Synthesis and evaluation of phenylcarbamate derivatives as ligands for nicotinic acetylcholine receptors

Article abstract of DOI:10.1016/j.bmc.2004.06.041

Phenylcarbamate derivatives were synthesized and evaluated in radioligand binding assays for different nicotinic acetylcholine receptor (nAChR) subtypes. Carbamate derivatives bearing a pyrrolidine or piperidine moiety 8-20 exhibited much lower affinity f

Full text of DOI:10.1016/j.bmc.2004.06.041

Bioorganic & Medicinal Chemistry 12(2004) 4953–4962
Synthesis and evaluation of phenylcarbamate derivatives as
ligands for nicotinic acetylcholine receptors
Daniela Gundisch,* Matthias Andra¨, Lenka Munoz and Maria Cristina Tilotta
¨
Department of Pharmaceutical Chemistry, Rhein. Friedr.-Wilhelm-University, Kreuzbergweg 26, D-53115 Bonn, Germany
Received 16 January 2004; accepted 28 June 2004
Available online 27 July 2004
Abstract—Phenylcarbamate derivatives were synthesized and evaluated in radioligand binding assays for different nicotinic acetyl-
choline receptor (nAChR) subtypes. Carbamate derivatives bearing a pyrrolidine or piperidine moiety 8–20 exhibited much lower
affinity for a7 nAChR than the analogues in the quinuclidine series 21–25, although the same structural elements are present. Fur-
*
thermore, in contrast to the quinuclidine analogues 21–25, all (S)-pyrrolidine derivatives 8–12 and the piperidine analogues 15 and
16 exhibited higher affinities for a4b2 nAChR.
*
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the past, acetylcholine and moreover choline have at-
tracted limited interest as lead compounds.8–12 The
structure of choline can be found in a variety of com-
pounds displaying multifarious pharmacological effects,
for example, in drugs with antihistaminic and analgesic
properties like diphenhydramine and nefopam, respec-
tively, which even display affinities in the micromolar
range for neuronal nAChRs.13 Aryl ether analogues of
choline are known as inhibitors of amine oxidase,14,15
and are also described as compounds with antibacterial,
cholesterol level lowering, and germicidal properties.16
Mono- and poly-substituted pyridyl ether analogues of
choline were patented for the use as pesticides.17 Very
recently, Simsek and co-workers18 showed that several
3-pyridyl ether analogues of choline displayed nanomo-
lar affinities for [3H](-)nicotine sensitive binding sites
and antinociceptive properties. Similar analogues of
choline, where the amine function is incorporated in a
Acetylcholine (ACh) is interacting with two major re-
ceptor classes, which can be subdivided into G-protein
coupled receptors (muscarinic receptors, mAChRs)
and ligand-gated ion channels (nicotinic receptors,
nAChRs). Over the past years, neuronal nicotinic acetyl-
choline receptors are subject of increasing interest being
involved in various physiological and pathophysiologi-
cal processes related to cognition and learning.1–3 Fur-
ther on, several nACh receptor subtypes exist in
peripheral neurons of autonomic and sensory ganglia,
and evidence exists for expression of nAChRs in other
tissues and cell types, including lymphocytes, fibro-
blasts, pulmonary neuroendocrine cells, spermatozoa,
keratinocytes, granulocytes, chondrocytes, placenta,
and several sensory organs.4–6 The search and develop-
ment of ligands for nAChRs were mostly focused on
selectivity for a4b2, the most abundant subtype in the
CNS. The interest is now growing to develop ligands
for a7 and a3-containing subtypes, which are addition-
ally implicated in different diseases of the PNS. Re-
cently, choline, the metabolite of ACh, has been
described as a selective activator of a7-type nAChRs in-
volved in neuroprotective activity despite its very low
affinity for this receptor subtype (Ki =2380lM).7 In
cyclic carbon skeleton are one of the most potent ligands
19
for a4b2nAChR.
Extending choline with an amide
moiety to obtain the carbamate function leads to carba-
choline, a known muscarinic ligand, whereas the N-
methylated analogues MCC and DMCC analogues have
been described as nicotinic ACh agonists.20,21 Carba-
mates, especially phenylcarbamate derivatives are
known as compounds exhibiting a broad pharmacolog-
ical spectrum, for example, interactions with muscarinic
and 5-HT3 receptors,22,23 local anaesthetic,24,25 spasmo-
lytic,26 and analgetic27 properties, and very recently
selective interaction with the a7 subtype of nicotinic
acetylcholine receptors (nAChRs).28,29
Keywords: Phenylcarbamate; Nicotinic acetylcholine receptor; Epibat-
idine; MLA (methyllycaconitine).
*
Corresponding author. Tel.: +49-228-73-2360; fax: +49-228-73-
2567; e-mail: d.guendisch@uni-bonn.de
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.06.041

4954
D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
In the course of our investigations, we prepared and eval-
uated known and novel carbamate derivatives to get more
insight into structural requirements for nAChRs, espe-
cially for the a7 nAChR. Firstly, we examined the nAChR
binding profile of the phenylether of choline 1 (Scheme 1),
which has been shown as a powerful ganglion stimulant
by Hunt and Renshaw in 1929.30 Starting from 1, we were
interested to evaluate the binding affinities for several
nAChR subtypes observed after the introduction of a car-
bamate functionality in 1 and related derivatives includ-
ing their azacyclic analogues (Scheme 1). Since it is
known that ortho and para substitutions at the phenyl
moiety in phenylcarbamate derivatives are strongly
enhancing the affinity for mAChRs,21,22 and the ortho
substitution is also favored for local anaesthetic proper-
ties,23,24 the meta position of the phenyl moiety was cho-
sen for further substitutions (Scheme 1).
perature with the exception of derivatives bearing a 3-
bromo- or 3-methyl-phenyl (10, 11, 15, 16, 23, 24) moi-
ety for which we found reduced yields and increased by-
products at reflux temperature. Therefore, these com-
pounds were synthesized at max. 50°C. The addition
of a basic catalyst, for example, triethylamine, which is
commonly used for the preparation of carbamate deriv-
atives, did not positively influence the yield of the de-
sired products. The derivatives 2 and 5 (DMAE und
TMAE phenylcarbamates) were already synthesized by
Abood et al.32 using toluene and a 16h refluxing period,
but were not analytically characterized in detail. The
prepared azabicyclic carbamate derivative 23, also men-
tioned as a ligand for a7 nAChR in a patent of Astra
Laboratories,28 was used for additional phenyl or styryl
substitution at the phenyl moiety (26, 27). Thus, com-
pounds 26 and 27 were prepared by the Suzuki coupling
reaction under microwave33 accelerated conditions in
moderate yields, demonstrating a high stability of the
azabicyclic carbamate derivatives (26, 27) during reac-
tion (Scheme 2). In contrast to our fast Suzuki method,
the biphenyl analogue 26 was synthesized by Naito
et al.22 and Astra Laboratories28 using biphenyl isocya-
nate, which was obtained by the addition of phosgene28
or DPPA22 (diphenylphosphoryl azide) and triethyl-
amine to 3-aminobiphenyl or biphenyl-3-carboxylic
acid, respectively.
2. Results and discussion
2.1. Chemistry
The phenylether of choline 1 was prepared according to
the method of Renshaw and Armstrong.31 The syntheses
of the phenylcarbamate derivatives 2–25 including the
compounds with different azacyclic cores were carried
out under a variety of conditions with regard to the sol-
vent, temperature, and the presence of a catalyst. In
summary, equimolar amounts of amino alcohols and
the appropriate phenylisocyanate in dry toluene were
stirred for 1.5–4h under argon atmosphere (Scheme 2)
to obtain the phenylcarbamate derivatives 2–25 in high
yields. The reactions were performed under reflux tem-
The carbamate derivatives 2–27 were purified by column
chromatography on silica gel. Quaternary salts were
prepared by adding methyliodide to the appropriate
compounds in acetone and purified by precipitating
them out. Compounds 2–27 were stable under binding
assay conditions using a HEPES salt solution (pH7.4).
R
N+
H C
H
H3C3
O
O
H3C
N
N+
Br
CH3
O
CH3
1
2-7
X
R = H, CH3
X = H, F, CF3
H
H
N
O
N
O
N
N
H3C
O
CH3
O
13-17
X = H, F, Br, CH3, CF3
8-12
X = H, F, Br, CH3, CF3
X
X
H
H
O
N
O
N
N
O
O
N
X
CH3
X
18-20
X = H, F, CF3
21-27
X = H, F, Br, CH3, CF3, Ph, styryl
Scheme 1.

D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
4955
H
O
C
N
O
N
toluene
A'
A
+
O
50-120°C
1.5-4h
X
X
X = H, F, Br, CH3, CF3
2-25
R2
OH
H3C
OH
A =
N
OH
N
N
R1
N
CH3
H3C
CH3
32
29
28
30: R1 = CH2OH, R2 = H
31: R1 = H, R2 = OH
Phenylboronic acid,
Pd(PPh3)4, toluene, Na2CO3
1. 22-120°C, 100 W
2. 120°C, 10 min, 60 W
H
N
O
N
O
H
N
O
Br
26
N
O
H
N
23
O
Styrylboronic acid,
Pd(PPh3)4, toluene, Na2CO3
N
O
1. 22-120°C, 60 W
2. 120°C, 10 min, 60 W
27
Scheme 2.
2.2. In vitro receptor binding
cally reduced affinities for nAChRs examined, an effect
frequently observed for nAChR ligands. Compounds
8–27 synthesized with the intention of a penetration
through the blood–brain barrier and to study the influ-
ence of the azacyclic core, exhibited different binding
profiles for diverse nAChR subtypes (Table 1). N-
Methyl-pyrrolidine derivatives 8–12 showed Ki values
in the higher nanomolar to lower micromolar range
Previously described receptor binding assays13,34–36 were
used to evaluate the prepared compounds 1–27 for their
abilities to compete for [3H]epibatidine and [3H]MLA
binding sites in rat forebrain (a4b2 , a7 ), pig adrenals
*
*
(a3b4 ) and Torpedo californica electroplax ((a1) b1cd)
*
2
membrane fractions (Table 1). The phenylether of cho-
line 1, evaluated for different nAChRs for the first time,
showed nanomolar affinities for neuronal nAChR sub-
types with a preference for a4b2 (Table 1). Compound
1 was transformed into an a7 nAChR selective com-
pound with nanomolar affinity when converting it to
the corresponding carbamate analogue 5. Abood and
coworkers32 have reported the ability of 2 and 5 to inhi-
bit the specific binding of [3H]nicotine and [3H]methyl-
carbamylcholine in rat brain membranes at milli- (for
2) and micromolar (for 5) concentrations, but no results
were obtained for other nAChR subtypes. Fluorine sub-
stitution at position 3 of the phenyl moiety led to a car-
bamate derivative 6 with slightly reduced affinities for
for a4b2 and lower affinity for the a7 subtype
*
*
(Table 1), which subtype selectivity is contrary to the
quaternary ammonium compounds 5–7. Despite of the
carbamate moiety, compounds 8–12 showed still the
subtype profile with affinities in the rank order of
a4b2*>a3b4*>a7*, which is mostly found for hitherto
existing nAChR ligands. Comparing with their S-confi-
gurated 2-(aryloxymethyl)pyrrolidine counterparts,37
which exhibit Ki values in the lower nanomolar range
*
*
for a4b2 , 8 and 9 showed a ca. 10- and 100-fold, respec-
*
tively, decreased affinity for a4b2 nAChR. SAR studies
*
within the N-methyl-piperidine series 13–20 explored the
effect of aromatic substitution and the position of the
phenylcarbamate moiety at the piperidine ring. Com-
pounds 18–20 showed a preference for a7 nAChR with
*
Ki values in the low micromolar range (Table 1) and no
a4b2 and a7 nAChR, but equal subtype selectivity
*
*
like 5, whereas the introduction of a trifluoromethyl
group enhanced the affinity and subtype selectivity for
a7 nAChR. In contrast to the quaternary derivatives
effect at a4b2 nAChR, whereas 13–17, displayed a
*
complex pattern of subtype selectivity. Analogues with
*
5–7, the tertiary amine analogues 2–4 showed dramati-

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D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
fluorine and trifluoromethyl substituents (14, 17) dem-
onstrated poor receptor binding affinities. Surprisingly,
the unsubstituted compound 13 was found to show
dine analogues 21–25, displayed highest affinities and
subtype selectivity for a7 . Surprisingly, all (S)-pyrrol-
*
idine derivatives 8–12 and the piperidine analogues 15
selectivity towards a3b4 . Only 15 and 16 being the
and 16 exhibited higher affinities and subtype selectivity
for a4b2 nAChR. The position of the phenylcarbamate
*
most potent analogues in the piperidine series for
*
moiety at the piperidine ring within the N-methyl-piper-
idine series 13–20 influenced the subtype selectivity
a4b2 nAChR gave a similar subtype profile like their
*
pyrrolidine analogues 8–12. The quinuclidine analogues
21 and 26, already developed for SAR studies on mu-
scarinic receptors22 and also claimed together with 22–
24 as a7 selective compounds in a patent of Astra
Laboratories28 were examined for different nAChR
subtypes. Like the phenylcarbamate derivatives 5–7
compounds 21–25 exhibit remarkable selectivity for
towards a7 and a3b4 nAChRs. The difference in sub-
*
*
type selectivity among the phenylcarbamate derivatives
could be discussed on the basis of the spatial distance
of the nitrogen and oxygen of the choline substructure
incorporated.
a7 versus a4b2 . Bulkier groups at the phenyl moiety
*
*
reduce affinity for a7 and subtype selectivity, which
4. Experimental
*
can be strongly observed in the styryl analogue 27. It
is interesting that carbamate derivatives bearing a pyrr-
olidine or piperidine moiety 8–20 possess much lower
4.1. General procedures
affinity for a7 nAChR than the analogues in the quinu-
Each starting material was obtained from commercial
suppliers with the exception of styrylboronic acid, which
was synthesized according to Brown and Gupta.38
Standard vacuum techniques (argon atmosphere) were
used in handling of air sensitive materials. Melting
*
clidine series 21–25, although the same structural ele-
ments are present, like a basic nitrogen, which can be
protonated providing a cationic center, a carbamate
moiety, and a p-electron system. Furthermore, in con-
trast to the quinuclidine analogues 21–25, all (S)-pyrrol-
idine derivatives 8–12 and the piperidine analogues 15
points were determined on a Buchi Melting Point B-
¨
545 and are uncorrected. Solvents were dried and freshly
distilled before use according to literature procedures.
IR spectra were obtained on a Perkin–Elmer 1310 IR
spectrometer; liquids were run as films, solids as KBr
and 16 exhibited higher affinities for a4b2 nAChR. It
*
seems that the carbamate moiety together with a certain
spatial distance between the oxygen and the nitrogen of
the choline fragment in these derivatives, are crucial for
1
pellets. H NMR and 13C NMR were recorded on a
the interaction with the a7 nAChR. The favorite dis-
Bruker DRX 500 at 298K. Chemical shifts (d) are re-
ported in ppm (J values in Hz) and are referenced to
the solvent (1H NMR: d/ppm=7.24 for chloroform,
2.49 for dimethylsulfoxid, 3.35, 4.78 for methanol; 13C
NMR: d/ppm=77.0 for chloroform, 39.7 for dimethyl-
sulfoxid, 49.3 for methanol). Mass spectra were meas-
ured with a MS-50 (Kratos) or MAT 95 (Thermo
Quest). Column chromatography was carried out on
Merck silica gel 60 (flash chromatography). Reactions
were monitored by thin-layer chromatography (TLC)
*
tance between the choline oxygen and nitrogen can
probably be fulfilled in the azabicyclic core of, for exam-
ple, the quinuclidine moiety or the acyclic variant. We
also investigated the binding affinities for the a3b4 sub-
*
type. Table 1 reveals that with exception of 23 all phe-
nylcarbamate derivatives examined show Ki values in
the micromolar range for the ganglionic subtype. Com-
pared with the pyrrolidine and piperidine series a higher
affinity for a3b4 is observed for the quinuclidine deriv-
*
atives 21–26. As indicated in Table 1, the 3-bromophe-
nyl carbamate derivatives 10, 15, 23 showed the most
interesting binding profiles. Within the bromo ana-
logues, 23 is the most potent compound for a7 with a
*
Ki value of 273nM, whereas the (S)-pyrrolidine ana-
by using plates of silica gel Merck silicagel-60F254.
Elemental microanalyses were performed internally.
Microwave irradiation was carried out using the
CEM-Discover microwave synthesis system (CEM
GmbH, Kamp-Lintfort, Germany).
logue 10 showed the highest affinity for a4b2
(Ki =526nM), both compounds displaying contrary pro-
*
4.2. General procedure for the preparation of phenyl-
carbamates 2–4, 8–25
files of subtype selectivity. The highest affinity for a3b4
*
nAChR was also obtained for 23, whereas 10 and 15
exhibited similar, but a ca. 9-fold lower affinity for the
ganglionic subtype. None of the phenylcarbamate deriv-
atives examined showed activity for the muscle type
nAChR. Interestingly, 3-quinuclidinole, the compound
used for the synthesis of 21–25 and which can be consi-
dered as a rigid choline derivative, displayed Ki values in
the mircomolar range for different neuronal nAChRs
Equimolar amounts of the amino alcohols 28–32 and
appropriate phenylisocyanate were stirred in toluene
(10mL) under argon atmosphere at 50–120°C for 1.5–
4h. The solvent was evaporated and the resulting oily
residue was purified by flash chromatography on a small
amount of silica gel (max. 50g) eluting with CH2Cl2/
MeOH (95:5).
with similar affinities for a4b2 and a7 nAChRs.
*
*
4.2.1. Trimethyl-(2-phenoxy-ethyl)-ammonium bromide
(1). (2-Bromo-ethoxy)-benzene (771.0mg, 3.8mmol)
and trimethylamine (0.08mL, 3.7mmol) in toluene
(2.5mL) were condensed in a pressure bottle and al-
lowed to stand 48h. Then the mixture was heated to
50°C for 1h. The crude product was separated and crys-
tallized from ethanol to give the bromide salt (756.6mg,
3. Conclusion
We demonstrated that phenylcarbamate derivatives led
to compounds with different subtype selectivity for
nAChRs. Compounds 5–7, together with their quinucli-

D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
4957
Table 1. Radioligand binding affinities of compounds 1–27, 3-quinuclidinole 32, epibatidine and nicotine for different nAChR subtypes
Compd
(Ster.)
R
X
[3H]epibatidine
a4b2*, rat brain
Ki (nM) ( SEM)a
[3H]MLA
[3H]epibatidine
[3H]epibatidine
a7*, rat brain
a3b4*, pig adrenal
(a1)2b1c d, Torpedo calif.
Ki (nM) ( SEM)a
Ki (nM) ( SEM)a
Ki (nM) ( SEM)a
1
22.3 (4.3)
>20,000
>20,000
196 (9.19)
12,836 (2,762)
11,000b
>20,000
38.9 (2.9)
62(5)
135 (11)
n.d.
697 (22)
n.d.
2
H
H
3
H
F
23,157b
n.d.
>20,000
n.d.
>20,000
4
H
CF3
H
>20,000
5
CH3
CH3
CH3
835 (0.7)
1412(17)
6000 (23)
1100 (223)
1633 (62)
526 (19)
1248 (126)
1050 (103)
>20,000
2200 (45)
2500 (35)
3800 (120)
2582 (211)
13,443b
6146 (294)
6000b
7790b
6100b
11,392b
6357b
14,392b
>20,000
23,712b
6963b
17,303b
1627 (123)
1581 (22)
715 (33)
1478 (78)
1200 (66)
1448 (66)
5976b
6
F
n.d.
7
8 (S)
CF3
H
29 (3)
5853b
>20,000
>20,000
>20,000
n.d.
9 (S)
F
Br
15,000b
10,810b
14,108b
13,000b
15,000b
22,000b
27,000b
31,800b
13,000b
3600 (230)
2600 (155)
4400 (167)
44 (2.3)
37.3 (5)
273 (25)
321 (3.5)
173 (23)
1135 (431)
6100b
10 (S)
11 (S)
12 (S)
13 (RS)
14 (RS)
15 (RS)
16 (RS)
17 (RS)
18 (RS)
19 (RS)
20 (RS)
21 (RS)
22 (RS)
23 (RS)
24 (RS)
25 (RS)
26 (RS)
27 (RS)
32 (RS)
(ꢀ)-epibatidine
(ꢀ)-nicotine
CH3
CF3
H
n.d.
>20,000
>20,000
>20,000
n.d.
F
Br
>20,000
3770 (79)
175 (12)
>20,000
CH3
CF3
H
>20,000
>20,000
>20,000
>20,000
>20,000
>20,000
>20,000
n.d.
>20,000
>20,000
>20,000
F
CF3
H
3084 (132)
4203 (98)
2988 (66)
2695 (90)
1718 (67)
7772b
F
Br
CH3
CF3
Ph
styryl
n.d.
>20,000
n.d.
n.d.
5350b
5924 (642)
0.008 (0.001)
0.84 (0.13)
7761b
14,604b
0.05 (0.003)
73.4 (10.1)
n.d.
2.0 (0.1)
n.d.
4 (0.3)
130 (15)
n.d.=not determined.
a Values are the mean from at least n=3 to 5 independent assays.
b Values are the mean from n=2.
* Naturally expressed nAChRs.
2.9mmol, 78.0%). Mp: 167–169°C. IR (KBr) 3014,
general method with 2-dimethyl-ethanol 28 (1.0mL,
10mmol) and m-fluoro-phenylisocyanate (1.08mL,
10mmol). The product was obtained as yellowish oil
(1341.0mg, 5.9mmol, 63.2%), which crystallized on
standing. Mp: 55–56°C. IR (KBr) 2957, 2823, 2776,
2934, 1600, 1586, 1480cmꢀ1 1H NMR (500MHz,
.
DMSO-d6) d 7.32(t, J=7.3Hz, 2H), 7.00 (m, 3H),
4.45 (m, 2H), 3.29 (m, 2H), 3.19 (s, 9H). 13C NMR
(125MHz, DMSO-d6) d 157.51, 129.70, 121.50, 114.85,
64.28, 61.65, 53.30. MS (EI) m/z (%)=180.0 (100)
[M+]. Anal. Calcd for C11H18NOBr (260.17): C, 50.78;
H, 6.97; N, 5.38. Found: C, 50.67; H, 6.94; N, 5.37.
1732, 1607, 1557cmꢀ1 1H NMR (500MHz, DMSO-
.
d6) d 9.98 (s, 1H), 7.38 (dt, J=12Hz, J=2.2Hz, 1H),
7.29 (dt, J=6.9Hz, J=8.2Hz, 1H), 7.23 (d, J=7.6Hz,
1H), 6.79 (dt, J=2.3Hz, J=8.1Hz, 1H), 4.16 (m, 2H),
2.52 (m, 2H), 2.17 (s, 6H). 13C NMR (125MHz, CDCl3)
d 162.47 (d, J=239.6Hz), 153.54, 141.26 (d, J=11.2Hz),
130.45 (d, J=9.4Hz), 114.07 (d, J=2.0Hz), 108.80 (d,
J=20.8Hz), 104.95 (d, J=26.26Hz), 62.13, 57.69,
45.38. MS (EI) m/z (%)=226.9 (100) [M+]. Anal. Calcd
for C11H15FN2O2 (226.25): C, 58.40; H, 6.68; N,
12.38. Found: C, 57.92; H, 6.82; N, 12.31.
4.2.2. Phenyl-carbamic acid 2-dimethylamino-ethyl ester
(2). The synthesis was done according to the general
method with 2-dimethylamino-ethanol 28 (0.24mL,
2.4mmol) and phenylisocyanate (0.26mL, 2.4mmol).
The final product was obtained as yellowish oil
(200.6mg, 1.0mmol, 40.0%), which crystallized on
standing. Mp: 163–165°C. IR (KBr) 3223, 3110, 3044,
1728, 1596, 1545, 1442cmꢀ1 1H NMR (500MHz,
.
DMSO-d6) d 9.90 (s, 1H), 7.48 (d, J=7.9Hz, 2H), 7.29
(t, J=7.6Hz, 2H), 6.96 (t, J=7.4Hz, 1H), 4.53 (m,
2H), 3.85 (m, 2H), 3.27 (s, 6H). 13C NMR (125MHz,
DMSO-d6) 152.64, 138.89, 128.92, 122.88, 118.54,
69.52, 61.60, 57.69, 49.64. MS (EI) m/z (%)=209.30
(100) [M+H]+.
4.2.4. (3-Trifluoromethyl-phenyl)-carbamic acid 2-dimeth-
ylamino-ethyl ester (4). The synthesis was done accord-
ing to the general method with 2-dimethyl-ethanol 28
(1.0mL, 10mmol) and m-trifluoromethyl-phenylisocya-
nate (1.40mL, 10mmol). The final product was
obtained as yellowish oil (2245.4mg, 8.1mmol, 61.0%),
which crystallized on standing. Mp: 75–78°C. IR
4.2.3. (3-Fluoro-phenyl)-carbamic acid 2-dimethylamino-
ethyl ester (3). The synthesis was done according to the
(KBr) 2958, 2825, 2777, 1733, 1608, 1559cmꢀ1 1H
.
NMR (500MHz, DMSO-d6) d 9.87 (s, 1H), 7.38 (dt,

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D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
J=2.2Hz, J=11.7Hz, 1H), 7.28 (dt, J=6.7, J=8.1Hz,
1H), 7.22 (d, J=8.2Hz, 1H), 6.78 (dt, J=2.2Hz,
J=8,1Hz, 1H), 4.15 (m, 2H), 2.50 (m, 2H), 2.18 (s,
6H). 13C NMR (125MHz, CDCl3) d 153.53, 141.21,
130.42, 129.72 (q, J=31.5Hz), 124.21 (q, J=270.9Hz),
123.13, 120.62, 119.24 (q, J=3.49Hz), 62.12, 57.69,
45.37. MS (EI) m/z (%)=277.4 (100) [M+H]+. Anal.
Calcd for C12H15F3N2O2 (276.26): C, 52.17; H, 5.47;
N, 10.14. Found: C, 51.71; H, 5.81; N, 9.44.
d 152.79, 139.78, 130.27, 129.72 (q, J=31.5Hz), 124.21
(q, J=270.9Hz), 123.13, 120.62, 119.24 (q, J=
3.49Hz), 114.45, 64.18, 58.45, 53.22. MS (EI) m/z
(%)=291.3 (100) [M+]. Anal. Calcd for C13H18F3N2O2I
(418.20): C, 37.34; H, 4.34; N, 6.70. Found: C, 37.35; H,
4.39; N, 6.73.
4.2.8. Phenyl-carbamic acid (S)-1-methyl-pyrrolidin-2-
ylmethyl ester (8). The synthesis was done according to
the general method with (S)-(ꢀ)-1-methyl-2-pyrrolidi-
nylmethanol 29 (0.25mL, 2.1mmol) and phenylisocya-
nate (0.2mL, 2.1mmol). The final product was
obtained as colorless oil (345.8mg, 1.48mmol, 69%).
4.2.5. Trimethyl-(2-phenylcarbamoyloxy-ethyl)-ammo-
nium iodide (5). Phenyl-carbamic acid 2-dimethylami-
no-ethyl ester 2 (150mg, 7.2mmol) and methyl iodide
(0.06mL, 9.3mmol) were stirred in acetone (3.5mL)
under argon atmosphere at room temperature for 12h.
The crude product was filtered, washed twice with
diethyl ether (5mL) and dried to give a white crystalline
solid (121.5mg, 3.6mmol, 48.2%). Mp: 132–133°C. IR
1
IR (film): 2954, 2789, 1716, 1600, 1531cmꢀ1. H NMR
(500MHz, DMSO-d6) d 9.58 (s, 1H), 7.45 (d, J=
8.0Hz, 2H), 7.26 (t, J=7.4Hz, 2H), 6.97 (t, J=7.4Hz,
1H), 4.06 (dd, J=4.9Hz, J=10.9Hz, 1H), 3.98 (dd,
J=5.7Hz, J=11.0Hz, 1H), 2.90–2.97 (m, 1H), 2.38–
2.46 (m, 1H), 2.31 (s, 3H), 2.12–2.20 (m, 1H), 1.84–
1.92 (m, 1H), 1.62–1.69 (m, 2H), 1.53–1.60 (m, 1H).
13C NMR (125MHz, DMSO-d6) d 153.70, 139.33,
128.8, 122.43, 118.36, 66.25, 63.70, 57.06, 41.19, 28.24,
22.56. MS (EI) m/z (%)=235.3 (100) [M+H]+. Anal.
Calcd for C13H18N2O2 (234.30): C, 64.64; H, 7.74; N,
11.96. Found: C, 63.23; H, 7.73; N, 11.550.
(KBr) 3121, 2970, 2770, 1741, 1595, 1537, 1441cmꢀ1
.
1H NMR (500MHz, DMSO-d6): 9.70 (s, 1H), 7.46 (d,
J=7.9Hz, 2H), 7.29 (t, J=7.3Hz, 2H), 7.01 (t, J=
7.4Hz, 1H), 4.52 (m, 2H), 3.68 (m, 2H), 3.16 (s, 9H).
13C NMR (125MHz, DMSO-d6) d 152.76, 138.82,
128.94, 122.92, 118.53, 64.28, 58.08, 53.25. MS (EI)
m/z (%)=223.2 (100) [M+]. Anal. Calcd for
C12H19N2O2I (350.20): C, 41.16; H, 5.47; N, 8.00.
Found: C, 41.18; H, 5.47; N, 7.96.
4.2.9. (3-Fluoro-phenyl)-carbamic acid (S)-1-methyl-pyrr-
olidin-2-ylmethyl ester (9). The synthesis was done
according to the general method with (S)-(ꢀ)-1-
methyl-2-pyrrolidinylmethanol 29 (0.24mL, 2mmol)
and m-fluoro-phenylisocyanate (0.23mL, 2mmol). The
final product was obtained as colorless oil (386.6mg,
1.53mmol, 77.4%). IR (film): 2957, 2793, 1718, 1609,
4.2.6. Trimethyl-[2-(3-Fluoro-phenylcarbamoyloxy)-eth-
yl]-ammonium iodide (6). (3-Fluoro-phenyl)-carbamic
acid 2-dimethylamino-ethyl ester 3 (111.2mg, 5.0mmol)
and methyl iodide (0.08mL, 6.5mmol) were stirred in
acetone (5mL) under argon atmosphere at room tem-
perature for 12h. The crude product was filtered,
washed twice with diethyl ether (5mL) and dried to yield
a white crystalline solid (179.2mg, 4.8mmol, 99.0%).
Mp: 113°C. IR (KBr) 3220, 3060, 3010, 2900, 1740,
1
1540cmꢀ1. H NMR (500MHz, CDCl3) d 9.83 (s, 1H),
7.38 (d, J=12Hz, 1H), 7.25–7.32 (m, 1H), 7.22 (d,
J=8.2Hz, 1H), 6.78 (t, J=8.2Hz, 1H), 4.08 (dd,
J=4.9Hz, J=10.9Hz, 1H), 3.98 (dd, J=5.7Hz,
J=11.0Hz, 1H), 2.88–2.97 (m, 1H), 2.38–2.45 (m, 1H),
2.32 (s, 3H), 2.11–2.19 (m, 1H), 1.84–1.93 (m, 1H),
1.62–1.72 (m, 2H), 1.52–1.60 (m, 1H), 13C NMR
(125MHz, CDCl3) d 162.45 (d, J=239.3Hz), 153.59,
141.24 (d, J=11.0Hz), 130.46 (d, J=9.72Hz), 114.11,
108.83 (d, J=20.95Hz), 104.98 (d, J=26.68Hz), 66.38,
63.63, 57.03, 41.15, 28.18, 22.56. MS (EI) m/z
(%)=253.3 (100) [M+H+]. Anal. Calcd for
C13H17FN2O2 (252.29): C, 61.89; H, 6.79; N, 11.10.
Found: C, 60.24; H, 6.74; N, 10.91.
1595, 1530, 1471cmꢀ1 1H NMR (500MHz, DMSO-
.
d6): 9.94 (s, 1H), 7.39 (d, J=11.7Hz, 1H), 7.33 (dt,
J=6.9Hz, J=8.2Hz, 1H), 7.22 (d, J=8.2Hz, 1H), 6.84
(dt, J=2.1Hz, J=8.5Hz), 4.53 (m, 2H), 3.69 (m, 2H),
3.16 (s, 9H). 13C NMR (125MHz, DMSO-d6) d 162.43
(d, J=241.3Hz), 152.67, 140.75 (d, J=11.2Hz), 130.65
(d, J=9.72Hz), 114.31, 109.99 (d, J=20.95Hz), 105.84
(d, J=23.44Hz), 64.30, 58.33, 53.23. MS (EI) m/z
(%)=241.2 (100) [M+]. Anal. Calcd for C12H18FN2O2I
(368.19): C, 39.15; H, 4.93; N, 7.61. Found: C, 39.19;
H, 4.89; N, 7.58.
4.2.10. (3-Bromo-phenyl)-carbamic acid (S)-1-methyl-
pyrrolidin-2-ylmethyl ester (10). The synthesis was done
according to the general method with (S)-(ꢀ)-1-
methyl-2-pyrrolidinylmethanol 29 (0.24mL, 2mmol)
and m-bromo-phenylisocyanate (0.25mL, 2mmol). The
final product was obtained as colorless oil (610mg,
1.94mmol, 97%), which crystallized on standing.
Mp: 49°C. n2D0 ¼ 1:3295. IR (KBr) 2942, 2857, 1714,
4.2.7. Trimethyl-[2-(3-trifluoromethyl-phenylcarbamoyl-
oxy)-ethyl]-ammonium iodide (7). (3-Trifluoromethyl-
phenyl)-carbamic acid 2-dimethylamino-ethyl ester 4
(131.5mg, 4.8mmol) and methyl iodide (0.08mL,
6.2mmol) were stirred in acetone (5mL) under argon
atmosphere at room temperature for 12h. The crude
product was filtered, washed twice with diethyl ether
(5mL) and dried to give a white crystalline solid
(173.5mg, 4.1mmol, 87.0%). Mp: 172–173°C. IR
(KBr) 3197, 3075, 3015, 2957, 1729, 1595, 1556,
1
1596cmꢀ1. H NMR (500MHz, CDCl3) d 7.62(s, 1H),
7.23 (s, 1H), 7.10–7.16 (m, 2H), 6.78 (s, 1H), 4.22 (dd,
J=4.4Hz, J=11.0Hz, 1H), 4.10 (dd, J=4.7Hz,
J=11.4Hz, 1H), 3.07 (dt, J=1.9Hz, J=7.9Hz, 1H),
2.42–2.47 (m, 1H), 2.39 (s, 3H), 2.20–2.25 (dt,
J=7.3Hz, J=9.5Hz, 1H), 1.82–1.93 (m, 1H), 1.63–
1.82(m, 3H). 13C NMR (125MHz, CDCl3) d 153.25,
1
1503cmꢀ1. H NMR (500MHz, DMSO-d6) d 10.07 (s,
1H), 7.91 (s, 1H), 7.69 (d, J=8.0Hz, 1H), 7.55 (t, J=
7.9Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 4.55 (m, 2H), 3.70
(m, 2H), 3.16 (s, 9H). 13C NMR (125MHz, DMSO-d6)

D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
4959
139.20, 130.26, 126.35, 122.73, 121.45, 117.0, 66.30,
64.12, 57.50, 41.15, 27.84, 22.68. MS (EI) m/z
(%)=312.1 (20) [M+], 314.0 (19) [M+2]. Anal. Calcd
for C13H17BrN2O2 (313.202): C, 49.85; H, 5.47; N,
8.94; found C, 49.01; H, 5.57; N, 8.54.
139.32, 128.81, 122.44, 118.33, 65.83, 62.37, 56.51,
43.26, 28.74, 25.35, 23.66. MS (EI) m/z (%)=249.4
(100) [M+H]+. Anal. Calcd for C14H20N2O2 (248.33):
C, 67.72; H, 8.12; N, 11.28. Found: C, 67.34; H, 8.33;
N, 10.48.
4.2.11. (3-Methyl-phenyl)-carbamic (S)-1-methyl-pyrroli-
din-2-ylmethyl ester (11). The synthesis was done accord-
ing to the general method with (S)-(ꢀ)-1-methyl-2-
pyrrolidinylmethanol 29 (0.24mL, 2mmol) and m-toly-
lisocyanate (0.26mL, 2mmol). The final product was
obtained as colorless oil (206mg, 0.83mmol, 42%).
Mp: 62°C. n2D0 ¼ 1:3295. IR (KBr) 3053, 2854, 2798,
4.2.14. (3-Fluoro-phenyl)-carbamic acid 1-methyl-piperi-
din-2-ylmethyl ester (14). The synthesis was done accord-
ing to the general method with 2-hydroxymethyl-N-
methylpiperidine 30 (0.25mL, 1.9mmol) and m-fluoro-
phenylisocyanate (0.21mL, 1.9mmol). The final product
was obtained as yellowish oil (499.4mg, 1.8mmol,
98.7%). IR (film) 2950, 2859, 2803, 2266, 1711, 1614,
1
1710, 1565cmꢀ1. H NMR (500MHz, CDCl3) d 7.21
1558, 1489, 1447cmꢀ1 1H NMR (500MHz, DMSO-
.
(s, 1H), 7.11–7.17 (m, 2H), 6.84 (d, J=6.9Hz, 1H),
6.67 (s, 1H), 4.22 (dd, J=4.4Hz, J=11.0Hz, 1H), 4.05
(dd, J=4.7Hz, J=11.4Hz, 1H), 3.08 (dt, J=1.9Hz,
J=8.2Hz, 1H), 2.43–2.48 (m, 1H), 2.40 (s, 3H), 2.30
(s, 3H), 2.20–2.26 (dt, J=7.6Hz, J=9.5Hz, 1H), 1.88–
1.93 (m, 1H), 1.64–1.81 (m, 3H). 13C NMR (125MHz,
CDCl3) d 153.54, 138.97, 137.77, 128.84, 124.21,
119.17, 115.64, 66.03, 64.23, 57.54, 41.16, 27.88, 22.68,
21.47. MS (EI) m/z (%)=248.1 (20) [M+]. Anal. Calcd
for C14H20N2O2 (248.33): C, 67.71; H, 8.05; N, 11.28.
Found: C, 67.21; H, 8.12; N, 10.65.
d6): d 9.86 (s, 1H), 7.39 (dt, J=2.1Hz, J=11.8Hz, 1H),
7.28 (dt, J=2.1Hz, J=8.2Hz, 1H), 7.22 (dd, J=2.1,
J=8.2Hz, 1H), 6.79 (dt, J=6.8, J=8.2Hz, 1H), 4.15
(dd, J=4.1Hz, J=11.4Hz, 1H), 4.09 (dd, J=4.9Hz,
J=11.4Hz, 1H), 2.71–2.78 (m, 1H), 2.22 (s, 3H), 2.03–
2.09 (m, 1H), 1.99 (dt, J=3.2, J=11.6, 1H), 1.61–1.71
(m, 2H), 1.48–1.55 (m, 1H), 1.39–1.47 (m, 1H), 1.29–
1.38 (m, 1H), 1.15–1.26 (m, 1H). 13C NMR (125MHz,
CDCl3) d 162.46 (d, J=240.9Hz), 153.59, 141.23 (d,
J=11.22Hz), 130.46 (d, J=9.47Hz), 114.11, 108.84 (d,
J=20.94), 104.98 (d, J=26.43), 66.04, 62.29, 56.49,
43.22, 28.71, 25.34, 23.67. MS (EI) m/z (%)=267.1
(100) [M+H]+. Anal. Calcd for C14H19FN2O2 (266.32):
C, 63.14; H, 7.19; N, 10.52. Found: C, 63.46; H, 7.22;
N, 10.62.
4.2.12. (3-Trifluoromethyl-phenyl)-carbamic acid (S)-1-
methyl-pyrrolidin-2-ylmethyl ester (12). The synthesis
was done according to the general method with (S)-
(ꢀ)-1-methyl-2-pyrrolidinylmethanol
29
(0.19mL,
1.7mmol) and m-trifluoromethyl-phenylisocyanate
(0.23mL, 1.7mmol). The final product was obtained as
colorless oil (382.0mg, 1.3mmol, 76.4%). IR (film):
4.2.15. (3-Bromo-phenyl)-carbamic acid 1-methyl-piperi-
din-2-ylmethyl ester (15). The synthesis was done accord-
ing to the general method with 2-hydroxymethyl-N-
methylpiperidine 30 (0.26mL, 2mmol) and m-bromo-
phenylisocyanate (0.25mL, 2mmol). The final product
was obtained as yellowish oil (555.2mg, 1.7mmol,
84.8%), which crystallized on standing. Mp: 67–68°C.
2956, 2794, 1715, 1604, 1552cmꢀ1
.
1H NMR
(500MHz, CDCl3) d 7.70 (s, 1H), 7.51 (d, J=8.2Hz,
1H), 7.39 (t, J=8.2Hz, 1H), 7.29 (d, J=7.9Hz, 1H),
6.89 (s, 1H), 4.23 (dd, J=4.3Hz, J=11.2Hz, 1H), 4.12
(dd, J=4.7Hz, J=11.1Hz, 1H), 3.06–3.11 (m, 1H),
2.43–2.49 (m, 1H), 2.40 (s, 3H), 2.20–2.29 (m, 1H),
1.89–1.97 (m, 1H), 1.72–1.84 (m, 1H), 1.64–1.71 (m,
1H). 13C NMR (125MHz, CDCl3) d 153.34, 138.48,
131.51 (q, J=32.4Hz), 129.55, 123.84 (q, J=272.5Hz),
121.50, 119.96 (q, J=3.8Hz), 115.25, 66.34, 64.15,
57.52, 41.14, 27.85, 22.69. MS (EI) m/z (%)=303.5
(100) [M+H]+. Anal. Calcd for C14H17F3N2O2
(302.30): C, 55.63; H, 5.67; N, 9.27. Found: C, 54.97;
H, 5.73; N, 9.38.
1
IR (KBr) 2936, 2856, 2794, 1729, 1705, 1533cmꢀ1. H
NMR (500MHz, CDCl3) d 7.66 (s, 1H), 7.26 (d,
J=7.8Hz, 1H), 7.12–7.20 (m, 2H), 7.04 (s, 1H), 4.28
(dd, J=3.8Hz, J=11.7Hz, 1H), 4.20 (dd, J=3.2Hz,
J=11.7Hz, 1H), 2.91 (d, J=11.7Hz, 1H), 2.35 (s, 3H),
2.06–2.12 (m, 2H), 1.76–1.80 (m, 1H), 1.51–1.68 (m,
4H), 1.25–1.35 (m, 1H). 13C NMR (125MHz, CDCl3)
d 153.25, 139.26, 130.24, 126.29, 122.73, 121.33,
116.89, 66.27, 62.83, 57.27, 43.02, 29.06, 25.60, 24.10.
MS (EI) m/z (%)=326.1 (10) [M+], 328.0 (9) [M+2].
Anal. Calcd for C14H19BrN2O2 (327.218): C, 51.39, H,
5.85, N, 8.56. Found: C, 50.81; H, 6.00; N, 8.12.
4.2.13. Phenyl-carbamic acid 1-methyl-piperidin-2-yl-
methyl ester (13). The synthesis was done according to
the general method with 2-hydroxymethyl-N-methylpi-
peridine 30 (0.26mL, 2.0mmol) and phenylisocyanate
(0.188mL, 2.0mmol). The final product was obtained
as yellowish oil (484.3mg, 1.9mmol, 96.8%). IR (film):
2939, 2857, 2805, 2266, 1938, 1711, 1601, 1556, 1500,
4.2.16. (3-Methyl-phenyl)-carbamic acid 1-methyl-piperi-
din-2-ylmethyl ester (16). The synthesis was done accord-
ing to the general method with 2-hydroxymethyl-N-
methylpiperidine 30 (0.26mL, 2mmol) and m-tolylisocy-
anate (0.26mL, 2mmol). The final product was obtained
as yellowish oil (210mg, 0.6mmol, 30%), which crystal-
lized on standing. Mp: 73–75°C. IR (KBr) 2937, 2852,
1
1444cmꢀ1. H NMR (500MHz, DMSO-d6): d 9.58 (s,
1H), 7.46 (d, J=7.5Hz, 2H), 7.25 (t, J=7.6Hz, 2H),
6.97 (t, J=7.4Hz, 1H), 4.14 (dd, J=4.1Hz, J=11.4Hz,
1H), 4.07 (dd, J=4.7Hz, J=11.4Hz, 1H), 2.71–2.78
(m, 1H), 2.22 (s, 3H), 2.03–2.09 (m, 1H), 2.00 (dt,
J=3.1, J=11.6, 1H), 1.61–1.71 (m, 2H), 1.49–1.55 (m,
1H), 1.40–1.48 (m, 1H), 1.29–1.39 (m, 1H), 1.16–1.26
(m, 1H). 13C NMR (125MHz, CDCl3): d 153.69,
1
2803, 1732cmꢀ1. H NMR (500MHz, CDCl3) d 7.23
(s, 1H), 7.15–7.19 (m, 2H), 6.87 (d, J=6.9Hz, 1H),
6.81 (s, 1H), 4.25 (dd, J=4.1Hz, J=11.7Hz, 1H), 4.23
(dd, J=3.2Hz, J=11.7Hz, 1H), 2.88–2.93 (m, 1H),
2.34 (s, 3H), 2.32 (s, 3H), 2.08–2.13 (m, 2H), 1.75–1.82
(m, 1H), 1.50–1.69 (m, 4H), 1.24–1.34 (m, 1H). 13C

4960
D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
NMR (125MHz, CDCl3) d 153.57, 138.98, 137.82,
128.86, 124.20, 119.13, 115.60, 66.25, 62.94, 57.38,
43.22, 29.21, 25.76, 24.18, 21.50. MS (EI) m/z
(%)=262.2 (38) [M+]. Anal. Calcd for C15H22N2O2
(262.353): C, 68.67; H, 8.45; N, 10.67. Found: C,
68.78; H, 8.47; N, 10.13.
46.43, 28.29, 21.88. MS (EI) m/z (%)=253.1 (100)
[M+H]+. Anal. Calcd for C13H18FN2O2 (252.29): C,
61.89; H, 6.79; N, 11.10. Found: C, 60.97; H, 6.81; N,
10.93.
4.2.20. (3-Trifluoromethyl-phenyl)-carbamic acid 1-
methyl-piperidin-3-yl ester (20). The synthesis was done
according to the general method with 3-hydroxy-1-
methylpiperidine 31 (0.2mL, 1.7mmol) and m-trifluoro-
methyl-phenylisocyanate (0.23mL, 1.7mmol). The final
product was obtained as yellowish oil (421.5mg,
1.4mmol, 84.5%). Mp: 112–114°C. IR (KBr) 2949,
4.2.17. (3-Trifluromethyl-phenyl)-carbamic acid 1-methyl-
piperidin-2-yl-methyl ester (17). The synthesis was done
according to the general method with 2-hydroxymeth-
yl-N-methylpiperidine 30 (0.20mL, 1.6mmol) and m-
trifluoromethyl-phenylisocyanate (0.22mL, 1.6mmol).
The final product was obtained as yellowish oil
(387.3mg, 1.2mmol, 77.5%). IR (film) 2939, 2860,
2862, 2796, 1725, 1601, 1551, 1445cmꢀ1 1H NMR
.
(500MHz, CDCl3) d 7.71 (s, 1H), 7.47 (d, J=8.2Hz,
1H), 7.37 (d, J=7. 9Hz, 1H), 7.27 (d, J=7.6Hz, 1H),
6.97 (s, 1H), 4.92–4.97 (m, 1H), 2.43–2.64 (m, 3H),
2.26 (s, 3H), 2.19–2.25 (m, 1H), 1.89 (s, 1H), 1.78–1.88
(m, 1H), 1.66–1.75 (s, 1H), 1.55–1.64 (m, 1H). 13C
NMR (125MHz, CDCl3) d 152.76, 138.60, 131.49 (q,
J=32.4Hz), 129.51, 123.86 (q, J=272.5Hz), 119.83 (q,
J=3.82Hz), 115.11, 70.26, 59.13, 55.39, 46.45, 28.32,
21.88. MS (EI) m/z (%)=303.5 (100) [M+]. Anal. Calcd
for C13H18F3N2O2 (302.30): C, 55.63; H, 5.67; N, 9.27.
Found: C, 55.09; H, 5.68; N, 9.23.
1713, 1604, 1557, 1489, 1450cmꢀ1 1H NMR (500
.
MHz, DMSO-d6) d 10.00 (s, 1H), 7.92(s, 1H), 7.68 (d,
J=7.9Hz, 1H), 7.50 (t, J=7.9Hz, 1H), 7.31 (d, J=
7.9Hz, 1H), 4.17 (dd, J=4.1Hz, J=11.4Hz, 1H), 4.12
(dd, J=4.7Hz, J=11.4Hz, 1H), 2.71–2.78 (m, 1H),
2.21 (s, 3H), 2.04–2.10 (m, 1H), 2.00 (dt, J=3.1, J=
11.6, 1H), 1.61–1.71 (m, 2H), 1.48–1.55 (m, 1H), 1.40–
1.47 (m, 1H), 1.30–1.39 (m, 1H), 1.16–1.27 (m, 1H).
13C NMR (125MHz, CDCl3) d 153.70, 140.21, 129.67
(q, J=31.6Hz), 124.27 (q, J=272.3Hz), 121.89, 118.77
(q, J=3.9Hz), 114. 24, 66.16, 62.27, 56.49, 43.23,
28.71, 25.34, 23.67. MS (EI) m/z (%)=316.0 (100)
[M+]. Anal. Calcd for C15H19F3N2O2 (316.33): C,
56.96; H, 6.05; N, 8.86. Found: C, 56.43; H, 6.47; N,
8.37.
4.2.21. Phenyl-carbamic acid 1-aza-bicyclo[2.2.2.]oct-3-yl
ester (21). The synthesis was done according to the gen-
eral method with 3-quinuclidinole 32 (258mg, 2mmol)
and phenylisocyanate (0.19mL, 2mmol). The solid was
crystallized from diethyl ether. The final product was
obtained as white crystals (228.3mg, 0.9mmol, 46%).
Mp: 120°C. IR (KBr) 2947, 2870, 1725, 1600,
4.2.18. Phenyl-carbamic acid 1-methyl-piperidin-3-yl
ester (18). The synthesis was done according to the gen-
eral method with 3-hydroxy-1-methylpiperidine 31
(0.25mL, 2.1mmol) and phenylisocyanate (0.23mL,
2.1mmol). The final product was obtained as yellowish
oil (413.3mg, 1.8mmol, 82.6%). IR (film): 2943, 2790,
1548cmꢀ1 1H NMR (500MHz, CDCl3) d 7.37 (d,
.
J=7.6Hz, 2H), 7.28 (t, J =7.9Hz, 2H), 7.04 (t,
J=7.4Hz, 1H), 6.87 (s, 1H), 4.80–4.85 (m, 1H), 3.27
(ddd, J=2.2Hz, J=6.3Hz, J=14.5Hz, 1H), 2.70–2.99
(m, 5H), 2.08–2.12 (m, 1H), 1.82–1.93 (m, 1H), 1.67–
1.75 (m, 1H), 1.54–1.62(m, 1H), 1.38–1.47 (m, 1H).
13C NMR (125MHz, CDCl3 +TMS) d 153.22, 137.86,
129.05, 123.44, 118.64, 71.78, 55.28, 47.27, 46.38,
25.32, 24.29, 19.35. MS (70eV, 25°C) m/z (%)=247.3
(100) [M+H]+. Anal. Calcd for C14H18N2O2 (246.31):
C, 68.27; H, 7.37; N, 11.37. Found: C, 68.74; H, 7.28;
N, 10.38.
1730, 1601, 1546, 1444cmꢀ1 1H NMR (500MHz,
.
DMSO-d6) d 7.37(d, J=7.9Hz, 2H), 7.29 (t, J=7.6Hz,
2H), 7.05 (t, J=7.4Hz, 1H), 6.83 (s, 1H), 4.93–4.98
(m, 1H), 2.45–2.65 (m, 3H), 2.29 (s, 3H), 2.21–2.28 (m,
1H), 1.97 (s, 1H), 1.81–1.91 (m, 1H), 1.72(s, 1H),
1.57–1.64 (m, 1H). 13C NMR (125MHz, CDCl3 +TMS)
d 152.97, 138.02, 129.04, 123.29, 118.48, 69.82, 59.29,
55.46, 46.52, 28.43, 21.99. MS (EI) m/z (%)=244.0
[M+H]+. Anal. Calcd for C13H18N2O2 (243.30): C,
66.64; H, 7.74; N, 11.96. Found: C, 66.41; H 7.74; N,
10.89.
4.2.22. (3-Fluoro-phenyl)-carbamic acid 1-aza-bicy-
clo[2.2.2.]oct-3-yl ester (22). The synthesis was done
according to the general method with 3-quinuclidinole
32 (241mg, 1.9mmol) and m-fluoro-phenylisocyanate
(0.22mL, 1.9mmol). The oily residue was crystallized
from diethyl ether to yield 22 as white crystalline powder
(437.3mg, 1.7mmol, 88%). Mp: 127–129°C. IR (KBr)
4.2.19. (3-Fluoro-phenyl)-carbamic acid 1-methyl-piperi-
din-3-yl ester (19). The synthesis was done according to
the general method with 3-hydroxy-1-methylpiperidine
31 (0.24mL, 2mmol) and m-fluoro-phenylisocyanate
(0.23mL, 2mmol). The final product was obtained as
yellowish oil (384.9mg, 1.5mmol, 76.3%). 1H NMR
(500MHz, CDCl3) d 7.30 (d, J=11.0Hz, 1H), 7.19 (dt,
J=6.5Hz, J=8.2Hz, 1H), 6.97 (d, J=1.3, J=8.2Hz,
1H), 6.94 (s, 1H), 6.71 (ddt, J=0.88Hz, J=2.48Hz,
J=8.35Hz, 1H), 4.91–4.95 (m, 1H), 2.42–2.63 (m, 3H),
2.26 (s, 3H), 2.15–2.24 (m, 2H), 1.78–1.87 (m, 1H),
1.68 (s, 1H), 1.55–1.63 (m, 1H). 13C NMR (125MHz,
CDCl3) d 163.17 (d, J=244.3Hz), 152.66, 139.66 (d,
J=11.0Hz), 130.06 (d, J=9.47Hz), 113.64, 109.87 (d,
J=21.19Hz), 105.81 (d, 26.68Hz), 70.00, 59.14, 55.38,
2947, 2869, 1727, 1606, 1568, 1495cmꢀ1 1H NMR
.
(500MHz, CDCl3) d 7.29 (d, J=10.7Hz, 1H), 7.21 (dt,
J=6,3Hz, J=8.2Hz, 1H), 7.07 (s, 1H), 7.01 (d,
J=7.9Hz, 1H), 6.72(dt, J=2.4Hz, J=8.3Hz, 1H),
4.79–4.85 (m, 1H), 3.26 (ddd, J=2.1Hz, J=8.5Hz,
J=14.6Hz, 1H), 2.69–2,95 (m, 5H), 2.06–2.11 (m, 1H),
1.79–1.87 (m, 1H), 1.66–1.74 (m, 1H), 1.53–1.62(m,
1H), 1.37–1.46 (m, 1H). 13C NMR (125MHz, CDCl3)
d 163.16 (d, J=244.6Hz), 153.03, 139.62 (d,
J=11.0Hz), 130.10 (d, J=9.47Hz), 113.83, 110.01 (d,
J=21.44Hz), 106.01 (d, J=28.67), 72.29, 55.29, 47.29,

D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
4961
46.45, 25.36, 24.43, 19.41. MS (70eV, 25°C) m/z
(%)=265.4 (100) [M+H]+. Anal. Calcd for
C14H17FN2O2 (264.30): C, 63.62; H, 6.48; N, 10.60.
Found: C, 64.09, H, 6.65, N, 11.02.
J=272.4Hz), 121.53, 119.91 (q, J=3.57Hz), 115.34,
72.56, 55.33, 47.31, 46.47, 25.36, 24.47, 19.43. MS
(70eV, 25°C) m/z (%)=315.5 (100) [M+H]+. Anal. Cal-
cd for C15H17F3N2O2 (314.31): C, 57.32; H, 5.45; N,
8.91. Found: C, 56.29; H, 5.41; N, 8.51.
4.2.23. (3-Bromo-phenyl)-carbamic acid 1-aza-bicyclo-
[2.2.2]oct-3-yl ester (23). The synthesis was done accord-
ing the general method with 3-quinuclidinole 32
(254mg, 2mmol) and 3-bromo-phenylisocyanate
(0.25mL, 2mmol). The oily residue was crystallized
from diethyl ether to yield 23 as white crystalline powder
(488mg, 1.5mmol, 75%). Mp: 162°C. IR (KBr) 3163,
4.2.26.
Biphenyl-3-yl-carbamic
acid
1-aza-bicy-
clo[2.2.2]oct-3-yl ester (26). In a 10-mL microwave glass
tube were placed 3-bromo-carbamic acid 1-aza-bicyclo-
[2.2.2]oct-3-yl ester 23 (325mg, 1mmol), phenylboronic
acid (244mg, 2mmol), tetrakis-(triphenylphosphin)-pal-
ladium(0) (58mg, 0.05mmol), Na2CO3 (233mg,
2.2mmol), toluene (5mL) and a magnetic stir bar. The
vessel was sealed with a septum and placed into the
microwave cavity. Enhanced microwave irradiation of
100W was used, the temperature being ramped from
room temperature to 120°C. Once 120°C was reached,
the reaction mixture was held for 20min. Then, the mix-
ture was allowed to cool to room temperature, the reac-
tion vessel was opened and the solvent was evaporated
under pressure. The oily residue was purified by column
chromatography on silica gel eluting with CH2Cl2/
MeOH (80:20). The final product was crystallized from
the mixture of diethyl ether/petroleum ether and ob-
2943, 2866, 1722, 1595cmꢀ1 1H NMR (500MHz,
.
CDCl3 +TMS) d 7.65 (s, 1H), 7.26 (s, 1H), 7.13–7.20
(m, 2H), 7.08 (s, 1H), 4.80–4.91 (m, 1H), 3.27 (ddd,
J=1.9Hz, J=8.4Hz, J=14.5Hz, 1H), 2.73–2.96 (m,
5H), 2.09–2.18 (m, 1H), 1.81–1.87 (m, 1H), 1.68–1.75
(m, 1H), 1.55–1.61 (m, 1H), 1.40–1.46 (m, 1H). 13C
NMR (125MHz, CDCl3 +TMS) d 153.08, 139.38,
130.30, 126.33, 122.76, 121.57, 117.05, 72.47, 55.37,
47.34, 46.50, 25.38, 24.53, 19.49. MS (70eV, 25°C) m/z
(%)=324.1 (40) [M+], 326.0 (39) [M+2]. Anal. Calcd
for C14H17BrN2O2 (325.21): C, 51.7; H, 5.27; N, 8.61.
Found: C, 51.05; H, 5.22; N, 8.60.
tained as
0.11mmol, 22.7%). Mp: 201–202°C. IR (KBr) 3189,
2934, 2868, 1716cmꢀ1 1H NMR (500MHz, DMSO-
a yellow crystalline powder (37.7mg,
4.2.24. m-Tolyl-carbamic acid 1-aza-bicyclo[2.2.2]oct-3-
yl ester (24). The synthesis was done according to the
general method with 3-quinuclidinole 32 (254mg,
2mmol) and m-tolylisocyanate (0.26mL, 2mmol). The
resulting oily residue was purified by column chroma-
tography eluting with CH2Cl2/MeOH (90:10!90:50)
and crystallized from diethyl ether. The final product
was obtained as white crystalline powder (150mg,
0.57mmol, 28%). Mp: 150°C. IR (KBr) 2938, 2866,
.
d6) d 9.66 (s, 1H), 7.79 (s, 1H), 7.58 (d, J=7.1Hz, 2H),
7.43–7.47 (m, 3H), 7.33–7.37 (m, 2H), 7.25 (d,
J=8.2Hz, 1H), 4.68–4.71 (m, 1H), 3.15 (ddd,
J=1.8Hz, J=7.9Hz, J=14.5Hz, 1H), 2.57–2.72 (m,
5H), 1.98 (sx, J=3.2Hz, 1H), 1.78–1.83 (m, 1H), 1.59–
1.65 (m, 1H), 1.47–1.54 (m, 1H), 1.33–1.39 (m, 1H).
13C NMR (125MHz, DMSO) d 153.6, 140.9, 140.4,
139.9, 129.4, 129.1, 127.6, 126.7, 120.9, 117.4, 116.6,
71.4, 55.3, 47.1, 46.1, 25.4, 24.4, 19.3. MS (70eV,
25°C) m/z (%)=322.2 (10) [M+]. Anal. Calcd for
C20H22N2O2 (322.41): C, 74.5; H, 6.88; N, 8.69. Found:
C, 74.28; H, 6.48; N, 8.15.
2780, 1710, 1598, 1559cmꢀ1 1H NMR (500MHz,
.
CDCl3) d 7.29 (s, 1H), 7.26 (d, J=8.2Hz, 1H), 7.18 (t,
J=7.6Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 4.84–4.85 (m,
1H), 3.34 (qui, J=1.7Hz, 1H), 3.25 (ddd, J=2.4Hz,
J=8.4Hz, J=14.7Hz, 1H), 2.77–2.95 (m, 5H), 2.34 (s,
3H), 2.10–2.14 (m, 1H), 1.98–2.06 (m, 1H), 1.78–1.85
(m, 1H), 1.66–1.72(m, 1H), 1.5–21.58 (m, 1H).
13C
4.2.27. [3-(Styryl)-phenyl]carbamic acid 1-aza-bicyclo-
[2.2.2]oct-3-yl ester (27). In a 10-mL microwave glass
tube were placed 3-bromo-carbamic acid 1-aza-bicy-
clo[2.2.2]oct-3-yl ester 23 (325mg, 1mmol), styrylboron-
ic acid (300mg, 2mmol), tetrakis-(triphenylphosphin)-
palladium(0) (115.5mg, 0.1mmol), Na2CO3 (233mg,
2.2mmol), toluene (5mL) and a magnetic stir bar. The
vessel was sealed with a septum and placed into the
microwave cavity. Microwave irradiation of 60W was
used, the temperature being ramped from room temper-
ature to 120°C. Once 120°C was reached, the reaction
mixture was held for 10min. Then the mixture was al-
lowed to cool to room temperature, the reaction vessel
was opened and the solvent was evaporated under pres-
sure. The oily residue was purified by column chroma-
tography on silica gel eluting with CH2Cl2/MeOH
(90:10). The final product was crystallized from the mix-
ture of diethyl ether/petroleum ether and obtained as a
yellow crystalline powder (101.1mg, 0.2mmol, 39%).
Mp: 174–175°C. IR (KBr): 3021, 2945, 2771, 2661,
NMR (125MHz, CDCl3) d 155.94, 140.34, 140.03,
129.96, 125.10, 120.75, 117.33, 72.54, 56.36, 48.28,
47.33, 26.82, 25.13, 21.86, 20.37. MS (70eV, 25°C) m/z
(%)=260.2 (25) [M+]. Anal. Calcd for C15H20N2O2
(260.34): C, 68.20; H, 7.74; N, 10.76. Found: C, 68.37;
H, 7.72; N, 10.98.
4.2.25. (3-Trifluoromethyl-phenyl)-carbamic acid 1-aza-
bicyclo[2.2.2.]oct-3-yl ester (25). The synthesis was done
according to the general method with 3-quinuclidinole
32 (202mg, 1.6mmol) and m-trifluoromethyl-phenyliso-
cyanate (0.22mL, 1.6mmol). The final product was ob-
tained as white crystalline powder (398.7mg, 1.3mmol,
80%). Mp: 147–149°C. IR (KBr) 2953, 2873, 1721,
1
1607, 1570cmꢀ1. H NMR (500MHz, CDCl3) d 7.70
(s, 1H), 7.54 (d, J=7.3Hz, 1H), 7.39 (t, J=7.9Hz,
1H), 7.28 (d, J=7.9Hz, 2H), 7.09 (s, 1H), 4.79–4.86
(m, 1H), 3.26 (ddd, J=2.1Hz, J=8.4Hz, J=14.5Hz,
1H), 2.70–2.90 (m, 5H), 2.07–2.12 (m, 1H), 1.79–1.87
(m, 1H), 1.66–1.74 (m, 1H), 1.53–1.62(m, 1H), 1.38–
1.46 (m, 1H). 13C NMR (125MHz, CDCl3) d 153.11,
138.57, 131.48 (q, J=32.3Hz), 129.57, 123.85 (q,
2589, 1728, 1589, 1547, 1224, 960cmꢀ1 1H NMR
.
(500MHz, DMSO-d6) d 9.81 (s, 1H), 7.70 (s, 1H), 7.59
(d, J=7.1Hz, 2H), 7.37 (t, J=7.4Hz, 3H), 7.26–7.29

4962
D. Gu¨ndisch et al. / Bioorg. Med. Chem. 12 (2004) 4953–4962
17. Zielinsky, J.; Kenilworth, N. J. U.S. Patent 3,535,328,
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19. Abreo, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.;
Hettinger, A.-M.; Wasicak, J. T.; Pavlik, P. A.; Martin, Y.
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(m, 2H), 7.20 (d, J=16.6Hz, 1H), 7.13 (d, J=16.6Hz,
1H), 4.93–5.00 (m, 1H), 3.68 (ddd, J=2.1Hz,
J=8.4Hz, J=13.7Hz, 1H), 3.15–3.25 (m, 5H), 2.28
(sx, J=2.9Hz, 1H), 2.03–2.12 (m, 1H), 1.73–1.91 (m,
4H). 13C NMR (125MHz, DMSO-d6) d 153.0, 139.3,
137.7, 136.9, 129.2, 128.8, 128.7, 128.5, 127.9, 126.7,
121.2, 118.03, 116.5, 67.6, 53.1, 45.9, 45.1, 24.0, 20.2,
16.9. MS (70eV, 25°C) m/z (%)=348.2(100) [M +]. Anal.
Calcd for C22H24N2O2 (348.45): C, 75.83; H, 6.94; N,
8.04. Found: C, 75.68; H, 6.96; N, 8.23.
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We thank the Deutsche Forschungsgemeinschaft GRK
677/1 for financial support. The excellent assistance of
Mark Thorand (University of Bonn) in conducting
NMR measurements is thankfully acknowledged.
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