Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

Article abstract of DOI:10.1016/S0223-5234(00)01206-X

Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl₂, or 3-CF₃ groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED₅₀ = 5.8 mg kg^-1, TD₅₀ = 36.4 mg kg^-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.

Full text of DOI:10.1016/S0223-5234(00)01206-X

Eur. J. Med. Chem. 36 (2001) 265–286
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(00)01206-X/FLA
Preliminary communication
Synthesis and structure–activity relationships of potential anticonvulsants based
on 2-piperidinecarboxylic acid and related pharmacophores
Bin Hoa,1, A. Michael Cridera*, James P. Stablesb
aDepartment of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe,
LA 71209-0470, USA
bPreclinical Pharmacology, NINDSP, Bethesda, MD 20892-95243, USA
Received 13 June 2000; revised 24 November 2000; accepted 29 November 2000
Abstract – Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(a-methylbenzyl)-2-piperidinecarboxamide (2) as struc-
tural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the
N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity.
Replacement of the a-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity.
Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide
carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring
decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone
nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and
6-positions gave the active norleucine derivative 75 (ED50=5.8 mg kg−1, TD50=36.4 mg kg−1, PI=6.3). Replacement of the
piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES
activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with
a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a
six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of
compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of
´
tonic–clonic and partial seizures in man. © 2001 Editions scientifiques et me´dicales Elsevier SAS
2,6-dimethylanilides / carboxamides / rotorod test / maximal electroshock seizure test / anticonvulsant
1. Introduction
Previously, the activity of several 2-piperidinecar-
boxamides in the maximal electroshock seizure (MES)
test in mice was reported. Receptor binding studies
indicated that these amides demonstrated weak bind-
ing affinity at the phencyclidine (PCP) site on the
Epilepsy is a major neurological disorder in the
United States and throughout the world [1, 2]. Al-
though 70–80% of epileptics are currently controlled
by a variety of drugs, seizure protection is frequently
accompanied by numerous adverse effects [3].
N-methyl- -aspartate (NMDA) receptor complex;
D
however, a correlation between binding affinity and
seizure protection in the MES test was not observed
[4]. As a continuation of this work, a structure–activ-
ity relationship (SAR) study of the 2-piperidinecar-
boxamide nucleus was initiated. The most active
compound arising from this study, the 2,6-dimethy-
lanilide (RS-1, figure 1), exhibited an ED50 =5.8
mg kg−1 in the MES test and a TD50 =33.2 mg kg−1
in the rotorod test to give a PI=5.7. The (R-1)-iso-
mer exhibited similar MES activity as the racemate
Abbreviations: SAR, structure–activity relationship; BOC, tert-bu-
toxycarbonyl; NMM, N-methylmorpholine; IBCF, isobutyl chlorofor-
mate; MES, maximal electroshock seizure; CBZ, carbamazepine; PTN,
phenytoin; ip, intraperitoneal; PI, protective index, TD50/ED50;
LAH, lithium aluminium hydride; THF, tetrahydrofuran; NMDA,
N-methyl-D-aspartate; PCP, phencyclidine.
* Correspondence and reprints
E-mail address: pycrider@alpha.ulm.edu (A. Michael Crider).
1 Nova Biomedical Corporation, Waltham, MA 02453, USA.

266
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
tution on the aromatic ring of compound 2, (2) re-
placement of the a-methyl substituent of 2 by other
alkyl or aryl groups, (3) introduction of substituents
on the piperidine ring nitrogen, (4) reduction of the
side chain carbonyl, (5) movement of the carboxam-
ide group to the 3- and 4-positions, (6) incorporation
of the piperidine ring into a tetrahydroisoquinoline or
diazahydrindanone nucleus, (7) opening of the pipe-
ridine ring, (8) replacement of the piperidine ring by
cycloalkyl or pyridine, and (9) simplification of the
2-piperidinecarboxamide nucleus into a glycinecar-
boxamide moiety.
but was more neurotoxic, whereas the (S-1)-isomer
was less active and less neurotoxic. Additionally, the
N-(a-methylbenzyl)-2-piperidinecarboxamides
2
(figure 1) also exhibited activity in the MES test;
however, the stereochemistry at the 2-position of the
piperidine ring or at the a-position of the side chain
did not significantly affect activity [5].
Although several new drugs such as vigabatrin,
lamotrigine, gabapentin, tiagabine, felbamate, topira-
mate, fosphenytoin, and levetiracetam have appeared
on the market, the development of novel agents,
particularly compounds effective against complex
partial seizures, remains a major focus of antiepileptic
drug research [6]. A review on new structural entities
having anticonvulsant activity has recently appeared
[7]. Since the 2-piperidinecarboxamides represent a
novel series of compounds that are active in the MES
test in mice, further exploration of the SAR was of
interest. Using compounds 1 and 2 as structural leads,
the following modifications were explored: (1) substi-
2. Chemistry
The synthesis of the N-[(a-alkyl or aryl-substi-
tuted)benzyl]-2-piperidine-carboxamides required the
preparation of the precursor a-substituted-benzyl-
amines which were prepared by the Leuckhart reac-
tion (figure 2). The starting ketones were either com-
mercially
available
or
were
prepared
by
Friedel–Crafts acylation of benzene with an appro-
priate acid chloride. In the case of solid ketones, the
reaction of the ketone with a mixture of formic acid
and formamide at 140°C usually required a reaction
time of about 24 h to afford the N-formylamine.
Some difficulty was encountered in maintaining the
reaction temperature due to the periodic addition of
formic acid. When liquid ketones were employed in
the reaction, a mixture of the ketone and formic acid
was added dropwise to a solution of formamide at
140°C. The intermediate imine was rapidly hydro-
genated by formic acid, and the total reaction time to
yield the N-formylamine was only 6–8 h. Removal of
the formyl group was accomplished by refluxing in
concentrated hydrochloric acid, and the free amines
were generally purified by vacuum distillation fol-
lowed by formation of the hydrochloride salts (table
I).
Figure 1. Structures of 2-piperidinecarboxamides with activity
against MES in mice.
The desired N-[(a-alkyl or aryl-substituted)benzyl]-
piperidinecarboxamides were prepared by a previ-
ously described [5] mixed anhydride coupling
procedure. The general method (shown in figure 4)
involved reaction of a tert-butoxycarbonyl (BOC)-
protected amino acid with isobutylchloroform (IBCF)
and an arylamine or an (a-alkyl or aryl-substi-
tuted)benzylamine in the presence of N-methylmor-
pholine (NMM). Deprotection of the resulting
BOC-protected carboxamide with hydrogen chloride
Figure 2. (a) SOCl2–benzene–pyridine; (b) AlCl3–benzene; (c)
HCOOH–HCONH2; (d) concentrated HCl.

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
Table I. a-Substituted-benzylamines.
267
Compound
R
X
Bp (°C), mmHg
Yield (%)
Mp (°C) a
5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
i-Pr
Bn
3-ClC6H4
cC5H9
cC6H11
3-OCH3
3,4-(OCH3)2
129–132 (17)
155–158 (13) c
77–81 (18) d
66
27
67
55
60
59
63
77
85
53
78
44
59
159–161 b
221–222 c
192–193 d
168–169 e
183–184 d
176–177 f
192–193 d
194–195 d
284–285 d
256–257 h
271–273 i
6
7
3-CF3
3-F
2-Cl
3-Cl
4-Cl
H
H
H
H
H
8
99–111 (23)
9
123–126 (25) d
112–115 (13) f
112–115 (13) d
105–108 (27) d
99–104 (14) d
165–180 (16) g
140–145 (1) i
10
11
12
13
14
15
16
17
\300 j
\325 j
H
180–183 (22)
a HCl salt. All salts were recrystallised from absolute ethanol–diethyl ether. b Ref. [31]. c Ref. [32]. d Ref. [33]. e Ref. [34]. f Ref. [35].
g Ref. [36]. h Ref. [37]. i Ref. [38]. j Ref. [39].
gas in methylene chloride gave the desired carboxam-
ides. The pyridinecarboxamide 50 was prepared from
isonicotinic acid by formation of the acid chloride in
pyridine followed by reaction of the crude acid chlo-
ride with 2,6-dimethylaniline in tetrahydrofuran
(THF).
moderate yield. The reaction occurred with complete
transesterification. The diester 53 was converted to
the acid 54 via saponification and subsequent decar-
boxylation during work-up. The isoquinoline-3-car-
boxylic acid 55 was obtained by refluxing 54 in 6 N
hydrochloric acid followed by neutralisation with am-
monium hydroxide. The desired carboxamides were
prepared by the standard mixed anhydride method to
yield 58–63. Catalytic hydrogenation of isoquinoline-
1-carboxylic acid using Adams’ catalyst gave the te-
trahydroisoquinoline-1-carboxylic acid 64. Reaction
of 64 with di-tert-butyl dicarbonate followed by
amide formation and deprotection gave the carbox-
amides 66 and 68. The physicochemical properties of
the 1,2,3,4-tetrahydroisoquinolinecarboxamides are
given in table III.
Ring-opened analogues of the 2-piperidinecarbox-
amide nucleus were prepared as shown in figure 4.
The carboxamides 75 and 77 represent analogues in
which the piperidine ring has been opened between
positions 1 and 6, whereas compounds 82 and 84
represent ring-opened analogues in which the pipe-
ridine ring has been cleaved between positions 2 and
3. The physicochemical properties of these derivatives
are given in Section 5.
Reaction of 2, as a mixture of diastereoisomers,
with either benzoyl chloride or benzyl bromide gave
the corresponding 1-benzoyl 39 and 1-benzyl deriva-
tives 35–38, respectively. Alkylation of 2 with methyl
iodide afforded 34 and some of the undesired disub-
stituted product. Reduction of 2 with refluxing
lithium aluminum hydride (LAH) in THF afforded
the diamine 51. In an effort to incorporate the 2-pipe-
ridinecarboxamide moiety into a more rigid frame-
work, 23 was reacted with formaldehyde in ethanol to
yield the diazahydrindanone 52. The physicochemical
properties of these compounds are given in table II.
Incorporation of the 2-piperidinecarboxamide moi-
ety into a tetrahydroisoquinoline nucleus required the
preparation of the key 1,2,3,4-tetrahydroisoquinoline
carboxylic acids 55 and 64 as shown in figure 3. Using
sodium methoxide as the base, cyclisation between
a,a-dichloro-o-xylene and diethyl-2-(acetylamino)-
malonate in refluxing methanol gave the diester 53 in

268
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
Table II. Piperidinecarboxamides and related derivatives.
Compound R1
R2
X
Ring position Mp (°C)
Yield (%)
Formula a
(recrystallisation solvent) b
18
BOC
H
H
H
H
H
H
H
BOC
H
H
H
H
H
H
H
CH(CH3)2
CH(CH3)2
CH3
CH3
3-CF3
4-CF3
3-CF3
3-OCH3
3-F
2
2
3
4
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
139–141
246–248
196–210
30
67
55
C21H32N2O3 (A)
19
C16H25ClN2O c (B)
C14H21ClN2O c (B)
C14H21ClN2O c (B)
20
21
263–265 d 41
22 e
23 e
24
H
H
H
99–101
63–64
103–105
195–210
238–248
179–183
80–88
217–225
288–289
74–85
43
31
70
83
80
52
37
58
46
38
54
39
53
53
86
53
63
50
46
47
43
40
65
75
63
58
C14H17F3N2O (C)
C15H22N2O2 (D)
C19H27FN2O3 (A)
C14H20ClFN2O c (B)
C14H20Cl2N2O c(E)
C14H20Cl2N2O c (B)
C14H19ClN2O (F)
C15H20ClF3N2O c (B)
C14H19Cl3N2O c (B)
C16H24N2O3 (D)
C15H22N2O (F)
25
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
26
27
3-F
28
2-Cl
3-Cl
4-Cl
3-CF3
3,4-Cl2
3,4-(OCH3)2
H
H
H
H
H
29
30
31
32
33
34
CH3
Bn
76–78
35
243–245
225–228
88–91
159–161
144–146
107–115
185–187
79–83
C21H27ClN2O c (B)
C21H26ClFN2O c (B)
C21H25BrN2O (F)
C21H25Cl3N2O c (B)
C21H24N2O2 (D)
C14H20N2O f (F)
C15H23ClN2O c (B)
C16H24N2O (F)
36
4-FC6H4
4-BrC6H4
3,4-Cl2C6H3 CH3
COC6H5
H
H
H
H
H
H
BOC
H
BOC
H
37
38
39
CH3
CH3
C2H5
i-Pr
H
H
H
H
40
41
42
43
C6H5
H
96–98
C19H22N2O (G)
(S,RS)-44
(S,RS)-45
46
C6H5 3-Cl
281–286
140–143
119–122
269–271
125–127
304–305
C19H21Cl2N2O c (E)
C20H24N2O (H)
Bn
H
H
H
H
H
cC5H9
cC5H9
cC6H11
cC6H11
C23H34N2O3 (A)
C18H27ClN2O c (B)
C24H36N2O3 (B)
47
48
49
C19H29ClN2O c (B)
50
157–159 g 30
h
51
H
CH3
H
–
214–216
67–70
44
86
C14H24Cl2N2 (I)
52
C15H17F3N2O (F)
a All compounds gave acceptable C, H, and N analyses, 90.4% of the calculated values, except where indicated.
b Recrystallisation solvents, A, EtOH–H2O; B, absolute EtOH–Et2O; C, petroleum ether–EtOAc; D, petroleum ether–Et2O; E,
absolute EtOH; F, petroleum ether; G, MeOH–H2O; H, EtOAc–hexane; I, i-PrOH–Et2O.
c Hydrochloride.
d [40] no reported m.p.
e Previously reported [5].
f Calc. 72.37; found, 71.42.
g [40] m.p. 154–155°C.
h Dihydrochloride.

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
3. Pharmacology
269
3.1. 2,6-Dimethylanilide series
The anticonvulsant activity and the neurotoxicity
(table V) of the target compounds of this investigation
were evaluated by the National Institutes of Neurologi-
cal Disorders and Stroke (NINDS) at the National
Institutes of Health (NIH) using established procedures
[5]. The ED50 in MES test and the TD50 in the rotorod
test were calculated at the time of peak effect for the
most active compounds according to a previously de-
scribed method [4]. In the previous study, the 2,6-
dimethylanilide (RS-1) was shown to exhibit potent
activity in the MES test in mice [5]. Replacement of one
of the ortho-methyl groups in RS-1 by an isopropyl
substituent (compound 19) resulted in similar MES ac-
tivity (ED50=8.3 mg kg−1). Although the nipecotamide
20 and the isonipecotamide 21 were weakly active in the
MES test, N-[(2,6-dimethyl)phenyl]-4-pyridinecarbox-
Figure 3. (a) NaOCH3–MeOH–CH3CONHCH(CO2Et)2; (b)
KOH; (c) 6 N HCl; (d) H2–PtO2–CH3COOH.
amide (50, ED50=9.7 mg kg−1; TD50=53.3 mg kg−1
;
The cycloalkylcarboxamides (85–93) were prepared
starting from the appropriate carboxylic acid. The
intermediate acid chlorides were obtained by treating
the cycloalkanecarboxylic acids with thionyl chloride
in dichloromethane. Using triethylamine as the base,
the acid chlorides gave moderate to high yields of the
amides upon treatment with the appropriate amine in
THF. The physicochemical properties of these com-
pounds are given in table IV.
The 1-aminocyclopentanecarboxamide 97 (figure 5)
was synthesised via the hydantoin 94. Using the typi-
cal coupling procedure, the 1-aminocyclohexanecar-
boxamide 99 was prepared from 1-aminocyclohexane
carboxylic acid. Hydrogenation of 4-aminobenzoic
acid with Adams’ catalyst in 30% ethanol yielded a
mixture of cis-and trans-4-aminocyclohexanecar-
boxylic acids 100 and 101, respectively. Fractional
crystallisation of the reaction mixture from aqueous
ethanol yielded cis-100. Concentration of the mother
liquor and recrystallisation of the resulting residue
from an aqueous ethanol–diethyl ether mixture gave
trans-101. The desired 2,6-dimethylanilides 104 and
105 (figure 5) were prepared from the corresponding
BOC-protected acids 102 and 103 in the normal man-
ner. The physicochemical properties of these com-
pounds are given in Section 5. The NMR spectra of
all final compounds were consistent with the assigned
structures.
PI=5.5) approached the MES activity of RS-1 with a
similar PI.
Incorporation of the 2-piperidinecarboxamide moiety
into a tetrahydroisoquinoline nucleus increased neuro-
toxicity while maintaining similar MES activity. The
isoquinolinecarboxamides (58 and 68) exhibited MES
activity at 10 mg kg−1 in mice, but with neurotoxicity in
the rotorod test at 30 mg kg−1. Apparently, the increase
in lipophilicity by the fusion of a phenyl ring either at
the 3,4- or 4,5-positions in these compounds contributes
to the increase in neurotoxicity.
Several open ring analogues exhibited potent activity
in the MES test. The norleucine derivative 75 (ED50=
5.8 mg kg−1, TD50=36.4 mg kg−1, PI=6.3) was among
the most potent compounds evaluated in the MES test
in this study. In these derivatives introduction of a
lipophilic n-butyl group at the a-position of the amino
acid portion increased MES activity by about five-fold
(compare compounds 75 and 76). Positioning the n-bu-
tyl group on the amine nitrogen (compound 84) led to a
decrease in MES activity. The conformationally con-
strained 1-amino-1-cyclohexanecarboxamide 99 did not
exhibit MES activity at 300 mg kg−1. Possibly, the cy-
clohexane ring exerts an unfavourable steric effect in
this compound.
The cyclobutanecarboxamide 89 exhibited the greatest
MES activity among the cycloalkanecarboxamides
(ED50=35 mg kg−1, TD50=203 mg kg−1, PI=5.8).
Compared with the cyclobutyl derivative, the cy-

270
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
clopentyl 90 (ED50=55 mg kg−1) and the cyclohexyl 91
(ED50=62 mg kg−1) derivatives were less active in the
MES test. However, the cyclohexyl derivatives 91 and
92 exhibited considerably less neurotoxicity with PIs of
>12.1 and >8.8, respectively. The cyclopropane 88 and
the cycloheptane 93 derivatives were the least potent of
the cycloalkanecarboxamides in the MES test. The pres-
ence of an ortho-chloro group in compound 92 in place
of a methyl substituent led to a decrease in MES activity
(ED50=85 mg kg−1). Introduction of a 4-amino group
into the cyclohexane ring (compound 104) did not elim-
inate MES activity (active at 100 mg kg−1), but greatly
increased the neurotoxicity (neurotoxic at 100 mg kg−1).
Compound 104 may be viewed as a saturated analogue
of the potent anticonvulsant ameltolide (ED50=2.6
mg kg−1) [8, 9]. Apparently, modification of the planar
aromatic ring in ameltolide greatly decreases the MES
activity.
3.2. (N-Benzyl)carboxamide series
The stereochemistry at the 2-position or at the a-posi-
tion of the N-(a-methylbenzyl) group (see the four
stereoisomers of 2 in table V) did not significantly affect
the MES activity. Introduction of a 3-Cl (29, ED50=20
mg kg−1) or a 3,4-Cl2 (32, ED50=28 mg kg−1) into the
aromatic ring led to a slight increase in MES activity;
however, the compounds were slightly more neurotoxic.
Substitution of an isopropyl group (42, ED50=22
mg kg−1) or a benzyl substituent (S,RS-45, ED50=22
mg kg−1) for the a-methyl group resulted in an increase
in MES activity, although an increase in neurotoxicity
Table III. 1,2,3,4-Tetrahydroisoquinolinecarboxamides.
Compound
R1
R2
X
Mp (°C)
Yield (%)
Formula a (recrystallisation solvent) b
57
58
59
60
61
62
63
66
67
68
BOC
H
H
H
H
H
H
140–141
255–258
221–223
141–143
88–98
100–103
124–126
164–166
198–200
283–285
40
82
62
66
46
51
23
37
29
71
C23H28N2O3 (A)
C18H21ClN2O c, d (B)
C17H18ClFN2O c (B)
C18H18ClFN2O c (C)
C19H19F3N2O e (D)
C18H19ClN2O (D)
C24H24N2O (E)
H
H
CH3
CH3
Bn
3-F
3-CF3
3-CF3
4-Cl
H
C18H21ClN2O c, f (B)
C23H28N2O3 (A)
C18H21ClN2O (B)
BOC
H
a All compounds gave acceptable C, H, and N analyses, 90.4% of the calculated values, except where indicated.
b Recrystallisation solvents, A, EtOH–water; B, absolute EtOH–Et2O; C, 95% EtOH–Et2O; D, Et2O–petroleum ether; E, EtOAc–
hexane.
c Hydrochloride.
d Calc. C, 68.24; found, 67.71.
e Calc. C, 65.50; found, 65.09.
f Calc. C, 68.23; found, 67.30.

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
271
Figure 4. (a) (BOC)2O–NaOH or BOC-ON–Et3N; (b) NMM–IBCF–2,6-dimethylaniline; (c) HCl (g)–CH2Cl2; (d) NMM–IBCF–
a-metylbenzylamine; (e) n-butylamine–benzene; (f) 25% NaOH.
Table IV. Cycloalkanecarboxamides.
Compound
R
X
Mp (°C)
Yield (%)
Formula a (recrystallisation solvent) b
85
86
87
88
89
90
91
92
93
cC5H9
cC6H11
cC6H11
cC3H5
cC4H7
cC5H9
cC6H11
cC6H11
cC7H13
3-Cl
3-Cl
H
2,6–Me2
2,6-Me2
2,6-Me2
2,6-Me2
2-Cl,6–Me
2,6-Me2
82–84
89
49
47
31
53
75
44
56
38
C14H18ClNO (A)
C15H20ClNO (A)
C15H21NO2 (A)
C12H15NO (B)
C13H17NO (B)
C14H19NO (B)
C15H21NO (B)
C14H18ClNO (A)
C16H23NO (B)
122–124
112–113
158–160
152–154
177–179
201–202
190–191
200–204
a All compounds gave acceptable C, H, and N analyses, 90.4% of the calculated values.
b Recrystallisation solvents, A, EtOAc–hexane; B, EtOAc.

272
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
was noted. Introduction of an a-cyclopentyl or a-cyclo-
hexyl substituent (compounds 47 and 49) afforded car-
amide functional group (compound 51) led to a loss
of anticonvulsant activity.
boxamides with MES activity at 100 and 30 mg kg−1
,
The incorporation of the piperidine ring into a
tetrahydroisoquinoline nucleus increased neurotoxic-
ity, while incorporation of the piperidine ring into a
diazahydrindanone moiety (compound 52) led to a
loss of anticonvulsant activity. Several open ring ana-
logues exhibited potent activity in the MES test. The
norleucine derivative 75 was among the most potent
compounds in the MES test, which were evaluated in
this study. In these derivatives the lipophilicity of the
compound and the substitution at the a-position of
the amino acid derivative played key roles in the
quantitative anticonvulsant activity.
respectively. However, both of these derivatives exhib-
ited neurotoxicity at 100 mg kg−1. Alkylation or acyla-
tion of the 1-position of the piperidine ring in the
N - (a - methylbenzyl) - 2 - piperidinecarboxamides (com-
pounds 34–39) essentially led to a loss of anticonvulsant
activity. Reduction of the carbonyl group of N-(a-
methylbenzyl)-2-piperidinecarboxamide (2) gave the di-
amine 51 which exhibited no MES activity.
Only in the cycloalkanecarboxamides did the N-(a-
methyl)benzyl-carboxamides approach the MES activity
of the 2,6-dimethylanilides (compare compounds 85 and
90). However, the neurotoxicities of these derivatives
Compared with the piperidinecarboxamides, the cy-
clohexanecarboxamides showed decreased neurotoxi-
city. In fact, the cyclohexanecarboxamides (91 and
92) had high PI values (>8.9) when evaluated in mice.
In general, these derivatives were, however, less po-
tent than derivatives containing a basic nitrogen.
Among the cyclohexanecarboxamides, the cyclobu-
tane, cyclopentane, and cyclohexane analogues were
active in the MES test, while the cyclopropane and
cycloheptane derivatives were much less active.
The 2,6-dimethylanilides were the most potent
compounds in the MES test in each group of com-
pounds evaluated. The anticonvulsant activity of car-
bamazepine and phenytoin has, in part, been
attributed to inhibition of voltage-dependent Na+
channels [10, 11]. Since the 2,6-dimethylanilides ex-
hibit a similar anticonvulsant profile as phenytoin and
carbamazepine, a similar mode of action is possible.
Further studies are needed to fully characterise the
mode of action of these novel anticonvulsants. The
pyridinecarboxamide 50 and the norleucinecarboxam-
ide 75 should serve as useful leads in the development
of compounds with therapeutic potential in the treat-
ment of tonic–clonic and partial seizures in man.
were
dimethylanilides.
greater
than
the
corresponding
2,6-
4. Conclusions
In agreement with previous findings on the N-(ben-
zyl)piperidinecarboxamides, introduction of 3-Cl, 4-
Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring of
N-(a-methylbenzyl)-piperidinecarboxamides led to an
increase in MES activity. Replacement of the a-
methyl group of a-methylbenzylamides with either
i-Pr (42, ED50=22 mg kg−1) or benzyl (S,RS-45,
ED50 =22 mg kg−1) increased MES activity with no
increase in neurotoxicity. In the piperidine series,
movement of the carboxamide moiety to either the 3-
or 4-positions of the piperidine ring led to a decrease
in anticonvulsant activity and neurotoxicity. Interest-
ingly, the 4-pyridinecarboxamide (50, ED50 =9.7
mg kg−1, TD50 =53.3 mg kg−1, PI=5.5) was highly
active in the MES test. Any substitution on the pipe-
ridine ring nitrogen resulted in a decrease in MES
activity and neurotoxicity. Also, reduction of the
5. Experimental protocols
5.1. Chemistry
All chemicals were of reagent grade and were used
without further purification. Melting points were deter-
mined on a Thomas Hoover melting point apparatus
and were not corrected. The IR spectra were recorded as
potassium bromide pellets or as liquid films on a Nicolet
Impact 400D spectrometer. The NMR spectra were
Figure 5. Structures of compounds 97, 99, 104, and 105.

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
273
Table V. Anticonvulsant activity of 2-piperidinecarboxamides and related derivatives in mice (all compounds were administered by
ip injection, ++++, +++, ++, and + denote antiseizure activity or toxicity at 10, 30, 100, and 300 mg kg−1, respectively; −
denotes no activity up to 300 mg kg−1). ED50 and TD50 values were determined at the time of peak effect of the experimental
compound and are reported as mg kg−1 with the 95% confidence limits in parentheses [4]).
a
Compound
MES
0.5 h
Toxicity
PI
4.0 h
0.5 h
4.0 h
(RS)-1
5.8 (4.7–7.5) b
46 (40–53) b
39 (34–44) b
35 (29–43) b
47 (39–55) b
8.3 (6.4–10.6) e
+
33.2 (28.6–37.1) b
5.7
b c
(2S,aS)-2
,
(2R,aR)-2
\150 d
\3.9
\4.5
3.5
(2R,aS)-2
159 (145–175) b
(2S,aR)-2
162 (143–185) b
19
+++ f
++
−
+
20
−
++
+
21
++
+
22
24 (21–26) b
42 (38–46) b
++
82 (78–87) b
3.4
3.1
23
132 (121–144) b
24
++
++
++
25
49 (43–55) e
++
135 (115–151) e
2.8
3.9
2.8
27
−
−
++
+
+
28
++
++
29
20 (17–25) e
+++
78 (71–84) e
30
++
++
++
−
+
31
+++
++
32
28 (23–33) e
−
79 (69–84) e
33
−
−
−
++
−
−
−
++
+
−
−
−
−
−
++
−
−
−
−
−
−
+
+
34
++
++
−
−
−
−
36
37
38
39
40
41
+++
++
42
22 (17–25) e
+++
66 (55–77) e
++
3.0
2.9
5.5
43
++
++
+
−
(S,RS)-44
(S,RS)-45
47
+++
++
22 (19–28) e
++
64 (56–75) e
++
−
++
++
++
49
+++
++
50
9.7 (7.9–11.3) e
−
53.3 (45.9–67.5) e
−
51
−
−
−
−
−
−
−
52
−
ND g
58
++++
++
++
++++
5.8 (4.5–6.9) e
30 (22–36) e
++
+++
++
++
+++
36.4 (31.6–40.2) e
82 (70–98) e
−
++
+
++
++
59
60
68
75
6.3
2.7
76
−
77
−
−
−
78
++
+++
−
84
−
++
85
59 (44–82) e
180 (156–216) h
76 (66–86) e
++
104 (83–118) e
\500i
1.8
2.8
3.0
86
87
230 (185–266) e
++
88
−
−
89
35 (28–43) e
55 (47–62) e
62 (49–74) i
203 (185–266) e
209 (184–243) e
\750 i
5.8
3.8
\12.1
90
91

274
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
Table V. (Continued)
a
Compound
MES
0.5 h
Toxicity
PI
4.0 h
0.5 h
4.0 h
92
85 (68–107) i
++
\750 i
\8.8
93
−
−
−
97
99
104
CBZ
PTN
43 (42–46) e
−
126 (106–155) e
−
2.9
−
++
−
+
−
++
9.85 (8.77–10.7) b
6.48 (5.65–7.24) b
47.8 (39.2–59.2) b
42.8 (36.4–47.5) b
4.85 b
6.60 b
a Neurotoxicity as measured by the rotorod test.
b Previously reported [5].
c Death at 80 mg kg−1
.
d Death at 170 mg kg−1
e Determined at 0.25 h.
.
f Unable to determine TD50.
g Not determined.
h Determined at 1 h.
i Determined at 2 h.
recorded on a JEOL FX 90Q spectrometer. Chemical
shifts were recorded in parts per million (l) relative to
tetramethylsilane (1%). Optical rotations were recorded
on a Perkin–Elmer 241 polarimeter. Ion exchange chro-
matography was performed on an Econo-Column (5
cm×10 cm) purchased from Bio-Rad using Amberlite
IR-120 (H+ form, 16–45 mesh) ion exchange resin which
was purchased from Fluka. Ninhydrin spray reagent
(0.1%) was purchased from Brinkmann Instruments Inc.
Analytical data were obtained from Oneida Research
Services Inc., Whitesboro, NY, Micro-Analysis Inc.,
Wilmington, DE, and Desert Analytics, Tucson, AZ.
The reaction mixture was refluxed for 1 h, cooled, and
poured into a mixture of concentrated hydrochloric acid
(200 mL) and ice. The aqueous solution was extracted
with diethyl ether (3×75 mL), and the combined ex-
tracts were washed with a saturated solution of
NaHCO3 followed by water, dried (Na2SO4), and con-
centrated under reduced pressure to give an oil. Vacuum
distillation afforded 9.8 g (56%) of 3 as a clear, colour-
less oil: b.p. 155–159°C; (27 mm) [12], b.p. 136–140°C;
(16 mm); IR (neat) 3061, 1680 (CꢀO), 1600, 1450, 991,
700 cm−1; 1H-NMR (CDCl3) l 1.82 (br m, 8H), 3.65 (m,
1H, CHCO), 7.52 (m, 3H, ArH), 8.02 (m, 2H, ArH);
13C-NMR (CDCl3) l 26.3, 30.0, 46.4, 128.5, 132.7,
137.0, 202.8 (CꢀO).
5.1.1. Cyclopentyl phenyl ketone (3)
The synthesis of this compound was accomplished
using the method described by Padwa and Eastman [12].
A solution of cyclopentanecarboxylic acid (11.4 g, 100
mmol) in dry benzene (60 mL) was treated in a dropwise
manner with a solution of thionyl chloride (22.8 g, 190
mmol) in dry benzene (20 mL) at room temperature
under nitrogen. The reaction mixture was heated to
50°C and treated with several drops of pyridine. After
stirring for 2 h, the mixture was evaporated under
reduced pressure. The resulting acid chloride was dis-
solved in dry benzene (100 mL) and added to a well-
stirred suspension of powered anhydrous aluminum
chloride (20.0 g, 150 mmol) in dry benzene (100 mL).
5.1.2. Cyclohexyl phenyl ketone (4)
Following the procedure used for the preparation of
3, cyclohexanecarboxylic acid (25.6 g, 200 mmol), thio-
nyl chloride (45.7 g, 380 mmol), and anhydrous alu-
minum chloride (40.0 g, 300 mmol) gave an oil.
Following vacuum distillation [b.p. 180–185°C (27
mm)], recrystallisation of the resulting solid from
petroleum ether gave 17.2 g (46%) of 4: m.p. 55–57°C
([13] m.p. 54°C); IR (KBr) 1682 (CꢀO) cm−1; H-NMR
(CDCl3) l 1.64 (br m, 10H), 3.25 (m, 1H, CHCO), 7.45
(m, 3H, ArH); 13C-NMR (CDCl3) l 25.9, 26.0, 29.4,
45.6, 128.3, 128.6, 132.7, 136.4, 203.9 (CꢀO).
1

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
275
5.1.3. General procedure for the synthesis of
(h-substituted)benzylamines by the Leuckhart reaction:
( )-1-(3-methoxyphenyl)ethylamine (5)
tracts were dried (sodium sulphate), filtered, and evapo-
rated to give a white solid upon trituration with hexane.
Recrystallisation from ethyl acetate–hexane yielded 7.8
g (70%) of 56: m.p. 150–151°C; IR (KBr) 1716 (CꢀO,
According to the method described by Moore [14], a
three-necked flask was equipped with a thermometer, an
addition funnel, and a reflux condenser. The top of the
condenser was connected to a short-path distillation
apparatus. The flask was charged with 3%%-
methoxyacetophenone (15.0 g, 100 mmol), for-
mamide(18.5 g, 400 mmol), and formic acid (2.1 g, 46.6
mmol), and the mixture was refluxed for 8 h at a
temperature of approximately 180°C. To prevent the
deposition of ammonium carbonate in the condenser
and to maintain a slightly acidic reaction mixture, for-
mic acid (2.6 g) was added portionwise on a hourly
basis. The solution was cooled and extracted with tolu-
ene (3×50 mL), and the toluene extracts were combined
and evaporated under reduced pressure to yield an oil.
The oil was suspended in concentrated hydrochloric acid
(20 mL) and refluxed for 1 h. The warm mixture was
treated with toluene (40 mL), and the aqueous portion
was separated, basified to pH 11 with 30% NaOH
solution, and extracted with ethyl acetate (3×75 mL).
The ethyl acetate extracts were combined, dried
(Na2SO4), filtered, and evaporated under reduced pres-
sure to yield an oil. Vacuum distillation gave 10.0 g of 5
1
acid), 1697 (CꢀO, carbamate); H-NMR (CDCl3) l 1.45
(s, 9H, C(CH3)3), 3.18 (d, 2H, CH2CHCOOH), 4.57 (m,
3H, CHNCH2), 7.14 (s, 4H, ArH), 9.82 (s, 1H, COOH);
13C-NMR (CDCl3) l 28.4, 31.2, 44.4, 53.5, 81.1, 126.3,
126.9, 128.2, 132.0, 134.0, 155.0, 176.6. Anal.
(C15H19NO4) C, H, N.
5.1.5. N-(tert-Butoxycarbonyl)glycine (72)
Following the method for the preparation of 56,
glycine (5.0 g, 66.6 mmol) in a mixture of water (50 mL)
and acetone (50 mL), triethylamine (10.2 g, 99.9 mmol),
and BOC-ON (18.1 g, 73.0 mmol) gave a white solid
upon cooling. Recrystallisation from ethyl acetate–
petroleum ether yielded 8.9 g (76%) of 72: m.p. 87–89°C
([16] m.p. 85–89°C); IR (KBr) 1749 (CꢀO, acid), 1670
(CꢀO, carbamate); 1H-NMR (CDCl3) l 1.46 (s, 9H,
C(CH3)3), 3.93 (br d, 2H, NHCH2COOH), 6.82 (br s,
1H, OCONH), 11.20 (s, 1H, COOH); 13C-NMR
(CDCl3) l 28.3, 42.3, 43.4, 80.5 (C(CH3)3), 156.2
(CONH), 174.7 (COOH).
1
as a colourless oil: H-NMR (CDCl3) l 1.38 (d, 3H,
5.1.6. Synthesis of 1-[(N-tert-butoxycarbonyl)amino]-1-
cyclopentanecarboxylic acid (96): general procedure for
the preparation of BOC-amino acids using di-tert-butyl
dicarbonate
J=6.6 Hz, CHCH3), 1.58 (s, 2H, CHNH2), 3.81 (s, 3H,
OCH3), 4.09 (q, 1H, CHCH3), 6.86 (br m, 3H, ArH),
7.26 (m, 1H, ArH); 13C-NMR (CDCl3) l 25.6, 51.3,
55.2, 111.3, 112.0, 118.0, 129.4, 149.6, 159.7. Using this
method, the a-substituted-benzylamines 6–17 were pre-
pared. The physicochemical properties of these deriva-
tives are given in table I.
According to the method of Shuman et al. [17],
1-amino-1-cyclopentane-carboxylic acid (95, 4.6 g, 35.9
mmol) was dissolved in a mixture of 2 N NaOH (40
mL) and tert-butanol (40 mL) and di-tert-butyl dicar-
bonate (9.4 g, 43.0 mmol) were added in one portion.
After stirring overnight, the tert-butanol was evaporated
under reduced pressure, and the remaining water layer
was extracted with diethyl ether (2×50 mL). The diethyl
ether was discarded, and the water layer was acidified
with cold 1 N HCl and extracted with ethyl acetate
(3×100 mL). The combined ethyl acetate extracts were
dried (sodium sulphate), filtered, and evaporated to
yield after recrystallisation from ethyl acetate–hexane
3.2 g (39%) of 96: m.p. 131–133°C ([18] m.p. 131–
133°C); IR (KBr) 1734 (CꢀO, acid), 1697 (CꢀO, carba-
5.1.4. Synthesis of ( )-2-(tert-butoxycarbonyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid (56): general
procedure for the preparation of BOC-amino acids
using BOC-ON
Following a previously reported procedure [15], the
acid 55 (7.1 g, 40.0, mmol) was dissolved in a mixture of
water (50 mL) and acetone (50 mL) and treated with
triethylamine (6.2 g, 60.0 mmol) followed by the addi-
tion of BOC-ON (10.9 g, 44.0 mmol). After stirring
overnight, a mixture of water (100 mL) and ethyl acetate
(150 mL) was added. The ethyl acetate layer was sepa-
rated and washed with water (100 mL). The combined
aqueous phase was washed with ethyl acetate (50 mL),
acidified with cold 1 N HCl, and extracted with ethyl
acetate (3×100 mL). The combined ethyl acetate ex-
1
mate) cm−1; H-NMR (CDCl3) l 1.44 (s, 9H, C(CH3)3),
1.91 (br m, 8H), 7.21 (br s, 1H, CONH), 9.45 (s, 1H,
COOH); 13C-NMR (CDCl3)
l
24.5, 25.1, 28.3
(C(CH3)3), 37.7, 66.0, 80.2 (C(CH3)3), 158.1 (OCONH),
179.5 (COOH).

276
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
5.1.7. ( )-N-(tert-Butoxycarbonyl)-
5.1.10. 1-[N-(tert-Butoxycarbonyl)amino]-
1,2,3,4-tetrahydro-1-isoquinolinecarboxylic acid (65)
Following the method for the preparation of 96, the
acid 64 (4.7 g, 26.6 mmol) and di-tert-butyl dicarbonate
(7.0 g, 31.9 mmol) gave 6.2 g (84%) of 65 as an oil:
1H-NMR (CDCl3) l 1.44 (s, 9H, C(CH3)3), 2.87 (m, 2H,
CH2CH2N), 3.45 (m, 2H, CH2CH2N), 5.53 (d, 1H,
CHCOOH), 7.35 (m, 4H, ArH), 9.45 (s, 1H, COOH);
13C-NMR (CDCl3) l 28.3, 28.7, 39.9, 41.0, 57.6, 58.7,
80.9, 81.3, 126.6, 128.0, 128.6, 129.7, 135.4, 135.8, 155.0,
155.5, 176.2, 176.8.
cyclohexanecarboxylic acid (98)
In a similar manner as described for the synthesis of
96, 1-amino-1-cyclohexanecarboxylic acid (5.0 g, 35.0
mmol) and di-tert-butyl dicarbonate (9.1 g, 42.0 mmol)
gave 5.1 g (60%) of 98 after recrystallisation from ethyl
acetate–hexane: m.p. 177–178°C ([20] m.p. 175–176°C);
1
IR (KBr) 1682 (CꢀO, acid and carbamate); H-NMR
(CDCl3) l 1.44 (s, 9H, C(CH3)3), 1.78 (br m, 10H), 6.90
(br s, 1H, NHCOO), 9.14 (br s, 1H, COOH); 13C-NMR
(CDCl3) l 21.2, 25.2, 28.3 (C(CH3)3), 32.6, 58.8, 80.8
(C(CH3)3), 155.7 (NHCOO), 179.7 (COOH).
The BOC-acid was dissolved in diethyl ether (100
mL), and dicyclohexylamine (1.8 g, 10 mmol) was added
to the solution. After standing in the freezer overnight,
the precipitate was filtered, washed with diethyl ether,
and dried under vacuum to afford 4.4 g (96%) of the
dicyclohexylamine salt as colourless crystals: m.p. 175–
177°C ([17] no reported m.p.); IR (KBr) 1697 (CꢀO,
5.1.11. cis-4-[N-(tert-Butoxycarbonyl)amino]-
cyclohexanecarboxylic acid (101)
The cis-acid 100 (3.2 g, 22.4 mmol) and di-tert-butyl
dicarbonate (5.9 g, 26.9 mmol) gave 4.2 g (76%) of
cis-102 after recrystallisation from ethyl acetate: m.p.
169–172°C ([21] m.p. 164–168°C); IR (KBr) 1701 (CꢀO,
carbamate) and 1633 (CꢀO, COO−) cm−1
.
acid), 1639 (CꢀO, carbamate) cm−1; H-NMR (DMSO-
1
5.1.8. ( )-N-(tert-Butoxycarbonyl)norleucine (71)
According to the method used for the preparation of
96, norleucine (5.0 g, 38.1 mmol) and di-tert-butyl dicar-
bonate (10.0 g, 45.7 mmol) gave 7.6 g (87%) of 71 after
recrystallisation from petroleum ether: m.p. 75–76°C
([19] no reported m.p.); IR (KBr) 1720 (CꢀO, acid),
1669 (CꢀO, carbamate); 1H-NMR (CDCl3) l 1.35 (br m,
9H), 1.45 (s, 9H, C(CH3)3), 4.30 (br m, 1H, CHCOOH),
5.16 (br s, 1H, OCONHCH), 10.8 (s, 1H, COOH);
13C-NMR (CDCl3) l 13.9, 22.3, 27.4, 28.3 (C(CH3)3),
32.2, 53.4, 54.7, 80.3 (C(CH3)3), 155.8 (CONH), 177.7
(COOH).
d6) l 1.37 (s, 9H, C(CH3)3), 1.55 (br m, 8H), 2.42 (m,
1H, CHCOOH), 3.43 (m, 1H, NHCH), 6.67 (br s, 1H,
NHCOO), 12.1 (br s, 1H, COOH); 13C-NMR (DMSO-
d6) l 24.8, 28.3 (C(CH3)3), 29.3, 39.2, 47.4, 77.3
(C(CH3)3), 154.9 (CON), 176.0 (COOH).
5.1.12. trans-4-[N-(tert-Butoxycarbonyl)amino]-
cyclohexanecarboxylic acid (103)
The trans-acid 101 (0.4 g, 2.8 mmol) and di-tert-butyl
dicarbonate (0.73 g, 3.4 mmol) gave 0.5 g (66%) of
trans-103 after recrystallisation from ethyl acetate–hex-
ane: m.p. 183–185°C ([22] no reported m.p.); IR (KBr)
;
1682 (CꢀO, acid and carbamate) cm−1 1H-NMR
5.1.9. N-(tert-Butoxycarbonyl)-2-(n-butyl)aminoacetic
acid (81)
(CDCl3) l 1.40 (s, 9H, C(CH3)3), 1.65 (br m, 8H), 1.95
(m, 1H, CHCOOH), 3.55 (br m, 1H, NHCH), 6.75 (br
s, 1H, NHCOO), 9.45 (s, 1H, COOH); 13C-NMR
(CDCl3) l 27.7, 28.3 (C(CH3)3), 31.7, 41.7, 48.7, 77.4
(C(CH3)3), 154.8 (CON), 176.5 (COOH).
The ethyl ester 79 (9.1 g, 57.2 mmol) was refluxed
with 25% NaOH solution (50 mL) for 2 h. The reaction
mixture was cooled, neutralised with 2 N HCl, and
evaporated to dryness under reduced pressure to yield a
solid which was used directly in the next step. Using the
general method described for 96, the crude amino acid
and di-tert-butyl dicarbonate (13.1 g, 61.9 mmol) gave
9.4 g (71%) of 81 as an oil: IR (neat) 1732 (CꢀO, acid),
5.1.13. Synthesis of ( )-1-(tert-butoxycarbonyl)-N-
[3-fluoro-h-(methyl)benzyl]-2-piperidinecarboxamide
(26): general procedure for the mixed anhydride method
Using the previously reported method [5], a solution
of (R,S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic
acid (4.6 g, 20.0 mmol) in dry THF (100 mL) was cooled
to 0–5°C, and NMM (2.0 g, 20.0 mmol) was added
under nitrogen. After stirring for 5 min, IBCF (2.7 g,
20.0 mmol) was added in one portion and immediately a
white precipitate formed. The reaction was allowed to
proceed for an additional 5 min, and a solution of
1
1699 (CꢀO, carbamate) cm−1; H-NMR (CDCl3) l 0.92
(t, 3H, CH3CH2), 1.35 (br m, 4H, CH3(CH2)2CH2), 1.45
(s, 9H, C(CH3)3), 3.28 (t, 2H, CH3(CH2)2CH2), 3.98 (br
s, 2H, NCH2COOH), 9.88 (br s, 1H, COOH); 13C-NMR
(CDCl3) l 13.8, 20.0, 28.4, 30.4, 48.4, 49.1, 80.6, 156.0,
174.8. Anal. Found: C, 55.87. Calc. for (C11H21NO4): C,
57.12%; H; N.

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
277
( ) - 3 - fluoro - a - (methyl)benzylamine (14, 2.8 g, 20.0
mmol) in THF (20 mL) was added over 10 min at
0–5°C. The reaction mixture was stirred at room tem-
perature for 1 h, and the precipitated NMM hydrochlo-
ride was suction filtered. Removal of the solvent under
reduced pressure gave a white solid upon trituration
with ethyl acetate. Recrystallisation from ethanol–water
yielded 4.9 g (70%) of 26: m.p. 102–105°C; IR (KBr)
(C(CH3)3), 127.4, 128.2, 135.3, 168.5 (CONH). Anal.
(C19H30N2O3) C, H, N.
5.1.16. Synthesis of ( )-n-[3-fluoro-h-(methyl)benzyl-
2-piperidinecarboxamide hydrochloride (27): general
procedure for the removal of the BOC-protecting group
A solution of 26 (3.7 g, 10.6 mmol) in dichloro-
methane (50 mL) was cooled to 0–5°C and was satu-
rated with hydrogen chloride gas. The mixture was
stirred for another 2 h, and the solvent was removed
under reduced pressure to yield an oil which solidified
upon trituration with diethyl ether. Recrystallisation
from absolute ethanol–diethyl ether yielded 2.52 g
(83%) of 27: m.p. 195–210°C; IR (KBr) 1682 (amide)
1
1697 (CꢀO, carbamate), 1655 (CꢀO, amide) cm−1; H-
NMR (CDCl3) l 1.46 (d, 3H, J=6.6 Hz, CHCH3), 1.47
(s, 9H, C(CH3)3), 2.10 (br m, 9H), 5.15 (m, 1H,
CHCH3), 6.45 (br s, 1H, CONH), 7.02 (m, 4H, ArH);
13C-NMR (CDCl3) l 20.4, 22.0, 24.8, 25.4, 28.3
(C(CH3)3), 42.0, 48.3 (CONHCH), 54.5 (NCCO), 80.8
(C(CH3)3), 112.4, 113.4, 113.7, 114.6, 121.6, 121.7,
130.0, 130.3, 146.1, 157.5 (NHCOO), 168.4, 170.3
(CONH), 170.5 (CONH). Anal. (C19H27FN2O3) C, H,
N. Using this procedure, the carboxamides 18, 46, 48,
57, and 67 were prepared. The physicochemical proper-
ties of these compounds are given in tables II and III.
1
cm−1; H-NMR (DMSO-d6) l 1.39 (d, 3H, J=6.8 Hz,
CHCH3), 1.78 (br m, 6H), 2.94 (br m, 2H, CH2NH2+
CH), 3.80 (m, 1H, NH2+CHCO), 4.96 (m, 1H, CHCH3),
7.24 (m, 4H, ArH), 9.15 (br s, 2H, NH+2), 9.35 (br d, 1H,
CONH); 13C-NMR (DMSO-d6) l 21.2, 21.6, 22.4, 26.9,
27.1, 43.2, 48.1, 56.7, 56.9, 112.1, 112.5, 113.1, 113.4,
114.0, 121.8, 122.0, 122.3, 122.4, 130.1, 130.5, 147.3,
147.6, 158.8, 167.6 (CONH); MS (CI, methane) m/z 251
(M++1). Anal. (C14H20ClFN2O) C, H, N.
5.1.14. ( )-2-(tert-Butoxycarbonyl)-
amino-N-[(2,6-dimethyl)phenyl]hexaneamide (73)
( )-N-(tert-Butoxycarbonyl)norleucine(71, 3.5 g, 15.0
mmol), NMM (1.5 g, 15.0 mmol), IBCF (2.0 g, 15.0
mmol), and 2,6-dimethylaniline (3.0 g, 25.0 mmol) gave
2.9 g (59%) of 73 after recrystallisation from ethanol–
water: m.p. 152–155°C; IR (KBr) 1710 (CꢀO, carba-
5.1.17. ( )-2-Amino-N-[(2,6-dimethyl)phenyl]-
hexaneamide hydrochloride (75)
The BOC-amide 73 (2.3 g, 6.9 mmol) gave 1.0 g (52%)
of 75 after recrystallisation from methanol–diethyl
ether: m.p. 215–217°C; IR (KBr) 1662 (CꢀO) cm−1
;
1
mate), 1622 (CꢀO, amide) cm−1; H-NMR (CDCl3) l
1H-NMR (DMSO-d6) l 0.93 (t, 3H, CH3(CH2)3), 1.62
(br m, 6H, CH3(CH2)3), 2.19 (s, 6H, 2,6-diCH3), 4.15 (t,
1H, NH+3CHCO), 7.07 (s, 3H, ArH), 8.53 (br s, 3H,
NH+3), 10.28 (s, 1H, CONH); 13C-NMR (DMSO-d6) l
13.7, 18.3, 21.9, 26.4, 31.0, 52.4, 126.7, 127.8, 134.1,
135.1, 167.2,; MS (CI, methane) m/z 235 (M++1). Anal.
Found: C, 59.16; N, 9.85. Calc. for (C14H23ClN2O): C,
62.10; H; N, 10.34%.
0.90 (t, 3H, CH3(CH2)3), 1.43 (s, 9H, C(CH3)3), 1.51 (br
m, 6H, CH3(CH2)3, 2.15 (s, 6H, 2,6-diCH3), 4.26 (m,
1H, CH3(CH2)3CH), 5.55 (br s, 1H, OCONH), 7.02 (s,
3H, ArH), 7.93 (br s, 1H, CONHAr); 13C-NMR
(CDCl3) l 13.9, 18.3, 22.4, 28.0, 28.3 (C(CH3)3, 32.0,
54.9, 80.1 (C(CH3)3), 127.2, 128.3, 133.6, 135.4, 156.0
(NCOO), 171.0 (CONH). Anal. (C19H30N2O3) C, H, N.
5.1.15. 2-{[N-(tert-Butoxycarbonyl)-N-(n-butyl)]amino}-
N-[(2,6-dimethyl)-phenyl]acetamide (83)
5.1.18. 2-Amino-N-[(2,6-dimethyl)phenyl]acetamide
hydrochloride (76)
The BOC-acid 81 (3.0 g, 13.0 mmol), NMM (1.3 g,
13.0 mmol), IBCF (1.8 g, 13.0 mmol), and 2,6-dimethyl-
aniline (3.0 g, 25.0 mmol) yielded 2.3 g (53%) of 83 after
recrystallisation from methanol–water: m.p. 85–87°C;
N-(tert-Butoxycarbonyl)glycine (72, 1.5 g, 8.3 mmol),
NMM (0.8 g, 8.3 mmol), IBCF (1.1 g, 8.3 mmol), and
2,6-dimethylaniline (2.4 g, 20.0 mmol) gave 1.4 g (59%)
of the BOC-amide after recrystallisation from ethanol–
water: m.p. 120–122°C; IR (KBr) 1696 (CꢀO, carba-
IR (KBr) 1780 (CꢀO, carbamate) cm−1
;
1H-NMR
1
(CDCl3) l 0.94 (t, 3H, CH3(CH2)3), 1.35 (br m, 4H,
CH3(CH2)2CH2), 1.50 (s, 9H, C(CH3)3), 2.22 (s, 6H,
2,6-diCH3), 3.35 (t, 2H, CH3(CH2)2CH2), 4.02 (s, 2H,
NCH2CO), 7.08 (s, 3H, ArH); 13C-NMR (CDCl3) l
13.8, 18.5, 19.9, 28.4 (C(CH3)3), 30.4, 48.8, 52.1, 81.0
mate), 1655 (CꢀO, amide); H-NMR (CDCl3) l 1.45 (s,
9H, C(CH3)3), 2.18 (s, 6H, 2,6-diCH3), 3.94 (d, 2H,
J=5.9 Hz, COCH2NH), 5.55 (br s, 1H, OCONH), 7.05
(s, 3H, ArH), 7.81 (br s, 1H, CONH). In the usual
manner, the BOC-amide (1.2 g, 4.3 mmol) gave 0.8 g

278
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
(81%) of 76 after recrystallisation from absolute etha-
nol–diethyl ether: m.p. 292–294°C; IR (KBr) 1674
(CꢀO, amide) cm−1; 1H-NMR (DMSO-d6) l 2.16 (s, 6H,
2,6-diCH3), 3.84 (s, 2H, CH2CONH), 7.08 (s, 3H, ArH),
8.34 (br s, 3H, NH3+), 10.11 (s, 1H, CONH); 13C-NMR
(DMSO-d6) l 18.2, 40.3, 126.7, 127.8, 134.2, 135.1,
164.6 (CONH); MS (CI, methane) m/z 179 (M++1).
Anal. (C10H15ClN2O) C, H, N.
CHCH3), 3.59 (s, 2H, CH2CONH), 4.96 (m, 1H,
NHCHCH3), 7.33 (m, 5H, ArH), 8.27 (br s, 3H, NH+3),
9.15 (d, 1H, J=8.0 Hz, CONH); 13C-NMR (DMSO-d6)
l 22.4, 40.0, 48.3, 126.0, 126.7, 128.2, 143.9, 164.8
(CONH). Anal. (C10H15ClN2O) C, H, N.
5.1.21. ( )-2-(n-Butylamino)-N-(h-methylbenzyl)-
acetamide hydrochloride (82)
The BOC-acid 81 (4.6 g, 20.0 mmol), NMM (2.0 g,
20.0 mmol), IBCF (2.7 g, 20.0 mmol), and ( )-a-methyl-
benzylamine (2.4 g, 20.0 mmol) gave an oil. After depro-
tection, the hydrochloride was recrystallised from
absolute ethanol–diethyl ether to yield 2.2 g (41%) of
5.1.19. Reaction of ( )-71 with
( )-(h-methyl)benzylamine: formation of the
diastereoisomeric mixture (77)
( )-71 (2.3 g, 10.0 mmol), NMM (1.0 g, 10.0 mmol),
IBCF (1.4 g, 10.0 mmol), and ( )-a-methylbenzylamine
(1.2 g, 10.0 mmol) afforded a diastereoisomeric mixture
as an oil. After deprotection in the normal manner, the
mixture was chromatographed on a silica gel column
using ethyl acetate–ammonium hydroxide (99:1) as the
mobile phase. Fractions homogeneous by TLC were
combined and concentrated under vacuum to yield 0.5 g
(21%) of a light yellow oil of the less-polar diastereoiso-
mer as a racemic mixture: IR (neat) 1655 (CꢀO, amide)
1
82: m.p. 129–131°C; IR (KBr) 1666 (CꢀO) cm−1; H-
NMR (CDCl3) l 0.86 (t, 3H, J=6.6 Hz, CH3CH2), 1.48
(d, 3H, J=6.8 Hz, CHCH3), 1.50 (br m, 4H,
CH3(CH2)2), 2.82 (m, 2H, CH3(CH2)2CH2), 3.85 (s, 2H,
NH+2CH2CO), 4.99 (m, 1H, CHCH3), 7.27 (m, 5H,
ArH), 9.00 (br m, 3H, NH+2 and CONH); 13C-NMR
(CDCl3) l 13.5, 19.8, 22.5, 27.9, 48.0, 48.7, 50.1, 126.2,
127.2, 128.6, 143.4, 164.2. Anal. Found: C, 60.93. Calc.
for (C14H23ClN2O): C, 62.09%; H; N.
1
cm−1; H-NMR (CDCl3) l 0.88 (t, 3H, CH3(CH2)3CH),
1.37 (br m, 6H), 1.49(d, 3H, J=6.8 Hz, CHCH3), 1.51
(s, 2H, NH2), 3.41 (m, 1H, NH2CHCO), 5.08 (m, 1H,
NHCHCH3), 7.31 (m, 5H, ArH), 7.53 (m, 1H, CONH);
13C-NMR (CDCl3) l 14.0, 22.1, 22.5, 28.0, 34.8, 48.1,
55.3, 126.1, 127.1, 128.6, 143.9, 174.2. Anal. Found: C,
69.99; N, 11.54. Calc. for (C14H22N2O): C, 71.75; H; N,
11.96%.
The more polar diastereoisomer was obtained as a
light yellow oil as a racemic mixture. The hydrochloride
was prepared and recrystallised from isopropanol–di-
ethyl ether to afford 0.7 g (26%): m.p. 198–200°C; IR
(KBr) 1678 (CꢀO) cm−1; 1H-NMR (DMSO-d6) l 0.78 (t,
3H, J=5.4 Hz, CH3(CH2)3CH), 3.76 (m, 1H, NH3+
CHCO), 4.96 (m, 1H, CONHCHCH3), 7.31 (m, 5H,
ArH), 9.07 (d, 1H, CONH); 13C-NMR (DMSO-d6) l
13.7, 21.7, 22.3, 26.1, 30.9, 48.3, 52.2, 125.9, 126.8,
128.2, 144.2, 167.9. Anal. (C14H23ClN2O) C, H, N.
5.1.22. 2-(n-Butylamino)-N-[(2,6-dimethyl)phenyl]-
acetamide hydrochloride (84)
The BOC-amide 83 (2.0 g, 6.0 mmol) gave 1.2 g (71%)
of 84 after deprotection and recrystallisation from abso-
lute ethanol: m.p. 139–141°C; IR (KBr) 1676 (CꢀO,
amide) cm−1 1H-NMR (DMSO-d6) l 0.89 (t, 3H,
;
CH3(CH2)3), 1.45 (br m, 4H, CH3(CH2)2CH2), 2.17 (s,
6H, 2,6-diCH3), 2.95 (br t, 2H, CH3(CH2)2CH2NH),
4.00 (s, 2H, NHCH2CO), 7.08 (s, 3H, ArH), 9.33 (br s,
2H, NH+2), 10.27 (s, 1H, CONH); 13C-NMR (DMSO-d6)
l 13.4, 18.1, 19.2, 27.2, 46.5, 47.5, 126.7, 127.6, 134.0,
135.0, 163.6 (CONH); MS (CI, methane) m/z 235 (M++
1). Anal. (C14H23ClN2O) C, H, N.
5.1.23. ( )-1-Amino-N-[(h-methyl)benzyl]-
cyclopentanecarboxamide (97)
The BOC-acid 96 (2.3 g, 10.0 mmol), NMM (1.0 g,
10.0 mmol), IBCF (1.4 g, 10.0 mmol), and ( )-a-methyl-
benzylamine afforded 1.1.g (48%) of 97 after deprotec-
tion and recrystallisation from diethyl ether–petroleum
ether: m.p. 77–78°C; IR (KBr) 1642 (CꢀO, amide)
5.1.20. 2-Amino-N-(h-methylbenzyl)acetamide
hydrochloride (78)
BOC-glycine (72, 1.8 g, 10.0 mmol), NMM (1.0 g,
10.0 mmol), IBCF (1.4 g, 10.0 mmol), and ( )-a-methyl-
benzylamine (1.2 g, 10.0 mmol) yielded an oil. After
deprotection, the hydrochloride was recrystallised from
absolute ethanol–diethyl ether to give 1.6 g (73%) of 78:
cm−1 1H-NMR (CDCl3) l 1.48 (d, 3H, J=7.1 Hz,
;
CH3CH), 1.81 (br m, 10H), 5.08 (m, 1H, CONHCH),
7.31 (s, 5H, ArH), 8.12 (br s, 1H, CONH); 13C-NMR
(CDCl3) l 22.3, 24.5, 40.6, 48.5, 65.1, 126.1, 127.1,
128.6, 143.9, 176.3 (CONH). Anal. (C14H20N2O) C, H,
N.
m.p. 124–127°C; IR (KBr) 1660 (CꢀO, amide) cm−1
;
1H-NMR (DMSO-d6) l 1.38 (d, 3H, J=7.1 Hz,

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
279
5.1.24. N-[(2,6-Dimethyl)phenyl]-1-
aminocyclohexanecarboxamide (99)
temperature and was stirred overnight. The solvent was
evaporated under reduced pressure, and additional
methylene chloride was added and again evaporated.
The resulting residue was dissolved in dry THF (80 mL),
cooled to 0–5°C, and triethylamine (2.0 g, 20.0 mmol)
was added under nitrogen. The cooled solution was
treated dropwise with ( )-a-methylbenzylamine (2.4 g,
20.0 mmol) in dry THF (20 mL). After warming to
room temperature, the reaction mixture was stirred for 2
h and filtered to remove the precipitated triethylamine
hydrochloride. Evaporation of the filtrate under reduced
pressure gave an oil which was partitioned between ethyl
acetate (100 mL) and 1 N HCl (50 mL). The ethyl
acetate layer was separated, washed with water (100
mL), dried (Na2SO4), filtered, and evaporated under
reduced pressure to afford a solid. Recrystallisation
from ethyl acetate–hexane yielded 2.2 g (47%) of 87:
m.p. 112–113°C; IR (KBr) 3321 (NH, amide), 1644
The BOC-acid 98 (2.4 g, 10.0 mmol), NMM (1.0 g,
10.0 mmol), IBCF (1.4 g, 10.0 mmol), and 2,6-dimethyl-
aniline (2.4 g, 20.0 mmol) gave, after deprotection and
recrystallisation from petroleum ether, 0.4 g (16%) of 99
as the free base: m.p. 133–135°C; IR (KBr) 1666 (CꢀO,
1
amide) cm−1; H-NMR (CDCl3) l 1.61 (m, 12H), 2.20
(s, 6H, 2,6-diCH3), 7.06 (s, 3H, ArH), 9.38 (br s, 1H,
CONH). Anal. (C15H22N2O) C, H, N.
5.1.25. cis-N-[(2,6-Dimethyl)phenyl]-4-
aminocyclohexanecarboxamide hydrochloride (104)
The cis-BOC-acid 102 (3.7 g, 15.0 mmol), NMM (1.5
g, 15.0 mmol), IBCF (2.0 g, 15.0 mmol), and 2,6-
dimethylaniline (2.4 g, 20.0 mmol) afforded, after depro-
tection and recrystallisation from absolute ethanol–
diethyl ether, 2.1 g (49%) of 104: m.p. 275°C; IR (KBr)
1
1651 (CꢀO, amide) cm−1; H-NMR (DMSO-d6) l 1.75
1
(CꢀO, amide) cm−1; H-NMR (CDCl3) l 1.44 (d, 3H,
(br m, 8H), 2.13 (s, 6H, 2,6-diCH3), 3.27 (br m, 2H,
CHNH2 and CHCONH), 7.05 (s, 3H, ArH), 8.21 (br s,
3H, NH+3), 9.32 (s, 1H, CONH); 13C-NMR (DMSO-d6)
l 18.2, 24.3, 27.1, 40.4, 47.4, 126.3, 127.6, 135.3, 172.9
(CONH); MS (CI, methane) m/z 247 (M++1). Anal.
Found: C, 62.96. Calc. for (C15H23ClN2O): C, 63.70%;
H; N.
J=6.8 Hz, CHCH3), 1.51 (br m, 11H), 5.19 (m, 1H,
CONHCHCH3), 6.05 (br s, 1H, CONH), 7.28 (s, 5H,
ArH); 13C-NMR (CDCl3) l 21.8, 25.7, 29.6, 45.5, 48.2,
126.1, 127.1, 128.5, 143.6, 175.2 (CONH). Anal.
(C15H21NO2) C, H, N. Following this method, the cy-
cloalkanecarboxamides 85, 86, and 88–93 were pre-
pared. The physicochemical properties of these
compounds are given in table IV.
5.1.26. trans-N-[(2,6-Dimethyl)phenyl]-4-
aminocyclohexanecarboxamide hydrochloride (105)
The trans-acid 103 (0.4 g, 1.4 mmol), NMM (0.1 g,
1.4 mmol), IBCF (0.2 g, 1.4 mmol), and 2,6-dimethyl-
aniline (1.0 g, 8.3 mmol) gave, after deprotection and
recrystallisation from absolute ethanol–diethyl ether,
0.15 g (38%) of trans-105: m.p. >325°C; IR (KBr) 1637
5.1.28. ( )-1-Benzyl-N-[(h-methylbenzyl)-2-
piperidinecarboxamide hydrochloride (35)
To a suspension of the carboxamide 2 (2.0 g, 8.6
mmol) and potassium carbonate (1.4 g, 10.3 mmol) in
DMF (40 mL), a solution of benzyl bromide (1.8 g, 10.3
mmol) in DMF (10 mL) was added dropwise under
nitrogen. The reaction mixture was heated at 50°C for 5
h, and the solvent was removed under reduced pressure.
The residue was partitioned between ethyl acetate (100
mL) and water (50 mL), and the ethyl acetate phase was
separated, dried (Na2SO4), filtered, and evaporated un-
der vacuum to afford an oil. A hydrochloride was
prepared and recrystallised from absolute ethanol–di-
ethyl ether to yield 1.2 g (39%) of 35: m.p. 243–245°C;
1H-NMR (DMSO-d6) l 1.46 (d, 3H, CHCH3), 1.64 (br
m, 6H), 3.68 (br m, 5H, CH2(CH2)NH+CH), 5.05 (m,
1H, CONHCHCH3), 7.41 (m, 10H, ArH), 9.48 (br s,
1H, NH+), 9.91 (m, 1H, CONH); 13C-NMR (DMSO-d6)
l 21.1, 21.7, 22.3, 28.2, 48.6, 50.8, 58.0, 64.7, 125.8,
126.9, 128.3, 128.7, 129.5, 131.5, 143.9, 166.9. Anal.
(C21H27ClN2O) C, H, N.
1
(CꢀO, amide) cm−1; H-NMR (DMSO-d6) l 1.75 (br m,
8H), 2.11 (s, 6H, 2,6-diCH3), 3.07 (br m, 2H, NH+3 and
CHCONH), 7.05 (s, 3H, ArH), 8.25 (br s, 3H, NH+3),
9.29 (s, 1H, CONH); 13C-NMR (DMSO-d6) l 18.0,
27.4, 29.5, 42.6, 48.8, 126.3, 127.6, 135.2, 173.0
(CONH). Anal. (C15H23ClN3O) C, H, N.
5.1.27. General procedure for the synthesis of
cycloalkanecarboxamides: synthesis of
( )-N-(h-methylbenzyl)cyclohexanecarboxamide (87)
A solution of cyclohexanecarboxylic acid (2.6 g, 20.0
mmol) in methylene chloride (50 mL) was cooled to
0–5°C under a nitrogen atmosphere, and the mixture
was treated in a dropwise manner with a solution of
SOCl2 (7.1 g, 59.7 mmol) in methylene chloride (20 mL).
The reaction mixture was allowed to warm to room

280
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
5.1.29. ( )-1-Benzoyl-N-(h-methylbenzyl)-2-
piperidinecarboxamide (39)
dry THF (40 mL) was added dropwise to a stirred
suspension of LAH (1.0 g, 25.8 mmol) in dry THF (60
mL) under a nitrogen atmosphere. The mixture was
refluxed for 12 h, cooled, treated carefully with water to
decompose the excess LAH, and basified with 1 N
NaOH to pH 10. The precipitate was filtered, and the
filtrate was evaporated under reduced pressure. The
resulting residue was partitioned between ethyl acetate
(100 mL) and water (100 mL), and the ethyl acetate
phase was separated, dried (Na2SO4), filtered, and evap-
orated to yield an oil. The crude product was subjected
to flash chromatography on a silica gel column using
ethyl acetate–methanol–ammonium hydroxide (80:20:1)
as the mobile phase. Fractions homogeneous by TLC
were combined and concentrated under reduced pres-
sure to afford an oil. A dihydrochloride was prepared
and recrystallised from 2-propanol–diethyl ether to
yield 1.1 g (44%) of 51: m.p. 214–216°C; 1H-NMR
(D2O) l 1.74 (d, 3H, J=7 Hz, CHCH3), 1.78 (br m,
6H), 3.25 (br m, 5H, CH2NH+2CHCH2NH2+), 4.53 (q,
1H, J=7 Hz, CHCH3), 7.55 (s, 5H, ArH); 13C-NMR
(D2O) l 17.6, 20.6, 20.8, 21.7, 23.5, 23.9, 28.9, 47.7,
49.6, 49.8, 55.7, 55.9, 57.0, 62.3, 62.5, 130.4, 132.2,
132.7, 137.4. Anal. (C14H24Cl2N2) C, H, N.
A solution of benzoyl chloride (0.6 g, 4.0 mmol) and
triethylamine (0.4 g, 4.0 mmol) in THF (50 mL) was
cooled to 0–5°C under nitrogen and treated dropwise
with a solution of the amide 2 (mixture of diastereoiso-
mers) (0.9 g, 4.0 mmol) in THF (20 mL). The mixture
was stirred at room temperature for 2 h, the precipitated
triethylamine hydrochloride was suction filtered, and the
filtrate was removed under reduced pressure to give a
yellow solid. The resulting solid was partitioned between
ethyl acetate (100 mL) and water (50 mL), and the
organic layer was washed with 1 N HCl, dried (Na2-
SO4), filtered, and evaporated under vacuum to afford
0.7 g (53%) of 39 after recrystallisation from petroleum
ether–diethyl ether: m.p. 144–146°C; 1H-NMR (CDCl3)
l 1.64 (d, 3H, CHCH3), 2.04 (br m, 6H), 3.35 (br m, 3H,
CH2NHCH), 5.21 (m, 1H, CONHCHCH3), 6.90 (br s,
1H, CONH), 7.35 (m, 10H, ArH); 13C-NMR (CDCl3) l
10.5, 22.2, 25.6, 46.1, 48.7, 52.8, 126.1, 127.2, 127.4,
129.1, 130.2, 135.4, 143.5, 169.9, 172.3. Anal.
(C21H24N2O2) C, H, N.
5.1.30. N-[(2,6-Dimethyl)phenyl]-4-pyridinecarboxamide
(50)
A suspension of isonicotinic acid (2.5 g, 20.0 mmol) in
pyridine (100 mL) was cooled to 0-5°C under a nitrogen
atmosphere and treated in a dropwise manner with a
solution of thionyl chloride (7.1 g, 60.0 mmol) in pyri-
dine (20 mL). The reaction mixture was allowed to
warm to room temperature and was stirred overnight.
The solvent was removed under vacuum, and the result-
ing residue was dissolved in THF (50 mL) and treated
with triethylamine (2.0 g, 20.0 mmol) followed by the
dropwise addition of 2,6-dimethylaniline (2.4 g, 20.0
mmol) in THF (20 mL) under a nitrogen atmosphere.
The reaction mixture was stirred at room temperature
for 1 h, the triethylamine hydrochloride was suction
filtered, and the filtrate was evaporated under vacuum
to give a solid upon trituration with hexane. Recrystalli-
sation from ethyl acetate–hexane gave 1.4 g (30%) of
5.1.32. ( )-2-[(4-Trifluoromethyl)benzyl]-2,3,5,6,7,8-
hexahydroimidazo[1,5-a]-pyridin-1-one (52)
Using the described method [23], a mixture of 23 (6.0
g, 21.0 mmol), formaldehyde (60 mL), and ethanol (5
mL) was refluxed under a nitrogen atmosphere for 2 h.
The reaction mixture was concentrated to half volume
under reduced pressure, diluted with water (60 mL), and
extracted with diethyl ether (3×30 mL). The combined
diethyl ether extracts were washed with water (50 mL),
dried (Na2SO4), filtered, and evaporated under reduced
pressure to give a solid upon cooling. Recrystallisation
from petroleum ether afforded 5.4 g (86%) of 52: m.p.
1
67–70°C; IR (KBr) 1696 (CꢀO, lactam) cm−1; H-NMR
(CDCl3) l 2.05 (br m, 9H), 3.81 (dd, 1H, J=2 Hz, 5.1
Hz, H-3ax), 4.04 (d, 1H, J=5.1 Hz, H-3eq), 4.52 (q, 2H,
NCH2Ar), 7.48 (m, 4H, ArH); 13C-NMR (CDCl3) l
23.2, 24.4, 24.9, 45.0, 49.6, 63.2, 67.7, 118.3, 125.8,
126.0, 126.1, 128.3, 140.6, 173.0. Anal. (C15H17F3N2O)
C, H, N.
1
50: m.p. 157–159°C; H-NMR (CDCl3) l 2.19 (s, 6H,
2,6-diCH3), 7.11 (s, 3H, ArH), 7.64 (dd, 2H, J=1.7, 4.5
Hz, H-3, H-5), 8.18 (br s, 1H, CONH), 8.66 (dd, 2H,
J=1.7, 4.5 Hz, H-2, H-6); 13C-NMR (CDCl3) l 18.3,
121.1, 127.8, 128.3, 133.3, 135.5, 141.4, 150.5, 164.1.
Anal. (C14H14N2O) C, H, N.
5.1.33. Dimethyl 2-acetyl-1,2,3,4-tetrahydro-3,3-
isoquinolinedicarboxylate (53)
5.1.31. [1-(Phenylethyl)piperidin-2-yl]methylamine (51)
A solution of the carboxamide 2 (2.0 g, 8.6 mmol) in
Using the method of Kammermeier et al. [24], a
stirred suspension of a,a%-dichloro-o-xylene (17.5 g, 100

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
281
mmol) and diethyl acetamidomalonate (21.7 g, 100
mmol) in methanol (175 mL) was treated dropwise with
30% sodium methoxide in methanol (20 mL, 111 mmol)
over 10 min at room temperature under nitrogen. The
reaction mixture was heated to reflux, treated with
additional 30% sodium methoxide in methanol (22 mL,
122 mmol) in a dropwise fashion over 2 h, and stirred
for another 2 h. The mixture was cooled to room
temperature and concentrated under reduced pressure.
The resulting solid residue was partitioned between wa-
ter (100 mL) and ethyl acetate (150 mL). The aqueous
phase was extracted with ethyl acetate (2×75 mL), and
the combined ethyl acetate extracts were washed with
brine (100 mL), dried (Na2SO4), filtered, and evaporated
under reduced pressure to give a solid. Recrystallisation
from 2-propanol–tert-butyl methyl ether gave 12.3 g
(43%) of 53: m.p. 141–143°C; ([24] m.p. 141–143°C); IR
327–330°C ([24] m.p. 321–325°C); IR (KBr) 1600
(CꢀO), 1497, 1460 cm−1
.
5.1.36. ( )-1,2,3,4-Tetrahydro-1-isoquinolinecarboxylic
acid (64)
Using the method of Shuman et al. [17], a mixture of
1-isoquinoline-carboxylic acid (12.5 g, 72.2 mmol) and
platinum(IV) oxide (1.0 g) in glacial acetic acid (100
mL) was shaken on a Parr hydrogenator at an initial
pressure of 60 psi for 24 h. The catalyst was filtered
through a Celite pad, and the solvent was removed
under reduced pressure to afford a solid. The solid was
triturated with water, filtered, and dried to give 7.51 g
(59%) of 64: m.p. 269–271°C ([17] no reported m.p.); IR
1614 (CꢀO).
5.1.37. Ethyl 2-(n-butyl)aminoacetate (79)
(KBr) 1745 (CꢀO, ester), 1649 (CꢀO, amide) cm−1
;
According to the method described by Speziale and
Jaworski [25], a solution of n-butylamine (16.8 g, 230
mmol) in benzene (100 mL) was treated dropwise with a
solution of ethyl bromoacetate (16.7 g, 10 mmol) in
benzene(15 mL) at room temperature. The reaction
mixture was heated at reflux for 2 h, cooled, and
basified with 2 N NaOH to pH 10. The organic layer
was separated, washed with water (2×50 mL), dried
(Na2SO4), filtered, and evaporated under reduced pres-
sure to give an oil. Vacuum distillation yielded 9.1 g
(57%) of 79 as a colourless oil: b.p. 57–60°C (1.1 mm,
1H-NMR (CDCl3) l 2.29 (s, 3H, NHCOCH3), 3.43 (s,
2H, ArCH2CHN), 3.68 (s, 6H, CH(COOCH3)2), 4.68 (s,
2H, ArCH2N), 7.20 (br m, 4H, ArH); 13C-NMR
(CDCl3) l 22.3, 37.6, 47.9, 52.9, 68.2, 126.1, 127.5,
127.8, 127.9, 132.3, 132.7, 168.5, 171.0.
5.1.34. ( )-2-Acetyl-1,2,3,4-tetrahydro-3-
isoquinolinecarboxylic acid (54)
Following the method of Kammermeier et al. [24], a
well-stirred suspension of 53 (10.7 g, 37.0 mmol) in a
mixture of methanol (100 mL) and water (20 mL) was
treated portionwise with KOH (4.6 g, 81 mmol) over 30
min. The mixture was refluxed for 5 h, cooled, and
evaporated to dryness under reduced pressure. The
residue was partitioned between ethyl acetate and 2 N
HCl (pH 1), and the aqueous phase was separated and
extracted with ethyl acetate (3×50 mL). The combined
extracts were dried (Na2SO4), filtered, and evaporated
under vacuum to yield 7.2 g (89%) of 54 after trituration
with tert-butyl methyl ether: m.p. 161–165°C ([24] m.p.
171–173°C); IR (KBr) 1738 (CꢀO, acid), 1649 (CꢀO,
[25] b.p. 52°C (1.1 mm); IR (neat) 1739 (CꢀO) cm−1
;
1H-NMR (CDCl3) l 1.04 (t, 6H, CH3(CH2)2 and
OCH2CH3), 1.42 (br m, 5H, CH3(CH2)2CH2NH), 2.60
(t, 2H, J=6.6 Hz, CH3(CH2)2CH2), 3.41 (s, 2H,
NCH2CO), 4.00 (q, 2H, OCH2CH3).
5.1.38. (5,5-Tetramethylene)hydantoin (94)
Using the method of Henze and Speer [26], a mixture
of ammonium carbonate (45.5 g, 470 mmol) and cy-
clopentanone (8.4 g, 100 mmol) in 50% ethanol (250
mL) was treated with NaCN (9.8 g, 200 mmol). After
heating at 58–60°C for 2 h, the reaction mixture was
cooled to room temperature, concentrated to a volume
of about 150 mL under reduced pressure, and chilled in
an ice-bath. The resulting precipitate was filtered to give
9.8 g (64%) of 94: m.p. 202–203°C ([26] m.p. 204–
205°C).
amide) cm−1
.
5.1.35. ( )-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic
acid (55)
Compound 54 (6.5 g, 30.0 mmol) was refluxed in 6 N
HCl (50 mL) for 5 h, cooled to 0–5°C in an ice-water
bath, and treated with aqueous NH3 (25%) to pH 7. The
mixture was stirred for an additional 1 h in an ice-water
bath. The resulting precipitate was filtered, washed with
water, and dried to yield 4.4 g (83%) of 55: m.p.
5.1.39. 1-Amino-1-cyclopentanecarboxylic acid (95)
Using the method of Conners and Ross [27], a mix-
ture of 94 (7.83 g, 50.8 mmol) and barium hydroxide

282
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
octahydrate (28.0 g, 88.8 mmol) in water (170 mL) was
heated to reflux for 3 h. The mixture was cooled to
room temperature, and the precipitated barium carbon-
ate was filtered. The filtrate was treated with ammonium
carbonate (6.3 g, 65.7 mmol) to remove the excess
barium. Evaporation of the filtrate under reduced pres-
sure gave 4.6 g (71%) of 95 after recrystallisation from
ethanol–water: m.p. >317°C ([27] m.p. 328°C).
25.8 (CHCH3), 51.1 (CHCH3), 56.2 (OCH3), 109.8,
111.9, 117.8, 140.9, 148.3, 149.5.
1
Compound 7. H-NMR (CDCl3) l 1.49 (s, 2H,
CHNH2), 2.90 (m, 2H, CHCH2), 4.18 (m, 1H,
CHCH3), 7.26 (m, 10H, ArH); 13C-NMR (CDCl3) l
46.7 (CHCH2), 57.7 (CHCH2), 126.4, 126.5, 127.1,
128.5, 129.4, 139.3, 145.9.
1
Compound 8. H-NMR (CDCl3) l 1.71 (s, 2H,
CHNH2), 5.13 (s, 1H, CHNH2), 7.28 (m, 9H, ArH);
13C-NMR (CDCl3) l 59.5 (CHNH2), 125.2, 126.9,
127.3, 128.7, 129.7, 134.5, 145.1, 147.9.
5.1.40. cis-4-Aminocyclohexanecarboxylic acid (100)
and trans-4-aminocyclohexanecarboxylic acid (101)
Using the method of Skaric et al. [28], a mixture of
4-aminobenzoic acid (1.6 g, 11.6 mmol) and platinum-
(IV) oxide (0.4 g) in 30% ethanol was shaken on a Parr
hydrogenator at an initial pressure of 52 psi for 24 h at
room temperature. This process was repeated six times,
and the solutions were combined. After removal of the
catalyst by filtration, the filtrate was removed under
reduced pressure to give 8.0 g (81%) of a mixture of
cis-and trans-diastereoisomers after recrystallisation
from aqueous ethanol–diethyl ether: m.p. >300°C ([28]
m.p. >300°C).
1
Compound 9. H-NMR (CDCl3) l 0.82 (t, 3H,
J=7.2 Hz, CH2CH3), 1.40 (s, 2H, CHNH2), 1.62 (m,
2H, CH2CH3), 3.71 (t, 1H, J=6.8 Hz, CHCH3), 7.24
(s, 5H, ArH); 13C-NMR (CDCl3) l 10.9 (CH2CH3),
32.5 (CHCH3), 57.8 (CHCH2), 126.4, 126.8, 128.3,
146.5.
1
Compound 10. H-NMR (CDCl3) l 0.77 (d, 3H,
J=6.6 Hz, CHCH3), 0.97 (d, 3H, J=6.6 Hz,
CHCH3), 1.54 (s, 2H, CHNH2), 1.75 (m, 1H,
CHCH(CH3)2), 3.58 (d, 1H, J= 7.3 Hz,
CHCH(CH3)2), 7.27 (s, 5H, ArH); 13C-NMR (CDCl3)
l 18.9, 19.8, 35.4, 62.5, 126.8, 127.0, 128.1, 145.5.
Using the method of Ferber and Bruker [29], the
diastereoisomeric mixture (8.0 g, 55.9 mmol) was dis-
solved in water, and ethanol was added to induce crys-
tallisation of the cis-isomer. The crystals were collected,
and the filtrate was treated in a similar manner to obtain
two additional crops of the cis-acid. Recrystallisation of
the combined crops from ethanol–water gave 3.9 g
(49%) of cis-100: m.p. 295–298°C ([30] m.p. 258–
264°C); 1H-NMR (D2O) l 1.77 (br m, 8H), 2.41 (m, 1H,
CHCOOH), 3.27 (m, 1H, CHNH2); 13C-NMR (D2O) l
27.6, 30.1, 44.3, 51.8, 186.4. The filtrates were combined
and concentrated under reduced pressure, and the re-
sulting solid was crystallised from aqueous ethanol–di-
ethyl ether to give the trans-acid. The filtrate yielded
two additional crops of the trans-acid. Recrystallisation
of the combined crops from aqueous ethanol–diethyl
ether yielded 1.3 g (16%) of trans-101: m.p. 297–302°C
1
Compound 11. H-NMR (DMSO-d6) l 1.75 (br m,
9H), 3.98 (d, 1H, J=9.5 Hz, CHNH+3), 7.48 (m, 5H,
ArH), 8.85 (br s, 3H, NH+3); 13C (DMSO-d6) l 24.4,
24.9, 29.6, 30.0, 44.6 (CHCHNH+3), 59.2 (CHNH3+),
127.8, 128.2, 128.5, 138.6.
1
Compound 12. H-NMR (CDCl3) l 1.48 (br m,
11H), 1.58 (s, 2H, CHNH2), 3.56 (d, 1H, J=7.1 Hz,
CHNH2), 7.25 (s, 5H, ArH); 13C-NMR (CDCl3) l
26.1, 26.3, 29.4, 30.0, 45.1 (CHCHNH2), 61.6
(CHNH2), 126.6, 126.9, 128.0, 145.4.
1
Compound 13. H-NMR (CDCl3) l 1.39 (d, 3H,
J=6.6 Hz, CHCH3), 1.52 (s, 2H, CHNH2), 4.19 (q,
1H, J=6.6 Hz, CHCH3), 7.55 (m, 4H, ArH); 13C-
NMR (CDCl3) l 25.8 (CHCH3), 51.1 (CHCH3),
118.1 (CF3), 122.7, 122.8, 123.0, 123.5, 123.6, 123.8,
124.0, 128.9, 129.3, 130.5, 148.9, 170.0, 182.0.
1
1
Compound 14. H-NMR (CDCl3) l 1.36 (d, 3H,
([30] m.p. 262–267°C); H-NMR (D2O) l 1.71 (br m,
4H), 2.13 (br m, 5H), 3.15 (m, 1H, CHNH2); 13C-NMR
(D2O) l 30.3, 32.3, 47.9, 52.5, 187.4.
J=6.6 Hz, CHCH3), 1.52 (s, 2H, CHNH2), 4.11 (q,
1H, J=6.6 Hz, CHCH3), 7.14 (m, 4H, ArH); 13C-
NMR (CDCl3) l 25.7 (CHCH3), 51.0 (CHCH3),
112.1, 113.1, 114.0, 121.3, 121.4, 129.7, 130.1, 150.4,
150.7, 157.6, 168.5.
6. NMR data
1
Compound 15. H-NMR (CDCl3) l 1.37 (d, 3H,
1
Compound 6. H-NMR (CDCl3) l 1.37 (d, 3H,
J=6.6 Hz, CHCH3), 1.53 (s, 2H, CHNH2), 4.53 (q,
1H, J=6.6 Hz, CHCH3), 7.32 (m, 4H, ArH); 13C-
NMR (CDCl3) l 23.6 (CHCH3), 47.5 (CHCH3),
126.2, 127.1, 127.7, 129.5, 132.6, 144.6.
J=6.4 Hz, CHCH3), 1.58 (s, 2H, CHNH2), 3.86 (s, 3
H, OCH3), 3.89 (s, 3H, OCH3), 4.09 (q, 1H, J=6.4
Hz, CHCH3), 6.87 (m, 3H, ArH); 13NMR (CDCl3) l

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
283
1
112.4, 112.6, 118.5, 129.7, 145.4, 160.1, 173.1
(CONH).
Compound 16. H-NMR (CDCl3) l 1.36 (d, 3H,
J=6.6 Hz, CHCH3), 1.50 (s, 2H, CHNH2), 4.11 (q,
1H, J=6.6 Hz, CHCH3), 7.27 (m, 4H, ArH); 13C-
NMR (CDCl3) l 25.7 (CHCH3), 51.0 (CHCH3),
124.0, 126.1, 126.9, 129.7, 134.5, 150.1.
Compound 28. 1H-NMR (DMSO-d6) l 1.37 (d, 3H,
J=7.1 Hz, CHCH3), 2.50 (br m, 6H), 3.01 (m, 2H,
CH2NH+2), 3.89 (m, 1H, CH2NH+2CH), 5.32 (m, 1H,
CONHCH), 7.36 (m, 4H, ArH), 9.15 (br s, 2H, NH+2),
9.45 (br d, 1H, CONH); 13C-NMR (DMSO-d6) l
20.8, 21.1, 21.5, 26.8, 43.2, 45.7, 56.6, 56.8, 126.7,
127.3, 127.5, 128.5, 129.3, 131.2, 131.4, 141.5, 167.5
(CONH).
1
Compound 17. H-NMR (CDCl3) l 1.35 (d, 3H,
J=6.6 Hz, CHCH3), 1.49 (s, 2H, CHNH2), 4.10 (q,
1H, J=6.6 Hz, CHCH3), 7.27 (m, 4H, ArH); 13C-
NMR (CDCl3) l 25.8 (CHCH3), 50.8 (CHCH3),
127.2, 128.6, 132.5, 146.4.
Compound 29. 1H-NMR (DMSO-d6) l 1.42 (d, 3H,
J=6.9 Hz, CHCH3), 2.01 (br m, 6H), 3.35 (br m, 3H,
CH2NH+2CH), 5.03 (m, 1H, CONHCH), 7.61 (m, 4H,
ArH), 8.95 (br s, 2H, NH+2), 9.45 (br d, 1H, CONH);
13C-NMR (DMSO-d6) l 21.1, 21.4, 21.9, 26.9, 43.2,
45.9, 48.0, 56.7, 56.8, 124.4, 124.8, 125.7, 125.9, 126.6,
130.0, 132.9, 146.4, 146.7, 167.5 (CONH).
1
Compound 18. H-NMR (CDCl3) l 1.20 (d, 6H,
J=6.8 Hz, CH(CH3)2), 1.51 (s, 9H, C(CH3)3), 1.85
(br m, 9H), 2.23 (s, 3H, 6-CH3), 3.09 (m, 1H,
CH(CH3)2), 7.16 (m, 3H, ArH), 7.46 (br s, 1H,
CONH); 13C-NMR (CDCl3) l 18.9, 20.7, 23.5, 25.0,
25.6, 28.4 (C(CH3)3), 28.7, 80.9 (C(CH3)3), 123.4,
127.9, 128.1, 135.9, 145.6, 155.1 (NCOO), 170.1
(CONH).
1
Compound 30. H-NMR (CDCl3) l 1.45 (d, 3H,
J=6.8 Hz, CHCH3), 1.57 (s, 1 H, CH2NHCH), 1.65
(br m, 6H), 2.85 (br m, 3H, CH2NHCH), 5.07 (m,
1H, CHCH3), 7.25 (br m, 5H, ArH and CONH);
13C-NMR (CDCl3) l 21.8, 24.1, 26.2, 30.0, 45.9, 47.6,
60.2, 127.6, 128.8, 133.0, 142.3, 173.1 (CONH).
Compound 31. 1H-NMR (DMSO-d6) l 1.42 (d, 3H,
J=6.8 Hz, CHCH3), 1.91 (br m, 6H), 3.05 (br m, 3H,
CH2NH+2CH), 5.07 (m, 1H, CONHCH), 7.62 (m, 4H,
ArH), 9.04 (br s, 2H, NH+2), 9.36 (br d, 1H, CONH);
13C-NMR (DMSO-d6) l 21.2, 21.5, 22.3, 26.8, 27.1,
43.2, 48.2, 56.6, 56.8, 118.1 (CF3), 122.4, 123.6, 129.5,
130.0, 145.5, 145.8, 167.7 (CONH).
1
Compound 19. H-NMR (CDCl3) l 1.11 (d, 6H,
CH(CH3)2), 1.62 (br m, 6H), 2.14 (s, 3H, 6-CH3), 3.15
(br m, 3H, CHNH2+CH2 and CH(CH3)2), 4.07 (s, 1H,
CHNH+2CH2), 7.16 (s, 3H, ArH), 9.20 (br s, 2H,
NH+2), 10.21 (s, 1H, CONH); 13C-NMR (CDCl3) l
18.4, 21.2, 21.7, 23.4, 27.3, 27.7, 43.2, 56.9, 123.1,
127.4, 127.5, 132.6, 135.7, 145.7, 167.7 (CONH).
1
Compound 20. H-NMR (DMSO-d6) l 1.71 (br m,
4H), 2.09 (s, 6H, 2,6-diCH3), 3.54 (br m, 5H,
CH2NH+2CH2CH), 7.04 (s, 3H, ArH), 9.26 (br s, 2H,
NH+2), 9.64 (s, 1H, CONH); 13C-NMR (DMSO-d6) l
18.0, 21.1, 26.5, 38.6, 42.8, 44.3, 126.5, 127.6, 134.6,
135.1, 170.3 (CONH).
Compound 32. 1H-NMR (DMSO-d6) l 1.39 (d, 3H,
J=6.8 Hz, CHCH3), 1.81 (br m, 6H), 3.25 (br m, 3H,
CH2NH+2CH), 4.90 (m, 1H, CONHCH), 7.50 (m, 3H,
ArH), 9.45 (br d, 1H, CONH); 13C-NMR (DMSO-d6)
l 21.2, 21.5, 21.9, 26.8, 43.1, 47.5, 56.6, 126.2, 127.9,
130.5, 130.9, 145.4, 167.8 (CONH).
1
Compound 21. H-NMR (DMSO-d6) l 1.81 (br m,
4H), 2.11 (s, 6H, 2,6-diCH3), 2.94 (br m, 5H,
CH2NH+2CH2 and CH2CHCH2), 7.05 (s, 3H, ArH),
9.34 (br s, 2H, NH2+), 9.52 (s, 1H, CONH); 13C-NMR
(DMSO-d6) l 18.1, 24.5, 38.9, 42.3, 126.4, 127.6,
135.0, 135.2, 171.7 (CONH).
1
Compound 33. H-NMR (CDCl3) l 1.47 (d, 3H,
J=6.8 Hz, CHCH3), 1.60 (s, 1H, CH2NHCH), 1.65
(br m, 6H), 2.90 (br m, 3H, CH2NHCH), 3.87 (s, 6H,
3,4-diOCH3), 5.08 (m, 1H, CHCH3), 6.85 (s, 3H,
ArH), 6.95 (br s, 1H, CONH); 13C-NMR (CDCl3) l
21.8, 24.2, 26.3, 30.1, 46.0, 47.8, 47.9, 56.2, 60.4,
110.7, 110.9, 112.0, 118.2, 118.3, 136.6, 148.7, 149.5,
173.0 (CONH).
1
Compound 24. H-NMR (CDCl3) l 1.68 (s, 1H,
CH2NHCH), 1.75 (br m, 6H), 2.89 (br m, 3H,
CH2NHCH), 4.47 (d, 2H, J=5.9 Hz, CONHCH2),
7.25 (br s, 1H, CONH), 7.55 (br m, 4H, ArH); 13C-
NMR (CDCl3) l 23.7, 26.2, 30.1, 42.3, 45.8, 60.1,
117.8 (CF3), 123.4, 123.6, 129.3, 131.2, 139.5, 174.5.
1
Compound 34. H-NMR (CDCl3) l 1.50 (d, 3H,
1
Compound 25. H-NMR (CDCl3) l 1.46 (d, 3H,
J=7.1 Hz, CHCH3), 1.67 (br m, 6H), 2.23 (s, 3H,
NCH3), 2.25 (br m, 2H, CH2N), 2.83 (m, 1H,
NCHCO), 5.17 (m, 1H, CONHCHCH3), 6.89 (br s,
1H, CONH), 7.31 (s, 5H, ArH); 13C-NMR (CDCl3) l
21.7, 23.4, 25.4, 30.9, 44.7, 47.6, 55.5, 69.9, 126.1,
127.2, 128.6, 143.4, 173.5 (CONH).
J=6.8 Hz, CHCH3), 1.59 (s, 1H, CH2NHCH), 1.65
(br m, 6H), 2.90 (br m, 3H, CH2NHCH), 3.80 (s, 3H,
OCH3), 5.08 (m, 1H, CHCH3), 7.05 (br m, 5H, ArH
and CONH); 13C-NMR (CDCl3) l 21.9, 24.2, 26.3,
30.1, 46.0, 48.2, 55.3 (OCH3), 60.5 (NHCHCO),

284
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
Compound 36. 1H-NMR (DMSO-d6) l 1.64 (d, 3H,
Compound (S,RS-44). 1H-NMR (DMSO-d6) l 1.64
(br m, 6H), 3.16 (br m, 2H, CH2NHCH), 3.95 (m,
1H, CH2NHCHCO), 6.18 (d, 1H, J=8.3 Hz, CON-
HCH), 7.36 (m, 9H, ArH); 13C-NMR (DMSO-d6) l
21.2, 21.6, 27.1, 43.3, 55.7, 56.7, 125.7, 126.2, 126.8,
127.0, 127.4, 128.6, 130.4, 133.1, 141.1, 141.3, 144.3,
144.5, 167.9 (CONH).
J=7.1 Hz, CHCH3), 2.02 (br m, 6H), 3.74 (br m, 5H,
CH2(CH2)NH+CH), 5.07 (m, 1H, CONHCHCH3),
7.36 (m, 9H, ArH), 8.86 (m, 1H, CONH); 13C-NMR
(DMSO-d6) l 18.0, 21.8, 22.3, 27.0, 27.7, 48.4, 49.7,
50.5, 52.1, 56.7, 57.6, 59.2, 70.0, 115.6, 115.9, 116.5,
116.9, 122.9, 123.0, 124.8, 126.0, 126.7, 127.3, 127.5,
128.7, 133.6, 134.0, 143.5, 158.1, 165.7, 166.6, 169.3.
1
Compound (S,RS-45). H-NMR (CDCl3) l 1.55
1
Compound 37. H-NMR (CDCl3) l 1.46 (d, 3H,
(br m, 7H), 2.75 (br m, 5H, ArCHCH2Ar and
CH2NHCH), 5.18 (m, 1H, ArCHCH), 7.23 (m, 11H,
ArH and CONH); 13C-NMR (CDCl3) l 23.9, 24.1,
26.1, 29.8, 30.0, 42.9, 45.6, 45.8, 53.8, 53.8, 60.1, 60.4,
126.5, 127.3, 128.3, 128.5, 129.4, 137.7, 141.9, 173.3.
Compound 46. 1H-NMR (DMSO-d6) l 1.48 (s, 9H,
C(CH3)3), 1.51 (br m, 15H), 3.10 (m, 2H, CHCO),
3.89 (m, 1H, NCHCO), 4.66 (m, 1H, CONHCH),
7.38 (s, 5H, ArH), 8.35 (m, 1H, CONH); 13C-NMR
(DMSO-d6) l 19.6, 24.3, 24.7, 24.9, 25.0, 28.0
(C(CH3)3), 29.6, 29.7, 29.9, 30.0, 45.0, 57.1, 78.7
(C(CH3)3), 126.6, 126.8, 127.0, 128.0, 143.6, 143.8,
155.1 (NCOO), 170.5 (CONH).
J=7.1 Hz, CHCH3), 1.65 (br m, 6H), 3.35 (br m, 5H,
CH2(CH2)NH), 5.13 (m, 1H, CONHCHCH3), 7.18
(m, 10H, ArH and CONH); 13C-NMR (CDCl3) l
21.3, 21.7, 23.4, 24.8, 30.4, 30.6, 47.9, 48.1, 51.6, 51.8,
60.0, 67.8, 120.8, 120.9, 126.0, 126.2, 127.3, 127.5,
128.7, 129.9, 130.1, 131.3, 131.5, 136.8, 137.1, 142.8,
143.2, 173.4 (CONH).
Compound 38. 1H-NMR (DMSO-d6) l 1.46 (d, 3H,
J=6.8 Hz, CHCH3), 1.88 (br m, 6H), 3.71 (br m, 5H,
CH2(CH2)NH+CH), 5.00 (m, 1H, CONHCHCH3),
7.57 (m, 8H, ArH), 9.82 (br s, 1H, NH+), 10.21 (m,
1H, CONH); 13C-NMR (DMSO-d6) l 21.1, 21.7,
22.4, 28.2, 48.7, 51.0, 56.6, 65.0, 125.6, 125.8, 126.8,
128.3, 130.2, 130.8, 131.2, 131.9, 132.5, 133.5, 144.1,
166.8 (CONH).
1
Compound 47. H-NMR (DMSO-d6) l 1.54 (br m,
15H), 3.07 (br m, 2H, NH+2CH2), 3.80 (m, 1H, NH+2
CHCO), 4.57 (m, 1H, CONHCH), 7.31 (m, 5H,
ArH), 9.01 (br s, 2H, NH+2), 9.35 (t, 1H, CONH);
13C-NMR (DMSO-d6) l 21.1, 21.5, 24.7, 24.9, 26.8,
27.4, 29.5, 29.7, 43.2, 45.1, 45.3, 56.7, 56.7, 56.9, 57.5,
57.6, 126.8, 127.2, 128.1, 142.8, 143.2, 167.6 (CONH).
1
Compound 40. H-NMR (CDCl3) l 1.43 (d, 3H,
CHCH3), 1.64 (br m, 4H), 1.84 (s, 1H, CH2NHCH2),
2.32 (m, 1H, CHCONH), 2.88 (br m, 4H,
CH2NHCH2), 5.15 (m, 1H, CHCH3), 7.34 (s, 5H,
ArH), 7.88 (br s, 1H, CONH); 13C-NMR (CDCl3) l
22.1, 23.7, 27.8, 42.3, 42.5, 46.7, 48.1, 48.3, 126.3,
127.2, 128.8, 144.1, 174.1 (CONH).
1
Compound 48. H-NMR (CDCl3) l 1.49 (s, 9H,
C(CH3)3), 1.51 (br m, 17H), 2.54 (br m, 2H,
CH2NCH), 4.03 (m, 1H, NCHCO), 4.75 (m, 1H,
CONHCH), 7.28 (s, 5H, ArH); 13C-NMR (CDCl3) l
20.4, 25.0, 25.2, 26.0, 26.2, 28.4 (C(CH3)3), 29.2, 30.1,
30.3, 42.0, 43.0, 43.3, 58.3, 80.7 (C(CH3)3), 126.9,
128.4, 141.5, 170.4 (CONH).
1
Compound 41. H-NMR (DMSO-d6) l 0.87 (t, 3H,
CH2CH3), 2.60 (br m, 8H), 3.45 (br m, 3H, CH2NH2+
CH), 4.75 (m, 1H, CONHCH), 7.25 (br m, 5H, ArH),
9.40 (br m, 3H, NH+2 and CONH); 13C-NMR
(DMSO-d6) l 11.1, 21.2, 21.6, 27.0, 27.4, 29.4, 43.3,
54.6, 56.7, 57.0, 126.3, 126.7, 128.2, 143.1, 143.4,
167.8 (CONH).
1
Compound 49. H-NMR (DMSO-d6) l 1.48 (br m,
17H), 3.17 (br m, 2H, CH2NH+2), 3.91 (m, 1H, NH+2
CHCO), 4.62 (m, 1H, CONHCH), 7.39 (s, 5H, ArH),
9.13 (m, 3H, CONH and NH+2); 13C-NMR (DMSO-
d6) l 21.1, 21.5, 25.5, 25.8, 26.9, 29.1, 29.6, 43.2, 56.7,
58.2, 126.7, 127.0, 128.1, 141.9, 167.8 (CONH).
Compound 57. 1H-NMR (DMSO-d6) l 1.55 (s, 9H,
C(CH3)3), 1.78 (s, 6H, 2,6-diCH3), 3.35 (br m, 2H,
CH2CHN), 4.55 (m, 2H, ArCH2N), 4.92 (m, 1H,
NCHCO), 6.97 (m, 2H, ArH), 7.23 (m, 6H, ArH and
1
Compound 42. H-NMR (CDCl3) l 0.85 (dd, 6H,
CH(CH3)2), 1.65 (s, 1H, CH2NHCH), 1.70 (br m,
7H), 2.80 (br m, 3H, CH2NHCH), 4.82 (t, 1H, CON-
HCH), 7.35 (br s, 6H, ArH and CONH); 13C-NMR
(CDCl3) l 18.8, 19.8, 24.1, 26.0, 30.4, 33.7, 45.8, 58.2,
60.6, 127.0, 128.4, 141.8, 173.3 (CONH).
1
Compound 43. H-NMR (CDCl3) l 1.34 (br m,
6H), 1.56 (s, 1H, CH2NHCH), 2.84 (br m, 3H,
CH2NHCH), 6.02 (d, 1H, J=8.8 Hz, CONHCH),
6.82 (br s, 1H, CONH), 7.15 (m, 10H, ArH); 13C-
NMR (CDCl3) l 24.2, 26.2, 30.1, 46.0, 48.2, 56.3,
60.5, 127.4, 127.6, 128.7, 142.1, 173.2 (CONH).
CONH); 13C-NMR (DMSO-d6)
l
17.8, 28.4
(C(CH3)3), 31.9, 32.1, 45.5, 56.0, 56.4, 81.6 (C(CH3)3),
126.4, 127.0, 127.3, 127.8, 128.0, 128.4, 133.2, 133.9,
135.3, 155.6 (NCOO), 170.0 (CONH).

B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
285
Compound 58. 1H-NMR (DMSO-d6) l 2.20 (s, 6H,
2,6-diCH3), 3.41 (br m, 2H, CH2CHN), 4.34 (m, 3H,
CH2NH+2CH), 7.10 (s, 3H, ArH), 7.27 (s, 4H, ArH),
9.95 (br s, 2H, NH2+), 10.49 (s, 1H, CONH); 13C-
NMR (DMSO-d6) l 18.2, 29.6, 43.6, 54.1, 126.6,
126.9, 127.4, 127.8, 128.6, 128.7, 130.9, 133.9, 135.2,
166.5 (CONH).
126.6, 127.0, 128.1, 128.4, 129.2, 132.7, 143.7, 165.9
(CONH).
1
Compound 67. H-NMR (CDCl3) l 1.52 (d, 9H,
C(CH3)3), 2.12 (s, 6H, 2,6-diCH3), 2.93 (m, 2H,
ArCH2), 3.73 (t, 2H, ArCH2CH2N), 5.65 (br s, 1H,
NCHCO), 7.16 (m, 8H, ArH and CONH); 13C-NMR
(CDCl3) l 18.3, 28.4 (C(CH3)3), 28.7, 41.0, 58.9, 59.1,
59.2, 81.2 (C(CH3)3), 126.5, 127.1, 127.7, 128.1, 128.3,
131.8, 133.6, 135.1, 135.3, 155.5 (NCOO), 169.2
(CONH).
1
Compound 59. H-NMR (DMSO-d6) l 3.15 (br m,
2H, CH2CHNH+2), 4.32 (m, 5H, CONHCH2 and
CH2NH+2CH), 7.26 (m, 8H, ArH), 9.57 (br t, 2H,
NH+2), 9.85 (br s, 1H, CONH); 13C-NMR (DMSO-d6)
l 29.4, 41.6, 43.8, 54.0, 113.3, 113.5, 114.2, 114.4,
123.2, 123.3, 126.6, 126.9, 127.5, 128.6, 130.2, 130.5,
131.1, 141.5, 141.9, 156.9, 167.7, 168.0.
1
Compound 68. H-NMR (DMSO-d6) l2.16 (s, 6H,
2,6-diCH3), 3.16 (br m, 2H, CH2CH2NH2), 3.65 (m,
2H, CH2CH2NH+2), 5.52 (s, 1H, NH+2CHCO), 7.10 (s,
3H, ArH), 7.33 (m, 4H, ArH), 7.74 (br d, 2H, NH+2),
10.77 (s, 1H, CONH); 13C-NMR (DMSO-d6) l 18.3,
24.5, 39.0, 55.3, 126.6, 126.9, 127.9, 128.1, 129.2,
132.8, 133.8, 135.1, 165.6 (CONH).
1
Compound 60. H-NMR (DMSO-d6) l 3.25 (br m,
2H, CH2CHNH+2), 4.35 (m, 5H, CONHCH2 and
CH2NH+2CH), 7.26 (s, 4H, ArH), 7.65 (s, 4H, ArH),
9.58 (br t, 2H, NH2+), 11.1 (br s, 1H, CONH); 13C-
NMR (DMSO-d6) l 29.5, 41.7, 43.7, 53.8, 123.7,
126.4, 126.7, 127.3, 128.5, 129.3, 130.9, 131.3, 140.1,
168.0.
Compound 85. 1H-NMR (DMSO-d6) l 1.32 (d, 3H,
J=7.1 Hz, CHCH3), 1.56 (br m, 8H), 2.54 (m, 1H,
CHCONH), 4.90 (m, 1H, CONHCHCH3), 7.23 (m,
4H, ArH), 8.24 (br d, 1H, CONH); 13C-NMR
(DMSO-d6) l 22.4, 25.6, 29.7, 30.0, 44.1, 47.4, 124.6,
125.7, 126.4, 130.1, 132.9, 147.7, 174.4 (CONH).
1
Compound 61. H-NMR (CDCl3) l 1.49 (d, 3H,
J=6.8 Hz, CHCH3), 1.92 (s, 1H, CH2NHCH), 3.25
(br m, 3H, CH2CHNH), 3.98 (s, 2H, CH2NH), 5.16
(m, 1H, CHCH3), 7.35 (m, 9H, ArH and CONH);
13C-NMR (CDCl3) l 22.0, 30.9, 47.5, 48.1, 56.4, 118.1
(CF3), 122.5, 122.7, 122.9, 123.0, 123.9, 124.1, 124.2,
124.4, 125.6, 126.3, 126.7, 129.2, 129.8, 130.2, 134.2,
135.8, 144.5, 172.4.
1
Compound 86. H-NMR (CDCl3) l 1.42 (d, 3H,
J=7.1 Hz, CHCH3), 1.61 (br m, 11H), 5.06 (m, 1H,
CONHCHCH3), 6.15 (br s, 1H, CONH), 7.23 (m,
4H, ArH); 13C-NMR (CDCl3) l 21.8, 25.7, 29.6, 45.4,
47.9, 124.4, 126.1, 127.3, 129.9, 134.4, 145.8, 175.3
(CONH).
1
Compound 88. H-NMR (CDCl3) l 0.52 (br m,
1
Compound 62. H-NMR (CDCl3) l 1.46 (d, 3H,
4H), 1.52 (m, 1H, CHCONH), 1.85 (s, 6H, 2,6-
diCH3), 6.76 (s, 3H, ArH), 9.19 (br s, 1H, CONH);
13C-NMR (CDCl3) l6.7, 13.8, 18.3, 126.6, 127.9,
135.5, 171.8 (CONH).
J=6.8 Hz, CHCH3), 1.69 (s, 1H, CH2NHCH), 3.15
(br m, 3H, CH2CHNH), 3.98 (s, 2H, CH2NH), 5.15
(m, 1H, CHCH3), 7.20 (m, 9H, ArH and CONH);
13C-NMR (CDCl3) l 21.9, 31.1, 47.4, 47.6, 47.7, 47.8,
56.4, 56.6, 125.6, 126.3, 126.8, 127.4, 127.6, 128.8,
129.2, 133.2, 134.5, 135..9, 142.2, 172.3.
1
Compound 89. H-NMR (CDCl3) l 2.10 (s, 6H,
2,6-diCH3), 2.11 (br m, 6H), 3.12 (m, 1H,
CHCONH), 6.98 (s, 3H, ArH), 7.25 (br s, 1H,
CONH); 13C-NMR (CDCl3) l 18.3, 25.1, 25.4, 39.7,
126.9, 127.9, 128.4, 134.0, 135.4, 173.5 (CONH).
1
Compound 63. H-NMR (CDCl3) l 1.56 (s, 1H,
CH2NHCH), 3.05 (br m, 5H, CH2CHNH and
ArCH2CH2), 3.88 (d, 2H, J=7.8 Hz, CH2NH), 5.28
(m, 1H, ArCHCH2), 7.20 (m, 15H, ArH), 7.57 (br d,
1H, CONH); 13C-NMR (CDCl3) l 30.7, 31.0, 42.9,
47.3, 53.7, 54.1, 56.3, 125.5, 126.2, 126.6., 127.3,
128.3, 128.5, 129.1, 129.4, 134.5, 135.9, 136.1, 137.5,
141.8, 172.3.
1
Compound 90. H-NMR (CDCl3) l 1.71 (br m,
8H), 2.10 (s, 6H, 2,6-diCH3), 2.62 (m, 1H,
CHCONH), 6.98 (s, 3H, ArH), 7.32 (br s, 1H,
CONH); 13C-NMR (CDCl3) l 18.3, 25.9, 30.6, 45.6,
126.9, 127.9, 135.4, 174.8 (CONH).
1
Compound 91. H-NMR (DMSO-d6) l 1,55 (br m,
Compound 66. 1H-NMR (DMSO-d6) l 1.48 (d, 3H,
J=6.6 Hz, CHCH3), 3.25 (m, 4H), 4.91 (m, 1H,
NHCHCH3), 5.16 (br s, 1H, NH+2CHCO), 7.33 (m,
9H, ArH), 9.75 (br d, 1H, CONH); 13C-NMR
(DMSO-d6) l 22.3, 24.4, 39.0, 48.8, 55.2, 126.1, 126.3,
11H), 2.09 (s, 6H, 2,6-diCH3), 7.03 (s, 3H, ArH), 9.05
(s, 1H, CONH); 13C-NMR (DMSO-d6) l 18.0, 25.3,
25.5, 29.4, 44.2, 126.2, 127.5, 135.2, 173.7 (CONH).
1
Compound 92. H-NMR (DMSO-d6) l 1.56 (br m,
10H), 2.14 (s, 3H, 6-CH3), 2.38 (m, 1H, CHCONH),

286
B. Ho et al. / European Journal of Medicinal Chemistry 36 (2001) 265–286
7.27 (m, 3H, ArH), 9.35 (s, 1H, CONH); 13C-NMR
(DMSO-d6) l 18.2, 25.3, 25.5, 29.2, 44.0, 126.8, 127.5,
128.8, 132.0, 134.0, 138.3, 173.9 (CONH).
[17] Shuman R.T., Rothenberger R.B., Campbell C.S., Smith G.F.,
Gifford-Moore D.S., Gesellchen P.D., J. Med. Chem. 36 (1993)
314–319.
[18] Jorgensen E.C., Rapaka S.R., Windridge G.C., J. Med. Chem.
1
Compound 93. H-NMR (CDCl3) l 1.66 (br m,
14 (1971) 904–906.
12H), 2.14 (s, 6H, 2,6-diCH3), 2.45 (m, 1H,
CHCONH), 7.01 (m, 4H, ArH and CONH); 13C-
NMR (DMSO-d6) l 18.4, 26.7, 28.1, 32.0, 47.7, 127.0,
128.0, 134.0, 135.6, 175.7 (CONH).
[19] Nicola A.D., Einhorn J., Lunhe J.-L., Tetrahedron Lett. 33
(1992) 6461–6464.
[20] Konopinska D., Rosinski G., Sobotka W., Pol. J. Pharmacol.
Pharm. 44 (1992) 505–514.
[21] Kleemann H.-W., Heitsch H., Henning R., Kramer W., Kocher
W., Lerch U., Linz W., Nickel W.-U., Ruppert D., Urbach H.,
Utz R., Wagnet A., Weck R., Wiegand F., J. Med. Chem. 35
(1992) 559–567.
References
[22] Japanese Patent 04,316,544 1992, Chem. Abstr. 118 (1993)
147316w.
[1] McNamara J.O., in: Hardman J.G., Limbird L.E., Molinoff
P.B., Ruddon R.W., Gilman A.G. (Eds.), The Pharmacological
Basis of Therapeutics, 9th ed., McGraw-Hill, New York, 1990,
pp. 461–486.
[23] Hoffman-LaRoche and Co., Grenzacherstrasse, Basle, Switzer-
land, Br. Patent 1,114,397, 1968.
[24] Kammermeier B.O.T., Lerch U., Sommer C., Synthesis 11
[2] Loscher W., Schmidt D., Epilepsy Res. 17 (1994) 95–134.
[3] Lin Z., Kadaba P.K., Med. Res. Rev. 17 (1997) 537–572.
(1992) 1157–1160.
[25] Speziale A.J., Jaworski E.G., J. Org. Chem. 25 (1960) 728–732.
[26] Henze H.R., Speer R.J., J. Am. Chem. Soc. 64 (1942) 522–523.
[27] T.A. Conners, W.C. Ross, J. Chem. Soc. (1960) 2119–2132.
[4] Hinko C.N., Crider A.M., Kliem M.A., Steinmiller C.I., Seo
T.H., Ho B., Venkatarangan P., El-Assadi A.A., Chang H.,
Burns C.M., Tietz E.I., Andersen P.H., Klitgaard H., Neu-
ropharmacology 35 (1996) 1721–1735.
[28] V. Skaric, M. Kovaceric, D. Skaric, J. Chem. Soc. Perkin
[5] Ho B., Venkatarangan P., Cruse S.F., Hinko C.N., Andersen
P.H., Crider A.M., Adloo A.A., Roane D.S., Stables J.P., Eur.
J. Med. Chem. 33 (1998) 23–31.
Trans. 1 (1976) 1199–1202.
[29] Ferber E., Brukner H., Chem. Ber. 76 (1943) 1019–1027.
[30] Snyder K.B., Murray T.F., DeLander G.E., Aldrich J.V., J.
[6] Wolfe J.F., Greenwood T.D., Mulheron J.M., Exp. Opin. Ther.
Patents 8 (1998) 361–381.
Med. Chem. 36 (1993) 1100–1103.
[7] Cosford N.D.P, McDonald I.A., Schweiger E.J., Annu. Rep.
[31] Redeuilh P.G., Rumpf P., Viel C., Bull. Soc. Chim. Fr. 9–10
(1973) 2668–2673.
Med. 33 (1998) 61–70.
[8] Clark C.R., Sanson R.T., Lin C.-M., Norris G.N., J. Med.
[32] Potapov V.M., Demyanovich V.M., Skvortsova T.V.,
Melekhina N.N., Vestn. Mosk. Univ. Ser. 2: Khim. 18 (1977)
446–450.
Chem. 28 (1985) 1259–1262.
[9] Clark C.R., Lin C.-M., Sanson R.T., J. Med. Chem. 29 (1986)
1534–1537.
[33] Roocker A.D., Radzitsky P.D., Bull. Soc. Chim. Belges 72
[10] Willow M., Gonoi T., Catterall W.A., Mol. Pharmacol. 27
(1963) 195–207 (Chem. Abstr. 59 (1963) 9845).
(1985) 547–558.
[34] Reiter I., Toldy L., Schafer I., Szondy E., Borsky J., Eur. J.
[11] Levy R.H., Mattson R.H., Meldrum B.S. (Eds.), Antiepileptic
Drugs, 4th ed., Raven Press, New York, 1995.
Med. Chem. 15 (1980) 41–53.
[35] Roocker A.D., Radzitzky P.D., Bull. Soc. Chim. Belges 73
[12] Padwa A., Eastman D., J. Am. Chem. Soc. 91 (1969) 462–467.
(1964) 181–188 (Chem. Abstr. 61 (1964) 597).
[13] Sidorova N.G., Tsukervanik I.P., J. Gen. Chem. 10 (1940)
[36] Fox H.H., Wenner W., J. Org. Chem. 16 (1951) 225–231.
[37] Gonzales C.T.Y., Bull. Soc. Chim. 37 (1925) 1591–1596.
2073–2076 (Chem. Abstr. 35 (1941) 3979).
[14] Moore M.L., in: Adams R., Bachmann W.E., Blatt A.H.,
Fieser L.F., Johnson J.R., Synder H.R. (Eds.), Organic Reac-
tions (V), Wiley, New York, 1949, pp. 301–330.
[38] H. Najer, P. Chabrier, R. Giudicelli, Bull. Soc. Chim. Fr.
(1959) 352–359.
[39] Grisar J.M., Claxton G.P., Wiech N.L., J. Med. Chem. 19
[15] Crider A.M., Tita T.T., Wood J.D., Hinko C.N., J. Pharm. Sci.
(1976) 365–369.
71 (1982) 1214–1219.
[40] Ekenstam B.T., Egner B., Pettersen G., Acta Chem. Scand. 11
[16] McKay F.C., Albertson N.F., J. Am. Chem. Soc. 79 (1957)
4686–4690.
(1957) 1183–1190.
.