Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists

Article abstract of DOI:10.1021/jm020895l

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H₁ receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M₁-M₅) and for human histamine H₁ receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [³H]N-methylscopolamine ([³H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M₂ receptors ((S)-dimethindene: pK_i = 7.52; (-)-19: pK_i = 7.37) with an improved selectivity pattern ((S)-dimethindene: M₂/M₁ = 6-fold, M₂/M₃ = 5-fold, M₂/M₄ = 10-fold, M₂/M₅ = 25-fold; (-)-19: M₂/M₁ = 36-fold, M₂/M₃ = 96-fold, M₂/M₄ = 42-fold, M₂/M₅ = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H₁ receptors (pK_i = 5.61) than (S)-dimethindene (pK_i = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK_i/M₂ = 7.49), which also exhibits a higher M₂ selectivity (M₂/M₁ = 19-fold; M₂/M₃ = 22-fold; M₂/M₄ 13-fold; M₂/M₅ = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H₁ receptors (pK_i = 8.14). The compound with the highest affinity for M₂ receptors (pK_i = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M₂ receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M₂ receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M₂-selective muscarinic antagonists useful for quantifying M₂ receptors in the central nervous system with positron emission tomography imaging.

Full text of DOI:10.1021/jm020895l

856
J . Med. Chem. 2003, 46, 856-867
Str u ctu r e-Activity Rela tion sh ip s of Dim eth in d en e Der iva tives a s New
M2-Selective Mu sca r in ic Recep tor An ta gon ists
Thomas M. Bo¨hme,† Christine Keim,‡ Kai Kreutzmann,‡ Matthias Linder,§ Theo Dingermann,§
Gerd Dannhardt,*,† Ernst Mutschler,‡ and Gu¨nter Lambrecht‡
Institute of Pharmacy, J ohannes Gutenberg-University of Mainz, Staudinger Weg 5, D-55099 Mainz, Germany, and
Department of Pharmacology and Pharmaceutical Biology, Biocenter Niederursel, University of Frankfurt,
Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany
Received April 2, 2002
A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H1
receptor antagonist dimethindene, have been synthesized and studied as muscarinic and
histamine receptor antagonists. The affinities of these compounds for the five human muscarinic
receptor subtypes (M1-M5) and for human histamine H1 receptors were determined in
radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO)
cells and [3H]N-methylscopolamine ([3H]NMS). The results demonstrate that the diisopropyl
analogue 19 has a similar high affinity as (S)-dimethindene at M2 receptors ((S)-dimethin-
dene: pKi ) 7.52; (-)-19: pKi ) 7.37) with an improved selectivity pattern ((S)-dimethindene:
M2/M1 ) 6-fold, M2/M3 ) 5-fold, M2/M4 ) 10-fold, M2/M5 ) 25-fold; (-)-19: M2/M1 ) 36-fold,
M2/M3 ) 96-fold, M2/M4 ) 42-fold, M2/M5 ) 275-fold). In addition, compound (-)-19 showed
35-fold lower affinity at histamine H1 receptors (pKi ) 5.61) than (S)-dimethindene (pKi )
7.16). Another interesting compound is the fluoroethyl derivative 20 (pKi/M2 ) 7.49), which
also exhibits a higher M2 selectivity (M2/M1 ) 19-fold; M2/M3 ) 22-fold; M2/M4 ) 13-fold; M2/
M5 ) 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity
for histamine H1 receptors (pKi ) 8.14). The compound with the highest affinity for M2 receptors
(pKi ) 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for
M2 receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that
blockade of muscarinic M2 receptors in the brain is a viable mechanism by which to produce
improved cognition. This second-generation dimethindene analogue might also be the starting
point for the development of M2-selective muscarinic antagonists useful for quantifying M2
receptors in the central nervous system with positron emission tomography imaging.
In tr od u ction
muscarinic receptor subtype. Currently, pirenzepine is
used for the inhibition of gastric acid secretion in the
treatment of peptic ulcers.4 An M2 antagonist might be
useful in the treatment of bradycardia,5 and an M3
selective compound in the treatment of obstructive
airways diseases.6 Another possible indication for an M2
and/or M3 antagonist could be urinary incontinence,7
and an M4 antagonist may be useful to treat tremor in
patients with Parkinson’s disease.8
Muscarinic receptors are present in the central and
peripheral nervous system as well as in organs in-
nervated by the autonomic nervous system. These
receptors play an important role in a wide range of
different functions such as central control of movement
and cognition as well as in the peripheral control of
smooth muscle tone and glandular secretion. Due to
their wide distribution, the use of nonselective antago-
nists as therapeutics involves potential side effects,
which could be avoided with subtype-selective com-
pounds.
The interest in muscarinic receptors arose with the
discovery of the pharmacological profile of pirenzepine,
which shows M1 receptor subtype selectivity. Four
muscarinic receptor subtypes (M1, M2, M3, and M4) were
subsequently characterized pharmacologically by the
use of selective antagonists,1,2 and five distinct subtypes
(M1-M5) were cloned.3 These developments have made
it possible to specifically target the blockade of one
Alzheimer’s disease (AD) is a chronic cognitive dis-
order, characterized by the progressive degeneration of
cholinergic neurons that project from the basal forebrain
to the cerebral cortex and hippocampus.9 AD is currently
treated with inhibitors of acetylcholinesterase, such as
donepezil, which enhance the acetylcholine concentra-
tion in the synaptic cleft by impeding its enzymatic
breakdown.10 Another possible mechanism for augment-
ing central cholinergic activity is to increase acetyl-
choline release by blockade of inhibitory presynaptic M2
autoreceptors in the CNS,11 making a selective M2
receptor antagonist useful in the treatment of AD.12
Such centrally acting M2 antagonists may improve
cognition without the side effects associated with other
cholinergic approaches provided there is sufficient
selectivity for the M2 subtype. Nonselective muscarinic
antagonists such as scopolamine are known to produce
cognitive deficits. Very few compounds with the requi-
* Address correspondence to: Prof. Dr. G. Dannhardt, J ohannes
Gutenberg-Universita¨t Mainz, Staudinger Weg 5, D-55099 Mainz,
Germany. Tel. +49 (0)6131 3925742. Fax +49 (0)6131 3923062.
dannhardt@uni-mainz.de.
† J ohannes Gutenberg-University of Mainz.
‡ Department of Pharmacology, University of Frankfurt.
§ Pharmaceutical Biology, University of Frankfurt.
10.1021/jm020895l CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003

M2-Selective Muscarinic Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5 857
Ch em istr y
The compounds 6-37 shown in Table 1 were prepared
by the synthetic routes illustrated in Scheme 1-3.
In Scheme 1, diethyl malonate was reacted with com-
mercially available benzyl chlorides 1a -h . 4-Methyl-
thiobenzyl chloride 1i was prepared following the pro-
cedure of Pines et al.21 The benzyl malonic diethyl esters
2a -i were alkylated with commercially available (2-
chloroethyl)dialkylamines to give the tertiary amines
3a -p . The (2-chloroethyl)dialkylamines 41a and 41b
were prepared from the corresponding alcohol, which
were treated with thionyl chloride.
Saponification of the corresponding malonic esters
yielded the amino acids 4a -p . The ring closure reaction
was carried out in polyphosphoric acid (PPA) to give the
indanone-1 derivatives 5a -p . Treatment of 5a -p with
the lithium salts of different commercially available
picolines, 2-ethyl-pyridine and 2-benzyl-pyridine formed
tertiary alcohols, which were refluxed in HCl (20%) and
yielded the indenes 6-19, 22-25, 27, 28, and 39.
2-Isopropylpyridine (45) was synthesized from 2-ethyl-
pyridine by deprotonation and subsequent alkylation
with methyl iodide. Compound 45 was used to synthe-
size compound 26 by addition to compound 5a and
elimination of water. Treatment of commercially avail-
able 1-(bromoethyl)benzene with lithium gave the cor-
responding lithium compound, to which compound 5a
was added to give the phenyl-substituted compound 30.
Reduction of compound 5a with sodium borohydride
and dehydration with hydrochloric acid gave compound
38, which in turn gave compound 29 by alkylation of
the lithium salt with 3-chloromethylpyridine. Com-
pound 39 was debenzylated by hydrogenation in the
presence of formic acid to yield the secondary amine 40,
which was converted by alkylation to the tertiary
amines 20 and 21.
The indanone intermediates 43 and 44 (Scheme 2)
were synthesized under standard Mannich reaction
conditions.22-24 Treatment of 43 and 44 with the lithium
salt of 2-ethylpyridine and subsequent reflux in HCl
(20%) gave 31 and 32, respectively, as illustrated in
Scheme 2.
The compounds 33-37 were prepared via the general
synthesis outlined in Scheme 3. To synthesize com-
pounds 33-37, treatment of commercially available
indene with commercially available oxalylbromide neat,
followed by addition of commercially available dimethyl-
aminoethylamine or dimethylaminoethanol, gave the
corresponding amides and esters 42a and 42b, respec-
tively. Treatment of 42a ,b with butyllithium formed the
anion, which was alkylated with different chloromethyl
pyridines to give the compounds 33-37.
F igu r e 1.
site selectivities are known, and many of these do not
penetrate into the brain to an appreciable extent.12
Particularly, M2/M1 selectivity is crucial since the drug
of interest should not functionally counteract its own
presynaptic action by blocking postsynaptic M1 recep-
tors, which mediate the acetylcholine effect.
Brains from AD patients show a number of typical
histopathologic alterations, e.g. axonal loss in the hippo-
campus and cortex. Due to their presynaptic location
the density of M2 receptors might therefore be reduced
in these regions.13 A labeled M2-selective muscarinic
antagonist suitable for positron emission tomography
(PET) might therefore also be used as a diagnostic tool
to provide information about the density of M2 receptors
in the brain.14-16
Racemic dimethindene maleate (Figure 1) is a hista-
minic H1 receptor antagonist, which penetrates readily
into the brain.17-19 It was also shown to possess anti-
muscarinic activities by inhibiting the contractile re-
sponses to carbachol in guinea-pig ileum.20 In an effort
to explore its affinity for muscarinic receptor subtypes,
the enantiomers of dimethindene, including the race-
mate, were examined in functional as well as in binding
studies at native muscarinic receptor subtypes M1-
M4.15 The results of these studies demonstrated that (S)-
dimethindene is a potent M2-selective muscarinic re-
ceptor antagonist (guinea-pig atrium and rabbit vas
deferens: pA2 ) 7.86/7.74; rat heart: pKi ) 7.78) with
lower affinities for the muscarinic M1 (rabbit vas def-
erens/rat duodenum: pA2 ) 6.83/6.36; NB-OK1-cells:
pKi ) 7.08), M3 (guinea-pig ileum/guinea pig trachea:
pA2 ) 6.92/6.96; rat pancreas: pKi ) 6.70) and M4
receptors (rat striatum: pKi ) 7.00). The (S)-enantiomer
of dimethindene was more potent (up to 41-fold) than
the (R)-isomer in all muscarinic assays. On the other
hand, the (S)-isomer showed a lower affinity for hista-
mine H1 receptors in guinea-pig ileum (pA2 ) 7.48) than
the (R)-enantiomer (pA2 ) 9.42).
The aim of the present study was to synthesize
analogues of dimethindene in order to increase affinity
and selectivity at muscarinic M2 receptors as well as to
diminish the binding toward histamine H1 receptors.
Structural modifications were made through functional
group substitution on the indene phenyl ring and at the
chiral center of the dimethindene molecule. Derivatives
with different basic side chains were also evaluated. The
new derivatives were examined for their affinities to
human recombinant muscarinic M1-M5 and histamine
H1 receptors in radioligand binding studies. All chiral
compounds, except dimethindene and 19, were tested
as racemates. (R)- and (S)-dimethindene were used as
reference drugs.15
Resu lts a n d Discu ssion
New dimethindene analogues were synthesized in
order to identify derivatives with improved M2 selectiv-
ity and affinity as compared with the parent compound.
The affinities of the new derivatives for the five human
muscarinic receptor subtypes (M1-M5) and for hista-
mine H1 receptors were determined in radioligand
binding studies using membranes from transfected
Chinese hamster ovary (CHO) cells and [3H]NMS and
[3H]mepyramine, respectively, as radioligands.25 All
chiral compounds, except dimethindene and 19, were

858 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Bohme et al.

M2-Selective Muscarinic Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5 859
Sch em e 1a
a
(a) Diethyl malonate, Na, EtOH, ∆; (b) NaH, R2-(CH2)x-Cl, toluene, ∆; (c) NaOH, ∆; (d) CH3COOH, 0 °C; (e) PPA, ∆; (f) 2-picolyl-
R3,R,4 BuLi, ether, -78 °C; (g) HCl (20%), ∆; (h) (1-bromoethyl)benzene, Li, ether, 25 °C; (i) HCl (20%), ∆; (j) NaBH4, EtOH, ∆; (k) HCl
concentrated, acetic acid, ∆; (l) BuLi, ether, 3-chloromethylpyridine, -78 °C; (m) Pd/H2, HCOOH, methanol; (n) K2CO3, Hal-alkyl, acetone.
Sch em e 2a
a
(a) Paraformaldehyde, N(CH3)R1, ethanol, ∆; (b) 2-ethylpyridine; BuLi, THF, -78 °C; (c) HCl (20%), ∆.
Sch em e 3a
a
(a) Oxalyl bromide, ∆; (b) 2-dimethylaminoethanol, N,N-dimethylethane-1,2-diamine resp., THF, ∆; (c) BuLi, THF, chloromethylpyridine,
-78 °C.
investigated as racemates. The respective pKi values are
listed in Tables 1 and 2. Unless stated otherwise, all
tested compounds behaved as competitive inhibitors of
radioligand binding with competition curves indicating
the existence of one single binding site, the Hill coef-
ficients being not significantly different from unity.
Our initial studies explored the effects of substituting
the indene moiety of dimethindene at position 5 and 6

860 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Bohme et al.
Ta ble 2. Binding Affinitiesa of Dimethindene (Dim), 13, (-)-19, (+)-19, 20, and 31 at Histamine H1 Receptors
Dim
R-(-)-Dim
9.36 ( 0.14
S-(+)-Dim
13
(+)-19
(-)-19
20
31
pKi valuea
9.16 ( 0.12
7.16 ( 0.06
9.09 ( 0.14
6.66 ( 0.10
5.61 ( 0.05
8.14 ( 0.06
7.54 ( 0.03
a
Values are means + SD of at least three independent experiments performed in duplicate.
with electron-withdrawing and electron-donating groups
(6-14). All compounds, except 13, synthesized with a
substituent at positions 5 or 6 showed lower affinity and
selectivity toward M2 receptors (pKi ) 5.71-6.97) than
(S)-dimethindene. Analogue 10, which contains a fluo-
rine atom, produced the smallest decrease in affinity
among the 5-substituted derivatives. Comparing the
fluoro-analogue 10 with compounds 6-9 suggests that
the bulk of the substituent has the highest impact on
receptor binding. Compound 13, which is substituted
with chlorine, demonstrates that this lipophilic electron-
withdrawing atom at position 6, in contrast to position
5 (compound 8), did not significantly affect the affinity
for M1-M5 receptors. Taken together, the functional
group variation at positions 5 and 6 of the indene moiety
of dimethindene was found to decrease the affinity and
selectivity at muscarinic receptors (6-12, 14). Only
compound 13 with a chloro-substituent in position 6
maintained affinity for muscarinic receptors.
On the basis of the assumption that the basic tertiary
amine moiety in muscarinic antagonists is important
for binding to muscarinic receptors,26 cyclic (15-17) as
well as acyclic (18-21) tertiary amine derivatives of
dimethindene were synthesized. Compounds 15-17 had
affinities for M1-M5 receptors lower than those of the
acyclic analogues 18-21 (up to 45-fold). In comparison
to (S)-dimethindene, compound 20 showed a significant
improvement in M2-selectivity maintaining high affinity
for M2 receptors (20: pKi - M2 ) 7.49, M2/M1 ) 19-
fold, M2/M3 ) 22-fold, M2/M4 ) 13-fold, M2/M5 ) 62-
fold). In general, (S)-dimethindene displayed a higher
affinity than the (R)-enantiomer in all muscarinic
assays. However, their stereoselectivity ratios were
found to be different at the five recombinant muscarinic
receptor subtypes, being greatest at M2 receptors (40-
fold). The same holds true for compound 19 (stereo-
selectivity ratio at M2 ) 14), the (-)-enantiomer being
the eutomer at M1-M4 receptors, but the distomer at
M5 receptors. However, the affinity of (+)- and (-)-19
for M5 receptors and the stereoselectivity ratio (2.3-fold)
are low and should therefore not be considered as an
unusual finding of reverse stereoselectivity between
receptor subtypes. Thus, it is tempting to speculate that
the compound (-)-19 has the (S)-configuration. How-
ever, further experiments are needed to clarify this
issue. Compound (-)-19 exhibited a similar high affinity
for the M2 receptor (pKi ) 7.37) as (S)-dimethindene
(pKi) ) 7.52), but an improved selectivity profile [(S)-
dimethindene ) M2/M1: 6-fold, M2/M3: 5-fold, M2/M4:
10-fold, M2/M5: 25-fold; (-)-19 ) M2/M1: 36-fold, M2/
M3: 96-fold, M2/M4: 42-fold, M2/M5: 275-fold]. Whereas
(R)-dimethindene had similar affinities for the five
muscarinic receptor subtypes, (+)-19 (the distomer) is
still an M2-selective muscarinic antagonist.
The pKi values of racemic 19 (Table 1) should be lower
by at most 0.3 log unit than the pKi values of the high
affinity enantiomer of 19 at M1-M5 receptors, due to
the presence of 50% of the low affinity enantiomer in
the racemic mixture. Unfortunately, this was not found.
In fact, the affinity of (()-19 for M1-M5 receptors is on
average 4-fold higher than expected (Table 1). How-
ever, this discrepancy is not due to chemical impurities
of the compounds under study (see Experimental Sec-
tion), and further experiments are needed to clarify this
issue.
The length of the tertiary amine side chain was varied
in compounds 22, 31, and 32. While the analogue 22
with an aminopropyl side chain showed a 6-fold de-
creased M2-affinity along with a lower selectivity com-
pared to (S)-dimethindene, compound 31 with an amino-
methyl chain displayed the highest affinity toward the
M2 receptor among all derivatives examined. Unfortu-
nately, the M2-selectivity of 31 is lower than that of the
parent compound. To restore the selectivity while main-
taining the affinity, analogue 32, bearing a methyl-
isopropylaminomethyl moiety, was synthesized. This
compound showed indeed a similar affinity profile as
(S)-dimethindene.
In comparison to (S)-dimethindene, compounds 33-
37 showed a decrease in affinity at the muscarinic
receptors up to 3090-fold. Each of these derivatives has
either an ester or an amide group introduced into the
molecule. The lengthening of these compounds by two
atoms in comparison to dimethindene might be respon-
sible for the substantial loss in affinity. However, the
introduction of a polar group can drastically alter the
physical properties of a compound and might also have
a dramatic impact on binding to muscarinic receptors.
The impact on affinity of an altered heteroaromatic
system was investigated by testing the phenyl analogue
(30) and the achiral 3- and 4-pyridyl derivatives 28 and
29. The phenyl derivative 30 showed similar M1 and
M
3-5 affinities as (S)-dimethindene while the M2-affinity
decreased 9-fold, resulting in a nonselective muscarinic
antagonist. The affinity of the compounds 28 and 29 for
M2 receptors was 23- and 29-fold, respectively, lower
than that of their achiral parent compound 27. As a
result, the M2-selectivity was completely lost. Taken

M2-Selective Muscarinic Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5 861
together, the pyridyl nitrogen seems to specifically
interact with the M2 receptor protein, since the presence
as well as the position of the heteroaryl nitrogen has a
major impact on affinity and selectivity.
36-fold) and M2/H1 receptor specificity (58-fold). It is also
noteworthy that (-)-19 is more selective for M2 versus
M1 and M3-5 receptors than any so-called M2-selective
antagonists recommended by the muscarinic receptor
Committee on Receptor Nomenclature and Drug Clas-
sifications of the International Union of Pharmacology.25
The antagonists recommended include methoctramine,
himbacine and tripitramine. The second generation
dimethindene analogue (-)-19 might become the start-
ing point for the development of M2-selective muscarinic
receptor antagonists useful as diagnostic tools for
quantifying M2 receptors in the central nervous system
with positron emission tomography imaging, and to test
the hypothesis that muscarinic M2 receptor antagonists
show beneficial effects in the treatment of cognitive
disorders. Due to the abundant presence of muscarinic
M1 and histamine H1 receptors in the brain, the high
M2 versus M1 (H1) selectivity (specificity) of compound
(-)-19 is of special importance. In particular, the M2
versus M1 receptor selectivity may guarantee that such
a compound does not counteract its acetylcholine releas-
ing action via blockade of presynaptic autoreceptors by
inhibition of postsynaptic M1 receptors.27
It is significant that dimethindene is a lipophilic com-
pound, both enantiomers of which were able to pen-
etrate into the brains of healthy human volunteers.17-19
In addition, it has been shown by Radler and Blaschke
that differences in metabolism of the (R)- and (S)-
enantiomers do not influence the ease with which they
cross the blood brain barrier.28 Although the same type
of investigation has not been carried out with (+)- or
(-)-19, it seems likely that the enantiomers of 19 behave
similarly due to their close chemical relationship to
dimethindene. Further experiments are needed to ad-
dress this point.
To examine the effect of the substitution of the chiral
center of dimethindene on selectivity and affinity,
analogues 23-26 were synthesized. The chiral com-
pound 23, which contains an ethyl substituent instead
of methyl, showed lower affinity (2-fold) and selectivity
at the M2 receptors. The derivatives with a propyl
substituent (24) or a phenyl group (25) were found to
be M1-selective compounds. The achiral analogue 26 had
a 2-fold higher affinity at M2 receptors than (S)-
dimethindene but showed less subtype selectivity.
The pharmacologically most interesting derivatives,
13, (+)-19, (-)-19, 20, and 31, were investigated for
their affinities at recombinant histamine H1 receptors
and compared with the results that were obtained for
(R)- and (S)-dimethindene (Table 2).
The affinity estimates of (R)- and (S)-dimethindene
at recombinant human histamine H1 receptors (Table
2; pKi/(R) ) 9.36; pKi/(S) ) 7.16) were found to be very
similar to that reported by Pfaff et al.,15 using a
functional guinea-pig ileum assay. In contrast with
muscarinic receptors (Table 1) the (R)-enantiomer proved
to be the eutomer at histamine H1 receptors, being
158-fold more potent than the (S)-configured stereo-
isomer. Accordingly, these results demonstrate an in-
verse stereoselectivity and imply that the stereo-
chemical requirements of the muscarinic receptors and
histamine H1 receptors, respectively, are different for
the enantiomers of dimethindene, being most stringent
at H1 receptors. Such an inverse stereoselectivity for
recognition of histamine H1 and muscarinic M1-M4
receptors has also been found for the enantiomers of
compound 19 (Table 2). As a result, (-)-19 has a 14-
fold higher affinity for muscarinic M2 receptors than (+)-
19, but (+)-19 is the eutomer at histamine H1 receptors.
As far as M2 receptor specificity is concerned, the data
show that (-)-19 is an M2-selective muscarinic antago-
nist possessing a 58-fold lower affinity for histamine H1
receptors. It is noteworthy, that the M2 versus H1
receptor specificity of (S)-dimethindene is much lower
than that of (-)-19 (only 2-fold). This is due to the fact
that the affinity for muscarinic M2 receptors did not
change significantly by replacing the two N-methyl
groups of (S)-dimethindene by two isopropyl substitu-
ents [(-)-19], whereas the affinity for histamine H1
receptors decreased significantly by a factor of 35. Taken
together, the analysis of the individual enantiomers of
compound 19 resulted in (-)-19 with improved M2
subtype selectivity and M2 receptor specificity.
Exp er im en ta l Section
High-field nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker Unity 200 MHz Spectrometer or Bruker
Unity 400 MHz Spectrometer. All chemical shifts are reported
in ppm downfield relative to the residual signal of the
deuterated solvent (CHCl3, δ 7.26). All spectra were obtained
in CDCl3. Infrared spectra were determined on a Perkin-Elmer
299 IR spectrophotometer. Elemental analysis for carbon,
hydrogen, and nitrogen were determined on a Carlo Erba
Strumentazione, model 1106 elemental analyzer and are
within 0.4% of theory unless noted otherwise. Mass spectra
were obtained by using a Varian CH 7a or MAT 311 A mass
spectrometer. Melting points were determined on a Dr. Tottoli
(Buechi) melting point apparatus and are uncorrected. All
target compounds were crystallized as salts of maleic acid
(C4H4O4) or toluenesulfonic acid except compounds (-)-19, (+)-
19, and 32.
Resolu tion of th e Ra cem a te 19 a n d P u r ity. Separation
of the enantiomers (-)-19 and (+)-19 was performed on a
GILSON/ABIMED HPLC (Sampling Injector 231 XL, UV/Vis-
Detector 119, Fraction Collector 202). The column was MERCK
Chiralpak ADH33, 250 mm × 4.6 mm. The eluent was
acetonitrile: 2-propanol:heptane 50:3:4 + 0.1 diethylamine. The
flow rate was: 1 mL/min. The retension times were 3.76 min
for (-)-19 and 4.20 for (+)19. (-)-19 and (+)-19 showed no
impurities.
The chloro-substituted dimethindene analogue 13
showed about the same high affinity for histamine H1
receptors as the (R)-enantiomer of the parent compound,
whereas introduction of a fluoroethyl moiety (20) or
shortening the aminoethylene chain to one methylene
group (31) reduced affinity for H1 receptors 17- and 66-
fold, respectively.
In conclusion, this study has generated the diiso-
propyl derivative (-)-19, which has the same high
affinity for muscarinic M2 receptors as the parent
compound, (S)-dimethindene. However, compound (-)-
19 exhibits an improved M2 receptor selectivity (at least
Deter m in a tion of Op tica l Rota tion of (-)-19 a n d (+)-
19. The optical rotation of the enantiomers was determined
on
a PerkinElmer Polarimeter Model 343 in chloroform
solution (c ) 0.0023 mol/L, 20 °C), result: (90.1°.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ma leic Acid
Sa lts. To a solution of tertiary amine (1 mmol) in absol ethanol
(1 mL) was added maleic acid (1 mmol) in absol ethanol (1

862 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Bohme et al.
mL). The clear solution was kept at 5 °C overnight. The white
precipitate was filtered and washed with a mixture of cold
absol ethanol and ether (1:1).
P r oced u r e for th e P r ep a r a tion of Tolu en esu lfon ic
Acid Sa lt of 19. To a solution of 19 (1 mmol) in absol ethanol
(1 mL) was added toluenesulfonic acid (1 mmol) in absol
ethanol (1 mL). The clear solution was kept at 5 °C for 1
month. The white precipitate was filtered and washed with a
mixture of cold absol ethanol and ether (1:1).
(4-Ch lor om eth ylp h en yl) Meth yl Su lfid e (1i).21 To a
stirred suspension of AlCl3 (61.4 g, 0.46 mol) in 1,2-dichloro-
methane (200 mL) was added dropwise dimethoxymethane
(18.2 g, 0.24 mol) over 30 min at 5 °C. Then, methyl phenyl
sulfide (24.8 g, 0.2 mol) was added under the same conditions.
The reaction mixture was stirred for 6 h at RT while crystals
precipitated. The suspension was kept below 25 °C with an
ice bath and stirred vigorously while adding ice chips (250 g).
The organic layer was separated and the water layer extracted
with 1,2-dichloroethane (2 × 100 mL). The combined organic
layers were washed with cold water (30 mL), dried (Na2SO4),
and evaporated to give a dark oil. The oil was used without
further purification.
h. The resulting suspension was extracted with HCl (5%) (3
× 50 mL). The aqueous layers were combined, basified with
NH4OH (pH > 10), and extracted with ether (3 × 50 mL). The
combined organic layers were dried (Na2SO4) and concentrated
to yield a yellow oil (9.2 g, 85%) 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.24 (t, J ) 7.3 Hz, 6H), 1.91-1.97 (m, 2H), 2.20 (s,
6H), 2.27-2.34 (m, 2H), 3.18 (s, 2H), 4.18 (q, J ) 7.3 Hz, 1H),
7.05-7.23 (m, 5H).
The following analogues were prepared using the procedure
outlined for 3a above.
2-[2-(Dim eth yla m in o)eth yl]-2-(4-m eth ylben zyl)m a lon -
ic a cid d ieth yl ester (3b): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.25 (t, J ) 7.3 Hz, 6H), 1.94 (t, J ) 7.5 Hz, 2H),
2.18 (s, 6H), 2.3 (s, 3H), 2.31 (t, J ) 7.5 Hz, 2H), 3.18 (s, 2H),
4.18 (q, J ) 7.3 Hz, 1H), 6.92-7.10 (A,A′, B,B′, 4H). MS: 335.1
(3%, [M•+]).
2-[2-(Dim et h yla m in o)et h yl]-2-(4-m et h oxyb en zyl)m a -
lon ic a cid d ieth yl ester (3c): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.22 (t, J ) 7.3 Hz, 6H), 1.94 (t, J ) 7.2 Hz, 2H),
2.18 (s, 6H), 2.28 (t, J ) 7.2 Hz, 2H), 3.16 (s, 2H), 3.75 (s, 3H),
4.18 (q, J ) 7.3 Hz, 4H), 6.74 (A,A′, 2H), 6.97 (B,B′, 2H).
2-(4-Ch lor o-ben zyl-2-[2-(d im eth yla m in o)eth yl]m a lon -
ic a cid d ieth yl ester (3d ): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.24 (t, J ) 7.3 Hz, 6H), 1.95 (t, J ) 8 Hz, 2H), 2.18
(s, 6H), 2.28 (t, J ) 8 Hz, 2H), 3.21 (s, 2H), 4.15 (q, J ) 7.3
Hz, 4H), 7.04 (A,A′, 2H), 7.19 (B,B′, 2H). MS: 355.2 (4%, [M•+]).
2-[2-(Dim eth ylam in o)eth yl]-2-(4-m eth ylsu lfan ylben zyl)-
m a lon ic a cid d ieth yl ester (3e): 1H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 1.23 (t, J ) 7.3 Hz, 6H), 1.92-1.99 (m, 2H), 2.22
(s, 6H), 2.33 (m, 2H), 2.43 (s, 3H), 3.18 (s, 2H), 4.16 (q, J ) 7.3
Hz, 4H), 7.04-7.36 (m, 4H).
2-(4-Meth ylben zyl)m a lon ic Acid Dieth yl Ester (2a ).
Sodium (0.1 mol, 2.3 g) was dissolved in 100 mL of dry ethanol,
and diethyl malonic acid ester (8 g, 0.1 mol) was added
dropwise at 50 °C to give a clear solution. To this solution was
added dropwise 4-methylbenzyl chloride (0.1 mol, 26.4 g), and
the reaction mixture was refluxed for 1 h. The precipitated
sodium chloride was filtered, the ethanol was evaporated, and
the residue was purified by distillation to give a colorless oil
1
(11.8 g, 45%). H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.18 (t,
J ) 7 Hz, 6H), 2.28 (s, 3H), 3.12 (t, J ) 7.3 Hz, 2H), 3.60 (t, J
) 7.3 Hz, 1H), 4.12 (q, J ) 7 Hz, 4H), 7.02 (m, 4H). MS: 264.1
(40%, [M•+]).
2-[2-(Dim eth yla m in o)eth yl]-2-(4-flu or oben zyl)m a lon -
ic a cid d ieth yl ester (3f): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.21 (t, J ) 7.3 Hz, 6H), 1.88-1.97 (m, 2H), 2.21 (s,
6H), 2.25-2.33 (m, 2H), 3.20 (s, 2H), 4.13 (q, J ) 7.3 Hz, 4H),
6.87-7.10 (m, 4H).
The following analogues were prepared using the procedure
outlined for 2a above.
2-(4-Meth oxyben zyl)m a lon ic a cid d ieth yl ester (2b):
1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.20 (t, J ) 7.2 Hz,
6H), 3.11 (d, J ) 7.8 Hz, 2H), 3.58 (t, J ) 7.8 Hz, 1H), 3.76 (s,
3H), 4.14 (q, J ) 7.2 Hz, 4H), 6.80 (A,A′, 2H), 7.11 (B,B′, 2H).
2-(4-Ch lor oben zyl)m a lon ic a cid d ieth yl ester (2c): 1H
NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.16 (t, J ) 7.3 Hz, 6H),
3.12 (d, J ) 7.6 Hz, 2H), 3.57 (t, J ) 7.6 Hz, 1H), 4.12 (q, J )
7.3 Hz, 4H), 7.06 (A,A′, 2H), 7.16 (B,B′, 2H). MS: 284.2 (37%,
[M•+]).
2-(4-Meth ylsu lfa n ylben zyl)m a lon ic a cid d ieth yl ester
(2d ): 1H NMR (CDCl3, 200 MHz, δδ [ppm]) ) 1.19 (t, J ) 7.3
Hz, 6H), 2.44 (s, 3H), 3.15 (d, J ) 7.8 Hz, 2H), 3.58 (t, J ) 7.8
Hz, 1H), 4.14 (q, J ) 7.3 Hz, 4H), 7.08-7.22 (m, 4H).
2-(4-F lu or o-ben zyl)-m a lon ic a cid d ieth yl ester (2e): 1H
NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.20 (t, J ) 7.2 Hz, 6H),
3.14 (d, J ) 7.6 Hz, 2H), 3.58 (t, J ) 7.6 Hz, 1H), 4.13 (q, J )
7.2 Hz, 4H), 6.90-7.17 (m, 4H).
2-[2-(Dim eth yla m in o)eth yl]-2-(3-m eth ylben zyl)m a lon -
ic a cid d ieth yl ester (3 g): IR (NaCl, ν [cm-1]) ) 1730 (CdO).
2-[2-(Dim et h yla m in o)et h yl]-2-(3-m et h oxyb en zyl)m a -
lon ic a cid d ieth yl ester (3h ): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.20 (t, J ) 7.3 Hz, 6H), 1.88-1.95 (m, 2H), 2.16 (s,
6H), 2.24-2.31 (m, 2H), 3.16 (s, 2H), 3.72 (s, 3H), 4.11 (q, J )
7.3 Hz, 4H), 6.60-6.72 (m, 3H), 7.06-7.14 (m, 1H).
2-(3-Ch lor o-ben zyl)-2-[2-(d im eth yla m in o)eth yl]m a lon -
ic a cid d ieth yl ester (3i): IR (NaCl, ν [cm-1]) ) 1725 (CdO).
2-Ben zyl-2-[2-(N-ben zyl-N-m eth yla m in o)eth yl]m a lon -
ic a cid d ieth yl ester (3j): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.19 (t, J ) 7.3 Hz, 6H), 2.00 (m, 2H), 2.20 (s, 3H),
2.41 (m, 2H), 3.16 (s, 2H), 3.48 (s, 2H), 4.12 (q, J ) 7.3 Hz,
4H), 6.95-7.21 (m, 10H).
2-Ben zyl-2-[2-(d iisop r op yla m in o)et h yl]m a lon ic a cid
d ieth yl ester (3k ): 1H NMR (CDCl3, 200 MHz, δ [ppm]) )
0.94 (d, J ) 6.8 Hz, 12H), 1.22 (t, J ) 7.3 Hz, 6H), 1.85-1.93
(m, 2H), 2.35-2.43 (m, 2H), 2.92-2.98 (m, 2H), 3.23 (s, 2H),
4.16 (q, J ) 7.3 Hz, 4H), 7.13-7.26 (m, 5H).
2-(3-Meth ylben zyl)m a lon ic a cid d ieth yl ester (2f): 1H
NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.21 (t, J ) 7.3 Hz, 6H),
2.3 (s, 3H), 3.17 (d, J ) 7.6 Hz, 2H), 3.62 (t, J ) 7.6 Hz, 1H),
4.15 (q, J ) 7.3 Hz, 4H), 7.0-7.19 (m, 4H). MS: 264.1 (41%,
[M•+]).
2-(3-Meth oxyben zyl)m a lon ic a cid d ieth yl ester (2 g):
1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.20 (t, J ) 7.3 Hz,
6H), 3.16 (d, J ) 7.8 Hz, 2H), 3.63 (t, J ) 7.8 Hz, 1H), 3.76 (s,
3H), 419 (q, J ) 7.3 Hz, 4H), 6.70-6.80 (m, 3H), 7.10-7.25
(m, 1H). MS: 280.1 (68%, [M•+]).
2-(3-Ch lor oben zyl)m a lon ic a cid d ieth yl ester (2h ): 1H
NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.20 (t, J ) 7.3 Hz, 6H),
3.16 (d, J ) 7.6 Hz, 2H), 3.60 (t, J ) 7.6 Hz, 1H), 4.15 (q, J )
7.3 Hz, 4H), 7.00-7.23 (m, 4H). MS: 284 (58%, [M•+]).
2-Ben zyl-2-[2-(d im eth yla m in o)eth yl]m a lon ic a cid d i-
eth yl ester (3a ). To a refluxing suspension of sodiumhydride
(1.2 g, 50 mmol) in toluene (500 mL) was added dropwise
2-benzylmalonic acid diethyl ester (12.6 g, 50 mmol). The
reaction mixture was refluxed for 1 h to give a clear yellow
solution. (2-Chloroethyl)dimethylamine (5.4 g, 50 mmol) was
added dropwise, and the reaction mixture was refluxed for 6
2-Ben zyl-2-[2-(d ieth yla m in o)eth yl]m a lon ic a cid d ieth -
yl ester (3l): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 0.98 (t,
J ) 7.1 Hz, 6H), 1.21 (t, J ) 7.2 Hz, 6H) 1.93 (t, J ) 7.7 Hz,
2H), 2.50 (q, J ) 7.1 Hz, 4H), 2.44-2.55 (m, 2H), 3.23 (s, 2H),
4.17 (q, J ) 7.2 Hz, 4H), 7.07-7.25 (m, 5H).
2-Ben zyl-2-(2-p ip er id in -1-yleth yl)m a lon ic a cid d ieth yl
ester (3m ): MS: 361.1 (7%, [M•+]).
2-Ben zyl-2-(2-m or p h olin -4-yleth yl)m a lon ic a cid d ieth -
yl ester (3n ): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.24 (t,
J ) 7.3 Hz, 6H), 1.96 (t, J ) 7.2 Hz, 2H), 2.35-2.41 (m, 6H),
3.24 (s, 2H), 3.66 (t, J ) 4.5 Hz, 4H), 7.05-7.25 (m, 5H), 4.20
(q, J ) 7.3 Hz, 4H). MS: 363.3 (1%, [M•+]).
2-Ben zyl-2-(2-p yr r olid in -1-yl-et h yl)m a lon ic a cid d i-
eth yl ester (3o): 1H NMR (CDCl3, 400 MHz, δ [ppm]) ) 1.20
(t, J ) 7.3 Hz, 6H), 1.72 (bs, 4H), 1.98-2.02 (m, 2H), 2.45-
2.50 (m, 6H), 3.22 (s, 2H), 4.14 (q, J ) 7.3 Hz, 4H), 7.07-7.23
(m, 5H). MS: 347.1 (2%, [M•+]).
2-Ben zyl-2-[2-(d im eth yla m in o)p r op yl]m a lon ic a cid d i-
eth yl ester (3p ): MS: 335.2 (0.2%, [M•+]).

M2-Selective Muscarinic Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5 863
2
2-Ben zyl-2-[2-(d im eth yla m in o)eth yl]m a lon ic Acid (4a ).
A solution of 3a (33.5 g, 0.1 mol), NaOH (14 g, 0.35 mol),
ethanol (100 mL) and water (50 mL) were refluxed for 4 h.
The resulting suspension was evaporated and the residue
dissolved in water (50 mL). Acetic acid was added dropwise
while cooling (5 °C) until a white solid was formed. The solid
product was filtered, washed with cold water (2 × 30 mL) and
ethanol (20 mL), and dried in a vacuum oven at 50 °C for 2
days to give a white-yellow solid (20.4 g, 77%).
3.08 (m, 2H), 3.34 (dd, J ) 18.5 Hz, J ) 8.3 Hz, 1H), 7.30-
7.75 (m, 4H).
2-[2-(Ben zylm eth yla m in o)eth yl]in d a n -1-on e (5o): IR
(NaCl, ν [cm-1]) ) 1705 (CdO).
2-[2-(Dim eth ylam in o)pr opyl]in dan -1-on e (5p): IR (NaCl,
ν [cm-1]) ) 1705 (CdO).
Dim eth yl{2-[5-m eth yl-3-(1-pyr idin -2-yleth yl)-1H-in den -
2-yl]eth yl}a m in e (6). To a solution of 2-ethylpyridine (2.35
g, 22 mmol) in dry ether (40 mL) was added 1.6 M butyllithium
(12.5 mL, 20 mmol) at -78 °C under nitrogen and stirred for
2 h at this temperature. To the dark red solution, 5b (2.18 g,
10 mmol) was added dropwise and stirred overnight at RT.
The reaction was quenched with cold water, washed with
saturated NaHCO3 (2 × 50 mL) and extracted with HCl (20%)
(2 × 25 mL). The water layer was refluxed for 1 h, cooled to
RT, basified with NH4OH sol. and extracted with ether (3 ×
50 mL). The ether was dried (Na2SO4) and evaporated to leave
a brown oil. This oil was purified by flash chromatography
eluting with toluene: acetone: methanol: NH4OH concentrated
2-[2-(Dim eth yla m in o)eth yl]in d a n -1-on e (5a ). 4a (13.25
g, 50 mmol) was added to polyphosphoric acid (80 g) at 90-
120 °C with overhead stirring. After the addition, the resulting
brown reaction mixture was heated to 140-150 °C and stirred
for 20 min at this temperature range. The reaction was
quenched with the cautious addition of ice chips, neutralized
with K2CO3 (2 M), and basified with NaOH (3 M). The mixture
was extracted with ether (3 × 100 mL), washed with water
(100 mL), dried (Na2SO4), and evaporated to give a yellow oil
(4.2 g, 41%) 1H NMR (CDCl3, 200 MHz, dδ [ppm]) ) 1.59-
1.64 (m, 1H), 2.10-2.16 (m, 1H), 2.23 (s, 6H), 2.39-2.45 (m,
2H), 2.69-2.75 (m, 1H), 2.79 (dd, 2J ) 17.3 Hz, J ) 4.4 Hz,
1
60:30:8:2, to yield a yellow oil (1.94 g, 63%). H NMR (CDCl3,
400 MHz, δ [ppm]) ) 1.75 (d, J ) 7.2 Hz, 3H), 2.22 (s, 3H),
2.25 (s, 6H), 2.37-2.52 (m, 2H), 2.61-2.74 (m, 2H), 3.33 (s,
2H), 4.45 (q, J ) 7.2 Hz, 1H), 6.85-7.51 (m, 6H), 8.60 (d, J )
4.8 Hz, 1H). MS: 306.1 (44%, [M•+]). Anal. (C21H26N2‚C4H4O4‚
0.1H2O) C, H, N, mp 117-118 °C.
2
1H), 3.31 (dd, J ) 17.3 Hz, J ) 9.4 Hz, 1H), 7.28 (d, J ) 7.4
Hz, 1H), 7.38 (t, J ) 7.4 Hz, 1H), 7.53 (t, J ) 7.4 Hz, 1H), 7.69
(d, J ) 7.4 Hz, 1H). MS: 203.2 (4%, [M•+]).
The following analogues were prepared using the procedure
outlined for 5a above.
The following analogues were prepared using the procedure
2-[2-(D im e t h y la m in o )e t h y l]-6-m e t h y lin d a n -1-o n e
(5b): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.39-1.57 (m,
1H), 1.99-2.13 (m, 1H), 2.15 (s, 6H), 2.30 (s, 3H), 2.31-2.40
outlined for 6 above.
{2-[5-Met h oxy-3-(1-p yr id in -2-ylet h yl)-1H -in d en -2-yl]-
m eth yl}d im eth yla m in e (7): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.74 (d, J ) 6.8 Hz, 3H), 2.28 (s, 6H), 2.47-2.54 (m,
2H), 2.67-2.76 (m, 2H), 3.32 (s, 2H), 3.65 (s, 3H), 4.44 (q, J )
6.8 Hz, 1H), 6.58-6.63 (m, 2H), 7.05-7.24 (m, 3H), 7.46-7.54
(m, 1H), 8.59 (d, J ) 4.9 Hz, 1H). MS: 322.2 (1%, [M•+]). Anal.
(C21H26N2O‚C4H4O4) C, H, N, mp 117-118 °C.
{2-[5-Ch lor o-3-(1-p yr id in -2-yle t h yl)-1H -in d e n -2-yl]-
m eth yl}d im eth yla m in e (8): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.72 (d, J ) 7.3 Hz, 3H), 2.23 (s, 6H), 2.41-2.48 (m,
2H), 2.59-2.67 (m, 2H), 3.34 (s, 2H), 4.43 (q, J ) 7.3 Hz, 1H),
6.96-7.19 (m, 5H), 7.46-7.50 (m,1H), 8.59 (d, J ) 4.5 Hz, 1H).
MS: 326.0 (16%, [M•+]). Anal. (C20H23ClN2‚C4H4O4) C, H, N,
mp 118-119 °C.
Dim eth yl{2-[5-m eth ylsu lfa n yl-3-(1-p yr id in -2-yleth yl)-
1H-in d en -2-yl]eth yl}a m in e (9): 1H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 1.74 (d, J ) 7.3 Hz, 3H), 2.32 (s, 6H), 2.35 (s, 3H),
2.49-2.77 (m, 4H), 3.35 (s, 2H), 4.45 (q, J ) 7.3 Hz, 1H), 6.96-
7.26 (m, 5H), 7.48-7.55 (m, 1H), 8.60 (d, J ) 4.8 Hz, 1H). Anal.
(C21H26N2S‚C4H4O4‚0.02H2O) C, H, N, mp 97-98 °C.
{2-[5-Flu or o-3-(1-pyr idin -2yleth yl)-1H-in den -2-yl]eth yl}-
d im eth yla m in e (10): 1H NMR (CDCl3, 200 MHz, δ [ppm])
) 1.72 (d, J ) 7.2 Hz, 3H), 2.23 (s, 6H), 2.45-2.53 (m, 2H),
2.66-2.74 (m, 2H), 3.32 (s, 2H), 4.43 (q, J ) 7.2 Hz, 1H), 6.67-
6.76 (m, 2H), 7.01-7.23 (m, 3H), 7.46-7.54 (m, 1H), 8.59 (d,
J ) 4.9 Hz, 1H). Anal. (C20H23FN2‚C4H4O4) C, H, N, mp 131-
132 °C.
{3-[6-Me t h yl-3-(1-p yr id in -2-yle t h yl)-1H -in d e n -2-yl]-
eth yl}d im eth yla m in e (11): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.72 (d, J ) 7.2 Hz, 3H), 2.22 (s, 3H), 2.26 (s, 6H),
2.42-2.49 (m, 2H), 2.63-2.70 (m, 2H), 3.34 (s, 2H), 4.43 (q, J
) 7.2 Hz, 1H), 6.85-7.49 (m, 6H), 8.60 (d, J ) 4.8 Hz, 1H).
Anal. (C21H26N2‚C4H4O4‚0.05H2O) C, H, N, mp 120-121 °C.
{3-[6-Met h oxy-3-(1-p yr id in -2-ylet h yl)-1H -in d en -2-yl]-
eth yl}d im eth yla m in e (12): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.72 (d, J ) 7.5 Hz, 3H), 2.26 (s, 6H), 2.42-2.49 (m,
2H), 2.63-2.70 (m, 2H), 3.34 (s, 2H), 3.75 (s, 3H), 4.43 (q, J )
7.5 Hz, 1H), 6.58-6.64 (m, 1H), 6.86-6.90 (m, 1H), 6.95-6.96
(m, 1H), 7.03-7.09 (m, 1H), 7.13-7.17 (m, 1H), 7.44-7.52 (m,
1H), 8.60 (d, J ) 4.8 Hz, 1H). Anal. (C21H26N2O‚C4H4O4) C, H,
N, mp 119-120 °C.
2
2
(m, 2H), 2.70 (dd, J ) 17.4 Hz, J ) 4.4 Hz, 1H), 3.21 (dd, J
) 17.4 Hz, J ) 9.3 Hz, 1H), 7.24-7.44 (m, 3H).
2-[2-(Dim eth ylam in o)eth yl]-6-m eth oxyin dan -1-on e (5c):
MS: 233.2 (25%, [M•+]).
6-C h lo r o -2-[2-(d im e t h y la m in o )e t h y l]in d a n -1-o n e
(5d ): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.45-1.59 (m,
1H), 2.00-2.15 (m, 1H), 2.13 (s, 6H), 2.24-2.32 (m, 2H), 2.61-
2
2.67 (m, 1H), 2.68-2.78 (m, 1H), 3.21 (dd, J ) 17.5 Hz, J )
9 Hz, 1H), 7.24-7.54 (m, 3H).
2-[2-(Dim eth yla m in o)eth yl]-6-m eth ylsu lfa n ylin d a n -1-
on e (5e): IR (NaCl, ν [cm-1]) ) 1700 (CdO).
2-[2-(Dim eth yla m in o)eth yl]-6-flu or oin d a n -1-on e (5f):
IR (NaCl, ν [cm-1])) ) 1710 (CdO).
2-[2-(Dim eth yla m in o)eth yl]-5-m eth ylin d a n -1-on e (5 g):
MS: 217 (5%, [M•+]).
2-[2-(Dim eth ylam in o)eth yl]-5-m eth oxyin dan -1-on e (5h ):
IR (NaCl, ν [cm-1]) ) 1700 (CdO).
5-Ch lor o-2-[2-(d im eth yla m in o)eth yl]in d a n -1-on e (5i):
1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.51-1.65 (m, 1H),
2.03-2.13 (m, 1H), 2.18 (s, 6H), 2.25-2.41 (m, 2H), 2.65-2.73
(m, 1H), 2.75-2.82 (m, 1H), 3.29 (dd, 2J ) 17.4 Hz, J ) 4.4
Hz, 1H), 7.30 (d, J ) 8.1 Hz, 1H), 7.40 (s, 1H), 7.63 (d, J ) 8.1
Hz, 1H). MS: 239.1 (0.4%) and 237.1 (1%) [M•+].
2-(2-Mor p h olin -4-yleth yl)in d a n -1-on e (5j): IR (NaCl, ν
[cm-1]) ) 1695 (CdO).
2-(2-P yr r olid in -1-yleth yl]in d a n -1-on e (5k ): 1H NMR
(CDCl3, 200 MHz, δ [ppm]) ) 1.63-1.75 (m, 5H), 2.10-2.22
(m, 1H), 2.47-2.61 (m, 6H), 2.62-2.71 (m, 1H), 2.81 (dd, 2J )
2
17.4 Hz, J ) 4.4 Hz, 1H), 3.32 (dd, J ) 17.4 Hz, J ) 9.4 Hz,
1H), 7.28-7.78 (m, 4H).
2-(2-P ip er id in -1-ylet h yl]in d a n -1-on e (5l): 1H NMR
(CDCl3, 200 MHz, δ [ppm]) ) 1.31-1.45 (m, 6H), 1.58-1.69
(m, 1H), 2.02-2.14 (m, 1H), 2.28-2.40 (m, 6H), 2.54-2.68 (m,
2
2
1H), 2.76 (dd, J ) 17 Hz, J ) 4.3 Hz, 1H), 3.24 (dd, J ) 17
Hz, J ) 7.9 Hz, 1H), 7.27-7.68 (m, 4H). MS: 242.9 (10%,
[M•+]).
2-[2-(Diet h yla m in o)et h yl]in d a n -1-on e (5m ): 1H NMR
(CDCl3, 200 MHz, δ [ppm]) ) 0.99 (t, J ) 7.1 Hz, 6H), 1.52-
1.66 (m, 1H), 2.06-2.21 (m, 1H), 2.45-2.56 (m, 4H), 2.55-
2.68 (m, 3H), 2.78 (dd, 2J ) 17.4 Hz, J ) 4.4 Hz, 1H), 3.31
{2-[6-Ch lor o-3-(1-p yr id in -2-yle t h yl)-1H -in d e n -2-yl]-
eth yl}d im eth yla m in e (13): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.72 (d, J ) 7.3 Hz, 3H), 2.23 (s, 6H), 2.41-2.48 (m,
2H), 2.59-2.67 (m, 2H), 3.34 (s, 2H), 4.44 (q, J ) 7.3 Hz, 1H),
6.87-6.95 (m, 1H), 7.00-7.17 (m, 3H), 7.31 (m, 1H), 7.46-
2
(dd, J ) 17.4 Hz, J ) 9.3 Hz, 1H), 7.28-7.77 (m, 4H).
2-[2-(Diisopr opylam in o)eth yl]in dan -1-on e (5n ): 1H NMR
(CDCl3, 200 MHz, δ [ppm]) ) 1.00 (m, 12H), 1.47-1.54 (m,
1H), 2.09-2.16 (m, 1H), 2.59 (m, 2H), 2.77-2.86 (m, 2H), 3.02-

864 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Bohme et al.
7.50 (m, 1H), 8.59 (d, J ) 4.5 Hz, 1H). Anal. (C20H23ClN2‚
C4H4O4) C, H, N, mp 115-116 °C.
Dim eth yl[2-(3-p yr id in -2-ylm eth yl-1H-in d en -2yl)eth yl]-
a m in e (27): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 2.34 (s,
6H), 2.55-2.63 (m, 2H), 2.76-2.84 (m, 2H), 3.41 (s, 2H), 4.09
(s, 2H), 7.05-7.52 (m, 7H), 8.52 (d, J ) 4.9 Hz, 1H). MS: 278.4
(0.1%, [M•+]). Anal. (C19H22N2‚C4H4O4) C, H, N, mp 139-140
°C.
Dim eth yl[2-(3-p yr id in -4-ylm eth yl-1H-in d en -2yl)eth yl]-
a m in e (28): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 2.22 (s,
6H), 2.40-2.50 (m, 2H), 2.63-2.73 (m, 2H), 3.41 (s, 2H), 3.90
(s, 2H), 6.96-7.20 (m, 5H), 7.37-7.43 (m, 1H), 8.42 (d, J )
4.9 Hz, 2H). Anal. (C19H22N2‚C4H4O4‚0.07H2O) C, H, N, mp
147-148 °C.
{2-[6-Ch lor o-3-(1-p yr id in -2-ylp r op yl)-1H -in d en -2-yl]-
eth yl}d im eth yla m in e (14): 1H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 0.93 (t, J ) 7.4 Hz, 3H), 2.30 (s, 6H), 2.44-2.81 (m,
6H), 3.39 (s, 2H), 4.13-4.21 (m, 1H), 7.01-7.31 (m, 5H), 7.42-
7.51 (m, 1H), 8.58 (d, J ) 4.8 Hz, 1H). Anal. (C21H25ClN2‚
C4H4O4) C, H, N, mp 119-120 °C.
2-{1-[2-(2-P ip er id in -1-ylet h yl)-1H -in d en -2-yl]et h yl}-
p yr id in e (15): 1H NMR (CDCl3, 400 MHz, δ [ppm]) ) 1.41-
1.44 (m, 2H), 1.60 (quint, 4H), 1.75 (d, J ) 7.3 Hz, 3H), 2.44-
2.57 (m, 6H), 2.72-2.77 (m, 2H), 3.37 (s, 2H), 4.47 (q, J ) 7.3
Hz, 1H), 6.99-7.08 (m, 4H), 7.16 (m, 1H), 7.35 (m, 1H), 7.47
(m, 1H), 8.59 (d, J ) 4.9 Hz, 1H). MS: 332.1 (2%, [M•+]). Anal.
(C23H28N2‚C4H4O4‚0.16H2O) C, H, N, mp 114-115 °C.
4-{-2-[3-(1-P yr id in -2-yle t h yl)-1H -in d e n -2-yl]e t h yl}-
m or p h olin e (16): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.78
(d, J ) 7.3 Hz, 3H), 2.47-2.60 (m, 6H), 2.70-2.79 (m, 2H),
3.41 (s, 2H), 3.71 (t, J ) 5.9 Hz, 4H), 4.48 (q, J ) 7.3 Hz, 1H),
7.0-7.21 (m, 5H), 7.33-7.40 (m, 1H), 7.48-7.52 (m, 1H), 8.61
(d, J ) 4.5 Hz, 1H). MS: 334.3 (2%, [M•+]). Anal. (C22H26N2O‚
C4H4O4) C, H, N, mp 119-120 °C.
2-{-1-[2-(3-P yr r olid in -1-yleth yl)-1H-in d en -2-yl]eth yl}-
p yr id in e (17): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.72-
1.80 (m, 7H), 2.57-2.82 (m, 8H), 3.40 (s, 2H), 4.48 (q, J ) 7.4
Hz, 1H), 6.98-7.11 (m, 4H), 7.17-7.20 (m, 1H), 7.34-7.39 (m,
1H), 7.48-7.53 (m, 1H), 8.60 (d, J ) 6.3 Hz, 1H). Anal.
(C22H26N2‚C4H4O4‚0.66 H2O) C, H, N, mp 131-132 °C.
Dieth yl{2-[3-(1-pyr idin -2-yleth yl)-1H-in den -2-yl]eth yl}-
a m in e (18): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.04 (t, J
) 7.6 Hz, 6H), 1.75 (d, J ) 7.3 Hz, 3H), 2.56 (q, J ) 7.6 Hz,
4H), 2.51-2.74 (m, 4H), 3.39 (s, 2H), 4.48 (q, J ) 7.3 Hz, 1H),
7.00-7.11 (m, 4H), 7.14-7.17 (m, 1H), 7.33-7.40 (m, 1H),
7.46-7.52 (m, 1H), 8.59 (d, J ) 4.5 Hz, 1H). Anal. (C22H28N2‚
C4H4O4) C, H, N, mp 90-91 °C.
Diisop r op yl{2-[3-(1-p yr id in -2-yleth yl)-1H-in d en -2-yl]-
eth yl}a m in e (19): 1H NMR (CDCl3, 200 MHz, δ [ppm]) )
1.04 (m, 12H) 1.77 (d, J ) 7.3 Hz, 3H), 2.62 (m, 4H), 3.06 (m,
2H), 3.41 (s, 2H), 4.46 (q, J ) 7.3 Hz, 1H), 7.00-7.22 (m, 5H),
7.33-7.37 (m, 1H), 7.43-7.48 (m, 1H), 8.59 (d, J ) 3.9 Hz,
1H). Anal. (C24H32N2‚C7H8SO3) C, H, N. Exact mass
(C24H33N2+‚C7H7SO3-): 349.2638 ( 1.2 ppm, mp 175-176 °C.
Dim eth yl{3-[5-m eth yl-3-(1-pyr idin -2-yleth yl)-1H-in den -
2-yl]p r op yl}a m in e (22): 1H NMR (CDCl3, 200 MHz, δ [ppm])
) 1.20-1.27 (m, 2H), 1.73 (d, J ) 7.2 Hz, 3H), 2.26 (s, 6H),
2.43-2.51 (m, 2H), 2.66-2.74 (m, 2H), 3.36 (s, 2H), 4.44 (q, J
) 7.2 Hz, 1H), 6.99-7.26 (m, 6H), 7.49-7.57 (m, 1H), 8.61 (d,
J ) 4.8 Hz, 1H). Anal. (C21H26N2‚C4H4O4) C, H, N, mp 149-
150 °C.
Dim et h yl{2-[3-(1-p yr id in -2-ylp r op yl)-1H -in d en -2-yl]-
eth yl}a m in e (23): 1H NMR (CDCl3, 200 MHz, δ [ppm]) )
0.93 (t, J ) 7.4 Hz, 3H), 2.27 (s, 6H), 2.43-2.78 (m, 6H), 3.39
(s, 2H), 4.15-4.23 (m, 1H), 7.03-7.47 (m, 7H), 8.58 (d, J )
4.8 Hz, 1H). Anal. (C21H26N2‚C4H4O4) C, H, N, mp 118-119
°C.
Dim e t h yl{2-[3-(1-p yr id in -2-ylb u t yl)-1H -in d e n -2-yl]-
eth yl}a m in e (24): 1H NMR (CDCl3, 200 MHz, δ [ppm]) )
0.94 (t, J ) 7.2 Hz, 3H), 1.24-1.39 (m, 2H), 2.09-2.23 (m, 2H),
2.29 (s, 6H), 2.42-2.53 (m, 2H), 2.71-2.86 (m, 2H), 3.40 (s,
2H), 4.27-4.34 (m, 1H), 7.01-7.50 (m, 7H), 8.57-8.60 (d, J )
4.8 Hz, 1H). Anal. (C22H28N2‚C4H4O4) C, H, N, mp 107-108
°C.
Dim et h yl{2-[3-(p h en ylp yr id in -2-ylm et h yl)-1H -in d en -
2-yl]eth yl}a m in e (25): 1H NMR (CDCl3, 200 MHz, δ [ppm])
) 2.13 (s, 6H), 2.25-2.33 (m, 2H), 2.52-2.61 (m, 2H), 3.43 (s,
2H), 5.82 (s, 1H), 6.79-7.38 (m, 11H), 7.51-7.60 (m, 1H), 8.58
(d, J ) 4.5 Hz, 1H). MS: 91.1 (100%, [C7H7•+]). Anal. (C25H31N2‚
C4H4O4‚H2O) C, H, N, mp 146-147 °C.
Dim eth yl[3-(1-p yr id in -2-yleth yl)-1H-in d en -2-ylm eth yl]-
a m in e (31): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.75 (d, J
2
) 7.3 Hz, 3H), 2.24 (s, 6H), 3.34 (d, J ) 14 Hz, 1H), 3.40 (d,
2J ) 14 Hz, 1H), 3.51 (s, 2H), 4.59 (q, J ) 7.3 Hz, 1H), 7.05-
7.16 (m, 5H), 7.39-7.41 (m, 1H), 7.48 (dt, J ) 7.8 Hz, 4J ) 1.9
Hz, 1H), 8.60 (d, J ) 4.4 Hz, 1H). Anal. (C19H22N2‚C4H4O4) C,
H, N, mp 162-163 °C.
Isop r op ylm et h yl[3-(1-p yr id in -2-ylet h yl)-1H -in d en -2-
ylm eth yl]a m in e (32). 1H NMR (CDCl3, 400 MHz, δ [ppm])
) 1.06 (d, J ) 6.8 Hz, 6H), 1.75 (d, J ) 6.8 Hz, 3H), 2.19 (s,
3H), 2.98 (sept, J ) 6.8 Hz, 1H), 3.50 (s, 2H), 3.56 (s, 2H),
4.58 (q, J ) 6.8 Hz, 1H), 7.05-7.16 (m, 5H), 7.36-7.53 (m,
2H), 8.58-8.60 (m, 1H). Anal. (C21H24N2) C, H, N, oil.
Ben zylm et h yl{2-[[3-(1-p yr id in -2-ylet h yl)-1H -in d en -2-
yl]eth yl}a m in e (39): 1H NMR (CDCl3, 200 MHz, δ [ppm]) )
1.72 (d, J ) 7.3 Hz, 3H), 2.28 (s, 3H), 2.58-2.77 (m, 4H), 3.33
(s, 2H), 3.56 (s, 2H), 4.43 (q, J ) 7.3 Hz, 1H), 7.03-7.49 (m,
12H), 8.58 (d, J ) 4.9 Hz, 1H).
Meth yl{2-[3-(1-p yr id in -2-yleth yl)-1H-in d en -2yl]eth yl}-
a m in e (40). To a solution of 39 (4.8 g, 12.7 mmol) in ethanol
(30 mL) was added formic acid (95%) (2.5 g, 51 mmol). This
solution was added to freshly activated palladium on charcoal
(10%) (0.72 g) in ethanol (20 mL) and stirred for 12 h under
H2. The catalyst was filtered and the solvent evaporated to
leave an orange oil. The oil was purified by flash chromatog-
raphy (silica gel) eluting with toluene:acetone:methanol:
NH4OH concentrated 60:30:8:2 to give a yellow oil (1.68 g,
47.6%). 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.75 (d, J )
7.3 Hz, 3H), 2.45 (s, 3H), 2.73-2.85 (m, 4H), 3.38 (s, 2H), 4.50
(q, J ) 7.3 Hz, 1H), 6.96-7.16 (m, 4H), 7.25 (d, J ) 7.8 Hz,
4
1H), 7.31-7.38 (m, 1H), 7.54 (dt, J ) 7.3 Hz, J ) 2 Hz, 1H),
8.54 (d, J ) 4.9 Hz, 1H).
(2-F lu or oet h yl)m et h yl{2-[3-(1-p yr id in -2-ylet h yl)-1H -
in d en -2-yl]eth yl}a m in e (20). To a suspension of K2CO3 (1.4
g, 10 mmol) in acetone (20 mL) was added 40 (1.39 g, 5 mmol)
and 1-bromo-2-fluoro-ethan (0.63 g, 5 mmol). The reaction
mixture was refluxed for 4 h. The suspension was filtered and
the solvent was evaporated to leave a yellow oil. This oil was
purified by flash chromatography (silica gel) eluting with
toluene: acetone: methanol: NH4OH concentrated 60:30:8:2 to
1
give a yellow oil (0.48 g, 29%). H NMR (CDCl3, 200 MHz, δ
[ppm]) ) 1.75 (d, J ) 7.3 Hz, 3H), 2.35 (s, 3H), 2.60-2.74 (m,
4H), 2.74 (dt, J HF ) 27.3 Hz, J HH ) 4.9 Hz, 2H), 3.39 (s, 2H),
4.47 (q, J ) 7.3 Hz, 1H), 4.53 (dt, J HF ) 47.3 Hz, J HH ) 4.9
Hz, 2H), 7.02-7.11 (m, 4H), 7.17 (d, J ) 7.8 Hz, 1H), 7.49 (dt,
J ) 7.3 Hz, 4J ) 2 Hz, 1H), 8.59 (d, J ) 4.9 Hz, 1H). Anal.
(C21H25FN2‚C4H4O4) C, H, N, mp 118-119 °C.
The following analogue was prepared using the procedure
outlined for 20 above.
Isopropyl-methyl-{2-[3-(1-pyridin-2-yl-ethyl)-1H-inden-2-yl]-
ethyl}-amine (21): 1H NMR (CDCl3, 200 MHz, δ [ppm]) ) 1.00
(d, J ) 6.8 Hz, 6H), 1.76 (d, J ) 6.8 Hz, 3H), 2.25 (s, 3H),
2.56-2.74 (m, 4H), 2.87 (sept, J ) 6.8 Hz, 1H), 3.39 (s, 2H),
4.47 (q, J ) 6.8 Hz, 1H), 6.98-7.10 (m, 4H), 7.18 (d, J ) 7.8
2
Hz, 1H), 7.43-7.37 (m, 1H), 7.48 (dt, J ) 7.3 Hz, J ) 2 Hz,
1H), 8.58 (d, J ) 4.9 Hz, 1H). Anal. (C22H28N2‚C4H4O4) C, H,
N.
Dim eth yl{2-[3-(1-m eth yl-1-pyr idin -2-yleth yl)-1H-in den -
1
2-yl]eth yl}a m in e (26): H NMR (CDCl3, 200 MHz, δ [ppm])
Dim et h yl{2-[3-(1-p h en ylet h yl)-1H -in d en e-2-yl]et h yl-
a m in e (30). To a solution of 1-bromo-ethyl-benzene (3.7 g, 20
mmol) in dry ether (50 mL) was added lithium (0.14 g, 20
mmol) under nitrogen and stirred for 1 h. 5a (4.05 g, 20 mmol)
was added dropwise and the reaction mixture was stirred
) 1.81 (s, 6H), 2.28 (s, 6H), 2.50-2.58 (m, 2H), 2.84-2.92 (m,
2H), 3.44 (s, 2H), 6.46 (d, J ) 7.3 Hz, 1H), 6.85-7.50 (m, 6H),
8.59 (d, J ) 4.8 Hz, 1H). Anal. (C21H26N2‚C4H4O4) C, H, N, mp
128-129 °C.

M2-Selective Muscarinic Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5 865
overnight. The suspension was quenched with ice chips. The
organic layer was washed with water (2 × 30 mL) and
extracted with HCl (20%) (2 × 25 mL). The water layer was
refluxed for 1 h, basified with NH4OH (pH>10), and extracted
with ether (3 × 30 mL). The ether layer was dried (Na2SO4)
and evaporated to leave a brown oil. This oil was purified by
flash chromatography (silica gel) eluting with toluene: acetone:
methanol: NH4OH concentrated 60:30:8:2 to give a yellow oil
(0.62 g, 21%). 1H NMR (CDCl3, 400 MHz, dδ [ppm]) ) 1.68 (d,
J ) 7.2 Hz, 3H), 2.27 (s, 6H), 2.41-2.54 (m, 4H), 3.37 (s, 2H),
4.37 (q, J ) 7.2 Hz, 1H), 6.96-7.36 (m, 9H). MS: 291 (0.2%,
[M•+]). Anal. (C21H25N‚C4H4O4) C, H, N, mp 159-160 °C.
[2-(1H-In d en -2-yl)eth yl]d im eth yla m in e (38). To a solu-
tion of 5a (8.1 g, 40 mmol) in ethanol (100 mL) was added
sodiumborohydride (0.96 g, 40 mmol) portionwise with stirring.
The reaction mixture was refluxed for 2 h, concentrated in
vacuo and diluted with water (150 mL). The emulsion was
extracted with ether (3 × 100 mL), dried (Na2SO4) and
evaporated to give a yellow oil of 2-[2-(dimethylamino)-ethyl]-
indan-1-ole. To this oil acetic acid (90 mL) and HCl concen-
trated (35 mL) were added and refluxed for 90min. Most of
the solvent was evaporated in vacuo, the residue diluted with
water (100 mL), basified with NH4OH (pH>10), extracted with
ether (2 × 100 mL), dried (Na2SO4) and concentrated to give
7.44-7.46 (m, 1H), 8.42 (m, 2H). Anal. (C20H23N3O‚2 C4H4O4)
C, H, N, mp 126-127 °C.
Ben zyl(2-ch lor oet h yl)m et h yla m in e H yd r och lor id e
(41a ). To 2-(benzyl-methyl-amino)-ethanol (40.3 g, 0.2 mol)
was added dropwise HCl (15%) to pH<2. Chloroform (200 mL)
was added and the emulsion was refluxed under Dean-Stark
conditions until water was no longer separated. Chloroform
was evaporated and to the oily residue was added dropwise
thionyl chloride (35.7 g, 0.3 mol) under external ice-cooling.
The reaction mixture was then refluxed for 3 h. The excess of
thionyl chloride was evaporated in vacuo, the residue was
washed with cold ethanol (100 mL) and dried in a vacuum oven
overnight at RT to give a white solid (41.7 g, 94%). CHN
theory/found (%): C: 54.76/54.82 H: 6.87/7.01 N: 6.36/6.35.
(2-Chloro-ethyl)-diisopropylamine (41b) was prepared by using
the procedure outlined for 41a above.
1H-In d en e-2-ca r boxylic Acid 2-(d im eth yla m in o)eth yl
Ester (42a ). The reagents indene (11.6 g, 100 mmol) and
oxalyl bromide (10.8 g, 50 mmol) were heated neat to 90 °C
for 5 h. The dark reaction mixture was cooled to RT and diluted
with THF (100 mL). 2-Dimethylaminoethanol (4.45 g, 50
mmol) was added and heated to reflux for 2 min. The
suspension was concentrated in vacuo, and the residue was
diluted with HCl (5%) (200 mL), washed with CH2Cl2 (3 × 50
mL), basified with NH4OH and extracted with CH2Cl2 (3 ×
50 mL). The organic layer was washed with water (3 × 50 mL),
dried (MgSO4), and evaporated to leave a yellow oil (6.4 g,
56%). The product was used without further purification. 1H-
Indene-2-carboxylic acid (2-(dimethylamino)ethyl)amide (42b)
was prepared using N,N-dimethylethane-1,2-diamine in the
procedure above.
2-(Dim eth yla m in om eth yl)in d a n -1-on e Hyd r och lor id e
(43) (Meth od A).22 To a solution of indan-1-one (5.3 g, 40
mmol) in ethanol (30 mL) were added paraformaldehyde (3.3
g) and dimethylamine hydrochloride (4.8 g, 60 mmol). The
mixture was refluxed for 15 min. Then, two drops of concen-
trated HCl were added in order to dissolve the surplus
paraformaldehyde, and the homogeneous mixture was allowed
to stand at RT overnight. The hygroscopic white solid was
filtered under nitrogen and dried in a vacuum oven at RT for
24 h (5.8 g, 64%).
2-[(Isop r op ylm et h yla m in o)m et h yl]in d a n -1-on e (44)
(Meth od B).22 To a solution of indan-1-one (2.6 g, 20 mmol)
in ethanol (60 mL) was added paraformaldehyde (0.6 g, 20
mmol) and isopropylmethylamine hydrochloride (2.0 g, 20
mmol). The mixture was refluxed until a homogeneous solution
was formed. The addition of paraformaldehyde (0.6 g, 20 mmol)
was repeated twice for a total of three additions. Concentrated
HCl (1.5 mL) was subsequently added in order to dissolve the
surplus paraformaldehyde. The mixture was concentrated,
NaOH (2 M) (100 mL) was added and the basic layer was
extracted with ether (3 × 100 mL). The ether layer was dried
(Na2SO4) and concentrated in vacuo to give a yellow oil (2.65
g, 61%).
1
a yellow oil (7.2 g, 96%). H NMR (CDCl3, 200 MHz, δ [ppm])
) 2.30 (s, 6H), 2.54-2.69 (m, 4H), 3.33 (s, 2H), 6.53 (s, 1H),
7.08-7.38 (m, 4H).
Dim eth yl[2-(3-p yr id in -3-ylm eth yl-1H-in d en -2-yl)eth yl]-
a m in e (29). To a solution of 38 (0.94 g, 5.0 mmol) in THF (50
mL) was added butyllithium 1.6 M (3.1 mL, 5.0 mmol). This
mixture was stirred for 1 h at -78 °C under nitrogen.
3-Chloromethylpyridine (0.64 g, 5.0 mmol) was added, the
reaction mixture was stirred for 6 h at RT and the solvent
was evaporated. The residue was diluted with ether (50 mL),
washed with water (2 × 30 mL), dried (Na2SO4) and concen-
trated in vacuo to leave a brown oil. This oil was purified by
flash chromatography (silica gel) eluting with toluene: acetone:
methanol: NH4OH concentrated 60:30:8:2 to give a yellow oil
(0.9 g, 64%). 1H NMR (CDCl3, 400 MHz, δ [ppm]) ) 2.27 (s,
6H), 2.47-2.51 (m, 2H), 2.70-2.74 (m, 2H), 3.41 (s, 2H), 3.90
(s, 2H), 7.04-7.17 (m, 3H), 7.22-7.25 (m, 1H), 7.38 (m, 1H),
7.44-7.47 (m, 1H), 8.39-8.41 (m, 1H), 8.53 (m, 1H). Anal.
(C19H22N2‚C4H4O4) C, H, N, mp 116-117 °C.
The following analogues were prepared using the procedure
outlined for 29 above.
3-P yr idin -2-ylm eth yl-1H-in den e-2-car boxylic acid 2-(di-
m eth yla m in o)eth yl ester (33): 1H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 2.35 (s, 6H), 2.72 (t, J ) 5.8 Hz, 2H), 3.76 (s, 2H),
4.39 (t, J ) 5.8 Hz, 2H), 4.68 (s, 2H), 7.04-7.09 (m, 1H), 7.18-
7.34 (m, 3H), 7.44-7.56 (m, 3H), 8.51 (d, J ) 4.4 Hz, 1H). Anal.
(C20H22N2O2‚2 C4H4O4‚0.42 H2O) C, H, N, mp 134-135 °C.
3-P yr idin -3-ylm eth yl-1H-in den e-2-car boxylic acid 2-(di-
1
m eth yla m in o)eth yl ester (34): H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 2.32 (s, 6H), 2.67 (t, J ) 5.8 Hz, 2H), 3.75 (s, 2H),
4.36 (t, J ) 5.8 Hz, 2H), 4.46 (s, 2H), 7.10-7.59 (m, 6H), 8.41
(m, 1H), 8.61 (m, 1H). Anal. (C20H22N2O2‚2 C4H4O4‚0.16 H2O)
C, H, N, mp 77-78 °C.
2-Isop r op ylp yr id in e (45). To a solution of 2-ethyl-pyridine
(16.5 g, 0.154 mol) in THF (50 mL) was added 1.6 M
butyllithium (94.4 mL, 0.151 mol) at -78 °C under nitrogen
and stirred for 2 h at this temperature. Iodomethane (21.4 g,
0.151mol) was added dropwise to the resulting dark red
solution and stirred overnight at RT. The solvent was evapo-
rated and the residue diluted with ether (200 mL). The organic
layer was washed with water (2 × 100 mL), dried (Na2SO4),
filtered and concentrated in vacuo to give a brown oil. The oil
was purified by distillation at 153 °C with a spinning band
3-P yr idin -2-ylm eth yl-1H-in den e-2-car boxylic acid 2-(di-
m eth yla m in o)eth yl a m id e (35): 1H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 2.23 (s, 6H), 2.51-2.58 (m, 2H), 3.52-3.61 (m, 2H),
3.73 (s, 2H), 4.28 (s, 2H), 7.07-7.28 (m, 3H), 7.40-7.45 (m,
3H), 7.57-7.62 (m, 1H), 8.43 (d, J ) 4.3 Hz, 1H), 9.85 (m, 1H).
Anal. (C20H23N3O‚C4H4O4‚0.13H2O) C, H, N, mp 114-115 °C.
3-P yr idin -3-ylm eth yl-1H-in den e-2-car boxylic acid 2-(di-
m eth yla m in oeth yl) a m id e (36): 1H NMR (CDCl3, 400 MHz,
δ [ppm]) ) 2.25 (s, 6H), 2.47 (t, J ) 5.9 Hz, 2H), 3.42-3.47
(m, 2H), 3.67 (s, 2H), 4.47 (s, 2H), 6.54 (m, 1H), 7.10-7.13 (m,
1H), 7.24-7.27 (m, 2H), 7.32-7.35 (m, 1H), 7.43-7.45 (m, 1H),
7.62 (m, 1H), 8.37 (d, J ) 3.8 Hz, 1H), 8.60 (m, 1H). Anal.
(C20H23N3O‚2 C4H4O4) C, H, N, mp 116-117 °C.
1
column (13.2 g, 71%). H NMR (CDCl3, 200 MHz, δ [ppm]) )
1.27 (d, J ) 6.9 Hz, 6H), 3.02 (sept, J ) 6.9 Hz, 1H), 7.02-
7.14 (m, 2H), 7.52-7.60 (m, 1H), 8.50 (d, J ) 4.4 Hz, 1H).
P h a r m a cology. Mu sca r in ic Recep tor Bin d in g Stu d ies.
Radioligand binding studies at the five cloned human musca-
rinic receptors stably expressed in CHO-K1 cells were per-
formed by the methods described by Do¨rje et al.29 and Buckley
et al.30 with the following modifications. Transfected CHO-
K1 cells were grown in Dulbecco’s modified Eagle’s medium
supplemented with 10% fetal calf serum, 100 IU/mL penicillin
3-P yr idin -4-ylm eth yl-1H-in den e-2-car boxylic acid 2-(di-
m eth yla m in o)eth yl a m id e (37): 1H NMR (CDCl3, 200 MHz,
δ [ppm]) ) 2.23 (s, 6H), 2.45-2.51 (m, 2H), 3.41-3.49 (m, 2H),
3.70 (s, 2H), 4.48 (s, 2H), 6.59 (m, 1H), 7.21-7.28 (m, 5H),

866 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
Bohme et al.
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substituted piperazinyl)-2-propanones and Related Compounds.
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G, 100 µg/mL streptomycin, 2 mM glutamine, and 0.1 mM
nonessential amino acids. At confluence, they were washed,
scraped into ice-cold binding buffer, and homogenized for 45 s
using a Branson Sonifier. Membranes were pelleted at 30.600g,
rehomogenized, and stored at _80 °C. Protein concentrations
were determined according to the method of Lowry et al.31
using a Bio-Rad protein assay kit. Final membrane protein
concentrations in the assay were (mg/mL): M1 ) 2, M2 ) 6,
M3 ) 2, M4 ) 2, M5 ) 5.
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Binding buffer consisted of 20 mM HEPES (pH 7.4), 10 mM
MgCl2, and 100 mM NaCl. Incubations were carried out at 25
°C for 2 h with 0.2 nM [3H]NMS (78-85 Ci/mmol; Amersham
International, Bucks, England). Assays were terminated by
filtration through a Brandell cell harvester onto Whatman
GF/B filters. Membranes were washed three times with 1 mL
buffer, transferred to 3 mL of scintillant (Quickszint 2000,
Zinsser Analytik, Frankfurt, Germany or Lumasafe Plus,
Packard Bioscience, Dreieich, Germany), and counted in a
Wallac beta counter.
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Data were analyzed by a curve fitting procedure using the
program GraphPad Prism. The Ki values of the test compounds
were derived from IC50 values using the Cheng-Prusoff equa-
tion,32 Ki ) IC50/(1 + L/Kd), with the radioligand concentration
L ) 0.2 nM and the following equilibrium dissociation con-
stants KD of [3H] NMS, determined in previous saturation
binding experiments (nM): M1: 0.19 ) M2 ) 0.33; M3 ) 0.17;
M4 ) 0.10; M5 ) 0.48.
Hista m in e Recep tor Bin d in g Stu d ies. Radioligand bind-
ing studies at the human histamine H1 receptor, stably
expressed in CHO-K1 cells, were carried out as described for
the muscarinic binding assay. The final membrane protein
concentration was 18 µg/mL, and nonspecific binding was
determined by adding 0.1 mM terfenadine. The radioligand
was [3H]mepyramine (1.0 nM; 28 Ci/mmol, Amersham Bio-
science Europe, Freiburg, Germany), the equilibrium dissocia-
tion constant of which (0.84 ( 0.09 nM) was determined in
previous saturation experiments.
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mine: The Resolution, Chiral Analysis, and Biological Evalua-
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Agents Actions 1992, C440-C443.
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Effects of Dimethindene Maleate (Fenistil) on Histaminic,
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Methylthiobenzyl Chloride - Case of Isomer Control in an
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All affinity data (pKi values) are presented as arithmetic
means ( SD from at least three experiments performed in
duplicate.
Ack n ow led gm en t. The authors thank the Institute
of Chemistry of the University of Mainz, Germany, for
spectral and analytical determinations, the Fonds der
Chemischen Industrie, Germany, and the Deutsche
Forschungsgemeinschaft (grant number: GRK 137/2
-98 and 137/3-01) for financial support. CHO-K1 cells
stably expressing cDNA encoding human histamine H1
receptors were generously provided by Dr. R. Leurs and
Dr. H. Timmermann (Free University of Amsterdam,
The Netherlands).
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