Synthesis and antimuscarinic activity of some ether- and thioether-bearing 1,3-dioxolanes and related sulfoxides and sulfones

Article abstract of DOI:10.1016/S0968-0896(98)00042-X

A series of 1,3-dioxolane-based ligands, bearing ether, thioether and related sulfoxide and sulfone functionalities, were synthesised and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor sub

Full text of DOI:10.1016/S0968-0896(98)00042-X

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 825±832
Synthesis and Antimuscarinic Activity of some Ether- and
Thioether-bearing 1,3-Dioxolanes and Related Sulfoxides and
Sulfones
Luca Malmusi,a Silvia Franchini,a Adele Mucci,b Luisa Schenetti,b
Ugo Gulini,c Gabriella Maruccic and Livio Brasilia,*
a
Á
Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Modena, Via Campi 183, 41100 Modena, Italy
b
Á
Dipartimento di Chimica, Universita degli Studi di Modena, Via Campi 183, 41100 Modena, Italy
Á
Dipartimento di Scienze Chimiche, Universita degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy
c
Received 13 November 1997; accepted 15 January 1998
AbstractÐA series of 1,3-dioxolane-based ligands, bearing ether, thioether and related sulfoxide and sulfone func-
tionalities, were synthesised and tested as potential muscarinic antagonists. The compounds display moderate to low
anity for the three receptor subtypes M1±M3, with some of them showing a signi®cant selectivity for the M1±M3 over
the M2 subtype. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
With this in mind we undertook a research project
aimed at developing selective antagonists, taking as a
lead compound 1, which has been reported to be a very
potent muscarinic antagonist11±13 but lacking in sig-
ni®cant selectivity.14 We focused our attention on posi-
tion 2 and, while keeping one of the two phenyl rings
constant, replaced the other with di€erent functionality
that could cause a discriminating interaction with the
receptor subtypes. Here, we report on the synthesis and
pharmacological evaluation of a series of 1,3-dioxolanes
carrying an ether or thioether function of varying
degrees of bulkiness in position 2.
Molecular cloning studies have shown that muscarinic
receptors consist of ®ve molecular forms (m1±m5)1,2
corresponding to the three pharmacologically-de®ned
M1±M3 subtypes.3,4 The pharmacological characteriza-
tion of these receptors is thus still incomplete, most
likely owing to the lack of an appropriate selective
ligand. Since muscarinic receptor subtypes are variously
involved in secretory and cardiovascular functions,
smooth muscle control and in central nervous system
transmission, selective ligands, which interfere speci®-
cally with one or other of the subtypes, would represent
potential therapeutic agents. Accordingly, M2 and M3
antagonists have been proposed for the treatment of
cardiac5 and gastrointestinal tract disorders,6,7 respec-
tively, while lipophilic M2 antagonists could serve to
improve memory and learning in neurodegenerative
disorders.8,9 A potential role as selective bronchodila-
tors has also been proposed for M3 or combined M1 and
M3 antagonists.10 Hence the urgent need to discover
selective antagonists which would make for a more
de®nitive classi®cation and represent potential thera-
peutic agents.
Chemistry
The syntheses of the compounds used in this study are
reported in Scheme 1. The ketones 10±13 were prepared
from the same precursor, bromoacetophenone. In the
case of compound 10, bromoacetophenone was allowed
*Corresponding author. Fax: 39 59 378 560.
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00042-X

826
L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
Compounds 14±18 were obtained as a mixture of dia-
stereoisomers which, in the case of 14, 15, and 18, were
separated by ¯ash chromatography. The a- and b-naph-
thoxy 16 and 17 were obtained as inseparable mixtures.
The a-isomers were separated following the amination
step (23c,t) while the b-isomers were not, and the corre-
sponding methyl iodide 6 was a mixture 2/3 of cis and
trans isomer.
The thiophenoxy intermediates 18c,t were oxidised with
m-chloroperbenzoic acid (MCPBA) in CH2Cl2 to sulf-
oxides ( 40 ꢀC) 19 and to sulfones (0 ꢀC to rt) 20. The
chloro derivatives 14±20 were then transformed into the
tertiary amines 21±27 by treatment with NH(CH3)2 at
100 ꢀC in a steel bomb. Finally, the tertiary amines were
converted into the quaternary salts 3±9 with CH3I in
Et2O. The con®gurational assignment of the diastereo-
isomeric pairs was obtained by 1-D Nuclear Overhaus
E€ect (1-D NOE)-di€erence experiments.16 The 1H
chemical shifts of compounds 3±9 (Table 1) parallel
those previously reported for some closely-related 1,3-
dioxolanes17,18 and con®rm some common trends. The
H-5a is always shielded with respect to its geminal
partner owing to the shielding e€ect of the vicinal
ammonium group. The di€erence Ád=dH-5a±dH-5b,
when a 2-phenyl group is present, is greater in the trans
than in the cis derivative, re¯ecting the remote shielding
e€ect of the aromatic substituent on the protons in cis
relationship with it. This e€ect is also seen, albeit to a
lesser extent, on H-4.
The 13C chemical shifts (Table 2) were obtained by
direct acquisition experiments with proton decoupling,
and their assignment, when not trivial, was based on the
value of the coupling constant between carbons and the
nitrogen atom of the CH2N+(CH3)3 group. In fact, C-5,
Scheme 1. (a) C6H5OH, K2CO3, (C2H5)2O, dicyclohexyl 18-
Crown ether-6, re¯ux; (b) C6H5SH, NaOH, C2H5OH, H2O; (c)
aC10H7OH (or bC10H7OH), CH2Cl2, H2O, NaOH, TBAB, rt;
(d) 3-chloro-propane-1,2-diol, CH3CN (or CH3NO2), tri¯ic
acid, molecular sieve 4 A, re¯ux; (e) MCPBA, CH2Cl2, 40 ꢀC
(or 0 ꢀC to rt); (f) (CH3)2, 100 ꢀC; (g) CH3I, an. (C2H5)2O, rt.
When the compound number is followed by c (cis) and t (trans)
the two isomers have been separated.
3
C-7, and N(CH3)3 carbons display a J(13C, 14N) cou-
pling constant of the order of 1±1.5 Hz and 1J(13C, 14N)
coupling constant of the order of 3±4 Hz. The presence
of these coupling constants enable us to distinguish
between C-5, C-6, and C-7, which fall in a very narrow
range. The detection of the J(13C, 14N) coupling con-
stant is due to the presence of the quaternary nitro-
gen.19±21 On the other hand the H-4 signal broadens
to react with phenol in ethereal solution, in the presence
of K2CO3 using 18-Crown-ether-6 as phase transfer
catalyst. The a-(11) and b-naphthoxy (12) derivatives
were prepared in like manner; in this case the base was
NaOH, the solvent a mixture of CH2Cl2/H2O and the
catalyst tetrabutylammonium bromide. The thiophen-
oxy 13, on the other hand, was prepared in homo-
geneous phase (CH3OH/H2O) using NaOH as a base.
3
owing to an unresolved J(1H, 14N) coupling constant,
and this behaviour is characteristic of all the compounds
examined.
Results and Discussion
Compounds 10±13 and the commercially available 2-
methoxyacetophenone were ketalized with 3-chloro-
propane-1,2-diol in anhydrous CH3CN (or CH3NO2)15
in the presence of molecular sieves 4 A and a catalytic
amount of tri¯ic acid.
All the newly-synthesized compounds were tested on
three di€erent preparations, namely, rabbit vas defe-
rens, guinea pig heart and ileum for M1, M2, and M3
antimuscarinic activity, respectively, and the results are
reported in Table 3.

L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
827
Table 1. 1H Chemical shifts (ppm relative to TMS), and coupling constants, J (Hz), of compounds 3±9a
3c
3t
4c
4t
5c
5t
6c
6t
7c
7t
8c
80c
8t
80t
9c
9t
H-4
H-5a
4.70 4.89 4.72 4.89 4.71 4.98 4.77 4.99 4.58 4.75 4.73 4.73 5.01 4.94 4.59 4.81
3.91 3.56 3.97 3.61 4.02 3.67 4.03 3.64 3.87 3.44 4.04 3.96 3.55 3.58 3.82 3.42
4.05 4.47 4.15 4.52 4.23 4.60 4.18 4.57 4.06 4.43 4.10 4.13 4.56 4.50 4.01 4.36
3.66 3.65 4.28 4.27 4.45 4.45 4.41 4.41 3.54 3.51 3.41 3.45 3.44 3.48 3.98 4.02b
3.66 3.66 4.31 4.32 4.55 4.49 4.44 4.44 3.59 3.60 3.45 3.48 3.47 3.52 4.03 4.02b
3.62 3.67 3.53 3.48 3.61 3.57 3.71 3.66 3.57 3.42 3.59 3.65 3.61 3.51 3.57 3.51
3.69 3.30 3.65 3.33 3.60 3.37 3.74 3.37 3.57 3.21 3.91 3.79 3.36 3.37 3.75 3.27
3.29 3.26 3.20 3.14 3.17 3.17 3.26 3.19 3.13 3.03 3.30 3.30 3.26 3.24 3.24 3.17
7.55 7.56 7.65 7.65 7.74 7.74 7.69 7.69 7.59 7.58 7.60 7.61 7.59 7.63 7.47 7.47
7.45 7.45 7.49 7.49 7.52 7.53 7.50 7.50 7.47 7.47 7.47 7.47 7.47 7.49 7.41 7.41
7.45 7.45 7.49 7.49 7.49 7.48 7.52 7.52 7.44 7.46 7.47 7.47 7.47 7.49 7.41 7.41
4.75 7.71 5.29 7.94 5.78 7.89 5.31 7.93 5.65 8.66 4.60 5.58 8.85 8.63 5.76 8.64
6.89 6.35 6.91 6.26 6.98 6.29 6.92 6.28 7.28 6.11 7.47 7.41 5.97 6.46 7.49 6.31
H-5b
H-6a
H-6b
H-7a
H-7b
N(CH3)3
H-ortho f
H-meta f
H-para f
J(H-4, H-5a)
J(H-4, H-5b)
J(H-4, H-7a)
J(H-4, H-7b)
J(H-5a, H-5b)
2.15 1.46 1.76 1.52 1.6c
9.44 9.55 9.66 9.59 9.6c
8.83 8.53 8.81 8.44 8.80 8.57 8.82 8.46 8.71 8.64 9.16 8.92 8.67 8.61 8.76 8.66
1.33 2.11 1.37 1.2c
9.57 9.66 9.60 9.6c
1.07 1.40 1.59 1.26 1.34 1.10 1.31
9.71 10.14 9.81 9.52 9.46 9.86 9.68
J(H-6a, H-6b) 11.20 11.10 11.22 11.20 10.82 10.72 11.16 11.17 14.64 14.83 14.44 14.34 14.20 14.32 15.27 b
J(H-7a, H-7b) 13.63 13.94 13.79 14.02 13.8c 13.94 14.00 13.99 13.8c 13.88 13.69 13.86 13.96 14.22 13.75 14.10
aSpectra were obtained in CD3CN.
bA2 spin system.
cBroad signals.
Table 2. 13C Chemical shifts (ppm relative to TMS) of compounds 3±9a
3cb 3tb
4c
4t
5c
5t
6c
6t
7c
7t
8c
80c
8t
80t
9c
9t
C-2
C-4
111.5 111.3 110.85 110.69 110.9b 110.77 110.90 110.73 111.73 111.80 110.30 110.27 109.83 109.8b 109.15 108.72
70.6 71.4 70.74 71.60 70.56 71.72 70.85 71.79 70.45 71.80 70.62 70.80 71.63 71.4b 70.54 71.37
67.6 67.7 67.95 67.85 67.27 67.94 68.08 68.00 67.90 67.54 67.90 67.48 67.65 67.53 67.33 67.14
75.9 76.5 70.92 71.65 71.77 72.00 71.14 71.88 42.91 43.16 67.24 68.00 68.26 68.07 62.17 62.18
68.4 67.9 68.30 67.52 68.38 67.79 68.40 67.65 68.22 67.38 68.66 68.20 67.09 67.1b 67.96 67.09
54.4 54.2 54.27 54.09 54.20 54.14 54.35 54.14 54.19 53.97 54.41 54.36 54.24 54.23 54.37 54.15
139.6 140.0 138.93 139.34 139.03 139.58 139.00 139.41 140.48 141.21 139.74 139.71 140.63 140.1b 139.29 139.92
C-5
C-6
C-7
N(CH3)3
C-10f
C-ortho f 125.9 125.9 126.03 125.90 126.23 126.05 126.14 126.02 125.74 125.59 125.57 125.64 125.41 125.54 125.64 125.53
C-meta f 128.2 128.2 128.21 128.19 128.31 128.29 128.32 128.30 128.34 128.30 128.57 128.58 128.53 128.56 128.41 128.30
C-para f
128.6 128.5 128.89 128.76 128.98 128.87 129.01 128.88 128.80 128.65 129.10 129.12 128.95 129.06 129.10 128.94
aSpectra were obtained in CD3CN.
bObtained from inverse detection experiments.
In a previous paper18 we reported on compounds
2c,t, which show an appreciable antimuscarinic activity
at the three receptor subtypes, with some degree of
diastereoselectivity. In an attempt to improve potency
and selectivity, we used these compounds as a starting
point. Methylation of the hydroxy group decreases
activity at the M1 and M3 receptor subtypes, while
leaving it una€ected at the M2 subtype. The observed
decrease, which is more pronounced for the trans isomer
(3t), might be explained by a lack of hydrogen bonding,
which may be operative in the case of compounds 2c,t,
or, alternatively, by a steric hindrance e€ect of the
bulkier methoxy group. In order to determine the steric
demand of the receptor subsite accommodating the
substituent in position 2 more accurately, we prepared
compounds 4±6. Interestingly, replacement of the

828
L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
Table 3. In vitro antimuscarinic activity and selectivity of compounds 1±9
pKb (pA2)
M1
M2
M1
M3
M3
M2
R
X
M1
M2
M3
1
8.36‹0.07a
6.35‹0.12
7.13‹0.10
5.88‹0.07
6.49‹0.09
7.76‹0.05a
7.51‹0.15a
6.17‹0.13
6.64‹0.16
<5
8.29‹0.06a
6.01‹0.15
6.49‹0.21
6.05‹0.12
6.33‹0.10
6.34‹0.12a
6.37‹0.13a
5.30‹0.11
5.54‹0.09
5.85‹0.10
5.87‹0.17
5.89‹0.12
<5
7.91‹0.07a
5.97‹0.21
7.01‹0.09
5.92‹0.08
6.10‹0.15
7.48‹0.10a
7.43‹0.07a
6.28‹0.10
6.17‹0.09
6.44‹0.18
7.06‹0.11a
6.97‹0.05a
5.40‹0.08
5.91‹0.21
5.35‹0.20
5.72‹0.19
<5
1.2
2.2
4.4
0.7
1.4
26
2.8
2.4
1.3
0.9
2.5
1.9
1.2
0.8
3.0
Ð
0.4
0.9
3.3
0.7
0.6
1.4
1.2
1.0
4.3
3.8
17
2c
2t
H
O
O
H
CH3
3c
3t
O
CH3
O
4c
4t
C6H5
C6H5
aC10H7
aC10H7
bC10H7
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
O
O
14
5c
5t
O
7.4
1.3
0.1
15
O
6c,t
7c
7t
O
S
7.04‹0.15a
6.90‹0.18a
<5
0.9
1.2
Ð
S
10
12
8c
80c
8t
80t
9c
9t
SO
SO
SO
SO
SO2
SO2
Ð
Ð
5.45‹0.13
<5
<5
5.45‹0.18
<5
<5
1.0
Ð
0.3
Ð
2.9
Ð
Ð
Ð
Ð
Ð
Ð
Ð
<5
<5
<5
<5
<5
Ð
Ð
Ð
apA2 values.
methyl group by a phenyl ring again leaves the M2
antagonist activity una€ected, while signi®cant
enhancement is observed at M1 and M3 receptors. A
further increase in the substituent size, a-(23) and b-
naphthyl (24) derivatives, reduces anity at the three
receptor subtypes.
As regard selectivity, the phenoxy derivatives 4 are the
most interesting of the series. Both cis and trans forms
show signi®cantly (10±26 times) greater selectivity for
the M1±M3 than for the M2 subtypes. Although isosteric
oxygen/sulphur substitution decreases anity for the
three receptor subtypes, it does not seem to a€ect selec-
tivity, as compounds 7c,t show the same selectivity pro-
®le as compounds 4t,c. Although not striking, this kind
of selectivity is of interest in view of a potential thera-
peutic application in the treatment of chronic obstructive
pulmonary disease, where cholinergic tone is the only
reversible component.10 We cannot preclude that the
relative anities presented here may represent species
di€erences or receptor tissues distribution; further
measures of relative anity against cloned human sub-
types may clarify these issues. E€orts to improve selec-
tivity are being made and ®ndings will be reported in
due course.
a
Regarding the hydrogen-bonding interaction, evoked in
the case of compounds 2c,t, it can be said that, at least
for M1 and M3 receptors, the good activity observed for
the phenoxy derivatives 4c,t can be explained if we allow
that the decrease in activity due to the lack of hydrogen
bonding is counterbalanced by a more productive inter-
action, probably of p±p type, between the phenyl ring
and a counterpart at the receptor subsite. Bearing in
mind that the compounds 2, 3, and 4 have similar a-
nities, the formation of hydrogen bonding might not
take place in the case of the M2 receptor subtype or,
alternatively, the hydroxy group might behave as a
hydrogen-bonding acceptor.
Experimental
Chemistry
Isosteric oxygen/sulphur substitution was also studied,
and the thioderivatives 7c,t turn out to be slightly less
active than the parent compounds 4c,t. Finally, the oxi-
dation of sulphur to sulfoxides 8 and 80 and to sulfones
9 a€ord virtually inactive compounds.
Melting points were taken in glass capillary tubes on a
Buchi apparatus and are uncorrected. Infrared (IR)

L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
829
spectra were measured on a Perkin±Elmer 1600 instru-
ment. Nuclear Magnetic Resonance (1H and 13C NMR)
spectra were obtained in CDCl3 or CD3CN, with Varian
XL-200 and Bruker AMX-400 WB spectrometers, and
peak positions are given in parts per million (d), down-
®eld from tetramethylsilane as the internal standard.
The typical resolution for 1H NMR spectra was 0.05 Hz
per point. Di€erential steady-state NOE experiments
were performed, acquiring 128 + 128 transients in
groups of eight, alternately irradiating on- and o€-reso-
nance, with a presaturation time of 10 s. Fully proton-
decoupled 13C NMR spectra were obtained with stan-
dard pulse sequence, and the resolution being 0.05 ppm.
The microanalyses were performed on a Carlo Erba
1106 Analyzer in the Microanalytical Laboratory of our
department. Chromatographic separations were per-
formed on silica gel columns (Kieselgel 40, 0.040±
0.063 mm, Merck) by ¯ash chromatography. Reaction
courses and product mixture were routinely monitored
by thin-layer chromatography (TLC) on silica gel-pre-
coated F254 Merck plates.
following the same procedure adopted for the prepara-
tion of 11, 8.99 g (34.3 mmol, 83.9%) of compound 12
(mp 92±94 ꢀC) were obtained: H NMR (CDCl3) d 5.38
1
(s, 2H), 7.11 (d, 1H), 7.25 (d, 1H), 7.24 (t, 1H), 7.42 (t,
1H), 7.50 (t, 2H), 7.62 (t, 1H), 7.70 (d, 1H), 7.76 (d, 2H),
8.04 (d, 2H).
1-Phenyl-2-phenylsulfanyl-ethanone (13). Benzenethiol
(5.2 mL, 50.9 mmol) was added dropwise to a cooled
(0 ꢀC) solution of 2.2 g (55.0 mmol) of NaOH in 40 mL
of H2O:C2H5OH (1:1). After the addition of 10 g
(48.9 mmol) of bromoacetophenone (97%) the reaction
was re¯uxed for 1 h. After cooling to rt, 80 mL of H2O
were added and the solution washed with NaOH 2 N,
and dried over MgSO4. Evaporation of the solvent
a€orded a residue, which was treated with anhydrous
diethyl ether, cooled to
(44.7 mmol, 91.4%) of compound 13 as a white solid
20 ꢀC, to give 10.2 g
(mp 54±55 ꢀC): H NMR (CDCl3) d 4.25 (s, 2H), 7.16±
1
7.28 (m, 3H), 7.36 (m, 2H), 7.43 (m, 2H) 7.55 (m, 1H),
7.91 (m, 2H).
2-Phenoxy-1-phenyl-ethanone (10). Bromoacetophenone
(7.30 g, 35.6 mmol, 97%), in 25 mL of anhydrous die-
thyl ether, was added dropwise to a solution of phenol
(4.5 g, 47.8 mmol), K2CO3 (6.0 g), and dicyclohexyl-18-
crown-6 (40 mg) in 30 mL of anhydrous diethyl ether.
The reaction was re¯uxed for 12 h under nitrogen.
After cooling to rt the solid was ®ltered o€ and the
solution was extracted with aqueous K2CO3
(3Â15 mL) and dried over MgSO4. The solvent was
evaporated and the residue was puri®ed by chromato-
graphy on silica gel column using cyclohexane:EtOAc
(95:5) as the eluant to give 6.52 g (30.7 mmol, 86.2%)
of compound 10: 1H NMR (CDCl3) d 5.24 (s, 2H),
6.94 (m, 3H), 7.20 (m, 2H), 7.47 (m, 2H), 7.58 (m,
1H), 7.95 (m, 2H).
General procedure for the preparation of compounds 14±
18. To a solution of methoxyacetophenone (95%) or
11±13 (1.5±10 g) and 3-chloro-propane-1,2-diol (1±
5 mL) in 50±300 mL of anhydrous CH3CN (or
CH3NO2), cooled at 0 ꢀC, was slowly added a catalytic
amount of tri¯uoro-methanesulfonic acid (tri¯ic acid)
and molecular sieve 4 A. The reaction was heated at
re¯ux under nitrogen for 36 h. After cooling to rt, Et2O
was added and the organic phase was extracted with
saturated solution of NaHCO3 (3Â25 mL) and dried
over Na2SO4 (or MgSO4). The solvent was evaporated
and the residue was puri®ed on a silica gel column
(cyclohexane:EtOAc, 95:5), to give cis (c) and trans (t)
isomer separated or as a mixture.
(2S*,4S*) cis-4-Chloromethyl-2-methoxymethyl-2-phenyl-
1
2-(Naphtalen-1-yloxy)-1-phenyl-ethanone (11). To 400 mL
of an emulsion of H2O:CH2Cl2 (1:1) were added, under
vigorous stirring, 16 g (78.0 mmol) of bromoacetophe-
none (97%), 5.9 g (40.9 mmol) of naphthalen-1-ol, 2.4g
(60.0 mmol) of NaOH and 350 mg (1.1 mmol) of TBAB.
The reaction was stirred at rt for 12 h, then the solid was
®ltered o€ and the solvent was evaporated. The residue
was dissolved in diethyl ether, extracted with NaOH 2 N
(3Â30 mL), and dried over MgSO4. Evaporation of the
solvent gave a gummy residue, which was dissolved in
DMF. Addition of H2O gave 8.9g (33.9 mmol, 82.9%)
[1,3]dioxolane (14c). (Yield 41.1%); H NMR (CDCl3)
d 3.37 (s, 3H), 3.56 (q, 2H), 3.59 (dd, 1H), 3.67 (ddd,
1H), 3.86 (ddd, 1H), 4.02 (dd, 2H), 4.25 (m, 1H), 7.33
(m, 3H), 7.47 (m, 2H).
(2R*,4R*) trans-4-Chloromethyl-2-methoxymethyl-2-
phenyl-[1,3]dioxolane (14t). (Yield 19.6%); 1H NMR
(CDCl3) d 3.17 (dd, 1H), 3.37 (s, 3H), 3.53 (dd, 1H),
3.54 (s, 2H), 3.73 (dd, 1H), 4.34 (dd, 1H), 4.52 (m, 1H),
7.33 (m, 3H), 7.47 (m, 2H).
of compound 11 as a yellowish solid (mp 95±97 ꢀC). H
4-Chloromethyl-2-phenoxymethyl-2-phenyl-[1,3]dioxolane
(15). (Yield 38.4%); 1H NMR (CDCl3) d 3.27, 3.67 (dd,
dd, 1H, 1H), 3.57, 3.70 (t, dd, 1H, 1H), 3.87, 3.96 (dd,
dd, 1H, 1H), 4.13, 4.16 (s, q, 2H, 2H), 4.45, 4.12 (dd, dd,
1H, 1H), 4.61, 4.35 (m, m, 1H, 1H), 6.89 (m, 2H, 2H),
6.94 (m, 1H, 1H), 7.25 (m, 2H, 2H), 7.38 (m, 3H, 3H),
7.58 (m, 2H, 2H).
1
NMR (CDCl3): d 5.40 (s, 2H), 6.75 (d, 1H), 7.31 (t, 1H),
7.41±750 (m, 5H), 7.59 (m, 1H), 7.78 (m, 1H), 8.03 (m,
2H), 8.32 (m, 1H).
2-(Naphthalen-2-yloxy)-1-phenyl-ethanone (12). Starting
from 16 g (78.0 mmol) of bromoacetophenone (97%),

830
L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
4-Chloromethyl-2-(naphthalen-1-yloxymethyl)-2-phenyl-
1
CH2Cl2, cooled at 0 ꢀC, 1 g (3.48 mmol) of MCPBA
(60%) in 10 mL of CH2Cl2, were added dropwise, and
left under stirring for 30 min at rt. The reaction mixture
was extracted with saturated solution of NaHCO3
(3Â5 mL) and dried over Na2SO4. The solvent was eva-
porated and the residue was puri®ed on a silica gel col-
umn (cyclohexane:EtOAc, 90:10), to give 0.4 g
(1.14 mmol, 52.3%) of 20c: 1H NMR (CDCl3) d 3.56
(dd, 1H), 3.64 (ddd, 1H), 3.76 (q, 2H), 3.86 (ddd, 1H),
3.95 (dd, 1H), 4.17 (m, 1H), 7.28 (m, 3H), 7.37 (m, 2H),
7.46 (m, 2H), 7.57 (m, 1H), 7.80 (m, 2H); 0.35 g
(0.99 mmol, 45.4%) of 20t: 1H NMR (CDCl3) d 3.09
(dd, 1H), 3.45 (dd, 1H), 3.62 (dd, 1H), 3.71 (q, 2H), 4.28
(dd, 1H), 4.45 (m, 1H), 7.26 (m, 3H), 7.36 (m, 2H), 7.47
(m, 2H), 7.57 (m, 1H), 7.82 (m, 2H);
[1,3]dioxolane (16). (Yield 40.3%); H NMR (CDCl3) d
3.29, 3.64 (dd, dd, 1H, 1H), 3.59, 3.71 (dd, dd, 1H, 1H),
3.92, 4.01 (dd, dd, 1H, 1H), 4.28, 4.33 (s, s, 2H, 2H), 4.50,
4.37 (m, m, 1H, 1H), 4.51, 4.13 (dd, dd, 1H, 1H), 6.78
(dd, 1H, 1H), 7.30 (m, 1H, 1H), 7.43±7.32 (m, 6H, 6H),
7.64 (m, 2H, 2H), 7.75 (m, 1H, 1H), 8.14 (m, 1H, 1H).
4-Chloromethyl-2-(naphthalen-2-yloxymethyl)-2-phenyl-
1
[1,3]dioxolane (17). (Yield 48.7%); H NMR (CDCl3) d
4.33, 4.36 (s, q, 2H, 2H), 3.34, 3.79 (dd, m, 1H, 1H),
3.64, 3.80 (dd, m, 1H, 1H), 3.97, 4.04 (dd, dd, 1H, 1H),
4.54, 4.22 (m, m, 1H, 1H), 4.75, 4.44 (m, m, 1H, 1H),
7.20 (t, 1H, 1H), 7.25 (dd, 1H, 1H), 7.39 (m, 1H, 1H),
7.52±7.42 (m, 4H, 4H), 7.84±7.67 (m, 5H, 5H).
(2S*,4S*) cis-4-Chloromethyl-2-phenyl-2-phenylsulfanyl
methyl-[1,3]dioxolane (18c). (Yield 21.3%); 1H NMR
(CDCl3) d 3.38 (s, 2H), 3.64 (d, 2H), 3.87 (dd, 2H), 4.02
(dd, 1H), 4.24 (m, 1H), 7.12 (m, 1H), 7.21 (m, 1H), 7.33
(m, 5H), 7.49 (m, 2H).
General procedure for the preparation of compounds 21±
27. Compounds 14±20 (0.2±1 g) and 2±10 mL of
NH(CH3)2 in a steel bomb were heated at 100 ꢀC for 24±
48 h. After evaporation of the excess NH(CH3)2 the
residue was chromatographed on a silica gel column
[EtOAc:NH(C2H5)2 (or NH4OH 30%), 98:2]. In the
case of compound 23, chromatography carried out
using EtOAc:C2H5OH:NH4OH 30% (97:1:2) as the
eluant, a€orded the cis and trans isomer in pure form.
The same procedure used in the attempt to separate the
diastereoisomeric mixture of 24 was unsuccessful. In all
cases the yields were higher than 90%.
(2R*,4R*) trans-4-Chloromethyl-2-phenyl-2-phenylsulfanyl
methyl-[1,3]dioxolane (18t). (Yield 20.6%); 1H NMR
(CDCl3) d 3.15 (dd, 2H), 3.40 (q, 2H), 3.51 (dd, 1H),
3.69 (dd, 1H), 4.37 (dd, 1H), 4.55 (m, 1H), 7.11 (m, 1H),
7.21 (m, 2H), 7.32 (m, 5H), 7.49 (m, 2H).
(2S*,4S*) cis-(19c) and (190c) and (2R*,4R*) trans-2-
Benzenesul®nylmethyl-4-chloromethyl-2-phenyl-[1,3]dioxo-
lane (19t) and (190t). To a solution of 1.1 g (3.43 mmol)
of 18c,t in 20 mL of CH2Cl2, cooled at 40 ꢀC, 0.95 g
(3.30 mmol) of MCPBA (60%) in 10 mL of CH2Cl2,
were added dropwise. After 15 min the reaction mixture
was extracted with saturated solution of NaHCO3
(3Â5 mL) and dried over Na2SO4. The solvent was eva-
porated and the residue was puri®ed on a silica gel col-
umn (cyclohexane:EtOAc, 60:40), to give: 0.35 g
(1.04 mmol, 30.3%) of 19c: 1H NMR (CDCl3) d 3.37 (q,
2H), 3.74 (dd, 1H), 3.83 (ddd, 1H), 3.98 (ddd, 1H), 4.16
(dd, 1H), 4.33 (m, 1H), 7.33±7.40 (m, 3H), 7.45±7.53 (m,
5H), 7.46 (m, 2H); 0.38 g (1.13 mmol, 32.9%) of 190c: 1H
NMR (CDCl3) d 3.33 (q, 2H), 3.76 (dd, 1H), 3.80 (dd,
1H), 3.92 (dd, 1H), 4.14 (dd, 1H), 4.32 (m, 1H), 7.27±
7.35 (m, 3H), 7.38±7.50 (m, 5H), 7.58±7.67 (m, 2H);
(2S*,4R*) (cis-2-Methoxymethyl-2-phenyl-[1,3]dioxolan-
4-ylmethyl)-dimethyl-amine (21c). 1H NMR (CDCl3) d
2.36 (s, 6H), 2.43 (dd, 1H), 2.64 (d, 1H), 3.38 (s, 3H),
3.58 (q, 2H), 3.77 (dd, 1H), 3.93 (dd, 1H), 4.12 (m, 1H),
7.33 (m, 3H), 7.51 (m, 2H).
(2R*,4S*) (trans-2-Methoxymethyl-2-phenyl-[1,3]dioxo-
1
lan-4-ylmethyl)-dimethyl-amine (21t). H NMR (CDCl3)
d 2.25 (dd, 1H), 2.26 (s, 6H), 2.45 (dd, 1H), 3.40 (s, 3H),
3.50 (t, 1H), 3.57 (q, 2H), 4.30 (dd, 1H), 4.48 (m, 1H),
7.34 (m, 3H), 7.53 (m, 2H).
(2S*,4R*) Dimethyl-(cis-2-phenoxymethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-amine (22c). 1H NMR (CDCl3) d
2.30 (s, 6H), 2.48 (dd, 1H), 2.67 (dd, 1H), 3.87 (dd, 1H),
4.02 (dd, 1H), 4.17 (s, 2H), 4.23 (m, 1H), 6.94 (m, 3H),
7.24 (m, 2H), 7.41 (m, 3H), 7.64 (m, 2H).
1
0.20 g (0.59 mmol, 17.2%) of 19t: H NMR (CDCl3) d
3.15 (dd, 1H), 3.31 (q, 2H), 3.62 (dd, 1H), 3.75 (dd, 1H),
4.49 (dd, 1H), 4.67 (m, 1H), 7.27±7.34 (m, 3H), 7.37±7.48
(m, 5H), 7.60±7.66 (m, 2H); 0.15 g (0.44 mmol, 12.8%) of
(2R*,4S*) Dimethyl-(trans-2-phenoxymethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-amine (22t). 1H NMR (CDCl3) d
2.27 (s, 6H), 2.31 (dd, 1H), 2.48 (dd, 1H), 3.58 (t, 1H),
4.15 (d, 2H), 4.36 (dd, 1H), 4.57 (m, 1H), 6.93 (m, 2H),
7.26 (m, 2H), 7.38 (m, 3H), 7.63 (m, 2H).
190t: H NMR (CDCl3) d 3.19 (dd, 1H), 3.32 (q, 2H),
1
3.56 (dd, 1H), 3.71 (dd, 1H), 4.48 (dd, 1H), 4.65 (m, 1H),
7.28±7.34 (m, 3H), 7.37±7.46 (m, 5H), 7.55±7.59 (m, 2H).
(2S*,4S*) cis-(20c) and (2R*,4R*) trans-2-Benzenesulf-
onyl methyl-4-chloromethyl-2-phenyl-[1,3]dioxolane (20t).
To a solution of 0.7 g (2.18 mmol) of 18c,t in 10 mL of
(2S*,4R*) Dimethyl-[cis-2-(naphthalen-1-yloxymethyl)-2-
phenyl-[1,3]dioxolan-4-ylmethyl]-amine (23c). 1H NMR
(CDCl3) 2.27 (s, 6H), 2.49 (dd, 1H), 2.66 (dd, 1H), 3.88

L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
831
(dd, 1H), 4.05 (dd, 1H), 4.23 (m, 1H), 4.32 (q, 2H), 6.75
(ddd, 1H), 7.28 (t, 1H), 7.46±7.29 (m, 6H), 7.65 (m, 2H),
7.73 (m, 1H), 8.15 (m, 1H).
(2S*,4R*) (cis-2-Benzenesulfonylmethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-dimethyl-amine (27c). 1H NMR
(CDCl3) d 2.21 (s, 6H), 2.46 (dd, 1H), 2.64 (dd, 1H),
3.70 (dd, 1H), 3.78 (q, 2H), 3.94 (dd, 1H), 4.08 (m, 1H),
7.24 (m, 3H), 7.39 (m, 2H), 7.46 (m, 2H), 7.58 (m, 1H),
7.82 (m, 2H).
(2R*,4S*) Dimethyl-[trans-2-(naphthalen-1-yloxymethyl)-
1
2-phenyl-[1,3]dioxolan-4-ylmethyl]-amine (23t). H NMR
(CDCl3) 2.25 (s, 6H), 2.31 (dd, 1H), 2.47 (dd, 1H), 3.61
(dd, 1H), 4.27 (q, 2H), 4.39 (dd, 1H), 4.62 (m, 1H), 6.74
(ddd, 1H), 7.29 (t, 1H), 7.45±7.29 (m, 6H), 7.65 (m, 2H),
7.72 (m, 1H), 8.15 (m, 1H).
(2R*,4S*) (trans-2-Benzenesulfonylmethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-dimethyl-amine (27t). 1H NMR
(CDCl3) d 2.28 (s, 6H), 2.46 (dd, 1H), 2.65 (dd, 1H),
3.91 (dd, 1H), 3.75 (q, 2H), 4.21 (dd, 1H), 4.34 (m, 1H),
7.38 (m, 3H), 7.41 (m, 2H), 7.49 (m, 2H), 7.59 (m, 1H),
7.85 (m, 2H).
Dimethyl-[2-(naphthalen-2-yloxymethyl)-2-phenyl-[1,3]-
dioxolan-4-ylmethyl]-amine (24). 1H NMR (CDCl3) d
2.24, 2.27 (s, s, 6H, 6H), 2.29, 2.46 (dd, dd, 1H, 1H),
2.48, 2.66 (dd, dd, 1H, 1H), 3.57, 3.87 (dd, dd, 1H,
1H), 4.22, 4.25 (q, s, 2H, 2H), 4.36, 4.01 (dd, dd, 1H,
1H), 4.58, 4.22 (m, m, 1H, 1H), 7.08 (m, 1H), 7.12
(m, 1H), 7.28 (m, 1H), 7.40±7.30 (m, 4H), 7.72±7.58
(m, 5H).
General procedure for the preparation of compounds 3±
9c,t. Amine (100±300 mg) was dissolved in 10 mL of
dry Et2O; an excess of methyl iodide was added and the
reaction left at rt for 12 h. After ®ltration (or evapora-
tion of the solvent) the solid (or residue) was recrys-
tallized to form EtOH:Et2O (i-PrOH in the case of
compound 3c,t). Elemental analysis was performed for
compounds 3±9c,t and the results (not shown) are
(2S*,4R*) Dimethyl-(cis-2-phenyl-2-phenylsulfanyl-
methyl-[1,3]dioxolan-4-ylmethyl)-amine (25c). 1H NMR
(CDCl3) d 2.24 (s, 6H), 2.43 (dd, 1H), 2.62 (dd, 1H),
3.40 (q, 2H), 3.76 (dd, 1H), 3.92 (dd, 1H), 4.10 (m, 1H),
7.09 (m, 1H), 7.20 (m, 2H), 7.25±7.35 (m, 5H), 7.51
(m, 2H).
within ‹0.4% of the theoretical values. For 1H and 13
C
NMR see Tables 1 and 2.
Pharmacology
(2R*,4S*) Dimethyl-(trans-2-phenyl-2-phenylsulfanyl-
methyl-[1,3]dioxolan-4-ylmethyl)-amine (25t). 1H NMR
(CDCl3) d 2.35 (s, 6H), 2.50 (dd, 1H), 2.91 (dd, 1H),
3.38 (q, 2H), 3.43 (dd, 1H), 4.35 (dd, 1H), 4.71 (m, 1H),
7.11 (m, 1H), 7.23 (m, 2H), 7.32 (m, 5H), 7.48 (m, 2H).
General considerations. Male guinea pigs (200±300 g)
and male New Zealand white rabbits (3.0±3.5 kg) were
killed by cervical dislocation. The organs required were
set up rapidly under 1 gr of tension in 20 mL organ
baths containing physiological salt solution (PSS)
maintained at an appropriate temperature (see below)
and aerated with 5% CO2 95% O2. Dose±response
curves were constructed by cumulative addition of ago-
nist. The concentration of agonist in the organ bath was
increased approximately threefold at each step, with
each addition being made only after the response to the
previous addition had attained a maximal level and
remained steady. Following 30 min of washing, tissues
were incubated with the antagonist for 30 min, and a
new dose±response curve to the agonist was obtained.
Contractions were recorded by means of a force trans-
ducer connected to a two-channel Gemini polygraph. In
all cases, parallel experiments in which tissues did not
receive any antagonist were run in order to check any
variation in sensitivity.
(2S*,4R*) (cis-2-Benzenesul®nylmethyl-2-phenyl-[1,3]di-
oxolan-4-ylmethyl)-dimethyl-amine (26c). 1H NMR
(CDCl3) d 2.35 (s, 6H), 2.60 (dd, 1H), 2.76 (dd, 1H),
3.39 (q, 2H), 3.92 (m, 1H), 4.03 (dd, 1H), 4.18 (m, 1H),
7.30±7.38 (m, 3H), 7.42±7.53 (m, 5H), 7.65 (m, 2H).
(2S*,4R*) (cis-2-Benzenesul®nylmethyl-2-phenyl-[1,3]di-
oxolan-4-ylmethyl)-dimethyl-amine (260c). 1H NMR
(CDCl3) d 2.38 (s, 6H), 2.54 (dd, 1H), 2.85 (dd, 1H),
3.36 (q, 2H), 3.95 (dd, 1H), 3.97 (dd, 1H), 4.26 (m, 1H),
7.32±7.39 (m, 3H), 7.44±7.51 (m, 5H), 7.64 (m, 2H).
(2R*,4S*) (trans-2-Benzenesul®nylmethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-dimethyl-amine (26t). 1H NMR
(CDCl3) d 2.26 (s, 6H), 2.27 (dd, 1H), 2.46 (dd, 1H),
3.37 (q, 2H), 3.53 (t, 1H), 4.42 (dd, 1H), 4.60 (m, 1H),
7.32±7.39 (m, 3H), 7.42±7.58 (m, 5H), 7.65 (m, 2H).
Guinea pig ileum.22,23 Two-centimetre long portions of
terminal ileum were taken about 5 cm from the ileum±
cecum junction and mounted in PSS at 37 ꢀC. The
composition of PSS was as follows (mM): NaCl (118),
NaHCO3 (23.8), KCl (4.7), MgSO4.7H2O (1.18),
KH2PO4 (1.18), CaCl2 (2.52), and glucose (11.7). Ten-
sion changes were recorded isotonically. Tissues were
equilibrated for 30 min, and dose±response curves to
(2R*,4S*) (trans-2-Benzenesul®nylmethyl-2-phenyl-[1,3]-
dioxolan-4-ylmethyl)-dimethyl-amine (260t). 1H NMR
(CDCl3) d 2.21 (dd, 1H), 2.27 (s, 6H), 2.44 (dd, 1H),
3.53 (q, 2H), 3.57 (t, 1H), 4.43 (dd, 1H), 4.62 (m, 1H),
7.32±7.39 (m, 3H), 7.42±7.57 (m, 5H), 7.64 (m, 2H).

832
L. Malmusi et al./Bioorg. Med. Chem. 6 (1998) 825±832
carbachol were obtained at 30 min intervals, the ®rst one
being discarded and the second one being taken as the
control.
3. Doods, H. N.; Mathy, M. J.; Davidesko, D.; Van Charl-
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Exp. Ther. 1987, 242, 257.
4. Receptor & Ion Channel Nomenclature. Trends Pharmacol.
Sci. (Suppl.), 1995.
Guinea pig stimulated left atria.22 The heart was rapidly
removed and the right and left atria were separately
excised. Left atria were mounted in PSS (the same as
used for ileum) at 30 ꢀC and stimulated through plati-
num electrodes by square-wave pulses (1 ms, 1 Hz, 10±
15 V). Inotropic activity was recorded isometrically.
Tissues were equilibrated for 2 h and a cumulative dose±
response curve to carbachol was constructed.
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and two epididymal portions approximately 1.5 cm in
length. The four segments were mounted in PSS with
the following composition (mM): NaCl (118.4), KCl
(4.7), CaCl2 (2.52), MgCl2 (0.6), KH2PO4 (1.18),
NaHCO3 (25), and glucose (11.1); 1 mM yohimbine was
included to block a2-adrenoceptors. The solution was
maintained at 30 ꢀC and tissues were stimulated through
platinum electrodes by square-wave pulses (0.1 ms, 2 Hz,
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equation pKb=log (DR±1)±log [B], where DR is the
ratio of ED50 values of agonist after and before treat-
ment with one or two antagonist concentration [B].25 In
some cases, antagonist potency is expressed in terms of
pA2, estimated by Schild plots26 constrained to slope
1.0, as required by the theory.27 Values are given as
mean ‹ standard error of four or ®ve independent
observations.
17. Mucci, A.; Schenetti, L.; Brasili, L.; Malmusi, L. Magn.
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Acknowledgements
21. Axenrod, T. In Nitrogen NMR; Witanowsky, M.; Webb,
G. A., Eds.; Plenum: London, 1973; pp 261±317.
This work was supported by a grant from MURST. The
authors express their gratitude to the Centro Inter-
dipartimentale Grandi Strumenti of University of Mod-
ena for the use of Varian XL-200 and Bruker AMX-400
WB spectrometers.
22. Angeli, P.; Brasili, L.; Gulini, U.; Marucci, G.; Paparelli, F.
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