Aroyl(aminoacyl)pyrroles, a new class of anticonvulsant agents

Article abstract of DOI:10.1021/jm9606655

2-Aroyl-4-(ω-aminoacyl)- (4) and 4-aroyl-2-(ω-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an ω-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel- Crafts aroylation of a 2-(ω-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5- trimethylpyrrole (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca²⁺ ions into cerebellar granule cells induced by K⁺ or veratridine.

Full text of DOI:10.1021/jm9606655

1578
J . Med. Chem. 1997, 40, 1578-1584
Articles
Ar oyl(a m in oa cyl)p yr r oles, a New Cla ss of An ticon vu lsa n t Agen ts
J ohn R. Carson,*,† Richard J . Carmosin,† Philip M. Pitis,† J effry L. Vaught,†,‡ Harold R. Almond,†
J ames P. Stables,§ Harold H. Wolf,| Ewart A. Swinyard,| and H. Steve White|
Drug Discovery, The R. W. J ohnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776,
Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Federal Building,
Room 114, Bethesda, Maryland 20892, and Anticonvulsant Screening Project, Department of Pharmacology and Toxicology,
University of Utah, Salt Lake City, Utah 84108
Received September 23, 1996X
2-Aroyl-4-(ω-aminoacyl)- (4) and 4-aroyl-2-(ω-aminoacyl)pyrroles (9) represent a new, structur-
ally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-
Crafts acylation of a 2-aroylpyrrole with an ω-chloroacyl chloride followed by displacement of
the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by
Friedel-Crafts aroylation of a 2-(ω-chloroacyl)pyrrole followed by displacement by an amine.
These compounds were active in the mouse and rat maximal electroshock tests but not in the
mouse metrazole test. The lead compound, RWJ -37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-
acetyl)-1,3,5-trimethylpyrrole (4d ), showed potency and therapeutic index comparable to those
of phenytoin and carbamazepine and greater than those of sodium valproate. This compound
blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of
metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or
veratridine.
In tr od u ction
New anticonvulsant agents continue to emerge.6-12
The polyazaaromatics of Kelley and co-workers9,10 and
Moreau and co-workers12 might be grouped with lam-
otrigine. The phenylacetyltriflamides of Wolfe and co-
workers8 may fall within the sulfamyl class. The
enaminones described by Scott and co-workers13 appear
to be a novel class. Of all the structural classes of
anticonvulsants, the only drug to show the pattern of
two aromatic rings and a dialkylaminoalkyl chain,
which is so prevalent among CNS drugs, is flunarizine.14
Flunarizine appears to act by preventing calcium over-
load. The structures of some newer anticonvulsants
have been summarized.15
The conditions grouped under the term epilepsy
constitute an area of continuing medical need. It has
been estimated that up to 20% of the patients with
epilepsy using the first generation of antiepileptic drugs
(phenobarbital, phenytoin, carbamazepine, sodium val-
proate, and diazepam) were not able to obtain adequate
control of seizures.1 A group of new drugs including
felbamate, gabapentin, lamotrigine, oxcarbamazepine,
topiramate, vigabatrin, and zonisamide are entering
clinical practice.2 The impact of these newly marketed
drugs has yet to be fully evaluated.
The classification of antiepileptic drugs by structure
and mechanism is difficult to do precisely, but some
generalizations can be formulated. Phenytoin, phe-
nobarbital, and carbamazepine contain a urea function
in proximity to phenyl rings. They prevent seizure
spread and are thought to act as sodium channel
modulators.3,4 Sodium valproate is the lone example of
a simple branched chain aliphatic carboxylate salt. It
elevates seizure threshold as well as preventing seizure
spread. The benzodiazepines (diazepam, clonazepam,
nitrazepam, and clobazam) are GABA-A receptor modu-
lators which elevate seizure threshold and are used to
treat generalized absence seizures. Vigabatrin, gaba-
pentin, and progabide, though they may not be mecha-
nistically homogeneous, all share the GABA backbone.
Topiramate5 and zonisamide both have a sulfamyl
group. Lamotrigine is a halophenyl amino-substituted
polyaza aromatic.
No general theories have gained acceptance, which
would explain why many epileptic patients are not
adequately treated with current therapy. The strategy
of seeking drugs that are structurally, mechanistically,
and pharmacologically unique and testing them in these
patients still seems to be an appropriate approach. We
describe herein a series of anticonvulsant aroyl(ami-
noacyl)pyrroles that, we believe, fulfill these criteria.
Ch em istr y
The compounds showing anticonvulsant activity are
of types 4 and 9. The compounds of type 4 were
prepared according to Scheme 1. Aroylpyrroles (2)
where R1 ) CH3, R2 and R3 ) H were prepared by
refluxing the requisite aroyl chloride with N-methylpyr-
role in toluene.16 The aroylpyrroles where R1, R2, and
R3 ) CH3 or H were prepared as previously de-
scribed.17,18 Friedel-Crafts acylation of the aroylpyr-
roles with a ω-chloroalkanoyl chloride followed by
displacement of chloride by the desired amine gave
compounds of type 4. Compounds of type 9 were
prepared by Scheme 2 in which the order of attachment
of the substituents was reversed. Compound 10 was
* Author to whom correspondence should be addressed.
† The R. W. J ohnson Pharmaceutical Research Institute.
‡ Present address: Cephalon, Inc., West Chester, PA 19380.
§ National Institutes of Health.
| University of Utah.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
S0022-2623(96)00665-6 CCC: $14.00 © 1997 American Chemical Society

New Class of Anticonvulsant Agents
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1579
Sch em e 1a
have been previously described.4 The compounds were
initially screened in the mouse maximal electroshock
seizure (MES) test and the subcutaneous metrazole
(scMET) test. Minimal motor impairment was mea-
sured by the rotorod (Tox) test. The compounds were
classified into the following categories: active at <100
mg/kg (class 1), active at >100 mg/kg (class 2), inactive
(class 3), and toxic or active but toxic (class 4). Com-
pounds of class 1 and certain compounds of class 4 were
then tested in the rat MES, scMET, and Tox tests. The
rat classifications are as follows: 4/4 animals active,
class 4; 3/4 animals active, class 3; 2/4 animals active,
class 2; 1/4 animals active, class 1. The results of the
classifications are shown in Table 1. The compounds
that were active in mouse and rat were then evaluated
quantitatively. The results of the quantitative studies
are shown in Table 3.
a
Reagents and conditions: (a) 110-140 °C; (b) Cl(CH2)nCOCl,
AlCl3; (c) R4NHR5.
Sch em e 2a
The aroyl(aminoacyl)pyrroles, in general, were active
in the MES test, indicative of their ability to prevent
seizure spread. They were inactive in the scMET test,
a test used to identify compounds that elevate seizure
threshold. The aroyl(aminoacyl)pyrroles thus fall in a
class with phenytoin and carbamazepine and are dif-
ferent in profile from the benzodiazepines, which are
only active in the scMET test, and from sodium val-
proate, which is active in both the MES and scMET
tests. The more potent compounds of the aroyl(ami-
noacyl)pyrrole series are comparable in potency to
phenytoin and carbamazepine. Their protective indices
in mice are slightly less than those of phenytoin and
carbamazepine. The compounds of the aroyl(amino-
acyl)pyrrole series, however, are substantially more
potent than sodium valproate, and many have a sub-
stantially greater protective indices.
The compounds that were found to have acceptable
potency and protective index in mouse and rat were
evaluated in a series of secondary tests. These tests,
the methods of which have been published elsewhere,4
included the following: sc bicuculline, sc picrotoxin, and
sc strychnine anticonvulsant tests, the kindled rat test
and seizure threshold following iv infusion of metrazole.
The biochemical tests performed included in vitro GABA
receptor binding, adenosine uptake, and Ca2+ influx into
cerebellar granule cells induced by elevated K+ or by
veratridine.
a
Reagents and conditions: (a) pyrrolidine; (b) 4-ClPhCOCo,
AlCl3; (c) R4NHR5.
prepared by PPA isomerization of 4a . Compounds 11
and 12 were obtained by reduction of 4a with DIBAL.
Compound 13 was prepared analogously to Scheme 1,
starting with ethyl 1-methylpyrrole-2-carboxylate in-
stead of a 2-aroylpyrrole. Reaction of 3a with sodium
formylformamide afforded the N,N-diformyl compound.
Hydrolysis of the N,N-diformyl compound gave 4jj.
Compound 4ii arose via nucleophilic aromatic substitu-
tion of chlorine by pyrrolidine. Compound 13 was
prepared analogously to compounds of type 4 using ethyl
1-methylpyrrole-2-carboxylate as the starting material.
The physical properties of the intermediates and final
products are summarized in Tables 1 and 2.
Resu lts a n d Discu ssion
Biologica l Activity. The pharmacological evalua-
tion of the compounds was carried out under the
Antiepileptic Drug Development (ADD) Program, Epi-
lepsy Branch of the NINDS. The methods employed
Compound 4d , RWJ 37868, was chosen as the com-
pound for more intensive scrutiny. Compound 4d
blocked seizures induced by bicuculline [ED50 (mg/kg,
Ta ble 1. Physical Data for Chloro Ketones
no.
n
R1
R2
R3
Ar
MP, °C
recrysta solv
formula
yield, %
3a
3b
3c
3d
3e
3f
3g
3h
3i
1
1
1
1
1
1
1
1
3
4
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
H
CH3
H
H
H
H
H
CH3
H
CH3
H
CH3
H
H
H
H
H
CH3
H
CH3
p-ClPh
p-ClPh
o-ClPh
p-CH3OPh
p-NO2Ph
m-ClPh
p-ClPh
2,4-ClPh
p-ClPh
152-154
141-143
121-124
157-159
173-176
116-119
196-197
100-102
95-97
CHCl3
C14H11Cl2NO2
C16H15Cl2NO2
C14H11Cl2NO2
C15H14ClNO2
C14H11ClN2O4
C14H11Cl2NO2
83
31
91
90
60
67
91
88
39
79
EtOAc/MCH
EtOAc/MCH
EtOAc/MCH
EtOAc/EtOH
toluene
b
MCH
MCH
c
C13H9Cl2NO2
C16H14Cl3NO2
C16H15Cl2NO2
C19H21Cl2NO2
3j
p-ClPh
60-65
a
b
MCH is methylcyclohexane. Used without purification. c Purified by flash chromatography on silica gel with 5% acetone in hexane.

1580 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Ta ble 2. Structure-Activity Data for Aroyl(aminoacyl)pyrroles
Carson et al.
mouse ratb
classa class
recryst
solv
no.
4a
4b
4c
4d
4e
4f
n
R1 R2 R3
R4/R5
-(CH2)4-
R5
Ar
mp, °C
formulac
1 CH3
1 CH3
H
H
H
H
p-ClPh
p-ClPh
p-ClPh
p-ClPh
1
1
1
1
1
1
3
1
4
4
3
4
4
4
3
3
118-122
114-116
96-98
102-104
182-185
115-117
195-197
210-213
2-PrOH C18H19ClN2O2
2-PrOH C19H21ClN2O2
2-PrOH C21H23ClN2O3
2-PrOH C21H25ClN2O2
CH3CN C18H21ClN2O2‚HCl
EtOH C20H23ClN2O2
-(CH2)5-
1 CH3 CH3 CH3 -(CH2)2O(CH2)2-
1 CH3 CH3 CH3 -(CH2)5-
1 CH3
H
H
-CH2CH3
CH2CH3 p-ClPh
p-ClPh
1 CH3 CH3 CH3 -(CH2)4-
1 CH3 CH3 CH3 -CHsNCHsCH-
1 CH3 CH3 CH3 -CH2CH2(3,4-
CH3OPh)
4g
4h
p-ClPh
p-ClPh
EtOH C19H18ClN3O2
EtOH C26H29ClN2O4‚HCl
H
4i
4j
4k
4l
4m
1 CH3
1 CH3 CH3 CH3 Bn
1 CH3
1 CH3
1 CH3
H
H
-(CH2)2O(CH2)2-
p-ClPh
p-ClPh
p-ClPh
o-ClPh
p-ClPh
2
1
1
4
1
4
4
3
2
1
131-135
155-156
195-198
113-116
258-260
CH3CN C18H19ClN2O3
EtOH C24H25ClN2O2‚C2H2O2
CH3CN C20H23ClN2O2‚HCl‚0.25H20
EtOH C18H19ClN2O2‚HCl
MeOH C20H23ClN2O3‚HCl
CH3
H
H
H
H
H
H
-(CH2)6-
-(CH2)4-
-CH2CH(CH3)OCH-
(CH3)CH2-
adamantane
-CH(CH2OH)(CH2)3-
adamantane
-(CH2)7-
-CHdNCHdCH-
-(CH2)5-
-CH2CH2C[(CH2)5]-
CH2CH2-
-CH2CH2CH(Bn)-
CH2CH2-
-CH2CH2CH(p-FBz)-
CH2CH2-
-(CH2)2O(CH2) 2-
cyclohexyl
-(CH2)2O(CH2)2-
-(CH2)5-
-CH2C(CH3)2(CH2)3-
-(CH2)5-
-(CH2)4-
-(CH2)2O(CH2)2-
-(CH2)4-
-(CH2)2O(CH2)2-
H
4n
4o
4p
4q
4r
1 CH3
1 CH3
1 CH3
1 CH3
1 CH3
1 CH3
1 CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
o-ClPh
p-ClPh
p-ClPh
p-ClPh
p-CH3OPh
p-CH3OPh
o-ClPh
1
1
3
2
1
1
3
3
4
248(d)
87-88
273(d)
211-213
136-138
190-192
268-271
MeOH C24H27N2O2‚HCl‚0.25H2O
MeOH C19H21ClN2O3‚0.8C4H4O4‚0.66H2O
MeOH C24H27ClN2O2‚HCl
CH3CN C21H25ClN2O2‚HCl‚0.25H2O
1
4
d
C18H17N3O3
4s
4t
2-PrOH C20H24N2O3‚HCl
EtOH C24H29ClN2O2‚HCl‚0.3H2O
4u
4v
1 CH3
1 CH3
H
H
H
H
p-ClPh
3
3
226-227
135-137
MeOH C26H27ClN2O2‚HCl
p-CH3OPh
EtOH C27H27FN2O2
4w
4x
4y
4z
1 CH3
1 CH3
1 CH3
1 CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
p-ClPh
CH2CH3 p-ClPh
p-NO2Ph
1
4
125-127
171-176
141-143
225-227
105-107
190-193
243-245
198-200
CH3CN C18H19ClN2O3
EtOH C22H27ClN2O2‚C4H4O4
EtOH C18H19N3O5
EtOH C19H21N3O4‚HCl
CH3CN C21H25ClN2O2
CH3CN C19H21ClN2O2‚HCl
CH3CN C18H19ClN2O2‚HClO4
CH3CN C18H19ClN2O3‚HCl
4
4
p-NO2Ph
p-ClPh
m-ClPh
m-ClPh
m-ClPh
p-ClPh
p-ClPh
1
2
1
1
1
1
1
1
1
1
1
1
4
4
4
1
1
1
1
3
1
4
1
3
3
3
3
4a a 1 CH3
4bb 1 CH3
4cc 1 CH3
4d d 1 CH3
4ee 1 H
2
0
2
4
3
4
4
243-245(d) CH3CN C17H17ClN2O2‚HClO4
4ff
1 H
173-176
259-262
165-168
203-206
290(d)
176-178
177-179
165-168
119
CH3CN C17H17ClN2O3
MeOH C16H17ClN2O2‚HCl‚0.25H2O
2-PrOH C19H24N2O3‚HCl
CH3CN C24H31N3O2‚HCl‚O.4CH3CN
MeOH C14H13ClN2O2‚HCl
4gg 1 CH3
4h h 1 CH3
4ii
4jj
4k k 1 CH3 CH3 CH3 -CH2CH3
4ll 1 CH3 CH3 CH3 -(CH2)4-
4m m 1 CH3 CH3 CH3 -CH2CH3
4n n 1 CH3 CH3 CH3 -CH3
4oo 1 CH3
4p p 4 CH3 CH3 CH3 -CH2CH3
4qq 1 CH3 CH3 CH3 -(CH2)5-
4r r
7
CH2CH3 p-ClPh
CH2CH3 p-CH3OPh
p-pyrrol-Ph
p-ClPh
CH2CH3 p-ClPh
2,4-diClPh
CH2CH3 2,4-diClPh
2,4-diClPh
p-ClPh
CH2CH3 p-ClPh
p-ClPh
-CH2CH3
3 CH3
1 CH3
-(CH2)4-
H
H
4
4
4
3
4
3
2
0
1
1
2
3
2
EtOH C20H25ClN2O2‚1.5C4H4O4‚0.1EtOH
2-PrOH C20H22Cl2N2O2‚HCl‚0.4H2O‚0.4(2-PrOH)
EtOH C20H24Cl2N2O2‚C4H4O4
CH3
EtOH C18H20Cl2N2O2‚HCl‚0.75H2O
H
H
-C(CH3)dNCHdCH-
218-219
71-73
d
C18H16ClN3O2
MeOH C23H31ClN2O2
MeOH C24H31ClN2O2‚C4H4O4
EtOH C19H21ClN2O2‚C4H4O4
2-PrOH C11H16N2O‚C4H4O4
2-PrOH C19H21ClN2O2
EtOH C18H19ClN2O2‚HCl
MeOH C18H19ClN2O3‚HCl
CH3CN C18H19ClN2O2
CH3CN C18H23ClN2O2
CH3CN C18H21ClN2O2
C14H20N3O3‚HCl
177-178
169-171
126-129
129-130
265-267
264-267
105-108
122-124
131-134
198-201
1 CH3
H
H
-(CH2)5-
o-ClPh
9a
9b
9c
1 CH3
1 CH3
1 CH3
H
H
H
H
H
H
-(CH2)5-
-(CH2)4-
-(CH2)2O(CH2)2-
p-ClPh
p-ClPh
p-ClPh
10
11
12
13
a
Mouse classifications: ip active at <100 mg/kg (class 1), active at >100 mg/kg (class 2), inactive (class 3), and toxic or active but toxic
b
(class 4). The rat classifications are as follows: po 4/4 animals active, class 4; 3/4 animals active, class 3; 2/4 animals active, class 2; 1/4
animals active, class 1. Purified by flash chromotography on silical gel 10:1 CH2Cl2/MeOH.
d
ip) 25.2 (8.84-61.1)]. Phenytoin and carbamazepine are
inactive in this test while sodium valproate is active.
Compound 4d did not block seizures induced by picro-
toxin or strychnine and was inactive in the kindled rat
procedure. Compound 4d showed no significant effect
on seizure threshold following iv infusion in mice. In
this test, phenytoin lowers seizure threshold, carbam-
azepine has no effect, and sodium valproate raises
minimal seizure threshold. These findings suggest that,
in contrast to phenytoin, compound 4d lacks procon-
vulsant activity. Compound 4d had potent, long-lasting
local anesthetic activity when injected into the mouse
hind limb. Compound 4d , at a concentration of 100 mM,
blocked influx of Ca2+ into cerebellar granule cells
induced by elevated K+ or by veratridine. Unpublished
results from the ADD laboratories have demonstrated
that flunarizine shows activity in this test. Compound
4d was not active in inhibiting in vitro GABA receptor
binding or adenosine uptake.
SAR. Starting with the basic structure 4, modifica-
tions were carried out to try to define the nature of the
pharmacophore. Both acyl functions seem to be neces-
sary for activity. Compound 7, which lacks an aroyl
group was inactive. Compounds 11 and 12 where one
or both of the carbonyl groups were reduced were also
inactive. Compound 13 where the aroyl group was
replaced by a carboxylic ester was inactive. Activity was
found in isomers 4 and 9 which, depending on the
rotational preferences of the carbonyl groups, can be

New Class of Anticonvulsant Agents
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1581
Ta ble 3. Quantitative Studies
a,e
no.
mouse MESa,e ED50
mouse toxb,e
mouse TIc
rat MES ED50
rat toxd,e
>500f
341.7 (274-401)
>500f
>500f
4a
4b
4c
4d
4e
4f
4k
4n
4cc
4d d
4ff
4h h
4k k
4ll
4m m
9a
49.1 (36.9-70)
24.4 (20.1-30.1)
87.6 (47.3-161)
23.9 (17.3-30.7)
14.4 (13.0-16.8)
15.2 (11.2-20.7)
27.5 (22.1-35.1)
159. (119-236)
16.5 (14.4-18.6)
37.4 (35.4-40.1)
86.2 (70.8-105)
33.0 (28.0-38.0)
10.3 (8.6-12.4)
10.3 (8.5-12.5)
14.9 (11.6-17.8)
59.71 (54.21-67.72)
6.48 (5.7-7.2)
240.40 (197.62-271.36)
74.2 (52.8-94.4)
233.4 (147.6-372.8)
113 (75.3-146)
40.5 (32.8-47.1)
54.8 (32.9-81.4)
46.1 (39.3-55.3)
4.89
3.05
2.66
4.73
2.81
3.60
1.67
>1.57
3.38
2.96
0.98
1.37
3.65
2.30
3.38
2.36
6.6
17.9 (13.7-24.4)
8.40 (5.64-12.1)
28.1 (16.7-41.3)
19.3 (31.0-41.8)
16.2 (10.3-23.2)
22.0 (11.8-38.3)
202.7 (131-270)
>500f
>250
55.6 (38.3-74.6)
110 (96.3-124)
72.0 (53.1-98.5)
41.0 (31.6-58.9)
>500f
84.1 (76.6-89.5)
45.1 (39.4-51.7)
37.7 (35.2-41.5)
23.79 (16.94-30.08)
50.6 (45.9-56.3)
141.00 (117.8-161.1)
42.8 (36.4-47.5)
47.8 (39.2-59.2)
483 (412-571)
88.0 (70-110)
15.5 (10.7-20.85)
19.0 (15.8-233.94)
19.4 (13.3-27.6)
>250f
>200f
>500f
phenytoinh
23.2 (21.4-25.4)
36 (24.1-47.2)
395 (332-441)
>500f
carbamazepineg
Na valproateg
9.9 (8.8-10.7)
287 (237-359)
4.93
1.7
859 (714-1148)
a
b
d
Maximal electroshock seizures ED50 (mg/kg) ip. TD50 (mg/kg) ip as measured by rotating rod test. c TD50/ED50
.
TD50 (mg/kg) ip as
measured by overt evidence of ataxia. e 95% confidence limits in parentheses. f Not toxic in a single two animal determination up to the
indicated dose. Values of the reference compounds were measured as part of the current study.
g
F igu r e 2.
than the corresponding 4-methoxy compound 4h h .
Compounds with an o-chloro group (4r r , 4ll, and 4m m )
had good potency.
F igu r e 1. Structural comparison of 4d and 14; carbonyl O,
amine N, and ring centers in superposition orientation.
Among substances reported in the literature to pos-
sess anticonvulsant activity, a class that could have
structural similarity to the aroyl(aminoacyl)pyrroles is
the series of N-aryl and N-benzyl enaminones described
by Scott and co-workers, typified by 14.13 Extensive
charge delocalization involving the nitrogen atom and
the carbonyl oxygen occurs in both acyl pyrroles19 and
enaminones.20 To evaluate these charge effects well,
structures 4d and 14 were modeled and minimized with
the SPARTAN program21 using the AM1 model with
geometry optimization. Superposition of the phenyl ring
centers, the nitrogen atoms, and the carbonyl groups
shows a congruent spatial relationship of like features
(Figure 1).
isosteric. Isomer 10, which is not isosteric with 4 and
9, showed only toxicity.
Some substituent effects at the amino group could be
seen. Primary (4jj), secondary (4gg), and tertiary
amines are all active. Compounds with very bulky
groups on nitrogen (e.g. 4t, 4u , and 4v) were inactive.
The N-cyclohexyl compound 4x showed toxicity. The
N-adamantyl compounds (4n and 4p ) were weakly
active or inactive. Optimal activity seemed to reside
in the compounds with moderate sized groups on
nitrogen. N,N-Diethylamino, pyrrolidino, and piperi-
dino groups all showed good activity and were somewhat
more active than the morpholino compounds (4c vs 4d ).
Chain lengths of one, three, and four carbon atoms
between the carbonyl group and the amino group were
tolerated without losing activity (4ii, 4p p ).
The aroyl(aminoacyl)pyrroles and flunarizine are both
anticonvulsants which possess a basic tail, and both are
able to block calcium reuptake.
Con clu sion s
Substituent effects on the aromatic rings are more
difficult to assess. The pyrroles bearing the 1,2,4-
trimethyl substitution pattern, in general, showed good
activity. In certain instances they were more potent
than the analogous 1-methyl compound (4f vs 4a ).
Compounds lacking methyl substitution on nitrogen
were active. Only minor changes in activity resulted
from varying the substitution pattern on the aroylphen-
yl group. The 4-chloro compound 4e was more potent
In summary, the 2-aroyl-4-(ω-aminoacyl)- (4) and
4-aroyl-2-(ω-aminoacyl)pyrroles (9) represent a new,
structurally novel class of anticonvulsant agents. Since
they are active in the in the MES but not the sc MET
assay, they would seem to fall within the phenytoin-
carbamazepine class. The prototype compound, 4d ,
lacked proconvulsant activity and showed activity in the
veratridine induced calcium entry assay.

1582 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Carson et al.
Sch em e 3a
and brine, and dried (MgSO4). The solvent was evaporated
in vacuo and the residue recrystallized from EtOH to give 3.68
g (26.5%) of product: mp 66-68 °C; mass spectrum CI-MS m/ z
1
216 (M+ + H); H NMR (CDCl3) δ 7.85 (d, 2H), 6.9-7.1 (d, s,
3H), 6.7 (d, 1H), 6.15 (d, 1H), 4.1 (s, 3H), 3.9 (s, 3H). Anal.
(C13H13NO3) C, H, N.
2-Ch lor o-1-[5-(4-ch lor oben zoyl)-1,2,4-tr im eth yl-1H-pyr -
r ol-3-yl]eth a n on e (3b). A 60 g (0.24 mol) sample of 2-(4-
chlorobenzoyl)-1,3,5-trimethyl-1H-pyrrole in 460 mL of 1,2-
dichloroethane was cooled in an ice bath. A sample of 79 g
(0.60 mol) of AlCl3 was added in portions. After the addition
was complete, stirring was continued for 30 min. A sample of
47.5 mL (0.60 mol) of chloroacetyl chloride was added drop-
wise. The reaction was stirred at room temperature for 72 h
and then poured into 3 N HCl and ice. The organic layer was
washed with water, 1 N NaOH, water, and brine and dried
(MgSO4). The solvent was evaporated in vacuo to give a solid.
Recrystallization from EtOAc/methylcyclohexane gave 60.5 g
1
(77%) of 3b: mp 141-143 °C; H NMR (CDCl3) δ 2.0 (s, 3H),
2.6 (s, 3H), 3.7 (s, 3H), 4.4 (s, 2H), 7.25 (s, 1H), 7.5 (d, 2H), 7.8
(d, 2H); CI-MS m/ z 324 (M+ + H). Anal. (C16H15Cl2NO2) C,
H, N.
a
1-[5-(4-Ch lor oben zoyl)-1,2,4-tr im eth yl-1H-p yr r ol-3-yl]-
2-(1-p ip er id in yl)eth a n on e (4d ). A 40 g (0.12 mol) sample
of 3b in 160 mL of ethanol was brought to reflux. A 42 mL
(0.36 mol) sample of piperidine was added, and refluxing was
continued for 45 min. The solvent was evaporated in vacuo,
and the residue was taken up in Et2O/THF mixture, washed
twice with water and brine, and dried (Na2SO4). Evaporation
of the solvent and recrystallization twice from 2-PrOH gave
Reagents: (a) PPA; (b) DIBAL.
Structure-activity requirements were examined. Iso-
mers of types 4 and 9 were active, but the isomer of
type 10 was not. Both the aroyl function and the
aminoacyl function were required for activity. Diverse
substituents were tolerated on the aryl ring of the aroyl
function and the pyrrole ring. Compact substituents
were preferred on the amino group.
1
37.07 g (83%) of 4d : mp 102-104 °C; H NMR (CDCl3) δ 1.4
(m, 2H), 1.6 (m, 4H), 2.0 (s, 3H), 2.4 (m, 4H), 2.5 (s, 3H), 3.45
(s, 2H), 3.7 (s, 3H), 7.4 (d, 2H), 7.75 (d, 2H); CI-MS m/ z 373
(M+ + H). Anal. (C21H25ClN2O2) C, H, N.
Exp er im en ta l Section
1-[5-(4-P yr r olid in -1-ylben zoyl)-1-m eth yl-1H-p yr r ol-3-
yl]-4-(p yr r olid in -1-yl)bu ta n on e (4ii). A 10 g (0.03 mol)
sample of 1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-4-
chlorobutanone was added to 18 mL (0.216 mol) of pyrrolidine
and refluxed for 4 h. The pyrrolidine solution was evaporated
in vacuo and the residue triturated with Et2O. The mixture
was filtered and the filtrate treated with ethereal HCl to give
the salt. Recrystallization from CH3CN gave 1.18 g (9% yield)
of a yellow solid: mp 203-206 °C; 1H NMR (Me2SO-d6) δ 1.85-
2.05 (m, 10H), 2.87-3.05 (m, 4H), 3.1-3.15 (m, 2H), 3.3-3.4
(m, 4H), 3.45-3.55 (br s, 2H), 3.9 (s, 3H), 6.62 (d, 2H), 6.96 (s,
1H), 7.72 (d, 2H), 7.92 (s, 1H). Anal. (C24H31N3O2‚HCl‚
0.4CH3CN) C, H, N.
1-[4-(4-Ch lor oben zoyl)-1-m eth yl-1H-p yr r ol-2-yl]-2-a m i-
n oeth a n on e (4jj). A 10 g (0.034 mol) sample of 1-[5-(4-
chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-2-chloroethanone, 3.8
g (0.041 mol) of sodium diformylamide, and 80 mL of CH3CN
were refluxed overnight under argon. Sodium diformylamide
(2.0 g) was added, and reflux was continued for 1.5 h. After
evaporation of the solvent in vacuo, the residue was passed
through a flash column (silica gel, 3:1 hexane/acetone then 2:1
hexane/acetone) to give 6.18 g of solid 2-[bis(formyl)amino]-
1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]ethanone: mp
279-282 °C; CI-MS m/ z 333 (M+ + H). This sample (0.0186
mol) was stirred 3 days in 5% HCl/EtOH. Concentrated HCl
(0.5 mL) was added, and the reaction mixture was stirred for
an additional 2 days. The solid was collected. Et2O was added
and a second crop taken. It was washed with hot MeOH: mp
290 °C dec; CI-MS m/ z 277 (M+ + H). 1HNMR (Me2SO-d6) δ
8.2 (br s, 4H), 7.85 (d, 2H), 7.6 (d, 2H), 7.2 (s, 1H), 4.3 (s, 2H),
4.0 (s, 3H). Anal. (C14H13ClN2O2) C, H, N.
Ch em istr y. Melting points were determined on a Thomas-
Hoover Unimelt and are uncorrected. 1H NMR spectra were
recorded on either a Bruker AC-300 (300 MHz), AM-360WB
(MHz), or AM-400 (400 MHz) spectrometer with (CH3)4Si as
the internal standard. Chemical ionization mass spectra (CI-
MS) were determined on a Finnegan 3300-6100 system with
methane as the reagent gas. Elemental analyses were carried
out by the Analytical Services group in Raritan, NJ . Where
elemental analyses are reported by the symbols of the ele-
ments, the results are within 0.4% of the calculated values.
The compounds of this paper have been described in prelimi-
nary form in
a
patent.22 Representative procedures are
presented here to illustrate each of the transformations shown
in in Schemes 1-3.
Biology. The maximal electroshock tests in mouse were
carried out by administration of a suspension of the test
compound at doses of 30, 100, and 300 mg/kg ip to one to four
mice. Separate tests were carried out, one with a 30 min
observation time and one with a 4 h observation time. The
maximal electroshock tests in rat were carried out by admin-
istration of a suspension of the test compound at doses 50 mg/
kg po to a group of four animals. Separate tests were carried
out with 0.25, 0.5, 1, 2, and 4 h observation times.
Molecu la r Mod elin g. Structures 4d and 14 were modeled
with the Spartan programs21 using the AM1 model with
geometry optimization. These conformations were transferred
to the SYBYL23 program where they were superimposed. The
phenyl ring centers, carbonyl oxygens, and nitrogens (pyrrole
to benzyl-N) were fit for minimum distances. The orientations
are shown, side by side, in Figure 1: RMS deviation ) 0.38
Å; volume 4d ) 320 Å3; volume 14 ) 254 Å3; common volume
) 168 Å3.
(4-Met h oxyp h en yl)(1-m et h yl-1H -p yr r ol-2-yl)m et h a -
n on e (2) (Ar ) 4-Meth oxyp h en yl, R1 ) CH3, R2, R3 ) H).
A solution of 5 g (0.060 mol) of N-methylpyrrole and 13.3 g
(0.078 mol) of 4-methoxybenzoyl chloride in 50 mL of dry
toluene was heated under reflux overnight with an argon
stream bubbling through the reaction mixture. After cooling,
40 mL of 20% 3-(dimethylamino)propylamine in H2O was
added and the mixture stirred for 45 min. Et2O added, the
organic solution was washed with 1 N HCl, NaHCO3, water,
2-[5-(4-Ch lor oben zoyl)-1,2,4-tr im eth yl-1H-p yr r ol-3-yl]-
1-(N,N-d ieth yla m in o)eth a n on e (4k k ). 1-[5-(4-Chloroben-
zoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-2-chloroethanone (5 g,
0.015 mol), 4.64 mL (0.045 mol) of diethylamine, and 50 mL
of toluene were heated for 5 h. After cooling, the organics were
washed with water and then extracted twice with 1 N HCl.
The acidic aqueous layer was washed with Et2O and then
made basic with NaHCO3. The aqueous layer was extracted
with Et2O, and the organics were washed with water and brine
and dried (MgSO4). The solvent was evaporated in vacuo and
the residue converted to the fumarate salt in 2-PrOH. The

New Class of Anticonvulsant Agents
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1583
resulting salt was recrystallized from 2-PrOH/EtOH to give
(d, 1H), 4.65 (q, 1H), 4.00 (s, 3H), 2.9-2.68 (m, 3H), 2.58-
2.48 (m, 3H), 1.8 (m, 4H). Anal. (C18H21ClN2O2) C, H, N.
1
the product: mp 176-178 °C; CI-MS m/ z 361 (M+ + H); H
NMR (Me2SO-d6) δ 7.7 (d, 2H), 7.6 (d, 2H), 6.6 (s, 1H), 3.8 (s,
2H), 3.4 (s, 3H), 2.7 (q, 4H), 2.5 (s, 3H), 1.95 (s, 3H), 1.0 (t,
6H). Anal. (C20H25ClN2O2‚0.66C4H4O4) C, H, N.
Eth yl 1-Meth yl-4-(1-p yr r olid yla cetyl)p yr r ole-2-ca r box-
yla te Hyd r och lor id e (13). A 30.6 g (0.2 mol) sample of ethyl
1-methylpyrrole-2-carboxylate in 100 mL of 1,2-dichloroethane
was stirred while cooling in an ice bath. A suspension of 80.0
g (0.6 mol) of AlCl3 and 68.0 g (0.6 mol) of chloroacetyl chloride
in 250 mL of 1,2-dichloroethane was added dropwise over 10
min. The reaction mixture was stirred at room temperature
for 1.5 h. The reaction mixture was poured into 3 N HCl/ice
and extracted twice with CHCl3. The organics were washed
twice with 10% NaOH and brine and dried (MgSO4). Evapo-
ration of the solvent in vacuo gave 44.8 g of a solid. Recrys-
tallization from EtOAc-hexane and then EtOAc gave 39.6 g
of ethyl 4-(chloroacetyl)-1-methyl-1H-pyrrole-2-carboxylate:
2-Ch lor o-1-[4-(4-ch lor oben zoyl)-1-m eth yl-1H-p yr r ol-2-
yl]eth a n on e (8). A 60 g sample of AlCl3 (0.45 mol) was added
in portions to an ice-cooled solution of 30 g (0.19 mol) of (1-
methyl-1H-pyrrol-2-yl)-2-chloroethanone24 in 180 mL of 1,2-
dichloroethane (DCE) under Ar. After 10 min of stirring, a
solution of 24 mL (0.19 mol) of p-chlorobenzoyl chloride in 110
mL of DCE was added dropwise. The mixture was stirred at
25 °C for 16 h. The reaction was poured into 1 N HCl/ice, and
the aqueous layer was extracted with CH2Cl2. The organics
were combined, washed with water, 1 N NaOH, water, and
brine, and dried (MgSO4). Evaporation of the solvent in vacuo
gave a solid which was recrystallized from EtOAc/methylcy-
clohexane to give 27.67 g (49.4%) of a solid: mp 130-132 °C;
1H NMR (CDCl3) δ 7.8 (m, 2H), 7.6-7.4 (m, 4H), 4.5 (s, 2H),
4.0 (s, 3H). Anal. (C14H11Cl2NO2) C, H, N.
1-[4-(4-Ch lor ob en zoyl)-1-m et h yl-1H -p yr r ol-2-yl]-2-(1-
p ip er id in yl)eth a n on e (9a ). 2-Chloro-1-[4-(4-chlorobenzoyl)-
1-methyl-1H-pyrrol-2-yl]ethanone (4 g, 0.013 mol), 4.08 mL
(0.039 mol) of piperidine, and 60 mL of 2-PrOH were refluxed
for 1 h. The solvent was evaporated in vacuo, and the residue
was taken up in Et2O/THF, washed with water and brine, and
dried (MgSO4). Evaporation of the solvent gave a tan solid
which was recrystallized from 2-PrOH to give 3.65 g (81.6%)
of product: mp 129-130 °C; CI-MS m/ z 345 (M+ + H); 1H
NMR (CDCl3) δ 7.8 (m, 2H), 7.6 (s, 1H), 7.45 (d, 2H), 7.35 (s,
1H), 4.0 (s, 3H), 3.6 (s, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.4 (m,
2H). Anal. (C19H21Cl2N2O2) C, H, N.
1-[4-(4-Ch lor ob en zoyl)-1-m et h yl-1H -p yr r ol-3-yl]-2-(1-
p yr r olid in yl)eth a n on e (10). 1-[5-(4-Chlorobenzoyl)-1-meth-
yl-1H-pyrrol-3-yl]-2-(1-pyrrolidinyl)ethanone (10 g, 0.03 mol)
was added to PPA (100 mL) and heated for 6 h at 95-97 °C
under argon. The reaction was basified to pH 8 with ice cold
3 N KOH and extracted with CH2Cl2. The organic layer was
dried (MgSO4) and evaporated to a solid. Recrystallized from
CH3CN to give 5.5 g (55%) of a tan solid: mp 105-108 °C;
CI-MS m/ z 331 (M++ H); 1H NMR (CDCl3) δ 7.85 (d, 2H),
7.42-7.3 (m, 3H), 6.8 (s, 1H), 3.7 (s, 3H), 3.47 (s, 2H), 2.35
(m, 4H), 1.5 (m, 4H). Anal. (C18H19ClN2O2) C, H, N.
1
mp 114-117 °C; CI-MS m/ z 344 (M+ + H); H NMR (CDCl3)
δ 7.49 (m, 1H), 7.34 (m, 1H), 4.43 (s, 2H), 4.32 (q, 2H), 3.97 (s,
3H), 1.37 (t, 3H). A 29.7 g (0.13 mol) sample of ethyl
4-(chloroacetyl)-1-methyl-1H-pyrrole-2-carboxylate was dis-
solved in 250 mL of benzene. A 18.4 g (0.26 mol) sample of
pyrrolidine was added, and the mixture was stirred for 15 min.
The reaction mixture was poured into 10% NaOH and ice and
extracted three times with 100 mL of benzene. The organics
were combined, washed with water and brine, and dried
(MgSO4). Evaporation of the solvent in vacuo gave a brown
oil which, upon crystallization, was recrystallized twice from
Et2O. Treatment with ethereal HCl gave 8.3 g (15.7%) of ethyl
1-methyl-4-(1-pyrrolidylacetyl)pyrrole-2-carboxylate hydro-
1
chloride as a white solid: mp 198-201 °C; H NMR (Me2SO-
d6) δ 8.0 (s,1H), 7.35 (s, 1H), 4.8 (s, 1H), 4.25 (q, 2H), 3.95 (s,
3H), 2.5 (m, 4H), 1.95 (m, 4H), 1.3 (t, 3H). Anal.
(C14H20N2O3‚HCl) C, H, N.
Ack n ow led gm en t. The authors would like to thank
the NINDS, Epilepsy Branch, and especially Dr. Harvey
Kupferberg, for the support and coordination of this
work. We would also like to thank Mr. William J ones
and Ms. Diane Gauthier for spectral support and Dr.
J effery Press for helpful discussions.
r-(4-Ch lor oph en yl)-1-m eth yl-r′-(1-pyr r olidin ylm eth yl)-
1H-p yr r ole-2,4-d im eth a n ol (11). To a solution of (10 g, 0.03
mol) 1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-2-(1-pyr-
rolidinyl)ethanone in CH2Cl2 (1 L) was added 40 mL of 1.5 M
DIBAL at -65 °C under argon and stirred for 2.5 h. Then an
additional 20 mL of 1.5 M DIBAL at -65 °C was added and
stirred an additional 1.25 h. MeOH was added, and the
organic layer was washed with 3 N NaOH. The CH2Cl2
solution was dried (MgSO4) and evaporated in vacuo to a solid
which was recrystallized from CH3CN to give 2.38 g (24%) of
a tan solid: mp 122.5-124.5 °C; CI-MS m/ z 335 (M+ + H;.
1H NMR (CDCl3) δ 7.32 (s, 4H), 6.62 (d, 2H), 5.8 (d, 2H), 4.6
(q, 1H), 3.55 (s, 3H), 2.88 (t, 1H), 2.78-2.68 (m, 2H), 2.55-
2.32 (m, 4H), 2.2 (s, 1H), 1.7 (m, 4H). Anal. (C18H23ClN2O2)
C, H, N.
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1
white solid: mp 131-134 °C; CI-MS m/ z 333 (M+ + H); H
NMR (CDCl3) δ 7.75 (d, 2H), 7.42 (d, 2H), 6.88 (d, 1H), 6.64

1584 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
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