Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: Indazole and benzimidazolone derivatives

Article abstract of DOI:10.1021/jm970857f

A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT₄ receptor in the rat esophagus. The endo-3-tropanamine derivatives in the indazole

Full text of DOI:10.1021/jm970857f

J . Med. Chem. 1998, 41, 1943-1955
1943
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of P oten t a n d Or a lly Active
5-HT4 Recep tor An ta gon ists: In d a zole a n d Ben zim id a zolon e Der iva tives
J ohn M. Schaus,* Dennis C. Thompson, William E. Bloomquist, Alice D. Susemichel, David O. Calligaro, and
Marlene L. Cohen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received December 22, 1997
A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carbox-
amides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat
esophagus. The endo-3-tropanamine derivatives in the indazole and benzimidazolone series
possessed greater 5-HT4 receptor affinity than the corresponding indole analogues. 5-HT4
receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic
heterocycle. In a series of 1-isopropylindazole-3-carboxamides, replacement of the bicyclic
tropane ring system with the monocyclic piperidine ring system or an acyclic aminoalkylene
chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic
amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4
receptor antagonist activity. While some of these compounds displayed high affinity for other
neurotransmitter receptors (in particular, 5-HT3, R1, and 5-HT2A receptors), as the conforma-
tional flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also
increased. From this series of compounds, we identified LY353433 (1-(1-methylethyl)-N-[2-
[4-[(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl]-1H-indazole-3-carboxam-
ide) as a potent and selective 5-HT4 receptor antagonist with clinically suitable pharmacody-
namics.
In tr od u ction
cisapride (2) has been shown to be a partial agonist at
5-HT4 receptors but also has high affinity for 5-HT2A
and R1 receptors.6 SDZ 205,557 (3a )7 and LY297524
(3b),8 both esters related to metoclopramide, are re-
ported to be 5-HT4 receptor antagonists but also have
considerable 5-HT3 receptor antagonist activity.8
GR113808 (4)9 and SB204070 (5)10 are the first reported
5-HT4 receptor antagonists with high affinity and
selectivity for the 5-HT4 receptor. However, neither of
these compounds has a clinically suitable duration of
action following oral administration, presumably be-
cause the ester linkage present in both molecules is
readily cleaved in vivo.2c,11 SB207266 (6)12 and RS100235
(7)13 are more recently reported 5-HT4 receptor antago-
nists. Both compounds demonstrated improved phar-
macodynamics over 4 and 5, presumably because the
amide and ketone systems of 6 and 7, respectively, are
more stable than the ester linkage found in 4 and 5.
We initiated studies with the goal of identifying
structurally distinct, potent, selective, and orally active
5-HT4 receptor antagonists with a clinically suitable in
vivo duration of action. The present report details the
structure-activity relationships (SAR), synthesis, and
pharmacological characterization of LY353433 (8, 1-(1-
methylethyl)-N-[2-[4-[(tricyclo [3.3.1.13,7]dec-1-ylcarbon-
yl)amino]-1-piperidinyl]ethyl]-1H-indazole-3-carboxam-
ide) a potent, selective, and long-acting compound from
this series.6
The neurotransmitter serotonin (5-HT) modulates the
activity of the central nervous system and peripheral
tissues through its actions at a number of receptor
subtypes.1 Because of the wide range of physiologic and
pathophysiologic systems in which 5-HT is known to
play a role, considerable attention has centered around
the identification of agents which act selectively at each
of these receptor subtypes. One of these receptor
subtypes, the 5-HT4 receptor,2 was first identified in
19883 and has recently been cloned.4 Based on the
localization of the 5-HT4 receptor in gastrointestinal
tissue, atrial tissue, urinary bladder tissue, and the
central nervous system, a number of therapeutic indica-
tions have been proposed for both agonists and antago-
nists at this receptor. Proposed therapeutic applications
for agents that block the 5-HT4 receptor include the
treatment of irritable bowel syndrome, atrial arrhyth-
mias, urinary incontinence, and various diseases of the
central nervous system. We were interested in identify-
ing a potent and selective 5-HT4 receptor antagonist as
a possible therapeutic agent.
Although a number of compounds have been identi-
fied which block 5-HT4 receptors, most do not have the
requisite selectivity or pharmacodynamic properties
which would make them ideal pharmacologic tools or
therapeutic agents. Tropisetron (1) (Chart 1) was
among the first compounds shown to possess 5-HT4
receptor antagonist activity.5 However, 1 has higher
affinity at 5-HT3 than 5-HT4 receptors. The benzamide
Tropisetron (1) and cisapride (2) served as starting
points for our structure-activity studies. While both
compounds have affinity for the 5-HT4 receptor, neither
is particularly potent and both have high affinity for
* To whom correspondence should be addressed.
S0022-2623(97)00857-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/02/1998

1944 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.
Ch a r t 1
Ch a r t 2
other receptors. A common pharmacophore (9) can be
drawn for the two compounds which is centered around
a piperidine ring system (Chart 2). For tropisetron, the
piperidine is further rigidified into a tropane ring
system. In each case, an aromatic acyl group is con-
nected to the 4-position of the piperidine through either
an ester or amide linkage. The basic nitrogen of the
piperidine is also a site for substitution. We explored
the modification of each of these elements of the
proposed pharmacophore: the aromatic acyl group, the
piperidine ring system, and the substituent on the basic
nitrogen. Because of the expected lability of the ester
linkage in compounds such as tropisetron, we focused
our synthetic efforts on compounds in which the acyl
group was connected to the piperidine ring through an
amide linkage.
Ch em istr y
The synthesis of the indolecarboxamides 11a -f and
the indazolecarboxamides 12a -f is outlined in Scheme
1. Treatment of indole-3-carboxylic acid with oxalyl
chloride provided the corresponding acid chloride which
was reacted with the known tropanamine 514 to give
11a . Alkylation at N-1 was achieved by sequential
treatment with sodium hydride and an alkyl halide to
yield 11b-f. The analogous indazoles were prepared
by carbonyldiimidazole-mediated coupling between in-
dazole-3-carboxylic acid15 and 10 to give 12a . Alkylation

Indazole and Benzimidazolone Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1945
Sch em e 1a
a
(a) X ) CH, oxalyl chloride, THF; X ) N, 1,1′-carbonyldiimidazole, DMF; (b) NaH, DMF; (c) RX; (d) MeCH(Cl)OCOCl, CH2Cl2; (e)
MeOH, heat; (f) 3-(4-fluorophenoxy)-1-(tosyloxy)propane, Na2CO3, DMF.
Sch em e 2a
a
(a) 1,1-Carbonyldiimidazole, DMF; (b) NaH, DMF; (c) i-PrI; (d) MeCH(Cl)OCOCl, CH2Cl2; (e) MeOH, heat; (f) R1X, Na2CO3, DMF; (g)
NH2NH2, MeOH, heat; (h) MsCl or PhCOCl or 1-adamantanecarbonyl chloride.
as before yielded the corresponding N-1 alkyl derivatives
12b-f with good regiocontrol.16 Modified von Braun
demethylation of 12e with 1-chloroethyl chloroformate
provided the corresponding desmethyltropane which
was alkylated with 3-(4-fluorophenoxy)-1-(tosyloxy)-
propane to give 12g. Amide 14 was prepared from
1-naphthalenecarboxylic acid and 10 using carbonyldi-
imidazole as the activating agent. Benzimidazolones
13a -f,17 amide 15,18 and zatosetron (16)19 were pre-
pared as outlined in the literature. By analogy with
12g, von Braun degradation of 13e followed by alkyla-
tion provided 13g. Reaction of 1-(chlorocarbonyl)benz-
imidazolone17 with 4-amino-N-methylpiperidine and
with 4-amino-N-(1-(3-(4-fluorophenoxy)propyl))piperi-
dine provided the desired amides which were alkylated
at N-1 with isopropyl iodide to yield compounds 17a ,b.
Amide 18 underwent regioselective alkylation at N-1
with sodium hydride and isopropyl iodide to yield 19c
(Scheme 2). Debenzylation gave the secondary amine
19a which was alkylated under standard conditions to
provide 19b,d -h ,l. Hydrazinolysis of the phthalimido-
ethyl derivative 19h produced the aminoethyl interme-
diate 19m which was reacted with methanesulfonyl
chloride, benzoyl chloride, and adamantane-1-carbonyl

1946 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.
Sch em e 3a
a
(a) 1,1-Carbonyldiimidazole, DMF; (b) NaH, DMF; (c) i-PrI.
Sch em e 4a
Resu lts a n d Discu ssion
In the carbamylcholine-contracted rat esophagus
preparation, serotonin produces a concentration-de-
pendent relaxation mediated through activation of
5-HT4 receptors.8,20 The 5-HT4 receptor antagonist
affinity of compounds was evaluated by their ability to
block serotonin-induced relaxation in carbamylcholine
(10-6 M)-contracted esophagus. Tissues were chal-
lenged with serotonin (1 µM), and relaxation of the
tissue in the presence of a given concentration of the
antagonist or vehicle was measured as reported in
Tables 1-5. In the presence of vehicle, 1 µM serotonin
produced 68.8 ( 4.3% (N ) 10) relaxation of the
carbamylcholine (10-6 M)-contracted rat esophagus.
Thus, the greater the antagonist affinity, the less
relaxation produced by serotonin (1 µM).
a
(a) Cbz-Cl, NaOH, H2O, CH2Cl2; (b) MeCH(Cl)OCOCl, CH2Cl2;
(c) MeOH, heat; (d) N-(2-bromoethyl)phthalimide, K2CO3, DMF;
(e) NH2NH2‚H2O, EtOH, heat.
Sch em e 5a
Mod ifica tion of th e Ar om a tic Acyl Gr ou p . Using
the amide analogue of tropisetron, 11a , as our starting
point, our initial goal was to study the effect of modi-
fication of the aromatic acyl group on 5-HT4 receptor
antagonist affinity. Our examination focused on a series
of bicyclic aromatic amides. Replacement of the ester
functionality in tropisetron by an amide linkage led to
a significant decrease in 5-HT4 receptor affinity (Table
1, 11a ). This finding is consistent with a study of
metoclopramide analogues in which ester derivatives
possessed an order of magnitude higher affinity than
the corresponding amide analogues at the 5-HT4 recep-
tor.21 Alkylation at N-1 of the indole-3-carboxamide
ring (Table 1, 11b-f) resulted in compounds which were
slightly more potent than tropisetron in inhibiting
serotonin-induced relaxation of the rat esophagus. The
potency of these 1-alkylindole derivatives increased with
the size of the N-1 substituent, the 1-isopropylindole
derivative 11e being the most potent of the 5-HT4
receptor antagonists. Extending the alkyl group further
as in the sec-butyl analogue 11f led to a significant
decrease in 5-HT4 receptor affinity.
Replacement of the indole C-2 with a nitrogen atom
(Table 1, 12a -f) provided a series of indazole analogues
that possessed higher 5-HT4 receptor antagonist affinity
than the corresponding indole counterparts. While the
unsubstituted indazole 12a was only weakly active as
a 5-HT4 receptor antagonist, methylation at N-1 led to
a significant increase in antagonist potency. Similar to
the indole derivatives, incorporation of larger N-1 alkyl
substituents increased 5-HT4 receptor antagonist affin-
ity.
a
(a) H2, Pd/C, MeOH; (b) RCOCl, NEt3, THF; or MsCl, NEt3,
THF.
chloride to yield 19i, 19j, and 19k , respectively. Amides
21a -l were prepared by carbonyldiimidazole-mediated
acylation of the corresponding aminoalkyl derivative
with indazole-3-carboxylic acid followed by regioselective
alkylation with sodium hydride and isopropyl iodide
(Scheme 3).
For the synthesis of 21k , the required aminoethyl
derivative, 22, was prepared according to Scheme 4.
Schotten-Bauman acylation of 4-amino-1-benzylpip-
eridine with benzyl chloroformate followed by removal
of the benzyl group using von Braun conditions pro-
duced 4-((carbobenzyloxy)amino)piperidine. Alkylation
with N-(2-bromoethyl)phthalimide and treatment with
hydrazine to remove the phthalimide protecting group
yielded 22. Hydrogenolytic cleavage of the carboben-
zyloxy protecting group of 21k provided 23a which
served as a key synthetic intermediate (Scheme 5).
Functionalization of 23a under standard conditions
provided compounds 8 and 23b-g,i-n .
Since the N-ethyl (13c, BIMU-1) and N-isopropyl
(13e, BIMU-8) derivatives were reported to possess
affinity for the 5-HT4 receptor,22 we included the N-
acylbenzimidazolone derivatives 13a -f in our study.
Interestingly, N-alkylbenzimidazolones possessed 5-HT4
receptor antagonist activity in the rat esophagus similar
to that of the indazole series (Table 1, 13a -f). The

Indazole and Benzimidazolone Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1947
Ta ble 1
5-HT4 receptor antagonist activity
(% relaxation to 10-6 M 5-HT ( SEM (no. of determinations))
antagonist concentration
compd
no. Ar
molecular
formula
solvent of
crystallization
R
mp (°C)
10-8
M
3 × 10-8
M
10-7
M
10-6
M
10-5
M
1
2
33.9 ( 3.9(3) 26.4 ( 5.4(13)
7.0 ( 2.0 (3) 20.3 ( 3.3(3)
60.0 ( 4.0(4)
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
12e
12f
13b
13c
13d
13e
13f
14
A
A
A
A
A
A
B
B
B
B
B
B
C
C
C
C
C
D
E
H
Me
Et
C
C
C
17H21N3O‚C4H4O4 EtOAc-MeOH
18H23N3O‚C4H4O4 EtOAc-MeOH
19H25N3O‚C2H2O4 EtOAc-MeOH
207
205-208
200-203
182-183
207-208
174-175
228-230
123-124
232-233
214-215
47.3 ( 11.0(4)
44.8 ( 10.1(4)
n-Pr C20H27N3O‚C2H2O4 EtOAc-MeOH
34.3 ( 9.1(3)
i-Pr
s-Bu
H
Me C17H22N4O
Et
C
C
C
20H27N3O‚C2H2O4 EtOAc-MeOH
21H29N3O‚C2H2O4 EtOAc-MeOH
25.3 ( 4.1(4)
57.8 ( 7.8(4)
17H20N4O
EtOAc
Et2O
50.5 ( 15.9(4)
21.0 ( 7.1(3)
C
C
C
18H24N4O‚C2H2O4 EtOAc-MeOH
19H26N4O‚C2H2O4 EtOAc-MeOH
19H26N4O‚C2H2O4 EtOAc-MeOH
6.7 ( 0.3(3)
2.5 ( 1.0(4)
n-Pr
i-Pr
185-187 43.2 ( 8.0(5)
9.0 ( 4.1(4) 8.0 ( 2.0(5)
s-Bu C20H28N4O‚C4H4O4 EtOAc-cyclohexane 130-132
Me
Et
n-Pr C19H26N4O2‚HCl
i-Pr
46.3 ( 5.6(4)
C
C
17H22N4O2‚HCl
18H24N4O2‚HCl
EtOAc-MeOH
acetone
MeOH
>250
227-230
222-223
138-140 55.0 ( 10.9(4) 13.8 ( 8.7(4)
205
7.3 ( 4.3(4)
37.5 ( 10.1(4)
30.7 ( 15.1(3)
4.3 ( 2.0(4)
2.7 ( 1.5(3)
8.8 ( 4.4(5)
C
C
19H26N4O2‚HCl
MeOH
20H28N4O2‚C2H2O4 Et2O
s-Bu
C19H22N2O‚C7H8O3S EtOH
16H22N3O2‚C4H4O4 EtOAc-MeOH
238-239
172
76.5 ( 7.0(4)
2.8 ( 1.5(4)
15
16
C
5.4 ( 2.5(5)
37.0 ( 7.7(7) 22.2 ( 6.3(6)
F
effect of N-alkylation on the benzimidazolones was also
similar to the indazole series with the N-isopropyl
derivative 13e providing potent inhibitors of serotonin-
induced relaxation in the rat esophagus.
can be understood in terms of increased conformational
rigidity of these systems. The amide N-H can partici-
pate in an intramolecular hydrogen bond with the
methoxy group of 15, the lone pair of N-2 in the indazole
amides 12a -f, and the carbonyl of the benzimidazolone
amides 13a -f. This hydrogen-bonding interaction en-
forces coplanarity of the aromatic ring with the atoms
of the amide linkage. While the less active indole and
naphthalene systems have similar steric requirements
as the indazole and benzimidazolone systems, they
cannot form a similar rigidifying intramolecular hydro-
gen bond. The importance of analogous intramolecular
hydrogen bonding interactions has been demonstrated
with a series of dopamine D2 receptor antagonists and
serotonin 5-HT3 receptor antagonists.18,25 While zato-
setron can theoretically form an intramolecular hydrogen-
bond, the gem-dimethyl substitution on the dihydroben-
zofuran ring may provide sufficient steric bulk that the
group can no longer participate in the required binding
interactions with the 5-HT4 receptor.
The effect of N-isopropyl substitution might have been
anticipated, since substitution of a heteroaromatic ring
with an isopropyl group has led to increases in antago-
nist potency at other 5-HT receptor subtypes, as well.
In a series of ergoline derivatives, N-1 isopropyl deriva-
tives had higher affinity for the rat 5-HT2A receptor and
were more potent 5-HT2A receptor antagonists than
their corresponding N-1 unsubstituted derivatives.23
Further, isopropyl substitution of tryptamine deriva-
tives served to convert agonist activity to antagonist
activity at the 5-HT2B receptor in the rat stomach
fundus and at the rat 5-HT2A receptor.23, 24
The 1-naphthalenecarboxamide 14 and the dihy-
drobenzofuran derivative zatosetron (16) are two bicyclic
aromatic amides which displayed only weak 5-HT4
receptor antagonism in the concentrations tested. The
tropane analogue of cisapride, 15, has been previously
characterized as a potent 5-HT3 receptor antagonist,18
and we found that 15 was also a potent 5-HT4 receptor
antagonist.
Mod ifica tion of th e Tr op a n e Gr ou p . These stud-
ies identified 1-isopropylindazole and 1-isopropylbenz-
imidazolone as platforms producing compounds with
relatively high affinity as 5-HT4 receptor antagonists.
To improve the affinity and selectivity of these deriva-
tives, we incorporated structural elements of cisapride
by replacing the tropane ring system with the piperidine
The increased 5-HT4 receptor affinity of 15 and the
indazole and benzimidazolone derivatives over the
acylindole and naphthalenecarboxylic acid derivatives

1948 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.
Ta ble 2
5-HT4 receptor antagonist activity
(% relaxation to 10-6 M 5-HT ( SEM
(no. of determinations))
antagonist concentration
compd
no.
molecular
formula
solvent of
crystallization
Ar
R1
R2
Ra
mp (°C)
3 × 10-8
M
10-7
22.2 ( 6.1(5)
M
10-6
M
12g
19b
19l
13g
17a
17b
B
B
B
C
C
C
-CH2-CH2-
H
H
-CH2-CH2-
H
H
X
Me
X
X
Me
X
C27H33FN4O2‚HCl
2-PrOH
245-247
185
17.7 ( 5.3(6)
H
H
C
C
17H24N4O‚C2H2O4 2-PrOH
37.3 ( 3.2(3)
25H31FN4O2‚HCl
EtOAc-MeOH 174-175 36.0 ( 6.2(6) 15.7 ( 5.5(6)
7.5 ( 3.5(8)
2.1 ( 6.5(6)
7.5 ( 2.7(4)
C27H33FN4O3‚HCl
EtOAc-MeOH 235-236
EtOAc-MeOH 203-205
EtOAc
29.5 ( 6.0(6)
40.8 ( 11.4(4)
62.0 ( 13.9(6)
H
H
C
C
17H24N4O2‚HCl
25H31FN4O3‚HCl
210-212
Ta ble 3
5-HT4 receptor antagonist activity
(% relaxation to 10-6 M 5-HT ( SEM (no. of determinations))
antagonist concentration
compd
no.
molecular
formula
solvent of
crystallization mp (°C)
10-8
M
3 × 10-8
M
10-7
M
10-6
M
a
R1
CH2Ph
19a
19c
H
C
16H22N4O‚HCl
C23H28N4O‚HCl
EtOAc-MeOH 145
32.0 ( 11.3(4)
3.85 ( 2.8(4)
1.3 ( 1.3(3)
3.7 ( 2.7(3)
4.0 ( 0.6(3)
43.7 ( 8.5(6)
7.5 ( 3.9(4)
6.8 ( 5.4(4)
6.0 ( 2.7(5)
1.0 ( 1.0(4)
EtOAc-MeOH 209-212 38.5 ( 9.0(4) 23.3 ( 8.9(4) 24.5 ( 7.9(6)
19d (CH2)2Ph
19e
19f
19g (CH2)5Ph
19h (CH2)2Phth
19i
19j
19k (CH2)2NHCOAd C29H41N5O2‚C2H2O4 EtOAc-MeOH 124
19b Me
19l
C24H30N4O‚C2H2O4 EtOH
C25H32N4O‚C2H2O4 EtOH
C26H34N4O‚C2H2O4 EtOH
188
184
167
133
(CH2)3Ph
(CH2)4Ph
C27H36N4O‚HCl
EtOAc
C26H29N5O3‚C2H2O4 EtOAc-MeOH 148-150
C19H29N5O3S‚C4H4O EtOH 180
(CH2)2NHCOPh C25H31N5O2‚C2H2O4 EtOAc-MeOH 115
(CH2)2NHMs
16.0 ( 4.8(4)
28.0 ( 8.7(4)
38.5 ( 11.8(4)
C
C
17H24N4O‚C2H2O4 2-PrOH
25H31FN4O2‚HCl EtOAc-MeOH 174-175
185
37.3 ( 3.2(3)
36.0 ( 6.2(6) 15.7 ( 5.5(6)
X
7.5 ( 3.5(8)
ring system and by incorporating the p-fluorophenoxy-
propyl side chain into the compounds.
substitution of the secondary amine increased 5-HT4
receptor antagonist affinity by greater than 10-fold
relative to the unsubstituted amine 19a . Likewise,
incorporation of a benzyl, phenethyl, phenylpropyl, or
phenylbutyl group led to compounds with improved
5-HT4 receptor antagonist activity (19c-f). Further
lengthening of the side chain to the phenylpentyl group
(19g) reduced 5-HT4 receptor antagonism. Thus, rela-
tively large groups were well-tolerated at the piperidine
nitrogen. Since the mesylamidoethyl side chain of the
known 5-HT4 receptor antagonist GR113808 (4) is
available to participate in a hydrogen bond, we wished
to incorporate that and similar functionality into the
series. As anticipated, the mesylamidoethyl derivative
19i and its corresponding phthalimido (19h ), benzamido
(19j), and adamantylamide (19k ) analogues were all
potent 5-HT4 receptor antagonists.
In the indazole series, incorporation of a p-fluorophe-
noxypropyl side chain (12g) led to a modest decrease in
5-HT4 receptor antagonist activity. However, the pip-
eridine analogue of this compound, 19l, retained most
of the activity of the original tropane derivative and was
equipotent with the N-methylpiperidine derivative 19b
(Table 2). In contrast, modifying the benzimidazolone
analogue 13e by either replacing the tropane nucleus
with the piperidine system (17a ) or incorporating the
p-fluorophenoxypropyl side chain (13g) decreased activ-
ity. When both of these modifications were made, the
resulting compound, 17b, was inactive as a 5-HT4
receptor antagonist at 10-7 M. Since the 1-isopropyl-
indazole series was more tolerant to these modifications,
we focused subsequent efforts on this series.
Table 3 outlines the effect of modification of the
substituent on the piperidine nitrogen of 19b. N-Methyl
P ip er id in e Rep la cem en t Str a tegy. In general, we
had found that modification of the rigid tropane skeleton

Indazole and Benzimidazolone Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1949

1950 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.

Indazole and Benzimidazolone Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1951
Ta ble 6. 5-HT3 Receptor Affinity of Selected Compounds
to the less rigid piperidine system increased 5-HT4
receptor antagonist activity. To explore further in-
creases in the flexibility of the side chain, replacement
of the piperidine ring with the acyclic diethylaminoethyl
group (21a ) resulted in a compound with only moderate
5-HT4 receptor antagonist activity (Table 4). However,
replacement of the diethylamino group with a cyclic
amine (21b-d ) significantly increased activity, similar
to previous observations with a series of metoclopramide
ester analogues.26 Increasing the length of the linking
methylene chain to three and four carbons (21e,f) did
not further increase 5-HT4 receptor antagonist activity.
Substitution with a morpholine (21g) or a substituted
piperazine (21h ,i) group slightly decreased 5-HT4 recep-
tor affinity, whereas the benzo-fused piperidine system
21j was well-tolerated and equipotent with the parent
piperidine system.
compd no.
5-HT3 receptor affinitya (pKb)
1
16
12e
13e
19b
21c
8.06 ( 0.05(16)b
8.78 ( 0.10(10)b
7.4 ( 0.59(4)
7.5 ( 0.29(3)
6.3 ( 0.80(3)
5.8 ( 0.3(4)
a
Determined from compound’s ability to block serotonin-
induced contraction of the guinea pig ileum.28 Data from ref 28.
b
Ta ble 7. R1 Adrenergic Receptor and 5-HT2 Receptor Affinity
of Selected Compounds
R1 receptor affinity
5-HT2 receptor affinityc
compd no.
pKb (nM)a
pKi (nM)b
pKb (nM)
2
6.7
6.7
<5.0
7.68
5.8
6.5
5.6
5.8
<5.0
7.89
6.8
19l
19c
19d
19e
19f
19g
19j
19i
19h
21b
21c
21d
21e
21f
23b
8
7.69
<4.0
5.5
Pursuing our hypothesis that hydrogen bonding in-
creased 5-HT4 receptor antagonist activity, we proposed
that incorporation of groups capable of hydrogen bond
formation into 21c would increase 5-HT4 receptor af-
finity. We chose to attach these groups through C-4 of
the piperidine of 21c since the resulting derivatives
would, because of the symmetry of the system, consist
of a single stereoisomer. The 5-HT4 receptor antagonist
activity of this series is outlined in Table 5. Although
the 4-aminopiperidine analogue 23a had lower affinity
than the parent piperidine derivative as a 5-HT4 recep-
tor antagonist, a series of aliphatic amide derivatives
of the 4-aminopiperidine (23b-g, 8) were potent 5-HT4
receptor antagonists in vitro. We propose that the
amide groups interact with the 5-HT4 receptor in an
area of steric tolerance since substituents as large as
tert-butyl and 1-adamantyl gave rise to potent 5-HT4
receptor antagonists. The benzamide (23i) and phena-
cyl (23j) derivatives were also 5-HT4 receptor antago-
nists as were the carbamate 21k , the urea derivatives
23k -m , and the methanesulfonamide 23n . Because
the 4-benzylpiperidine analogue 21l was less potent
than the other 4-substituted analogues, the C-4 sub-
stituent likely interacts with the 5-HT4 receptor in a
hydrogen-bonding interaction rather than strictly a
hydrophobic interaction.
6.62
<4.0
<5.0
<5.0
<4.0
4.8
5.0
4.9
<4.5
5.2
<4.0
4.3
5.9
21k
<5.0
a
As determined by block of norepinephrine-induced contraction
of the rat aorta.31 b As determined by displacement of [3H]prazosin
from rat whole brain.30 c As determined by block of serotonin-
induced contraction of the rat aorta.31
receptor antagonists have a basic nitrogen constrained
within a polycyclic framework,29 we proposed that
conformationally labile derivatives would have lower
affinity at the 5-HT3 receptor. Indeed, the piperidine
19b had 10-fold lower 5-HT3 receptor affinity than its
tropane analogue, 12e. In 21c, the flexibility of the
system is further increased by replacing the piperidine
ring with the acyclic ethylene linker, and this compound
showed a further decrease in 5-HT3 receptor affinity
with a pKb of 5.8. By replacement of the tropane system
of 12e with the more flexible piperidine or acyclic
systems, we significantly minimized the interactions of
these compounds with the 5-HT3 receptor.
We then explored the interactions of compounds
containing the piperidine and acyclic linkers with R1
adrenergic receptors. The affinity for the R1 adrenergic
receptor was determined by displacement of [3H]pra-
zosin from rat whole brain tissue30 or by blockade of
norepinephrine-induced contractions of rat aorta.31 The
results are reported in Table 7. Cisapride (2) blocked
R1 receptors in the rat aorta with a pKb of 6.7. Com-
pound 12g, the piperidine derivative containing the
p-fluorophenoxypropyl side chain, was a similarly potent
R1 receptor blocker. Compound 19d , in which the
p-fluorophenoxypropyl group is replaced by a phenethyl
group, possessed 10-fold higher affinity than cisapride
as an R1 receptor blocker. Increasing the length of the
phenylalkylene side chain decreased R1 receptor affinity
(19e-g), but none of these compounds had pKb’s lower
than 5.6. On the other hand, the N-benzylpiperidine
5-HT3, 5-HT2A, a n d r1 Ad r en er gic Recep tor Se-
lectivity. Throughout the development of this SAR
directed toward obtaining high affinity 5-HT4 receptor
antagonists, careful attention was paid to the specificity
of the 5-HT4 receptor interactions. We had chosen
tropisetron and cisapride as the leads for these studies.
Since tropisetron is a potent 5-HT3 receptor antagonist27
and cisapride has high affinity for 5-HT2A and R1
receptors,6 we initially focused our attention on interac-
tions with these three receptors.
As the SAR progressed, selected compounds were
tested as 5-HT3 receptor antagonists in the guinea pig
ileum. Serotonin induces a contraction in this tissue
which is blocked by 5-HT3 receptor antagonists.27 The
affinities of selected compounds are found in Table 6.
The tropane derivatives tropisetron (1) and zatosetron
(16) potently block 5-HT3 receptors in the guinea pig
ileum with pKb’s of 8.06 and 8.78, respectively.28 Potent
5-HT3 receptor antagonist activity was also seen for 12e
and 13e, the tropane analogues in the indazole and
benzimidazolone series. Since many high-affinity 5-HT3

1952 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.
analogue 19c had virtually no affinity for the R1 recep-
tor. While the (mesylamidoethyl)piperidine derivative
19i was not an R1 receptor antagonist, the analogous
benzamidoethyl derivative 19j did block R1 receptors.
In the acyclic-linked series, none of the compounds
studied (8, 21b-f,k , 23b) had significant affinity for the
R1 adrenergic receptor.
The 5-HT2A receptor antagonist activity of selected
compounds was determined by their ability to block the
contractile effect of serotonin in the rat aorta (Table 7).31
Cisapride (2) was an antagonist in this assay with a pKb
of 7.89. The N-(p-fluorophenoxypropyl)piperidine de-
rivative 19l was also a 5-HT2A receptor antagonist but
with 10-fold lower affinity than cisapride. Replacing the
p-fluorophenoxypropyl side chain with a benzyl (19c)
or phthalimidoethyl (19h ) group led to further decreases
in 5-HT2A receptor affinity. In the acyclic series, 21c
was inactive as a 5-HT2A receptor blocker in the
concentrations tested.
The trend from these selectivity studies is clear. In
progressing from the highly constrained tropane skel-
eton through the less rigid piperidine ring system and
onto the flexible acyclic systems, we were able to
progressively increase the selectivity of these com-
pounds for the 5-HT4 receptor versus 5-HT3, R1 adren-
ergic, and 5-HT2A receptors. Next, we focused our
attention on the oral in vivo activity of these acyclic
derivatives and, to a lesser extent, on selected substi-
tuted piperidines that possessed the highest 5-HT4
receptor affinity and selectivity.
In Vivo 5-HT4 Recep tor An ta gon ist Activity fol-
low in g Or a l Ad m in istr a tion . During these SAR
studies, our interest centered upon obtaining a potent
and orally active 5-HT4 antagonist with a long duration
of in vivo activity for clinical studies. However, conve-
nient and well-documented functional consequences of
5-HT4 receptor activation were not readily available in
vivo. Although 5-HT4 receptor antagonist activities can
be estimated by several complex gastrointestinal assays
in dogs12,32 and by tachycardia in pigs,33 we utilized ex
vivo rat esophageal relaxation to serotonin as a simple,
efficient comparative estimate of the in vivo 5-HT4
receptor antagonist activity of these compounds. We
selected 3 h after oral administration of antagonist to
rats to remove the esophagus and challenge with
serotonin ex vivo. The time (3 h) was selected to
minimize any mechanical effects of the gavage on the
esophagus and to measure activity at a time that would
support a relatively long duration of action necessary
for clinical utility.34
receptor antagonist with pharmacodynamic properties
suitable for clinical development.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All solvents and reagents were
used as commercially available. Moisture- and/or air-sensitive
reactions were run under a positive pressure of nitrogen. The
solvent system used for flash chromatographic purification is
reported in parentheses. “(NH4OH)” indicates that ca. 0.1%
ammonium hydroxide solution was added to the eluting
solvent. Analytical thin-layer chromatography (TLC) was
performed on 0.25-mm Merck silica gel 60 F254 plates. Rf’s
are reported using the same solvent system that was used for
the flash column. Melting points were determined on a
Hoover-Thomas Uni-Melt capillary melting point apparatus
and are uncorrected. NMRs were recorded at 300 MHz.
Chemical shifts are reported in parts per million downfield
(δ) from tetramethylsilane in the form: chemical shift (mul-
tiplicity, coupling constant, number of protons). J values are
reported in hertz (Hz). Mass spectra were recorded using field
desorption (FD) ionization on
a Varian MAT 731 mass
spectrometer. Mass spectral data are reported in the form:
m/e of parent ion (relative intensity). Elemental analyses were
performed by the Physical Chemistry Research department
of the Lilly Research Laboratories.
N-(1-Ben zylp ip er id in -4-yl)-1H -in d a zole-3-ca r b oxa m -
id e (18). To a solution of 1H-indazole-3-carboxylic acid (8.11
g, 50 mmol) in DMF (140 mL) under a nitrogen atmosphere
was added in one portion 1,1′-carbonyldiimidazole (8.92 g, 55
mmol). The resulting solution was warmed at 60 °C for 2 h
and then cooled to room temperature before adding a solution
of 4-amino-1-benzylpiperidine (9.51 g, 50 mmol) in DMF (20
mL). The resulting solution was heated at 60 °C for 2 h. The
DMF was evaporated under reduced pressure and the residue
dissolved in CH2Cl2 (ca. 250 mL). This solution was washed
sequentially with water, 1 N NaOH solution, water, and brine,
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The residue was recrystallized twice from EtOH to give
the product as light-yellow crystals (10.63 g, 76%); mp 198-
200 °C. 1H NMR (DMSO-d6): 1.60-1.84 (m, 4H), 1.97-2.11
(m, 2H), 2.77-2.90 (m, 2H), 3.48 (s, 2H), 3.77-3.94 (m, 1H),
7.19-7.45 (m, 7H), 7.6 (d, 1H, J ) 9.0 Hz), 8.10-8.20 (m, 2H),
13.55 (s, 1H). MS: 334 (100). Anal. (C20H22N4O) C,H,N.
N-(1-Ben zylp ip er id in -4-yl)-1-isop r op ylin d a zole-3-ca r -
boxa m id e Hyd r och lor id e (19c). To a solution of N-(1-
benzylpiperidin-4-yl)-1H-indazole-3-carboxamide (9.94 g, 29.7
mmol) in DMF (200 mL) under a nitrogen atmosphere was
added sodium hydride (60% dispersion in mineral oil, 1.2 g,
30 mmol), and the resulting mixture was allowed to stir at
room temperature for 3 h. The reaction mixture was cooled
to about 20 °C, and 2-iodopropane (3.3 mL, 33 mmol) was
added. The resulting solution was allowed to stir at room
temperature for about 18 h. The DMF was evaporated under
reduced pressure, and the residue was dissolved in EtOAc (300
mL). This solution was washed sequentially with 10% aqueous
sodium carbonate solution, water, and brine, dried (Na2SO4),
filtered, and evaporated under reduced pressure to give an oil
which crystallized. The crude product was purified via
preparative HPLC (silica gel, CH2Cl2, 0-2% MeOH, 0.5% NH4-
OH) to give 8.77 g (78%) of product. A sample of this product
(753 mg, 2 mmol) was dissolved in EtOH (30 mL) and treated
with ethanolic HCl solution. The mixture was evaporated
under reduced pressure, and the residue was stirred in about
40 mL of Et2O for 2 h. The resulting precipitate was collected
by filtration and recrystallized from MeOH/EtOAc to give the
hydrochloride salt (478 mg, 58%), mp 209-212 °C. 1H NMR
(DMSO-d6): 1.56 (d, 6H, J ) 8.0 Hz), 1.94-2.12 (m, 4H), 3.00-
3.45 (m, 4H), 3.97-4.17 (m, 1H), 4.30 (d, 2H, J ) 6.0 Hz), 5.08
(septet, 1H, J ) 7.0 Hz), 7.27 (t, 1H, J ) 8.0 Hz), 7.38-7.70
(m, 6H), 7.80 (d, 1H, J ) 9.0 Hz), 8.15 (d, 1H, J ) 9.0 Hz),
8.34 (d, 1H, J ) 8.0 Hz), 10.36 (br s, 1H). MS: 376 (100). Anal.
(C23H29N4ClO) C,H,N.
Of the cyclic amines studied (Table 4) several were
evaluated for ex vivo activity. Of these, 21e showed
excellent activity to inhibit ex vivo serotonin-induced
relaxation of the rat esophagus after oral administration
of 0.1 mg/kg. However, 21e did possess some modest
affinity at both alpha2 and muscarinic receptors which
precluded our further interest (data not shown).
A number of the 4-substituted piperidinoethyl deriva-
tives, in particular 23a ,g, 8, 21k ,l, and 23m ,n , were
effective in blocking 5-HT4 receptors ex vivo following
oral administration. The selectivity profile and duration
of action of compound 8 dictated further investigation
and development of this analogue.35 Thus, compound
8 has been identified as a potent and selective 5-HT4
N-(P ip er id in -4-yl)-1-isop r op ylin d a zole-3-ca r b oxa m -
id e Hyd r och lor id e (19a ). 1-Chloroethyl chloroformate (2.86

Indazole and Benzimidazolone Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11 1953
g, 20 mmol, 2 equiv) was added dropwise to a solution of N-(1-
benzylpiperidin-4-yl)-1-isopropylindazole-3-carboxamide hy-
drochloride (3.76 g, 10 mmol) in CH2Cl2 (50 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature
and then heated to reflux for 1 h. The reaction mixture was
concentrated under vacuum and the residue dissolved in
MeOH (50 mL) and heated to reflux for 1 h. The reaction
mixture was concentrated to give a white solid which was
recrystallized from MeOH/EtOAc to give the product (2.92 g,
91%), mp 145 °C. 1H NMR (DMSO-d6): 1.57 (d, 6H, J ) 6.0
Hz), 1.80-2.05 (m, 4H), 2.93-3.01 (m, 2H), 4.05-4.20 (m, 1H),
5.08 (septet, 1H, J ) 8.0 Hz), 7.25 (t, 1H, J ) 8.0 Hz), 7.44 (t,
1H, J ) 8.0 Hz), 7.80 (d, 1H, J ) 9.0 Hz), 8.30 (d, 1H, J ) 9.0
Hz), 8.85 (br s, 1H). MS: 286 (100). Anal. (C16H23N4ClO)
C,H,N.
N-(1-(2-(P h th a lim id -1-yl)eth yl)p ip er id in -4-yl)-1-isop r o-
p ylben zim id a zole-3-ca r boxa m id e Oxa la te (19h ). To a
solution of N-(piperidin-4-yl)-1-isopropylindazole-3-carboxam-
ide hydrochloride (2.24 g, 6.9 mmol) in DMF (35 mL) under a
nitrogen atmosphere was added sodium carbonate (2.94 g, 28
mmol). N-(2-Bromoethyl)phthalimide (1.76 g, 6.9 mmol) in
DMF (10 mL) was then added, and the resulting solution was
heated at 100 °C for about 18 h. The DMF was evaporated
under reduced pressure to provide a residue which was taken
up in EtOAc (ca. 250 mL). The solution was washed with
water and brine, dried (Na2SO4), filtered, and evaporated
under reduced pressure to give 3.08 g of crude product. The
free base was purified via flash chromatography (silica gel,
and concentrated to yield 36.3 g of crude product as an orange
oil. Flash chromatography (2:1 ether/hexanes (NH4OH))
provided the pure product (Rf 0.21, 15.3 g, 65%) as a colorless
oil which solidified upon standing. Recrystallization of a
sample of this material (Et2O/hexanes) gave the product as
fine white needles, mp 78-80 °C. 1H NMR (CDCl3): 1.46 (br
q, 2H, J ) 11), 1.92 (br d, 2H, J ) 11), 2.11 (br t, 2H, J ) 11),
2.79 (br d, 2H, J ) 11), 3.49 (s, 2H), 3.42-3.60 (m, 1H), 4.58-
4.70 (m, 1H), 5.07 (s, 2H), 7.20-7.45 (m, 10H). MS: 324 (100).
Anal. (C20H24N2O2) C,H,N.
4-((Ca r boben zyloxy)a m id o)p ip er id in e Hyd r och lor id e.
A solution of 1-chloroethyl chloroformate (2 equiv, 84.4 mmol,
12.5 g) in CH2Cl2 (25 mL) was added to a solution of 1-benzyl-
4-((carbobenzyloxy)amido)piperidine (42.2 mmol, 13.7 g) in
CH2Cl2 (200 mL) at room temperature. After stirring at room
temperature for 1 h, the reaction mixture was concentrated,
dissolved in MeOH (200 mL), and heated to reflux for 1 h. The
reaction mixture was concentrated to give a white solid.
Recrystallization (MeOH/EtOAc) gave the title compound as
a white solid (7.56 g, 67%), mp 210.0-210.5 °C. 1H NMR
(DMSO-d6): 1.61 (br q, 2H, J ) 11), 1.84 (dd, 2H, J ) 3, 14),
2.76-2.96 (m, 2H), 3.14 (br d, 2H, J ) 13), 3.47-3.60 (m, 1H),
5.47 (s, 2H), 7.22-7.34 (m, 5H), 7.51 (d, 1H, J ) 7), 8.97 (br s,
1H), 9.19 (br s, 1H). MS: 234 (100), 235 (40). Anal.
(C13H18N2O2‚HCl) C,H,N.
1-(2-N-P h th a lim id oeth yl)-4-((ben zyloxyca r bon yl)a m i-
n o)p ip er id in e. Sodium carbonate (2.83 g, 26.6 mmol) was
added to a solution of 4-((carbobenzyloxy)amido)piperidine
hydrochloride (2.07 g, 7.6 mmol) and N-(2-bromoethyl)phthal-
imide (1.94 g, 7.6 mmol) in DMF (40 mL) and the reaction
mixture stirred at 100 °C for 18 h. The reaction mixture was
concentrated, diluted with water, and extracted with EtOAc.
The extracts were washed with water and brine, dried (Na2-
SO4), and concentrated to give a solid. Crystallization from
EtOH provided the desired product as colorless crystals (1.58
g, 51%), mp 159-161 °C. 1H NMR (DMSO-d6): 1.20-1.38 (m,
2H), 1.60-1.77 (m, 2H), 1.93-2.10 (m, 2H), 2.76-2.94 (m, 2H),
3.62-3.78 (m, 2H), 5.00 (s, 2H), 7.12-7.24 (m, 1H), 7.24-7.45
(m, 5H), 7.77-7.97 (m, 4H). MS: 407 (100). Anal. (C23H25N3O4)
C,H,N.
EtOAc/EtOH, 100:5) to give a viscous oil (2.14 g, 68%).
A
sample of the above oil was converted to the oxalate salt in
warm EtOAc and recrystallized from MeOH/EtOAc to give the
title product as colorless crystals, mp 148-150 °C. 1H NMR
(DMSO-d6): 1.55 (d, 6H, J ) 7.0 Hz), 1.68-2.06 (m, 4H), 2.63-
2.88 (m, 2H), 2.97-3.20 (m, 2H), 3.25-3.55 (m, 2H), 3.78-
4.15 (m, 4H), 5.08 (septet, 1H, J ) 7.0 Hz), 7.25 (t, 1H, J )
8.0 Hz), 7.42 (t, 1H, J ) 8.0 Hz), 7.68-8.02 (m, 5H), 8.03-
8.31 (m, 2H). MS: 459 (100). Anal. (C28H31N5O7Å) C,H,N.
N-(1-(2-Am in oeth yl)piper idin -4-yl)-1-isopr opylin dazole-
3-ca r boxa m id e (19m ). To a solution of N-(1-(2-(phthalimid-
1-yl)ethyl)piperidin-4-yl)-1-isopropylindazole-3-carboxamide (1.86
g, 4.0 mmol) in EtOH (80 mL) at 60 °C was added hydrazine
hydrate (2.0 mL), and the resulting solution was stirred at 60
°C for about 4 h. The reaction mixture was cooled to 0 °C and
filtered. The filtrate was evaporated under reduced pressure,
and to the residue was added 1 N NaOH solution. This
mixture was extracted four times with Et2O. The extracts
were washed with brine, dried (Na2SO4), and evaporated under
reduced pressure to give a colorless solid (1.21 g, 92%) which
was used in the next step without further purification.
N-(2-(4-((Ben zyloxyca r b on yl)a m in o)-1-p ip er id in yl)-
eth yl)-1-isop r op ylin d a zole-3-ca r boxa m id e Oxa la te (21k ).
The following steps were performed without purification of the
intermediates.
1-(2-N-Am in oeth yl)-4-((ben zyloxyca r bon yl)a m in o)p i-
p er id in e (22). A mixture of 1-(2-N-phthalimidoethyl)-4-
((benzyloxycarbonyl)amino)piperidine (11.9 g, 29.2 mmol),
hydrazine hydrate (15.8 mL, 16.4 g, 32.5 mmol), and EtOH
(600 mL) was heated to reflux for 4 h. The reaction mixture
was cooled to room temperature and filtered. The filtrate was
concentrated. The resulting residue was taken up in 1 N
NaOH solution. This mixture was saturated with NaCl and
extracted with Et2O. The ether extracts were dried (Na2SO4)
and concentrated to provide the desired product as an oil (8.19
g, 100%) which was used directly in the subsequent reaction.
MS: 278 (100).
N-(2-(4-((Ben zyloxyca r b on yl)a m in o)-1-p ip er id in yl)-
eth yl)-1H-in d a zole-3-ca r boxa m id e (20k ). 1,1′-Carbonyl-
diimidazole (4.70 g, 29 mmol) was added to a solution of 1H-
indazole-3-carboxylic acid (4.70 g, 29 mmol) in DMF (120 mL)
and the reaction mixture stirred at room temperature for 4 h.
A solution of 1-(2-N-aminoethyl)-4-((benzyloxycarbonyl)amino)-
piperidine (8.1 g, 29 mmol) in DMF (18 mL) was added
dropwise and the reaction mixture stirred at room temperature
for 18 h. The reaction mixture was concentrated to remove
the DMF and the residue taken up in water and extracted with
EtOAc. The extract was washed with water and brine, dried
(Na2SO4), and concentrated to the desired product (11.17 g,
91%) which was sufficiently pure for use in the next reaction,
mp 184-187 °C. MS: 422 (100).
N-(1-(2-((N′-Met h ylsu lfon yl)a m in o)et h yl)p ip er id in -4-
yl)-1-isop r op ylin d a zole-3-ca r boxa m id e Ma lea te (19i). To
a solution of N-(1-(2-aminoethyl)piperidin-4-yl)-1-isopropylin-
dazole-3-carboxamide (264 mg, 0.8 mmol) in THF (5 mL) under
a nitrogen atmosphere at about 15 °C were added triethy-
lamine (0.12 mL, 0.84 mmol) and methanesulfonyl chloride
(0.06 mL, 0.8 mmol). The resulting mixture was allowed to
stir for about 18 h at room temperature. The mixture was
filtered and the filtrate evaporated under reduced pressure
to give a cloudy oil. The maleate salt was made in warm
EtOAc and was recrystallized from about 10 mL of EtOH to
give the title product as colorless crystals (250 mg, 60%) mp
180 °C. 1H NMR (DMSO-d6): 1.56 (d, 6H, J ) 6.0 Hz), 1.80-
2.15 (m, 4H), 2.94-3.68 (m, 13H), 3.98-4.20 (m, 1H), 5.10
(septet, 1H, J ) 7.0 Hz), 6.05 (s, 2H), 7.22-7.38 (m, 2H), 7.45
(t, 1H, J ) 7.0 Hz), 7.80 (d, 1H, J ) 9.0 Hz), 8.17 (d, 1H,
J
) 9.0 Hz), 8.22-8.40 (m, 1H). MS: 407 (100). Anal.
(C23H33N5O7S) C,H,N.
1-Ben zyl-4-((ca r boben zyloxy)a m id o)p ip er id in e. A so-
lution of benzyl chloroformate (2 equiv, 144 mmol, 24.4 g) in
CH2Cl2 (100 mL) was added to a mixture of 4-amino-1-
benzylpiperidine (72 mmol, 13.7 g) in CH2Cl2 (200 mL) and 1
N NaOH solution (100 mL) at room temperature. The reaction
mixture was stirred vigorously for 20 min, poured into water,
and extracted with CH2Cl2. The extract was dried (Na2SO4)
N-(2-(4-((Ben zyloxyca r b on yl)a m in o)-1-p ip er id in yl)-
eth yl)-1-isop r op ylin d a zole-3-ca r boxa m id e Oxa la te (21k ).
Sodium hydride (60% dispersion in mineral oil, 1.05 g, 26.3
mmol) was added to a solution of N-(2-(4-((benzyloxycarbonyl)-

1954 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 11
Schaus et al.
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Miller, A. B.; Leung, E.; Eglen, R. M. Ketones Related to the
Benzoate 5-HT4 Receptor Antagonist RS-23597 are High Affinity
Partial Agonists. Bioorg. Med. Chem. Lett. 1994, 20, 2477.
(12) Wardle, K. A.; Bingham, S.; Ellis, E. S.; Gaster, L. M.; Rushant,
B.; Smith, M. I.; Sanger, G. J . Selective and functional 5-hy-
droxytryptamine4 receptor antagonism by SB 207266. Br. J .
Pharmacol. 1996, 118, 665.
(13) Clark, R. D.; J ahangir, A.; Flippen, L. A.; Miller, A. B.; Leung,
E.; Bonhaus, D. W.; Wong, E. H. F.; J ohnson, L. G.; Eglen, R.
M. RS-100235: A high affinity 5-HT4 receptor antagonist.
BioOrg. Med. Chem. Lett. 1995, 5, 2119.
(14) McGill, J .; LaBell, E.; Williams, M. Hydride Reagents for
Stereoselective Reductive Amination. An Improved Preparation
of 3-endo-Tropanamine. Tetrahedron Lett. 1996, 37, 3977.
(15) Ainsworth, C. Indazole Analogue of Tryptamine: A New Syn-
thesis of Indazoles. J . Am. Chem. Soc. 1957, 79, 5242.
(16) While the alkylation of indazole-3-carboxylic esters and of
indazole itself is known to give regiochemical mixtures of N-1
and N-2 alkylated products, the alkylation of amide 12a
predominantly gave the N-1 alkylated product. It is believed that
internal hydrogen bonding between the amide N-H and N-2 (i)
deactivates N-2 to alkylation and directs alkylation to N-1.
amino)-1-piperidinyl)ethyl)-1H-indazole-3-carboxamide (11.1 g,
26.3 mmol) in DMF (100 mL) and the reaction mixture stirred
at room temperature for 4 h. The reaction was cooled to 15
°C, 2-iodopropane (2.9 mL, 5.13 g, 29 mmol) was added
dropwise, and the reaction mixture was stirred at room
temperature for 18 h. The DMF was removed in vacuo and
the residue dissolved in EtOAc and water. The EtOAc layer
was washed sequentially with 10% sodium carbonate solution,
water and brine and evaporated to give the crude product.
Flash chromatography (5% MeOH in CH2Cl2) provided the
product as an oil (10.6 g, 87%). Crystallization of the product
as the oxalate salt provided colorless crystals, mp 149-151
°C. 1H NMR (DMSO-d6): 1.55 (d, 6H, J ) 8.0 Hz), 1.55-1.75
(m, 1H), 1.85-2.02 (m, 2H), 2.60-4.40 (m, 12H), 5.03 (s, 2H),
5.10 (septet, 1H, J ) 7.0 Hz), 7.23-7.55 (m, 7H), 7.82 (d, 1H,
J ) 9.0 Hz), 8.18 (d, 1H, J ) 9.0 Hz), 8.40-8.50 (m, 1H). MS:
463 (100). Anal. (C28H35N5O7) C,H,N.
N-[2-(4-Am in o-1-piper idin yl)eth yl)-1-isopr opylin dazole-
3-ca r boxa m id e d ioxa la te (23a ). A solution of N-(2-(4-
((benzyloxycarbonyl)amino)-1-piperidinyl)ethyl)-1-isopropylin-
dazole-3-carboxamide (8.71 g, 18.8 mmol) in EtOH (135 mL)
was hydrogenated over 5% palladium on carbon (3.0 g) at 60
psi and room temperature for 18 h. The reaction mixture was
filtered to remove the catalyst and concentrated to give an oil
(5.0 g, 81%). Crystallization of this oil as the dioxalate salt
gave colorless crystals, mp 232 °C. 1H NMR (DMSO-d6): 1.55
(d, 6H, J ) 7.0 Hz), 1.60-1.80 (m, 2H), 1.90-2.10 (m, 2H),
2.50-2.70 (m, 2H), 2.80-3.00 (m, 2H), 3.05-3.24 (m, 1H),
3.24-3.40 (m, 2H), 3.48-3.67 (m, 2H), 5.10 (septet, 1H, J )
7.0 Hz), 7.28 (t, 1H, J ) 8.0 Hz), 7.82 (d, 1H, J ) 9.0 Hz), 8.18
(d, 1H, J ) 9.0 Hz), 8.30-8.42 (m, 1H). MS: 329 (100). Anal.
(C22H31N5O9) C,H,N.
N-(2-(4-(1-Adam an tylcar boxam ido)-1-piper idin yl)eth yl)-
1-isop r op ylin d a zole-3-ca r boxa m id e Oxa la te (8). 1-Ada-
mantanecarbonyl chloride (199 mg, 1 mmol) was added to a
solution of N-(2-(4-amino-1-piperidinyl)ethyl)-1-isopropylin-
dazole-3-carboxamide (330 mg, 1.0 mmol) and triethylamine
(0.15 mL, 1.07 mmol) in THF (10 mL) at 0 °C. The reaction
mixture was allowed to warm to room temperature, stirred
for 18 h, and filtered. The filtrate was concentrated to give
an oil. Crystallization of the oxalate salt (MeOH/EtOAc) gave
the title compound as colorless crystals (267 mg, 46%), mp 228
°C. 1H NMR (DMSO-d6): 1.55 (d, 6H, J ) 8.0 Hz), 1.56-1.90
(m, 16H), 1.95 (br s, 3H), 2.80-3.05 (m, 2H), 3.05-3.20 (m,
2H), 3.30-3.55 (m, 2H), 3.55-3.70 (m, 2H), 3.70-3.90 (m, 1H),
5.10 (septet, 1H, J ) 7.0 Hz), 7.23-7.32 (m, 1H), 7.27 (t, 1H,
J ) 8.0 Hz), 7.46 (t, 1H, J ) 8.0 Hz), 7.80 (d, 1H, J ) 9.0 Hz),
8.18 (t, 1H, J ) 9.0 Hz), 8.40-8.55 (m, 1H). MS: 491 (100).
Anal. (C31H43N5O6) C,H,N.
(17) Turconi, M.; Nicola, M.; Quintero, M. G.; Maiocchi, L.; Micheletti,
R.; Giraldo, E.; Donetti, A. Synthesis of a New Class of 2,3-
Dihydro-2-oxo-1H-benzimidazole-1-carboxylic Acid Derivatives
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J M970857F