Solution phase parallel synthesis of substituted 3-phenylsulfonyl-[1,2,3] triazolo[1,5- a ]quinazolines: Selective serotonin 5-HT6 receptor antagonists

Article abstract of DOI:10.1021/cc1000049

Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5- a]quinazolines and a study of the relation of their structure with a 5-HT ₆ receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT₆R antagonists. The most active 5-HT₆R antagonists have IC₅₀ <100 nM in a functional assay, and K _i <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.

Full text of DOI:10.1021/cc1000049

J. Comb. Chem. 2010, 12, 445–452
445
Solution Phase Parallel Synthesis of Substituted
3-Phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines:
Selective Serotonin 5-HT6 Receptor Antagonists
Alexandre V. Ivachtchenko,†,‡ Elena S. Golovina,† Madina G. Kadieva,†
Angela G. Koryakova,† Sergiy M. Kovalenko,§ Oleg D. Mitkin,*,† Ilya M. Okun,‡
Irina M. Ravnyeyko,| Sergey E. Tkachenko,‡ and Oleg V. Zaremba|
Chemical DiVersity Research Institute, 114401 Khimki, Moscow Reg, Russia, ChemDiV, Inc., 6605
Nancy Ridge DriVe, San Diego, California 92121, Institute of Combinatorial Organic Chemistry,
KharkiV, Ukraine, and National Pharmaceutical UniVersity, KharkiV, Ukraine
ReceiVed January 11, 2010
Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new
substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure
with a 5-HT6 receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive
binding. We have found highly active and selective 5-HT6R antagonists. The most active 5-HT6R antagonists
have IC50 <100 nM in a functional assay, and Ki <10 nM in a binding assay, which is 100 times higher
than the activity with respect to other serotonin receptors.
Introduction
In this paper, we describe a solution phase parallel
synthesis of combinatorial libraries (CL), which includes 776
new PSTQ compounds (Figure 1), and a study of the 5-HT6R
antagonist structure-activity relationship (SAR).
Serotonin 5-HT6 receptor (5-HT6R) is a very unusual
member of the family of serotonin receptors. It is distributed
almost exclusively within the central nervous system (CNS).1,2
5-HT6Rs in mammals are located primarily in the areas of
the brain responsible for learning and memory.3 It is also
known4 that 5-HT6Rs act as modulators of several neu-
rotransmitter systems including the cholinergic, noradren-
ergic, glutamatergic, and dopaminergic systems. Given the
fundamental role of such systems in normal cognitive
processes and their dysfunction in neurodegeneration, the
exclusive role of 5-HT6R becomes apparent in the formation
of normal or pathologic memory. In this regard, application
of 5-HT6R antagonists is considered to be a promising
treatment for some CNS diseases.5,6
Results and Discussion
A CL of substituted 5-amino-PSTQ was prepared by solution
phase parallel synthesis (Scheme 1) based on 5-chloro-PSTQ
1{1-14} and amines 2{1-60} (Chart 1). The reaction was
carried out in N,N-dimethylformamide (DMF) in the presence
of tetraethylammonium (TEA) at 100-120 °C. A total of 773
5-Amino-PSTQs 3 {1-14,1-60} were isolated with 70-90%
yield by precipitation with water and subsequent recrystallization
from methanol.
Key building blocks 1{1-14} for the synthesis of PSTQ
CL were obtained with high yield in a three-stage synthesis
(Scheme 2) based on anthranilic acid esters 4{1,2}.
Azides 5{1,2} were formed by diazotization of 4{1,2} and
treatment of the formed diazonium salts with sodium azide.
Reaction of azides 5{1,2} with arylsulfonylacetonitriles
6{1-11}, by analogy with phenylacetonitrile,13 in ethanol
in the presence of sodium ethoxide resulted in 5-hydroxy-
PSTQ 7{1-14} (Scheme 2). As acetonitriles 6{1-11}, along
with unsubstituted phenylsulfonylacetonitrile 6{1}, we used
4-methyl- 6{2}, 4-ethyl- 6{3}, 4-tert-butyl- 6{4}, 4-fluoro-
6{5}, 4-chloro- 6{6}, 4-bromo- 6{7}, 2,5-dimethyl- 6{8},
3,4-dimethyl- 6{9}, 2,4,6-trimethyl- 6{10}, and 2,5-dimethox-
Another attractive feature of 5-HT6R antagonists is their
ability to suppress appetite, which may lead to the creation
of a fundamentally new means to treat obesity.7
Since the discovery of 5-HT6R,1,2 many ligands have been
synthesized, the vast majority of which are heterocyclic
compounds possessing sulfonyl substituents.5,8 A number of
5-HT6R antagonists have reached clinical trials.9,10 Indeed,
interest for developing 5-HT6R antagonists as CNS drugs
so far has not weakened.6
As a result of screening a focused library of 2880
compounds containing the sulfonyl group, we found a new
group of 5-HT6R antagonists, represented by a 3-phenylsul-
fonyl-[1,2,3]triazolo[1,5-a]quinazolin (PSTQ) core.
* To whom correspondence should be addressed. E-mail: mod@
chemdiv.com.
† Chemical Diversity Research Institute.
‡ ChemDiv, Inc.
§ Institute of Combinatorial Organic Chemistry.
| National Pharmaceutical University.
Figure 1. PSTQ compounds.
10.1021/cc1000049  2010 American Chemical Society
Published on Web 03/29/2010

446 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Ivachtchenko et al.
Chart 1. List of Amines 2{1-60} for Combinatorial Library of 773 Substituted 5-Amino-PSTQ 3
Scheme 1. CL Synthesis of Substituted 5-Amino-PSTQ
Scheme 2. 5-Chloro-PSTQ 1{1-14} Synthesis
ybenzene-sulfonylacetonitrile 6{11}. 5-Hydroxy-PSTQ
7{1-14} were converted into key building blocks 1{1-14}
by the action of phosphorus oxychloride in the presence of
triethylamine.
For a more complete SAR of PSTQ, we synthesized
unsubstituted PSTQ 8, 5-ethylthio-PSTQ 9, and 5-(2-methoxy-
ethyloxy)-PSTQ 10 (Scheme 3). PSTQ 8 was formed by
hydrogenation of 5-chloro-PSTQ 1{1} on Pd /C in methanol-
benzene mixture. 5-Ethylthio-PSTQ 9 was obtained by reaction
of 5-chloro-PSTQ 1{1} with EtSK in dimethylsulfoxide (DMSO),
and 5-(2-methoxyethyloxy)-PSTQ 10 - with 2-methoxyethanol
in the presence of TEA (Scheme 3).
For the reaction with 5-chloro-PSTQ 1{1-14} we used
ammonia 2{1}, primary amines: alkylamines 2{2-23},
cycloalkylamines 2{24-29}, anilines 2{30-39} and second-
ary amines: dialkylamines 2{40-46}, pyrrolidine 2{47},
piperidines 2{48-52}, azepan 2{53}, morpholine 2{54},
thiomorpholin 2{55}, piperazines 2{56-59}, and 2,3-dihy-
dro-1H-indole 2{60}.
The purities and structural identities of the synthesized
PSTQs were confirmed by liquid chromatography-mass
spectroscopy (LC-MS) analysis and NMR spectroscopy.

3-Phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines
Scheme 3. Synthesis of PSTQ 8, 9, 10
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 447
Table 1. Antagonistic 5-HT6R Activity of PSTQ 1, 7-10
In the NMR spectra of 5-hydroxy-PSTQ 7{1-3} there
is a broad signal at 12.09-12.85 ppm characteristic of
the enolic forms of these compounds. Hydroxy state of
5-hydroxy-PSTQ 7 is also confirmed by IR spectrum
of 7{1}, where there are no valence vibration signals in
the 1690-1650 cm-1 characteristic for the carbonyl group
of an amide fragment. Note that the described11 3-phenyl
analogue had the structure of 3-phenyl-[1,2,3]triazolo[1,5-
a]quinazolin-5(4H)-one with valence vibration signals in
compd
R1
R2
R3
IC50, nM, (%)a
7{1}
7{2}
7{3}
1{1}
1{2}
8
H
H
H
H
H
H
H
H
H
4-t-Bu
4-MeO
H
Cl
H
H
H
OH
OH
OH
Cl
Cl
H
(18)
(25)
(0)
(42)
(27)
5736.0
1049.0
1374.0
9
10
EtS
MeOCH2CH2O
a Percentage of inhibition of adenylyl cyclase activity at
concentrations of 10 µM PSTQ.
the 1680 cm-1
.
In the NMR spectra of the synthesized PSTQs, chemical
shifts of protons are consistent with their structure. In the
experimental section there are some examples of PSTQ NMR
According to the LC-MS, purity of the synthesized PSTQs
exceeded 98%, while the masses of their molecular ions were
consistent with their molecular weights.
Table 2. Antagonistic 5-HT6R Activity of 5-Alkylamino-PSTQ 3
* Percentage of inhibition of adenilylciclaze activity at concentrations as indicated in the footnotes a and b. a 5 µM. b 10 µM PSTQ.** Indol-3-yl.

448 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Ivachtchenko et al.
Chart 2. Dependence of 5-HT6R Antagonist Activity on the Structure of PSTQ 3{1,12-13; 1,21-23; 1,25; 2,13; 3,27; 6,37; 9,13; 9,31}
spectra, which are characterized by the signals of aromatic
protons of quinazoline moiety and arylsulfonyl substituents.
The former (if unsubstituted) are represented by two doublets:
C(6)H at 8.39-8.77 ppm and C(9)H at 8.35-8.51 ppm, and
two triplets: C(7)H at 7.95-8.08 ppm and C(8)H at
7.55-7.86 ppm. The amino group in 5-amino-PSTQ 3 gave
rise to several broad range signals because of the shift in a
strong field. In 7-chloro-PSTQ 3{12-14, 1-60} NMR
signals of the proton at C(6) appear as a singlet and at C(8)
as a doublet. Chemical shifts of the protons at C(6), C(8),
and C(9) remained virtually unchanged throughout the series.
NMR signals of protons of arylsulfonyl substituents vary
depending on the location and nature of substituents in the
aryl group. The signals of protons in the unsubstituted
phenylsulfonyl substituents PSTQ 3{1,1-60}, 3{12,1-60}
presented as a doublet at 8.25 ppm (2H), a triplet at 7.65
ppm (1H) and multiplet at 7.55 ppm (2H), while in the
4-substituted PSTQ 3{2-7,1-60}, 3{13,1-60} proton
signals appear as two doublets at 8.0-7.8 ppm and 7.8-7.5
ppm.
In the spectrum of 5-(2-methylcyclohexylamino)-PSTQ
3{1,27} the signals of the secondary amino group and the
methyl group appear in a form of two doublets (8.70, 8.22
and 0.89, 0.86 ppm, respectively), because of the cis-trans
isomerism, characteristic of the 2-methylcyclohexyl fragment.
Screening of PSTQ for 5-HT6R antagonistic activity was
performed in vitro by testing the ability to inhibit functional
cellular responses to serotonin at compound concentrations
of 1 µM, 5 µM, and 10 µM. Stimulation of the HEK 293
cells, stably expressing recombinant human 5-HT6R, activates
adenylyl cyclase, which leads to increased synthesis of
intracellular cAMP, which was estimated with the help of
LANCE technology.12 PRX-07034 and SB-742,457 were
used as standards of comparison.
For 37 of the PSTQ that inhibited the synthesis of cAMP
by more than 50% at a concentration of 5 µM, we determined
the IC50, namely, the concentration of a substance that leads
to the 50% inhibition of adenylyl cyclase activity (Figure 1,
Tables 1-6).
Among PSTQ 1, 7-10 (Figure 1, Table 1), 5-ethylthio-
PSTQ 9 is the most active with IC50 ) 1049.0 nM, and the
least active are the 5-hydroxy-PSTQ 7{1-3}, which weakly
inhibit 5-HT6R (from 0% to 25%) at a concentration of 10
µM. PSTQ 8, which is unsubstituted at position 5, also has
weak activity (IC50 ) 5736.0 nM).
Signals of substituents at C-5 are different for each
substance; their shape and chemical shifts depend upon the
structure of the substituents. In the NMR spectrum of PSTQ
8 unsubstituted at position 5, the corresponding singlet at
9.31 ppm appears, and 5-ethylthio-PSTQ 9 has signals
characteristic to the ethyl group: quadruplet at 3.55 and triplet
at 1.58 ppm.
The activities of 5-alkylamino-PSTQ 3{1,2; 1,4; 1,7; 2,10;
3,11; 6,9; 8,4; 9,9; 10,3-4; 13,1; 13,6} (Figure 1, Table 2)

3-Phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 449
Table 3. Antagonistic 5-HT6R Activity of 5-Benzylamine-PSTQ
and Their Hetero Analogues 3
vary widely, and it is not possible to establish a clear link
between their structures and activities. These activities
strongly depend on the presence and position of substituents
in the molecule PSTQ. We note only that in this series of
compounds the most active were 5-(2-phenylpropylamino)-
PSTQ 3{2,10} with IC50 ) 606.0 nM and 5-s-butylamino-
PSTQ 3{10,4} with IC50 ) 964 nM.
Better 5-HT6R antagonists were found among 5-benzyl-
amine-PSTQ, their hetero analogues 3{1,12-13; 1,20-23;
2,12-13; 2,20-21; 3,12; 6,20; 9,13; 9,18; 9,20-21; 10,21;
12,21; 13,22} and 5-(2-phenylpropylamino)-PSTQ 3{2,10}
(Tables 2, 3). In the series of 5-benzylamine-PSTQ
3{1,12-13; 1,20; 2,12-13; 2,20; 3,12; 6,20; 9,13; 9,18;
9,20} the most active are 5-(2-chloro-benzylamino-PSTQ
3{1,13; 2,13; 9,13}. Note, that the introduction of methyl
substituents in the 3-phenylsulfonyl fragment leads to a
decrease in activity (Chart 2).
The transition from 5-benzylamino-PSTQ to their het-
eroanalogues is accompanied by a significant change in their
activity (Chart 2). Thus, 5-(pyridin-3-ylmethylamino)-PSTQ
3{1,23} is 2.6 times less active than 5-benzylamino-PSTQ
3{1,12}, and the latter is 2.7 times less active than 5-(furan-
2-ylmethylamino-PSTQ 3{1,22}, and 5 times less active than
5-(tetrahydrofuran-2-ylmethylamino-PSTQ 3{1,21}. It should
be noted that the introduction of any additional substituents
in the molecule of 5-(tetrahydrofuran-2-ylmethylamino)-
PSTQ 3{2,21; 9-10,21; 12,21} leads to a drastic reduction
in activity. For example, 5-(tetrahydrofuran-2-ylmethy-
lamino)-7-chloro-PSTQ 3{12,21} has IC50 ) 1802.0 nM, and
5-(tetrahydrofuran-2-ylmethylamino)-3-(4-methylphenylsul-
fonyl)-derivative 3{2,21} has IC50 ) 1483.0 nM (Figure 1,
Table 3).
Among the investigated 5-cycloalkylamino- and 5-ary-
lamino-PSTQ (Figure 1, Table 4) the most active were
antagonists 3{1,25; 3,27; 6,37; 9,31} with IC50 from 294.8
nM to 579.9 nM (Chart 2). At the same time, among the
5-azaheterocyclyl-PSTQ only one moderately active PSTQ
3{9,58} was found with IC50 ) 1198.0 nM (Figure 1, Table
5).
In the series of 5-dialkylamino-PSTQ 3{1,40-44; 1,46;
1,50; 1,54; 3,60; 7,43; 7,52; 9,44; 9,53; 9,58; 12,41; 12,44;
12,58; 13,56; 14,43; 14,50} (Table 5) 5-(N-alkyl-N-benzy-
lamino)-PSTQ 3{1,43-44; 9,44} are active, with 3{1,44}
IC50 ) 163.9 nM being the most potent one.
* Percentage of inhibition of adenilylciclaze activity at concentrations
of 5 µM PSTQ.
radioligand from complexes with 5-HT1A, 5-HT1B, 5-HT2B,
5-HT2C, 5-HT3, 5-HT4, and 5-HT7 receptors, and 46% from
the radioligand’s complex with 5-HT2AR. These data suggest
that the efficiency of interaction of PSTQ 3{1,21} with
5-HT6R is more than 100 times higher than the interaction
with other serotonin receptors.
In summary, we have invented a new scaffold for 5-HT6R
antagonists, which is a (3-phenylsulfonyl-[1,2,3]triazolo[1,5-
a]quinazolin-5-yl)-amine, and synthesized a combinatorial
library, which includes 776 new ligands. A study of 5-HT6R
activity in a functional cell (HEK 293) analysis and radio-
ligand competitive binding assay was performed. The most
active 5-HT6R ligands in a binding assay were secondary
amines with Ki from 2.9 nM to 50.0 nM, among which the
most active were N-(2-methylcyclohexyl)-3-(phenylsulfonyl)-
We studied 5-HT6R activity of several PSTQ 3 in a
competitive radioligand binding assay. The results are
presented in Table 6, which shows that PSTQ 3 effectively
displace radioligand from its complex with 5-HT6R. The
most active ligand is 5-(2-methylcyclohexylamino)-PSTQ
3{1,27} with Ki ) 2.86 nM, and the least active is 5-iso-
propylamino-PSTQ 3{1,3} with Ki ) 49.5 nM. Note that
the activity PSTQ 3 in a competitive radioligand binding
and functional cell analyses varies greatly (Figure 1, Table
6), apparently because of the kinetics of interaction of PSTQ
3 with 5-HT6R.
In a competitive radioligand binding, we investigated the
activity of one of our most active compounds, PSTQ 3{1,21},
on a panel of serotonin receptors (Figure 2). At a concentra-
tion of 1 µM, PSTQ 3{1,21} displaces less than 12% of

450 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Ivachtchenko et al.
Table 4. Antagonistic 5-HT6R Activity of
5-Cycloalkylamino-PSTQ 3 and 5-Arylamino-PSTQ 3
Table 5. Antagonistic 5-HT6R Activity of 5-Dialkylamino- and
Azaheterocyclyl-PSTQ 3
* Percentage of inhibition of adenilylciclaze activity at concentrations
as indicated in the footnotes a and b. a 5 µM. b 10 µM PSTQ.
* Percentage of inhibition of adenilylciclaze activity at concentrations
of 5 µM PSTQ.
[1,2,3]triazolo[1,5-a]quinazolin-5-amine 3{1,27} with Ki )
2.9 nM and N-(furan-2-ylmethyl)-3-(phenylsulfonyl)-[1,2,3]tri-
azolo[1,5-a]quinazolin-5-amine 3{1,22} with Ki ) 3.5 nM.
Additionally, it was shown that PSTQ 3{1,21} possesses
selective binding to 5-HT6R over a panel of other serotonin
receptors.
nm). According to LC-MS data, purity of the compounds
obtained exceeded 98.0%. H NMR spectra were recorded
on a Varian (400 MHz, 27 °C) using DMSO-d6 and CDCl3
as solvents. IR spectra of PSTQ 7 were recorded on a
Specord 75 IR in nujol.
1
5-HT6R binding activities of synthesized PSTQ were
determined in a radioligand binding assay using a panel of
8 serotonin receptors.13
Experimental Section
LC-MS analyses were performed with a Shimadzu HPLC
equipped with a Waters XBridge C18 3.5 µm (4.6 × 150
mm) column, mass detector PE SCIEX API 150 EX and
spectrophotometric detector Shimadzu (λmax 220 and 254
General Procedure for Synthesis of 3-Arylsulfonyl-5-
hydroxy-[1,2,3]triazolo[1,5-a]quinazolines 7{1-14}. A so-
lution of NaNO2 (3.33 mmol) in water (10 mL) was added
gradually with stirring to a solution of anthranilic acid methyl

3-Phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 451
Table 6. 5-HT6R Activity of PSTQ 3 in a Competitive Radioligand Binding Assay
* As hydrochloride.
ester 4{1,2} (2.34 mmol) in 18% HCl (25 mL) at 5 °C. The
mixture was allowed to stir for 15 min at room temperature,
then it was added dropwise to a stirred solution of NaN3
(3.33 mmol) in water (10 mL) at -5 °C. The resulting
mixture was stirred at 0 °C for 5 min and then stirred for 90
min at room temperature. The precipitate was filtered and
washed with water, with hexane, and dried to give 2-azido-
benzoic acid methyl esters. Yield 81%.
precipitate was collected, washed with water, hexane, and dried
to give the desired product with a yield from 80% to 90%.
General Procedure for the Synthesis of 3-Arylsulfonyl-
5-chloro-[1,2,3]triazolo[1,5-a]quinazolines 1{1-14}. To a
mixture of triazoloquinozaline 7{1-14} (1.75 mmol) and
TEA (12 mL) was added POCl3 (8 mL) with ice-cooling.
The resulting mixture was refluxed for 12 h, cooled, poured
into crushed ice, and extracted with CHCl3. The organic layer
was washed with 5% aqueous NaHCO3, then water, dried
with anhydrous Na2SO4, and concentrated in vacuo to give
5-chloro-PSTQ 1{1-14} in yields from 70% to 90%.
Sodium (21.7 mmol) was added portion wise to absolute
ethanol (15 mL) at room temperature. After complete
dissolution of sodium, 2-arylsulfonylacetonitrile 6{1-11}
(9.5 mmol) was added and the solution was stirred for 20
min. A solution of 2-azidobenzoic acid methyl ester (6.1
mmol) in ethanol (50 mL) was added gradually, and the
resulting mixture was refluxed for 20 h. After cooling to
room temperature, ethanol was removed in vacuo, the residue
was dissolved in water, and extracted with CHCl3. The water
layer was acidified with 18% HCl (to pH 2), the formed
3-Phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazoline 8. To
a suspension of 5-chloro-PSTQ 1{1} (0.87 mmol) in a
mixture of MeOH (60 mL) and PhH (20 mL), Pd/C (10%,
100 mg) was added. The mixture was stirred for 24 h in an
atmosphere of H2, filtered through Celite and concentrated
in vacuum. Product 8 was isolated by HPLC (yield 21%).
1
ESI-MS m/z 311; H NMR (DMSO-d6, 400 MHz) δ 9.31

452 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Ivachtchenko et al.
(DMSO-d6, 75 MHz) δ 162.12, 141.05, 138.53, 135.91,
134.23, 133.87, 129.45, 128.82, 127.25, 125.70, 115.23,
112.11, 69.40, 67.59, 58.25.
General Procedure for Solution Phase Parallel Syn-
thesis of Substituted 5-Amino-3-arylsulfonyl-[1,2,3]tria-
zolo[1,5-a]quinazolines 3{1-14,1-60}. To a mixture of
5-chloro-PSTQ 1{1-14} (1 mmol) and TEA (1 mL) in DMF
(2 mL) amine 2{1-60} (1.1 mmol) was added. The resulting
mixture was heated for 1 h at 100-120 °C then cooled to
room temperature and water (10 mL) was added. The
resulting precipitate was separated and crystallized from
MeOH (yields from 70% to 90%).
Figure 2. Selectivity profile of PSTQ 3{1,21} against serotonin
receptors as measured in a competitive radioligand binding assay
at a concentration of 1 µM.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(s, 1H), 8.74 (d, J ) 8.4 Hz, 1H), 8.28 (m, 2H), 8.18 (d, J
) 8.0 Hz, 1H), 8.13 (m, 1H), 7.87 (t, J ) 8.0 Hz, 1H), 7.61
(m, 1H), 7.54 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ
159.50, 141.42, 138.91, 137.42, 136.50, 133.90, 132.61,
129.92, 129.50, 129.15, 127.32, 119.27, 115.07.
References and Notes
5-Ethylthio-3-phenylsulfonyl-[1,2,3]triazolo[1,5-
a]quinazoline 9. To a mixture of EtSK (2.09 mmol) in
DMSO (10 mL) 5-chloro-PSTQ 1{1} (1.74 mmol) was
added portionwise and stirred for 1 h at room temperature.
The reaction mixture was poured into water and extracted
with EtOAc. The organic layer was separated, dried over
Na2SO4, and concentrated in vacuum. Product 9 was isolated
by column chromatography, eluent PhH/AcOEt ) 50:1 (yield
32%). ESI-MS m/z 371;1H NMR (DMSO-d6, 400 MHz) δ
8.64 (dd, J1 ) 8.4 Hz, J2 ) 0.8 Hz, 1H), 8.23 (m, 3H), 8.00
(m, 1H), 7.73 (m, 1H), 7.60 (m, 1H), 7.53 (m, 2H), 3.55 (q,
J ) 7.2 Hz, 2H), 1.58 (t, J ) 7.2 Hz, 3H); 13C NMR (DMSO-
d6, 75 MHz) δ 168.84, 141.52, 137.97, 136.08, 135.16,
133.81, 131.36, 129.48, 129.08, 127.30, 125.68, 117.88,
115.80, 24.73, 13.81.
(1) Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.;
Sibley, D. R. Mol. Pharmacol. 1993, 43, 320–327.
(2) Ruat, M.; Traiffort, E.; Arrang, J. -M.; Tardivel-Lacombe, J.;
Diaz, J.; Leurs, R.; Schwartz, J.-C. Biochem. Biophys. Res.
Commun. 1993, 193, 268–276.
(3) Ge´rard, C.; Martres, M.-P.; Lefe`vre, K.; Miquel, M.-C.; Verge´,
D.; Lanfumey, L.; Doucet, E.; Hamon, M.; El Mestikawy, S.
Brain Res. 1997, 746, 207–219.
(4) Dawson, L. A.; Nguyen, H. Q.; Li, P. Neuropsychopharma-
cology 2001, 25, 662–668.
(5) Holenz, J.; Pauwels, P. J.; D´ıaz, J. L.; Merce`, R.; Codony,
X.; Buschmann, H. Drug DiscoVery Today 2006, 11, 283–
299.
(6) Heal, D. J.; Smith, S. L.; Fisas, A.; Codony, X.; Buschmann,
H. Pharmacol. Ther. 2008, 117, 207–231.
(7) Geldenhuys, W. J.; Van der Schyf, C. J. Curr. Top. Med.
Chem. 2008, 8, 1035–1048.
(8) Kim, H.-J.; Doddareddy, M.;R.; Choo, H.; Cho, Y. S.; No,
K. T.; Park, W.-K.; Pae, A. N. J. Chem. Inf. Model. 2008,
48, 197–206.
(9) Upton, N.; Chuang, T. T.; Hunter, A. J.; Virley, D. J.
Neurotherapeutics 2008, 5, 458–469.
5-(2-Methoxyethoxy)-3-phenylsulfonyl-[1,2,3]triazolo[1,5-
a]quinazoline 10. A mixture of 5-chloro-PSTQ 1{1} (0.29
mmol) and TEA (0.44 mmol) in 2-methoxyethanol (2 mL)
was stirred at 110 °C for 12 h. After reaction completion,
the reaction mixture was poured into water (100 mL). The
precipitate was filtered, washed with water, dried in air, and
recrystallized from EtOH. Yield 46 mg (41%). ESI-MS m/z
385; 1H NMR (DMSO-d6, 400 MHz) δ 8.52 (d, J ) 8.4 Hz,
1H), 8.24 (d, J ) 8.4 Hz, 1H), 8.11 (m, 3H), 7.84 (t, J )
7.6 Hz, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 4.78 (t, J ) 3.8
Hz, 2H), 3.86 (t, J ) 3.8, Hz, 2H), 3.37 (s, 3H); 13C NMR
(10) http://integrity.prous.com.
(11) Tennant, G. J. Chem. Soc. C 1966, 2290–2295.
(12) Kasila, P.; Harney, H. http://las.perkinelmer.com/Content/
RelatedMaterials/Posters/PST_LANCEcAMPGasGaiCouple-
dReceptors.pdf
(13) Okun, I.; Tkachenko, S. E.; Khvat, A.; Mitkin, O.; Kazey,
V.; Ivachtchenko, A. V. Curr. Alzheimer Res. 2010, 7, 97–112.
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