxyeth ylcar bon yl-2,7-dioxo-2,3,4,5,6,7-h exa-
h yd r o-1H-ben zo[h ][1,4]d ia zon in e (39). Step m : The benzyl
protecting group of 11i was removed according to step e, and
the resultant acid reacted with tert-butyl lithioacetate using
a literature method27 to give (1R,3S)-1-[(1-adamantyl)methyl]-
2-acetyl-1-(2-fluorobenzyl)-3-tert-butyloxycarbonylmethylcar-
bonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (17): 1H NMR
(CDCl3) δ 7.57 (m, 1H, Ar H), 7.27-7.12 (m, 5H, Ar H), 6.93
(m, 1H, Ar H), 6.23 (m, 1H, Ar H), 5.36 (m, 2H, CH2Ar), 5.00
(d, J ) 9.9 Hz, 1H, H-1), 4.36 (m, 1H, H-3), 3.69 (d, J ) 15.0
Hz, 1H, COCHHCO), 3.30 (d, J ) 15.0 Hz, 1H, COCHHCO),
3.20 (m, 1H, H-4), 3.12 (m, 1H, H-4), 2.02 (br s, 3H, 3 × CH),
1.90 (s, 3H, COCH3), 1.79-1.50 (m, 14H, 6 × CH2 and CH2-
Ad), 1.48 (s, 9H, C(CH3)3).
Step j: 14 (921 mg, 1.31 mmol) in trifluoroacetic acid (20
mL) was stirred at room temperature in a lightly stoppered
flask for 2 h. The reaction mixture was evaporated to dryness
and re-evaporated from ether (2 × 40 mL). The solid obtained
was dissolved in CH2Cl2 (40 mL), washed with saturated
NaHCO3 (40 mL), brine (2 × 40 mL) and dried (Na2SO4).
Filtration and evaporation of the solvent gave (1R,3S)-1-[(1-
adamantyl)methyl]-9-benzyl-3-benzyloxycarbonylmethylami-
nocarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole as a yel-
low solid (741 mg, 94%): 1H NMR (CDCl3) δ 7.64 (m, 1H,
CONH), 7.57 (m, 1H, Ar H), 7.36-7.11 (m, 12H, Ar H), 6.90
(m, 1H, Ar H), 5.35-5.19 (m, 4H, CH2Ar and CH2Ar′), 4.28
(d, J ) 10.8 Hz, 1H, H-1), 4.20-4.13 (dd, J ) 14.1, 5.7 Hz,
2H, CONHCH2CO), 3.89 (dd, J ) 11.1, 5.1 Hz, H-3), 3.47 (dd,
J ) 15.9, 4.8 Hz, 1H, H-4), 3.33 (dd, J ) 15.9, 11.4 Hz, 1H,
H-4), 1.97 (br s, 3H, 3 × CH), 1.70-1.56 (m, 13H, 6 × CH2
and CHHAd), 1.27(m, 1H, CHHAd).
Step n : A solution of 17 (663 mg, 1.1 mmol) in dry THF (20
mL) was added dropwise over 10 min to a suspension of NaH
(60% dispersion in mineral oil/51 mg, 1.3 mmol) in dry THF
(5 mL) under argon at 0 °C. After stirring at 0 °C for 20 min,
benzyl bromoacetate (0.2 mL, 1.2 mmol) was added, and the
mixture stirred at room temperature for 2 h. The reaction
mixture was poured into EtOAc-H2O (1:1/60 mL), the organic
layer separated, washed with brine (30 mL), and dried (Na2-
SO4). Filtration and evaporation of the solvent gave 18 as a
yellow foam (864 mg, 100%): 1H NMR (CDCl3) δ 7.57 (m, 1H,
Ar H), 7.38-7.15 (m, 10H, Ar H), 6.94 (m, 1H, Ar H), 6.25 (m,
1H, Ar H), 5.37 (m, 2H, CH2Ar), 5.22 (s, 2H, CH2Ar′), 5.05 (m,
1H, H-1), 4.55 (m, 1H, H-3), 4.30 (m, 1H, COCH(CH2CO2Bn)-
CO), 3.29-3.20 (m, 2H, COCH(CH2CO2Bn)CO), 3.09 (m, 1H,
H-4), 2.83 (m, 1H, H-4), 2.01 (br s, 3H, 3 × CH), 1.90 (s, 3H,
COCH3), 1.77-1.48 (m, 14H, 6 × CH2 and CH2Ad), 1.42 (s,
9H, C(CH3)3).
Step k : (1R,3S)-1-[(1-Adamantyl)methyl]-9-benzyl-3-ben-
zyloxycarbonylmethylaminocarbonyl-2-bromoacetyl-1,2,3,4-tet-
rahydro-9H-pyrido[3,4-b]indole (15) was obtained on treatment
of (1R,3S)-1-[(1-adamantyl)methyl]-9-benzyl-3-benzyloxycar-
bonylmethylaminocarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-
b]indole according to step b using bromoacetyl bromide in
place of acetyl chloride: 1H NMR (CDCl3) δ 7.59 (m, 1H, Ar
H), 7.36-7.13 (m, 12H, Ar H), 6.92 (m, 1H, Ar H), 5.56 (m,
1H, CHHAr), 5.33 (m, 3H, CHHAr and CH2Ar′), 5.20 (s, 2H,
COCH2Br), 5.07 (m, 1H, H-1), 4.97 (m, 1H, CONH), 4.17 (m,
1H, H-3), 4.03 (m, 2H, CONHCH2CO), 3.55 (m, 1H, H-4), 3.35
(m, 1H, H-4), 1.89 (br s, 3H, 3 × CH), 2.02 (m, 1H, CHHAd),
1.66-1.27 (m, 13H, 6 × CH2, and CHHAd).
Step o: A solution of (3R,5S)-4-acetyl-3-[(1-adamantyl)-
methyl]-1-(2-fluorobenzyl)-5-benzyloxycarbonylethylcarbonyl-
2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine (ob-
tained on reacting 18 according to step s j and d ) (232 mg,
0.35 mmol) was stirred under hydrogen with palladium on
charcoal (75 mg) at room temperature for 17 h. The reaction
mixture was filtered through a pad of Celite and the filtrate
evaporated to give (3R,5S)-4-acetyl-3-[(1-adamantyl)methyl]-
1-(2-fluorobenzyl)-5-carboxyethylcarbonyl-7-hydroxy-2-oxo-
2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine as a white
solid (200 mg, 95%): 1H NMR (DMSO-d6) δ 7.43 (m, 1H, Ar
H), 7.36-7.12 (m, 6H, Ar H), 6.90 (m, 1H, Ar H), 5.60 (m, ex.
D2O, 1H, OH), 5.47 (d, J ) 10.2 Hz, 1H, CHHAr), 5.00 (br s,
1H, ArCHOH), 5.13 (m, 2H, CH2Ar′), 4.99 (m, 1H, H-1), 4.10
(m, 1H, H-3), 3.22 (m, 1H, H-4), 3.08 (m, 1H, H-4), 2.97 (m,
1H, COCHHCH2CO2Bn), 2.84 (m, 2H, COCH2CH2CO2Bn), 2.63
(m, 1H, COCHHCH2CO2Bn), 2.01 (br s, 3H, 3 × CH), 1.88 (s,
3H, COCH3), 1.78-1.53 (m, 13H, 6 × CH2 and CHHAd), 1.45
(m, 1H, CHHAd).
Step l: 15 (690 mg, 0.95 mmol) and Cs2CO3 (311 mg, 0.95
mmol) in DMF 910 mL) were heated at 100 °C for 2 h. On
cooling, the mixture was diluted with H2O (30 mL), and
extracted with EtOAc (2 × 30 mL). The combined extracts were
washed with 10% citric acid (30 mL), saturated NaHCO3 (30
mL), brine (2 × 30 mL) and dried (MgSO4). Filtration and
evaporation of the solvent gave the crude product which was
purified by chromatography with EtOAc-DCM (1:40) as
eluant to give 16 as an oil (196 mg, 33%): 1H NMR (CDCl3) δ
7.47 (m, 1H, Ar H), 7.45 (m, 4H, Ar H), 7.33-7.25 (m, 3H, Ar
H), 7.13 (m, 3H, Ar H), 7.02 (m, 2H, Ar H), 6.10 (m, 1H, Ar
H), 5.30-5.17 (m, 5H, CH2Ar, H-1 and CH2Ar′), 4.70 (m × 2,
2H, H-3 and COCHHN), 4.28 (m, 1H, NCHHCO2Bn), 3.95 (m,
1H, COCHHN), 3.83 (m, 1H, NCHHCO2Bn), 3.35 (m, 1H, H-4),
3.00 (m, 1H, H-4), 1.91 (br s, 3H, 3 × CH), 1.73-1.43 (m, 1H,
13H, 6 × CH2, and CHHAd), 1.28 (m, 1H, CHHAd).

Design of CCK2 Receptor Antagonists
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A mixture of (3R,5S)-4-acetyl-3-[(1-adamantyl)methyl]-1-(2-
fluorobenzyl)-5-carboxyethylcarbonyl-7-hydroxy-2-oxo-2,3,4,5,6,7-
hexahydro-1H-benzo[h][1,4]diazonine (187 mg, 0.31 mmol),
NMO (60 mg, 0.5 mmol), TPAP (19 mg, 0.05 mmol) and
crushed 4A molecular sieves (206 mg) was stirred in MeCN-
CH2Cl2 (1:4/5 mL) at room temperature for 20 h. The reaction
mixture was diluted with CH2Cl2 (20 mL), washed with 5%
KHSO4 (20 mL), brine (20 mL), and dried (Na2SO4). Filtration
and evaporation of the solvent gave 39 as a pale solid which
was purified by preparative HPLC (Dynamax-60A C18, 65%
MeCN-H2O (containing 0.5% HOAc), tR 17.7min) (48 mg,
26%): 1H NMR (MeOH-d4) δ 7.53 (m, 3H), 7.32 (m, 2H), 7.06
(m, 3H), 5.38 (m, 1H), 4.29-4.10 (m, 3H), 3.86 (m, 2H), 2.95
(m, 1H), 2.59 (m, 1H), 1.90 (m, 3H), 1.60 (m, 6H), 1.45 (m,
6H), 1.23 (m, 3H), 1.18 (s, 3H); further characterized as the
N-methyl-D-glucamine salt. Anal. (C35H39FN2O6‚C7H17NO5‚
0.5H2O) C, H, N.
(3R,5S)-4-Acetyl-3-[(1-a d a m a n tyl)m eth yl]-1-(2-flu or o-
b en zyl)-5-ca r b oxym et h ylca r b on yl-2,7-d ioxo-2,3,4,5,6,7-
h exa h yd r o-1H-ben zo[h ][1,4]d ia zon in e (40): obtained as
a yellow solid by treatment of 17 according to step s d and j;
1H NMR (DMSO-d6) δ 7.55 (m, 3H), 7.32 (m, 2H), 7.13 (m,
3H), 5.21 (m, 1H), 4.25 (m, 1H), 3.99 (m, 1H), 3.89 (m, 1H),
3.72 (m, 1H), 3.38 (m, 1H), 3.14 (m, 1H), 2.76 (m, 1H), 2.40
(m, 1H), 1.92 (s, 3H), 1.65-1.25 (m, 13H), 1.04 (s, 3H); [R]20
D
-78.4° (c 0.60, MeOH); further characterized as the N-methyl-
D-glucamine salt. Anal. (C34H37FN2O6‚C7H17NO5‚0.25H2O) C,
H, N.
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Ack n ow led gm en t. The authors thank their col-
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