Synthesis and anticonvulsant activity of a new class of 2- [(arylalkyl)amino]alkanamide derivatives

Article abstract of DOI:10.1021/jm970599m

Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

Full text of DOI:10.1021/jm970599m

579
J . Med. Chem. 1998, 41, 579-590
Syn th esis a n d An ticon vu lsa n t Activity of a New Cla ss of
2-[(Ar yla lk yl)a m in o]a lk a n a m id e Der iva tives
Paolo Pevarello,*,† Alberto Bonsignori,‡ Philippe Dostert,∇ Franco Heidempergher,† Vittorio Pinciroli,§
Maristella Colombo,§ Robert A. McArthur,‡ Patricia Salvati,‡ Claes Post,‡ Ruggero G. Fariello, and
Mario Varasi†
Department of Chemistry, CNS Preclinical Research, Structural and Predevelopment Analysis Department,
and Pharmacokinetics & Metabolism, Pharmacia & Upjohn SpA, Viale Pasteur, 10, I-20014 Nerviano (MI), Italy,
and Department of Neurology, Thomas J efferson University, Philadelphia, Pennsylvania 19107
Received September 9, 1997
Although most epilepsies are adequately treated by conventional antiepileptic therapy, there
remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from
milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we
discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here
we report the structure-activity relationship (SAR) study within this series of compounds.
Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were
thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this
study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-
151774E) emerged as a promising candidate for further development for its potent anticon-
vulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.
In tr od u ction
1960s; and valproic acid (VPA), available in several
European countries as of the late 1960s.2 The total
market of anticonvulsants in 1992 was 1065 million
USD; projections for the year 2000 are of about 2 billion
USD.
Epilepsy collectively describes a wide variety of
disorders more properly referred to as the human
epilepsies. Despite their different nature and causes,
they are all characterized by the common feature of
recurrent seizure attacks. Seizures are due to the
abrupt, paroxysmal discharge of a large population of
neurons firing synchronously and are divided into two
major categories depending on whether the initial
discharge arises within a system of neurons localized
in a discrete area of the cerebral gray matter (partial
or focal seizures) or diffusely in both hemispheres
(generalized seizures). Generalized seizures may be
convulsive (tonic myoclonic, tonic clonic, depending on
the characteristics of the muscle contraction) or non-
convulsive, as in the case of the so-called pure petit mal
where the paroxysmal discharge can be accompanied
only by suspension of consciousness without motor
phenomena. It is estimated that in developed countries
0.5-1% of the population suffers from epilepsy, the
highest incidence being found in children and the
elderly.1
With the available AEDs on the market, about 70%
of people with epilepsy achieve satisfactory seizure
control. Better responses are obtained in certain types
of seizures (typical absence), whereas poor responses are
frequently seen in patients with mixed seizure types,
atonic seizures, and Lennox-Gastaut syndrome. Still
about 30% (600 000 people in the United States) do not
respond to the available AEDs administered either in
monotherapy or in combination. The need for newer
anticonvulsants is not restricted to those unresponsive
patients: particularly, dose-related adverse effects, ter-
atogenicity, idiosyncratic reactions, and drug-drug
interactions are important limiting factors preventing
the achievement of the full therapeutic potential for all
major AEDs.
In the past decade, there has been an increase in the
availability of AEDs for clinical evaluation.3 As a result,
since 1989, six new AEDs have been licensed in Europe
(vigabatrin, lamotrigine, gabapentin, oxcarbazepine,
felbamate, and piracetam), three in the United States
(felbamate, gabapentin, and lamotrigine), and one in
J apan (zonisamide). Although none of the new drugs
have been yet shown to have greater efficacy than
currently used products in monotherapy, they are
perceived as being better tolerated.4
Epilepsy is not an orphan disease. Actually epilepsy
has been the first neurological condition for which an
effective treatment, bromide salts, became available as
early as 1857. A significant number of effective anti-
epileptic drugs (AEDs) are now on the market. Classical
AEDs comprise phenobarbital (PB), available since
1911; phenytoin (PHT), marketed in 1939; carbam-
azepine (CBZ), used for epilepsy in Europe from the mid-
Milacemide (1, 2-(n-pentylamino)acetamide; Chart 1)
had been reported to be an antagonist of iv-bicuculline
(iv-BIC)-induced seizures with a novel mechanism of
action, being less effective or inactive in inhibiting other
chemically or physically induced seizures in animal
models of epilepsy.5 Due to marginal effects seen in
* To whom correspondence should be addressed. Phone: ++39-2-
4838-3481. Fax: ++39-2-4838-3937. E-mail: paolo.pevarello@
eu.pnu.com.
† Department of Chemistry.
‡ CNS Preclinical Research.
§ Structural and Predevelopment Analysis Department.
∇ Pharmacokinetics & Metabolism.
Thomas J efferson University.
S0022-2623(97)00599-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/28/1998

580 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Pevarello et al.
Ch a r t 1
Standard methods were used to alkylate the precursors
of compounds 13, 14, and 18, while the reductive
amination protocol was followed for the synthesis of
compounds 38 and 39.
Physical properties of the compounds are reported in
Tables 1-3 and in the Experimental Section. Prepara-
tions of compounds 35, 44, 48, 50, and 70 and their
precursors have been already described.10 Previously
unreported aldehydes were synthesized by methods in
analogy to those reported in the literature.11
Biology
Compounds were tested and selected for more exten-
sive pharmacological evaluation on the basis of a widely
accepted screening funnel for new anticonvulsants.12
Considering that the anticonvulsant activity of 1 was
originally described using the iv-BIC test in mice,6 this
test was selected for preliminary screening. Observa-
tion of gross behavioral toxicity signs such as loss of
righting reflex, impaired gait, impaired breathing, and
hypotonia was also considered as criteria for select-
ing compounds to be submitted for further anticon-
vulsant evaluation using the maximal electroshock
test (MES) and for a quantitative determination of
toxicity using motor impairment as measured by the
rotorod test (RT) (see Tables 4 and 5). A restricted
number of products were evaluated in other chemi-
cally induced seizures (Table 6). These tests are con-
sidered to predict the clinical efficacy of new compounds
against the most common types of seizures in epileptic
patients.
Sch em e 1
clinical trials, development of the compound was no
longer pursued.
Our aims were to verify the mechanism(s) of action
of milacemide and to identify compounds more potent
and with a wider range of anticonvulsant spectrum than
milacemide. Following the suggestion that anticonvul-
sant activity of milacemide could be related to its MAO-
B-mediated degradation,6,7 we first designed a set of
molecules involving retention of the acetamide portion
but replacement of the pentylamino moiety with resi-
dues present in the structures of substrates and inhibi-
tors of the MAO (Chart 1).8 None of the tested mol-
ecules were shown to be substrates for MAOs, but some
of them were found to be inhibitors of both forms of
MAO, mainly the B form. No relationship between the
anticonvulsant activity and inhibition of MAO could be
established. Furthermore R-methylmilacemide (2; Chart
1), which is not oxidized by either MAO-A or MAO-B,
was equipotent to milacemide in the iv-BIC test.9
Nevertheless the significant increase in anticonvulsant
activity observed with the first derivatives of milacemide
led us to explore the 2-substituted amino amide class
and allowed us access to a new series of potent anti-
convulsant compounds.
Resu lts a n d Discu ssion
A first group of molecules (3-6; Chart 1) was designed
to evaluate the role played by the N-pentyl chain of
milacemide in determining its, albeit weak, anticonvul-
sant activity (Table 4).8 The N-(phenylethyl)glycina-
mide (3) emerged as a more effective agent, while the
N-benzyl derivative (4) was endowed with weaker
activity. When a 4-(3-chlorobenzoxy) group was placed
into 3 and 4, a reversal in anticonvulsant potency was
observed. Compound 6, being the most active in the
BIC and confirming its efficacy in the MES test (Table
4), was then chosen as a lead for developing a new class
of anticonvulsants. Several structural parts of 6 might
be envisaged as critical determinants for activity (Figure
1). As a first issue we decided to evaluate the impor-
tance of the amide function versus activity (A, Figure
1). A set of compounds (6-12) was therefore synthe-
sized (Table 1) and tested (Table 4). Anticonvulsant
activity was found to reside in the amides: in particular,
beside the unsubstituted (6), the monomethylamide (7)
was also effective, and since this feature was always
confirmed throughout the whole series, primary and
secondary amides were considered interchangeable for
further structure-activity relationship (SAR) studies.
Similarly, the presence of a 3-chloro substituent on the
remote aromatic ring was shown to be optional for
activity throughout the whole series, as exemplified by
comparison of 6 with 9. The tertiary amide (8) was also
active but showed clear signs of gross behavioral toxicity
at lower doses. The amino acid derivative (10) and the
ethyl (11) and benzyl (12) esters displayed only weak
activity in the iv-BIC test.
Ch em istr y
The synthesis of most of the compounds (7, 9-12, 15-
16, 19-37, 40-75) (Tables 1 and 2) was accomplished
by reductive alkylation of the appropriate R-amino
amide derivative with the corresponding aldehyde using
a previously described protocol (Scheme 1).10 The
reductive amination of a variety of aldehydes (particu-
larly substituted benzaldehydes) with different R-amino
acid derivatives is of broad scope and occurs with
moderate to good yields using sodium cyanoborohydride
in methanol as a reducing agent. Scheme 2 reports the
syntheses of compounds 8, 13, 14, 17, 18, 38, and 39.

New Class of 2-[(Arylalkyl)amino]alkanamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 581
Sch em e 2
Ta ble 1. Structural and Physical Data for Compounds 7, 9-12, 15, 16, and 19-37 (Scheme 1)
a
entry
R
X
m
n
R1
R2
conf
mp (°C)
[R]D
7
9
3-Cl-C6H4-
C6H5-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
1
1
1
1
1
2
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
H
H
H
H
H
H
H
NHCH3
NH2
OH
OEt
OBn
NH2
NH2
NH2
NH2
NHCH3
NHCH3
NHCH3
NH2
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NH2
224-225
250 dec
150 dec
10
11
12
15
16
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
3-Cl-C6H4-
3-Cl-C6H4-
3-Cl-C6H4-
3-Cl-C6H4-
3-Cl-C6H4-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
118-121.5
161.5-164
192-195
219-222
229-232
228-231
188-191
134-137
102-104
128-130
100-103
224-227
223-227
150-152
150-153
160-163
161-164
141-144
141-144
187.5-191
ref 10
CH3
CH3
CH3
CH3
CH2OH
CH2OH
CH2OH
CH2Ph
CH2Ph
CH2CH2SCH3
CH2CH2SCH3
CH(CH3)2
CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2(OH)CH3
CH2(OH)CH3
CH2CH3
S
R
S
R
S
S
R
S
R
S
R
S
R
S
R
+13.3
-13.0
-4.9b
-13.0
+13.7
+16.5
-12.9
+40.3
-39.9
+27.0
-27.5
+21.3
-21.2
+17.7
-16.9
-11.4
ref 10
+19.1
+18.4
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
2R,3S
2S,3R
S
197-199
198-200
CH2CH3
NH2
R
a
b
See Experimental Section. c ) 0.5, HCl-EtOH, 1:1.
The importance of the relative position of the amino
and amido groups with respect to the central aromatic
ring and the type of spacer used (B and C, Figure 1)
were also explored, but no active compounds were
identified (compounds 13-17). A preserved amino
function was also found to be mandatory for robust
activity since its replacement with oxygen (16) or its
transformation into an amidic nitrogen (17) gave far
less-active compounds. When the amino group was
tertiarized by introducing a methyl group (18), some

582 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Pevarello et al.
Ta ble 2. Structural and Physical Data for Compounds 40-75 (Scheme 1)
a
entry
R
X
m
n
R1
R2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
conf
mp (°C)
>250
211-213
180-183
229-231
ref 10
[R]D
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
bond
-O-
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
+20.3
+15.1
+12.0
+14.0
ref 10
+8.4
-CH2-
-CH2CH2-
-CH2S-
-CH2NH-
-OCH2-
-(CH2)2O-
-CH2N(CH3)
-NHCH2-
-(CH2)3O-
-CONH-
-CHdCH-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
-CH2O-
173 dec
214-217
179-181
ref 10
134-137
ref 10
200 dec
>250
134-136
132-134
214-216.5
238-239
210 dec
+12.6
+11.1
ref 10
+1.8b
ref 10
+17.3
+25.4
+12.4
-12.1
+13.2
+12.2
+12.9
+11.9
+12.3
+12.6
+12.7
+13.2
+11.5
+11.1
+11.4
+11.4
+19.4
+21.4
+21.5
ref 10
+12.8
+18.6
+18.6
+20.7
+12.7
C6H5-
2-Cl-C6H4-
2-Cl-C6H4-
4-F-C6H4-
2-F-C6H4-
3-F-C6H4-
3-MeO-
3-NO2-C6H4-
3-CN-C6H4-
4-Cl-C6H4-
3-CH3-C6H4-
3-CF3-C6H4-
2-CF3-C6H4-
2-F-C6H4-
3-F-C6H4-
2-pyridyl-
3-pyridyl-
4-pyridyl-
2-thienyl-
3-thienyl-
2-furyl-
NH2
NH2
NH2
CH3
CH3
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NHCH3
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
85-87
171-173
132-134
139-141
183-185
115-117
120.5-124
129-131
135-138
154-157
165-168
182-185
ref 10
192-195
206-208
195-196
114-116
224-226
3-furyl-
cyclopropyl-
cyclohexyl-
a
b
See Experimental Section. c ) 0.5, EtOH.
Ta ble 3. Physical Data for Compounds 13, 14, 17, 18, 38, and
39 (Scheme 2)
signs of gross behavioral toxicity at doses lower than
those of the S-enantiomers. Only when the bulkier
phenylalanine residue was introduced (26 vs 27) did the
R-enantiomer (27) display some activity, the S-enanti-
omer (26) being inactive.
a
entry
salt
subst
conf
mp (°C)
[R]D
8
13
14
17
18
38
39
123-125
204-207
123-124.5
197-198
111.5-113.5
179-181
135-137
HCl
HCl
Thus, the first part of our SAR analysis on the
benzylamino amide moiety of 6 provided the alanine and
the serine derivatives 19 and 23 as further lead com-
pounds. These compounds were then used to assess the
influence of changes in the benzoxybenzyl part of the
structure. Further changes were devised, aimed at
defining the effect of the relative position of the benzy-
loxy and the amino amide functions (Figure 1, D), the
role of a different spacer (E) between the aromatic rings,
and the substitution pattern of the remote aromatic ring
or its replacement with a heteroaromatic moiety (F).
Modification of the relative position of the methylamino
and benzyloxy moieties (Figure 1, D) from para to meta
and ortho resulted in a clear decrease in anticonvulsant
activity (19 vs 38 and 39). The effect on activity by
placing different spacers between the aromatic rings (E,
Figure 1) was modulated by the length of the bridge as
well by the presence of heteroatoms in the spacer. The
biphenyl derivative (40) was much less active. Notably,
the (E)-styryl derivative (52) proved inefficacious as did
the benzamido derivative (51). Several variations in
the interaromatic chain yielded active compounds (41-
50). The most active compounds beside the benzyloxy
derivative (19) were the benzylamino (45) and 3-phe-
nylpropoxy (50) derivatives.
HCl
CH3SO3H
CH3SO3H
3-
2-
S
S
+12.6
+17.7
a
See Experimental Section.
activity was still retained but signs of motor impairment
were observed at doses lower than those for the second-
ary amine derivative (6).
At this stage we felt that variation in the “amino
acidic” part of the molecule (B, Figure 1) could give us
the most relevant information. Replacement with dif-
ferent R-amino amide derivatives for the glycinamide
part of 6 enabled us with several potent anticonvulsants
(19-36, Table 1). The alanine (19-22) and serine (23-
25) derivatives were both potent and boasted high
therapeutic indexes (TIs) when compared with classical
and new-generation anticonvulsants. The result of this
part of the SAR indicated that a wide range of stereo-
electronic features was tolerated as far as R-substitution
on the amino amide center was regarded. Noteworthly,
there was no stereoselectivity in the anticonvulsive
effect since several couples of (R)- and (S)-amino amide
residues were tested and found to be roughly equally
active. In general, however, R-enantiomers showed

New Class of 2-[(Arylalkyl)amino]alkanamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 583
Ta ble 4. Pharmacological Data in Mice for Compounds 1-39
Ta ble 5. Pharmacological Data in Mice for Compounds 40-75
neurological
neurological
anticonvulsant potency ED50
(mg/kg)
impairment
TD50 (mg/kg)
anticonvulsant potency ED50
(mg/kg)
impairment TD50
(mg/kg)
entry
iv-BIC
MES
rotorod
entry
iv-BIC
MES
rotorod
1
2
3
4
5
6
7
8
9
701 (270-1817)
640 (312-1313)
286 (209-392)
490 (105-2273)
192 (148-249)
107 (40.1-284)
30.5 (14.7-63.3)
54.2 (35.5-82.8)a
68.6 (49.6-94.7)
4/20@400 mg/kg
3/20@400 mg/kg
6/20@400 mg/kg
5/20@400 mg/kg
7/20@400 mg/kg
8/20@400 mg/kg
8/20@400 mg/kg
5/20@400 mg/kg
114 (44.6-294)
23.8 (16.2-35.1)
16.9 (12.5-22.8)a
40.5 (27.1-60.4)
8.4 (6.8-10.3)
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
231 (169-312)
64.0 (44.5-91.7)
15.7 (11.5-21.4)
40.3 (29.7-54.9)
24.8 (18.9-32.7)
9.3 (7.3-12.0)
41.5 (26.2-57.1)
22.5 (17.5-28.0)
17.8 (13.5-23.6)
8.6 (5.9-12.5)
11.5 (9.0-14.7)
10.6 (7.42-15.1)
12.2 (8.9-17.6)
6.5 (4.0-8.8)a
752 (404-1401)
630 (519-765)
633 (538-745)
217 (195-238)
597 (524-681)
1121 (909-1384)
28.5 (20.8-39.0)
48.6 (35.5-66.6)
40.3 (30.3-53.6)
24.9 (12.5-49.3)
39.6 (30.9-50.8)a
119 (91.2-155)
19.0 (11.6-31.0)
1/10@400 mg/kg
5/20@400 mg/kg
17.4 (12.3-24.7)
18.4 (12.8-26.4)a
132 (99.3-175)
25.8 (19.8-39.5)
26.9 (22.3-32.5)
109 (63.8-185)
7/20@400 mg/kg
11.5 (8.31-15.5)
473 (404-556)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
6.7 (5.2-8.8)
584 (410-831)
525 (410-673)
50.8 (35.9-71.7)
16.3 (7.2-37.1)
7.0 (5.3-9.1)
8.0 (7.0-9.1)
549 (406-741)
626 (557-703)
70 (49.2-294)
17.1 (10.2-28.7)
328 (254-424)
7.0 (3.5-9.5)
7.0 (6.1-8.1)
353 (304-411)
224 (166-303)
24.0 (10.1-91.9)b 15.2 (8.5-27.3)b
216 (120-387)
16.3 (12.5-21.2)a 22.8 (17.8-30.2)a
133 (100-177)
41.3 (31.7-53.8)
19.5 (15.6-24.4)
85.6 (71.2-103)
12.4 (10.1-15.4)
25.1 (6.0-39.5)
172 (145-204)
0/20@400 mg/kg
2/10@400 mg/kg
61.6 (46.7-81.2)
114 (73-185)
30.6 (10.7-87.5) 1247 (835-1836)
13.1 (8.8-19.5)
750 (646-1067)
15.0 (11.6-19.4)
2/20@400 mg/kg
61.2 (41.4-90.7)
0/20@400 mg/kg
239 (174-318)
112 (95.2-132)
55.4 (27.2-113)
192 (148-249)
5/20@100 mg/kg
21.0 (13.4-32.8)a
34.2 (20.3-57.4)a
55.0 (40.3-74.9)
119 (91.3-154)
79.7 (46.7-136)
210 (166-267)
9.9 (8.2-11.9)
167 (132-211)
19.8 (14.1-27.8)
13.0 (8.8-18.8)
371 (291-474)
915 (725-1378)
116 (73-185)
152 (122-190)
124 (103-149)
131 (91.5-187)
7.2 (3.0-10.8)
277 (215-358)
a
Compound at 200 mg/kg induced impaired gait, loss of the
b
righting reflex, and impaired breathing. Compound at 400 mg/
kg induced slight hypotonia.
a
Compound at 200 mg/kg induced impaired gait, loss of the
righting reflex, and impaired breathing.
liminarly, 57 has been shown to be a potent voltage-
and frequency-dependent neuronal sodium channel
blocker13 and glutamate release inhibitor.14 Repeated
treatment with 57 in mice increased the MES ED50 by
only 17.6%, and the acute and repeated treatment MES
ED50’s in these conditions overlap. These data suggest
lack of tolerance.15
Some of the compounds of the series were also
endowed with MAO-B reversible inhibitory activity (e.g.,
57).16 While this feature can be regarded as a plus due
to the recent association between MAO-B inhibition and
neuroprotection,17 no direct relationship between en-
zyme inhibition and anticonvulsant activity could be
drawn within this series. The value of 57 as a potential
new agent against resistant epilepsies is underscored
by its outstanding activity in a rat kindling model at
doses well below those causing toxicity.15 57 was also
found to be active in preventing neuronal cell loss and
protecting from status epilepticus (SE) evoked by sys-
temic administration of an excitotoxin kainic acid, a
rigid analogue of glutamate.15
Further structure-activity work was planned in order
to explore the effect of the substitution pattern (53-
66, Tables 2 and 5) and of replacement of the aromatic
moiety with a heteroaromatic moiety or a cycloalkyl ring
(67-75). By introducing different substituents in vari-
ous positions of the remote aromatic ring, it was shown
that 2- and 3-halo-substituted compounds were the most
active compounds. Replacement of the aromatic ring
with a heteroaromatic or cycloalkyl moiety did not bring
about any advantage in terms of potency.
As a final outcome of the SAR study of this class of
molecules, four compounds (45, 50, 57, and 66) were
chosen as further leads to be studied in more detail.
These compounds were evaluated in a battery of anti-
convulsant tests for assessing the broadness of their
anticonvulsant efficacy (Table 6). Comparison with
established and new-generation anticonvulsants fueled
the interest in this class of compounds for the very broad
spectrum of anticonvulsant activity as well as for the
outstanding TIs displayed.
After preliminary absorption-disposition-metabo-
lism-excretion (ADME) studies and toxicology, 57
emerged as the most promising compound for further
preclinical studies. Studies are ongoing to elucidate the
mechanism of action of this class of compounds: pre-
Con clu sion s
Starting from a weak anticonvulsant such as mila-
cemide (1) and trying to define its mechanism of action,
we found a novel class of potent, orally active, safe

584 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Pevarello et al.
Ta ble 6. Pharmacological Data for Selected Compounds versus Reference Standards (Mice, po)a
compd
MES
BIC
PTX
3-MPA
STRY
rotorod
45
50
57
66
11.5 (9.0-14.7)
[18.9]
6.7 (5.2-8.8)
[87.1]
8.0 (7.0-9.1)
[78.2]
13.0 (8.8-18.8) 25.1 (6.0-39.5)
[70.4] [36.4]
3.8 (2.3-6.1)
[17.0]
9.8 (8.2-11.7)
[10.8]
189 (169-212) 414 (360-478)
[6.2]
2.2 (1.3-3.8)
[38.2]
9.3 (7.3-12.0)
37.5 (28.8-48.8)
[5.8]
35.4 (24.9-50.1)
[16.5]
60.6 (39.6-92.6)
[10.3]
120 (78-204)
[7.6]
16.3 (10.8-24.4)
[13.3]
16.2 (6.2-42.0)
[36.0]
21.5 (16.8-27.5)
[29.1]
35.6 (27.8-45.5) >250
[25.7]
11.3 (4.6-27.9)
[21.5]
20.1 (15.5-25.7)
[5.3]
167 (126-222)
[7.0]
>40
[<2.1]
0.62 (0.42-0.92)
[11.0]
50.3 (30.1-66.0)
[4.3]
75.4 (55.2-103)
[7.7]
104.1 (67.5-160.7) 626 (557-703)
[6.0]
217 (195-238)
[23.3]
19.0 (11.6-31.0)
[30.7]
26.9 (22.3-32.5)
[23.3]
584 (410-831)
915 (725-1378)
243 (142-415)
106 (93-121)
1178 (1020-1360)
84 (75-95)
[<3.6]
>200
[<1.2]
43.8 (24.1-79.3)
[2.4]
538 (478-607)
[2.2]
>40
[<2.1]
0.58 (0.45-0.74)
[11.7]
phenytoin
42.1 (29.0-61.1) >100
[5.8]
6.7 (5.5-8.0)
[15.8]
[<2.4]
40.6 (32.6-50.6)
[2.6]
350 (276-443)
[3.4]
>40
[<2.1]
0.52 (0.41-0.66)
[13.1]
carbamazepine
valproate
[2.8]
10.2 (6.4-16.0)
[8.2]
0.29 (0.21-0.42)
[23.4]
lamotrigine
diazepam
1.2 (0.57-2.5)
[5.7]
6.8 (5.0-9.3)
a
Therapeutic index calculated by ED50(test)/TD50(rotorod), in brackets. MES, maximal electroshock test; BIC, bicuculline test; PTX,
picrotoxin test; 3-MPA, 3-mercaptopropionic acid test; STRY, strychnine test.
Meth od A (Sch em e 1): Gen er a l P r oced u r e for Red u c-
t ive Alk yla t ion of R-Am in o Acid Der iva t ives. To a
suspension of starting R-amino acid amide or ester hydrochlo-
ride (11 mmol) and powdered 3-Å molecular sieves (2.5 g) in
dry methanol (70 mL) kept under nitrogen was added NaBH3-
CN (8 mmol), and the mixture was stirred at room temperature
for 15 min. Then the appropriate aldehyde (10 mmol) was
added in a single portion. (CAUTION: sodium cyanide is
produced). The reaction mixture was allowed to reach 30-35
°C and then stirred at room temperature for 3 h. After
filtration, the solvent was evaporated to give a residue which
was flash-chromatographed using CH2Cl2-CH3OH-30% NH4-
OH (99:1:0.1 to 95:5:0.5 depending on the type of R-amino acid
derivative and aldehyde used) to give the N-alkylated com-
pound. The final products were tested as either the free base
or its hydrochloride or methanesulfonate salt. Following the
procedure above the following compounds were prepared (for
mp and [R]25D, see Tables 1-3).
2-[[4-(3-Ch lor oben zoxy)ben zyl]a m in o]-N-m eth yla ceta -
m id e, h yd r och lor id e (7): 42%; 1H NMR (200 MHz, DMSO-
d6) 2.62 (d, J ) 4.6 Hz, 3H, CONHCH3), 3.56 (s, 2H,
NHCH2CO), 4.06 (s, 2H, ArCH2NH), 5.14 (s, 2H, ArCH2O), 7.05
(m, 2H, H3, H5), 7.3-7.6 (m, 6H, H2, H6, H2′, H4′, H5′, H6′),
8.37 (q, J ) 4.6 Hz, 1H, CONHCH3), 9.3 (br s, 2H, NH2+); MS
m/z 318 (M•+), 260, 246, 231, 125 (100). Anal. (C17H19ClN2O2‚-
HCl) C, H, Cl, N.
F igu r e 1. Regions of compound 6 targeted for chemical
modifications.
anticonvulsants. Extensive SAR analysis allowed us to
choose from this class (S)-2-[[4-(3-fluorobenzoxy)benzyl]-
amino]propanamide methanesulfonate (57), a promising
candidate to further development. The detailed mech-
anism of action of this class of compounds is under
active investigation. Preliminary results point toward
a potent sodium channel-blocking activity.
Exp er im en ta l Section
Ch em istr y. Melting points were determined in open glass
capillaries, with a Buchi 535 melting point apparatus and are
uncorrected. Elemental analyses were performed on a Carlo
Erba 1106 instrument, and C, H, and N results were within
(0.4% of theoretical values (15 out of 64 compounds were
within (0.43-1.11% in the C result). 1H NMR spectra were
recorded on either a Varian VXR-200 or Bruker WP-80 SY
spectrometer, using the solvent as internal standard; chemical
shifts are expressed in ppm (δ). Electron impact (EI) mass
spectra (MS) were obtained on Varian MAT CH7 instrument.
Optical activity was measured with a J asco DIP 140 polarim-
eter, operating at 25 °C, and at λ ) 589 nm, using a 10-cm
cuvette; a concentration of 1.1% in 98% acetic acid was used
unless otherwise indicated (see Tables 1-3). Organic solu-
tions, where applicable, were dried over anhydrous Na2SO4
and evaporated using a Heidolph VV 2000 rotary evaporator
at 15-20 mmHg. Flash column chromatographic separations
were carried out on 40/60 µm silica gel (Carlo Erba). Thin-
layer chromatography was performed on Whatman silica gel
60 plates coated with 250-µm layer, with fluorescent indicator.
Components were visualized by UV light (λ ) 254 nm), by
iodine vapor, or by spraying with 2,4-dinitrophenylhydrazine
reagent. Amino acids were visualized using a ninhydrin spray
reagent. Dichloromethane was distilled from P2O5 and stored
over 4-Å molecular sieves. All experiments dealing with
moisture-sensitive compounds were conducted under dry
nitrogen. Starting materials, unless otherwise specified, were
commercially available (Aldrich, Fluka), of the best grade, and
used without further purification.
2-[(4-Ben zoxyben zyl)a m in o]a ceta m id e, h yd r och lor id e
1
(9): 38%; H NMR (80 MHz, DMSO-d6) 3.53 (s, 2H, NHCH2-
CO), 4.05 (s, 2H, ArCH2NH), 5.1 (s, 2H, ArCH2O), 7.03 (m,
2H, H3, H5), 7.2-7.6 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′),
7.8, 7.4 (2 br s, 2H, CONH2), 9.3 (br s, 2H, NH2+); MS m/z 270
(M•+), 226, 212, 197, 91 (100). Anal. (C16H18N2O2‚HCl) C, H,
N, Cl.
2-[[4-(3-Ch lor oben zoxy)ben zyl]a m in o]a cetic a cid , h y-
1
d r och lor id e (10): 75%; H NMR (80 MHz, DMSO-d6) 3.73
(s, 2H, NHCH2COOH), 4.04 (s, 2H, ArCH2NH), 5.04 (s, 2H,
ArCH2O), 7.04 (m, 2H, H3, H5), 7.2-7.6 (m, 7H, H2, H6, H2′,
H4′, H5′, H6′), 9.4 (br s, 2H, NH2+); MS m/z 305 (M•+), 260,
246, 231, 125 (100). Anal. (C16H16ClNO3‚HCl) C, H, Cl, N.
Eth yl 2-[[4-(3-Ch lor oben zoxy)ben zyl]a m in o]a ceta te,
h yd r och lor id e (11): 34%; 1H NMR (200 MHz, DMSO-d6)
1.15 (t, J ) 7.0 Hz, 3H, COOCH2CH3), 3.95 (s, 2H, NHCH2-
COO), 4.01 (q, J ) 7.0 Hz, 2H, COOCH2CH3), 4.12 (s, 2H,
ArCH2NH), 5.12 (s, 2H, ArCH2O), 7.04 (m, 2H, H3, H5), 7.3-
7.6 (m, 6H, H2, H6, H2′, H4′, H5′, H6′), 9.7 (br s, 2H, NH2+);
MS m/z 333 (M•+), 246, 231, 125 (100). Anal. (C18H20ClNO3‚-
HCl) C, H, Cl, N.
Ben zyl 2-[[4-(3-Ch lor oben zoxy)ben zyl]a m in o]a ceta te,
h yd r och lor id e (12): 18%; 1H NMR (200 MHz, DMSO-d6)
3.97 (s, 2H, NHCH2COO), 4.09 (s, 2H, ArCH2NH), 5.15, 5.21
(2 s, 4H, ArCH2O, COOCH2Ph), 7.05 (m, 2H, H3, H5), 7.3-

New Class of 2-[(Arylalkyl)amino]alkanamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 585
7.6 (m, 6H, H2, H6, H2′, H4′, H5′, H6′), 9.5 (br s, 2H, NH2+);
H2′, H3′, H4′, H5′, H6′); MS m/z 314 (M•+), 256, 212, 197, 91
(100). Anal. (C18H22N2O3) C, H, N.
MS m/z 395 (M•+), 304, 231, 125 (100), 91. Anal. (C23H22
-
ClNO3‚HCl) H, N; C: calcd, 63.90; found, 63.07. Cl: calcd,
16.40; found, 17.14.
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]-3-p h en yl-N-m eth -
1
ylp r op a n a m id e, h yd r och lor id e (26): 77%; H NMR (200
3-[[[4-(3-C h lo r o b e n zo x y )p h e n y l]e t h y l]a m in o ]p r o -
p a n a m id e, h yd r och lor id e (15): 22%; 1H NMR (80 MHz,
DMSO-d6) 2.3-3.4 (m, 8H, ArCH2CH2NHCH2CH2), 5.07 (s, 2H,
ArCH2O), 6.7-7.8 (m, 10H, CONH2+ aromatics), 9.1 (br s, 2H,
MHz, DMSO-d6) 2.48 (d, J ) 4.8 Hz, 3H, CONHCH3), 3.00
(dd, J ) 9.7, 13.2 Hz, 1H, ArCHAHBCHCO), 3.29 (dd, J ) 4.6,
13.2 Hz, 1H, ArCHAHBCHCO), 3.8-4.1 (m, 3H, ArCH2NH,
CHCO), 5.12 (s, 2H, ArCH2O), 6.9-7.5 (m, 14H, aromatics),
8.38 (q, J ) 4.8 Hz, 1H, CONHCH3), 9.4, 10.0 (2 br s, 2H,
NH2+); MS m/z 374 (M•+), 316, 283, 212, 197, 91 (100). Anal.
(C24H26N2O2‚HCl) H, Cl, N, S; C: calcd, 70.15; found, 69.43.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-3-p h en yl-N-m eth -
ylp r op a n a m id e, h yd r och lor id e (27): 84%; 1H NMR (200
MHz, DMSO-d6) 2.48 (d, J ) 4.8 Hz, 3H, CONHCH3), 2.98
(dd, J ) 9.5, 13.5 Hz, 1H, ArCHAHBCHCO), 3.23 (dd, J ) 4.1,
13.5 Hz, 1H, ArCHAHBCHCO), 3.7-4.0 (m, 3H, ArCH2NH,
CHCO), 5.12 (s, 2H, ArCH2O), 6.9-7.5 (m, 14H, aromatics),
8.28 (q, J ) 4.8 Hz, 1H, CONHCH3), 9.4, 9.7 (2 br s, 2H, NH2+);
MS m/z 374 (M•+), 316, 283, 212, 197, 91 (100). Anal.
(C24H26N2O2‚HCl) H, Cl, N; C: calcd, 70.15; found, 69.34.
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]-4-(m eth ylth io)bu -
ta n a m id e, h yd r och lor id e (28): 69%; 1H NMR (200 MHz,
DMSO-d6) 1.8-2.3 (m, 2H, CH2CH2S), 2.02 (s, 3H, SCH3), 2.3-
2.5 (m, 2H, CH2CH2S), 2.65 (d, J ) 4.6 Hz, 3H, CONHCH3),
3.74 (m, 1H, NHCHCO), 3.95 (s, 2H, ArCH2NH), 5.12 (s, 2H,
ArCH2O), 7.02 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′,
H3′, H4′, H5′, H6′), 8.63 (q, J ) 4.6 Hz, 1H, CONHCH3), 9.2,
9.7 (2 br s, 2H, NH2+); MS m/z 358 (M•+), 300, 212, 197, 91
(100). Anal. (C20H26N2O2S‚HCl) C, H, Cl, N, S.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-4-(m eth ylth io)bu -
ta n a m id e, h yd r och lor id e (29): 62%; 1H NMR (200 MHz,
DMSO-d6) 1.8-2.3 (m, 2H, CH2CH2S), 2.02 (s, 3H, SCH3), 2.3-
2.5 (m, 2H, CH2CH2S), 2.65 (d, J ) 4.6 Hz, 3H, CONHCH3),
3.72 (m, 1H, NHCHCO), 3.94 (m, 2H, ArCH2NH), 5.11 (s, 2H,
ArCH2O), 7.02 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′,
H3′, H4′, H5′, H6′), 8.63 (q, J ) 4.6 Hz, 1H, CONHCH3), 9.2,
9.7 (2 br s, 2H, NH2+); MS m/z 358 (M•+), 300, 212, 197, 91
(100). Anal. (C20H26N2O2S‚HCl) C, H, Cl, N, S.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-3-m eth yl-N-m eth -
ylbu ta n a m id e, h yd r och lor id e (30): 64%; 1H NMR (200
MHz, DMSO-d6) 0.88, 0.93 (2 d, J ) 6.8 Hz, 6H, (CH3)2CH),
2.2 (m, 1H, (CH3)2CH), 2.61 (d, J ) 4.5 Hz, 3H, CONHCH3),
3.45 (m, 1H, NHCHCO), 3.8-4.1 (m, 2H, ArCH2NH), 5.11 (s,
2H, ArCH2O), 7.01 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6,
H2′, H3′, H4′, H5′, H6′), 8.51 (q, J ) 4.5 Hz, 1H, CONHCH3),
9.0, 9.5 (2 br s, 2H, NH2+); MS m/z 326 (M•+), 268, 212, 197,
91 (100). Anal. (C20H26N2O2‚HCl) H, Cl, N; C: calcd, 66.19;
found, 65.70.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-3-m eth yl-N-m eth -
ylbu ta n a m id e, h yd r och lor id e (31): 62%; 1H NMR (80 MHz,
DMSO-d6) 0.88, 0.93 (2 d, J ) 6.8 Hz, 6H, (CH3)2CH), 1.9-2.4
(m, 1H, (CH3)2CH), 2.61 (d, J ) 4.5 Hz, 3H, CONHCH3), 3.45
(m, 1H, NHCHCO), 3.96.1 (s, 2H, ArCH2NH), 5.11 (s, 2H,
ArCH2O), 7.01 (m, 2H, H3, H5), 7.2-7.6 (m, 7H, H2, H6, H2′,
H3′, H4′, H5′, H6′), 8.43 (q, J ) 4.5 Hz, 1H, CONHCH3), 9.2
(br s, 2H, NH2+); MS m/z 326 (M•+), 268, 212, 197, 91 (100).
Anal. (C20H26N2O2‚HCl) C, H, Cl, N.
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]-4-m eth yl-N-m eth -
ylp en ta n a m id e, h yd r och lor id e (32): 63%; 1H NMR (200
MHz, DMSO-d6) 0.82, 0.86 (2 d, J ) 6.3 Hz, 6H, (CH3)2CH),
1.3-1.8 (m, 3H, (CH3)2CHCH2), 2.64 (d, J ) 4.6 Hz, 3H,
CONHCH3), 3.66 (m, 1H, NHCHCO), 3.75-4.1 (m, 2H, ArCH2-
NH), 5.11 (s, 2H, ArCH2O), 7.02 (m, 2H, H3, H5), 7.2-7.5 (m,
7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 8.72 (q, J ) 4.6 Hz, 1H,
CONHCH3), 9.2, 9.6 (2 br s, 2H, NH2+); MS m/z 340 (M•+), 282,
212, 197, 91 (100). Anal. (C21H28N2O2‚HCl) H, Cl, N; C: calcd,
66.92; found, 65.16.
NH2+); MS m/z 332 (M•+), 232, 125, 101 (100). Anal. (C18H21
ClN2O2‚HCl) C, H, Cl, N.
-
3-[[[4-(3-C h lo r o b e n z o x y )p h e n y l]p r o p y l]a m i n o ]-
1
a ceta m id e, h yd r och lor id e (16): 60%; H NMR (200 MHz,
DMSO-d6) 1.87 (m, 2H, ArCH2CH2CH2NH), 2.4-3.0 (m, 4H,
ArCH2CH2CH2NH), 3.63 (s, 2H, CH2CO), 5.08 (s, 2H, ArCH2O),
6.93 (m, 2H, H3, H5), 7.12 (m, 2H, H2, H6), 7.3-7.5 (m, 4H,
H2′, H4′, H5′, H6′), 7.54, 7.9 (2 s, 2H, CONH2), 9.0 (br s, 2H,
NH2+); MS m/z 332 (M•+), 288, 231, 125 (100). Anal. (C18H21
ClN2O2‚HCl) C, H, Cl, N.
-
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]p r op a n a m id e, h y-
1
d r och lor id e (19): 65%; H NMR (200 MHz, DMSO-d6) 1.39
(d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3SO3-), 3.69 (q, J
) 7.0 Hz, 1H, CH3CH), 4.0 (s, 2H, ArCH2NH), 5.12 (s, 2H,
ArCH2O), 7.05 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′,
H3′, H4′, H5′, H6′), 7.62, 7.89 (2 s, 2H, CONH2), 9.0 (br s, 2H,
NH2+); MS m/z 284 (M•+), 240, 212, 197, 91 (100). Anal.
(C17H20N2O2‚HCl) C, H, Cl, N.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]p r op a n a m id e, h y-
1
d r och lor id e (20): 61%; H NMR (200 MHz, DMSO-d6) 1.39
(d, J ) 6.9 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3SO3-), 3.70 (m,
1H, CH3CH), 4.0 (s, 2H, ArCH2NH), 5.11 (s, 2H, ArCH2O), 7.05
(m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′,
H6′), 7.62, 7.89 (2 s, 2H, CONH2), 9.0 (br s, 2H, NH2+); MS
m/z 284 (M•+), 240, 212, 197, 91 (100). Anal. (C17H20N2O2‚-
HCl) C, H, Cl, N.
(S)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-N-m eth ylp r op a n a -
m id e, h yd r och lor id e (21): 52%; 1H NMR (200 MHz, DMSO-
d6) 1.37 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3SO3-),
2.65 (d, J ) 4.5 Hz, 3H, CONHCH3), 3.70 (m, 1H, CH3CH),
3.98 (m, 2H, ArCH2NH), 5.12 (s, 2H, ArCH2O), 7.05 (m, 2H,
H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 8.40
(q, J ) 4.5 Hz, 1H, CONHCH3), 9.0 (2 br s, 2H, NH2+); MS
m/z 298 (M•+), 240, 212, 197, 91 (100). Anal. (C18H22N2O2‚-
HCl) C, H, Cl, N.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-N-m eth ylp r op a n -
a m id e, m eth a n esu lfon a te (22): 31%; 1H NMR (200 MHz,
DMSO-d6) 1.36 (d, J ) 6.9 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 2.65 (d, J ) 4.6 Hz, 3H, CONHCH3), 3.69 (q, J ) 6.9
Hz, 1H, CH3CH), 3.97 (s, 2H, ArCH2NH), 5.12 (s, 2H, ArCH2O),
7.05 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′,
H5′, H6′), 8.38 (q, J ) 4.6 Hz, 1H, CONHCH3), 9.0 (2 br s, 2H,
NH2+); MS m/z 298 (M•+), 240, 212, 197, 91 (100). Anal.
(C18H22N2O2‚CH3SO3H) C, H, N, S.
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]-3-h yd r oxy-N-m e-
th ylp r op a n a m id e (23): 59%; 1H NMR (200 MHz, DMSO-
d6) 2.3 (s, 3H, CH3SO3-), 2.64 (d, J ) 4.6 Hz, 3H, CONHCH3),
3.5-3.8 (m, 3H, CHCH2OH), 4.02 (s, 2H, ArCH2NH), 5.11 (s,
2H, ArCH2O), 5.48 (t, J ) 5.0 Hz, 1H, CH2OH), 7.03 (m, 2H,
H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 8.34
(q, J ) 4.6 Hz, 1H, CONHCH3), 9.0 (br s, 2H, NH2+); MS m/z
314 (M•+), 256, 212, 197, 91 (100). Anal. (C18H22N2O3) C, H,
N.
(S )-(+)-2-[(4-B e n zo x y b e n zy l)a m in o ]p r o p a n a m id e
1
(24): 57%; H NMR (200 MHz, DMSO-d6) 2.28 (s, 3H, CH3-
SO3-), 3.61 (m, 1H, CHCH2OH), 3.77 (m, 2H, CHCH2OH), 4.05
(m, 2H, ArCH2NH), 5.11 (s, 2H, ArCH2O), 5.5 (br s, 1H,
CH2OH), 7.04 (m, 2H, H3, H5), 7.2-7.5 (m, 7H, H2, H6, H2′,
H3′, H4′, H5′, H6′), 7.65, 7.84 (2 s, 2H, CONH2), 9.0 (br s, 2H,
NH2+); MS m/z 300 (M•+), 256, 212, 197, 91 (100). Anal.
(C17H20N2O3) C, H, N.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-3-h yd r oxy-N-m e-
th ylp r op a n a m id e (25): 44%; 1H NMR (200 MHz, CDCl3)
1.79 (d, J ) 4.9 Hz, 3H, CONHCH3), 3.2 (t, J ) 5.4 Hz, 1H,
CHCH2OH), 3.6-3.9 (m, 4H, ArCH2NH, CHCH2OH), 5.05 (s,
2H, ArCH2O), 6.98 (m, 2H, H3, H5), 7.1-7.5 (m, 7H, H2, H6,
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-4-m eth yl-N-m eth -
ylp en ta n a m id e, h yd r och lor id e (33): 58%; 1H NMR (200
MHz, DMSO-d6) 0.82, 0.86 (2 d, J ) 6.3 Hz, 6H, (CH3)2CH),
1.3-1.8 (m, 3H, (CH3)2CHCH2), 2.64 (d, J ) 4.6 Hz, 3H,
CONHCH3), 3.66 (m, 1H, NHCHCO), 3.75-4.1 (m, 2H, ArCH2-
NH), 5.11 (s, 2H, ArCH2O), 7.02 (m, 2H, H3, H5), 7.2-7.5 (m,
7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 8.74 (q, J ) 4.6 Hz, 1H,

586 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Pevarello et al.
CONHCH3), 9.2, 9.6 (2 br s, 2H, NH2+); MS m/z 340 (M•+), 282,
212, 197, 91 (100). Anal. (C21H28N2O2‚HCl) H, Cl, N; C: calcd,
66.92; found, 65.23.
(S )-(+)-2-[[4-(Be n zyla m in o)b e n zyl]a m in o]p r op a n -
a m id e, d ih yd r och lor id e (45): 24%; 1H NMR (200 MHz,
DMSO-d6) 1.39 (d, J ) 7.0 Hz, 3H, CH3CH), 3.67 (m, 1H,
CH3CH), 3.88 (m, 2H, ArCH2NHCH), 4.32 (s, 2H, ArCH2-
NHAr), 6.77 (m, 2H, H3, H5), 7.1-7.5 (m, 7H, H2′, H3′, H4′,
H5′, H6′, H2, H6), 7.59, 7.98 (2 s, 2H, CONH2), 8.9, 9.4 (2 br
s, 2H, NH2+); MS m/z 283 (M•+), 211, 196, 91 (100). Anal.
(C17H21N3O‚2HCl) H, Cl, N; C: calcd, 57.30; found, 56.56.
(S )-(+)-2-[[4-(P h e n oxym e t h yl)b e n zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (46): 42%; 1H NMR (200 MHz,
DMSO-d6) 1.41 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.75 (q, J ) 7.0 Hz, 1H, CH3CH), 4.09 (s, 2H, ArCH2-
NH), 5.12 (s, 2H, ArCH2O), 6.8-7.6 (m, 9H, aromatics), 7.65,
7.92 (2 s, 2H, CONH2), 9.1 (br s, 2H, NH2+); MS m/z 284 (M•+),
240, 212, 197, 104 (100). Anal. (C17H20N2O2‚CH3SO3H). C,
H, N, S.
(2R,3S)-(-)-2-[(4-Ben zoxyben zyl)a m in o]-3-h yd r oxy-N-
m eth ylbu ta n a m id e, h yd r och lor id e (34): 65%; 1H NMR
(200 MHz, DMSO-d6) 1.05 (d, J ) 6.4 Hz, 3H, CH3CHOH),
2.61 (d, J ) 4.5 Hz, 3H, CONHCH3), 3.34 (d, J ) 7.7 Hz, 1H,
NHCHCONH), 3.8-4.1 (m, 3H, ArCH2NH, CH3CHOH), 5.1
(s, 2H, ArCH2O), 5.7 (br s, 1H, OH), 7.02 (m, 2H, H3, H5),
7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 8.57 (q, J )
4.5 Hz, 1H, CONHCH3), 9.2 (br s, 2H, NH2+); MS m/z 328
(M•+), 270, 212, 197, 91 (100). Anal. (C19H24N2O3‚HCl) C, H,
Cl, N.
(S)-(+)-2-[(4-Ben zoxyben zyl)a m in o]bu ta n a m id e, m eth -
a n esu lfon a te (36): 49%; 1H NMR (200 MHz, DMSO-d6) 0.88
(t, J ) 7.5 Hz, 3H, CH2CH3), 1.6-2.0 (m, 2H, CH2CH3), 2.3 (s,
3H, CH3SO3-), 3.58 (dd, J ) 5.2, 7.1 Hz, 1H, CHCH2CH3), 3.98
(s, 2H, ArCH2NH), 5.12 (s, 2H, ArCH2O), 7.05 (m, 2H, H3, H5),
7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 7.69, 7.93 (2
s, 2H, CONH2), 8.9 (br s, 2H, NH2+); MS m/z 298 (M•+), 254,
212, 197, 91 (100). Anal. (C18H22N2O2‚CH3SO3H) C, H, N, S.
(R)-(-)-2-[(4-Ben zoxyben zyl)a m in o]bu ta n a m ide, m eth -
a n esu lfon a te (37): 46%; 1H NMR (200 MHz, DMSO-d6) 0.86
(t, J ) 7.5 Hz, 3H, CH3CH2), 1.7 (m, 2H, CH3CH2), 2.3 (s, 3H,
CH3SO3-), 3.3 (m, 1H, CHCH2CH3), 3.76, 3.87 (2 d, J ) 13.1
Hz, 2H, ArCH2NH), 5.11 (s, 2H, ArCH2O), 7.01 (m, 2H, H3,
H5), 7.2-7.5 (m, 7H, H2, H6, H2′, H3′, H4′, H5′, H6′), 7.45,
7.71 (2 s, 2H, CONH2); MS m/z 298 (M•+), 254, 212, 197, 91
(100). Anal. (C18H22N2O2‚CH3SO3H) C, H, N, S.
(S )-(+)-2-[(3-Be n zoxyb e n zyl)a m in o]p r op ion a m id e ,
m eth a n esu lfon a te (38): 52%; 1H NMR (200 MHz, DMSO-
d6) 1.41 (d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-),
3.73 (q, J ) 7.0 Hz, 1H, CH3CH), 4.06 (s, 2H, ArCH2NH), 5.11
(s, 2H, ArCH2O), 7.05 (m, 2H, H6, H4), 7.18 (t, J ) 1.9 Hz,
1H, H2), 7.2-7.5 (m, 6H, H2′, H3′, H4′, H5′, H6′, H5), 7.62,
789 (2 s, 2H, CONH2), 9.1 (br s, 2H, NH2+); MS m/z 284 (M•+),
240, 212, 197, 91 (100). Anal. (C17H20N2O2‚CH3SO3H) C, H,
N, S.
(S)-(+)-2-[(2-Ben zoxyben zyl)am in o]pr opan am ide, m eth -
a n esu lfon a te (39): 25%; 1H NMR (200 MHz, DMSO-d6) 1.39
(d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-), 3.75 (q, J )
7.0 Hz, 1H, CH3CH), 4.12 (s, 2H, ArCH2NH), 5.18 (s, 2H,
ArCH2O), 7.0 (m, 1H, H5), 7.14 (d, J ) 7.9 Hz, 1H, H3), 7.2-
7.6 (m, 7H, H2′, H3′, H4′, H5′, H6′, H4, H6), 7.61, 7.88 (2 s,
2H, CONH2), 8.9 (br s, 2H, NH2+); MS m/z 284 (M•+), 240, 212,
197, 91 (100). Anal. (C17H20N2O2‚CH3SO3H) C, H, N, S.
(S)-(+)-2-[(4-P h en ylben zyl)a m in o]p r op a n a m id e, m eth -
a n esu lfon a te (40): 48%; 1H NMR (200 MHz, DMSO-d6) 1.43
(d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-), 3.77 (q, J )
7.0 Hz, 1H, CH3CH), 4.13 (s, 2H, ArCH2NH), 7.3-7.8 (m, 9H,
aromatics), 7.65, 792 (2 s, 2H, CONH2), 9.1 (br s, 2H, NH2+);
MS m/z 254 (M•+), 210, 182, 167 (100). Anal. (C16H18N2O‚CH3-
SO3H) C, H, N, S.
(S)-(+)-2-[[4-(2-P h en ylet h oxy)b en zyl]a m in o]p r op a n -
1
a m id e, m eth a n esu lfon a te (47): 50%; H NMR (200 MHz,
DMSO-d6) 1.39 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.03 (t, J ) 7.0 Hz, 2H, OCH2CH2), 3.68 (q, J ) 7.0 Hz,
1H, CH3CH), 4.00 (s, 2H, ArCH2NH), 4.20 (t, J ) 7.0 Hz, 2H,
OCH2CH2), 6.99 (m, 2H, H3, H5), 7.1-7.5 (m, 7H, H2′, H3′,
H4′, H5′, H6′, H2, H6), 7.63, 7.88 (2 s, 2H, CONH2), 8.9 (br s,
2H, NH2+); MS m/z 298 (M•+), 254, 226, 211, 105 (100). Anal.
(C18H22N2O2‚CH3SO3H) C, H, N.
(S)-(+)-2-[[4-[(P h e n yla m in o)m e t h yl]b e n zyl]a m in o]-
1
p r op a n a m id e, d ih yd r och lor id e (49): 45%; H NMR (200
MHz, DMSO-d6) 1.43 (d, J ) 7.0 Hz, 3H, CH3CH), 3.73 (m,
1H, CH3CH), 4.03 (m, 2H, ArCH2NHCH), 4.42 (s, 2H,
ArNHCH2Ar), 6.9-7.4 (m, 5H, H2′, H3′, H4′, H5′, H6′), 7.48
(s, 4H, H2, H3, H5, H6), 7.62, 8.04 (2 s, 2H, CONH2), 9.2, 9.8
(2 br s, 2H, ArCH2NH2+CH); MS m/z 283 (M•+), 239, 211, 196
(100), 104. Anal. (C17H21N3O‚2HCl) C, H, N.
(S )-(+)-2-[[4-(Be n zoyla m in o)b e n zyl]a m in o]p r op a n -
1
a m id e, m eth a n esu lfon a te (51): 53%; H NMR (200 MHz,
DMSO-d6) 1.42 (d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3-
SO3-), 3.72 (q, J ) 7.0 Hz, 1H, CH3CH), 4.04 (s, 2H, ArCH2-
NH), 7.3-8.0 (m, 11H, aromatics, CONH2), 9.1 (br s, 2H,
NH2+), 10.38 (s, 1H, CONHAr); MS m/z 297 (M•+), 253, 225,
210, 105 (100). Anal. (C17H19N3O2‚CH3SO3H) H, N, S; C:
calcd, 54.95; found, 54.41.
(S )-(+)-2-[(4-(E )-St yr ylb e n zyl)a m in o]p r op a n a m id e ,
1
m eth a n esu lfon a te (52): 26%; H NMR (200 MHz, DMSO-
d6) 1.42 (d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-),
3.73 (q, J ) 7.0 Hz, 1H, CH3CH), 4.09 (s, 2H, ArCH2NH), 7.1-
7.8 (m, 11H, aromatics, ArCHdCHAr), 7.9, 7.62 (2 s, 2H,
CONH2), 9.05 (br s, 2H, NH2+); MS m/z 280 (M•+), 236, 208,
193 (100). Anal. (C18H20N2O‚CH3SO3H) C, H, N, S.
(S)-(+)-2-[[4-(2-Ch lor ob en zoxy)b en zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (53): 30%; 1H NMR (200 MHz,
DMSO-d6) 1.40 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.71 (q, J ) 7.0 Hz, 1H, CH3CH), 4.0 (s, 2H, ArCH2-
NH), 5.17 (s, 2H, ArCH2O), 7.08 (m, 2H, H3, H5), 7.3-7.7 (m,
6H, H2, H6, H3′, H4′, H5′, H6′), 7.64, 7.91 (2 s, 2H, CONH2),
9.0 (br s, 2H, NH2+); MS m/z 318 (M•+), 274, 246, 231, 125
(100). Anal. (C17H19ClN2O2‚CH3SO3H) C, H, Cl, N, S.
(R)-(-)-2-[[4-(2-Ch lor ob en zoxy)b en zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (54): 31%; 1H NMR (200 MHz,
DMSO-d6) 1.39 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.70 (q, J ) 7.0 Hz, 1H, CH3CH), 4.01 (s, 2H, ArCH2-
NH), 5.17 (s, 2H, ArCH2O), 7.08 (m, 2H, H3, H5), 7.3-7.7 (m,
6H, H2, H6, H3′, H4′, H5′, H6′), 7.63, 7.89 (2 s, 2H, CONH2),
9.0 (br s, 2H, NH2+); MS m/z 318 (M•+), 274, 246, 231, 125
(100). Anal. (C17H19ClN2O2‚CH3SO3H) C, H, Cl, N, S.
(S)-(+)-2-[[4-(4-F lu or ob en zoxy)b en zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (55): 42%; 1H NMR (200 MHz,
DMSO-d6) 1.40 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.70 (q, J ) 7.0 Hz, 1H, CH3CH), 4.01 (s, 2H, ArCH2-
NH), 5.10 (s, 2H, ArCH2O), 7.0-7.6 (m, 8H, aromatics), 7.62,
7.88 (2 s, 2H, CONH2), 9.0 (br s, 2H, NH2+); MS m/z 302 (M•+),
258, 230, 215, 109 (100). Anal. (C17H19FN2O2‚CH3SO3H) C,
H, F, N, S.
(S)-(+)-2-[(4-P h en oxyben zyl)am in o]pr opan am ide, m eth -
1
a n esu lfon a te (41): 44%; H NMR (200 MHz, DMSO-d6) 1.4
(d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-), 3.76 (q, J )
7.0 Hz, 1H, CH3CH), 4.03, 4.10 (2 d, J ) 13.2 Hz, 2H, ArCH2-
NH), 6.9-7.6 (m, 9H, aromatics), 7.5, 7.87 (2 s, 2H, CONH2),
9.0 (br s, 2H, NH2+); MS m/z 270 (M•+), 226, 198, 183 (100),
77. Anal. (C16H18N2O2‚CH3SO3H) C, H, N, S.
(S)-(+)-2-[(4-Ben zylben zyl)a m in o]p r op a n a m id e, m eth -
a n esu lfon a te (42): 37%; 1H NMR (200 MHz, DMSO-d6) 1.40
(d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-), 3.72 (q, J )
7.0 Hz, 1H, CH3CH), 3.96 (s, 2H, ArCH2Ar), 4.03 (s, 2H, ArCH2-
NH), 7.1-7.5 (m, 9H, aromatics), 7.64, 7.90 (2 s, 2H, CONH2),
9.0 (br s, 2H, NH2+); MS m/z 268 (M•+), 224, 196, 181 (100),
91. Anal. (C17H20N2O‚CH3SO3H) C, H, N, S.
(S )-(+)-2-[[4-(2-P h e n yle t h yl)b e n zyl]a m in o]p r op a n -
1
a m id e, m eth a n esu lfon a te (43): 42%; H NMR (200 MHz,
DMSO-d6) 1.37 (d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3-
SO3-), 2.88 (s, 4H, ArCH2CH2Ar), 3.61 (q, J ) 7.0 Hz, 1H,
CH3CH), 3.97 (s, 2H, ArCH2NH), 7.1-7.4 (m, 9H, aromatics),
7.55, 7.82 (2 s, 2H, CONH2), 8.5 (br s, 2H, NH2+); MS m/z 238,
210, 195, 91 (100). Anal. (C18H22N2O‚CH3SO3H) C, H, N, S.
(S)-(+)-2-[[4-(2-F lu or ob en zoxy)b en zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (56): 60%; 1H NMR (200 MHz,

New Class of 2-[(Arylalkyl)amino]alkanamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 587
1
DMSO-d6) 1.39 (d, J ) 6.9 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.71 (q, J ) 6.9 Hz, 1H, CHCH3), 4.01 (m, 2H, ArCH2-
NH), 5.15 (s, 2H, ArCH2O), 7.08 (m, 2H, H3, H5), 7.1-7.6 (m,
6H, H3′, H4′, H5′, H6′, H2, H6), 7.63,7.89 (2 s, 2H, CONH2),
9.0 (br s, 2H, NH2+); MS m/z 302 (M•+), 258, 230, 215, 109
(100). Anal. (C17H19FN2O2‚CH3SO3H) C, H, F, N, S.
(S)-(+)-2-[[4-(3-F lu or ob en zoxy)b en zyl]a m in o]p r op a -
n a m id e, m eth a n esu lfon a te (57): 45%; 1H NMR (200 MHz,
DMSO-d6) 1.39 (d, J ) 6.8 Hz, 3H, CH3CH), 2.29 (s, 3H, CH3-
SO3-), 3.70 (q, J ) 6.8 Hz, 1H, CHCH3), 4.01 (s, 2H, ArCH2-
NH), 5.15 (s, 2H, ArCH2O), 7.06 (m, 2H, H3, H5), 7.1-7.4 (m,
4H, H2′, H4′, H5′, H6′), 7.39 (m, 2H, H2, H6), 7.60, 7.86 (2 s,
2H, CONH2), 8.96 (br s, 2H, NH2+); MS m/z 302 (M•+), 258,
230, 215, 109 (100). Anal. (C17H19FN2O2‚CH3SO3H) C, H, F,
N, S.
(S)-(+)-2-[[4-(3-Met h oxyb en zoxy)ben zyl]a m in o]-3-h y-
d r oxy-N-m eth ylp r op a n a m id e (58): 21%; 1H NMR (200
MHz, DMSO-d6) 2.4 (br s, 1H, ArCH2NH), 2.59 (d, J ) 4.8
Hz, 3H, CONHCH3), 2.97 (t, J ) 5.4 Hz, 1H, CHCH2OH), 3.3-
3.7 (m, 4H, ArCH2NH, CHCH2OH), 3.74 (s, 3H, OCH3), 4.72
(t, J ) 5.7, 1H, CH2OH), 5.04 (s, 2H, ArCH2O), 6.8-7.4 (8H,
aromatics), 7.76 (q, J ) 4.8 Hz, 1H, CONHCH3); MS m/z 286
(M•+), 242, 227, 121 (100). Anal. (C19H24N2O4) H, N; C: calcd,
66.23; found, 65.43.
(S)-(+)-2-[[4-(3-Nitr oben zoxy)ben zyl]am in o]-3-h ydr oxy-
N-m eth ylp r op a n a m id e (59): 20%; 1H NMR (200 MHz,
DMSO-d6) 2.58 (d, J ) 4.8 Hz, 3H, CONHCH3), 2.98 (t, J )
5.5 Hz, 1H, CHCH2OH), 3.3-3.7 (m, 4H, ArCH2NH, CHCH2-
OH), 4.73 (t, J ) 5.7 Hz, 1H, CHCH2OH), 5.24 (s, 2H,
ArCH2O), 6.96 (m, 2H, H3, H5), 7.26 (m, 2H, H2, H6), 7.68 (t,
J ) 7.9 Hz, 1H, H5′), 7.77 (q, J ) 4.8 Hz, 1H, CONHCH3),
7.89 (dd, J ) 7.9, 1.9 Hz, 1H, H6′), 8.17 (dd, J ) 7.9, 1.9 Hz,
1H, H4′), 8.29 (t, J ) 1.9 Hz, 1H, H2′); MS m/z 359 (M•+), 301,
257, 242, 136 (100). Anal. (C18H21N3O5) H, N; C: calcd, 60.15;
found, 59.49.
fon a te (64): 45%; H NMR (200 MHz, DMSO-d6) 2.3 (s, 3H,
CH3SO3-), 2.64 (d, J ) 4.6 Hz, 3H, CONHCH3), 3.5-3.8 (m,
3H, CHCH2OH), 4.04 (s, 2H, ArCH2NH), 5.23 (s, 2H, ArCH2O),
5.48 (t, J ) 4.9 Hz, 1H, CH2OH), 7.04 (m, 2H, H3, H5), 7.4
(m, 2H, H2, H6), 7.5-7.9 (m, 4H, H3′, H4′, H5′, H6′), 8.34 (q,
J ) 4.6 Hz, 1H, CONHCH3), 9.0 (br s, 2H, NH2+); MS m/z 382
(M•+), 324, 280, 265, 159 (100). Anal. (C19H21F3N2O3‚CH3-
SO3H‚0.37H2O) C, H, F, N, S, H2O.
(S )-(+)-2-[[4-(2-F lu or ob e n zoxy)b e n zyl]a m in o]-3-h y-
d r oxy-N-m eth ylp r op a n a m id e, m eth a n esu lfon a te (65):
56%; 1H NMR (200 MHz, DMSO-d6) 2.3 (s, 3H, CH3SO3-), 2.64
(d, J ) 4.6 Hz, 3H, CONHCH3), 3.5-3.8 (m, 3H, CHCH2OH),
4.05 (s, 2H, ArCH2NH), 5.14 (s, 2H, ArCH2O), 5.5 (br s, 1H,
CH2OH), 7.0-7.6 (m, 9H, aromatics), 8.34 (q, J ) 4.6 Hz, 1H,
CONHCH3), 9.1 (br s, 2H, NH2+); MS m/z 332 (M•+), 274, 230,
215, 109 (100). Anal. (C18H21FN2O3‚CH3SO3H) C, H, F, N, S.
(S )-(+)-2-[[4-(3-F lu or ob e n zoxy)b e n zyl]a m in o]-3-h y-
d r oxy-N-m eth ylp r op a n a m id e, m eth a n esu lfon a te (66):
61%; 1H NMR (200 MHz, DMSO): 2.3 (s, 3H, CH3SO3H), 2.64
(d, J ) 4.6 Hz, 3H, CONHCH3), 3.5-3.8 (m, 3H, CHCH2OH),
4.03 (s, 2H, ArCH2NH), 5.15 (s, 2H, ArCH2O), 5.45 (t, J ) 5.0
Hz, 1H, CH2OH), 7.0-7.5 (m, 9H, aromatics), 8.33 (q, J ) 4.6
Hz, 1H, CONHCH3), 8.9 (br s, 2H, NH2+); MS m/z 332 (M•+),
274, 230, 215, 109 (100). Anal. (C18H21FN2O3‚CH3SO3H) C,
H, F, N, S.
(S )-(+)-2-[[4-(2-P yr id ylm e t h oxy)b e n zyl]a m in o]p r o-
p a n a m id e (67): 65%; H NMR (200 MHz, DMSO-d6) 1.1 (d,
1
J ) 6.7 Hz, 3H, CH3CH), 2.97 (q, J ) 6.7 Hz, 1H, CH3CH),
3.44, 3.58 (2 d, J ) 13.3 Hz, 2H, ArCH2NH), 5.14 (s, 2H,
CH2O), 6.94 (m, 3H, CONHA, H3, H5), 7.22 (m, 2H, H2, H6),
7.3 (m, 2H, CONHB, H5′), 7.48 (d, J ) 7.8 Hz, 1H, H3′), 7.81
(ddd, J ) 7.8, 7.8, 1.9 Hz, 1H, H4′), 8.56 (dd, J ) 4.8, 1.9 Hz,
1H, H5′); MS m/z 285 (M•+), 241, 213, 198 (100), 92. Anal.
(C16H19N3O2) H, N; C: calcd, 67.35; found, 65.94.
(S )-(+)-2-[[4-(3-P yr id ylm e t h oxy)b e n zyl]a m in o]p r o-
p a n a m id e (68): 12%; H NMR (200 MHz, DMSO-d6) 1.1 (d,
1
(S)-(+)-2-[[4-(3-Cyan oben zoxy)ben zyl]am in o]-3-h ydr oxy-
N-m eth ylp r op a n a m id e (60): 45%; 1H NMR (200 MHz,
DMSO-d6) 2.3 (br s, 1H, CH2NH), 2.58 (d, J ) 4.8 Hz, 3H,
CONHCH3), 2.97 (t, J ) 5.6 Hz, 1H, CHCH2OH), 3.3-3.7 (m,
J ) 6.9 Hz, 3H, CH3CH), 2.3 (br s, 1H, ArCH2NH), 2.98 (q, J
) 6.9 Hz, 1H, CH3CH), 3.45, 3.59 (2 d, J ) 13.2 Hz, 2H, ArCH2-
NH), 5.12 (s, 2H, CH2O), 6.9, 7.3 (2 br s, 2H, CONH2), 6.95
(m, 2H, H3, H5), 7.23 (m, 2H, H2, H6), 7.41 (ddd, J ) 7.9, 4.9,
0.9 Hz, 1H, H5′), 7.85 (ddd, J ) 7.9, 1.9, 1.9 Hz, 1H, H4′), 8.53
(dd, J ) 4.9, 1.9 Hz, 1H, H6′), 8.65 (dd, J ) 1.9, 0.9 Hz, 1H,
H2′); MS m/z 285 (M•+), 241, 213, 198 (100), 92. Anal.
(C16H19N3O2) C, H, N.
4H, ArCH2NH, CHCH2OH), 4.73 (t,
J ) 5.7 Hz, 1H,
CHCH2OH), 5.14 (s, 2H, ArCH2O), 6.94 (m, 2H, H3, H5), 7.25
(m, 2H, H2, H6), 7.59 (t, J ) 7.7 Hz, 1H, H5′), 7.7-8.0 (m,
4H, H2′, H4′, H6′, CONHCH3); MS m/z 339 (M•+), 281, 237,
222, 116 (100). Anal. (C19H21N3O3) H, N; C: calcd, 67.24;
found, 66.13.
(S )-(+)-2-[[4-(4-P yr id ylm e t h oxy)b e n zyl]a m in o]p r o-
p a n a m id e (69): 46%; H NMR (200 MHz, CDCl3) 1.32 (d, J
1
(S)-(+)-2-[[4-(4-Ch lor ob e n zoxy)b e n zyl]a m in o]-3-h y-
d r oxy-N-m eth ylp r op a n a m id e (61): 71%; 1H NMR (200
MHz, DMSO-d6) 2.3 (br s, 3H, ArCH2NH), 2.59 (d, J ) 4.8
Hz, 3H, CONHCH3), 2.97 (t, J ) 5.6 Hz, 1H, CHCH2OH), 3.3-
3.7 (m, 4H, ArCH2NH, CHCH2OH), 4.73 (t, J ) 5.7, 1H,
CH2OH), 5.07 (s, 2H, ArCH2O), 6.92 (m, 2H, H3, H5), 7.24 (m,
2H, H2, H6), 7.44 (s, 4H, H2′, H3′, H5′, H6′), 7.78 (q, J ) 4.8
Hz, 1H, CONHCH3); MS m/z 348 (M•+), 290, 246, 231, 125
(100). Anal. (C18H21ClN2O3) C, H, Cl, N.
(S)-(+)-2-[[4-(3-Met h ylb en zoxy)b en zyl]a m in o]-3-h y-
d r oxy-N-m et h ylp r op a n a m id e, m et h a n esu lfon a t e (62):
63%; 1H NMR (80 MHz, DMSO-d6) 2.3 (s, 6H, CH3SO3-, CH3-
Ar), 2.65 (d, J ) 4.6 Hz, 3H, CONHCH3), 3.5-3.9 (m, 3H,
CHCH2OH), 4.05 (s, 2H, ArCH2NH), 5.1 (s, 2H, ArCH2O), 6.9-
7.5 (m, 9H, aromatics), 8.33 (q, J ) 4.6 Hz, 1H, CONHCH3),
9.0 (br s, 2H, NH2+); MS m/z 328 (M•+), 270, 226, 211, 105
(100). Anal. (C19H24N2O3‚CH3SO3H) C, H, N, S.
) 7.0 Hz, 3H, CH3CH), 3.22 (q, J ) 7.0 Hz, 1H, CH3CH), 3.65,
3.73 (2 d, J ) 13.0 Hz, 2H, ArCH2NH), 5.07 (s, 2H, CH2O),
5.4, 7.0 (2 br s, 2H, CONH2), 6.89 (m, 2H, H3, H5), 7.20 (m,
2H, H2, H6), 7.32 (m, 2H, H3′, H5′), 8.58 (m, 2H, H2′, H6′);
MS m/z 285 (M•+), 241, 213, 198 (100), 92. Anal. (C16H19N3O2)
C, H, N.
(S )-(+)-2-[[4-(3-Th ie n yloxy)b e n zyl]a m in o]p r op a n a -
m id e, m eth a n esu lfon a te (71): 52%; 1H NMR (200 MHz,
DMSO-d6) 1.40 (d, J ) 7.0 Hz, 3H, CH3CH), 2.3 (s, 3H, CH3-
SO3-), 3.72 (q, J ) 7.0 Hz, 1H, CH3CH), 4.0 (s, 2H, ArCH2-
NH), 5.11 (s, 2H, ArCH2O), 7.05 (m, 2H, H3, H5), 7.16 (dd, J
) 1.6, 4.8 Hz, 1H, H4′), 7.38 (m, 2H, H2, H6), 7.55 (m, 2H,
H2′, H5′), 7.62, 7.89 (2 s, 2H, CONH2), 9.0 (br s, 2H, NH2+);
MS m/z 290 (M•+), 246, 218, 203, 97 (100). Anal.
(C15H18N2O2S‚CH3SO3H) C, H, N, S.
(S )-(+)-2-[[4-(2-F u r fu r yloxy)b e n zyl]a m in o]p r op a n -
a m id e, m eth a n esu lfon a te (72): 52%; H NMR (200 MHz,
1
(S )-(+)-2-[[4-[3-(Tr iflu or om e t h yl)b e n zoxy]b e n zyl]-
a m in o]-3-h yd r oxy-N-m et h ylp r op a n a m id e, m et h a n e-
DMSO-d6) 1.39 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.69 (q, J ) 7.0 Hz, 1H, CH3CH), 4.0 (s, 2H, ArCH2-
NH), 5.07 (s, 2H, ArCH2O), 6.46 (dd, J ) 1.9, 3.3 Hz, 1H, H4′),
6.59 (dd, J ) 3.3, 0.8 Hz, 1H, H3′), 7.07 (m, 2H, H3, H5), 7.39
(m, 2H, H2, H6), 7.6, 7.87 (2 s, 2H, CONH2), 7.68 (dd, J ) 1.9,
0.8 Hz, 1H, H5′), 8.9 (br s, 2H, NH2+); MS m/z 274 (M•+), 230,
202, 187, 81 (100). Anal. (C15H18N2O3‚CH3SO3H) C, H, N, S.
(S )-(+)-2-[[4-(3-F u r fu r yloxy)b e n zyl]a m in o]p r op a n -
1
su lfon a te (63): 13%; H NMR (200 MHz, DMSO-d6) 2.3 (s,
3H, CH3SO3-), 2.64 (d, J ) 4.6 Hz, 3H, CONHCH3), 3.5-3.8
(m, 3H, CHCH2OH), 4.03 (s, 2H, ArCH2NH), 5.23 (s, 2H,
ArCH2O), 5.48 (t, J ) 4.8 Hz, 1H, CH2OH), 7.07 (m, 2H, H3,
H5), 7.39 (m, 2H, H2, H6), 7.5-7.9 (m, 4H, H2′, H4′, H5′, H6′),
8.34 (q, J ) 4.8 Hz, 1H, CONHCH3), 9.0 (br s, 2H, NH2+);
MS m/z 382 (M•+), 324, 280, 265, 159 (100). Anal.
(C19H21F3N2O3‚CH3SO3H) C, H, F, N, S.
1
a m id e, m eth a n esu lfon a te (73): 36%; H NMR (200 MHz,
(S)-(+)-2-[[4-[2-(Tr iflu or om et h yl)b en zoxy]b en zyl]a -
m in o]-3-h yd r oxy-N-m et h ylp r op a n a m id e, m et h a n esu l-
DMSO-d6) 1.39 (d, J ) 7.0 Hz, 3H, CH3CH), 2.30 (s, 3H, CH3-
SO3-), 3.69 (q, J ) 7.0 Hz, 1H, CH3CH), 4.0 (s, 2H, ArCH2-

588 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Pevarello et al.
NH), 4.98 (s, 2H, ArCH2O), 6.55 (d, J ) 2.1 Hz, 1H, H4′), 7.04
(m, 2H, H3, H5), 7.38 (m, 2H, H2, H6), 7.6, 7.87 (2 s, 2H,
CONH2), 7.66, 7.78 (2 m, 2H, H2′, H5′), 8.9 (br s, 2H, NH2+);
MS m/z 274 (M•+), 230, 202, 187, 81 (100). Anal.
(C15H18N2O3‚CH3SO3H) C, H, N, S.
portionwise. Stirring was maintained for 1 h; then glycina-
mide (5.68 g, 0.0766 mol) and triethylamine (7.22 mL, 5.24 g,
0.052 mol) were added. The mixture was kept at room
temperature for 24 h and then taken up with water; a bright
solid precipitated and was filtered and recrystallized from 90%
ethanol to afford 4.15 g (26%) of 17: 1H NMR (200 MHz,
DMSO-d6) 3.77 (d, J ) 5.9 Hz, 2H, CONHCH2), 5.18 (s, 2H,
ArCH2O), 7.0, 7.33 (2 s, 2H, CONH2), 7.07 (m, 2H, H3, H5),
7.3-7.6 (m, 4H, H2′, H4′, H5′, H6′), 7.84 (m, 2H, H2, H6), 8.52
(t, J ) 5.9 Hz, 1H, CONHCH2); MS m/z 318 (M•+), 244, 125
(100). Anal. (C16H15ClN2O3) C, H, Cl, N.
(S )-(+)-2-[[4-(Cyclop r op ylm e t h oxy)b e n zyl]a m in o]-
1
p r op a n a m id e (74): 37%; H NMR (200 MHz, CDCl3) 0.2-
1.4 (m, 5H, cyclopropyl), 1.31 (d, J ) 6.9 Hz, 3H, CH3CH), 3.21
(q, J ) 6.9 Hz, 1H, CH3CH), 3.63, 3.7 (2 d, J ) 12.9 Hz, 2H,
ArCH2NH), 3.77 (d, J ) 7.0 Hz, CH2O), 5.5, 7.1 (2 br s, 2H,
CONH2), 6.84 (m, 2H, H3, H5), 7.17 (m, 2H, H2, H6); MS m/z
248 (M•+), 204, 176, 161, 107 (100). Anal. (C14H20N2O2) H,
N; C: calcd, 67.78; found, 67.26.
2-[[4-(3-C h lo r o b e n zo x y )b e n zy l]m e t h y la m in o ]a c e -
ta m id e, Hyd r och lor id e (18). The amino amide 6 (2 g, 6.56
mmol) was dissolved in methanol (30 mL) in a flask fitted
with an outlet device connected to a ferrous sulfate solution.
To the stirred mixture was added 0.33 g (5.24 mmol) of
sodium cyanoborohydride in a single portion. Stirring was
continued for 15 min at room temperature; then 1 mL (13
mmol) of 40% aqueous formaldehyde was dropped while
maintaining the temperature below 30 °C. After 1 h the
mixture was evaporated, taken up with dichloromethane, and
flash-chromatographed on silica gel using dichloromethane-
methanol (99:1) as eluent. The tertiary amine 18 was obtained
as a white solid (42%): 1H NMR (200 MHz, CDCl3) 2.28 (s,
3H, NCH3), 3.01 (s, 2H, NCH2CO), 3.51 (s, 2H, ArCH2N), 5.02
(s, 2H, ArCH2O), 5.8, 7.0 (2 br s, 2H, CONH2), 6.91 (m, 2H,
H3, H5), 7.1-7.5 (m, 6H, H2, H6, H2′,H4′, H5′, H6′); MS m/z
318 (M•+), 260, 246, 231, 125 (100). Anal. (C17H19ClN2O2) C,
H, N, Cl.
(S)-(+)-2-[[4-(Cycloh exylm et h oxy)b en zyl]a m in o]p r o-
p a n a m id e, m eth a n esu lfon a te (75): 33%; 1H NMR (200
MHz, DMSO-d6) 0.9-1.9 (m, 11H, cyclohexyl), 1.39 (d, J ) 6.9
Hz, 3H, CH3CH), 2.3 (s, 3H, CH3SO3-), 3.68 (q, J ) 6.9 Hz,
1H, CH3CH), 3.78 (d, J ) 6.1 Hz, 2H, OCH2), 4.0 (s, 2H, ArCH2-
NH), 6.96 (m, 2H, H3, H5), 7.36 (m, 2H, H2, H6), 7.6, 7.87 (2
s, 2H, CONH2), 8.95 (br s, 2H, NH2+); MS m/z 290 (M•+), 246,
218, 203, 107 (100). Anal. (C17H26N2O2‚CH3SO3H) C, H, N,
S.
Meth od B (Sch em e 2): Alk yla tion s w ith 2-Ch lor oa c-
eta m id e. A portion of 17.5 g (0.065 mol) of 4-(2-chloroben-
zoxy)aniline hydrochloride was mixed with 13.6 g (0.162 mol)
of sodium bicarbonate (0.162 mol) and 6.06 g (0.065 mol) of
2-chloroacetamide in anhydrous ethanol (300 mL). The mix-
ture was refluxed for 40 h, filtered, and evaporated. The crude
residue was taken up with water, extracted with ethyl acetate
(4 × 40 mL), washed with brine, evaporated, and treated with
the stoichiometric amount of 2 N HCl; the crude hydrochloride
was recrystallized from anhydrous ethanol (9.1 g, 41%) to give
2-[[4-(3-ch lor oben zoxy)p h en yl]a m in o]a ceta m id e, h yd r o-
ch lor id e (13): 1H NMR (80 MHz, DMSO-d6) 3.87 (s, 2H,
NHCH2CO), 5.1 (s, 2H, ArCH2O), 7.0 (m, 2H, H3, H5), 7.26
(m, 2H, H2, H6), 7.2-7.9 (m, 6H, CONH2, H2′, H4′, H5′, H6′);
MS m/z 290 (M•+), 246, 165 (100). Anal. (C15H15ClN2O2‚HCl)
C, H, Cl, N.
To a solution of 4-(3-chlorobenzoxy)benzyl alcohol (15 g,
0.0603 mol) in anhydrous THF (120 mL) was added 0.9 g
(0.00243 mol) of tetrabutylammonium iodide at room temper-
ature. To the stirred mixture was added 2.41 g (0.0603 mol)
of 60% sodium hydride portionwise. After stirring for 1 h at
room temperature, 7.5 g (0.080 mol) of 2-chloraacetamide in
anhydrous THF (20 mL) was added. The mixture was heated
at 50 °C for 18 h and then treated with an excess of 0.1 N HCl
(50 mL), the THF was evaporated, and the aqueous suspension
was extracted with ethyl acetate (3 × 40 mL), washed with
brine, and evaporated. The crude residue was chromato-
graphed on silica gel (CH2Cl2-CH3OH-30% NH4OH, 170:30:
2) to afford 13.9 g (67%) of 2-[4-(3-ch lor ob en zoxy)b en z-
oxy]a ceta m id e, h yd r och lor id e (14): 1H NMR (200 MHz,
CDCl3) 3.96 (s, 2H, OCH2CONH2), 4.51 (s, 2H, ArCH2OCH2-
CONH2), 5.04 (s, 2H, ArCH2OAr), 5.6, 6.5 (2 br s, 2H, CONH2),
6.94 (m, 2H, H3, H5), 7.2-7.5 (m, 6H, H2, H6, H2′, H4′, H5′,
H6′); MS m/z 305 (M•+), 247, 125 (100). Anal. (C17H19ClN2O2)
C, H, Cl, N.
Biological Testin g. Maxim al Electr osh ock Test (MES):
Male Crl:CD-1(ICR)BR mice (Charles River, Italy) weighing
between 19 and 21 g and male Crl:(WI)BR rats (Charles River,
Italy) weighing between 190 and 210 g at time of testing were
used. Animals were housed in groups of 10 and kept in a
temperature (21 ( 1 °C-controlled) and relative humidity
(60%)-controlled room on a 12-h light/dark cycle (lights on
between 06:00 and 18:00 h). The procedure described by White
et al.18 was used. Briefly, an electrical stimulus sufficient to
produce a hindlimb tonic extensor response in at least 97% of
control animals was delivered using an Ugo Basile electro-
convulsive generator (model ECT UNIT 7801). The stimulus
was delivered intra-aurally through clip electrodes in both rats
(0.2 s of a 160-mA shock, with a pulse train of 60 Hz having
a pulse duration of 0.4 ms19) and mice (0.7 s of a 28-mA shock,
with a pulse train of 80 Hz having a pulse duration of 0.4 ms20).
The acute effects of compounds administered 60 min orally
(po) or 30 min intraperitoneally (ip) before MES induction were
examined. The volume of administration was 5 mL/kg.
Complete suppression of the hindlimb tonic extensor compo-
nent of seizures was taken as evidence of anticonvulsant
activity. The ED50 of each compound (95% confidence interval)
was calculated using Probit analysis.21 Group sizes of 10-20
animals/dose were used.
Ch em ica lly In d u ced Seizu r es: For tonic extensor sei-
zures, male Crl:CD-1(ICR)BR mice (Charles River, Italy)
weighing between 22 and 24 g were used under the same
experimental conditions as reported above. The doses of
chemical convulsants used were those able to induce tonic
extensor convulsions in at least 97% of vehicle-treated mice.
These doses were bicuculline (BIC), 0.6 mg/kg intraventricu-
larly (icv);22 picrotoxin (PTX), 6 mg/kg subcutaneously (sc)23
(with modifications, i.e., the hindlimb tonic extension was used
as end point); 3-mercaptopropionic acid (3-MPA), 60 mg/kg
(sc)22 (with modifications, i.e., the hindlimb tonic extension was
used as end point); strychnine (STRY), 0.55 mg/kg (iv)24 (with
modifications, i.e., the hindlimb tonic extension was used as
end point). The compounds were orally administered to mice
60 min before either iv administration of BIC and STRY or
subcutaneous injection of PTX and 3-MPA. Mice were treated
with a dose of 85 mg/kg (sc) PTZ according to the method
described by Lo¨scher and Schmidt.24 This dose of PTZ induces
seizures in at least 97% of mice treated. Compounds were
administered ip to mice 30 min before a sc administration of
PTZ. Mice were individually housed and observed for the
2-[[4-(3-Ch lor ob en zoxy)b en zyl]a m in o]-N,N-d im et h -
yla ceta m id e, Hyd r och lor id e (8). Ethyl ester 11 (3 g, 8.99
mmol) was dissolved in diethylamine (70 mL), and the mixture
was heated at 60 °C for 7 h. After standing overnight at room
temperature, the solution was evaporated and the residue
chromatographed on silica gel (CHCl3-CH3OH-30% NH4H,
98:2:0.2) to give 0.7 g (22%) of a colorless fluid which was
transformed into its hydrochloride salt: 1H NMR (200 MHz,
DMSO-d6) 2.86, 2.89 (2 s, 6H, N(CH3)2), 3.9-4.1 (m, 4H, CH2-
NHCH2CO), 5.15 (s, 2H, ArCH2O), 7.04 (m, 2H, H3, H5), 7.3-
7.6 (m, 6H, H2, H6, H2′, H4′, H5′, H6′), 9.3 (br s, 2H, NH2+);
MS m/z 332 (M•+), 260, 246, 231, 125 (100%). Anal. (C18H21
ClN2O2‚HCl) H, Cl, N; C: calcd, 57.74; found, 57.07.
-
2-[4-(3-Ch lor oben zoxy)ben za m id o]a ceta m id e (17). A
solution of 4-(3-chlorobenzoxy)benzoic acid (13.5 g, 0.05 mol)
was dissolved in anhydrous DMF (250 mL). To this solution
was added 10.83 g (0.0668 mol) of carbonyldiimidazole (CDI)

New Class of 2-[(Arylalkyl)amino]alkanamides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 589
presence of loss of righting reflexes lasting at least 3 s for the
30 min following treatment with the chemical convulsant. The
volume of administration was 5 mL/kg. The ED50 of each
compound (95% confidence interval) was calculated using
Probit analysis.21 Group sizes of 10-20 animals/dose were
normally used.
Refer en ces
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Rotor od Test: Male Crl:CD-1(ICR)BR mice (Charles River,
Italy) weighing between 22 and 24 g were used. Animals were
housed in the same environmental conditions as reported
above. The compounds were administered po to trained
mice 60 min before being placed on an Ugo Basile rotorod
(special model). This rotorod had a 3-cm diameter rod which
rotated at 10 rpm. The number of animals falling over a 2-min
test period was monitored.25 The toxic dose causing 50% of
treated animals to fall from the rotorod (TD50) of each
compound was calculated. This dose was combined with the
effective dose of each anticonvulsant in each test necessary to
protect 50% of the animals treated (ED50) in order to calculate
therapeutic indexes (TI) of each compound relative to the
specific anticonvulsant test. The acute effects of compounds
administered (po) 60 min before the test were examined. The
volume of administration was 5 mL/kg. The ED50 of each
compound (95% confidence interval) was calculated using
Probit analysis.21 Group sizes of 10-20 animals/dose were
normally used.
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under Registry Numbers are listed in the Supporting Informa-
tion.
Ack n ow led gm en t. The skillful technical assistance
of Mr. Gianni Scappi, Piero Sansonna, Maurizio Meroni,
Vito Antongiovanni, and Ciro Napolitano is gratefully
acknowledged. We also thank Mr. Luciano Bedoni
(microanalyses) of the Pharmaceutical Development
Department of Pharmacia & Upjohn, Nerviano.
R egist r y Nu m ber s: 4-(3-chlorobenzoxy)benzalde-
hyde (59067-43-5), 4-(2-chlorobenzoxy)benzaldehyde
(70627-21-3), 4-(3-fluorobenzoxy)benzaldehyde (66472-
57-2), 4-(2-fluorobenzoxy)benzaldehyde (70627-20-8),
4-(4-chlorobenzoxy)benzaldehyde (59067-46-8), 4-[3-(tri-
fluoromethyl)benzoxy)benzaldehyde (70627-18-8), 4-(2-
furfuryloxy)benzaldehyde (149806-87-1), 4-(phenylcar-
bamoyl)benzaldehyde (65854-93-5), 4-benzylbenzaldehyde
(67468-65-9), 3-benzoxybenzaldehyde (1700-37-4), 2-ben-
zoxybenzaldehyde (5896-17-3), 4-[(phenylamino)benzyl]-
benzaldehyde (BRN 3265597), 4-(3-chlorobenzoxy)-
aniline, hydrochloride (130461-76-8), 4-(3-chlorobenzoxy)-
benzyl alcohol (134561-23-2), 4-(3-chlorobenzoxy)benzoic
acid (84403-70-3), L-alaninamide, hydrochloride (33208-
99-0), L-serinamide, hydrochloride (65414-74-6), D-seri-
namide, hydrochloride (122702-20-9), L-serinamide, N-
methyl, hydrochloride (90762-13-3), D-serinamide,
N-methyl, hydrochloride (90762-14-4), L-leucinamide,
N-methyl, hydrochloride (99145-71-8), D-leucinamide,
N-methyl, hydrochloride (108131-54-0), L-valinamide,
N-methyl, hydrochloride (87105-26-8), D-valinamide,
N-methyl, hydrochloride (132204-10-5), L-threonina-
mide, N-methyl, hydrochloride (79009-37-3), L-methio-
nine, N-methyl, hydrochloride (94847-37-7), (S)-2-ami-
nobutanamide, hydrochloride (53726-14-0), (R)-2-ami-
nobutanamide (73240-11-0), L-phenylalaninamide, N-
methyl, hydrochloride (35373-92-3), D-phenylalaninamide,
N-methyl, hydrochloride (144836-90-8).
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PNU-151774E, a New Anticonvulsant Compound in the Model
of Global Ischaemia in Gerbils; Society for Neuroscience, New
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Su p p or tin g In for m a tion Ava ila ble: Synthesis, spectro-
scopic data, and physicochemical data for previously unre-
ported aldehyde precursors (3 pages). Ordering information
is given on any current masthead page.

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