New substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with α2-adrenoceptor antagonist activity

Article abstract of DOI:10.1021/jm991121g

The emergence of a novel theory concerning the role of noradrenaline in the progression and the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases has provided a new impetus toward the discovery of novel compounds acting at α₂-adrenoceptors. A series of substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series of compounds proved to be potent α₂-adrenoceptor antagonists with good selectivity versus α₁-adrenergic and D₂-dopamine receptors. Particular emphasis is given to compound 33g which displays potent α₂-adrenoceptor binding affinity in vitro and central effects in vivo following oral administration.

Full text of DOI:10.1021/jm991121g

J . Med. Chem. 2000, 43, 3653-3664
3653
New Su bstitu ted 1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip er id in -4-yl
Der iva tives w ith r2-Ad r en ocep tor An ta gon ist Activity
Patrice Mayer,# Pascale Brunel,# Ce´line Chaplain,# Christel Piedecoq,# Francis Calmel,# Philippe Schambel,†
Philippe Chopin,§ Thierry Wurch,‡ Petrus J . Pauwels,‡ Marc Marien,§ J ean-Louis Vidaluc,*,# and
Thierry Imbert*,#
Division of Medicinal Chemistry, Department of Analytical Chemistry, Division of Neurobiology, and Department of Cellular
and Molecular Biology, Centre de Recherche Pierre Fabre, 17, Avenue J ean Moulin, 81100 Castres, France
Received J uly 19, 1999
The emergence of a novel theory concerning the role of noradrenaline in the progression and
the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases
has provided a new impetus toward the discovery of novel compounds acting at R2-adrenoceptors.
A series of substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives
bearing an amide, urea, or imidazolidinone moiety was studied. Some members of this series
of compounds proved to be potent R2-adrenoceptor antagonists with good selectivity versus
R1-adrenergic and D2-dopamine receptors. Particular emphasis is given to compound 33g which
displays potent R2-adrenoceptor binding affinity in vitro and central effects in vivo following
oral administration.
Ch a r t 1. Structure of Reference R2-Adrenoceptor
Antagonist Compounds
In tr od u ction
Deterioration of the locus coeruleus-noradrenergic
(LC-NA) system has been proposed to be a critical
factor in the aetiology and progression of central neu-
rodegenerative disorders such as Parkinson’s and Alz-
heimer’s diseases.1 In squirel monkeys, lesioning of the
locus coeruleus, the major nucleus of noradrenergic
neurones in the mammalian brain, was shown to impair
spontaneous recovery of motor function following N-meth-
yl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) admin-
istration (a model of Parkinson’s disease).2 The discov-
ery of new compounds that enhance central noradrener-
gic transmission may be useful to compensate the
endogenous deficit of noradrenaline and thus reactivate
impaired function.
Some preliminary studies with a 1-(2,3-dihydrobenzo-
[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivative, R 472433
(1), in a MPTP-induced parkinsonian model in monkeys
showed promising results. Colpaert et al.3 observed a
progressive reversion of MPTP-induced parkinsonian
symptoms in a 20-year-old J ava monkey following
administration of this nonselective R2-adrenoceptor
antagonist. In particular, a normalization of blink rate
and a notable reduction of rigidity, MPTP-induced
hypokinesia, and resting tremor were observed. In
addition, a study in patients with progressive supra-
nuclear palsy (a motor disorder involving the nigrostri-
atal system)4 described improvement in motor function
following administration of the R2-adrenoceptor antago-
nist idazoxan (2). Based on these findings, a new
interest in the discovery of novel compounds selectively
acting on R2-adrenoceptors has been generated. R2-
Adrenoceptor antagonists have been studied for nearly
two decades for their therapeutic application in depres-
sion, owing to their noradrenergic enhancing activity
in the central nervous system and their expected rapid
onset of antidepressive activity in the clinic. However,
the clinical development of most of them has been
discontinued on account of their relative lack of efficacy.
There are many types of chemically unrelated structures
that have the capacity to block R2-adrenoceptors. One
group of compounds is derived from yohimbine (3)5
(Chart 1), a natural plant alkaloid present in Rubiaceae
and Apocynaceae families and includes synthetic ana-
logues such as RS 15385-1376 and MK 912.7 Another
group of R2-adrenoceptor antagonists features idazoxan
(2)8 (Chart 1), whose structure merged as an hybrid
between piperoxan (a weak nonselective R2-adrenoceptor
antagonist) and clonidine (a potent R2-adrenoceptor
partial agonist). This group also comprises Efaroxan,9
RX 821002,10 Fluparoxan,11 and Atipamezole.12 Our
continuing research in this area has led to the design
* To whom correspondence should be addressed. For T. Imbert: tel,
33 05 63 71 4203; fax, 33 05 63 71 4299; e-mail, thierry.imbert@
pierre-fabre.com.
#
Division of Medicinal Chemistry.
† Department of Analytical Chemistry.
§ Division of Neurobiology.
‡ Department of Cellular and Molecular Biology.
10.1021/jm991121g CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

3654 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Mayer et al.
Sch em e 1. Synthesis of Amides, Sulfonamides, Carbamates, Ureas, and 3,4-Dihydro-1H-quinazolin-2-onea
a
(a) LiAlH4/THF; (b) SOCl2/CH2Cl2/reflux; (c) KCN/DMSO/120 °C; (d) ArNCO, ArNCS or PhMeNCOCl/CH2Cl2; (e) (i) ethyl chloroformate/
Et3N, (ii) LiAlH4/THF, (iii) RNCO or PhMeNCOCl/CH2Cl2; (f) 2-nitrobenzaldehyde/NaBH4/EtOH; (g) Fe/HCl; (h) urea/150 °C; (i) EtOCOCl/
Et3N/CH2Cl2; (j) RCOCl or RSO2Cl/CH2Cl2/Et3N; (k) PhOCOCl/CH2Cl2/Et3N.
of new drugs, inspired by piperoxan as an archetypal
structure of R2-adrenoceptor antagonists and R 47243
(1), that reveal high binding affinities for R2-adreno-
ceptors.
Ch a r t 2. General Formula 4
The two main criteria selected to evaluate the new
compounds were (1) the in vitro binding affinity at R2-
adrenoceptors and their selectivity versus rat R1-
adrenoceptor and D2-dopamine receptors and (2) their
in vivo properties to inhibit the hypothermia induced
by the centrally active R2-adrenoceptor agonist guana-
benz. R1-Adrenoceptor affinity was evaluated as a
criterion to select compounds without potential cardio-
vascular side effects. Furthermore, compounds were
selected to be devoid of any D2-receptor affinity in order
to ensure specificity and to avoid potential dopamine
antagonist activity. We describe here the chemical
synthesis of a series of compounds of the general
formula 4 (Chart 2), where modifications on parts A and
B were made to determine the optimal structural
requirements for R2-adrenoceptor activity and selectiv-
ity. Variation on the piperidinylalkyl spacer (part A)
concerned in particular the length of the carbon chain
attached to position 4 of the piperidine ring. In vitro
potency at R2-adrenoceptors proved to be closely related
to this moiety. The nature of the modifications on part
B appeared to influence the in vivo antagonist properties
of these compounds.
Ch em istr y
The previously described [1-(2,3-dihydrobenzo[1,4]-
dioxin-2-ylmethyl)piperidin-4-yl]methylamine (6)13 was
synthesized according to the pathway depicted in Scheme
1, by reduction of the corresponding (piperidin-4-yl)-
carboxamide 5 with lithium aluminum hydride and
treated with phenyl isocyanate or phenyl isothiocyanate
to give respectively 7a ,b. 2-(1H)-Quinazolidinone 10 was
synthesized by a slightly modified literature procedure14

(Dihydrobenzo[1,4]dioxinylmethyl)piperidin-4-yls
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3655
Sch em e 2. Synthesis of 1-Phenylimidazolin-2-one and 1-Phenyltetrahydropyrimidin-2-onea
a
(a) 28 or 29/NaH/DMA/100 °C; (b) (i) 30/EtOH/reflux, (ii) LiAlH4/THF/reflux, (iii) Im2CO/MeCN/reflux.
(Scheme 1). The (piperidin-4-yl)methylamine derivative
6 was successively treated by 2-nitrobenzaldehyde and
sodium borohydride. The resulting (piperidin-4-yl)-
methyl-2-nitrobenzylamine intermediate 8 was sub-
jected to reduction with iron in hydrochloric acid.
Cyclization of the resulting (piperidin-4-yl)methyl-2-
aminobenzylamine compound 9 with urea at 150 °C
yielded 2-(1H)-quinazolidinone 10 in a 35% yield. The
[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-
yl]-2-ethylamine (13) was obtained as depicted in
Scheme 1. Debenzylation of 1-benzyl(piperidin-4-yl)-
acetonitrile (11) with 1-chloroethyl chloroformate15 and
reaction with 2,3-dihydro-2-tosylmethylbenzo[1,4]dioxin16
in the presence of sodium hydroxide yielded the (pip-
eridin-4-yl)acetonitrile 12 which reduction with lithium
aluminum hydride afforded the (piperidin-4-yl)-2-ethyl-
amine intermediate 13 in a 44% overall yield. Reaction
of 13 with carboxylic acid chlorides or sulfonyl chlorides
in the presence of triethylamine gave amides 14a -f or
sulfonamides 15a ,b (for pattern of substitution see
Table 2). Reaction of 13 with phenyl isocyanates, phenyl
isothiocyanates, and carbamoyl chlorides in methylene
chloride yielded phenylureas 16a -h or phenylthioureas
17a ,b (Scheme 1; for pattern of substitution see Table
2). The N-methyl derivatives 20a ,b were obtained via
prior methylation of the (piperidin-4-yl)-2-ethylamine
compound 13 in a two-step procedure: reaction of 13
with ethyl chloroformate yielded carbamate 18 which
was reduced to N-methylamine derivative 19 with
lithium aluminum hydride. Ureas 20a ,b were then
obtained by action of phenyl isocyanate or N-methyl-
N-phenylcarbamoyl chloride. The [1-(2,3-dihydrobenzo-
[1,4]dioxin-2-ylmethyl)piperidin-4-yl]-3-propylamine (24)
was obtained starting from (piperidin-4-yl)-2-ethanol,17
which afforded the [1-(2,3-dihydrobenzo[1,4]dioxin-2-
ylmethyl]piperidin-4-yl]-2-ethanol intermediate (21) by
reaction with 2-bromomethyl-2,3-dihydrobenzo[1,4]-
dioxine in a 66% yield. Treatment of this alcohol with
thionyl chloride in refluxing methylene chloride gave
rise to [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)pip-
eridin-4-yl]-2-chloroethyl hydrochloride (22). The free
base of 22 was reacted with potassium cyanide in
dimethyl sulfoxide at 120 °C to produce the (piperidin-
4-yl)propionitrile 23 in a 64% yield which was subjected
to reduction by lithium aluminum hydride in tetrahy-
drofuran to obtain the (piperidin-4-yl)-3-propylamine
derivative 24 in 96% yield. Reaction of this amine with
phenyl isocyanate led to compound 25 (Scheme 1).
Carbamate 26 was obtained by reaction of the (piperi-
din-4-yl)-2-ethanol derivative 21 with phenyl isocyanate.
The isomeric carbamate derivative 27 was obtained by
reaction of the (piperidin-4-yl)-2-ethylamine derivative
13 with phenyl chloroformate (Scheme 1).
Synthesis of the cyclic ureas 33a -i and 34 was
achieved following two different routes (Scheme 2). The
first route involved the direct alkylation of the appropri-
ate N-phenylimidazolidinone 28 or the N-phenyltet-
rahydropyrimidinone 29 with the (piperidin-4-yl)-2-
chloroethyl derivative 22 to render directly the target
molecule. Synthesis of the cyclic ureas 28 and 29, and
their substituted analogues, was achieved by a two-step
procedure: reaction of anilines with 2-chloroethyl or
3-chloropropyl isocyanate followed by a cyclization
under basic conditions.18 The second route (Scheme 2)
was based on the coupling reaction of an phenyloxalamic
acid ester 30 with the (piperidin-4-yl)-2-ethylamine
intermediate 13, followed by a reduction of intermediate
31 with lithium aluminum hydride. Reaction of the
resulting diamino compound 32 with carbonyldiimida-
zole in refluxing acetonitrile afforded the cyclic ureas
33a -i and 34.
Condensation of phthalic anhydride and compound 13
in refluxing acetic acid yielded the phthalimide 35
(Scheme 3). Reduction of 35 with tin in a mixture of
hydrochloric and acetic acid gave the isoindolinone 36.
The 3-{2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-
piperidin-4-yl]ethyl}-3,4-dihydro-1H-quinazolin-2-one (37)
was synthesized in the same way as compound 10 from
the (piperidin-4-yl)-2-ethylamine intermediate 13
(Scheme 1). The benzo[d][1,3]diazepin-2-one derivative
40 (Scheme 3) was obtained starting from (piperidin-
4-yl)-2-ethylamine 13 and the tosylate of 2-nitrophen-
ylethanol.19 The obtained 2-nitrophenyl-2-ethylamine
derivative 38 was subjected to reduction by tin chloride
in ethanol to afford 2-(2-{2-[1-(2,3-dihydrobenzo[1,4]-
dioxin-2-ylmethyl)piperidin-4-yl]-2-ethylamino}ethyl)-
phenylamine (39). Cyclization with carbonyldiimidazole
yielded the benzo[d][ 1,3]diazepin-2-one derivative 40.
The 3-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)pip-
eridin-4-yl]-3,4-dihydro-1H-quinazolin-2-one (41) (Scheme
1) was synthesized by reaction of the previously de-
scribed 3-(piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-
one14 with 2,3-dihydro-2-tosylmethylbenzo[1,4]dioxin.16
Resu lts a n d Discu ssion
Three major objectives were addressed in the present
study. We first focused on the discovery of new com-

3656 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Mayer et al.
Sch em e 3. Synthesis of Benzo[d][1,3]diazepin-2-one and 2,3-Dihydro-1H-isoindole Derivativesa
a
(a) Phthalic anhydride/AcOH/reflux; (b) Sn/HCl/AcOH; (c) 2-(2-nitrophenyl)ethyl 4-toluenesulfonate; (d) SnCl2, 2H2O/EtOH; (e) Im2CO/
CH3CN.
Ta ble 1. In Vitro Binding Assays at R2-, R1-, and D2-Receptors
prepared from C6-glial cells transfected with the cDNA
encoding R2A-, R2B-, or R2C-adrenoceptors.20 No signifi-
cant subtype selectivity for any of the compounds in
these series was revealed (binding affinities being in the
nanomolar range; data are available as Supporting
Information). The chain length modifications did not
consistently alter the R1-adrenoceptor potency. In con-
trast, high affinity at D2-receptor was shown for com-
pounds 16a , 17a , and 37. Owing to the high potency at
R2-sites and despite the low selectivity of 16a in the
binding profile, we fixed the 4-ethylpiperidine frame-
work as the optimum spacer and studied some 1-[(2,3-
dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl]eth-
ylamine derivatives. Modifications at part B, shown in
the general formula 4 (Chart 2), provide a series of
amides, sulfonamides, carbamates, ureas, thioureas,
and cyclic ureas. The binding profiles at R1- and R2-
adrenoceptors and the D2-receptor for these derivatives
and some reference compounds are given in Table 2. As
shown, all the amide derivatives 14a -f exhibited high
affinities for R2-adrenoceptors, while sulfonamides 15a ,b
are weakly potent at R2-adrenoceptor. The potent af-
finity displayed by phenylurea 16a at the R2-adreno-
ceptor led to the synthesis and evaluation of some
substituted aromatic ureas 16b-d . The 4-MeO (16b)
and 4-HO (16c) derivatives proved equipotent, while
4-NO2 (16d ) was 1 order of magnitude less potent. Other
ureas 16e-h showed the same potency at the R2-
adrenoceptor in the nanomolar range. It was noted that
the thiourea 17a was approximately equipotent, while
the benzoylthiourea 17b was 20-fold less potent than
its benzoylurea analogue 16h at the R2-adrenoceptor
and 50-fold less at the D2-receptor. Thus an improved
D2/R2 selectivity was not obtained with these amide,
urea, and thiourea derivatives. The second main criter-
ion of our selection was the in vivo antagonist efficacy
against guanabenz-induced hypothermia in mice. The
results of these experiments are given in Table 3. The
potency of the studied compounds was characterized by
their ED50 which represents the dose (mg/kg) producing
a significant inhibition in 50% of the animals (temper-
ature > 36 °C). These values were established for both
an intraperitoneal (ip) and a per os (po) mode of
administration (see Experimental Section). This param-
receptor affinity IC50 (nM)a
compd (Chart 2)
n
R2
R1
D2
phenylureas
7a
16a
25
1
2
3
15
1
10
46
40
62.5
750
10
90
phenylthioureas
7b
17a
1
2
13.5
3.4
100
34
750
10
quinazolidinones
41
10
37
0
1
2
300
25
5
30
70
18
nd
550
16
a
IC50 values were determined according to refs 23 and 24 and
are the mean values of duplicates of one experiment. Standard
deviation between duplicates is less than 10%.
pounds exhibiting high affinity at the R2-adrenoceptor
with an IC50 in the nanomolar range. The most potent
compounds were then tested in vivo for their ability to
inhibit the hypothermia in mice induced by the R2-
adrenoceptor agonist guanabenz. A complete reversion
of the hypothermic effect was considered as a charac-
teristic of highly efficient R2-antagonists, i.e., having
little or no intrinsic agonist activity. Finally, some
modifications were done on the lead molecule to improve
in vitro selectivity versus R1-adrenoceptor and D2-
dopaminergic receptors. Starting from the 1-(2,3-dihydro-
[1,4]benzodioxin-2-ylmethyl)piperidine skeleton, some
modifications at the part A of general formula 4 (Chart
2) were carried out and the influence of the chain length
at position 4 was determined with respect to the in vitro
binding profile, within the phenylurea (7a , 16a and 25),
thiourea (7b and 17a ), and 3,4-dihydro-1H-quinazolin-
2-one (10, 37 and 41) series. Table 1 shows the R2- and
R1-adrenoceptor and D2-dopamine receptor binding af-
finity values.
A two-carbon atom alkyl chain (n ) 2) led to an
optimum in potency at the R2-adrenoceptor in each
series, i.e., compounds 16a , 17a , and 37. To be empha-
sized is the outstanding potency of the unsubstituted
phenylurea derivative 16a , with an IC50 of 1 nM, similar
to the order of magnitude of the most potent reference
compounds. Binding assays at different human R2-
adrenoceptor subtypes were studied on membranes

(Dihydrobenzo[1,4]dioxinylmethyl)piperidin-4-yls
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3657
Ta ble 2. Structures and Binding Assay Results at R2-, R1-, and D2-Receptors of Compounds of General Structures A and B
IC50 (nM)a
compd
structure
X
R1
R2
R3
R2
67
21
20
10
2
1.2
10
1
24
30
87
1
R1
D2
1
2
3
yohimbine
idazoxan
R 47243
1580
1650
100
27
20
20
70
11.5
170
30
135
40
56
15
90
42
62.5
42
17
34
200
50
40
34
60
60
85
50
180
95
70
200
46
14
105
17
17.5
1125
>10000
50
14a
14b
14c
14d
14e
14f
15a
15b
16a
16b
16c
16d
16e
16f
16g
16h
17a
17b
20a
20b
26
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
O
O
O
O
O
O
SO2
SO2
O
O
O
O
O
O
O
O
S
Ph
24
25
24
50
2-NO2Ph
2-MeOPh
2-MeOPhCH2
2-NO2PhCH2
Ph2CH
4-CH3Ph
Me
1.8
41
30
800
10
15
15
11
35
45
11.5
2.6
10
120
36
32
26
52
4.5
80
2.3
480
210
135
320
<10
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-MeOPh
4-OHPh
4-NO2Ph
c-hexyl
PhCH2
Ph
0.9
1
12.5
2
3.5
1.1
2.3
3.4
46
4.5
27
1.7
2.9
2
Me
H
PhCO
B
B
B
B
Ph
H
H
H
S
O
O
PhCO
Ph
Ph
Me
Me
Me
OCN carbamate
NCO carbamate
27
33a
33b
33c
33d
33e
33f
33g
33h
33i
34
B
B
B
B
B
B
B
B
O
O
O
O
O
O
O
O
O
O
Ph
CH2-CH2
2,6-Me2Ph
2,6-Cl2Ph
2,6-iPr2Ph
2,6-MeO2Ph
2,6-EtO2Ph
2,4,6-MeO3Ph
4-FPh
CH2-CH2
CH2-CH2
CH2-CH2
CH2-CH2
CH2-CH2
CH2-CH2
CH2-CH2
CH2-CH2
1.8
1.6
36
3
4
4.5
1.5
0.7
1.8
11
1
B
B
4-pyrido
Ph
1.4
CH2-CH2-CH2
38
10
35
36
37
40
phthalimide
isoindolidinone
quinazolidinone
benzodiazepine
3.8
5
4.4
18
50
16
28
a
IC50 values were determined according to refs 23 and 24 and are the mean values of duplicates of one experiment. Standard deviation
between duplicates is less than 10%.
eter was used to characterize potent centrally active R2-
antagonists, by determining the active dose range of the
compounds as indicated in Table 3, i.e., the range of
doses (mg/kg) which produced an inhibition of guana-
benz-induced hypothermia in more than 80% of the
animals. The range of active doses represents the
propensity of the compound to be a centrally active
antagonist without any intrinsic activity (agonism).
While most of the compounds displayed high potency
at the R2-adrenoceptor in vitro, they antagonized gua-
nabenz-induced hypothermia in vivo to a poor extent.
Within the amide series, only 14a exhibited in vivo
antagonist activity over a wide dose range (0.16-2.5 mg/
kg). Within the urea series, the phenylurea 16a showed
potent antagonism (ED50 ) 0.16 mg/kg), but the activity
was maintained only at higher doses. In the same way,
substitution on the phenyl ring of the urea (16b,c) or
other ureas (16e,f) did not show consistent activity along
with increasing doses.
ureas 16g and 20a displayed an IC50 of 1.1 and 4.5 nM,
respectively, at the R2-adrenoceptor in vitro. Potent
central in vivo antagonism was shown irrespective of
the route of administration with 20a (ED50 ) 0.02 mg/
kg ip) and over a wide dose range. In contrast, 16g was
less active (ED50 ) 0.56 mg/kg ip) and inactive po, which
might suggest differential sensitivity to metabolism.
Furthermore, a loss of R2-adrenoceptor affinity was
observed with the methylated derivative at both nitro-
gen atoms (compound 20b). The hypothesis to explain
such a difference in activity was based on conforma-
tional studies of phenylurea derivatives.21 Indeed, the
more stable conformer of the nonmethylated phenylurea
molecule 16a is the trans-cis conformer described in
Chart 3 (the difference of energy between the two
conformers has been calculated to be almost 2 kcal/mol).
Methylation of the alkyl-linked nitrogen atom (20a )
shifts the equilibrium toward the trans-trans conforma-
tion of the urea (calculations gave a difference in energy
of 3 kcal/mol between the two conformers). The presence
of a methyl group on the aromatic linked nitrogen (16g)
A particular feature was observed with the N-methyl
derivatives of ureas (16g and 20a ,b). Monomethylated

3658 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Mayer et al.
Ta ble 3. In Vivo Activities in the Guanabenz-Induced Hypothermia Test in Mice
in vivo inhib of guanabenz-induced hypothermia ED50 (mg/kg)a
range of active doses (mg/kg)
compd
D2/R2 IC50 ratio
ip
po
ip
po
yohimbine
idazoxan
R 47243
14a
14f
16a
16b
16c
16e
17
79
2.5
20
1.7
10
17
15
17.5
13
8
0.56 [0.33-0.96]
0.31 [0.16-0.61]
1.30 [0.71-2.37]
0.11 [0.06-0.18]
inactive
0.16 [0.06-0.40]
0.27 [0.12-0.63]
inactive
0.69 [0.14-3.34]
1.78 [0.70-4.50]
0.56 [0.17-1.79]
0.10 [0.03-0.34]
0.02 [0.007-0.05]
inactive
0.02 [0.005-0.07]
0.86 [0.26-2.85]
0.32 [0.16-0.61]
inactive
0.02 [0.006-0.07]
0.41 [0.17-0.98]
0.10 [0.04-0.25]
0.29 [0.12-0.73]
0.89 [0.66-4.80]
0.41 [0.17-0.98]
2.51 [0.74-8.59]
0.29 [0.12-0.73]
0.08 [0.04-0.15]
0.64 [0.19-2.13]
0.23 [0.08-0.64]
1.23 [0.20-7.44]
0.89 [0.17-4.80]
1.23 [0.35-4.29]
0.76 [0.24-2.39]
inactive
1.26 [0.36-4.41]
nd
inactive
inactive
1
10
0.63-10
10-40
2.5-10
2.5-10
2.5-10
0.16-2.5
0.63-2.5
0.63
10
2.5
16f
nd
nd
16g
16h
17a
17b
20a
20b
26
27
33a
33b
33c
33e
33f
0.16-2.5
0.16-10
0.04-0.16
1
3
0.24 [0.16-0.37]
nd
inactive
0.63-10
2.6
10
1.2
15
18
2.3
44
2
70
33
71
7
0.09 [0.04-0.20]
0.29 [0.07-1.12]
0.34 [0.15-0.78]
inactive
0.06 [0.03-0.13]
5.01 [2.66-9.43]
0.69 [0.22-2.19]
5.01 [1.43-17.61]
0.53 [0.15-1.79]
1.07 [0.46-2.47]
nd
0.16-2.5
2.5-10
0.63-2.5
0.16-2.5
2.5-10
0.63-10
0.16-2.5
2.5-10
0.63-10
0.63-10
10
2.5-10
10-40
0.16-10
10-40
2.5-40
40
2.5-40
2.5-40
33g
33h
33i
34
36
2
0.76 [0.24-2.39]
0.28 [0.11-0.72]
0.46 [0.18-1.21]
5.09 [0.84-30.71]
0.63-2.5
0.16-2.5
2.5-10
2.5-10
0.63-40
2.5-10
10
21
3.8
6
40
0.63-2.5
a
Values in square brackets are 95% confidence limits. nd, value could not be determined.
Ch a r t 3. Conformation of Urea Derivatives
brought us to our third criterion of selection which was
the selectivity versus the D2-receptor.
R 47243 (1), the lead structure used in the early
investigations, proved to be poorly selective at both R1-
adrenoceptor and D2-receptor sites with respect to the
R2-adrenoceptor. With the imidazolidinone 33a , a series
of compounds substituted at the phenyl ring was evalu-
ated for their affinities at R1- and D2-receptors. Modi-
fication of the torsion angle between the two cyclic
systems was thought to be a putative requirement to
lose affinity at the D2-receptor. Ortho-ortho substituents
at the phenyl ring could break thoroughly the planarity
with the imidazolidinone moiety (i.e. the rotation energy
for the aromatic ring in the 2,6-dimethoxyphenylimi-
dazolidinone has been calculated to be approximately
30 kcal/mol).21 Interestingly, the 2,6-Me2 (33b), 2,6-(i-
Pr)2 (33d ), 2,6-(MeO)2 (33e), and 2,4,6-(MeO)3 (33g)
derivatives exhibited a fair R2- versus D2-receptor
selectivity. The R2/D2 ratio reached 70 for compounds
33e,g. However the 2,6-disubstitution pattern proved
to be not a sufficient condition to achieve D2-receptor
selectivity; indeed, the 2,6-Cl2-substituted derivative
33c exhibited high affinity at both the R2-adrenoceptor
and D2-receptor. Nevertheless, the in vivo profile of the
trimethoxy derivative 33g was more interesting than
that of the dimethoxy analogue 33e on account of its
activity following oral administration. A balance of all
the assigned criteria was fulfilled with trimethoxyphe-
nylimidazolidinone derivative 33g, which displayed high
binding affinity at the R2-adrenoceptor, fair selectivity
versus R1-adrenoceptor and D2-dopaminergic receptor,
and potent antagonist property as demonstrated by its
efficacy in vivo in the guanabenz-induced hypothermia
test in mice.
or on both nitrogens (20b) favored again the trans-cis
conformation (the difference in energy being 2 and 1
kcal/mol, respectively). Within this series, compound
20a , bearing a methyl at the alkyl-linked nitrogen,
displayed the most potent in vivo activity. This latter
compound was the only derivative featuring the more
stable trans-trans conformer. The trans-cis conformation
seemed to be unfavorable within this series. Starting
from this hypothesis we designed and evaluated some
rigid urea analogues bearing trans-trans (i.e. imidazo-
lidinones 33 and pyrimidinone 34) or trans-cis blocked
conformations (i.e. 3,4-dihydro-1H-quinazolin-2-one 37
and benzo[d][1,3]diazepin-2-one 40). All these com-
pounds retained high in vitro binding affinity for R2-
adrenoceptors in the nanomolar range. However, only
the imidazolidinones 33a -i and pyrimidinone 34 po-
tently antagonized the guanabenz-induced hypothermia.
Compound 33a was particularly interesting owing to its
wide range of active doses po (0.16-10 mg/kg). Analysis
of the in vitro binding profile of the imidazolidinone 33a
showed a good selectivity for R2- versus R1-adrenoceptors
(ratio R1/R2 ) 30), but the affinity of this molecule for
dopaminergic D2-receptor remained important. This

(Dihydrobenzo[1,4]dioxinylmethyl)piperidin-4-yls
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3659
dropwise a solution of 6 (1.3 g, 50 mmol) in 5 mL of CH2Cl2
and was stirred at room temperature for 20 h. The cooled
reaction mixture was evaporated and the residue was purified
by flash chromatography CH2Cl2/MeOH 95/5) affording 1.35
g of 7a (71%): 1H NMR (CDCl3) δ 7.31 (m, 4H), 7.09 (m, 1H),
6.96 (s, 1H), 6.84 (m, 4H), 5.26 (m, 1H), 4.26 (m, 2H), 3.96
(dd, J ) 9.7 and 7.6 Hz, 1H), 3.13 (m, 2H), 2.93 (m, 2H), 2.67
(dd, J ) 13.3 and 5.9 Hz, 1H), 2.54 (dd, J ) 13.4 and 6.0 Hz,
1H), 2.06 (m, 2H), 1.67 (m, 2H), 1.47 (m, 1H), 1.29 (m, 2H).
Hyd r och lor id e: mp 210-212 °C. Anal. (C22H27N3O3‚HCl) C,
H, N.
[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip er id in -
4-ylm eth yl]-2-n itr oben zyla m in e (8). To a solution contain-
ing 6 (0.8 g, 3 mmol) in 15 mL of EtOH was added dropwise
a solution of 2-nitrobenzaldehyde (0.47 g, 3 mmol) in 5 mL of
EtOH. After stirring for 16 h NaBH4 (0.15 g, 3 mmol) was
added and the solution was refluxed for 1.5 h. The solvent was
evaporated and the residue diluted in AcOEt. After washing
with water, the organic phase was dried over Na2SO4, filtered,
and evaporated to dryness. The crude material was purified
by flash chromatography (CHCl3/MeOH 95/5). We obtained 0.5
g (50%) of pure 8 as a light yellow oil: 1H NMR (CDCl3) δ
7.93 (d, J ) 7.7 Hz, 1H), 7.51-7.60 (m, 2H), 7.41 (m, 1H),
6.79-6.90 (m, 4H), 4.24-4.35 (m, 2H), 4.03 (s, 2H), 3.93 (m,
1H), 2.87-3.03 (m, 1H), 2.65 (dd, J ) 13.2 and 5.6 Hz, 1H),
2.60 (dd, J ) 13.2 and 5.0 Hz, 1H), 2.50 (d, J ) 6.3 Hz, 2H),
2.00-2.15 (m, 2H), 1.65-1.80 (m, 2H), 1.45 (m, 1H), 1.20-
1.40 (m, 2H).
Con clu sion
A series of substituted 1-(2,3-dihydrobenzo[1,4]dioxin-
2-ylmethyl)piperidin-4-yl derivatives was synthesized
and tested in vitro and in vivo for their R2-adrenoceptor
antagonist properties. Almost all compounds exhibited
very high affinity at R2-adrenoceptors together with
potent affinity for the dopaminergic D2-receptor. Among
these derivatives, the imidazolidinones 33a -i were
found to be the more potent compounds in vivo for
inhibiting the guanabenz-induced hypothermia in mice.
Modulation of the substituents on the phenyl group
attached to the imidazolidine ring greatly influenced the
affinity for the D2-receptor.
With the discovery of 2,4,6-trimethoxyphenylimida-
zolidinone compound 33g, we attained three of the main
goals of our project: high binding affinity for the R2-
adrenoceptor, potent R2-antagonist properties evaluated
by an efficient in vivo inhibition of guanabenz-induced
hypothermia in mice, and fair binding selectivity versus
the R1-adrenoceptor and D2-dopaminergic receptor. More-
over, compound 33g displayed a long duration of action
(8 h) and good bioavailability, indicated by the favorable
ip/po ED50 ratio in vivo.
Exp er im en ta l Section
2-{[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip er i-
d in -4-ylm eth yl]a m in om eth yl}p h en yla m in e (9). 2.2 mL of
concentrated HCl were added dropwise (26.4 mmol) to a
suspension of 8 (0.6 g, 1.5 mmol) and 0.3 g iron powder (4.5
mmol) in EtOH/H2O (50/50) at reflux. After 1.5 h the mixture
was cooled in an ice bath and basified with an ethanolic 15%
KOH solution. The solution was filtered and evaporated to
dryness. The residue was dissolved in CH2Cl2, washed with
brine, dried over Na2SO4, filtered and evaporated to dryness.
The crude material was purified by flash column chromatog-
raphy (CHCl3/MeOH 90/10). We obtained 0.4 g of pure 9 (73%)
as an orange oil: 1H NMR (CDCl3) δ 7.06 (m, 2H), 6.87 (m,
4H), 6.68 (m, 2H), 4.32 (m, 2H), 3.97 (dd, J ) 11.6 and 7.7 Hz,
1H), 2.94 (m, 2H), 2.62 (dd, J ) 13.2 and 5.6 Hz, 2H), 2.52 (d,
J ) 6.2 Hz, 2H), 2.10 (m, 2H), 1.71 (m, 2H), 1.42 (m, 1H), 1.35
(m, 2H).
Gen er a l Notes. All solvents and reagents used were
commercially available in ‘pure for synthesis’ grade and were
used without further purification unless otherwise indicated.
The reaction progress was monitored by TLC on silica gel
plates 60F-254 (Merck art. 1.05554). Flash chromatography
was run on silica gel 60-chromagel, 35-70 µm. Melting points
were determined on a Electrothermal IA9300 melting point
apparatus and are uncorrected. NMR spectra were recorded
on a Brucker DPX400 (1H, 400 MHz) spectrometer in CDCl3
or in DMSO-d6 with tetramethylsilane as internal standard.
Elemental analyses were performed on a Fisons 1108 mi-
croanalyzer and were within 0.4% of the theoretical value.
Salts were obtained by dissolution of the base in ethanol and
addition of 1 mol equiv of the corresponding acid. The resulting
salt was filtered and dried under vaccum.
3-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-ylm eth yl]-3,4-d ih yd r o-1H-qu in a zolin -2-on e (10). A mix-
ture of 0.4 g of 9 (1.1 mmol) and 0.07 g of urea (1.1 mmol) was
heated at 150 °C during 2 h. The resulting orange gum was
purified by flash column chromatography (CHCl3/MeOH 95/
5) and crystallized from isopropyl ether/hexane. We obtained
0.1 g of 10 (23%) as beige crystals: mp 185 °C; 1H NMR
(CDCl3) δ 7.18 (m, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.85 (m,
4H), 6.66 (m, 1H), 4.46 (s, 2H), 4.28 (m, 2H), 3.97 (dd, J )
11.5 and 7.5 Hz, 2H), 3.32 (d, J ) 6.9 Hz, 2H), 2.96 (m, 2H),
2.63 (m, 2H), 2.10 (m, 2H), 1.70 (m, 3H), 1.42 (m, 2H). 10‚
fu m a r a te: mp 225-226 °C. Anal. (C23H27N3O3‚C4H4O4) C, H,
N.
1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip er id in e-
4-ca r boxa m id e (5). A mixture of isonipecotamide (10.4 g, 81
mmol) and 2,3-dihydro-2-tosylmethylbenzo[1,4]dioxine16 (26 g,
81 mmol) was heated at 120 °C for 16 h. Cooled to room
temperature, the mixture was added to ammonia water and
extracted with EtOAc. The organic layer was washed with
H2O, brine, dried over Na2SO4 and concentrated under reduced
pressure. The residue was recrystallized from hexane to yield
12.38 g of 5 (55%) as white crystals: mp 132-134 °C; 1H NMR
(CDCl3) δ 6.80-6.90 (m, 4H), 5.84 (s, 1H), 5.67 (s, 1H), 4.25-
4.40 (m, 1H), 4.29 (dd, J ) 11.2 and 2.1 Hz, 1H), 4.00 (dd, J )
11.2 and 6.9 Hz, 1H), 2.95-3.10 (m, 2H), 2.74 (dd, J ) 13.3
and 5.9 Hz, 1H), 2.64 (dd, J ) 13.4 and 9.9 Hz, 1H), 2.10-
2.35 (m, 3H), 1.65-1.95 (m, 4H).
1-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]m et h yla m in e (6). To a mixture of LiAlH4 (3.29 g, 86
mmol) in THF was added dropwise a solution of 5 (12 g, 43
mmol) in THF and then was refluxed for 4 h. The cooled
reaction mixture was hydrolyzed with a solution MgSO4/
NaOH. After filtration, the aqueous layer was extracted with
EtOAc. The organic layer was washed with brine, dried (Na2-
SO4) and evaporated to dryness to yield 9.9 g of 6 (88%) as an
oil: 1H NMR (CDCl3) δ 6.70-6.90 (m, 4H), 4.24-4.34 (m, 2H),
3.94 dd, J ) 4.1 and 7.7 Hz, 1H), 2.90-3.04 (m, 2H), 2.64 (dd,
J ) 5.6 and 13.3 Hz, 1H), 2.52 (dd, J ) 6.1 and 13.3 Hz, 1H),
2.32 (broad s, 2H), 2.10 (m, 2H), 1.71 (m, 2H), 1.50 (m, 2H),
1.15-1.40 (m, 3H).
Compound 37 was synthesized following the same route
starting from amine 13. F u m a r a te: mp 182-184 °C. Anal.
(C24H29N3O5‚C4H4O4) C, H, N.
[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip er id in -
4-yl]a ceton itr ile (12). A mixture of 19.3 g (156 mmol) of (1-
benzylpiperidin-4-yl)acetonitrile15 (11) and 50 g (156 mmol)
of 2,3-dihydro-2-tosylmethylbenzo[1,4]dioxine16 was heated at
140 °C for 20 h and was treated with Na2CO3/CH2Cl2. The
organic layer was washed with H2O, dried (Na2SO4) and
evaporated to dryness. The residue was purified by flash
column chromatography (CH2Cl2/MeOH 98/2) affording 26.8
g (64%) of 12 as a colorless oil: 1H NMR (CDCl3) δ 7.00-6.78
(m, 4H), 4.34-4.16 (m, 2H), 4.00 (dd, J ) 7.6 and 11,6 Hz,
1H), 3.12-2.84 (m, 2H), 2.70 (dd, J ) 13.3 and 5.6 Hz, 1H),
2.56 (dd, J ) 13.4 and 6.13 Hz, 1H), 2.28 (d, J ) 6.4 Hz, 2H),
2.14 (m, 2H), 1.80 (m, 2H), 1.68 (m, 1H), 1.40 (m, 2H).
1-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-ylm eth yl]-3-p h en ylu r ea (7a ). To a mixture of phenyl
isocyanate (0.56 mL, 50 mmol) in 10 mL of CH2Cl2 was added
2-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -

3660 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Mayer et al.
4-yl]-2-eth yla m in e (13). To a suspension of LiAlH4 (3.7 g,
97 mmol) in THF was added dropwise a solution of 12 (10.5 g,
39 mmol) in 10 mL of THF. This solution was refluxed for 3
h. The cooled reaction mixture was hydrolyzed with Na2SO4/
H2O. After filtration, the organic layer was concentrated under
reduced pressure to give 10.2 g (95%) of 13 as an oil: 1H NMR
(CDCl3) δ 6.81 (m, 4H), 4.26 (m, 2H), 3.94 (dd, J ) 11.6 and
7.8 Hz, 1H), 2.94 (m, 2H), 2.73 (m, 2H), 2.61 (dd, J ) 13.3 and
7.6 Hz, 1H), 2.53 (dd, J ) 13.3 and 6.1 Hz, 1H), 2.36 (s broad,
2H), 2.08 (m, 2H), 1.64 (m, 2H), 1.50-1.07 (m, 5H).
N-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip -
er id in -4-yl]eth yl}ben za m id e (14a ). To a solution of 13 (1.9
g, 6.9 mmol), triethylamine (1.75 mL, 1.27 g, 12.6 mmol) in
CH2Cl2 was added dropwise a solution of benzoyl chloride (0.76
g, 5.4 mmol). The mixture was stirred at 0 °C for 1 h and
washed twice with H2O and brine, dried over Na2SO4 and
evaporated to dryness. The residue was recrystallized from
Et2O to yield 1.26 g 14a (61%) of white crystals: mp 106-108
°C; 1H NMR (CDCl3) δ 7.78 (m, 2H), 7.46 (m, 3H), 6.86 (m,
4H), 6.13 (m, 1H), 4.41 (m, 1H), 4.31 (dd, J ) 11.3 and 2.2 Hz,
1H), 4.00 (dd, J ) 11.3 and 7.0 Hz, 1H), 3.50 (m, 2H), 3.06 (m,
2H), 2.67 (m, 2H), 2.19 (m, 2H), 1.76 (m, 2H), 1.57 (m, 2H),
1.39 (m, 3H). Anal. (C23H28N2O3) C, H, N.
The residue was purified by flash column chromatography
(CH2Cl2/MeOH, 95/5) to yield 1.15 g of 16g (76%): 1H NMR
(CDCl3) δ 7.40 (dd, J ) 13.0 and 6.9 Hz, 2H), 7.24 (m,3H),
6.75-6.90 (m, 4H), 4.25-4.35 (m, 2H), 3.94 (dd, J ) 11.6 and
7.7 Hz, 1H), 3.26 (s, 3H), 3.17 (m, 2H), 2.80-3.05 (m, 2H), 2.61
(dd, J ) 13.2 and 5.6 Hz, 1H), 2.53 (dd, J ) 13.3 and 6.1 Hz,
1H), 2.03 (m), 1.61 (m, 2H), 1.44-1.03 (m, broad, 5H). Oxa la te:
mp 105-106 °C. Anal. (C24H31N3O3‚C2H4O4) C, H, N.
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-3-p h en ylth iou r ea (17a ). To a solution of
phenyl isothiocyanate (0.75 g, 5 mmol) in CH2Cl2 was added
dropwise 13 (1.5 g, 5 mmol). This mixture was stirred at room
temperature for 1 h and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(EtOAc/MeOH, 95/5) to yield 1.3 g of 17a (65%) as white
crystals: mp 145-146 °C; 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.45
(m, 2H), 7.32 (m, 1H), 7.19 (m, 2H), 6.83 (m, 4H), 5.96 (m,
1H), 4.30 (m, 2H), 3.96 (dd, J ) 11.6 and 7.5 Hz, 1H), 3.64 (m,
2H), 2.98 (m, 2H), 2.64 (dd, J ) 13.2 and 5.8 Hz, 1H), 2.55
(dd, J ) 13.3 and 5.8 Hz, 1H), 2.08 (m, 2H), 1.68 (m, 2H), 1.50
(m,), 1.30(m, 3H). Hem ifu m a r a te: mp 198-200 °C. Anal.
(C23H29N3O2S‚C2H2O2) C, H, N.
Compound 17b was synthesized following the same proce-
Compounds 14b-f were synthesized following the same
procedure. 14b (ba se): yield 55%; mp 122-124 °C. Anal.
(C23H27N3O5) C, H, N. 14c‚oxa la te: yield 47%; mp 175-176
°C. Anal. (C24H30N2O4‚C2H2O4) C, H, N. 14d ‚oxa la te: yield
60%; mp 146 °C. Anal. (C25H32N2O4‚C2H2O4) C, H, N. 14e
(ba se): yield 39%; mp 135-136 °C. Anal. (C24H29N2O5) C, H,
N. 14f‚oxa la t e: yield 57%; mp 142 °C. Anal. (C30H34N2O3‚
C2H2O4) C, H, N.
N-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip -
er id in -4-yl]eth yl}tolu en e-4-su lfon a m id e (15a ). To a solu-
tion of 13 (1 g, 3.6 mmol) and 1.26 mL of Et3N (0.9 g, 9 mmol)
in 100 mL of CH2Cl2, cooled at 0 °C in an ice bath, was added
dropwise a solution of p-toluenesulfonyl chloride (0.7 g, 3.7
mmol) in 10 mL of CH2Cl2. The solution was stirred for 1 h
and then washed successively with brine and water. The
organic layer was dried over Na2SO4 and evaporated to
dryness. Purification by flash chromatography (CHCl3/MeOH
95/5) yielded 1.05 g of pure 15a (68%) as a colorless oil which
crystallized from isopropyl ether: mp 94-95 °C. Anal.
(C23H30N2O4S) C, H, N.
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-3-p h en ylu r ea (16a ). To a mixture of
phenyl isocyanate (0.65 g, 5.4 mmol) in CH2Cl2 was added
dropwise a solution of 13 (1.5 g, 5.4 mmol) in CH2Cl2 and was
stirred at room temperature for 1 h. The cooled reaction
mixture was evaporated to dryness. The residue was succes-
sively purified by flash column chromatography (EtOAc/MeOH
95/5) and recrystallized from isopropyl ether to yield 1.13 g
16a (53%) as white crystals: mp 112-114 °C; 1H NMR (CDCl3)
δ 7.29 (m, 4H), 7.08 (m, 1H), 6.87 (m, 5H), 5.04 (m, 1H), 4.30
(m, 2H), 3.96 (dd, J ) 11.6 and 7.6 Hz, 1H), 3.25 (m, 2H), 2.94
(m, 2H), 2.62 (dd, J ) 13.1 and 5.7 Hz, 1H), 2.60 (dd, J ) 13.4
and 5.9 Hz, 1H), 2.50 (m, 2H), 1.64 (m, 2H), 1.50-1.08 (m,
5H). Hem ifu m a r a te: mp 186-187 °C. Anal. (C23H29N3O3‚
C2H2O4) C, H, N.
dure. Hyd r och lor id e: yield 61%; mp 162 °C. Anal. (C24H29
N3O3S‚HCl) C, H, N.
-
2-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]eth ylca r ba m ic Acid Eth yl Ester (18). At 0 °C, to a
solution of 13 (1.4 g, 5 mmol), triethylamine (0.8 mL, 0.6 g,
5.7 mmol) in 15 mL of THF was added dropwise a solution of
ethyl chloroformate (0.55 mL, 0.62 g, 5.7 mmol). The mixture
was stirred at room temperature for 30 min and was then
refluxed for 4 h. The cooled reaction mixture was evaporated
to dryness. The residue was dissolved in CH2Cl2, and washed
twice with H2O. The organic layer was dried, filtered and
evaporated to dryness. The residue was purified by flash
column chromatography (EtOAc/MeOH, 95/5) to yield 0.9 g
(52%) of 18 as a colorless oil: 1H NMR (CDCl3) δ 6.87 (m, 4H),
4.63 (s large, 1H), 4.34 (m, 2H), 4.14 (q, J ) 7.1 Hz, 2H), 4.00
(dd, J ) 11.5 and 7.4 Hz, 1H), 3.24 (m, 2H), 3.00 (m, 2H), 2.69
(dd, J ) 13.2 and 5.7 Hz, 1H), 2.56 (dd, J ) 13.4 and 6.2 Hz,
1H), 2.13 (m, 2H), 1.70 (m, 2H), 1.56-1.09 (m broad, 8H).
2-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]eth ylm eth yla m in e (19). Under N2, to a suspension of
LiAlH4 (0.5 g, 13 mmol) in 10 mL of THF, was added dropwise
a solution of 18 (0.9 g, 2.6 mmol) in 5 mL of THF and was
then refluxed for 2.5 h. The cooled reaction mixture was
hydrolyzed with 4 N MeOH/NaOH, filtered and extracted twice
with EtOAc. The organic layer was washed with brine, dried,
filtered and concentrated under reduced pressure to yield 0.5
g of 19 (66%) as a pale yellow oil: 1H NMR (CDCl3) δ 6.75-
6.85 (m,4H), 4.25-4.35 (m, 2H), 3.96 (dd, J ) 11.6 and 7.7
Hz, 1H), 2.80-3.05 (m, 2H), 2.50-2.70 (m, 4H), 2.00-2.20 (m,
2H), 1.80 (s broad, 1H), 1.67 (m, 2H), 1.53-1.08 (m broad, 5H).
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-1-m eth yl-3-p h en ylu r ea (20a ). To a solu-
tion of phenyl isocyanate (0.26 mL, 0.28 g, 2.4 mmol) in 10
mL of CH2Cl2 was added dropwise a solution of 19 (0.7 g, 2.4
mmol) in 10 mL of CH2Cl2. The mixture was stirred at room
temperature for 1.5 h and evaporated to dryness. The residue
was successively purified by flash column chromatography
(EtOAc) and recrystallized from EtOAc/isopropyl ether to yield
0.25 g of 20a (25%) as white crystals: mp 132-133 °C; 1H
NMR (CDCl3) δ 7.25-7.40 (m, 4H), 7.04 (tt, J ) 7.1 and 1.4
Hz, 1H), 6.80-6.95 (m, 4H), 6.27 (s, 1H), 4.25-4.35 (m, 2H),
3.98 (dd, J ) 11.6 and 7.7 Hz, 1H), 3.40 (dd, J ) 7.7 and 7.5
Hz, 2H), 3.02 (s, 3H), 2.92 (m, 2H), 2.67 (dd, J ) 13.2 and 5.6
Hz, 1H), 2.55 (dd, J ) 13.3 and 6.1 Hz, 1H), 2.00-2.20 (m,
2H), 1.60-1.80 (m, 2H), 1.56 (m, 2H), 1.20-1.40 (m, 3H).
F u m a r a te: mp 168-170 °C. Anal. (C24H31N3O3‚C2H2O4) C,
H, N.
Compounds 16b-f,h were synthesized following the same
procedure. 16b‚oxa la te: yield 60%; mp 176 °C. Anal. (C24H31
-
N3O4‚C2H2O4) C, H, N. 16c (ba se): yield 47%; mp 98 °C. Anal.
(C23H29N3O4) C, H, N. 16d ‚oxa la te: yield 50%; mp 241-242
°C. Anal. (C23H28N4O5‚C2H2O4) C, H, N. 16e‚oxa la te: yield
52%; mp 177-178 °C. Anal. (C24H35N3O3‚C2H2O4) C, H, N. 16f‚
oxa la te: yield 39%; mp 200 °C. Anal. (C24H31N3O3‚C2H2O4)
C, H, N. 16h ‚oxa la te: yield 43%; mp 199-200 °C. Anal.
(C24H29N3O4‚C2H2O4) C, H, N.
3-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-1-m eth yl-1-p h en ylu r ea (16g). To a solu-
tion of N-methyl-N-phenylcarbamoyl chloride (0.61 g, 3.6
mmol) in CH2Cl2 at 0 °C were added dropwise 13 (1 g, 3.6
mmol) and triethylamine (1.26 mL, 0.9 g, 9.1 mmol). The
mixture was stirred at room temperature for 1 h and washed
with H2O, brine, dried over Na2SO4, and evaporated to dryness.
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-1,3-d im eth yl-3-p h en ylu r ea (20b). To a
solution of 19 (0.5 g, 1.7 mmol), triethylamine (0.25 mL, 0.18
g, 1.8 mmol) in 10 mL of CH2Cl2 was added dropwise a solution

(Dihydrobenzo[1,4]dioxinylmethyl)piperidin-4-yls
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3661
of N-phenyl-N-methylcarbamoyl chloride (0.3 g, 1.8 mmol) in
10 mL of CH2Cl2 and was then stirred at room temperature
for 18 h. The mixture was poured into H2O, and extracted twice
with CH2Cl2. The organic layer was washed with H2O, dried,
filtered and evaporated to dryness. The residue was purified
by flash chromatography (CH2Cl2/MeOH, 95/5) to yield 0.65 g
of 20b (90%) as a colorless oil: 1H NMR (CDCl3) δ 7.34 (dd, J
) 13.7 and 7.4 Hz, 2H), 7.08 (m, 3H), 6.84 (m,4H), 4.31 (m,
2H), 3.98 (dd, J ) 11.6 and 7.7 Hz, 1H), 3.10-3.30 (m, 3H),
2.80-3.05 (m, 2H), 2.50-2.70 (m, 3H), 1.90-2.20 (m, 2H), 1.64
(m, 2H), 1.50-1.04 (m broad, 5H). Oxa la te: mp 176-178 °C.
Anal. (C25H33N3O3‚C2H2O4) C, H, N.
2-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]-2-eth a n ol (21). To a solution containing (piperidin-4-
yl)-2-ethanol (4.1 g, 32 mmol), K2CO3 (4.15 g, 30 mmol), KI (5
g, 30 mmol) in 40 mL of CH3CN was added dropwise a solution
of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (6.9 g, 30 mmol)
in 15 mL of CH3CN. The mixture was refluxed for 3 h. The
cooled reaction mixture was concentrated under reduced
pressure. The residue was poured into water, and extracted
with CH2Cl2. The organic layer was washed with brine, dried,
filtered and evaporated to dryness. The residue was purified
by flash column chromatography (CH2Cl2/MeOH, 95/5) afford-
ing 5.5 g of 21 (66%) as a colorless oil: 1H NMR (CDCl3) δ 6.80-
6.90 (m, 4H), 4.25-4.38 (m, 2H), 3.98 (dd, J ) 11.5 and 7.5
Hz, 1H), 3.66-3.75 (m, 2H), 3.10-2.80 (m, 2H), 2.66 (dd, J )
13.5 and 5.5 Hz, 1H), 2.55 (dd, J ) 13.1 and 5.9 Hz, 1H), 2.24-
1.95 (m, 3H), 1.70 (m, 2H), 1.60-1.16 (m, 5H).
4-(2-Ch lor oeth yl)-1-(2,3-d ih yd r oben zo[1,4]d ioxin -2-yl-
m eth yl)p ip er id in e Hyd r och lor id e (22). To a solution of 21
(10.5 g, 38 mmol) in 50 mL of CH2Cl2 was added dropwise 7
mL of SOCl2 (11.4 g, 96 mmol). The mixture was refluxed for
4 h. The cooled reaction mixture was concentrated under
reduced pressure. The residue was crystallized in ether to yield
10.5 g of 22 (93%): mp 174-176 °C; 1H NMR (DMSO-d6) δ
6.80 (m, 4H), 4.25-4.35 (m, 2H), 3.92 (dd, J ) 11.7 and 7.4
Hz, 1H), 3.66 (t, J ) 6.7 Hz, 2H), 2.80-3.00 (m, 2H), 2.52 (d,
J ) 5.8 Hz, 2H), 1.90-2.10 (m, 2H), 1.55-1.70 (m, 4H), 1.30-
1.50 (m, 1H), 1.05-1.28 (m, 2H).
3-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]p r op ion itr ile (23). The hydrochloride salt 22 was quan-
titatively converted to its base with 1 N NaOH/CH2Cl2. To a
solution of this base in 100 mL of DMSO were added KCN
(1.3 g, 20 mmol) and KI (0.1 g, 0.6 mmol). The reaction mixture
was heated at 120 °C for 6 h. The cooled solution was poured
into 60 mL of H2O, and extracted with EtOAc. The organic
layer was washed with H2O, dried over Na2SO4, filtered and
evaporated to dryness. The residue was purified by flash
chromatography (CH2Cl2/MeOH 95/5) to yield 1.8 g of 23 (64%)
as an oil: 1H NMR (CDCl3) δ 6.80-6.90 (m, 4H), 4.25-4.35
(m, 2H), 4.00 (dd, J ) 11.9 and 7.9 Hz, 1H), 2.87-3.08 (m,
2H), 2.68 (dd, J ) 13.1 and 5.5 Hz, 1H), 2.56 (dd, J ) 13.1
and 5.9 Hz, 2H), 2.47 (t, J ) 7.4 Hz, 2H), 2.01-2.22 (m, 2H),
1.55-1.77 (m, 4H), 1.52-1.17 (m, 3H).
evaporated to dryness. The residue was purified successively
by flash column chromatography (EtOAc/MeOH, 95/5) and
recrystallized from isopropyl ether/hexane to yield 0.55 g of
25 (22%) as white crystals: mp 126-127 °C; 1H NMR (CDCl3)
δ 7.25-7.35 (m, 4H), 7.00-7.09 (m, 2H), 6.82-6.92 (m, 4H),
5.22 (m, 1H), 4.30 (m, 2H), 3.97 (dd, J ) 11.5 and 7.5 Hz, 1H),
3.20 (m, 2H), 2.82-3.05 (m, 2H), 2.67 (dd, J ) 13.1 and 5.2
Hz, 1H), 2.52 (dd,, J ) 13.1 and 6.3 Hz, 1H), 21.96-2.18 (m,
2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.40-1.04 (m large, 5H).
Oxa la te: mp 162-163 °C. Anal. (C24H31N3O3‚C2H2O4) C, H,
N.
2-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]eth ylca r ba m ic Acid P h en yl Ester (27). To a solution
of 13 (2.76 g, 10 mmol), triethylamine (1.5 mL, 1.09 g, 11
mmol) in 25 mL of THF was added dropwise at 0 °C a solution
of phenyl chloroformate (1.56 g, 10 mmol) in 5 mL of THF.
The mixture was stirred at room temperature for 52 h and
evaporated to dryness. The residue was dissolved in CH2Cl2,
washed twice with H2O, dried, filtered and evaporated to
dryness. The residue was successively purified by flash column
chromatography (CH2Cl2/MeOH 95/5) and recrystallized from
isopropyl ether to yield 1.40 g of 27 (35%) as white crystals:
mp 108-110 °C; 1H NMR (CDCl3) δ 7.35-7.42 (m, 2H), 7.18-
7.25 (m, 1H), 7.10-7.17 (m, 2H), 6.81-6.93 (m, 4H), 5.03 (m,
1H), 4.25-4.40 (m, 2H), 4.00 (dd, J ) 11.5 and 7.5 Hz, 1H),
3.32 (m, 2H), 2.85-3.10 (m, 2H), 2.67 (dd, J ) 13.5 and 5.9
Hz, 1H), 2.58 (dd, J ) 13.5 and 5.9 Hz, 1H), 2.02-2.25 (m,
2H), 1.73 (m, 2H), 1.45-1.61 (m, 2H), 1.25-1.45 (m, 3H). Anal.
(C23H28N2O4) C, H, N.
Compound 26 was synthesized following the same procedure
starting from 21 and phenyl isocyanate. Oxa la te: yield 40%;
mp 118-120 °C. Anal. (C23H28N2O4‚C2H2O4) C, H, N.
1-(2,4,6-Tr im et h oxyp h en yl)im id a zolid in -2-on e (28g).
To a solution of 2,4,6-trimethoxyaniline (3 g, 16 mmol) in THF
was added 2-chloroethyl isocyanate (1.5 mL, 1.8 g, 17 mmol)
at 0 °C. The mixture was stirred at room temperature for 16
h. This mixture was evaporated to dryness, filtered through a
pad of silica gel (CH2Cl2/MeOH 95/5) and concentrated under
reduced pressure. The residue was recrystallized from Et2O
to yield 4 g of 1-(2′,4′,6′-trimethoxyphenyl)-3-(2′-chloroethyl)-
urea (84%): 1H NMR (CDCl3) δ 6.16 (s, 2H), 3.83 (m, 9H),
3.70-3.44 (m broad, 4H). To a suspension of NaH (0.5 g, 21
mmol) in THF under N2 was added a solution of the above
compound (3 g, 10 mmol) in THF. The mixture was stirred at
room temperature for 1 h and refluxed for 30 min. The cooled
reaction mixture was evaporated to dryness. The residue was
poured into water, and extracted with CH2Cl2. The organic
layer was dried, filtered and evaporated. The residue was
recrystallized from isopropyl ether to yield 1.5 g of 28g (58%)
1
as pink crystals: mp 238 °C; H NMR (CDCl3) δ 6.08 (s, 2H),
3.74 (s, 6H), 3.73 (s, 3H), 3.70-3.40 (m broad, 4H).
Compounds 28b-f,h ,i were synthesized following the same
procedure starting respectively from 2,6-dimethylaniline, 2,6-
dichloroaniline, 2,6-diisopropylaniline, 2,6-dimethoxyaniline,
2,6-diethoxyaniline,22 4-fluoroaniline and 4-aminopyridine.
28b: yield 75%; mp 172 °C. 28c: yield 80%; mp 220 °C. 28d :
yield 75%; mp 208 °C. 28e: yield 70%; mp 218 °C. 28f: yield
70%; mp 149 °C. 28h : yield 80%; mp 150 °C. 28i: yield 40%;
oil.
3-[1-(2,3-Dih ydr oben zo[1,4]dioxin -2-ylm eth yl)piper idin -
4-yl]p r op yla m in e (24). To a suspension of LiAlH4 (0.5 g, 12.6
mmol) in 20 mL of THF was added dropwise a solution of 23
(1.8 g, 6.3 mmol) in 10 mL of THF and was then refluxed for
4 h. The cooled reaction mixture was hydrolyzed with 2 N
NaOH/EtOAc. The organic layer was dried, filtered and
concentrated under reduced pressure to yield 1.75 g of crude
24 (96%): 1H NMR (CDCl3) δ 6.83-6.87 (m, 4H), 4.24-4.36
(m, 2H), 3.98 (dd, J ) 12.0 and 7.9 Hz, 1H), 2.83-3.05 (m,
2H), 2.49-2.73 (m, 4H), 2.15 (s broad, 2H), 2.08 (m, 2H), 1.61-
1.75 (m, 2H), 1.55 (m, 1H), 1.18-1.34 (m, 6H).
1-{3-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]p r op yl}-3-p h en ylu r ea (25). A solution of 1.7 g
(6 mmol) of 24 in 5 mL of CH2Cl2 was added to a solution of
phenyl isocyanate (0.65 mL, 0.71 g, 6 mmol) in 10 mL of CH2-
Cl2. The solution was stirred at room temperature for 18 h
and then evaporated to dryness. The residue was dissolved in
HCl (2 N) and washed with EtOAc. The aqueous layer was
basified with 1 N NaOH and extracted twice with CH2Cl2. The
organic layer was washed with brine, dried, filtered and
1-P h en yltetr a h yd r op yr im id in -2-on e (29). To a solution
of aniline (3 g, 32.2 mmol) in THF was quickly added
3-chloropropyl isocyanate (3.3 mL, 3.8 g, 32.2 mmol). The
mixture was stirred at room temperature for 3 h and evapo-
rated to dryness. The residue was recrystallized with ether/
isopropyl ether (1/1) to yield 6.2 g of 1-phenyl-3-(3-chloropropyl)-
1
urea (89%) as white crystals: mp 130 °C; H NMR (CDCl3) δ
7.76 (s, 1H), 6.96 (d, J ) 7.5 Hz, 2H), 6.81 (dd, J ) 8.3 and 7.4
Hz, 2H), 6.48 (t, J ) 7.3 Hz, 1H), 5.72 (s broad, 1H), 3.20 (t, J
) 6.5 Hz, 2H), 2.99 (m,2H), 1.55 (m, 2H). To a suspension of
NaH (1.5 g, 62.5 mmol) in THF was added a solution of the
above compound (6 g, 28.2 mmol) in THF and was then stirred
at room temperature for 3 h. The mixture was poured into H2O
and the THF was evaporated. The residue was dissolved in
CH2Cl2, washed twice with H2O, once with brine, dried over

3662 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Mayer et al.
Na2SO4, filtered and evaporated to dryness. The residue was
recrystallized from isopropyl ether to yield 4.2 g of 29 (85%)
as white crystals: 1H NMR (CDCl3) δ 7.22-7.39 (m, 4H), 7.15
(m, 1H), 5.90 (s, 1H), 3.62 (dd, J ) 5.8 and 5.6 Hz, 2H), 3.33
(ddd, J ) 8.1, 5.9 and 2.4 Hz, 2H), 2.03 (m, 2H).
N-P h en yloxa la m ic Acid Eth yl Ester (30). To a solution
of diethyl oxalate (25.7 g, 175.8 mmol) in CHCl3 was added
slowly a solution of aniline (16.4 g, 176.1 mmol) in CHCl3. The
mixture was refluxed for 24 h and evaporated to dryness. The
residue was purified successively by recrystallization from
EtOH and flash column chromatography (hexane/EtOAc 90/
10) to yield 13.6 g of 30 (40%): 1H NMR (CDCl3) δ 8.92 (s
broad, 1H), 7.64 (d, J ) 8.2 Hz, 2H), 7.37 (dd, J ) 8.2 and 7.4
Hz, 2H), 7.19 (t, J ) 7.4 Hz, 1H), 4.40 (q, J ) 7.2 Hz, 2H),
1.40 (t, J ) 7.2 Hz, 3H).
Compounds 33b-f,h ,i were synthesized following the same
procedure. 33b‚oxa la te: yield 31%; mp 141-142 °C. Anal.
(C27H35N3O3‚C2H2O4‚0.5 H2O) C, H, N. 33c‚h yd r och lor id e:
yield 28%; mp 216-218 °C. Anal. (C25H29N3O3‚HCl) C, H, N.
33d (ba se): yield 43%; mp 138-140 °C. Anal. (C31H43N3O3)
C, H, N. 33e (ba se): yield 20%; mp 108-109 °C. Anal.
(C27H35N3O5) C, H, N. 33f (ba se): yield 28%; mp 95-96 °C.
Anal. (C29H39N3O5) C, H, N. 33h (ba se): yield 25%; mp 148-
150 °C. Anal. (C25H30FN3O3) C, H, N. 33i‚h em ioxa la te: yield
22%; mp 198-200 °C. Anal. (C24H30N3O3‚0.5C2H2O4‚H2O) C,
H, N.
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]et h yl}-3-p h en ylt et r a h yd r op yr im id in -2-on e
(34). To a suspension of NaH (0.18 g, 7.5 mmol) in DMA was
added a solution of 29 (1 g, 5.7 mmol). To this mixture was
added dropwise a solution of 22 (0.7 g, 2.7 mmol) and then it
was heated at 100 °C for 4 h. The cooled slurry was poured
into H2O and extracted with EtOAc. The organic layer was
washed with H2O, brine, dried over Na2SO4 and evaporated
to dryness. The residue was recrystallized from isopropyl ether
to yield 0.7 g of 34 (43%) as white crystals: mp 130 °C; 1H
NMR (CDCl3) δ 7.20-7.38 (m, 4H), 7.13 (m, 1H), 6.75-6.95
(m, 4H), 4.20-4.35 (m, 2H), 3.96 (dd, J ) 11.5 and 7.7 Hz,
1H), 3.66 (dd, J ) 5.7 and 5.5 Hz), 3.30-3.50 (m, 4H), 2.80-
3.05 (m, 2H), 2.65 (dd, J ) 13.2 and 5.6 Hz, 1H), 2.52 (dd, J )
13.3 and 6.1 Hz, 1H), 1.95-2.20 (m, 2H), 1.65-1.85 (m, 2H),
1.52 (m, 2H), 1.18-1.38 (m, 3H). Anal. (C26H33N3O3) C, H, N.
N-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip -
er id in -4-yl]eth yl}-N′-p h en yloxa la m id e (31). To a solution
of 13 (1.8 g, 6.5 mmol) in 30 mL of EtOH was added 30 (1.15
g, 5.9 mmol). The reaction mixture was refluxed for 3 h, cooled,
diluted with EtOH and filtered. The filtered crystals were
washed once with EtOH and twice with isopropyl ether. After
1
drying 1.2 g of 31 (48%) was obtained as white crystals: H
NMR (CDCl3) δ 9.28 (s, 1H), 7.66 (d, J ) 7.8 Hz, 2H), 7.57 (s,
1H), 7.40 (m,2H), 7.21 (m, 1H), 6.89 (m, 4H), 4.15 (m, 2H),
4.00 (m, 1H), 3.42 (dd, J ) 13.3 and 6.3 Hz, 2H), 3.00 (m, 2H),
2.62 (m, 2H), 2.13 (m, 2H), 1.94-1.13 (m broad, 7H).
N-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip -
er id in -4-yl]eth yl}-N′-p h en yleth a n e-1,2-d ia m in e (32). To
a suspension of LiAlH4 (0.9 g, 22.4 mmol) in 30 mL of THF
was added 31 (1.2 g, 2.8 mmol) and the slurry was refluxed
for 14 h under N2. The cooled reaction mixture was hydrolyzed
with Na2SO4/H2O, filtered and washed with THF. The organic
layer was evaporated to dryness. The residue was purified by
flash column chromatography (CH2Cl2/MeOH 95/5) to yield 0.5
g of 32 (45.5%) as an oil: 1H NMR (CDCl3) δ 7.17 (dd, J ) 8.4
and 7.3 Hz, 2H), 6.86 (m, 4H), 6.71 (t, J ) 7.3 Hz, 1H), 6.65
(d, J ) 8.4 Hz, 2H), 4.20 (m, 2H), 3.98 (dd, J ) 11.7 and 7.7
Hz, 1H), 3.22 (dd, J ) 6.1 and 5.4 Hz, 2H), 3.00 (m, 2H), 2.87
(dd, J ) 6.1 and 5.4 Hz, 2H), 2.73-2.45 (m, 4H), 2.08 (m, 2H),
1.67 (m, 2H), 1.64-1.15 (m, 5H).
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-3-p h en ylim id a zolid in -2-on e (33a ). To a
solution of 32 (0.5 g, 1.3 mmol) in 20 mL of CH3CN was added
carbonyldiimidazole (0.25 g, 1.3 mmol) and was refluxed for 3
h. The cooled reaction mixture was evaporated to dryness. The
residue was purified successively by recrystallization from
EtOH/isopropyl ether and flash chromatography (EtOAc/
MeOH, 90/10) to yield 0.1 g of 33a (18.8%) of white crystals:
1H NMR (CDCl3) δ 7.56 (d, J ) 6.6 Hz, 2H), 7.31 (dd, J ) 8.6
and 7.4 Hz, 2H), 7.04 (t, J ) 7.3 Hz, 1H), 6.80-6.95 (m, 4H),
4.25-4.35 (m, 2H), 4.00 (dd, J ) 11.6 and 7.7 Hz, 1H), 3.83
(m, 2H), 3.48 (m, 2H), 3.33 (t, J ) 7.5 Hz, 2H), 2.80-3.05 (m,
2H), 2.67 (dd, J ) 13.2 and 5.4 Hz, 1H), 2.54 (dd, J ) 13.3
and 6.2 Hz, 1H), 2.00-2.20 (m, 2H), 1.76 (m, 2H), 1.50 (m,
2H) 1.20-1.40 (m, 3H). F u m a r a te: mp 155-156 °C. Anal.
(C25H31N3O3‚C4H4O4) C, H, N.
1-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]et h yl}-3-(2,4,6-t r im et h oxyp h en yl)im id a zoli-
d in -2-on e (33g). To a suspension of NaH (0.1 g, 4 mmol) in
DMA was added dropwise a solution of 28g (0.5 g, 2 mmol) in
DMA. The mixture was stirred at room temperature for 30
min. To this mixture was added dropwise a solution of 22 (0.5
g, 2 mmol). The mixture was heated at 100 °C for 4 h. The
cooled reaction mixture was washed with water, and extracted
twice with EtOAc. The organic layer was dried, filtered and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (CH2Cl2/MeOH 90/10) to yield
0.25 g of 33g (25%) as white crystals: mp 110-112 °C; 1H
NMR (CDCl3) δ 6.76-6.89 (m, 4H), 6.10 (s, 2H), 4.25-4.35 (m,
2H), 3.94 (dd, J ) 11.5 and 7.6 Hz, 1H), 3.76 (m, 9H), 3.60-
3.44 (m broad, 4H), 3.25 (m, 2H), 3.06-2.80 (m broad, 2H),
2.64 (dd, J ) 13.2 and 5.7 Hz, 1H), 2.55 (dd, J ) 13.3 and 6.0
Hz, 1H), 1.98-2.17 (m, 2H), 1.74 (m, 2H), 1.49 (m, 2H), 1.30
(m, 3H). Anal. (C28H37N3O6) C, H, N.
2-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}isoin d ole-1,3-d ion e (35). To a solution of
13 (2.45 g, 8.8 mmol) in 15 mL of AcOH was added phthalic
anhydride (1.35 g, 8.8 mmol). The mixture was refluxed for 5
h. The cooled reaction mixture was evaporated to dryness. The
residue was taken up in Na2CO3 10%, and extracted twice with
CH2Cl2. The organic layer was washed with brine, dried,
filtered and evaporated to dryness. The residue was purified
successively by flash column chromatography (CH2Cl2/MeOH
95/5) and recrystallization with EtOH to yield 0.7 g 35 (20%)
1
as white crystals: mp 120 °C; H NMR (CDCl3) δ 7.84 (dd, J
) 5.7 and 3.1 Hz, 2H), 7.73 (dd, J ) 5.6 and 3.1 Hz, 2H), 4.25-
4.35 (m, 2H), 3.96 (dd, J ) 11.6 and 7.7 Hz, 1H), 3.70 (m, 2H),
2.90-3.05 (m, 2H), 2.64 (dd, J ) 13.3 and 5.7 Hz, 1H), 2.54
(dd, J ) 13.4 and 6.1 Hz, 1H), 2.09 (m, 2H), 1.79 (m, 2H), 1.61
(m, 2H), 1.25-1.35 (m, 3H). Hyd r och lor id e: mp 185-186 °C.
Anal. (C24H26N2O4‚HCl) C, H, N.
2-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl)p ip -
er id in -4-yl]eth yl}-2,3-d ih yd r oisoin d ol-1-on e (36). To a
solution of 35 (1.35 g, 3.3 mmol) in 20 mL of AcOH was added
tin powder (0.95 g, 8 mmol). To this mixture was added
dropwise concentrated HCl (2 mL, 22 mmol) and it was then
heated at 120 °C for 20 h. The cooled reaction mixture was
evaporated to dryness. The residue was poured into 1 N HCl.
After neutralization with 1 N NaOH, the aqueous layer was
extracted twice with CH2Cl2. The organic layer was washed
with brine, 2 N NaOH, H2O, dried, filtered and evaporated to
dryness. The residue was successively purified by flash column
chromatography (EtOAc/MeOH, 95/5) and recrystallized from
isopropyl ether/hexane to yield 0.5 g of 36 (42.5%) as white
crystals: mp 119-120 °C; 1H NMR (CDCl3) δ 7.85 (d, J ) 6.7
Hz, 1H), 7.42-7.55 (m, 3H), 6.85 (m, 4H), 4.22-4.45 (m, 4H),
3.98 (dd, J ) 11.5 and 7.9 Hz, 1H), 3.67 (m, 2H), 2.82-3.08
(m, 2H), 2.65 (dd, J ) 13.5 and 5.95 Hz, 1H), 2.57 (dd, J )
13.1 and 5.95 Hz, 1H), 1.98-2.22 (m, 2H), 1.70-1.85 (m, 2H),
1.55-1.70 (m, 2H), 1.22-1.45 (m, 3H). Anal. (C24H28N2O3) C,
H, N.
N-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p ip -
er id in -4-yl]eth yl}-2-(2-n itr op h en yl)eth yla m in e (38). To a
solution of 13 (1.7 g, 6.1 mmol) in 2 mL of DMSO was added
dropwise a solution of 2-(2-nitrophenyl)ethyl 4-toluenesulfonate19
(2 g, 6.2 mmol) The mixture was heated at 140 °C for 2 h. The
cooled reaction mixture was poured into a solution of concen-
trated NH4OH and ice and extracted with EtOAc. The organic
layer was washed twice with H2O, dried, filtered and evapo-
rated to dryness. The residue was purified by flash column
chromatography (EtOAc/MeOH 50/50) to yield 0.5 g of 38 (19%)

(Dihydrobenzo[1,4]dioxinylmethyl)piperidin-4-yls
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3663
as an oil: 1H NMR (CDCl3) δ 7.92 (dd, J ) 9.6 and 1.6 Hz,
1H), 7.53 (dd, J ) 8.7 and 1.3 Hz, 1H), 7.36 (m, 2H), 6.86 (m,
4H), 4.34 (m, 1H), 4.29 (m, 1H), 3.96 (dd, J ) 11.6 and 7.7 Hz,
1H), 2.98 (m, 6H), 2.61 (m, 4H), 2.09 (m, 2H), 1.68 (m, 2H),
1.43 (m, 1H), 1.27 (m, 2H).
obtained by means of the method of Lichfield and Wilcoxon25
using the PHARM/PCS program no. 46 of Tallarida and
Murray. 26
Molecu la r Mod elin g. Structures were built using standard
bond lengths and angles in SYBIL (version 6.5) developed and
distributed by Tripos Associates Inc., St. Louis, MO. Geometry
optimizations were carried out using the semiempirical AM1
method in the MOPAC program (version 6 from QCPE).21
2-(2-{2-[1-(2,3-Dih yd r oben zo[1,4]d ioxin -2-ylm eth yl)p i-
p er id in -4-yl]eth yla m in o}eth yl)p h en yla m in e (39). To a
solution of 38 (0.5 g, 1.17 mmol) in 20 mL of ethanol was added
tin chloride dihydrate (1.35 g, 5.87 mmol) by small fractions.
The solution was refluxed for 4 h and then evaporated nearly
to dryness. The residue was hydrolyzed by addition of crushed
ice and 10 mL of 1 N NaOH. The aqueous solution was
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and evaporated to dryness. The crude
compound was subjected to the next step without further
purification: 1H NMR (CDCl3) δ 6.92-7.09 (m, 1H), 6.76-6.92
(m, 5H), 6.60-6.75 (m, 2H), 4.34 (m, 1H), 4.25-4.40 (m, 2H),
3.96 (dd, J ) 11.7 and 7.7 Hz, 1H), 3.40 (large s, 2H), 2.50-
3.10 (m, 10H), 1.90-2.15 (m, 2H), 1.70-1.75 (m, 2H), 1.40-
1.53 (m,1H), 1.20-1.35 (m, 2H).
3-{2-[1-(2,3-Dih yd r ob en zo[1,4]d ioxin -2-ylm et h yl]p ip -
er idin -4-yl]eth yl}-1,3,4,5-tetr ah ydr oben zo[d][1,3]diazepin -
2-on e (40). To a solution of crude 39 (0.4 g, 1 mmol) in 12 mL
of CH3CN was added carbonyldiimidazole (0.2 g, 1 mmol) and
was then refluxed for 2.5 h. The cooled reaction mixture was
filtered and evaporated to dryness. The residue was dissolved
in CH2Cl2 and washed with H2O. The aqueous layer was
extracted with CH2Cl2. The organic layer was washed with
brine, dried, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(CH2Cl2/MeOH, 95/5) to yield 0.2 g of 40 (50%) as beige
crystals: 1H NMR (CDCl3) δ 7.05-7.15 (m, 2H), 6.80-7.00 (m,
4H), 6.65-6.80 (m, 2H), 4.43 (m, 1H), 4.32 (dd, J ) 11.3 and
2.2 Hz, 1H), 4.00 (dd, J ) 11.3 and 7.0 Hz, 1H), 3.45-3.55 (m,
4H), 2.90-3.15 (m, 4H), 2.67 (m, 2H), 2.02-2.30 (m, 2H), 1.60-
1.90 (m, 2H), 1.50-1.60 (m, 2H), 1.25-1.50 (m, 3H). F u m a -
r a te: mp 188-190 °C. Anal. (C25H31N3O3‚C4H4O4) C, H, N.
Ack n ow led gm en t. The authors thank Dr. J . P.
Ribet and the Analytical Department for their work.
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
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