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Synthesis and Dopaminergic Properties of 3- and 4-Substituted 1-{2-[5-1H-Benzimidazole-2-thione]ethyl}piperidines and Related Compounds.

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1- { 2-[5-( 1H-Benzimidazole-2-thione)]ethyl)piperidines
Synthesis and Dopaminergic Properties of 3- and 4-Substituted
1-{2454lH-Benzimidazole-2-thione)]ethyl}piperidinesand Related
Sladjana Dukic a), Sladjana Kostic-Rajacicb),Vukic S ~ S k i c ~ and
' ~ ) ,Jelena Joksimovic*a)
a)Institutefor Biological Research, 11060 Belgrade, 29. Novembra 142; b'Institute for Chemistry, Technology and Metallurgy, 1 1 000 Belgrade,
NjegoSeva 12, Yugoslavia
Key Words: Substituted arylpiperidines, dopaminergic, D1, D2, dopamine receptors
With an aim of creating new, high affinity dopaminergic ligands.
six different 3- and 4-substituted I - ( 2-[5-( IH-benzimidazole-2thione)]ethyl ] piperidines and nine related heterocyclic congeners
were synthesized and evaluated for in vitr-o binding affinity at DI
and D2 dopamine receptors. Synaptosomal membranes prepared
from fresh bovine caudate nuclei were used as a source of the
dopamine receptors. Only 4-[bis-(4-fluorophenyI)methylene]piperidines, compounds 9e, lod, and lld, expressed moderate
affinity for the D I rece tors, while all other compounds were
inactive competitors of [ HlSCH 23390. Compounds 9c, 9d, lOc,
lla, and llc were inactive in the D2 receptor binding assay, as
well. Derivatives of 4-phenylpiperidine (9-llb) and 3-phenylpiperidine (10a) expressed a moderate to low affinity for the D2
receptors. However, racemic (*)- 1-(2-[5-(lH-benzimidazole-2thione)]ethyl]-3-phenylpiperidine 9a and its enantiomer (+)-9a
behaved as selective, high affinity D2 receptor ligands, the latter
being some four times more active than the racemate.
The dopaminergic (DA-ergic) system plays a pivotal role
in the mammalian brain. Disturbances at the level of this
system are closely connected with several serious neurolo ical, psychiatric,and endocrinologicaldiseases in humans[ I 5 1 .
Dopamine produces its effect in vivo through the binding to
five differentreceptor subtypesbelonging to two main classes
D1 and D$'].
Several DA-ergic ligands synthesized so far represent not
only useful tools for fundamental research but also valuable
pharmaceuticals applied in the treatment of the above disord e r ~ [ ~However,
due to undesirable side effects of these
compounds, there is an increasing interest for the creation of
new, more selective and active DA-ergic agonists and antagonists that would express minimum adverse effectsL4].
We have reported previously the synthesis of several new
flexible DA-ergic ligands (compounds 1 4 ; Scheme l)[51.
The present work was aimed at further elaboration of stereochemical and topological demands of this class of ligands for
the binding at the central DA receptors. For this purpose, new
compounds containing a semirigid piperidine ring in the side
chain were synthesizedconsideringN-n-propyl-N-(2-phenylethyl)-5-(benzimidazole)ethylamine (1), N-n-propyl-N-(2phenylethy1)J-( 1H-benzimidazole-2-thi0ne)ethylamine (3)
and N-n-propyl-N-(phenylethyl)-6-(1,4-dihydroquinoxaline2,3-dione)ethylamine (4) as the leading structures. The ef-
Arch. Phann. Phann. Med Chem.
3:x: -C(S)-
4: x: -C(O)-C(O)-
Scheme 1. Structures of the parent compounds.
fects of these chemical modifications on the binding of the
new ligands to the Dl and D2 DA receptors were studied.
Structuresof the compounds synthesizedduring the present
work and the corresponding synthetic pathways are shown in
Scheme 2. Procedures for the synthesis of 2-nitro-4-(chloroethyl)-aniline (5)[*], (f)3-phenylpiperidine (7a)l7], 4-[ 1(benzimidazole-2-0ne)Ipiperidine(7cf9], 4 - [bis(4-fluoropheny1)methylenelpiperidine (7e)[lo1have already been described. Compound 5 readily alkylates piperidines (6a-g) in
DMF in the presence of Na2C03 and KI at elevated temperature producing o-nitroanilines (7a-e). Reduction of o-ni-
7 a-e
8 a-e
7a-11% RI=H, Rz=Phenyl; 7b-llb: RI=Phenyl. RZ=H; 7c-11c: RI= l-Ben2imidazol&+ne
Rz=H; 76-96: R1=l-Phenyl-l,3-diazaspirocyclopent-4-one.
RZ=H: 7d41d: R?=bis-(4-fluoro:
Scheme2. a) NazC03, KI, DMF; b) Ra-Ni, NzHtH20, EtOH, c) CS2, KOH,
EtOH, reflux; d) oxalic acid; e) HCOOH, 100 "C.
0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheim, 1997
0365-6233/97/0102-0025 $1 7.50 +.50/0
Joksimovic and co-workers
Table 1. Affinity and selectivity of the new ligands for the
binding at the Dl and D2 dopamine receptors.
Ki + S.E.M (nM)
2.9 t 0.3
622 43
> 10000
> 10000
> 10000
1 5 9 2 17
938 101
>I 0000
> 10000
1 10000
1 10000
> 10000
> 10000
SCH 23390
204 21
270 2 34
421 65
1050 & 320
2.7 & 0.4
> 10000
385 2 42
453 64
> 10000
> 10000
1.1 +0.1
Values are the means of three independent experiments performed in triplicate at eight ligand concentrations ( lo4M).
troanilines 7a-e with Ra-Nithydrazine gives o-phenylenediamines 8a-e. Target benzimidazole-2-thiones 9a-e, 1,4dihydroquinoxaline-2,3-diones 10a-d and benzimidazoles
lla-d were prepared as described elsewhere[’ I ] starting from
diamines 8a-e and CS2/KOH in EtOH, oxalic acid and boiling formic acid, respectively. Physical and chemical characteristics of the compounds prepared in this way are given
under Experimental.
Results and Discussion
DA-ergic activity of compounds 9a+, 1Oa4, and lla-d
was evaluated by in vitro competition binding experiments
using [3H]SCH 23390 (D1 receptor selective) and
[3H]spiperone (D2 receptor selective) as the radioligands.
Synaptosomal membranes prepared from fresh bovine caudate nuclei were em loyed as a source of the DA receptors.
Compounds 1,3,4[$ haloperidol, and SCH 23390 were run
simultaneously in competition binding assays as references.
Binding characteristics of the new ligands are given in Table 1. As seen, only compounds 9e, lod, and l l d expressed
a moderate affinity for the D I receptors, while the remaining
ones were completely inactive competitors of
[3H]SCH 23390 binding. Compounds l l a , 9-11c, and 9d
were also inactive as [3H]spiperone competitors. The other
tested compounds expressed fair to low affinity in
[3H]spiperone binding assay in the following rank order of
potency 9b-10b>9e>10d>lld>10a>llb. However, novel
benzimidazole-2-thiones 9a and (+)-9a strongly competed
with [3H]spiperone for the binding to the D2 receptors, with
the (+)-enantiomer having about four times higher affinity
than the racemate 9a.
We have shown earlier that substituted benzimidazole-2thiones and related heterocyclic systems could be considered
as catechol bioisosteres in the newly synthesized DA-ergic
ligands[”]. The affinity of these compounds for the binding
to the D2 DA receptors was increased upon the introduction
of phenyl group into the N,N-di-n-propyl side chain of the
parent compounds. In this way ligands 1-4 were obtained[51.
A similar effect was reported for other structurally different
DA-ergic ligands what led to the conclusion on the existence
of an accessory “pocket” in the receptor molecule responsible
for the bindin of aromatic group in the side chain of the
l i g a n d ~ [ ~ , ~ .I.’ ~This
. ’ prompted us to perform the present
study in order to define more closely stereochemical demands
of the accessory binding site for the side chain aromatic
group, which could be of benefit in the design of new, highly
potent and selective DA-ergic agonists and antagonists. With
this aim, we decided to replace the flexible N-n-propyl-N-(2phenylethy1)-aminoethyl “tail” in ligands 1, 3, and 4IS1with
a piperidine ring because of its semirigid nature and because
several known DA-ergic ligands contain this motif within
their structure. In order to limit the number of possible aminoethyl “tails”, most of the amines were selected on the basis
of either being subunits of known DA-ergic ligands or their
close analogues. Thus, phenylpiperidines 9a and 9b are structurally related to DA-ergic agonist (-)-3-PPP and DA-ergic
neurotoxin MPTP[14].Compounds 9c, 9d, and 9e have aminoethyl “tails” corresponding to unique amine subunits associated with antipsychotic drugs imozide and spiperone[I4]
and 5-HT2 antagonist r i t a n ~ e r i n e ~respectively.
Compounds with the structural motifs of pimozide (9-11c),
spiperone (9d), and 3-phenylpiperidine (lla) were absolutely
inactive i n competition binding assays both with
[3H]SCH 23390 and [3H]spiperone. Derivatives of 4-[bis(4fluorophenyl)methylene]piperidine 9e, 10d, and l l d acted as
nonselective competitors for the binding of the radioligands
both at the D1 and D2 DA receptors and exhibited only
moderate affinity. Affinity of these three compounds for the
Dl receptor was rather surprising since none of the 1-( 2-[5-
Arch. Phann. Pharm. Med. Chem. 330,25-28 (1997)
1- ( 2-[5-( 1 H-Benzimidazole-2-thione)]ethyl]piperidines
( 1H-benzimidazole-2-thione)]ethyl]
piperidines and related
compounds evaluated so far competed for [3H]SCH 23390
binding sites[59''I. On the other hand 4-[bis(4-fluorophenyl)methylenelpipendine is a common structural motif present in
the 5 - H T 2 rather than in the DI DA receptor ligands.
Derivatives of both 3-phenylpiperidine (9a and 10a) and
4-phenylpiperidine (9-llb) expressed a strict D2 receptor
selectivity. Among these compounds, benzimidazole-2-thiones 9a and 9b were more potent competitorsof [3H]spiperone
10a and 10b
binding than 1,4-dihydroquinoxaline-2,3-diones
or benzimidazole llb.This order ofpotenc was reported and
discussed earlier for flexible ligands l-&' 'I. Racemic 3phenylpiperidine9a expressed approximately 5 times higher
affinity for the D2 receptor than the flexible congener 3, while
4-phenylpiperidines 9b, 10b and llb appear to be less efficient. One of the enantiomeric forms, 3-phenylpiperidine
(+)-9a had an apparent K i of 2.9 nM in [3H]spiperonebinding
assay being some 23 times more active than the parent compound 3 (Table 1). Enantioselectiveproperties were reported
earlier for the structurally related presynaptic DA-ergic
agonist (-)-3-PPP and its enantiomer (+)-3-PPP[16].
In conclusion, we have demonstrated here rather strict
stereochemical demands of the D2 DA receptor for the aminoethyl "tails" in 3-phenylpiperidinederivatives. The ligand
(+)-9a expressing high affinity and stereoselectivity for the
binding to the D 2 receptor was obtained by complete replacement of the flexible N-n-propyl-N-(2-phenylethyl)motif in
compound 3 by its more rigid analogue (+)-3-phenylpiperidine. Chemical modifications of this class of DA-ergic ligands
in aminoethyl part of the molecule could be expected to
produce stereoselective and high affinity ligands. Further
studies along this line are in progress.
This work was supported by Ministry for Science and Technology of
and V.S.) andW3E20 (S.D., V.S. and J.J.).
Melting points were determined on a Boetius PHMK apparatus (VEB
Analytic, Dresden, Germany) and are uncorrected. The results of microanalyses were within 0.4% of the calculated values. 'H-NMR spectra were
recorded on a IT-80A spectrometer (Varian, Palo Alto, CA, USA) with
CDC13 as a solvent unless otherwise stated and are reported in ppm (6)
downfield from the internal standard tetramethylsilane. The IR spectra were
run on a Perkin Elmer457 Grating Infrared Spechophotometer (Perkin Elmer
Beaconsfield, England). The mass spectra were determined by a Finnigan
Mat 8230 mass spectrometer (Finnigan, Brehmen, Germany). Analytical
TLC was performed using E. Merck (Dam-stadt, Germany) F-256 plasticbacked thin-layer silica gel plates. Chromatographic purifications were
accomplished on Merck-60 silica gel columns, 2 3 0 4 0 0 mesh ASTM under
medium pressure (MPLC). Solutions were routinely dried over anhydrous
Na2S04 prior to evaporation. Piperidines 6b and 6c were purchased from
Aldrich (Milwaukee,WI, USA).
(+)-3-Phenylpiperidine (+)-6a
5.0 g of (+)-3-phenylpiperidine1'] and 4.6 g of L-tartaric acid in 66 ml of
MeOH were gently heated. The solution was slowly cooled to4 "C. The solid
Arch P h a m P h a m Med. Chem. 330,25-28 ( I 997)
formed was removed by filtration and recrystallized from 15 ml of hot
MeOH. Recrystallization was repeated using the same volume of hot MeOH.
Finally, 1.4 g of (+)-6a as a tartarate were obtained, mp 205 "C. To prepare
(+)-6a as a free base, the tartarate was dissolved in 30 ml of water and the
pH adjusted to 10-1 1 by saturated sodium carbonate solution. The mixture
was extracted with CHzClz (2 x 10 rnl), the combined extracts were washed
with water, dried over anhydrous NazS04 and filtered. The solvents were
removed in vacuo to afford 0.55 g of (+)-6a as a free base characterized by
[a]6'= +5.8 (c = 0.882, EtOH) which remained constant in separate experiments including severalfold recrystallizations of the tartarate. -'H NMR: 6
7.4-7.1 (m,5H,phenyl), 3.2-2.90(m, 2H). 2.9G2.30(m,4H, NH, piperidine
CH), 2.0-1.4 (m, 4H).
Synthesis of 3- and 4-substituted 1-[2-(3-nitro-4-amiriophenyl)ethyl]piperidines 7a-e
To 10.0 mmol solutions of amines 6a-e in 40 ml of DMF, 12.0 mmol of
2-nitro-4-(chloroethyl)anilinehydrochloride 5.6.1 g NazC03 and 0.2 g of KI
were added. The mixture was stirred at 90 "C for 12 h, cooled, the precipitate
removed and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using a MeOH gradient (0-2%) in CHzCIz as the
eluent. o-Nitroanilides 7a, (+)-7a, and 7e were isolated as orange, gummy
substances while 7b (mp 93-94 "C), 7c (mp 206-208 "C) and 7d (mp 188190 "C) were obtained as yellow crystals after crystallization from
EtOWEtOAc mixture.
Synthesis of 3- and 4-substituted I -[2-(3,4-diaminophenyl)ethyl]piperidines
Ra-Ni (0.4-0.5 g) was added in small portions to a stirred solution of the
nitro compounds 7a-e (1 2 mmol) in a mixture of 12 ml EtOH, 24 ml 1,2-dichloroethane and 4.0 ml (40mmol) hydrazine hydrate at 30 "C. After the
addition of Ra-Ni was completed, the mixture was heated in a water bath
(50 "C, 60 min) and filtered through celite. The filtrate was evaporated in
vacuo producing almost pure diamines used in the next step without further
purification. Diamines 8a-e were obtained as almost colorless oils, some of
which crystallized as hydrochlorides from EtOH (&.HCI, mp 210-212 "C
and Sd'HCI, mp 261-265 "C).
Synthesis of 3- and 4-substituted I-(2-[5-(lH-benzimidazole-2thione)]ethyl]-piperidines 9a-e
Carbon disulfide (0.36 ml, 6.0 mmol) and KOH solution (0.37 g in 0.90 ml
water) were added to a 3 mmol solution of 8a-e in 5 ml of EtOH. After
refluxing for 3 h, the solvent was removed in vacuo. The residue was
resuspended in 10 ml 10% NaHCO3, extracted with CHzCIz and concentrated in vacuo. Resulting benzimidazolethiones 9a-e were purified by silica
gel chromatography using a MeOH gradient (0-2%) in CHzCIz as the eluent.
Purified benzimidazole-2-thiones were recrystallized from hot EtOH.
9a: IR (KBr): v = 2927, 1620,1493, 1465, 1183 cm-'.- 'H NMR: 6 9.50
(br s, 2H, NH), 7.22 (br s, 8H, ArH), 3.1G2.70 (m, 9H. piperidine,
ArCHzCHzN), 2.12-1.53 (m, 4H, piperidine).- MS (70 eV); d z (%) = 74
(100). 337 [M']; mp 131-133 "C; Anal. (CzoHz3N3S) C, H, N.
(+)9a: [a]&*= +7.14 (c = 0.812, EtOH), mp 137-139 "C; Anal.
(CzoHz3N3S) C, H, N.
9b: IR (KBr): v =2928,1617,1463 cm?- 'H NMR ([D6]DMSO): 6 8.25
(br s, 2H, NH), 6.95 (br s, 8H, ArH), 3.43-2.90 (m, 2H, piperidine), 2.912.43 (m, 6H, piperidine, AKHzCHzN), 2.02-1.43 (m, 4H, pipendine).- MS
(70 eV); d z (%) = 174 (loo), 337 [M']; rnp 247-249 "C (EtOH); Anal.
( C Z O H Z ~ NC,
~ SH,
) N.
9c: IR(KBr):v=3036,1681,1484cm-'.-'HNMR([D~]DMSO):
6 10.71
(br s, IH, NH),7.24 (br s, 2H, NHCSNH), 7.14-6.95 (m,7H, ArH), 4.634.28 (m, IH, CHN), 3.8G3.10 (m,4H, piperidine), 3.10-2.43 (m,6H,
pipendine, ArCH2CH2N). 1.75-2.05 (m, 2H, pipedine).- MS (70 eV);
d z (%) = 174 (loo), 393 [M']; mp 235 "C (70% EtOH); Anal.
( C ~ I H ~ ~ N ~ O S ' C,
~ HH,ZN.
9d: IR (KBr): v = 3063, 1704, 1684, 1599, 1463, 1371 cm-'.- 'H NMR
([DbIDMSO): 6 12.21 (br s, IH, NH), 8.46 (br s, 2H, NHCSNH ), 7.28-6.55
(m, 8H, ArH), 4.62 (s, 2H, CHz), 3.78-3.10 (m, 4H, piperidine), 3.10-2.43
(m, 6H, pipendine, AICH~CHZN),1.64 (d, J = 15 Hz, 2H).- MS (70 eV);
d z (%) = 244 (100). 409 [M']; mp 252 "C (70% EtOH); Anal.
( C ~ Z H ~ ~ N J C.
O SH,) N.
9e: IR (KBr): v = 3420,1662,1506,1223 cm-'.- 'H NMR ([D6]DMSO):
6 8.36 (br s, 2H, NHCSNH), 7.15-6.75 (m,1IH, ArH), 2.92-2.15 (m,12H,
piperidine, ArCH2CH2N).- MS (70 eV); d z (%) = 298 ( 100). 460 [M']; mp
155-157 "C (EtOH); Anal. ( C ~ ~ H ~ S C,
N H,
~ SN.
Joksimovic and co-workers
AICH~CH~N).-MS (70 eV); d z (%) = 298 (100). 429 [M']; mp 92-9 "C
(EtOH); Anal. (C27H25F2N3) C, H, N.
Radioligand Binding Studies
Synaptosomal membrane preparation from fresh bovine caudate nuclei,
radioligand binding assays and data analyses were performed as previously
and [3H]spiperone
Synthesis of 3- a n d 4-substituted I-(2-[6-(IH,4H-quinoxaline-2,3- described[61. [3H]SCH 23390 (spec. act. 80 Ci M')
(spec. act. 70.5 m K ' ) used to label DI and D2 receptors, respectively, were
dione)]ethyl]-pipendines load
purchased from Amersham Buchler GmbH (Braunschweig, Germany).
4 mmol of either diamine 8a-c or 8e and 1.0 g (8 mmol) of oxalic acid
Briefly [3H]spiperone binding was assayed in 1 mM EDTA, 4 mM MgC12,
dihydrate were heated to 200 "C in an oil bath under a nitrogen atmosphere
1.5 mM CaC12, 5 mM KCI, 120 mM NaCI, 25 mM Tris-HC1 solution,
for 30 min. Upon cooling to ambient temperature the residue was resuspH 7.4 at membrane protein concentration of 0.7 mg ml-' at 37 "C for 20 min
pended in boiling dil. EtOH and the pH of the solution adjusted to pH 3.0
in a total volume of incubation mixture of 1.0 ml. Binding of the radioligand
with 4 N HCl. The warm solution was filtered through cotton wool. Quinoxto 5-HT2 receptors was prevented by 50 nM ketanserin. IC50 values of tested
alinediones 1Oa-d crystallized from the filtrate as hydrochlorides. Analytical
compounds were determined by competition binding at 0.2 nM of the radisamples were obtained after recrystallization from 70% EtOH.
oligand and eight different concentrations of each compound (1 nM1Oa (HCI salt): IR (KBr): v = 3505,2939, 1675, 1402 cm-'.- 'H NMR
0.1 mM). Nonspecific binding was measured in the presence of 1.0 mM
(+)-butaclamol. The reaction was terminated by rapid filtration through
([D6]DMSO): 6 12.90 (br s, 2H, NH), 7.28 (br s, 5H, ArH), 7.09 (br s, 3H,
Whatman GF/C filters, which were further washed three times with 5.0 ml
ArH), 3.83-3.25 (m,9H, piperidine, A~CHZCH~N),
2.20-1.65 (m,4H,
pipendine).- MS (70 eV); d z (%) = 333 [M']; mp 247-249 "C; Anal.
of ice cold incubation buffer. Each point was determined in triplicate.
Retained radioactivity was measured by introducing dry filters into 10 ml of
(C~iH23N302.HCl)C, H, N.
toluene-based scintillation liquid and counting in a 1219 Rackbeta Wallac
10b (HCI salt): IR (KBr): v = 3419, 2931, 1687, 1392 cm-'.- 'H NMR
scintillation counter at an efficiency of 51-55% for tritium.
([D6]DMSO): 6 12.10 (br s, 2H, NH), 7.25 (br s, 5H, ArH), 7.05 (br s, 3H,
Binding of L3H]SCH 23390 was examined by the same rapid filtration
ArH), 3.80-3.20 (m, 9H, piperidine, AICH~CH~N),
2.25-1.65 (m,4H,
assay discussed for [3H]spiperone in the absence of ketanserin.
pipetidine).- MS (70 eV); d z (%) = 333 [M']; mp 257-261 "C; Anal.
Competition binding data were analyzed by the iterative non-linear
(C2iH23N302.HCI) C, H, N.
least-squares curve-fitting program LIGAND"".
1Oc (HC1 salt): IR (KBr): v = 3417, 1690, 1485, 1391 cm-'.- 'H NMR
([D6]DMSO): 6 11.80 (br s, 2H, NH), 10.95 (br s, IH, NH), 7.21-6.82 (m,
7H, ArH), 4.654.35 (m, IH, CHN), 3.80-3.10 (m, 4H,piperidine), 3.1 1References
2.41 (m,6H, piperidine, AICH~CH~N),
2.10-1.75 (m, 2H, pipendine).-MS
(70 eV); d z (%) = 387 [M'l; mp 265 "C; Anal. (C22H23Ns02.HC1.3H20)
P. Seeman, Trends PhannacoISci. 1994,15, 264-267.
C, H, N.
D.M. Jackson, A. Westlind-Danielsson, Pharmac. Ther. 1994,64,2911Od (HCI salt): IR (KBr): v = 3420,2940, 1692, 1401 cm-'.- 'H NMR
([D6]DMSO): 6 11.80 (br s, 2H, NH), 8.30 (br s, lH, NH), 7.40-6.82 (m,
1 lH, ArH), 3.71-2.80 (m, 1lH, piperidine, ArCH2CH2N).- MS (70 eV); d z
H.R. Howard,T.F. Seeger,(l993)In:Annu. Rep.Med. Chem. (Ed.: J.A.
Bristol), Academic Press, San Diego, U.S.A, 1993.28, 39-47.
(%) = 298 (loo), 473 [M'l; mp 205-207 "C;Anal. (C28H25 FzN302.HCl) C,
H, N.
M.D.Tricklebank, L.J. Bristow, P.H. Huston, Prog. Drug Res. 1992,
Synthesis of 3- and 4- substituted I -[2-(5-benzimidazole)ethyl]piperidines
Z. Tuce, V. SoSkic, J. Joksimovic, Drug Design Discovery 1994, I I ,
25 1-258.
3.0 mmol of diamines 8a-c or 8e and 0.44 ml (7.3 mmol) of 98% formic
V. SoSkic, A. Maelicke, G. Petrovic, B. Ristic, J. Petrovic, J. Pharm.
acid were heated in an oil bath at 100 "C for 2 h. After cooling to ambient
Pharmacol. 1990,43,27-3 1.
temperature, 15 ml of 10% NaHCO3 were added and the product was
extracted with CHC13. The solvent was removed in vacuo and crude benzimiL.A. Walters, S.M. McElvain, J. Am. Chem. Soc. 1933,55,4625-4629.
dazoles lla-d were purified by silica gel column chromatography using a
V. SoSkic, S. Dukic, D. Dragovic, J. Joksimovic, Arzneim.-Forsch.(in
MeOH gradient (&2%) in CH2C12. Purified compounds were crystallized
from EtOH as free bases or hydrochlorides.
l l a : IR (KBr): v = 2928, 1725, 1451, 1276, 1401 cm-'.- 'H NMR
P.A.J. Janssen U.S. Pat. 3, 161,645,1964.
([D6]DMSO): 6 10.00 (s, IH, NH),8.01 (s, IH, ArH, H-2), 7.60 (br s, 2H,
L.E.J. Kennis, J. Vandenberk,J.C. Martens, U.S.Put. 4,533,665.1985.
ArH, H-4 and H-7), 7.22 (br s, 5H, ArH), 7.00 (d, J = 8Hz, lH, ArH, H-5).
3.45-2.91 (m,2H, piperidine), 2.962.38 (m, 6H, piperidine, ArCH2CH2N),
S. Kostic, V. SoSkic, J. Joksimovic, Arzneim.-Forsch. 1994,44, 6972.03-1.42 (m, 4H, pipendine).- MS (70 eV); d z (%) = 174 (loo), 306 [M'];
mp 136138 "C (EtOH); Anal. ( C ~ O H ~ ~ NH,~N.
F. Claudi, G. Giorgioni, A. Di Stefano, M.P. Abbracchio, A.M. Paoletti,
l l b : IR (KBr): v = 2927, 1620. 1493, 1460, 1401 cm-'.- 'H NMR
W. Balduini, J.Med.Chem. 1992,35,4408-4414.
([DslDMSO): 6 9.80 (s, IH, NH), 8.00 (s, IH, ArH, H-2), 7.60 (br s, 2H,
[ 131 H.E. Katerinopoulos ,D.I. Schuster, Drugs F u m e 1987,12,223-253.
ArH, H-4 and H-7). 7.23 (br s, 5H, ArH), 7.05 (d, J = 8Hz, IH, ArH, H-5).
3.40-2.90 (m,2H, piperidine), 2.90-2.40 (m, 6H, piperidine, ArCH2CH2N).
[ 141 A S . Horn, In: Comprehensive Medicinal Chemistry (Ed.: C. Hansch).
2.00-1.42 (m,4H, piperidineh-MS (70 eV); d z (%) = 174 (loo), 306 [M'];
Pergamon Press, New York, 1990, pp. 229-291.
mp 157-159 "C (EtOH); AnaL(C20Hz4N3)C, H, N.
M.F. Hibert, A.K. Mir, J.R. Fozard, In: Comprehensive Medicinal
l l c (HCI salt): IR (KBr): v = 3418, 1665, 1492, 1401 an-'.- 'H NMR
Chemistry (Ed.: C. Hansch), Pergamon Press, New York, 1990 , pp.
([D61DMSO): 6 10.95 (s, IH, NH), 7.90 (s, lH, ArH, H-2), 7.55 (br s, 2H,
ArH, H-4 and H-7). 7.20-7.00 (m, 7H, ArH), 4.65-4.30 (m,lH, CHN),
3.80-3.10 (m, 4H, piperidine), 3.10-2.40 (m,6H, piperidine, AKH~CHZN), [I61 S. Hjorth, A. Carlsson, D. Clark, K. Svensson, H. Wikstrom, D.
2.05-1.75 (m, 2H, pipendine).-MS (70eV); d z (%) = 361 [M']; mp 290 "C
Sanchez, P. Lindberg, U. Hacksell, L.-E, Arvidsson, A. Johansson,
(dil. EtOH); Anal. ( C ~ I H ~ ~ N S O . ~ H Z OC,
. ~ H,
H CN.I )
J.L.G. Nilsson, Psychophannacology 1983,81,89-99.
l l d : IR (KBr): v = 2920, 1601, 1505, 1222, 1401 cm-'.- 'H NMR
[ 171 P.J. Munson, D. Rodbard, Anal.Biochern.1980, 107,220-239.
([D61DMSO): 6 11.15 (s, IH, NH), 7.96 (s, IH, ArH, H-2). 7.58 (br s, 2H,
lOH,ArH), 3.15-2.25 (m,12H,piperidine,
Received: October 21, 1996 [FP157]
Arch Pham Phann. Med. Chem 330,25-28 ( I 997)
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synthesis, properties, piperidines, compounds, dopaminergic, thione, related, substituted, ethyl, benzimidazole
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