Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands

Article abstract of DOI:10.1016/S0223-5234(00)00163-X

The indole derivative GR 113808 is currently used as the reference ligand for labelling the 5-HT₄ serotoninergic receptors. Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged within this novel series as it displayed high and selective affinity at 5-HT₄ receptors (Ki 5-HT₄ = 6 nM, Ki 5-HT₃ = 100 nM, Ki values at other 5-HT receptors were higher than 1 000 nM). Compound 8 is currently undergoing further pharmacological evaluation. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00163-X

Eur. J. Med. Chem. 35 (2000) 699−706
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S022352340000163X/FLA
Preliminary communication
Synthesis and preliminary pharmacological results on new naphthalene
derivatives as 5-HT4 receptor ligands
Ousmane Dioufa, Patrick Depreuxa*, Philippe Chavattea, Jacques Henri Poupaertb
aInstitut de chimie pharmaceutique Albert Lespagnol, 3, rue du Professeur Laguesse, BP 83, 59006 Lille cedex, France
bEcole de pharmacie, université catholique de Louvain, avenue E. Mounier 73, B-1200 Bruxelles, Belgium
Received 7 October 1999; revised 9 February 2000; accepted 10 February 2000
Abstract – The indole derivative GR 113808 is currently used as the reference ligand for labelling the 5-HT4 serotoninergic receptors.
Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin
receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly,
the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged
within this novel series as it displayed high and selective affinity at 5-HT4 receptors (Ki 5-HT4 = 6 nM, Ki 5-HT3 = 100 nM, Ki values at other
5-HT receptors were higher than 1 000 nM). Compound 8 is currently undergoing further pharmacological evaluation. © 2000 Éditions
scientifiques et médicales Elsevier SAS
serotonin / 5-HT receptor
1. Introduction
advances have been made in the understanding of the
physiology and pharmacology of the 5-HT4 receptor.
These advances have led to the development of several
5-HT4 receptor agonists and antagonists that may have
therapeutic usefulness in the treatment of peripheral
disorders such as irritable bowel syndrome, gastroparesis,
urinary incontinence and cardiac arrhythmias [13]. The
5-HT4 receptors are activated by indoles [14–16], benza-
mides [17, 18], benzimidazolones [19] and 1,8-
naphthalimides (i.e. 5-hydroxytryptamine, mixed 5HT3
antagonist-5HT4 agonist such as cisapride, BIMU 1 and
(S)-RS 56532, respectively, figure 1).
During the last decade the multiplicity of serotoniner-
gic receptors and the variety of diseases in which they are
implicated have given an enormous impetus in the search
for selective serotoninergic ligands with useful therapeu-
tic values. The 5-HT4 receptors are of high clinical
interest because of their role in the regulation of gas-
trointestinal motility in certain cardiac effects and their
potential implication in the management of various affec-
tive disorders [1–7]. The 5-HT4 receptor that is a member
of the seven transmembrane spanning G-protein-coupled
family of receptors is positively coupled to adenylate
cyclase and exists in two isoforms (5-HT4S and 5-HT4L)
that differ in the length and sequence of their carboxy
termini [8, 9]. The 5-HT4 receptor is widely distributed in
the central nervous system and peripheral tissues [10–12].
In the periphery, the receptor plays an important role in
the function of several organ responses, including the
alimentary tract, bladder, heart and adrenal gland. These
wide localizations are predictive of a potentially large
therapeutic usefulness. Since its discovery, significant
5-HT4 antagonists include benzoates [20, 21], indole-
carboxylates [22] and benzodioxanes [23] (i.e. SDZ
205557, GR 113808, ICS 205930 and SB 204070, respec-
tively, figure 2). GR 113808 and SB 204070 are two
highly potent and selective 5-HT4 antagonists [21, 24–26].
However, there is no clear evidence as to their in vivo
activity as they are predicted to be rapidly inactivated by
esterases. On the other hand, most 5-HT4 antagonists
generally display relatively poor 5-HT4 versus 5-HT3
selectivity [27]. For example, the indole-tropane deriva-
tive tropisetron (ICS 205930, figure 2), an anti-emetic
* Correspondence and reprints: pdepreux@phare.univ-lille2.fr

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O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
Figure 1. Structures of some 5HT4
agonists.
5HT3 antagonist used in the prophylaxis and treatment of
nausea and vomiting induced by chemotherapy or radio-
therapy, and in the postoperative period [28] behaves like
a 5-HT4 antagonist at high concentrations [29–31].
However, in contrast the indole derivative GR 113808
has greatly facilitated the studies on 5-HT4 receptors
since it exhibited a selectivity for the 5-HT4 receptor over
rat cerebrocortical 5-HT3 receptors; its tritiated form is
currently used to label 5-HT4 sites [25, 32, 33].
The various 5-HT4 ligands may find a wide variety of
therapeutic applications, both at peripheral and central
levels. The most interesting 5-HT4-related pathogenesis
is in the gastrointestinal tract [34]. Indeed, the benzamide
derivatives such as cisapride have been shown to possess
therapeutic value in this area; this compound has been
shown to have beneficial effects on dyspepsia, gastro-
oesophagial reflux disease and to a lesser extent gastro-
paresis [15]. It has also been suggested that 5-HT4
Figure 2. Structures of some 5HT4
antagonists.

O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
701
agonists could be helpful in treating tachycardia and
some other more serious heart diseases [1, 4]. At a central
level, many speculations have been advanced concerning
the treatment of neuropsychiatric disorders [35, 36] and
consequently selective 5-HT4 agonists or antagonists may
find applications as psychotherapeutic drugs.
Considering GR 113808 as a very promising pharma-
cological tool we attempted the synthesis of GR 113808
analogues with hopefully improved metabolic stability
[37]. We therefore introduced two structural modifica-
tions on this lead:
1) we first replaced the indole ring present in GR
113808 with a naphthalene one. Indeed, previous works
established the bioisosteric equivalency of indole and
naphthalene among a series of melatonin and sumatriptan
analogues [38–40]. Among the melatonin analogues,
several compounds were found to be more active than the
endogenous ligand itself. In the same way, some sumatrip-
tan analogues were found to display 5-HT1-like affinity as
important as that exhibited by sumatriptan.
2) The ester linkage of GR 113808 was replaced by a
benzamide group, which is expected to confer higher
metabolic stability.
This paper describes the synthesis of six naphthalenic
analogues of GR 113808 (6–8 and 13–15) and their
affinity for two serotoninergic receptors, 5HT3 and 5HT4
receptor.
2. Chemistry
Access to compounds 6–8 is reported on figure 3:
isonipecotic acid (1) was transformed into its ethyl ester
(2) by action of thionyl chloride in absolute ethanol.
Introduction of an N-benzyl protecting group on 2 was
performed in absolute ethanol using benzyl chloride and
anhydrous potassium carbonate to give compound 3,
which was then reduced using LiAlH4 in dry THF to yield
(1-benzyl-piperidin-4-yl)methanol (4). Reaction of
1-naphthoyl chloride with 4 in anhydrous chloroform led
to the ester 6, which was N-debenzylated to 7 by
hydrogenolysis in methanol in the presence of ammo-
nium formate and 10% palladium on charcoal. Com-
pound 7 was finally reacted with N-(2-chloroethyl)-
methylsulfonamide in dry acetone in the presence of
potassium carbonate to give compound 8.
The amide analogues 13–15 were synthesized accord-
ing to the approach shown on figure 4.
Reaction of 4-aminomethylpiperidine (9) with benzal-
dehyde in absolute ethanol gave the imino derivative 10
which was then protected with a benzyl group using the
same procedure as that previously described for the
synthesis of compound 3 to give 11. Hydrolysis of the
Figure 3. Synthesis of compounds 6–8.
imino group of 11 was performed in acid aqueous
medium to give 12 which was then reacted with
1-naphthoyl chloride (5) using the same procedure as that
previously employed for the synthesis of 6. This led to
compound 13 which was then debenzylated in methanol
under hydrogen pressure in the presence of palladium on
activated charcoal to yield 14. Substitution by the meth-
ylsulfonamidoethyl side-chain to give final target com-
pound 15 was performed in the same way as above for
compound 8.

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O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
Table I. 5-HT3 and 5-HT4 affinities (Ki in nM) for compounds 6–8
and 13–15*.
a
b
Compound
5-HT3
5-HT4
6
1
3
7
8
3
100
100
6
13
14
15
> 1000
500
>1 000
>1 000
>1 000
>1 000
* Tissue preparations and radioligands used for affinity determina-
tions: a NG-108-15 cells and [3H]-BRL 43694; b guinea-pig hip-
pocampus and [3H]-GR 113808.
(6 nM) is 40 times less active than GR 113808 (0.15 nM)
that exhibits a 5-HT4 versus 5-HT3 selectivity (Ki (5-
HT4)/Ki (5-HT3) = 17) [41]. Deletion of the substituent
on the nitrogen atom of the piperidine ring (compound 7)
leads to a loss of 5-HT4 affinity (about 20-fold) combined
with a higher 5-HT3 affinity (30-fold). This is not
surprising since it was known that an aromatic group, a
connecting acyl group (or an equivalent pharmacophore),
and a basic amine are the general components of the
structure–activity relationships required for high 5-HT3
affinity [42]. Substitution of the piperidine nitrogen with
a lipophilic group such as a benzyl (compound 6) leads to
high affinities both at 5-HT3 and 5-HT4 receptors (in the
nanomolar range). Replacement of the ester group of GR
113808 with its bioisosteric amide equivalent led to
compounds (13–15), devoid of affinity for all the 5-HT
receptors tested.
In an effort to understand the reason for this apparent
discrepancy in our design, we undertook molecular mod-
elling studies to explore the conformational behaviour of
GR 113808 and the naphthalene analogues 8 and 15. We
used the classical ‘random search’ procedure as imple-
mented in SYBYL [43].
The outcome produced by the random search proce-
dure for compound GR 113808 consists of 450 conform-
ers. 230 duplicates are removed on the basis of their
similarity with the lower energy conformation. The 220
remaining conformers spread over an energy range of
10.5 kcal.mol–1 above the most stable one. The lowest
energy conformer is reported in figure 5.
The random search procedure applied to compound 8
retains 931 conformers. Similar structures are eliminated
to produce a conformational space containing 609 con-
formers, spread over an energy range of 10.2 kcal.mol–1
above the lowest energy minimum. The lowest energy
conformer is presented in figure 5.
Figure 4. Synthesis of compounds 13–15.
3. Results and discussion
Affinity for 5-HT receptors including 5-HT1A, 5-HT1B,
5-HT1D, 5-HT2A, 5-HT2C, 5-HT3 as well as 5-HT4
subtypes were determined. Except at 5-HT3 and 5-HT4
receptors, all tested compounds were found with weak or
no affinity at the other 5-HT receptors (Ki > 1 000 nM).
Table I displays the affinity values which were obtained
on 5-HT3 and 5-HT4 receptors.
The most interesting compound 8 is the strict naphtha-
lene analogue of GR 113808. Its 5-HT4 receptor affinity
Using the random search procedure for generating the
compound 15 conformational space, we retained 525

O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
703
tives and the amidic derivative are to be related to the
difference of configuration between the ester and the
amide moieties. The ester function favours a Z configu-
ration, while the amide function always adopts an E
configuration in low-energy conformers, as shown in
figure 5. For GR 113808 we registered an energy differ-
ence of 8.2 kcal.mol–1 between Z and E configurations of
the most stable conformers. This difference also appears
for compound 8 for which it reaches a value of 5.6 kcal-
.mol–1.
4. Conclusion
In conclusion, we have designed, synthesized and
tested a limited series of naphthalene analogues of GR
113808, among which one compound (8) emerged since
it displayed 5-HT4 affinity and selectivity closely com-
parable to those displayed by GR 113808. Compound 8
has been selected for further pharmacological evaluations
in animal models.
5. Experimental section
5.1. Chemistry
Compounds 6–8 and 13–15 were characterized by
1
elemental analyses, IR and H-NMR spectra. IR spectra
were recorded on a Perkin-Elmer 297 spectrometer using
KBr tablets; wave numbers are expressed in cm–1. The
1H-NMR spectra were obtained on a Brücker WP 80 SY
(80 MHz) apparatus with Me4Si as internal standard and
with CDCl3 or DMSO-d6 as solvent. Chemical shifts
(ppm) are reported in the δ scale. Melting points were
determined using a Büchi SMP-20 apparatus and are
uncorrected. Elemental analyses were determined at the
CNRS analytical centre of Vernaison (France) and are
within ± 0.4% of the theoretical values. Compounds 1, 5
and 9 were purchased from Aldrich Chemicals.
5.1.1. (Piperidin-4-yl)ethylcarboxylate hydrochloride 2
Isonipecotic acid (0.01 mol, 1.29 g) was dissolved in
absolute ethanol (50 mL). The solution was cooled to
0 °C and SOCl2 (0.04 mol) was added dropwise. The
mixture was then heated under reflux for 3 h, the solvent
was evaporated in vacuo and the residue was dissolved in
a 10% aqueous solution of NaOH (50 mL) and extracted
with chloroform. The organic layer was dried over CaCl2,
and evaporated in vacuo. The residue was dissolved in
dry ethanol and HCl was bubbled to give the hydrochlo-
ride derivative 2 which was recrystallized from absolute
ethanol. Yield = 95%, m.p. 140–142 °C. IR ν (cm–1):
Figure 5. Lowest energy conformers of compounds GR 113808,
8 and 15.
conformers. 223 similar structures were eliminated to
provide a conformational space containing 302 conform-
ers spread over an energy range of 4.8 kcal.mol–1 above
the most stable. The lowest energy conformer is reported
in figure 5.
From these studies it appears that the side-chains of
both molecules are highly flexible and the difference in
the pharmacological activities between the ester deriva-

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O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
1
3 000–2 400 (NH+), 1 710 (CO). H-NMR (CDCl3) δ
(ppm): 1.3 (m, 3H, CH3), 2.0–2.7 (m, 5H, COCH +
N(CH2)2), 3.0–3.5 (m, 4H, C(CH2)2), 4.2 (m, 2H,
0 °C and (1-benzylpiperidin-4-yl)methanol (4)
(0.01 mol, 2.05 g) previously dissolved in chloroform
(50 mL) was added dropwise. The mixture was refluxed
for 6 h; the solvent was evaporated in vacuo, ether
(100 mL) was added and the resulting precipitate was
filtered, dried and recrystallized from toluene.
Yield = 70%, m.p. 123–125 °C. IR ν (cm–1) 3 100–2 800
(CH alkyles), 2 700–2 300 (NH+), 1 700 (CO). 1H-NMR
(CDCl3) δ (ppm): 1.90–2.60 (m, 8H, N(CH2CH2)2), 3.50
(m, 1H, CH), 4.10–4.50 (m, 4H, CH2CO2 + CH2aryl),
12.50 (s, 1H, NH+). Anal. C24H25NO2 (C, H, N).
+
CH2CO), 9.5 (s, 2H, NH2 ). Anal. C8H15NO2. HCl (C, H,
N).
5.1.2. (1-Benzylpiperidin-
4-yl)ethylcarboxylate hydrochloride 3
A suspension of compound 2 (0.01 mol, 1.57 g) in
ethanol (50 mL) was stirred at room temperature. Benzyl
chloride (0.012 mol, 1.50 g) and K2CO3 (0.02 mol, 2.80 g)
were added and the reaction was pursued for 72 h. The
solvent was then evaporated in vacuo and water added
(50 mL). The desired compound was extracted by ether;
and the organic layer was dried over CaCl2 and evapo-
rated in vacuo. The resulting residue was dissolved in dry
acetone and HCl was bubbled into the solution to produce
a precipitate of the hydrochloride. This precipitate was
then filtered, dried and recrystallized from acetone to give
compound 3. Yield = 88%, m.p. 116–118 °C. IR ν (cm–1):
3 000–2 900 (CH alkyles), 2 700–2 500 (NH+), 1 720
(CO). 1H-NMR (DMSO, d6) δ (ppm): 1.10 (m, 3H, CH3),
1.80–2.10 (m, 6H, CH2N(CH2)2), 2.80 (m, 5H,
CH(CH2)2), 4.20 (m, 2H, CO2CH2), 7.30–7.80 (m, 5H, H
aromatic), 11.50 (s, 1H, NH+). Anal. C15H21NO2. HCl (C,
H, N).
5.1.5. 1-[(Piperidin-4-yl)methyloxy-
carbonyl]naphthalene hydrochloride 7
Compound 6 (0.01 mol, 0.36 g) was dissolved in
methanol (50 mL), palladium on charcoal (2 g) and
ammonium formate (0.1 mol, 6.3 g) were added. The
mixture was heated under reflux for 3 h. After cooling,
the mixture was filtered and the filtrate was evaporated in
vacuo; 1 N aqueous solution of NaOH was added to
basify the solution which was then extracted with ethyl
acetate. The organic layer was dried over CaCl2, evapo-
rated and the residue was dissolved in dry acetone. HCl
was bubbled into the solution and the resulting precipitate
was filtered, dried and recrystallized from ethanol/ether
(1:1). Yield = 53%, m.p. 182–184 °C. IR ν (cm–1):
3 000–2 700 (NH+), 1 700 (CO). 1H-NMR (DMSO, d6) δ
(ppm): 1.5–2.3 (m, 5H, CH(CH2)2), 2.9–3.3 (m, 4H,
N(CH2)2), 4.3 (m, 2H, CH2CO2), 7.5–8.7 (m, 7H, H
aromatic). Anal. C17H19NO2.HCl (C, H, N).
5.1.3. (1-Benzylpiperidin-4-yl)methanol 4
A suspension of AlLiH4 (0.04 mol, 1.5 g) in dry THF
was stirred at 0 °C; A solution of compound 3 (0.01 mol,
2.5 g) in dry THF (50 mL) was added dropwise. The
obtained mixture was refluxed for 3 h and then cooled.
Ethylacetate (200 mL), water (40 mL), and a 2 N aqueous
solution of NaOH (10 mL) were added. The obtained
mineral precipitate was filtered; the filtrate was evapo-
rated and water (50 mL) was added. Extraction with
chloroform, drying over CaCl2 and evaporation of the
organic layer gave an oily residue which was immedi-
ately used for the following step. Yield = 80%. IR ν
(cm–1) 3 500–3 200 (OH), 3 000–2 700 (CH alkyles).
5.1.6. 1-[(1-(2-(Methylsulfonamido)ethyl)piperidin-
4-yl)methyloxycarbonyl]naphthalene hydrochloride 8
A suspension of compound 7 (0.01 mol, 2.7 g) in dry
acetone, K2CO3 (0.04 mol, 5.5 g) and (1-chloro-2-
methylsulfonamido)ethane (0.015 mol, 2.4 g) was heated
to reflux for 24 h. The mixture was cooled, the filtrate was
evaporated and petroleum ether was added under stirring.
The obtained precipitate was filtered, dried and dissolved
in absolute ethanol into which HCl was bubbled. The
formed precipitate was filtered, dried and recrystallized
from absolute ethanol. Yield = 45%, m.p. 170–172 °C. IR
ν (cm–1): 3 300 (NHSO2), 3 000–2 700 (CH alkyles),
1H-NMR (CDCl3)
δ (ppm): 1.20–2.00 (m, 8H,
N(CH2CH2)2), 2.80–3.00 (m, 2H, CH + OH), 3.50 (m,
4H, CH2 OH + CH2Ph), 7.30–7.50 (m, 5H, H aromatic).
Anal. C13H19NO (C, H, N).
1
1 700 (CO), 1 310, 1 160 (SO2). H-NMR (CDCl3) δ
(ppm): 1.5–2.3 (m, 5H, CH(CH2)2), 2.7 (s, 3H, SO2CH3),
3.0–3.2 (m, 4H, N(CH2)2), 3.4–3.6 (m, 4H, -CH2–CH2-),
4.5 (d, 2H, CH2CO2 J = 12.63 Hz), 7.2 s, 1H, NH),
7.7–9.2 (m, 7H, H aromatic). Anal. C20H26N2O4S.HCl
(C, H, N).
5.1.4. 1-[(1-Benzylpiperidin-
4-yl)carboxymethyl]naphthalene 6
1-Naphthoic acid (5) (0.01 mol, 1.72 g) was dissolved
in dry chloroform; SOCl2 (0.04 mol, 4.8 g) was added
and the mixture was refluxed for 4 h. The solvent and the
residual SOCl2 were removed in vacuo. Dry chloroform
was then added to the residual solid material correspond-
ing to naphthoylchloride. The suspension was cooled to
5.1 7. 4-Benzylideneaminomethylpiperidine 10
4-Aminomethylpiperidine (0.01 mol, 1.15 g) was dis-
solved in absolute ethanol (20 mL), benzaldehyde

O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
705
(0.01 mol, 0.11 g) was added, and the mixture was heated
under reflux for 24 h. After cooling, the solvent was
stripped in vacuo. The resulting oil was used as such for
the next synthetic step. IR ν (cm–1): 3 500–3 200 (NH),
2.9 (m, 1H, CH), 3.0 (t, 2H, CH2-piperidinyl, J = 6.2 Hz),
3.6 (s, 2H, CH2Ph), 6.10 (s, 1H, CONH), 7.20–7.90 (m,
12H, aromatic). Anal. C24H26N2O (C, H, N).
1
5.1.11. N-(Piperidin-4-yl-
2 900 (CH alkyles), 1 650 (C=N). H-NMR (CDCl3) δ
methyl)naphth-1-yl carboxamide hydrochloride 14
Compound 13 (0.01 mol, 3.6 g) was dissolved in
methanol (100 mL). Palladium on charcoal was added
and the mixture was heated under hydrogen atmosphere
at 50 °C for 4 days. After cooling, the solvent was
evaporated in vacuo. The residue was dissolved in ac-
etone and HCl was bubbled. The obtained precipitate was
filtered, dried and recrystallized from acetonitrile. Yield
62%, m.p. 118–119 °C. IR ν (cm–1): 3 250 (NH),
2 900–2 800 (CH alkyles), 2 500 (NH+), 16 315 (CO).
1H-NMR (CDCl3) δ (ppm): 1.3–2.1 (m, 5H, CH(CH2)2),
2.6–3.3 (m, 6H, CH2-piperidinyl + N(CH2)2), 7.0–8.3 (m,
(ppm): 1.5–3.0 (m, 9H, CH(CH2–CH2)2), 2.1 (s, 1H,
NH), 3.5 (d, 2H, NCH2, J = 9.2 Hz), 7.3–7.8 (m, 5H, H
aromatic), 8.25 (s, 1H, CH=N). Anal. C13H18N2 (C, H,
N).
5.1.8. 1-Benzyl-4-benzylideneaminomethylpiperidine 11
4-Benzylideneaminomethylpiperidine (10) (0.01 mol,
2 g), benzyl chloride (0.012 mol, 1.5 g), anhydrous K2CO3
(0.02 mol, 2.8 g) and acetone (50 mL) were stirred for
12 h at room temperature. The mixture was filtered, the
filtrate was evaporated and the obtained oil was used as
such in the next step. IR ν (cm–1): 2 900 (CH alkyles),
1 650 (C=N). Anal. C20H24N2 (C, H, N).
+
7H, H aromatic), 8.70 (s, 1H, CONH), 9.0 (s, 2H, NH2 ).
Anal. C17H20N2O.HCl (C, H, N).
5.1.9. 1-Benzyl-4-amino-
methylpiperidine hydrochloride 12
5.1.12. N-(1-Methylsulfonamidoethylpiperidin-
A suspension of compound 11 (0.01 mol, 2.9 g) in a
10% aqueous solution of HCl (10 mL) was heated at
40 °C for 4 h. After cooling, chloroform (50 mL) was
added. The aqueous layer was isolated and a 40%
aqueous solution of NaOH was added (pH 7–8) and
extracted with chloroform (50 mL). The organic layer
was dried over CaCl2, evaporated and the residue was
dissolved in anhydrous diethyl ether in which HCl was
bubbled. The obtained precipitate was filtered, dried and
recrystallized from acetone. Yield = 55%, m.p. > 230 °C.
4-ylmethyl)naphth-1-yl carboxamide hydrochloride 15
Starting from 14 (0.01 mol, 2.7 g), compound 15 was
synthesized in the same way as 8. Recrystallization was
performed from absolute ethanol. Yield = 55%, m.p.
168–170 °C. IR ν (cm–1): 3 240 (CONH + SO2NH),
2 900–2 800 (CH alkyles), 2 500 (NH+), 1 615 (CO),
1 300, 1 135 (SO2). 1H-NMR (DMSO, d6) δ (ppm):
1.6–2.0 (m, 5H, CH(CH2)2), 2.9 (s, 3H, SO2CH3), 3.4 (m,
6H, (CH2)2NCH2), 3.5 (d, 2H, CH2-piperidinyl, J =
10.52 Hz), 7.10 (s, 1H, NHSO2), 7.40–8.10 (m, 7H, H
aromatic), 8.6 (s, 1H, NHCO), 10.4 (s, 1H, NH+). Anal.
C20H27N3O3 S.HCl (C, H, N).
IR ν (cm–1): 3 600–3 200 (NH3 ), 2 500–2 400 (NH+),
+
3 100–2 800 (CH alkyles). 1H-NMR (DMSO, d6), δ
(ppm): 1.5–2.1 (m, 5H, CH(CH2)2), 2.5–3.0 (m, 4H,
N(CH2)2), 3.3 (d, 2H, NCH2, J = 8.6 Hz), 4.2 (s, 2H,
NCH2 aryl), 7.4–7.7 (m, 5H, H aromatic), 8.35 (s, 3H,
5.2. Molecular modelling studies
+
Molecular modelling studies were performed using
SYBYL software version 6.5 running on Silicon Graphics
Indigo 2 R4000 workstation.
NH3 ), 11.25 (s, 1H, NH). Anal. C13H20N2.HCl (C, H,
N).
5.1.10. N-[(1-Benzylpiperidin-4-
yl)methyl)]naphth-1-yl carboxamide 13
Three-dimensional models of all compounds were built
from standard fragments library and their geometry was
subsequently optimized using the Tripos force field in-
cluding the electrostatic term calculated from Gasteiger
and Hückel atomic charges. The method of Powell
available in Maximin2 procedure was used for energy
minimization until the gradient value was smaller than
10–3 kcal.mol–1.Å. Throughout all calculations, an 8 Å
cut-off radius was used to properly take into account all
the non-bonded interactions and the dielectric constant
was set to 1.0.
Naphthoyl chloride was synthesized as described above.
A mixture of 1-benzyl-4-aminomethylpiperidine (12)
(0.01 mol, 2 g) and K2CO3 (0.02 mol, 2.8 g) in
chloroform/water (15 mL and 5 mL, respectively) was
stirred for 0.5 h at room temperature. Naphthoyl chloride
(0.01 mol, 1.9 g) previously dissolved in chloroform
(10 mL) was added dropwise and the mixture was stirred
at room temperature for 12 h. The organic layer was then
dried over CaCl2, evaporated and the residue was recrys-
tallized from ethanol/water (40:60). Yield = 60%, m.p.
146–148 °C. IR ν (cm–1): 3 280 (NH), 1 630–1 610 (CO).
1H-NMR (CDCl3) δ (ppm): 13–2.0 (m, 8H, N(CH2CH2)2),
For each compound, a conformational search using the
process ‘random search’ as implemented in SYBYL was
performed to identify its lowest energy conformations by

706
O. Diouf et al. / Eur. J. Med. Chem. 35 (2000) 699–706
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perturbing randomly all the rotatable bonds of the mol-
ecule. The completeness of the search was reached when
3 000 conformations were generated or when each con-
formation was found at least six times. An RMS value of
0.2 Å was set to differentiate two conformers. The
conformations produced by the random conformational
search are fully optimized and can be used immediately
for further analysis.
Then they were ordered by increasing energy and the
similarity between the minimized structures was evalu-
ated by comparing the RMS measured between all heavy
atoms. Equivalent conformations (with an RMS less than
0.4 Å) are discriminated and the remaining low-energy
conformations are used for further investigations.
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3
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