Thiazoloindans and thiazolobenzopyrans: A novel class of orally active central dopamine (partial) agonists

Article abstract of DOI:10.1021/jm000087z

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5,4-f]-[1]benzopyran (12) and 6-amino-2-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D₃ receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D₂ receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.

Full text of DOI:10.1021/jm000087z

J . Med. Chem. 2000, 43, 3549-3557
3549
Th ia zoloin d a n s a n d Th ia zoloben zop yr a n s: A Novel Cla ss of Or a lly Active
Cen tr a l Dop a m in e (P a r tia l) Agon ists
L. Alexander van Vliet,* Nienke Rodenhuis, and Håkan Wikstro¨m
Department of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1,
NL-9713 AV Groningen, The Netherlands
Thomas A. Pugsley, Kevin A. Serpa, Leonard T. Meltzer, Thomas G. Heffner, and Lawrence D. Wise
Departments of Chemistry and Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert
Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105
Mary E. Lajiness, Rita M. Huff, and Kjell Svensson
CNS Diseases Research, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49001
Guido R. M. M. Haenen and Aalt Bast
Department of Pharmacology, Faculty of Medicine, University of Maastricht, Postbus 616,
NL-6200 MD Maastricht, The Netherlands
Received February 25, 2000
The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and
lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine
(DA) agonists with good oral availability. To further explore its use in the development of DA
agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminoben-
zopyrans, which are known templates for DA agonists. In this study we have synthesized
6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5,4-f]-[1]benzopyran (12) and 6-amino-
2-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The
affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which
revealed compound 20 to have high affinity for DA D3 receptors. In addition, the compounds
were screened for their potential to inhibit lipid peroxidation, to determine their radical
scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological
evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied
with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-
DA lesioned rats (to determine their potential as DA agonists). These studies selected compound
20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in
unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual
agonist/antagonist action is best accounted for by its partial agonism at striatal DA D2 receptors.
Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA
lesioned rats, making this compound potentially useful for the treatment of Parkinson’s disease.
In tr od u ction
of PD are needed. New DA agonists for the treatment
of PD should not display prooxidant activity like L-
DOPA, but preferably antioxidant activity.4,5
Parkinson’s disease (PD) is a neurodegenerative
disease of the substantia nigra, causing a dopamine
(DA) deficiency in the striatum, which in turn causes
movement disorders (rigidity, hypokinesia). Probably,
this degeneration of neurons is inflicted by reactive
oxygen(-derived) free radicals.1,2 Restoring nigrostriatal
DA neurotransmission by administration of L-DOPA,
possibly with the coadministration of DA agonists, is
still the dominant therapy for PD. This therapy relieves
the symptoms but does not cure PD. Paradoxically, it
has been suggested that the prooxidant properties of
L-DOPA may contribute to the progression of the
disease.3 Therefore, new approaches for the treatment
The 2-aminothiazole functionality has been success-
fully applied as a heterocyclic bioisostere of the phenol
moiety in DA agonists such as talipexole (1; Chart 1), a
DA agonist with some selectivity for the DA autorecep-
tor,6 PD 118440 (2), a DA autoreceptor agonist,7 and
pramipexole (3), a DA agonist with preference for the
DA D3 (over DA D2) receptor.8,9 In these compounds, the
amino group on the 2-aminothiazole moiety effectively
replaces the hydroxy group of a phenol (or catechol)
moiety, to form a presumed hydrogen bond with the
receptor binding site. Compared to a phenol group, a
2-aminothiazole moiety is more lipophilic and displays
improved oral availability.7 In addition, some com-
pounds with a 2-aminothiazole moiety were found to
* To whom correspondence should be addressed. Phone: +31-50-
363 3296. Fax: +31 50 363 6908. E-mail: l.a.van.vliet@farm.rug.nl.
10.1021/jm000087z CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/26/2000

3550 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
van Vliet et al.
Ch a r t 1. Chemical Structures of DA Agonists with
2-Aminothiazole Functionality: Talipexole (1), PD
118440 (2), and Pramipexole (3)
Sch em e 2a
a
Reagents: (a) propionyl chloride, NaHCO3, H2O, EtOAc; (b)
HNO3/H2SO4/H2O, MeNO2, 0 °C; (c) NH4CO2H, 10% Pd/C, MeOH,
50 °C; (d) BH3 in THF, Et2O, rt f reflux; (e) KSCN, Br2, AcOH.
Sch em e 1a
Sch em e 3a
a
Reagents: (a) propionyl chloride, NaHCO3, H2O, EtOAc; (b)
BH3 in THF, Et2O, rt f reflux; (c) propionyl chloride, Et3N,
CH2Cl2; (d) HNO3/H2SO4/H2O, MeNO2, 0 °C; (e) NH4CO2H, 10%
Pd/C, MeOH, 50 °C; (f) BH3 in THF, Et2O, rt f reflux; (g) KSCN,
Br2, AcOH; (h) separation of isomers with column chromatography
on SiO2.
Nitration of 5 was performed with a mild nitrating
mixture to avoid double nitration,14 and the 6- and
8-nitrated products (6 and 7, respectively) were sepa-
rated with column chromatography on SiO2. 6 and 7
were reduced catalytically to yield aniline amides 8 and
9, respectively, which were reduced with LiAlH4 to
afford the aniline amines 10 and 11, respectively.
Finally, 10 and 11 were treated with potassium thio-
cyanate and bromine,12 to give thiazolobenzopyrans 12
and 13, respectively.
a
Reagents: (a) propionyl chloride, Et3N, CH2Cl2, 0 °C; (b) 10%
Pd/C, H2, EtOH; (c) LiAlH4, Et2O, 0 °C f reflux; (d) propionyl
chloride, Et3N, CH2Cl2; (e) HNO3/H2SO4/H2O, MeNO2, 0 °C; (f)
separation of 6- and 8-nitrated product with column chromatog-
raphy on SiO2; (g) 10% Pd/C, H2, EtOH; (h) LiAlH4, Et2O, 0 °C f
reflux; (i) KSCN, Br2, AcOH.
have free radical scavenging properties.10 Pramipexole
(3) was recently reported to have neuroprotective prop-
erties which are probably related to its antioxidant
properties.11
Compounds 17, 20, and 21 were synthesized analo-
gously to the above-described synthesis of 12 and 13,
although some different reagents were used (Schemes
2 and 3).
These observations, together with the fact that 2-ami-
nothiazoles are chemically easily accessible from ani-
lines,12 encouraged us to prepare a series of 3-amino-
[1]benzopyran- or 2-aminoindan-derived 2-aminothia-
zoles and to investigate the concept of combining DA
agonism with free radical scavenging properties in a
single molecule.5 This study describes the synthesis of
five 3-amino-1-benzopyran- or 2-aminoindan-derived
2-aminothiazoles (compounds 12, 13, 17, 20, and 21)
and the pharmacological evaluation of their action on
DA receptors. In addition, these compounds were tested
for their ability to inhibit nonenzymatic lipid peroxida-
tion.
Compound 17 was synthesized starting from 2-ami-
noindan 14 (Scheme 2) which was propionylated to give
the intermediate amide, then nitrated14 to give mainly
the 5-nitrated product, and reduced to the aniline amide
15 with Pd/C and ammonium formate as hydrogen
donor. Compound 15 was purified from the minor
byproduct (probably 4-substituted product) with MPLC
on SiO2. Reduction of the amide was performed with
BH3 in THF,9 to give aniline amine 16. Reaction of 16
with potassium thiocyanate and bromine12 afforded the
aminothiazoloindan 17, which was the only product of
thiazole ring closure that was isolated.
Ch em istr y
The synthesis of 12 and 13 is outlined in Scheme 1,
starting from amino ketone 4, which was prepared as
described previously.13 According to standard methods,
amino ketone 4 was propionylated and the benzylic
ketone was reduced catalytically (Pd/C). Then the amide
was reduced with LiAlH4, and a second propyl group
was introduced by propionylation affording amide 5.
Compounds 20 and 21 were synthesized analogously
to 17, but with the insertion of an extra reduction and
propionylation step to obtain di-n-propyl products
(Scheme 3). Briefly, 2-aminoindan 14 was propionylated
and reduced to give the previously described 2-N-n-
propylaminoindan.15 Propionylation, subsequent nitra-
tion, and catalalytic reduction afforded the aniline

Thiazoloindans and Thiazolobenzopyrans
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3551
Ta ble 1. Affinity for Human DA D2L, D3, and D4 Receptors (left) and Inhibitory Properties on Lipid Peroxidation (LPO, right) of
Thiazolobenzopyrans and Thiazoloindans (pramipexole (3, PPX) as reference compound)
affinity for DA receptors, Kia (nM)
inhib of LPO,
IC50 (µM)
a
compd
D2L (agonist radioligand)
D2L [3H]spip
D3 [3H]spip
D4.2 [3H]spip
12
13
17
20
47 ([3H]N-0437)
536 ([3H]N-0437)
1350 ([3H]NPA)
27 ([3H]NPA)
500 ([3H]NPA)
ND
5920
3510
ND
510
NDb
ND
>3.33 µM
272
50
5
>100
60
1400
>10 µM
1.4
ND
21
ND
11
IC50 > 10 µM
138d
30
3c
139d
2.07e
2.78d
0.49e
neuroprotectivef
(PPX)
2.76e
a
b
Ki and IC50 values are means of three separate experiments, the results of which did not vary by more than 25%. ND means not
determined. c Binding data from ref 8. KiL, low-affinity binding. KiH, high-affinity binding. f Pramipexole displays neuroprotective effects
d
e
against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons.11
Ta ble 2. Agonist and Antagonist Effects of Selected
amide 18. Amide reduction gave aniline amine 19,
Compounds as Measured in the Mitogenesis Assay at the Rat
D2L and D3 Receptors
which was reacted with potassium thiocyanate and
bromine,12 to afford the products 20 and 21, which could
be separated with MPLC on SiO2. NMR spectroscopy
showed that these compounds were products of thiazole
ring closure in two different directions.
inhib of quinpirole
(30 nM)-stimulated
[3H]thymidine uptake
[3H]thymidine uptake
EC50, nM (IAa)
compd
12
DA D2L DA D3
DA D2L
Ab
DA D3
A
148 ( 23
(7% ( 1)
5.7 ( 2.2
(28% ( 7)
18.7 ( 2.9
(71% ( 6)
1.7 ( 0.4
>1000
(0%)
>1000
(0%)
>1000
(0%)
0.21 ( 0.04
P h a r m a cology
20
A
A
DA Recep tor Bin d in g. Aminothiazoles 12, 13, 17,
20, and 21 were tested for their in vitro binding affinity
for human dopamine (DA) D2L, D3, or D4.2 receptors,
expressed in Chinese hamster ovary (CHO) K-1 cells.
In the antagonist binding studies, the affinity of the
compounds was determined by their ability to displace
[3H]spiperone from D2L, D3, or D4.2 DA receptors. In the
agonist binding studies, the affinity for the D2L DA
receptor was determined using [3H]N-0437 (5-hydroxy-
2-(N-n-propyl-N-(2-thienylethyl)amino)tetralin) or [3H]-
NPA (N-propylnorapomorphine) as the radioligand. The
affinity data obtained with [3H]NPA are comparable to
those obtained with [3H]N-0437. Receptor affinities are
presented in Table 1.
21
NAc
NTe
NA
A
3 (PPX)d
NT
NA
(90 ( 10%) (98 ( 2.2%)
quinpirole 2.2 (100%) 1.7 (100%)
a
b
IA means intrinsic activity. A means active (test concentra-
tions ranging from 0.1 nM to 1 µM). c NA means not active. IA
data from ref 8. e NT means not tested. All values are the means
of three determinations ( SEM. Pramipexole (3, PPX) and
quinpirole are included as reference compounds.
d
Ra d ica l Sca ven gin g P r op er ties. The radical scav-
enging/antioxidant properties of the thiazoloindans and
thiazolobenzopyrans were determined with the (non-
enzymatic) lipid peroxidation assay.16 In this assay,
radical formation is iron-dependent and the peroxida-
tion of polyunsaturated fatty acids within the mi-
crosomes is induced by the addition of 10 µM Fe2+. By
scavenging radicals the target compounds can inhibit
lipid peroxidation. IC50 values are presented in Table
1.
In tr in sic Activity. The intrinsic activity (IA) of
compounds 12, 20, and 21 was determined with a
functional test, the mitogenesis assay.17,18 [3H]Thymi-
dine uptake was determined in CHO-L6 cells trans-
fected with the rat DA D2L or D3 receptor, as a measure
of agonism at these receptors (Table 2). The IA was
compared with that of quinpirole, which is a full agonist
at both receptors (IA ) 100%). In the same cells the
ability of 12, 20, and 21 to inhibit quinpirole-stimulated
[3H]thymidine uptake was determined, which is a
measure of antagonism (Table 2).
F igu r e 1. Effect on turning behavior of 20 in unilaterally
6-OH-DA lesioned rats. Each point is the mean ( SEM of five
(3.5 µmol/kg) or three (10.4 µmol/kg) rats. Total number of full
contraversive rotations for 3.5 µmol/kg: 3350 ( 460, for 10.4
µmol/kg: 3890 ( 390.
to develop on the lesioned side.19 Upon systemic admin-
istration of a DA agonist, the rat will start to turn
contralaterally, i.e., toward the nonlesioned side.20 The
evoked turning behavior is a measure of the DA (D1 and/
or D2) agonist properties of a compound.
In addition, the effect of 20 was studied in combina-
tion with haloperidol (Figure 2), which selectively blocks
DA D2-like receptors. Rotation behavior was compared
with an equal dose of 20, combined with an ip injection
of vehicle.
Con tr a la ter a l Tu r n in g in 6-OH-DA Lesion ed
Ra ts. Compound 20 was further evaluated in rats
unilaterally lesioned with 6-OH-DA (Figure 1). In this
model, the DA neurons of one side (left or right) of the
nigrostriatal DA system are selectively and completely
degenerated by intracebral injection of the neurotoxin
6-OH-DA. This causes a postsynaptic supersensitivity
Furthermore, the rotation model was employed to
study the oral availability of compound 20. Figure 3
depicts the rotation behavior of orally (po) administered

3552 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
van Vliet et al.
F igu r e 2. Effect on turning behavior of 20 alone or in
combination with haloperidol, in unilaterally 6-OH-DA le-
sioned rats. Each point is the mean ( SEM of four rats. Total
number of full contraversive rotations for 3.5 µmol/kg +
vehicle: 2700 ( 670, for 3.5 µmol/kg + haloperidol: 930 ( 510.
F igu r e 4. Effect of 20 on DA turnover in rat striatum. Each
point is the mean ( SEM of three to four determinations. The
arrow indicates the time of injection. *p < 0.05 vs time ) 0
min.
in the 2-aminoindan structure. Especially the affinity
for the DA D3 receptor of di-n-propyl compound 20 is
enormously increased, as compared to that of the
monopropyl analogue 17. Such an effect is not observed
in the related 2-aminotetralin series, where introduction
of a second n-propyl group only marginally increases
affinity for the DA D3 receptor and even decreases
affinity for the DA D2L receptor subtype (if measured
with an agonist radioligand).23
Unexpectedly, compounds 20 and 21 display an
interesting DA D3-preferring binding profile. Compound
20 binds with moderate affinity to DA D2 and with high
affinity to DA D3 receptors (see Table 1). Although 20
is “quasi-symmetrical” (its asymmetry is created by the
inequivalency of the thiazole nitrogen and sulfur atoms),
resolving this compound may reveal even higher DA D3
selectivity for one of its enantiomers.
F igu r e 3. Effect on turning behavior of 20 administered orally
(po) or subcutaneously (sc). Each point is the mean ( SEM of
four (po) or five (sc) rats. Total number of full contraversive
rotations for 3.5 µmol/kg sc: 3350 ( 460, for 3.5 µmol/kg po:
3700 ( 390.
20 in comparison with an equal dose administered
subcutaneously (sc).
Micr od ia lysis in Ra t Str ia tu m . The effects of 20
on in vivo DA turnover in rat striatum were assessed
with microdialysis methods (Figure 4).
Resu lts a n d Discu ssion
DA Recep tor Bin d in g. Both 3-amino-1-benzopy-
rans21 and 2-aminoindans,22 substituted with a hydroxy
group on the aromatic ring, are known templates for
DA agonists. In these molecules, both the phenolic
oxygen and the basic amine are supposed to interact
with the receptor binding sites. Strictly speaking, the
2-aminothiazole moiety, as used in the here-described
aminothiazoles, is not a bioisosteric replacement of the
phenol group but rather an extension of the aromatic
part of the molecule. Nevertheless, the aminothiazole
exocyclic amino group may substitute for the hydroxy
group of a phenol or catechol and form a hydrogen bond
with the receptor. The position of this amino group
relative to the aromatic nucleus and basic nitrogen
probably plays a critical role for DA receptor affinity.
This may explain the low affinity of the thiazoloben-
zopyrans 12 and 13 for DA receptors (Table 1).
The DA receptor binding profile of 12, 20, and 21
encouraged us to study the action of these compounds
on DA D2 and D3 receptors in a functional assay (see
below).
Ra d ica l Sca ven gin g P r op er ties. As shown in Table
1, the thiazolobenzopyrans and thiazoloindans inhibit
lipid peroxidation, although with marked potency dif-
ferences. This inhibition may be caused by radical
scavenging properties of the test compounds. However,
within this assay other processes (like iron chelation)
may play a role in the observed inhibition. Insofar as
these processes actually take place within lipid mem-
branes, the observed lower potency of the monopropyl
analogue 17 may be explained by its lower lipophilicity
(log D ) 0.19 for 17, compared to log D ) 1.66 for 20,
as predicted with the computer program Pallas 1.224).
The thiazoloindans show a more interesting DA
receptor binding profile. Compared to the thiazoloben-
zopyrans, di-n-propylthiazoloindans 20 and 21 show a
higher affinity for DA D3 receptors.
The affinity of the thiazoloindans is remarkably
increased when a second n-propyl group is introduced
In contrast to DA agonism or antagonism, the process
of free radical scavenging is not a specific interaction
with a protein. The scavenger has to compete with

Thiazoloindans and Thiazolobenzopyrans
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3553
various cell components for reactive species. As a
consequence, a radical scavenging drug probably needs
to be dosed in high amounts to exert an effect in vivo.
For the above-described compounds it remains to be
established whether radical scavenging properties in
vitro will provide neuroprotective properties in vivo.
nate, and a blockade of presynaptic DA receptors would
then explain the observed increase in DA turnover.
Compound 20 was also tested in rats which were
reserpinized 18 h beforehand (data not shown), where
it turned out to be inactive. In reserpinized rats
postsynaptic DA receptors are relatively insensitive, and
the partial DA D2 agonism of 20 does not give an effect
in this model.
The potent DA D3 antagonism of 20 may contribute
to the observed profile. As has been suggested previ-
ously, the DA D3 receptor may be either a postsynaptic
receptor with an inhibitory influence on rat locomotor
activity27,28 or a striatal autoreceptor with a DA syn-
thesis inhibiting influence,29 or both. As a consequence,
blockade of postsynaptic DA D3 receptors by 20 may
produce increased locomotor activity. In microdialysis,
blockade of DA D3 autoreceptors may increase DA
synthesis. However, in rats the striatal density of DA
D3 receptors is believed to be relatively low. Further
pharmacological evaluation of compound 20 may reveal
the actual role of DA D3 receptors in the observed
profile.
In tr in sic Activity. The action of compounds 12, 20,
and 21 at DA D2L and D3 receptors was assessed in the
mitogenesis assay: agonism stimulates cell division,
which can be measured with uptake of [3H]thymidine.
From the results listed in Table 2 it can be concluded
that compounds 20 and 21 display (partial) agonism at
DA D2 sites and antagonism at DA D3 sites, whereas
12 appears to be an antagonist at both receptors (but
with low potency). This contrasts with the related
2-aminothiazole pramipexole (3), which is a full agonist
at both DA D2 and D3 receptors.8 The observed potencies
(EC50 values) to stimulate [3H]thymidine uptake reflect
in part the DA D2 affinity: compound 20 (Ki D2 ) 27
nM) displays the highest potency at DA D2 receptors,
whereas the potency of compound 21 is higher than
expected, regarding its receptor binding profile.
Within this model, activation of rotation may reflect
activation of DA D1 or D2 receptors, or a combined
activation of both DA D1 and D2 receptors. Administra-
tion of haloperidol blocks the activation of DA D2(-like)
receptors. Figure 2 displays the effects of 20 in combi-
nation with haloperidol. It was observed that haloperi-
dol greatly reduces the rotation activation of 20, thereby
excluding activation of DA D1 receptors by this com-
pound.
The oral activity of 20 was also studied with unilater-
ally 6-OH-DA lesioned rats. As can be seen in Figure 3,
compound 20 has an excellent oral activity, which is
comparable to its activity upon subcutaneous adminis-
tration. To our surprise, orally administered 20 gives a
faster onset of action as compared to subcutaneous
administration. This may be explained by a slow
subcutaneous diffusion process after administration of
20 in the neck region. Alternatively, the quicker onset
of action after oral administration of 20 might be
explained by the formation of active metabolites.
In the microdialysis experiments we observed that,
after an initial increase in DA turnover, compound 20
causes a (dose-dependent) decrease of DA turnover
(Figure 4: 3 and 10 µmol/kg). This may be explained
with different receptor binding and agonist/antagonist
properties of the two enantiomers of 20. One of the
enantiomers may have more intrinsic (agonist) activity
than the other, and this effect may predominate in the
course of the experiments, which causes the observed
decrease of DA turnover. If this is true, the situation
compares to the observed differences for the enanti-
omers of 3-PPP: (+)-3-PPP was found to behave as a
full agonist, whereas (-)-3-PPP displayed agonist and
antagonist actions, which depended on the DA receptor
which was studied (pre- or postsynaptic)26 and the state
it was in (super- or normosensitive).30
Taking the intrinsic activity data and receptor binding
profile together, it can be concluded that compound 20
is a potent and partially selective antagonist at DA D3
receptors. In addition, it displays partial agonism at DA
D2 receptors, but with a moderate affinity and potency.
Con tr a la ter a l Tu r n in g in 6-OH-DA Lesion ed
Ra ts a n d Micr od ia lysis in Ra t Str ia tu m . The DA
agonist properties of 20 were evaluated in rats with a
unilaterally lesioned nigrostriatal DA system. Also, the
effects of (several doses of) 20 on DA turnover in rat
striatum were studied.
As is obvious from Figure 1, compound 20 produced
a strong and long-lasting activation of rotation behavior.
Furthermore, 20 caused a dose-dependent increase of
DA turnover in rat striatum (Figure 4). On first sight,
these observations seem contradictory: An activation
of rotation behavior in unilaterally 6-OH-DA lesioned
rats implies agonism at postsynaptic receptors, whereas
an increase of DA turnover (due to the blockade of
presynaptic DA receptors) as measured with micro-
dialysis would imply antagonism.
Carlsson proposed that the extent of previous (endog-
enous) agonist occupancy determines DA receptor re-
sponsiveness and thereby in part the intrinsic efficacy
of agents interacting with the receptors.25 This proposi-
tion was based on the pharmacology of the partial
agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine
((-)-3-PPP), which was found to act as an agonist in
pharmacological models with supersensitive DA recep-
tors and as an antagonist on normosensitive DA recep-
tors.26 The dual character of compound 20 also appears
to be accounted for by its partial agonism at DA D2
receptors. In unilaterally 6-OH-DA lesioned rats, a
postsynaptic supersensitivity of DA receptors in stria-
tum develops,19 which “amplifies” the DA agonist action
of a compound. In this situation, the DA agonist
properties of compound 20 predominate, which explains
the observed rotation activation. On the other hand, in
nonpretreated rats used in the microdialysis experi-
ments, DA receptors are normosensitive. In this situa-
tion, the antagonist properties of compound 20 predomi-
In view of this (one of the enantiomers of) compound
20 may deserve closer examination as a potential
(atypical) antipsychotic. Selective stimulation of dopa-
minergic autoreceptors decreases DA synthesis via
negative feedback, thereby decreasing dopaminergic
neurotransmission. As has been suggested for (-)-3-

3554 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
van Vliet et al.
PPP26 and other DA autoreceptor-selective agents, this
approach may lead to antipsychotic action without the
concomitant side effects observed for the classical neu-
roleptics.
δ 9.3, 11.0, 23.8, 26.7, 28.5, 48.0, 49.9, 67.3, 116.5, 120.6, 127.3,
129.7, 138.5, 155.6, 174.2; HRMS calcd (obsd) for C15H21NO2
247.1572 (247.1580).
6- a n d 8-Nitr o-3-(N-n -p r op yl-N-p r op ion yla m in o)-3,4-
d ih yd r o-2H-[1]ben zop yr a n (6 a n d 7). Amide 5 (1.7 g, 6.9
mmol) was dissolved in nitromethane (22 mL), and cooled on
ice. A nitrating mixture consisting of 0.51 mL concentrated
nitric acid, 1.17 mL of water and 6.92 mL of concentrated
sulfuric acid was added dropwise over a 20-min period. After
the addition was completed the reaction mixture was stirred
on ice for 45 min. The reaction was quenched with ice, and
the reaction mixture was extracted with ethyl acetate. The
combined organic layers were washed once with brine, dried
over MgSO4, and concentrated under reduced pressure, which
gave a brown oil. The two products were separated with
column chromatography (eluent 100% Et2O), which yielded
1.12 g of the 6-nitrated product as a brown oil (55%, Rf ) 0.35
in 100% Et2O) and 0.63 g of the 8-nitrated product as a brown
oil (31%, Rf ) 0.26 in 100% Et2O). Both nitro products solidified
upon standing and were used without further purification.
In conclusion, compound 20 is a partial DA D2 agonist,
with excellent oral activity. The long-lasting activity and
excellent oral activity in unilaterally 6-OH-DA lesioned
rats suggest that compound 20 is potentially useful for
the treatment of PD. In addition, 20 displays selective
DA D3 antagonism. Whether this contributes to the
observed in vivo actions of 20 remains to be studied.
Furthermore, the potential neuroprotective properties
of compound 20 and its analogues may prove valuable
in the treatment of PD.
Resolution of 20 is needed for further pharmacological
investigations. This may reveal different DA agonist or
antagonist actions for the enantiomers of 20 and pos-
sibly a difference in the preference for DA autoreceptors.
The potential antipsychotic action of (one of the enan-
tiomers of) 20 needs further study.
6-Nitr o-3-(N-n -p r op yl-N-p r op ion yla m in o)-3,4-d ih yd r o-
2H-[1]ben zop yr a n (6): mp 109-111 °C; 1H NMR (CDCl3, 200
MHz) δ 0.89 (t, J ) 7.4, 3H), 1.12 (t, J ) 7.4, 3H), 1.49-1.64
(m, 2H), 2.35 (q, J ) 7.4, 2H), 2.85-2.94 (m, 1H), 3.13-3.21
(m, 2H), 3.36-3.46 (m, 1H), 4.22-4.35 (m, 2H), 4.40-4.50 (m,
1H), 6.85 (d, J ) 9.6, 1H), 7.93-7.96 (m, 2H); 13C NMR δ 9.4,
11.1, 23.9, 27.0, 28.5, 48.8, 50.1, 67.8, 117.1, 121.7, 123.6, 126.0,
141.2, 159.5, 174.3; MS (EIPI) m/e 292 (M+). Anal. (C15H20N2O4‚
1/4H2O) C,H,N.
Exp er im en ta l Section
Ch em istr y. Gen er a l. Melting points were determined in
open glass capillaries on an Electrothermal digital melting
point apparatus and are uncorrected. 1H NMR spectra were
recorded at 200 MHz on a Varian Gemini 200 spectrometer;
the chemical shifts are given in δ units (ppm) relative to the
solvent. Coupling constants are given in hertz (Hz). The
spectra recorded were consistent with the proposed structures
of intermediates and final compounds. IR spectra were ob-
tained on an ATI-Mattson spectrophotometer, and only the
important absorptions are given. Electronic ionization (EI)
mass spectra were obtained on a Unicam 610-Automass 150
GC-MS system. Elemental analyses were performed by the
Analytical Chemistry Section at Parke Davis, Ann Arbor, MI,
and were within 0.4% of the theoretical values, except where
noted. Compounds that were obtained as an oil, or as a solid
in a very small amount, were analyzed by high-resolution mass
spectrometry (HRMS), performed on a J EOL MSroute J MS-
600H by the Department of Chemistry, University of Gronin-
gen.
8-Nitr o-3-(N-n -p r op yl-N-p r op ion yla m in o)-3,4-d ih yd r o-
2H-[1]ben zop yr a n (7): mp 93-95 °C; 1H NMR (CDCl3, 200
MHz) δ 0.89 (t, J ) 7.4, 3H), 1.12 (t, J ) 7.4, 3H), 1.49-1.64
(m, 2H), 2.35 (q, J ) 7.4, 2H), 2.88-2.99 (m, 1H), 3.16-3.24
(m, 2H), 3.42-3.57 (m, 1H), 4.11-4.36 (m, 2H), 4.49-4.59 (m,
1H), 6.88-6.97 (m, 1H), 7.26 (d, J ) 6.3, 1H), 7.67 (d, J ) 7.7,
1H); 13C NMR δ 9.4, 11.2, 23.7, 27.1, 28.7, 49.4, 50.6, 68.0,
120.0, 123.7, 124.6, 134.5, 139.4, 158.8, 174.2; MS (EIPI) m/e
292 (M+). Anal. (C15H20N2O4) C,H,N.
6-Am in o-3-(N-n -pr opyl-N-pr opion ylam in o)-3,4-dih ydr o-
2H-[1]ben zop yr a n (8). A solution of 6 (0.80 g, 2.7 mmol) in
100 mL of ethanol was treated (under N2) with 10% Pd/C (0.8
g), placed in a Parr apparatus, and shaken for 2 h with a
hydrogen gas pressure of 4.5 atm. The Pd/C was removed by
filtration over Celite, and the solvent was removed under
reduced pressure, which yielded 8 as a light-red oil (0.61 g,
85%): 1H NMR (CDCl3, 200 MHz) δ 0.84 (t, J ) 7.4, 3H), 1.13
(t, J ) 7.3, 3H), 1.49-1.61 (m, 2H), 2.28-2.40 (m, 2H), 2.73-
2.84 (m, 1H), 3.04-3.16 (m, 3H), 3.59 (br s, 2H), 4.04-4.24
(m, 2H), 4.41-4.46 (m, 1H), 6.38 (s, 1H), 6.45 (d, J ) 8.4, 1H),
6.62 (d, J ) 8.4, 1H); 13C NMR δ 9.3, 11.0, 23.8, 26.6, 28.5,
47.9, 49.9, 67.3, 115.1, 115.9, 117.0, 121.4, 139.7, 147.0, 174.2;
HRMS calcd (obsd) for C15H22N2O2 262.1681 (262.1696).
If necessary, compounds were purified with medium-pres-
sure chromatography (MPLC) on silica gel, starting with an
apolar eluent (usually 100% hexane) and gradually increasing
its polarity (usually by adding ethyl acetate), finishing with
an eluent mixture that gave a Rf value of approximately 0.3
on TLC.
Ma ter ia ls. The starting compounds 3,4-dihydro-2H-[1]-
benzopyran-4-one (4-chromanone) and 2-aminoindan hydro-
chloride were purchased from Acros and Aldrich, respectively.
All other reagents and solvents were also commercially avail-
able and were used without further purification, with the
exception of diethyl ether, which was distilled from sodium/
benzophenone.
8-Am in o-3-(N-n -pr opyl-N-pr opion ylam in o)-3,4-dih ydr o-
2H-[1]ben zop yr a n (9). Compound 7 (0.63 g, 2.2 mmol) was
converted to 9 (0.47 g, 83%), as described for 6, and was
obtained as a light-brown oil: 1H NMR (CDCl3, 200 MHz) δ
0.87 (t, J ) 7.3, 3H), 1.15 (t, J ) 7.3, 3H), 1.52-1.64 (m, 2H),
2.30-2.43 (m, 2H), 2.78-2.90 (m, 1H), 3.11-3.19 (m, 3H), 3.70
(br s, 2H), 4.16-4.34 (m, 2H), 4.40-4.55 (m, 1H), 6.44-6.73
(m, 3H); 13C NMR δ 9.3, 11.0, 23.9, 26.7, 28.3, 47.9, 50.0, 67.4,
112.8, 118.9, 120.5, 120.7, 135.3, 141.8, 174.2; HRMS calcd
(obsd) for C15H22N2O2 262.1681 (262.1709).
3-(N-n -P r op yl-N-p r op ion yla m in o)-3,4-d ih yd r o-2H-[1]-
ben zop yr a n (5). 3-N-n-Propylamino-3,4-dihydro-2H-[1]ben-
zopyran (2.95 g, 15.5 mmol) was dissolved in 50 mL of
methylene chloride, and triethylamine (4.3 mL, 30 mmol) was
added. A solution of propionyl chloride (1.6 mL, 18.5 mmol) in
15 mL of methylene chloride was added dropwise over a 30-
min period. After the addition was completed, the reaction
mixture was stirred for 30 min. The mixture was washed with
water, then with brine and dried over MgSO4. Evaporation of
the solvent gave a brown oil, which was purified with column
chromatography (eluent diethyl ether:hexane ) 2:1), yielding
5 as a yellow oil (2.72 g, 71%): 1H NMR (CDCl3, 200 MHz) δ
0.87 (t, J ) 7.2, 3H), 1.10-1.19 (m, 5H), 1.49-1.65 (m, 2H),
2.36 (q, J ) 7.3, 2H), 2.89 (dd, J 1 ) 15.7, J 2 ) 5.7, 1H), 3.12-
3.31 (m, 2H), 4.14-4.44 (m, 2H), 6.80-7.14 (m, 4H); 13C NMR
6-Am in o-3-(N,N-d i-n -p r op yla m in o)-3,4-d ih yd r o-2H-[1]-
ben zop yr a n (10). LiAlH4 (0.23 g, 5.7 mmol) was suspended
in 4.5 mL of dry ether, and the suspension was cooled on ice.
A solution of amide 8 (0.60 g, 2.3 mmol) in 75 mL of dry ether
was added dropwise. After the addition was completed, the
mixture was stirred on ice for 1 h, then at room temperature
for 1 h, and then heated to reflux for 2h. After cooling to room
temperature, the reaction was quenched by the cautious
addition of 0.23 mL of water, 0.23 mL of 4 N NaOH and 0.69
mL of water (in that order). The mixture was heated to reflux
until all precipitates had turned white (10 min), cooled to room

Thiazoloindans and Thiazolobenzopyrans
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3555
temperature, and filtered over Celite. The filtrate was dried
over Na2SO4 and concentrated under reduced pressure, which
yielded 10 as a brown oil (0.51 g, 89%): 1H NMR (CDCl3, 200
MHz) δ 0.87 (t, J ) 7.3, 6H), 1.36-1.50 (m, 4H), 2.46-2.53
(m, 4H), 2.75 (d, J ) 8.6, 2H), 3.08-3.22 (m, 3H), 3.74 (t, J )
10.3, 1H), 4.22 (dd, J 1 ) 10.3, J 2 ) 7.3, 1H), 6.42-6.49 (m,
2H), 6.63 (d, J ) 8.8, 1H); 13C NMR δ 11.5 (2C), 21.6 (2C),
28.2, 52.5 (2C), 53.3, 67.8, 114.8, 116.3, 116.7, 122.4, 139.5;
HRMS calcd (obsd) for C15H24N2O 248.1889 (248.1891).
stirred at 50 °C for 45 min. After cooling to room temperature,
the Pd/C was removed by filtration over Celite, and the
methanol was evaporated under reduced pressure. The re-
maining pink solid was purified with MPLC on silica (initial
eluent 100% hexane, final eluent 100% ethyl acetate). The pure
fractions were pooled and concentrated to dryness, which gave
1
15 as a white solid (0.67 g, 76%): mp 127-128 °C; H NMR
(CDCl3, 200 MHz) δ 1.08 (t, J ) 7.7, 3H), 2.10 (q, J ) 7.6,
2H), 2.62 (dt, J 1 ) 16.1, J 2 ) 4.2, 2H), 3.14 (dd, J 1 ) 16.2,
J 2 ) 7.1, 2H), 3.61 (s, 2H), 4.59-4.67 (m, 1H), 6.12 (d, J )
7.3, 1H), 6.45-6.51 (m, 2H), 6.94 (d, J ) 7.8, 1H); 13C NMR δ
9.6, 29.4, 38.9, 40.0, 50.5, 111.5, 113.7, 125.1, 130.5, 142.2,
145.4, 173.6; MS (EIPI) m/e 204 (M+). Anal. (C12H16N2O)
C,H,N.
8-Am in o-3-(N,N-d i-n -p r op yla m in o)-3,4-d ih yd r o-2H-[1]-
ben zop yr a n (11). Compound 9 (0.46 g, 1.8 mmol) was
converted to 11 (0.41 g, 92%), as described for 8, and was
obtained as an oil: 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J )
7.3, 6H), 1.37-1.55 (m, 4H), 2.47-2.55 (m, 4H), 2.81 (d, J )
8.3, 2H), 3.08-3.28 (m, 1H), 3.65 (br s, 2H), 3.81 (t, J ) 10.3,
5-Am in o-2-N-n -p r op yla m in oin d a n (16). Amide 15 (0.62
g, 3.0 mmol) was dissolved in 8 mL of dry ether, and BH3 (16
mL of a 1 M solution in THF) was added dropwise, over a 1-h
period. After the addition was completed, the reaction mixture
was heated to reflux for 1 h. The mixture was cooled to room
temperature, and 1.6 mL of water was added cautiously.
Subsequently, 3.2 mL of 10% HCl was added, and all volatile
solvents were evaporated under reduced pressure. The re-
maining aqueous solution was basified with 10% NaOH and
extracted with ethyl acetate (2 × 20 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure, which yielded 16 as a clear oil (0.52 g,
90%): 1H NMR (CDCl3, 200 MHz) δ 0.92 (t, J ) 7.3, 3H), 1.43-
1.61 (m, 2H), 2.58-2.71 (m, 4H), 3.00-3.11 (m, 2H), 3.52-
3.65 (m, 4H), 6.49 (d, J ) 7.8, 1H), 6.55 (s, 1H), 6.96 (d, J )
7.8, 1H); 13C NMR δ 11.6, 23.2, 38.9, 39.9, 50.0, 59.8, 111.5,
113.4, 125.0, 131.6, 142.9, 145.0; MS (EIPI) m/e 190 (M+). Part
of the product was converted to the dihydrochloride and
recrystallized from ethanol, yielding white crystals: mp 238-
242 °C. Anal. (C12H18N2‚2HCl) C,H,N.
1H), 4.36 (dd, J 1 ) 10.3, J 2 ) 3.1, 1H), 6.45-6.72 (m, 3H); 13
C
NMR δ 11.5 (2C), 21.5 (2C), 27.8, 52.5 (2C), 53.3, 68.0, 112.7,
119.4, 120.4, 121.5, 135.2, 142.2; HRMS calcd (obsd) for
C
15H24N2O 248.1889 (248.1895).
6-Am in o-3-(N,N-di-n -pr opylam in o)-3,4-dih ydr o-2H-th ia-
zolo[5,4-f]-[1]ben zop yr a n (12). Aniline 10 (0.20 g, 0.80
mmol) and potassium thiocyanate (0.16 g, 1.66 mmol) were
dissolved in 1.9 mL of glacial acetic acid. A solution of bromine
(40 µL, 0.80 mmol) in 0.9 mL of glacial acetic acid was added
dropwise over a period of 15 min. After the addition was
completed, the reaction mixture was stirred for 1.5 h, then
basified with 10% NaOH and extracted with ethyl acetate. The
combined organic layers were washed once with brine, dried
over MgSO4, and concentrated under reduced pressure. The
product was purified with column chromatography over silica
(eluent 100% Et2O) which yielded 12 as a white solid (0.11 g,
45%): 1H NMR (CDCl3, 200 MHz) δ 0.90 (t, J ) 7.4, 6H,
-CH3), 1.39-1.57 (m, 4H, -CH2-), 2.50-2.57 (m, 4H, -N-
CH2-), 2.72-2.89 (m, 2H, Ph-CH2-), 3.23-3.33 (m, 1H, -CH-
N-), 3.84 (t, J ) 10.3, 1H, -O-CH-), 4.29-4.35 (m, 1H, -O-
CH-), 5.62 (s, 2H, -NH2), 6.81 (d, J ) 8.6, 1H, PhH), 7.27 (d,
J ) 8.6, 1H, PhH); 13C NMR δ 11.7 (2C), 22.0 (2C), 28.1, 52.7
(2C), 53.2, 68.0, 114.8, 115.0, 117.6, 132.4, 145.5, 150.0, 164.0;
IR (KBr, cm-1) 2968, 2632, 1645, 1580, 1484; MS (EIPI) m/e
305 (M+). The product was converted to the dihydrochloride
and recrystallized from ethanol, yielding an off-white solid:
mp 209-212 °C. Anal. (C16H23N3SO‚2HCl‚H2O) C,H,N.
8-Am in o-3-(N,N-di-n -pr opylam in o)-3,4-dih ydr o-2H-th ia-
zolo[5,4-h ]-[1]ben zop yr a n (13). Aniline 11 (0.14 g, 0.57
mmol) was converted to 13 (0.095 g, 55%), as described for
10, and was obtained as a light-brown oil. The product failed
to crystallize as the dihydrochloride: 1H NMR (CDCl3, 200
MHz) δ 0.91 (t, J ) 7.3, 6H, -CH3), 1.40-1.58 (m, 4H,
-CH2-), 2.44-2.80 (m, 4H, -N-CH2-), 2.85-2.95 (m, 1H,
Ph-CH-), 3.03-3.07 (m, 1H, Ph-CH-), 3.14-3.26 (m, 1H,
-CH-N-), 3.84 (t, J ) 10.2, 1H, -O-CH-), 4.05 (s, 2H,
-NH2), 4.34-4.42 (m, 1H, -O-CH-), 6.55 (d, J ) 8.3, 1H,
PhH), 7.08 (d, J ) 8.3, 1H, PhH); 13C NMR (CDCl3, 500 MHz)
δ 11.5 (2C), 21.8 (2C), 26.7, 52.6 (2C), 53.1, 67.8, 108.8, 110.6,
111.6, 112.5, 128.1, 138.6, 166.5; IR (KBr, cm-1) 2966, 2353,
1632, 1485; HRMS calcd (obsd) for C16H23N3OS 305.1562
(305.1547).
6-Am in o-2-N-n -p r op yla m in oth ia zolo[4,5-f]in d a n (17).
Compound 16 (0.48 g, 2.5 mmol) was converted to 17 (0.29 g,
46%), as described for 10. The product was converted to the
dihydrochloride and recrystallized from methanol/ethanol,
1
which yielded a white solid: mp 285-290 °C; H NMR (D2O,
200 MHz) δ 0.81 (t, J ) 7.3, 3H, -CH3), 1.48-1.60 (m, 2H,
-CH2-), 2.92 (t, J ) 7.7, 2H, -N-CH2-), 2.96-3.08 (m, 2H,
PhCH2-), 3.26-3.38 (m, 2H, PhCH2-), 3.95-4.08 (m, 1H,
-CH-N-), 7.15 (s, 1H, PhH), 7.40 (s, 1H, PhH); 13C NMR δ
9.9, 19.1, 34.9, 35.2, 47.5, 57.9, 109.7, 118.3, 121.9, 136.1, 136.2,
139.5, 169.2; IR (KBr, cm-1) 2967, 2805, 2658, 1651, 1459; MS
(EIPI) m/e 247 (M+). Anal. (C13H17N3S1‚2HCl‚1/2H2O) C,H,N.
5-Am in o-2-(N-n -p r op yl-N-p r op ion yl)a m in oin d a n (18).
2-(N-n-Propyl-N-propionyl)aminoindan (0.70 g, 3.0 mmol) was
converted to 5-nitro-2-(N-n-propyl-N-propionyl)aminoindan,
which subsequently was reduced to 18 as described for the
conversion of 2-propionamidoindan to 15. The product was
purified with MPLC on silica (initial eluent 100% hexane, final
eluent hexane:ethyl acetate ) 1:1), yielding 18 as a light-yellow
oil (0.49 g, 66%): 1H NMR (CDCl3, 200 MHz) δ 0.83 (t, J )
7.3, 3H), 1.15 (t, J ) 7.3, 3H), 1.48-1.65 (m, 2H), 2.32-2.43
(m, 2H), 2.93-3.01 (m, 4H), 3.05-3.21 (m, 2H), 3.61 (br s, 2H),
4.60-4.77 (m, 1/2H), 5.10-5.28 (m, 1/2H), 6.50 (d, J ) 7.6, 1H),
6.54 (s, 1H), 6.96 (d, J ) 7.6, 1H); 13C NMR (CD3OD, 200 MHz)
δ 8.6, 10.0, 22.4, 26.3, 35.9, 36.0, 43.9, 57.1, 111.4, 114.3, 124.2,
130.4, 141.5, 145.4, 175.0; HRMS calcd (obsd) for C15H22N2O
246.1732 (246.1720).
5-Am in o-2-(N,N-d i-n -p r op yla m in o)in d a n (19). Com-
pound 18 (0.43 g, 1.8 mmol) was converted to 19 (0.39 g, 96%)
as described for 15 and was obtained as an oil: 1H NMR
(CDCl3, 200 MHz) δ 0.88 (t, J ) 7.3, 6H), 1.42-1.57 (m, 4H),
2.47-2.55 (m, 4H), 2.77-3.00 (m, 4H), 3.55-3.67 (m, 1H), 6.49
(d, J ) 7.8, 1H), 6.54 (s, 1H), 6.95 (d, J ) 7.8, 1H); 13C NMR
δ 11.7 (2C), 19.7 (2C), 35.4, 36.5, 53.2 (2C), 63.3, 111.3, 113.4,
124.8, 131.8, 142.9, 144.9; HRMS calcd (obsd) for C15H24N2
232.1939 (232.1936).
5-Am in o-2-p r op ion a m id oin d a n (15). 2-Propionamido-
indan (1.0 g, 5.5 mmol) was dissolved in nitromethane (18 mL),
and cooled on ice. A nitrating mixture consisting of 0.74 mL
concentrated nitric acid, 1.6 mL of water and 10 mL of
concentrated sulfuric acid was added dropwise over a 30-min
period. After the addition was completed, the reaction mixture
was stirred for 1 h, while gradually warming to room temper-
ature. The reaction was quenched with ice, and the reaction
mixture was extracted with ethyl acetate. The combined
organic layers were washed once with brine, dried over MgSO4,
and concentrated under reduced pressure, yielding a yellow
solid (1.2 g, 95%), which consisted mainly (82% according to
GC) of 5-nitro-2-propionamidoindan.
The nitro compound (1.2 g, containing 4.3 mmol of 5-nitro-
2-propionamidoindan) and ammonium formate (1.4 g, 22.2
mmol) were dissolved in 55 mL of methanol. This mixture was
treated (under N2) with 10% Pd/C (0.56 g) and subsequently
6-Am in o-2-(N,N-d i-n -p r op yla m in o)t h ia zolo[4,5-f]in -
d a n (20) a n d 5-Am in o-2-(N,N-d i-n -p r op yla m in o)th ia zolo-
[5,4-e]in d a n (21). Compound 19 (0.35 g, 1.5 mmol) was
converted to a mixture of 20 and 21, as described for 10. The

3556 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
van Vliet et al.
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products were separated with MPLC on silica (initial eluent
hexane:ethyl acetate ) 1:1, final eluent ethyl acetate:ethanol
) 1:1), which yielded 20 as a light-yellow solid (0.18 g, 41%)
and 21 as a light-yellow solid (0.11 g, 25%).
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20: 1H NMR (CD3OD, 200 MHz) δ 0.94 (t, J ) 7.3, 6H,
-CH3), 1.57-1.66 (m, 4H, -CH2-), 2.70-2.78 (m, 4H, -N-
CH2-), 2.92-3.25 (m, 4H, PhCH2-), 3.65-3.88 (m, 1H, -CH-
N-), 7.20 (s, 1H, PhH), 7.37 (s, 1H, PhH); 13C NMR δ 10.3
(2C), 17.8 (2C), 35.1, 35.4, 52.5 (2C), 63.3, 113.1, 116.0, 129.1,
134.0, 138.4, 150.8, 168.2; IR (KBr, cm-1) 2967, 2632, 1638;
MS (EIPI) m/e 289 (M+). The compound was converted to the
dihydrochloride and recrystallized from 100% ethanol, which
yielded an off-white solid: mp 273-275 °C dec. Anal.
(C16H23N3S‚2HCl‚1/2H2O) C,H,N.
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