688 J . Med. Chem.

1989, 32, 688-693

bronchospasm and salivation generally varied within a range of 86371-48-4;6r,118513-98-7;6r.2HC1,86371-54-2;6s, 86371-75-7;

10-20%. 6t, 118513-99-8; 6te2HC1, 86371-59-7; 6u, 118514-00-4; 6v,
Registry No. 3 (R,= MeO; R2= H), 54504-36-8; 3 (R,= Et; 86371-51-9; 6w,86371-53-1; 6x, 86371-49-5;6y, 86371-50-8;62,
% = H), 86371-00-8; 3 (R,= (Me),CH; & = H), 118514-03-7;3a, 86371-71-3;7 (R,= Rz H; R4 Et), 86371-40-6;7 (R,= R =
59456-03-0; 4a, 41806-52-4; 4b, 118513-80-7;4b-2HC1,61709-32-8; Me; R2 = H), 86371-44-0; 7 (R,= Me; R2 = H; R4 = Et),
4c, 118513-81-8; 4c-2HC1, 118514-08-2; 4d, 118513-82-9; 4e, 86371-43-9;7 (R,= MeO; R2 = H; R4 = Me), 86371-46-2;7 (R,
118513-83-0; 4e2HC1, 118514-09-3; 4f, 118513-84-1; 4f.2HC1, = MeO; Rz= H;R4 = Et), 86371-45-1; 7 (R,= R2= MeO; R4=
118514-10-6; 4g, 118513-85-2; 4h, 118513-86-3; 4h.2HC1, Me), 86371-47-3;7a,86371-40-6;7b, 86371-43-9;7c, 86371-45-1;
7d, 118514-02-6;8e,118514-04-8;8j, 118514-05-9;8r, 87942-41-4;
118514-11-7;4i, 118513-87-4;4i.2HC1,118514-12-8;4j, 59456-04-1;
4j-2HC1, 54504-40-4; 4k, 62124-26-9; 41, 118537-26-1; 4m,
87942-30-1; 4n, 118513-88-5;4n.2HC1,87942-25-4;40,87942-54-9;
.
9, 50461-27-3; 12.HC1, 118514-06-0; 12.2HC1, 118514-07-1;
(CH2)8NH,111-49-9;butanoic acid, 107-92-6;propionic acid, 79-
40.2HC1, 87942-31-2; 4p, 118513-89-6; 4q, 87942-53-8; 4r, 09-4; 1-(2-~hloroethyl)piperidine, 1932-03-2;N-(2-chloroethyl)-
87942-43-6; 4s, 87942-35-6; 4t, 87942-45-8; 4u, 87942-46-9; 4v, hexamethylimine, 2205-31-4; 2-chloro-NJV-dimethylethanamine,
87942-50-5;4w, 87942-51-6; 5 (R,= R2 = H), 86371-21-3; 5 (R, 107-99-3; 2-chloro-N,N-diethylethanamine, 100-35-6; 2-chloro-
= Me; Rg = H), 86371-16-6;5 (R1= Rz= Me), 86371-12-2;5 (R, NJV-dipropylethamhe, 36716-60-6;1-(2-chloroethyl)pyrrolidine,
= Rz= MeO), 60629-83-6; 6a, 118513-90-9;6a.2HC1,118514-13-9; 5050-41-9;N-(2-chloroethyl)morpholine,3240-94-6; l-(2-chloro-
6aa,118514-01-5; 6b, 118575-11-4; 6b-2HC1, 118514-14-0;6bb, ethyl)-2,2,6,6-tetramethylpiperidine,773-50-2; 3-(2-chloro-
86371-52-0; 6c, 118513-91-0;~ C C86371-77-9;
, 6d, 60629-85-8; 6dd, ethyl)-3-azabicyclo[3.2.2]nonane,54777-55-8;3-(2-chloroethyl)-
86371-64-4; 6e, 118513-92-1;6f, 118513-93-2;6g, 118513-94-3;6h, 3-azabicyclo[3.3.l]nonane,87942-52-7; 2-(2-chloroethyl)-2-aza-
95571-28-1; 6i, 60629-86-9; 6j, 118513-95-4;6k, 118513-96-5;61, bicyclo[2.2.2]octane, 59882-35-8; 1-(3-~hloropropyl)piperidine,
60629-84-7; 6m, 86371-74-6; 6n, 86371-76-8; 60, 118513-97-6; 1458-63-5;pyrrolidine, 123-75-1;piperidine, 110-89-4;morpholiie,
60.2HC1, 86371-61-1; 6p, 86371-73-5; 6q, 86503-95-9; 6q2HC1, 110-91-8.

Heterocyclic Analogues of Benzamide Antiarrhythmic Agents'

Reda G. Hanna,t J o h n W. Lampe,*it William C. Lumma, Jr.,t Paul W. Erhardt,' Samuel S. Wong,s
and Mark E. Sullivan*
Berler Laboratories, Inc., 110 East Hanover Avenue, Cedar Knolls, New Jersey 07927. Received May 12, 1988

A series of heterocyclic N - [(diethy1amino)alkyllarenamidesrelated to acecainide was prepared and examined for

antiarrhythmic activity. The compounds were synthesized from the correspondingknown heterocyclic carboxylic
acids or esters by using standard amide formation methods. The effects of the compounds on the electrophysiological
properties of canine Purkinje fibers and ventricular muscle strips were determined. Most of the compounds showed
effects consistent with weak class I activity. Two compounds, N-[2-(diethylamino)ethyl]-3,4,5-trimethyl-lH-
pyrrole-2-carboxamideand N-[2-(diethylamino)ethyl]-lH-indole-2-carboxide, displayed prolongation of the action
potential duration and functional refractory period indicative of modest class I11 electrophysiological activity.
Representative compounds were examined by using molecular modeling techniques. Compounds of differing activity
classes displayed qualitatively different electrostatic potential maps.

In the course of our studies aimed at the preparation 0 0

of novel antiarrhythmic agents,2 we noted structural sim-
ilarities (highlighted below) between the known antiar-
rhythmic compounds procainamide, 1, and acecainide, 2,
and t h e dopamine antagonists metoclopramide, 3, a n d
piquindone, 4.3 We noted that for the dopamine antag-
I,R=H
onists, certain heterocycles such as the pyrrole subunit 2 . R - Ac
found in 4 can substitute for the aniline seen in compounds 0
such as 3. In both 3 and 4 a hydrogen-bearing nitrogen 7 II!
is positioned so as to be in conjugation with a carbonyl
group. Given the structural similarities between antiar-
rhythmic compounds such as 1 and 2 and the dopamine
antagonist 3, we reasoned that substitution of certain
4
heterocycles for aniline might also be applicable to the
preparation of analogues of benzamide antiarrhythmic less than half the activity of quinidine against aconitine-
agents. induced arrhythmias in the isolated guinea pig heart. To
There is some suggestion in t h e literature that this
substitution might yield antiarrhythmic activity. I n a (1) Presented in part at the 192nd National Meeting of the Am-
study of t h e antiarrhythmic activity of a series of (di- erican Chemical Society, Anaheim, CA, Sept 7-12, 1986.
alkylamino)ethylamides, Giannini and co-workers4 pre- (2) (a) Morgan, T. K., Jr.; Wohl, R. A.; Lumma, W. C., Jr.; Wan,
pared compound 5; they reported however that it displayed C.-N.; Davey, D. D.; Gomez, R. P.; Marisca, A. J.; Briggs, M.;
Sullivan, M. E.; Wong, S. S. J.Med. Chem. 1986,29,1398. (b)
Lis, R.; Morgan, T. K., Jr.; DeVita, R. J.; Davey, D. D.; Lum-
ma, W. C., Jr.; Wohl, R. A,; Diamond, J.; Wong, S. S.; Sullivan,
* Author to whom correspondence should be addressed. M. E. J. Med. Chem. 1987, 30, 696. (c) Lumma, W. C., Jr.;
Department of Medicinal Chemistry. Wohl, R. A.; Davey, D. D.; Argenteri, T. M.; DeVita, R. J.;
* Department of Pharmacology. Gomez, R. P.; Jain, V. K.; Marisca, A. J.; Morgan, T. K., Jr.;
8 Present address: Pfizer International, New York, New York, Reiser, H. J.; Sullivan, M. E.; Wiggins, J.; Wong, S. S. J. Med.
10017. Chem. 1987,30, 755.

0022-2623I89 11832-0688%01.50
I O @ 1989 American Chemical Societv
Analogues of Benzamide Antiarrhythmic Agents Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3 689

Table I. Physical Properties of Compounds 6-19

recrystnc
compd n X methoda yield,* % mp, "C solvent formulad
6 2 A 29 60-62 A C14H2SN30
7 3 B 25 117-119 A C15H27N30
8 2 B 39 125-126 B C14H2SN30
9 3 A 26 78-80 A C16H27N30
10 2 B 22 243-245 C C14H23N302*2HCle
11 3 B 41 225-227 C CiSH2SN302'2HCl
12 2 H B 27 129-131 D C1SH21N30
13 3 H B 15 142-144 A C16H23N30
14 2 OBn B 12 121-123 E C22H27N302
15 3 OBn B 6 105-107 A C23H29N302
16 2 OH C 49 157-159 F C15H21N302*HC1*0.25.H~Oe
17 3 OH C 35 192-194 F C1GH~3N302.HCI.O.50*H~Oe
18 2 B 46 oil C15H21N30
19 3 B 28 oil C18H23N30f
a Method of preparation. See text for description. *Yields are for analytically pure products and are not optimized. A, ethyl acetate-
hexanes; B, acetonitrile; C, ethyl acetate-ethanol; D, ethyl acetate; E, toluene, F, methanol. dThe analyses for C, H, and N were within
f0.4% of the calculated values unless otherwise stated. 'C1 analysis was within f0.4% of the calculated value. fCalcd C, 70.30. Found:
C, 69.85.
further test this relationship, we prepared the series of Scheme I
heterocyclic amides 6-19. method A
We were particularly interested in examining these
structures because of the possibility that they would dis-
play differing electrophysiological profiles. In compounds
such as 1 and 2, the nature of the aniline nitrogen plays
an important role in determining the compound's elec-
trophysiological profile. Acetylation changes 1, a class Ia
antiarrhythmic agent, into 2, which is a relatively selective,
albeit weak, class I11 agente5 We expected that the het-
erocyclic structures 6-19 would be more closely related to
compound 2 in terms of the character of their nitrogen H
atoms, and thus would display a greater propensity for
class I11 antiarrhythmic activity.
0
II H

fi
method 8
0 0

C02Et Me2AIN(CH2),NEt2
H oz(CH2)nNEt2
'd 6.7
5 CHZCIZ
0 0 H H
II II
Chemistry
The compounds for this study were prepared by one of
two routes. Amides 6-9 could be prepared from the cor-
responding known pyrrole carboxylic acids6 as shown in
8 10,ll Scheme I, method A. Activation of the acids by the me-
8.9 thod of Woodman and Davidson' gave both the 2- and
0 3-substituted activated esters in fair yields after isolation
II
CNH (CH
and purification. Reaction of the activated esters with the
Et 2 appropriate diamines gave the pyrrole amides in modest
I
yields. This method failed, however, when applied to
targets 10 and 11. No activated ester was formed, and only
starting acid could be isolated from the activation reaction.
I After several unsuccessful attempts to prepare amides from
X 18,19 the pyridonecarboxylic acid, Weinreb's amide synthesis8
12-17
(a) 3,4,5-Trimethylpyrrole-2-carboxylicacid: Bullock, E.;
Johnson, A. W.; Markham, E.; Shaw, K. B. J. Chem. SOC.1958,
(3) Olson, G. L.; Cheung, H.-C.; Morgan, A. D.; Blount, J. F.; 1430. (b) 2,4,5-Trimethylpyrrole-3-carboxylic acid: McKin-
Todaro, L.; Berger, L.; Davidson, A. B.; Boff, E. J . Med. Chem. non, D. M. Can J. Chem. 1965, 43, 2628. (c) 2,6-Dimethyl-4-
1981, 24, 1026. pyridone-3-carboxylic acid Ziegler, E.; Herbst, I.; Kappe, T.
(4) Giannini, M.; Bons, P.; Fedi, M.; Bonacchi, G. Farmco, Ed. Sci. Monatsh. Chem. 1969, 100, 132. (d) 7-(Benzyloxy)indole-2-
1973, 28, 429. carboxylic acid ethyl ester: Heindl, J.; Loge, 0. Eur. Pat. Appl.
(5) (a) For a discussion of the classification of antiarrhythmic EP 62,919, 20 Oct 1982.
agents, see: Vaughan Williams, E. M. In Symposium on Woodman, D. J.; Davidson, A. I. J. Org. Chem. 1973,38,4228.
Cardiac Arrhythmias; Sandoe, E., Flensted-Jansen, E., Olsen, (a) Basha, A.; Lipton, M. F.; Weinreb, S. M. Tetrahedron Lett.
K. H., Eds.;AB Astra, 1970;pp 449-472. (b) Dangman, K. H.; 1977,4171. (b) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org.
Hoffman, B. F. J . Pharmacol. Erp. Ther. 1981, 217, 851. Syn. 1979, 59, 49.
690 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3 Hanna et al.

was found to give satisfactory results. Thus, as shown in among the more potent class I agents, as judged from their
method B, reaction of the pyridone ester with the necessary effects on V,. Substitution of the indole nucleus with
dimethylaluminum amides afforded the corresponding alkoxy groups abolished class I11 activity (12 compared to
pyridone amides in fair yield. 14, 16), while increases in lipophilicity tended to increase
Since method B thus proved to be a generally more class I activity (14 compared to 12). The pyridone- and
useful route, it was adopted for the syntheses of the re- indole-Ccarboxamide compounds were only weakly active.
maining compounds in this study. Hydroxyindole targets Compound 8 and its close analgoue 9 were examined in
were prepared by hydrogenolysis of the corresponding vivo in the pentobarbital-anesthetized dog by using the
benzyloxy compounds (method C). Table I lists the com- method of Carson and Dresel.lo These compounds showed
pounds prepared and provides a summary of physical data only minimal effects on conduction time, functional re-
and the methods used to synthesize each of the amides. fractory period, heart rate, and blood pressure when given
Pharmacology in doses up to 3 mg/kg iv. Thus, the class I11 activity seen
with these compounds in vitro did not translate into in vivo
The electrophysiologicaleffects for each compound were activity.
determined in vitro in isolated canine Purkinje fibers by The dopamine receptor affinities for compounds 6 and
using standard microelectrode technique^.^ The effects 7 were determined in vitro by measuring their ability to
of the compounds on the action potential duration at 95% displace specifically bound [3H]ADTN from pig brain
repolarization (APD,,) and the rate of rise of phase 0 of striatal membrane preparati0n.l' The affinities for these
the action potential (V-) were recorded simultaneously. compounds were found to be quite low; affinities for 6 and
The results are presented in Table I1 as the percent change 7, expressed relative to unlabeled ADTN as the ratio of
in APDg5 (A%APDg5)at 10 pM, the maximum percent the concentrations producing a 50% inhibition of binding,
change observed in APDg5(maxA%APDg5)along with the were 500 and 1800, respectively.
concentration at which. the maximum occurred, the percent
change in V,, (A% V,,,) at 10 pM, and the maximum Molecular Modeling
percent change in V,, (maxA% V,,,) with the concen- In an effort to understand better the differing activities of the
tration a t which this maximum was observed. Increases compounds prepared in this study, we have compared repre-
in APDg5 are taken as indications of class I11 activity; sentative compounds. by using molecular modeling techniques.
increases in V,, are taken as indications of class I activity. Compounds 1 and 2 were studied as standard class I and class
Compounds were also studied in vitro in canine ven- I11 agents, respectively; from among the new compounds reported
tricular muscle strips by using an adaptation of the in vivo here, compounds 6 and 12 were chosen as representative com-
method of Carson and Dresel.lo The effects of the com- pounds with class I and class I11 electrophysiological properties,
pounds on the functional refractory period (FRP) and respectively. Structures for the four compounds were optimized
by using molecular mechanics calculations.12 A large number
conduction time (CT) of the muscle strips were deter- of conformations of approximately equal energy were found for
mined. In Table I1 we show the percent change in FRP each compound; conformations chosen for further study do not
(A%FRP) at 10 wM, the maximum percent change ob- necessarily represent global minima, but are of energies such that
served in FRP (maxA%FRP) along with the concentration they should be easily accessible to the molecules. Rather,
at which the maximum occurred, the percent change in CT structures were chosen in which the side chains were in ap-
(A%CT) at 10 pM, and the maximum percent change in proximately the same conformation for all compounds studied.
CT (maxA%CT) with the concentration at which this Net atomic charges were determined for these conformations via
maximum was observed. Changes in CT of <lo% from a single-point calculation by using the MNDO method,13 as im-
control values were considered minimal (marked "M" in plemented in AMPAC.'I Electrostatic potential maps were then
the table). Increases in FRP are taken as indications of generated in the plane of the aromatic systems, as well as 1.5 and
3.0 A above and below the plane, using the point charge ap-
class I or class I11 activity, whereas increases in CT are pr~ximation.'~The potential maps taken at +1.5 A proved to
taken as indications of class I activity. be most informative and are shown in Figure 1.
In order to assess potential cardiodepressant properties The class I active compounds 1 and 6 show very similar maps,
of the compounds, inotropic effects of the compounds were which are characterized by a region of attractive potential centered
determined in vitro in guinea pig papillary muscle. The about the carbonyl oxygen and side-chain nitrogen and by a region
concentrations of compounds leading to a 20% decrease of repulsive potential near the aniline or ring nitrogen, approx-
in the force of contraction (EC-,,) are given in Table 11. imately 7-8 A away from the carbonyl oxygen. The class I11 active
The electrophysiology screens revealed modest class I compounds 2 and 12 are differentiated from 1 and 6 in that they
activity in most of the compounds tested. The compounds both show a significantly larger area of attractive potential that
extends out over the aromatic system and that contains an ad-
showed minimal effects on action potential duration and ditional local minimum in potential. One measure of the increase
functional refractory period and varying degrees of de- in area of attractive potential is the greatest distance from the
pression of V,,. Two compounds, 14 and 15, were more carbonyl oxygen to the -10 kcal contour in the direction of the
potent in this regard, showing an EC-20for V,, 5 5 yM. aromatic ring; this distance is increased by 2-4 A in 2 and 12 over
The negative inotropic effects evoked by many of the that measured in 1 and 6. The distances between the minimum
compounds tested support this general picture of local at the benzamide carbonyl oxygen and the minimum in the vicinity
anesthetic activity. Two compounds, 8 and 12, showed
combined effects on Purkinje fiber and ventricular muscle
comparable to those of acecainide, 2, suggesting some Davis, A,; Woodruff, G. N.; Poat, J. A.; Freedman, S.B. Bio-
modest class I11 activity in these compounds. chem. Pharmacol. 1980,29, 1645.
Molecular mechanics calculations were carried out by using the
The pyrrole- and indole-2-carboxamides with two carbon MMFF program within CHEMLAB-11, Revision 9.1, a product
side chains (8, 12) were the most potent class I11 agents of Molecular Designs, Ltd., San Leandro, CA 94577.
in the series, as judged from their effects on APDg5and Dewar, M. J. S.; Theil, W. J. Am. Chem. SOC.1977, 99, 4899.
FRP; in contrast, pyrrole-3-carboxamides (6, 7) were AMPAC, Quantum Chemistry Program Exchange, Program
506, Indiana University Chemistry Department.
Weinstein, H.; Osman, R.; Green, J. P.; Topiol, S.Chemical
(9) Davis, L. D.; Temte, J. V. Circ. Res. 1969, 24, 639. Applications of Atomic and Molecular Electrostatic Poten-
(10) Carson, D. L.; Dresel, P. F. J. Cardiouasc. Pharmacol. 1981,3, tials; Politeer, P., Truhlar, D. G., Eds.; Plenum Press: New
924. York, 1981; pp 309-334.
Analogues of Benzamide Antiarrhythmic Agents Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3 691

v m 3 3 N 3 3 3 3 N 0113 N 3 N
F
z F
z

m
-
W
h
El

s fs s
w
E! 1 m
w N w

EEE E E m-
E E E? *
w
7 m- E 7
692 Journal of Medicinal Chemistry, 1989, Vol. 32,No.3 Hanna et al.

9 5 9 5

3 e 3 e
1

-3 5 -3 5

-18 e
-!e e -3 5 3.e 9 5 -10 e -3 5 3 e 9 5

9 5

313 3 @
12
2

-3 5 -3 5

-le e 1 1 1 1 1 1 1 1 1 IlrlII, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 , , 1 le e
-10 e -3 5 3 0 9 s -18 e -3 5 3 e 9 s
Figure 1. Electrostatic potential maps of 1, 2, 6,and 12. Contour interval is 1 kcal.
of the aromatic ring for 2 and 12 are approximately 8 and 5 A, Galbraith Laboratories, Microlit Laboratories, or the Berlex
respectively. These features in the potential maps are indicative Analytical Section; results are within 3~0.4%of the calculated
of differences in electronic structure in these molecules that may values unless otherwise stated. Solid products were routinely dried
play a role in determining their behavior at their sites of biological at 60 "C under reduced pressure for a minimum of 12 h. Reactions
action, and as such may be responsible for their differing activities. were monitored by thin-layer chromatography on silica gel (Merck)
and alumina (Merck) plates and visualized by UV and Dragendorff
Discussion reagent.
Although two of the compounds in this study displayed General Synthetic Methods. The following procedures are
a class I11 electrophysiological profile comparable to that representative of the general methods that are described in the
of acecainide, 2, the predominant electrophysiological ef- text.
Method A. 2,4,5-Trimethyl-lH-pyrrole-3-carboxylic Acid
fect of most of the compounds was a weak class I action. [[ (1,l-Dimethylethyl)amino]carbonyl]- 1-methylethenyl
This is consistent with the work of Giannini and co- Ester. To a solution of 2-tert-butyl-5-methylisoxazolium per-
workers.* These workers found optimum activity with chlorate (6.80 g, 28.4 "01) in dry CH3CN (50 mL) under nitrogen
lipophilic bicyclic aromatic amides derived from naph- was added a solution of 2,4,5-trimethyl-1H-pyrrole-3-carboxylic
thalenes and quinolines. Similarly, our lipophilic indole- acid (4.36 g, 28.4 mmol) and triethylamine (3.01 g, 29.8 mmol)
derived targets 14 and 15 were among the most potent in CH3CN (50 mL) and DMF (10mL). The reaction solution was
within our,series in their class I activity, as measured by stirred at room temperature for 72 h. A precipitate formed and
effects on V,, in Purkinje fibers. Compound 8, our closest was collected by filtration. Recrystallizationfrom CH3CN afforded
analogue of compound 5, was one of the more active of our the title compound as light brown needles (4.0 g, 48%): mp 185
compounds from the standpoint of class I11 activity mea- "C (partial melt at 167-169 "C); 'H NMR (CDCl,) 6 1.20 (s, 9 H),
1.36 (s, 9 H), 2.03 (s, 3 H), 2.16 (s, 6 H), 2.40 (s, 3 H), 2.50 (s, 3
sured in vitro. This in vitro class I11 activity demonstrates H), 5.50 (s, 1 H), 5.66 (s, 1 H), 5.60-6.50 (br m, 1 H), 7.90-8.60
in principle our basic premise that the substitution of (br m, 1 H). Anal. (CI6H2,N203)C , H: N.
heterocyclic systems for aniline could be a viable route for N-[2-(Diethylamino)ethyl]-2,4,5-trimethyl- 1H-pyrrole-3-
the modification of benzamide antiarrhythmic agents to carboxamide (6). To a suspension of 2,4,5-trimethyl-lH-
give class I11 compounds. pyrrole-3-carboxylic acid [ [ (1,l-dimethylethy1)aminol-
carbonyl]-1-methylethenylester (5.60 g, 233 mmol) in CH3CN
Experimental Section (200 mL) was added N,N-diethylethylenediamine(2.98 g, 25.7
Melting points were recorded on a Thomas-Hoover capillary "01) followed by triethylamine (2.60 g, 25.7 "01). The reaction
melting point apparatus and are uncorrected. Infrared spectra mixture was heated at reflux overnight under nitrogen after which
were recorded on a Sargent-Welch 3-300 or a Beckman Acculab it was cooled to room temperature. The resulting precipitate was
2 infrared spectrophotometer. NMR spectra were recorded at removed by filtration, and the filtrate was concentrated in vacuo
60 MHz on a Varian EM-360 or at 300 MHz on a Varian XL-300 to an oil. Chromatography of the oil over silica gel, eluting first
spectrometer. Chemical shifts are reported in parts per million with CH&N and then with CH3CN-NH40H (955)followed by
(a) downfield from an internal standard of tetramethylsilane for trituration of the product with ethyl acetate-hexanes afforded
all solvents except D20,where sodium 3-(trimethylsilyl)propionate 6 as a cream-colored solid (1.70 g, 29%): mp 60-62 "C; 'H NMR
was used as standard. Elemental analyses were performed by (CDCl,) 6 1.00 (t,6 H), 2.16 (s, 6 H), 2.46 (s, 3 H), 2.56 (9, 6 H),
Analogues of Benzamide Antiarrhythmic Agents Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3 693

3.50 (q, 2 H), 6.00-6.70 (br m, 1 H), 7.50-8.00 (br m, 1 H). Anal. upstroke velocity, and action potential duration at 50% and 95%
(CI~HZSN~O) C, H, Ne repolarization. Fibers were stabilized for up to 1 h before control
Met hod B. N 4 2 - (Diethy1amino)ethyll- lH-indole-2- measurementa were taken. Test compounds were screened in the
carboxamide (12). To a solution of Nfl-diethylethylenediamine range of to M concentrations. Data were collected for
(5.40 g, 465 mmol) in CH2Cl2(50 mL) under nitrogen was added each compound after 30 min of exposure to a given concentration.
trimethylaluminum(2 M in toluene, 23.4 mL, 46.5 "01) dropwise Only one compound was tested per Purkinje fiber preparation,
via syringe. The reaction solution was stirred for 0.5 h, after which and the appropriate vehicle controls were conducted in every
a solution of ethyl 2-indolecarboxylate(8.0 g, 42.2 "01) in CH2Cl2 experiment.
(50 mL) was added dropwise via syringe. The reaction solution Extracellular Electrophysiological Canine
was then heated at reflux for 24 h, cooled to room temperature, ventricular muscle strips taken from the right ventricle papillary
and concentrated in vacuo to an oil. The oil was partitioned muscle near the base (5-6 mm long X 1-2 mm wide) were mounted
between water and ethyl acetate. The aqueous layer was made on a silicone washer and placed in a 3.5-mL tissue bath. The
slightly acidic (pH 6.5) and extracted with ethyl acetate, and the preparation was continuously superfused with warmed (36 A 0.5
layers were separated. The aqueous layer was then made basic "C), physiological saline equilibrated with a gas mixture of 95%
and extracted with ethyl acetate. The organic washes were oxygen+% carbon dioxide. The preparation was stimulated at
combined, dried over MgS04,and concentrated in vacuo to a solid one end through bipolar, stainless steel, Teflon-coated electrodes
(10 9). Recrystallization from ethyl acetate afforded 12 as off-white (0.005 in.) impaled into the muscle. A bipolar electrogram was
crystals (2.92 g, 27%): mp 129-131 "C; 'H NMR (CDClJ 6 1.07 recorded at the opposite end of the muscle strip with the same
(t, 6 H), 2.61 (4, 4 H), 2.69 (t, 2 H), 3.55 (4, 2 H), 6.84 (s, 1 H), type of bipolar electrodes described above. The output of the
7.67 (d, 1 H), 9.78 (br m, 1 H).Anal. (C1SH21N30)C, H, N. electrical signal was amplified and displayed on an oscilloscope.
Method C. N-[2-(Diethylamino)ethyl]-7-hydroxy-lH- The diastolic threshold (DT) of the muscle preparation was de-
indole-2-carboxamide Hydrochloride (16). To a solution of termined with bipolar stimuli 2 ms in duration at a cycle length
N - [ 2- (diethy1amino)ethyll-7-(pheny1methoxy)-lH-indole-2- of 4000 ms. The muscle tissue was then stimulated at 4 times
carboxamide (9.27 g, 25 mmol) in methanol (100 mL) were added the diastolic threshold for an initial equilibration period of 60
concentrated HCl(2.11mL, 25 "01) and 10% Pd/C (4.0 9). The min. The functional refractory period was determined at a cycle
reaction mixture was placed in a Parr apparatus under an at- length of 1000 ms by applying a premature stimulus (S2) of the
mosphere of hydrogen for 2 h at 45 psi, after which the solids were same duration and strength after every tenth basic stimulus (Sl)
removed by filtration through Celite. The filtrate was concen- at decreasing S1-S2 intervals until refractoriness occurred.
trated in vacuo to a solid. Recrystallization from methanol af- Conduction time (CT), measured as the time interval from the
forded 16 as an off-white solid (3.75 g, 45%): mp 157-159 "C dec; stimulus to the peak of the electrogram,was determined for each
'H NMR (DzO)6 1.33 (t, 6 H), 3.29 (m, 6 H), 3.66 (q,2 H), 4.85 S1-S2 interval that produced a propagated response. The rela-
(s, 4 H), 6.85 (d, 2 H), 7.10 (t, 2 H), 7.33 (d, 1 H). Anal. (C15- tionship between the degree of prematurity (S1-S2 interval) and
Hz1N302.HCl.0.25H~O)C, H, N, C1. conduction time of the premature stimulus (S2) was constructed
Pharmacology. Papillary muscle studies,16in vivo studies in as a conduction-interval curve. The tissue was then superfused
anesthetized dogs,'O and dopamine receptor binding studies" were with various concentrations of test compound. Only one com-
carried out by using reported methods. pound was tested per ventricular muscle strip preparation, and
Intracellular Electrophysiological Profile?b Canine cardiac the appropriate vehicle controls were conducted in every ex-
Purkinje fibers (free running false tendons) were anchored in a periment.
tissue bath and perfused at a rate of 6 mL/min with modified Acknowledgment. We thank Dr. Walton B. Caldwell
Tyrode's solution containing the following ions in mmol/L Na',
149.8; K+,4.0; Mg2+,0.5; Ca2+,2.5; C1-, 134.0; HzP04-,1.8; HCO,, and members of the Medicinal Chemistry Analytical
24.0; and glucose, 5.5. The solution was gassed with a mixture Section for their help in the physical characterization of
of 95% oxygen-5% carbon dioxide (pH 7.35-7.40) and maintained the compounds in this study. Thanks are also due to Dr.
at 36 i 0.5 "C. The tissues were stimulated at a control rate rate E. Schillinger of Schering AG, West Germany, for carrying
of 1.0 Hz through bipolar Teflon-coatedplatinum electrodeswith out the dopamine receptor binding assay, and to Ellen
square wave pulses of 2-ms duration and twice the diastolic Ambelas and Hannah Troy of our Pharmacology De-
threshold current. Intracellular action potentials were recorded partment for their technical assistance in the course of this
with glass microelectrodes (3 M KCl) by using standard recording work. We are grateful to Dr. Sidney Topiol and Michael
techniquesee Parameters measured were resting membrane po- Sabio for their help in carrying out the molecular modeling
tential, threshold current, action potential amplitude, maximum studies, and to Dr. Thomas Morgan for many helpful
discussions. Finally, we thank Dorothy Gula for the
(16) Hagedorn, A. A., 111; Erhardt, P. W.; Lumma, W. C., Jr.; Wohl,
preparation of this manuscript.
R. A,; Cantor, E.; Chou, Y.-L.; Ingebretsen,W. R.; Lampe, J. Supplementary Material Available: 'H NMR spectral data
W.; Pang, D.; Pease, C. A.; Wiggins, J. J.Med. Chem. 1987,30, for compounds 7-11, 13-15, and 17-19 (2 pages). Ordering in-
1342. formation is given on any current masthead page.