Enaminones 9. Further studies on the anticonvulsant activity and potential type IV phosphodiesterase inhibitory activity of substituted vinylic benzamides

Article abstract of DOI:10.1016/j.bmc.2005.09.023

Structure-activity relationship studies were employed to synthesize a series of 3- and 3,4-substituted benzamides from 3-amino-2-cyclohexenones. An improved method for the synthesis of benzamides from 3-amino-2-cyclohexenones is presented which provided s

Full text of DOI:10.1016/j.bmc.2005.09.023

Bioorganic & Medicinal Chemistry 14 (2006) 997–1006
Enaminones 9. Further studies on the anticonvulsant activity
and potential type IV phosphodiesterase inhibitory activity
of substituted vinylic benzamides
Alan J. Anderson,a, Jesse M. Nicholson,a Oladapo Bakare,a Ray J. Butcher,a
Tiffany L. Wilsonb,à and K. R. Scottb,*
aDepartment of Chemistry, Graduate School, Howard University, Washington, DC 20059, USA
bDepartment of Pharmaceutical Sciences, School of Pharmacy, Howard University, Washington, DC 20059, USA
Received 19 August 2005; revised 6 September 2005; accepted 6 September 2005
Available online 10 October 2005
Abstract—Structure–activity relationship studies were employed to synthesize a series of 3- and 3,4-substituted benzamides from 3-
amino-2-cyclohexenones. An improved method for the synthesis of benzamides from 3-amino-2-cyclohexenones is presented which
provided significantly higher yields (71–79%) for the reported compounds. NMR and X-ray structural analyses were undertaken to
note the possible intra- and intermolecular interactions of the synthesized analogs. Molecular modeling studies were used to deter-
mine the minimized configuration and were compared to their X-ray structures for correlation. These new entities were evaluated as
potential anticonvulsants and type IV phosphodiesterase inhibitors (PDE4).
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cellular responses is associated with elevated levels of
cAMP. It has been shown that among the 11 major fam-
ilies,1,7 PDE4 (cAMP-specific) is the predominant PDE
subtype in such cells. Inhibition of PDE4 in inflammato-
ry cells influences several of the cell-specific responses.
PDE4 activity, when localized in airways of the smooth
muscle cells, is associated with several inflammatory
states, for example, asthma, chronic obstructive and pul-
monary disease. Thus, selective inhibition of PDE4
could potentially be a mechanism of treating these dis-
eases.7 Asthma is one of the most common chronic dis-
eases8 worldwide and antiasthma medications are widely
prescribed. Asthma treatments account for 1–2% of the
total health budget in industrialized countries.9,10 The
prototype agent was (R)-rolipram 111 (Fig. 1). However,
1 exhibited several untoward side effects, such as emesis
and nausea, which has precluded its clinical develop-
ment. Ariflo, 212 (Fig. 1) evolved from this initial re-
search. Ariflo was a potent second-generation PDE4
inhibitor followed with a decreased potential for side ef-
fects. Additionally, it has been noted that a number of
benzamide derivatives using the rolipram pharmaco-
phore, 1 (Fig. 1) possessed selective inhibition of cyclic
AMP-specific phosphodiesterase (PDE4) for use as anti-
asthmatics. The research of Ashton et al. led to a series
of active benzamides 3 (Fig. 1).13 We were intrigued with
the similarity of the active amides 3 with the enaminone
Cyclic nucleotides are soluble second messengers found
in all tissues throughout the body. Many drugs, hor-
mones, and other agents modify physiological processes
by causing changes in the steady state levels of cyclic
adenosine monophosphate (cAMP) and cyclic guano-
sine monophosphate (cGMP) in cells. Levels of these
nucleotide second messengers can be controlled by alter-
ing the activity of the cyclic nucleotide phosphodiester-
ases (PDEs) that degrade them. PDE isoenzyme
families have been classified on the basis of their sub-
strate specificities (cAMP or cGMP), kinetic characteris-
tics (Km and Vmax), and their regulation by specific
inhibitors or activators.1–6 In a wide range of immune
and inflammatory cells, including neutrophils, T-lym-
phocytes, macrophages, and eosinophils, inhibition of
Keywords: Enaminones; Benzamides; Base-catalyzed parallel synthesis;
PDE4 inhibition; Anticonvulsant evaluation; X-ray analysis; QSAR
analysis.
*
Corresponding author. Tel.: +1 202 806 7288; fax: + 1 202 806
7805; e-mail: kscott@howard.edu
Present address: Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, MA 02138, USA.
à
Present address: Department of Natural Sciences, ACAD 216,
Albany State University, Albany, GA 31705, USA.
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.09.023

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A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
CO2H
NH
NH
O
O
O
O
O
CN
R
H3CO
H3CO
H3CO
1
2
3
Figure 1. Structures of (R)-rolipram 1, ariflo 2, and an active pharmacophore (after Ashton13).
pharmacophore that we have studied (Fig. 2). The Ash-
ton pharmacophore could be adapted to this area as well
(Fig. 3). We herein report the results of our study as well
as further studies of the vinylic benzamides as potential
anticonvulsants.
benzoyl chloride 15a–e to 10a–c, producing the amide
salt intermediate 10d. The reaction mixture was
quenched with water and neutralized with HCl, which
liberated the amide from its salt and destroyed the ex-
cess NaH to yield the crude enamides 11a–l and 14a–c.
Table 1 provides the yields of the enamides after purifi-
cation in this procedure in comparison to other
methods.
2. Chemistry
The synthesis of the benzamides was previously reported
from our laboratories.17 This procedure (Scheme 1)
involved amination of the respective b-diketones25
followed by acylation with the respective benzoyl chlo-
rides 15, and using triethyl-amine as the acid scavenger
to provide the target compound, 11. Careful monitoring
of this latter reaction minimized the possible a-acyla-
tion, 16. The synthesis of vinylogous amides has been
extensively reported,25–32 however the base-catalyzed
coupling of enaminones from cyclohexane-1,3-diones
with substituted benzoyl chlorides has only recently
been reported in our laboratories.22
The above procedure was subjected to solution-phase
parallel synthesis in a RadleyÕs Carousel reaction station
to generate a 12-member library of desired benzamide
derivatives, Table 2 provides data on the new benza-
mides generated by this method.
As noted in Table 2, the yields ranged from 63% to
90%, with the yields of the dimethoxy catechol ethers
11g–i being the lowest of the series. The ClogP values
ranged from 1.21 (3,4-dimethoxy analog, 11g) to 3.83
(3-butoxy-4-methoxy, 11l).33
Scheme 1 has been modified as shown in Scheme 2.
3-Aminocyclohex-2-enone, 10a, 3-amino-5-methylcyclo-
hex-2-enone, 10b, or 3-amino-5,5-dimethylcyclohex-
2-enone, 10c, was prepared either by the method of
Baraldi et al.31 aminating the respective diketone precur-
sor with ammonium acetate and acetic acid in benzene
and collecting the water produced in a Dean–Stark trap,
or by treatment with gaseous ammonia in benzene with
the analogous water collection method used previous-
ly.17 N-Acylation of enaminones producing 11 has been
made use of by several laboratories as well;27,28 however,
these methods were limited in several areas: (1) the
reported yields were moderately low, ranging from 6%
to 32%; (2) the reaction conditions varied, with no single
procedure being ideal; and (3) extensive purification
techniques were needed to obtain the desired product.
The factors contributing to the above include: (1) poor
nucleophilicity of the cyclic enaminone system; (2) com-
peting side reactions, that is, O, Ca, and N-acylation, in
theory, can occur; and (3) the rapacious HCl by-product
which, in theory, can consume an equivalent amount of
unreacted enaminone 10, thus cutting the theoretical
yield by 50%. These obstacles make this method limited
as an attractive candidate for parallel synthesis or other
high throughput synthetic methods. Our current meth-
odology involves the N-deprotonation of the enaminone
system with 2 equiv of sodium hydride in tetrahydrofu-
ran (THF) under a nitrogen atmosphere.13 The subse-
quent reaction involved the addition of 1 equiv of the
3. IR and NMR analysis
The amido and enaminone C@O stretching frequen-
cies for all of the benzamides, as well as the N–H
stretching frequency of each imide, were identified in
the infrared (IR) spectra (see Section 9). The presence
1
of the amido proton in the H NMR spectra in each
of the imides ranged from d 8.10 to 9.81 ppm and ver-
ified the presumption that the reaction occurred as
predicted. As reported previously,17 the vinyl proton
assignments were indicative of hydrogen bonding be-
tween it and the carbonyl oxygen of the amide group
and were deshielded appearing downfield ranging from
d 6.76 to 6.82 ppm. The current study also verified
this downfield tendency with the vinyl proton appear-
ing at d 6.50–6.82 ppm. The presence of the catechol
ether moiety was also confirmed with 1H NMR
employing integration.
4. X-ray crystallography
X-ray analyses of the 3-chlorobenzamide, 11f, and two
catechol ethers 11g and i were performed. The results
are shown in Figures 1–3, respectively, and the atomic
coordinates provided in Tables 5–7. In our original inves-
tigation,17 the X-ray crystal structures of two benzamides
that were determined {methyl 4-(4-methoxy-benzoyl-
amino)-6-methyl-2-oxocyclohex-3-ene carboxylate (11,

A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
999
Cl
N
X
H
H
H
N
N
N
X
n
R1
R2
R1
R2
R1
R2
O
O
O
R
R
R
7
6
5
CH3
CH3
H
N
H
n
O
N
OH
N
n
N
O
R1
R2
R1
R2
R1
R2
O
O
O
R
R
R
8
4
9
O
O
CH3
H
HN
R
NH2
N
O
N
X
R1
R2
R1
R2
R1
R2
O
O
O
R
R
11
10
12
O
S
H
N
X
O
R1
R2
O
R
13
Figure 2. Enaminones and their analogs (after Scott et al.14–24).
R = CO2CH3; R1 = CH3; R2 = H; X = 4-OCH3) and
4-cyano-N-(5-methyl-3-oxocyclohex-1-enyl)benzamide
(11, R = H; R1 = CH3; R2 = H; X = 4-CN)}, demon-
strated strong hydrogen bonding between the vinyl pro-
ton and the carbonyl oxygen of the amido group in
each structure providing a pseudo-three-ring structure.
By contrast, however, 11f,g, and i displayed no such
property. Instead, these latter compounds resembled
benzylamines as shown by Kubicki and Codding34 in
which intermolecular, rather than intramolecular, hydro-
gen bonding was displayed. In compound 11f (Fig. 4),
intermolecular hydrogen bonding occurred between the
carbonyl oxygen (O2A) and the hydrogen on the adjacent
amido group; while in 11g and i, bonding occurred be-
tween the aromatic hydrogen on C2 (Figs. 5 and 6), the
N–H hydrogen of the amido group, and one of the hydro-
gens on C13 (Fig. 5) or C15 (Fig. 6), each with the adja-
cent carbonyl oxygen.

1000
A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
5. Pharmacology
O
O
Pharmacological testing of the compounds listed in
Table 2 has been provided by the Antiepileptic Drug
Development (ADD) Program, Epilepsy Branch Neuro-
logical Disorders Program, National Institute of Neuro-
logical Disorders and Stroke (NINDS). These testing
procedures have been described.35–37 Phase I study in-
volved three tests: maximal electroshock seizure
(MES), subcutaneous pentylenetetrazol (scPTZ), and
neurologic toxicity (Tox). Intraperitoneal (ip) adminis-
O
HN
R
HN
R
OCH3
R1
R2
R1
R2
O
O
14
11
Figure 3. Potential PDE4 analogs.
O
Cl
OH
NH2
NH3
R1
R2
R
R1
R2
+
O
O
X
R
15
4
X
10
(C2H5)3N
O
NH2
O
O
H
N
R1
R2
R1
R2
X
X
O
R
R
16
11
Scheme 1.
O
Cl
NH2
N
NaH/THF
R1
R2
+
O
R1
R2
X
O
15a X=H
15b X=3-Cl
15c X=3,4-di OCH3
15d X=3-O(CH2)3CH3;
10a R1=R2=H
10b R1=CH3; R2=H
10c R1=R2=CH3
10d
4-OCH3;
15e X=3-O-cyclopentyl;
4-OCH3
O
H
N
R1
R2
O
X
11a-c X=H;
11d-f X=3-Cl;
11g-i X=3,4-di OCH3
11j-l X=3-O(CH2)3CH3,
4-OCH3;
14a-c X=3-O-cyclopentyl;
4-OCH3
Scheme 2.

A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
Table 1. Yields of benzamides 11a–c compared to reported values
1001
Compound
R1
R2
Reaction time (min)
Mp (ꢁC)
Mp (ꢁC) (literature)
Yield (%)
Yield (%) (literature)
11a
11b
11c
H
H
40
40
40
177–178
135–137
144–146
178–17928
136.5–1388
146–14826
79
71
76
14.926
29.425
25.027
CH3
CH3
H
CH3
Table 2. Parallel solution-phase synthesis of benzamides 11d–l and 14a–c
Compound
R1
R2
Mp (ꢁC)
Yield (%)
ClogPa
11d
11e
11f
11g
11h
11i
H
H
138–139
128–129
138.5–140
187.5–189
152–154
163–165
120–121
160–161
119–121
171–172
128–129
149–150
79
84
90
63
71
69
80
82
81
85
84
85
2.25
2.77
3.29
1.21
1.73
2.24
2.79
3.31
3.83
2.68
3.20
3.72
CH3
CH3
H
H
CH3
H
CH3
CH3
H
H
CH3
H
11j
11k
11l
CH3
CH3
H
H
CH3
H
14a
14b
14c
CH3
CH3
H
CH3
a Ref. 33.
Figure 4. X-ray crystal structure of 3-chloro-N-(5,5-dimethyl-3-oxocyclohex-1-enyl)benzamide (11f). Note intramolecular hydrogen boding between
O2A and the hydrogen on N1.
tration of the test compounds was carried out as a
suspension in 0.5% methylcellulose. As previously
reported,14–24 active compounds in the phase I evalua-
tion were subsequently tested either for an ED50 quanti-
tation in mice (phase II) or qualitatively in rats (phase
VIA). The anticonvulsant screening project (ASP) classi-
fications are as follows: class 1 = activity at 100 mg kgÀ1
or less; class 2 = activity > 100 mg kgÀ1, but less than
300 mg kgÀ1; class 3 = no activity at doses up to and
including 300 mg kgÀ1. Further, to differentiate the re-
sults between distinct rodent species, several of the ana-
logs were evaluated for oral (po) activity (phase VIA) in
the rat. Data are summarized in Table 3. Several of the
compounds (11e and l) were further evaluated by a 6 Hz
test. It has recently been found that the above evaluative
tests may miss novel antiepileptic drugs that may be use-
ful for the treatment of therapy resistant partial seizures
(e.g., levetiracetam). In contrast to the MES test, leveti-
racetam has been found to be highly effective (ED50(mice)
19 mg kgÀ1) in the 6 Hz model originally described by
Toman et al.38 Thus, the ADD program has determined
that selected moieties that were found to be inactive in
either the MES or scPTZ tests will be screened for their
ability to block seizure induced by a low-frequency
(6 Hz), long-duration (3 s) stimulus delivered through
corneal electrodes.

1002
A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
Table 4. PDE4 evaluation
Compound
% Inhibition results (10 lM)a
14a
14b
14c
À7
35
6
a Negative values correspond to stimulation of binding or enzyme
activity. Significance criteria = P50% of maximum inhibition.
7. Results and discussion
7.1. Anticonvulsant evaluation
The current synthetic approach varied from our previous
studies that utilized the Free–Wilson analysis41 success-
Figure 5. X-ray crystal structure of 3,4-dimethoxy-N-(3-oxocyclohex-
1-enyl)benzamide (11g).
Table 5. Atomic coordinates (·104) and equivalent isotropic displace-
ment parameters (ꢀ2 · 103) for 3-chloro-N-(5,5-dimethyl-3-oxocyclo-
hex-1-enyl)benzamide (11f)
X
Y
Z
U(eq)
Cl
2154(1)
1219(1)
5613(1)
7013(1)
4256(2)
2401(2)
3012(2)
3949(2)
4250(2)
3622(2)
2688(2)
4691(2)
4744(2)
5716(2)
6161(2)
5572(2)
4370(2)
4080(2)
3979(2)
3854(2)
2580(1)
5095(1)
8706(1)
5876(2)
2970(2)
3835(2)
4167(2)
3622(2)
2756(2)
2414(2)
5080(2)
6871(2)
7257(2)
8314(2)
8901(2)
8810(2)
7495(2)
9555(2)
9260(2)
27(1)
27(1)
25(1)
17(1)
19(1)
19(1)
19(1)
23(1)
25(1)
23(1)
19(1)
16(1)
18(1)
18(1)
20(1)
17(1)
17(1)
21(1)
23(1)
O(1)
O(2)
N(1)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
2562(2)
5667(2)
4135(2)
1519(3)
2477(2)
1963(3)
511(3)
Figure 6. X-ray crystal structure of 3,4-dimethoxy-N-(5,5-dimethyl-3-
oxocyclohex-1-enyl)benzamide (11i).
À424(3)
75(3)
2903(3)
5095(2)
4887(2)
5922(3)
7318(2)
7144(2)
6413(2)
6202(3)
8653(3)
6. PDE4 analysis
PDE4 inhibitory studies on 14a–c were performed by
MDS Pharma Services, Taipei, Taiwan, Republic of
China employing standard assay procedures,39,40 on hu-
man U937 cells with Ro 20-1724 as the reference com-
pound (IC50 1.22 lM). The results are summarized in
Table 4. Significance criterion was P50% of maximum
inhibition.
U(eq) is defined as one-third of the trace of the orthogonalized Uij
tensor.
Table 3. Anticonvulsant evaluation
Compound
Anticonvulsant resultsa
3-Chloro analogs:
11d
11e
No activity or toxicity noted at 10–100 mg kgÀ1
Marginal toxicity at 100 mg kgÀ1; no protection; 6 Hz screen: 2/4 animals protected at 100 mg kgÀ1
neurotoxicity noted at that 100 mg kgÀ1 at 30 min and 1 h
Class 3
;
11f
3,4-Dimethoxy analogs:
11g
11h
11i
Class 3
Inactive in mice screen; inactive in oral rat screen
Marginal toxicity at 100 mg kgÀ1; no protection inactive in 6 Hz screen
3-n-Butoxy-4-methoxy analogs:
11j
11k
11l
No protection; some toxicity at 100 mg kgÀ1
Toxic: 3/8b animals toxic at 100 mg kgÀ1
Class 3
3-Cyclopentyloxy-4-methoxy analogs:
14a
14b
14c
Increased toxicity (3/8)b at 100 and at 300 mg kgÀ1 at 30 min and (1/2)b at 300 mg kgÀ1 at 4 h
Increased toxicity (3/8)b at 100 and at 300 mg kgÀ1 at 30 min and (1/2)b at 300 mg kgÀ1
Increased toxicity (1/8)b at 100 mg kgÀ1
a Phase I in mice activity—class 1 = activity at 100 mg kgÀ1 or <; class 2 = activity between 100 and 300 mg kgÀ1; class 3 = no activity at 300 mg kgÀ1
b Data in parenthesis under toxicity indicate the number of animals exhibiting toxicity (numerator) over the number of animals tested (denominator).
.

A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
1003
Table 6. Atomic coordinates (·104) and equivalent isotropic displace-
ment parameters (ꢀ2 · 103) for 3,4-dimethoxy-N-(3-oxocyclohex-1-
enyl)benzamide (11g)
hex-1-enyl)benzamide (11, R = H; R1 = R2 = CH3; X =
4-OCH3) being modestly active [po MES ED50(rat)
183.5 mg kgÀ1
,
TD50 > 400 mg kgÀ1 PI (PI = TD50/
X
Y
Z
U(eq)
ED50) > 2.2]. Thus, a variety of disubstituted benzamides
were prepared (Table 2). As noted in Table 3, phase I eval-
uation of the 3-chloro derivatives indicated that they were
universally inactive. This paralleled the initial work by
Foster et al., who synthesized comparable 4-chloro ana-
logs.17 3,4-Dimethoxy compounds were also inactive, as
were the 3-n-butoxy-4-methoxy series with increased tox-
icity. Disubstitution of 4-methoxy pharmacophore thus
leads to inactive compounds. The 3-cyclopentyloxy-4-
methoxy series proved the most toxic, with all analogs
exhibiting significant toxicity at all doses tested. Although
the 6 Hz test was employed, no viable candidates were
noted.
O(3)
O(4)
O(7)
O(10)
N
4421(1)
643(1)
243(1)
2485(1)
18(1)
17(1)
20(1)
28(1)
16(1)
14(1)
15(1)
14(1)
18(1)
14(1)
19(1)
15(1)
15(1)
15(1)
15(1)
17(1)
18(1)
18(1)
22(1)
22(1)
1717(1)
9232(1)
13441(1)
7274(1)
6020(2)
6037(2)
4579(2)
6006(2)
3071(2)
172(2)
À524(1)
5099(1)
7869(2)
4139(1)
2837(2)
3306(2)
2165(2)
4024(2)
493(2)
À1042(1)
À2641(1)
À1836(1)
À886(1)
À297(1)
68(1)
C(1)
C(2)
C(3)
C(31)
C(4)
C(41)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
907(1)
À152(1)
45(1)
À2235(2)
12(2)
3076(2)
4551(2)
7657(2)
8566(2)
10462(2)
11707(2)
10809(2)
9031(2)
7640(2)
À730(1)
À1098(1)
À1249(1)
À2283(1)
À2213(1)
À2707(1)
À3293(1)
À3362(1)
À2872(1)
1187(2)
4129(2)
5023(2)
6082(2)
6977(2)
6818(2)
4937(2)
4664(2)
7.2. PDE4 analysis
From Table 7, only 14b provided modest inhibition
(30%) that was not significant. Thus, the aromatic ring,
in addition to the 3-cyclopentyloxy, 4-methoxy substitu-
tion, was deemed essential in PDE4 activity.
U(eq) is defined as one-third of the trace of the orthogonalized Uij
tensor.
8. Conclusion
In conclusion, we have shown a rapid, versatile method
for the preparation of vinylic benzamides readily adapt-
able to combinatorial synthesis. This method also
provides higher yields than those previously reported.
X-ray crystal analyses and NMR studies have indicated
that the benzamides synthesized in this study are able
to form intermolecular hydrogen bonds; however,
they were devoid of anticonvulsant activity or PDE4
activity.
Table 7. Atomic coordinates (·104) and equivalent isotropic displace-
ment parameters (ꢀ2 · 103) for 3,4-dimethoxy-N-(5,5-dimethyl-3-oxo-
cyclohex-1-enyl)benzamide (11i)
X
Y
Z
U(eq)
N
3662(2)
2740(2)
4875(1)
1984(1)
988(2)
1597(1)
4623(2)
3211(2)
1667(1)
5431(1)
7595(2)
3818(2)
3902(2)
3177(2)
4066(3)
2327(2)
891(2)
45(1)
68(1)
61(1)
61(1)
77(1)
42(1)
46(1)
47(1)
81(1)
46(1)
70(1)
53(1)
52(1)
43(1)
41(1)
47(1)
49(1)
53(1)
54(1)
100(1)
85(1)
58(1)
O(3)
O(4)
O(7)
O(9)
C(1)
C(2)
C(3)
C(31)
C(4)
C(41)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
À1467(1)
À1325(1)
863(1)
2984(1)
392(1)
3529(2)
2851(2)
3313(2)
1581(3)
4480(2)
6132(2)
5133(2)
4666(2)
2980(2)
3321(2)
2261(2)
1955(2)
2794(2)
4345(2)
4990(3)
5319(2)
4228(2)
À255(1)
À814(1)
À1577(1)
À740(1)
À1287(1)
À102(1)
460(1)
9. Experimental
9.1. Chemistry
2236(2)
2976(2)
4691(2)
5290(2)
6167(2)
6787(2)
6388(2)
6018(2)
5389(3)
7348(3)
4916(2)
Melting points were determined with Thomas–Hoo-
ver capillary melting point apparatus. The IR spectra
were obtained on a Nicolet Magna-IR 560 spectrom-
eter. The samplers were recorded as KBr pellets. The
1H and 13C NMR spectra were determined either on
a Bruker 1 Ultra Shield-400 MHz NMR spectrome-
959(1)
2207(1)
2276(1)
2929(1)
3554(1)
3391(1)
4037(1)
3161(1)
2812(1)
ter or
a General Electric QE 300 MHz NMR
spectrometer. The samples were dissolved either in
deuterated dimethylsulfoxide (DMSO-d6) or chloro-
form (CDCl3) containing 0.03% tetramethylsilane
(TMS) as an internal reference. Elemental analyses
(C, H, N, and Cl) were determined by Schwarzkopf
Microanalytical Laboratory, Woodside, NY 11377,
USA. The analytical results for the elements were within
0.4% of the theoretical values. 3-Aminocyclohex-2-en-
one, 10a,28 3-amino-5-methylcyclohex-2-enone, 10b,17
and 3-amino-5,5-dimethylcyclohex-2-enone, 10c,28 were
prepared by the literature methods. All reagents were
obtained from Aldrich Chemical Company, Milwaukee,
WI, USA. Compounds 15d and e were prepared by
literature methods.13
U(eq) is defined as one-third of the trace of the orthogonalized Uij
tensor.
fully employed by Craig.42,43 However, in this study, our
prior research17 provided us with a different approach:
that was used previously with an investigation of the imi-
dooxy anticonvulsants,44 employing the Topliss ap-
proach.45,46 This was due to inactivity of the initial
series with only 4-methoxy-N-(5,5-dimethyl-3-oxocyclo-

1004
A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
9.2. General synthetic procedure
9.2.4. 3,4-Dimethoxy-N-(3-oxocyclohex-1-enyl)benzam-
ide (11g). Yield: 63%; yellow solid from EtOAc/MeOH,
mp: 187.5–189 ꢁC. mmax 3267.71, 1680.23, 1634.40 cmÀ1
Employing a RadleyÕs Carousel Reaction Station, com-
prised of twelve reaction tubes (24 · 150 mm), the appro-
priate amino ketones, 10a–c, (0.75 g) and anhydrous
tetrahydrofuran (THF, 35 mL) were added under a
nitrogen atmosphere. Each reaction tube was then cau-
tiously treated with NaH [(2.4 equiv), 60% dispersion
in oil, previously washed with petroleum ether]. THF
(<6 mL) was used to rinse the residual NaH into each
reaction vessel. The reaction tubes were capped, magnet-
ically stirred, and refluxed for 25 min. After cooling to
room temperature, the appropriate benzoyl chloride,
15a–e (1.05 equiv), in dry THF (10 mL), was carefully
added to each tube. Each reaction vessel was capped
and stirred for an additional 10 min, the reaction then
quenched with 10 mL water. The mixtures of the individ-
ual reaction tubes were transferred to 250 mL Erlenmey-
er flasks, neutralized with concentrated HCl (ꢁ5 mL),
and transferred to a 250 mL separatory funnel contain-
ing dichloromethane (25 mL). After separation, the
aqueous phase was discarded, the organic phase was
washed successively with water (25 mL), 10% NaHCO3
(25 mL), and again with water (25 mL). The organic
phase was dried over sodium sulfate, evaporated in vac-
uo, and the resulting residue was washed twice with
anhydrous ether (25 mL). The crude compounds that
separated were recrystallized and characterized.
.
1
d H (DMSO-d6) 1.94 (2H, quint, J = 7.21 Hz CH2);
2.26 (2H, t, J = 6.87 Hz, CH2); 2.63 (2H, t, J = 5.62 Hz,
CH2); 3.83 (6H, s, 2· OCH3); 6.76 (1H, s, @CH); 7.07
(1H, d, J = 8.52 Hz, aromatic H); 7.44 (1H, d,
J = 2.08 Hz, aromatic H); 7.56 (1H, dd, J = 6.35 Hz, aro-
matic H); 9.32 (1H, s, NH). 13C (DMSO-d6) d 21.82;
28.16; 28.23; 36.97; 56.08; 56.18; 111.27; 111.53; 111.59;
111.66; 122.12; 126.52; 126.57; 148.76; 152.66; 157.54;
157.68; 166.50; 166.58; 199.24. Anal. Calcd for
C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.15; H, 6.05; N, 4.99.
9.2.5. 3.4-Dimethoxy-N-(5-methyl-3-oxocyclohex-1-enyl)-
benzamide (11h). Yield: 84%; white solid from EtOAc/
MeOH, mp: 168.5–169 ꢁC. mmax 3283.07, 1680.23,
1
1623.90 cmÀ1. d H (DMSO-d6) 1.03 (3H, d, J = 6.23 Hz
CH3); 2.03–2.73 (3H, m, cyclohexene ring); 3.84 (6H, s,
2· OCH3); 6.76 (1H, s, @CH); 7.07 (1H, d, J = 8.44 Hz,
aromatic H); 7.45 (1H, s, aromatic H); 7.57 (1H, d,
J = 8.38 Hz, aromatic H); 9.32 (1H, s, NH). 13C (DMSO-
d6) d 21.20; 29.20; 36.28; 45.09; 56.07; 56.16; 111.18;
111.28; 111.63; 112.10; 122.10; 122.15; 123.11; 126.49;
148.76; 152.68; 152.99; 156.90; 166.52; 167.27; 199.34.
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.43; H, 6.68; N, 4.66.
9.2.1. 3-Chloro-N-(3-oxocyclohex-1-enyl)benzamide (11d).
Yield: 79%; pale yellow crystals from ethyl acetate
(EtOAc), mp: 138–139 ꢁC. mmax 3339.41, 1685.35,
9.2.6. 3,4-Dimethoxy-N-(5,5-dimethyl-3-oxocyclohex-1-
enyl)benzamide (11i). Yield: 83%; light-yellow solid from
EtOAc/MeOH, mp: 163–165 ꢁC. mmax 3359.89, 1690.47,
1
1618.78 cmÀ1
.
d
1H (CDCl3) 2.10 (2H, quint,
1613.66, 1608.31 cmÀ1. d H (DMSO-d6) 1.04 (6H, s,
J = 6.54 Hz, CH2); 2.41 (2H, t, J = 6.78 Hz, CH2); 2.74
(2H, t, J = 5.73 Hz, CH2); 6.72 (1H, s, @CH); 7.28–7.81
(4H, m, aromatic ring); 8.10 (1H, s, NH). 13C (CDCl3) d
21.68; 28.59; 36.73; 112.77; 125.61; 127.72; 130.15;
134.97; 135.64; 156.17; 165.08; 200.30. Anal. Calcd for
C13H12ClNO2: C, 62.53; H,4.84; Cl, 14.20; N,5.61. Found:
C, 62.52; H, 4.67; Cl, 14.27; N, 5.59.
gem CH3); 2.16 (2H, s, CH2); 2.57 (2H, s, CH2); 3.84
(6H, s, 2 · OCH3); 6.79 (1H, s, @CH); 7.08 (1H, d,
J = 8.44 Hz, aromatic H); 7.46 (1H, s, aromatic H); 7.58
(1H, d, J = 8.34 Hz, aromatic H); 9.77 (1H, s, NH). 13C
(DMSO-d6) d 28.32; 32.78; 41.81; 50.56; 56.10; 56.17;
110.44; 111.29; 111.63; 122.16; 126.45; 148.76; 152.69;
155.44; 166.59; 167.27; 199.21. Anal. Calcd for
C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.05; H, 6.84; N, 4.63.
9.2.2. 3-Chloro-N-(5-methyl-3-oxocyclohex-1-enyl)benz-
amide (11e). Yield: 84%; white solid from EtOAc/MeOH,
mp: 168–169 ꢁC. mmax 3350.34, 1688.51, 1617.51 cmÀ1. d
1H (DMSO-d6) 1.13 (3H, d, J = 6.52 Hz, CH3); 2.07–2.79
(5H, cyclohexene ring); 6.71 (1H, s, @CH); 7.28–7.34
(4H, m aromatic ring); 8.18 (1H, s, NH). 13C (DMSO-d6)
d 21.00 (CH2), 29.31; 36.77; 44.91; 112.39; 125.55; 127.68;
130.20; 132.58; 135.05; 135.59; 155.41; 164.92; 200.28.
Anal. Calcd for C14H14ClNO2: C, 63.76; H, 5.35;
Cl, 13.44; N, 5.31. Found: C, 63.74; H, 5.25; Cl, 13.55; N,
5.30.
9.2.7. 3-n-Butoxy-4-methoxy-N-(3-oxocyclohex-1-enyl)benz-
amide (11j). Yield: 80%; pale-white solid from EtOAc, mp:
1
120–121 ꢁC. mmax 3283.07, 1675.11, 1623.90 cmÀ1. d H
(DMSO-d6) 0.94 (3H, d, J = 7.44 Hz CH3); 1.45 (2H,
quint, J = 7.35 Hz, CH2); 1.72 (2H, t, J = 6.87 Hz, CH2);
1.92 (2H, t, J = 5.98 Hz, CH2); 2.25 (2H, t, J = 6.09 Hz,
CH2); 2.33 (2H, t, J = 5.54 Hz, CH2); 3.84 (3H, s,
OCH3); 4.02 (2H, t, J = 6.44 Hz, OCH2); 6.75 (1H, s,
@CH); 7.07 (1H, d, J = 8.43 Hz, aromatic H); 7.43 (1H, s,
aromatic H); 7.55 (1H, d, J = 8.95 Hz, aromatic H); 9.82
(1H, s, NH). 13C (DMSO-d6) d 14.17; 19.23; 21.82; 28.23;
31.25; 36.97; 56.21; 68.49; 111.45; 111.58; 112.77; 122.11;
126.55; 148.16; 152.88; 157.70; 166.58; 199.25. Anal. Calcd
for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C,
67.85; H, 7.32; N, 4.35.
9.2.3. 3-Chloro-N-(5,5-dimethyl-3-oxocyclohex-1-enyl)benz-
amide (11f). Yield: 90%; white solid from EtOAc, mp:
138.5–140 ꢁC. mmax 3288.19, 1690.47, 1639.26, 1618.78
1
cmÀ1. d H (DMSO-d6) 1.08 (6H, s, gem 2· CH3); 2.19
(2H, s, CH2); 2.56 (2H, s, CH2); 6.82 (1H, s, @CH); 7.35–
7.80 (4H, m aromatic ring); 8.88 (1H, s, NH). 13C (DMSO-
d6) d 28.24; 32.86; 42.28; 50.51; 111.50; 125.79; 127.85;
130.01; 132.40; 134.79; 135.64; 154.70; 165.60; 200.75.
Anal. Calcd for C15H16ClNO2: C, 64.87; H, 5.81; Cl, 12.76;
N, 5.04. Found: C, 64.82; H, 5.60; Cl, 12.70; N, 4.87.
9.2.8.
3-n-Butoxy-4-methoxy-N-(5-methyl-3-oxocyclo-
hex-1-enyl)benzamide (11k). Yield: 82%; white solid from
EtOAc/MeOH, mp: 160–161 ꢁC. mmax 3316.93, 1675.11,
1
1629.02, 1603.41 cmÀ1. d H (DMSO-d6) 0.94 (3H, d,

A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
1005
1
J = 7.34 Hz CH3); 1.03 (3H, d, J = 6.18 Hz, CH3); 1.43–
1.56 (2H, quint, J = 6.95 Hz, CH2); 1.69–1.76 (2H, m,
CH2); 2.01–2.72 (5H, m, cyclohexene ring); 3.84 (3H,
s, OCH3); 4.02 (2H, t, J = 6.36 Hz, OCH2); 6.75 (1H,
s, @CH); 7.07 (1H, d, J = 8.45 Hz, aromatic H); 7.43
(1H, s, aromatic H); 7.55 (1H, d, J = 8.42 Hz, aromatic
H); 9.73 (1H, s, NH). 13C (DMSO-d6) d 14.18;
19.23; 21.21; 29.19; 31.25; 36.27; 45.09; 56.21; 68.45;
111.16; 111.47; 112.73; 122.14; 126.47; 148.15; 152.89;
156.93; 166.55; 199.35. Anal. Calcd for C19H25NO4:
C, 68.86; H, 7.60; N, 4.23. Found: C, 68.88; H, 7.60;
N, 4.03.
3359.89, 1685.35, 1608.31, 1598.29 cmÀ1. d H (DMSO-
d6) 1.03 (6H, s, 2 · CH3); 1.59–1.90 (8H, m, cyclopentyl);
2.15 (2H, s, CH2); 2.56 (2H, s, CH2); 3.83 (3H, s, OCH3);
4.87 (1H, m, OCH–); 6.76 (1H, s, @CH); 7.07 (1H, d,
J = 8.47 Hz, aromatic H); 7.42 (1H, s, aromatic H); 7.55
(1H, d, J = 7.91 Hz, aromatic H); 9.85 (1H, s, NH). 13C
(DMSO-d6) d 24.06; 28.33; 32.68; 32.78; 50.57; 56.21;
80.29; 110.40; 111.65; 114.64; 122.11; 126.46; 147.00;
153.63; 155.56; 166.64; 199.18. Anal. Calcd for
C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C,
70.35; H, 7.64; N, 3.93.
9.3. X-ray analysis
9.2.9. 3-n-Butoxy-4-methoxy-N-(5,5-dimethyl-3-oxocyclo-
hex-1-enyl)benzamide (11l). Yield: 81%; light-tan solid
from EtOAc/MeOH, mp: 119–121 ꢁC. mmax 3334.28,
3-Chloro-N-(5,5-dimethyl-3-oxocyclohex-1-enyl)benzam-
ide, 11f, 3,4-dimethoxy-N-(3-oxocyclohex-1-enyl)benz-
amide, 11g, and 3,4-dimethoxy-N-(5,5-dimethyl-3-
oxocyclohex-1-enyl)benzamide, 11i, were recrystallized
from ethyl acetate. All experimental details related to the
structural analysis are provided in Figures 1–3, Tables 5–
7, and Supplementary material. The structure was solved
by direct methods of the SHELXTLPC program and re-
fined by the SHELXTL program.47 The full crystallo-
graphic data were deposited at the Cambridge
Crystallographic Data Center. Copies of the data can be
obtained free of charge, on application to CCDC, 12 Un-
ion Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033, or email: deposit@ccdc.camac.uk.). Compounds
11f,g, and i are designated CCD 226697, CCD 219084,
and CCDC 219085, respectively.
1
1685.35, 1603.41, 1598.29 cmÀ1. d H (DMSO-d6) 0.94
(3H, d, J = 7.34 Hz CH3); 1.03 (6H, s, 2 · CH3);
1.40–1.50 (2H, m, CH2); 1.67–1.76 (2H, quint,
J = 7.56 Hz, CH2); 2.15 (2H, s, CH2); 2.56 (2H, s,
CH2); 3.84 (3H, s, OCH3); 4.02 (2H, t, J = 6.36 Hz,
OCH2); 6.76 (1H, s, @CH); 7.06 (1H, d, J = 8.50 Hz,
aromatic H); 7.45 (1H, s, aromatic H); 7.55 (1H, d,
J = 8.35 Hz, aromatic H); 9.75 (1H, s, NH). 13C
(DMSO-d6) d 14.17; 19.24; 28.31; 31.26; 32.77; 41.80;
50.56; 56.19; 68.50; 110.42; 111.44; 112.15; 126.42;
148.16; 152.91; 155.46; 166.59; 199.21. Anal. Calcd for
C20H27NO4: C, 69.54; H, 7.88; N, 4.05. Found: C,
69.61; H, 7.97; N, 4.05.
9.2.10. 3-Cyclopentyloxy-4-methoxy-N-(3-oxocyclohex-
1-enyl)benzamide (14a). Yield: 81%; pale-white solid
from EtOAc, mp: 171–172 ꢁC. mmax 3271.00, 1675.98,
1621.70 cmÀ1. d 1H (DMSO-d6) 1.58–1.93 (10H, m,
cyclopentyl Hs and CH2); 2.22–2.38 (2H, m, CH3);
2.63–2.69 (2H, m, CH2); 3.35 (3H, s, OCH3); 4.87 (1H,
m, OCH); 6.50 (1H, s, @CH); 7.08 (1H, d, J = 8.63 Hz,
aromatic H); 7.40 (1H, s, aromatic H); 7.53 (1H, d,
J = 8.41 Hz, aromatic H); 9.81 (1H, s, NH). 13C
(DMSO-d6) d 21.83; 24.04; 28.22; 36.98; 56.21; 80.29;
111.60; 111.65; 114.65; 122.08; 126.56; 147.02; 153.61;
157.69; 166.59; 199.21. Anal. Calcd for C19H23NO4:
C, 69.28; H, 7.04; N, 4.25. Found: C, 69.39; H, 7.02; N,
4.21.
9.4. Pharmacology
Initial evaluations for anticonvulsant activity were
performed by the ADD Program, epilepsy branch,
Neurological Disorders Program, NINDS. These evalu-
ations included the phase I test which has been de-
scribed.35–37 These tests were performed in Carworth
Farms no. 1 (CF1) mice (weighing 18–25 g). Phase I,
a qualitative anticonvulsant ip evaluation in mice,
included three tests: MES, scPTZ, and the rotorod test
for Tox. Compounds were suspended in 30% poly(eth-
yleneglycol) 400 and were administered at four dosage
levels (10, 20 200, and 300 mg kgÀ1) with anticonvulsant
activity and motor impairment noted 30 min and 4 h
after administration. Phase VIA was a similar qualita-
tive evaluation; however, the test drug was administered
orally (po) in rats utilizing the three tests noted previ-
ously. The 6 Hz ÔPsychomotorÕ seizure test is described.
Twenty mice were pretreated ip with 200 mg kgÀ1 of the
test analog (11h). At varying times (0.25, 0.5, 1, 2, and
4 h) after treatment, individual mice (four at each time
point) were challenged with sufficient current (32 mA
at 6 Hz for 3 s) delivered through corneal electrodes
to elicit a psychomotor seizure. Typically, the seizure
is characterized by a minimal clonic phase that is
followed by stereotyped, automatistic behaviors
described originally38 as being similar to the aura of
human patients with partial seizures. Animals not
displaying this behavior were considered protected.
Results were expressed as the number of animals pro-
tected over the number of animals tested over time.
The results are listed in Table 3.
9.2.11. 3-Cyclopentyloxy-4-methoxy-N-(5-methyl-3-oxo-
cyclohex-1-enyl)benzamide (14b). Yield: 84%; pale-
yellow solid from EtOAc, mp: 128–129 ꢁC. mmax
3310.18, 1678.17, 1613.17, 1603.41 cmÀ1
.
d
1H
(DMSO-d6) 1.03 (3H, d, J = 6.10 Hz, CH3); 1.58–1.89
(8H, m, cyclopentyl); 2.25–2.86 (5H, m, cyclohexene);
3.83 (3H, s, OCH3); 4.88 (1H, m, OCH–); 6.75 (1H, s,
@CH); 7.06 (1H, d, J = 8.47 Hz, aromatic H); 7.42
(1H, s, aromatic H); 7.55 (1H, d, J = 8.42 Hz, aromatic
H); 9.85 (1H, s, NH). 13C (DMSO-d6) d 21.22; 24.05;
29.20; 32.68; 36.26; 45.11; 56.21; 80.27; 111.18; 111.66;
114.63; 122.13; 126.47; 147.00; 153.61; 156.99; 166.57;
199.33. Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34;
N, 4.08. Found: C, 69.78; H, 7.18; N, 4.00.
9.2.12. 3-Cyclopentyloxy-4-methoxy-N-(5,5-dimethyl-3-
oxocyclohex-1-enyl)benzamide (14c). Yield: 85%; pale-
yellow solid from EtOAc, mp: 149–150 ꢁC. mmax

1006
A. J. Anderson et al. / Bioorg. Med. Chem. 14 (2006) 997–1006
El-Assadi, A.; Nicholson, J. M. J. Med. Chem. 1993, 36,
19477.
9.5. Phosphodiesterase inhibition
16. Scott, K. R.; Rankin, G. O.; Stables, J. M.; Alexander, M.
S.; Edafiogho, I. O.; Farrar, V. A.; Kolen, K. R.; Moore, J.
A.; Sims, L. D.; Tonnu, A. D. J. Med. Chem. 1993, 36, 4033.
17. Foster, J. F.; Nicholson, J. M.; Butcher, R.; Stables, J. P.;
Edafiogho, I. O.; Goodwin, A. M.; Henson, M. C.; Smith,
C. A.; Scott, K. R. Bioorg. Med. Chem. 1999, 7, 2415.
18. Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Stables, J. P.;
Powell, C. B.; Scott, K. R. Curr. Med. Chem. 2000, 7, 417.
19. Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Butcher, R. J.;
Edafiogho, I. O.; Stables, J. P.; Cooke, N.; Goodwin, A. M.;
Smith, C. A.; Scott, K. R. Eur. J. Med. Chem. 2002, 37, 635.
20. Khurana, K.; Salama, N. N.; Scott, K. R.; Nemieboka, N.
N.; Bauer, K.; Eddington, N. D. Biopharm. Drug Dispos.
2003, 24, 397.
Phosphodiesterase inhibition studies on compounds
14a–c were performed by MDS Pharma Services by a
referenced procedure.39,40 The data are provided in
Table 4.
Acknowledgments
This was taken, in part from the dissertation of A.J.A.,
submitted in partial fulfillment of the Ph.D. degree,
Howard University, 2003. This research was supported
by a grant from the National Institutes of Health (1
R21 GM634940-02) for which K.R.S. is the principal
investigator as well as by Grant 2 G12 RR003048 from
the RCMI Program, Division of Research Infrastruc-
ture, ÔNational Center for Research Resources, NIHÕ.
21. Eddington, N. D.; Cox, D. S.; Khurana, M.; Salama, N.
N.; Stables, J. P.; Harrison, S. J.; Negussie, A.; Taylor, R.
S.; Tran, U. Q.; Moore, J. A.; Barrow, J. C.; Scott, K. R.
Eur. J. Med. Chem. 2003, 38, 49.
22. Anderson, A. J.; Nicholson, J. M.; Bakare, O.; Butcher, R.
J.; Scott, K. R. J. Comb. Chem. 2004, 6, 950.
23. Wilson, T. L.; Jackson, P. L.; Hanson, C. D.; Xue, Z.;
Eddington, N. D.; Scott, K. R. Med. Chem. 2005, 1, 371.
24. Hanson, C. D.; Jackson, P. L.; Farrell, A. K.; Wilson, T.
L.; Butcher, R. J.; Eddington, N. D.; Scott, K. R. J. Med.
Chem., submitted for publication.
25. Ostercamp, D. L. J. Org. Chem. 1970, 30, 1633.
26. Zymalkowski, F.; Rimek, H. Arch. Pharm. 1961, 294, 759.
27. Benary, E. J. Am. Chem. Soc. 1927, 60, 1826.
28. Ninomiya, I.; Naito, T.; Kiguchi, T. J. Chem. Soc., Perkin
Trans. 1 1973, 2257.
Supplementary material
Supplementary data associated with this article (Tables
8–24) can be found, in the online version, at
doi:10.1016/j.bmc.2005.09.023.
References and notes
1. Beavo, J. A.; Conti, M.; Heaslip, R.. J. Mol. Pharmacol.
1994, 46, 399.
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