Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT(2A) and α1 receptor binding affinity

Article abstract of DOI:10.1021/jm970700n

A series of triazolopyridine derivatives (compounds 2a-1) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT(2A) and α₁ receptors. All of the synthesized compounds show a decrease of affinity for both 5HT(2A) and α₁ receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an α position to the aliphatic nitrogen atom N₁. These compounds showed a decrease of affinity only for the α₁ receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)- 2c showed the most significant differences between 5HT(2A) and α₁ receptor affinity (IC₅₀ values) and among the corresponding functional properties (pA₂ values). Since (S)-2c cannot generate the metabolite 4-(3- chlorophenyl)piperazine this product was selected for further pharmacological studies.

Full text of DOI:10.1021/jm970700n

336
J . Med. Chem. 1999, 42, 336-345
Articles
Effect of Mod ifica tion s of th e Alk ylp ip er a zin e Moiety of Tr a zod on e on 5HT2A
a n d r1 Recep tor Bin d in g Affin ity
Marilena Giannangeli,*,† Nicola Cazzolla,† Maria Rita Luparini,‡ Maurizio Magnani,‡ Massimo Mabilia,§
Giuseppe Picconi,† Mauro Tomaselli,† and Leandro Baiocchi†,∇
Departments of Medicinal Chemistry and Neuropharmacology, Angelini Ricerche S.p.A., P.le della Stazione,
00040 S. Palomba-Pomezia (Rm), Italy, and S.IN - Soluzioni Informatiche S.a.s., Via Salvemini 9, 36100 Vicenza, Italy
Received October 16, 1997
A series of triazolopyridine derivatives (compounds 2a -l) were synthesized in order to explore
the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding
affinity for 5HT2A and R1 receptors. All of the synthesized compounds show a decrease of affinity
for both 5HT2A and R1 receptors, as compared to trazodone, with the exception of compounds
2b,c which bear a methyl group in an R position to the aliphatic nitrogen atom N1. These
compounds showed a decrease of affinity only for the R1 receptor. The stereochemical influence
of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)-2c showed the
most significant differences between 5HT2A and R1 receptor affinity (IC50 values) and among
the corresponding functional properties (pA2 values). Since (S)-2c cannot generate the metabolite
4-(3-chlorophenyl)piperazine this product was selected for further pharmacological studies.
Ta ble 1. 1,2,4-Triazolo[4,3-a]pyridin-3-one Derivatives 2a -l
In tr od u ction
Many of the drugs effective in the treatment of
depression and anxiety act on the serotonergic system,
either as serotonin reuptake inhibitors or as agonists
or antagonists for some subtypes of serotonin receptors.1
Among the serotonin receptors identified2 thus far, the
5HT1A, 5HT2A, and 5HT2C subtypes seem to be involved
in anxiety and depression. As an example, ligands
specifically acting as 5HT1A antagonists or partial
agonists or as 5HT2A and 5HT2C antagonists may act
as antidepressant drugs with reduced side effects.3
Trazodone (1) (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]-
propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one) is a widely
used antidepressant drug.4 Its clinical success has
prompted additional investigations. Trazodone has me-
dium to high affinity for several serotonin receptors, in
particular 5HT2A and the R1 adrenergic receptor.
Some of the molecules related to trazodone that have
been studied5 have been used for human therapy, e.g.,
etoperidone6 and nefazodone.7 These trazodone ana-
logues are characterized by the same fragment A, with
two distinct basic nitrogen atoms: one anilinic (N4) and
the other aliphatic (N1).
compd
R
R1
R2
R3
R4
R5
2a
2b
2c
2d
2e
2f
2g
2h
2i
CH3
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
CH3
H
C2H5
H
H
H
H
H
H
H
H
CH3
H
CH3
CH3
H
H
H
-CH2-CH2-
-CH2-CH2-
-CH2-CH2-
-CH2-CH2-
-CH2-CH2-
-CH2-CH2-
-C(CH3)2-CH2-
H
H
H
CH3
H
2j
2k
2l
H
H
H
CH3
H
H
H
H
H
H
-CH2-CO-
-CH(CH3)-CO-
This paper describes the synthesis and properties of
a novel series of trazodone analogues (2a -l) (Table 1)
in which the alkylpiperazine moiety (fragment A) has
been modified in several ways, while the triazolopyri-
dine and 3-chlorophenyl moieties were held fixed. The
following chemical modifications were considered: (a)
a small (methyl or ethyl) alkyl group was introduced
on each carbon atom of the A fragment (compounds 2a -
g); (b) an open chain replaced the piperazine ring
(compounds 2h -j); and (c) an oxo group was introduced
in the piperazine ring (compounds 2k ,l).
* Address correspondence to: Marilena Giannangeli, Department
of Medicinal Chemistry, Angelini Ricerche S.p.A.
† Department of Medicinal Chemistry, Angelini Ricerche S.p.A.
‡ Department of Neuropharmacology, Angelini Ricerche S.p.A.
§ S.IN.
All new molecules were tested for binding affinity to
R1 and 5HT2A receptors, to verify how and to what
∇ Present address: Department of Pharmaceutical Chemistry, Uni-
versita` “G. D'Annunzio”, 66100 Chieti, Italy.
10.1021/jm970700n CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/11/1999

Effect of Modifications of Trazodone
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 337
Sch em e 1a
a
Reagents and conditions: (a) xylene-isobutyl alcohol (10/1), reflux; (b) ClCH2CH(R)CH(R1)Br, (CH3)2CO, 0.6
CH3(CH)2COOEt, EtOH, EtONa; (d) Red-Al, Et2O; (e) SOCl2, CHCl3.
N NaOH; (c)
extent small chemical modifications in the A fragment
can modulate the affinity for the cited receptors. The
compounds that showed, in a preliminary binding
profile, an affinity value for the 5HT2A receptor similar
to that of trazodone were then taken into account for
further investigations.
Resolution of compound 2c, which has a methyl
substituent on the piperazine ring R to N1, was also
performed. The 2c enantiomers were tested to evaluate
the influence of the stereochemistry of the piperazine
moiety on the binding affinity of the above-mentioned
receptors and on the related pharmacological activities.
Computer-assisted conformational analyses were car-
ried out on selected compounds to tentatively relate
structural modifications with the modulation of binding
affinity for 5HT2A and R1 receptors.
reduce the presence of bis-alkylated products. Com-
pound 4b is prepared by addition of ethyl crotonate to
the commercially available 1-(3-chlorophenyl)piperazine
(5a ) and reduction of the obtained ester 10b to the
corresponding alcohol 11b which, on reaction with
thionyl chloride, yields the desired product (Scheme 1).
A very large number of arylpiperazines have been
described. Many of them have been investigated for
their pharmacological activities, but relatively few C-
substituted derivatives on the piperazine ring have been
reported.10
The synthesis of the new 1-(3-chlorophenyl)pipera-
zines 5c-g is achieved by reduction of the corresponding
1-(3-chlorophenyl)piperazinones 9c-g with LiAlH4 or,
as an alternative, with NaBH4/AlCl3 in diglyme. Com-
pounds 9c,e are obtained starting from the common
intermediate N-(3-chlorophenyl)-1,2-ethanediamine (7a)11
which is synthesized through a procedure suitable to
industrial scale-up, by reaction of 3-chloroaniline (12)
and 2-aminoethanol in an aqueous solution of hydro-
bromic acid. Compounds 9d ,g are prepared starting
from N-(3-chlorophenyl)-1-methyl-1,2-ethanediamine (7b),
synthesized by standard procedures (Scheme 2). After
alkylation of 7a or 7b with the appropriate haloacetate,
the obtained diamino esters 8c-g are cyclized to pip-
erazinones 9c-g directly or through the corresponding
acyl chlorides (Scheme 2). The known procedures for the
syntheses of piperazinones from diamino esters require
thermal or basic cyclization with severe reaction condi-
tions. A new acid aqueous cyclization of the diamino
esters 8 that utilizes milder reaction conditions and
Ch em istr y
The general synthetic procedure for the preparation
of compounds 2a -g, with the exception of 2d , is based
on the N-alkylation of the sodium salt of 1,2,4-triazolo-
[4,3-a]pyridin-3(2H)-one (3)8 with the appropriate 1-(3-
halopropyl)-4-(3-chlorophenyl)piperazine 4a -g in a xy-
lene-isobutyl alcohol solution (Scheme 1). Compound
2b is synthesized, in a slightly different manner, by
N-alkylation of the piperazine 5d with 1-(3-chloropro-
pyl)-1,2,4-triazolo[4,3-a]pyridin-3-one9 in toluene and in
the presence of equimolar triethylamine (Scheme 1).
The halopropyl derivatives 4a -g are generally pre-
pared by alkylation with 1,3-dihalopropanes of the
corresponding key intermediates 1-(3-chlorophenyl)-
piperazines 5a -g under reaction conditions suitable to

338 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Giannangeli et al.
Sch em e 2a
a
Reagents and conditions: (a) BrCH(CH3)CO2C2H5, N(C2H5)3; (b) MeOH, MeONa, NH3; (c) LiAlH4, Et2O; (d) HBr, OH(CH2)2NH2; (e)
toluene, N(C2H5)3; (f) 2 N HCl; (g) LiAlH4, Et2O.
Sch em e 3a
The two enantiomers (S)-2c and (R)-2c are obtained
by resolution of 2-[3-[4-(3-chlorophenyl)-2-methylpiper-
azin-1-yl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (2c),
according to the fractional crystallization method.14
These compounds are also prepared by means of an
enantiospecific synthesis, starting with the correspond-
ing piperazines (S)-5c and (R)-5c which are obtained
by resolution of 1-(3-chlorophenyl)-3-methylpiperazine
(5c) with (+)-tartaric acid. The synthetic steps from (S)-
5c and (R)-5c to (S)-2c and (R)-2c, respectively, are
carried out with retention of configuration of all inter-
mediates. To assign the absolute configuration to the
enantiomers of the piperazine key intermediate, 1-(3-
chlorophenyl)-3-methylpiperazine (S)-5c is also pre-
pared with a total stereospecific synthesis, starting with
(S)-ethyl lactate (15) as outlined in Scheme 4. Com-
pound 15 is converted, according to literature,15 into the
corresponding (R)- ethyl 2-bromopropionate (16), which
alkylates the diamine 7a to give the amino ester (S)-
8c. Both of these reactions take place with Walden
inversion at the chiral C atom. Compound (S)-8c is
cyclized in diluted HCl solution, and the obtained
piperazinone (S)-9c is reduced by means of NaBH4/AlCl3
in diglyme to the corresponding piperazine (S)-5c
without appreciable racemization and with retention of
configuration.
g
a
Reagents and conditions: (a) (C2H5)3N, 90 °C, 20 h; (b) C6H6,
1.07 N NaOH, (CH3)2SO4, t.a., 20 h; (c) ClCH2COOEt, (C2H5)3N,
90 °C, C6H5CH3, NaH; (d) BrCH(CH3)COOEt, (C2H5)3N, 90 °C, 2
h, C6H5CH3, NaH; (e) Br(CH2)2Br, 120 °C, 18 h; (f) 1,3-isoindo-
linedione, DMF, 80 °C, 5 h, concd HCl; (g) (C2H5)3N, 90 °C, 18 h.
provides better yields of compound 9 was recently
described.12
Compounds 2h ,j, which have an ethylenediamine
chain instead of a piperazine ring, are synthesized
by alkylation of the diamine 7a and, respectively,
N-(3-chlorophenyl)-N-methyl-1,2-ethanediamine (7c)
with 1-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-3-one
(Scheme 3). Compound 7c is prepared according to
Gabriel’s method13 by reaction of N-(2-bromoethyl)-N-
methyl-3-chloroaniline with potassium phthalimide and
subsequent deprotection of the amine group by hydrazi-
nolysis. Compound 2i is prepared by alkylation of
compound 2h with dimethyl sulfate in alkaline aqueous
medium, while compounds 2k ,l are obtained by alkyl-
ation of compound 2h with ethyl chloroacetate and ethyl
2-bromopropionate, respectively, followed by cyclization
of the obtained aminoesters intermediates (Scheme 3).
Resu lts a n d Discu ssion
(1) Bin d in g Affin ities a n d F u n ction a l Stu d ies.
The synthesized compounds 2a -l were evaluated in
vitro in a preliminary binding screening to assess their
affinity for the receptors shown in Table 2.
Compounds 2h -j, in which fragment A is an open
ethylenic chain, and compounds 2k ,l, in which an oxo
function is present on the piperazine moiety, showed a
lack of affinity for all receptors taken into account. A
rather important loss of affinity was shown by com-

Effect of Modifications of Trazodone
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 339
Sch em e 4a
16
a
Reagents and conditions: (a) N-(3-chlorophenyl)-1,2-ethanediamine, toluene, N(C2H5)3; (b) 2 N HCl; (c) diglyme, AlCl3, NaBH4; (d)
optical resolution; (e) 6 N NaOH, acetone, Cl(CH2)3Br; (f) 1 sodium salt, xylene-isobutyl alcohol (10/1), EtOH, (+)-tartaric acid.
a
Ta ble 2. Preliminary Binding Studiesa
percentage of inhibition at 10-7
Ta ble 4. Comparison of Binding Affinity IC50 and pA2
Valuesb for Enantiomers of 2c
M
pA2
compd
5HT2A
R1
5HT-R
D2
NE-R
H1
σ1
IC50 (nM)
rat
rat vas
deferens
1
78b
52b
65b
69b
34b
60b
20
40b
4b
49b
27b
26b
37b
25b
44b
7b
38b
4
12b
3
0
0
0
2
0
0
0
0
0
4
0
0
0
5b
7
29b
34b
58b
43b
68b
43b
65b
81b
29b
30
compd
5HT2A
R1
aorta
2a
2b
2c
2d
2e
2f
2g
2h
2i
63b
45b
15b
20b
6
2
31b
13b
7b
14b
12b
9
(S)-2c
25.4 (22.1-29.4) 981 (841-1140) 8.5 ( 0.6 5.4 ( 0.7
8b
0
(R)-2c 234 (80.8-378)
533 (372-764) 7.9 ( 0.7 6.8 ( 0.2
a
b
See footnotes of Table 3. pA2 values were calculated as
10b
0
described in the Experimental Section.
11b
8
38b
10b
15
23b
2
3b
3b
2
0
0
0
2
receptor, compounds 2b,c showed either the same value
or a slightly lower value of IC50 as compared to traz-
odone, while compounds 2a ,e showed a consistent
reduction.
0
10
2j
2k
2l
0
12b
5
4
0
4
65b
12
5b
0
2
0
4
9b
To evaluate the influence of stereochemistry, the two
enantiomers (S)-2c and (R)-2c of compound 2c were
prepared and IC50 values for 5HT2A and R1 receptors
were determined (Table 4). The (S)-enantiomer showed
a consistent reduction of R1 adrenergic affinity, while
the (R)-enantiomer showed a marked decrease in affin-
ity to the 5HT2A receptor. To investigate the pharma-
cological meaning of these results, the functional activity
of the two products on the adrenergic and serotonergic
systems was determined, using in vitro smooth muscle
preparations. To investigate the effects of the com-
pounds on R1 receptors,16 a cumulative dose-response
inhibition curve of rat vas deferens contractions induced
by the adrenergic agonist norepinephrine (NE) was
determined. The contractile response to serotonin from
rat aorta strips was used for functional studies on the
serotonergic system.17
a
The assays were carried out using methods described in the
b
Experimental Section. Data were checked with a verification
screen. Differences with respect to the verification screen were
less than 20% for inhibition values of 50% and over, higher than
40% for inhibition values from 0 to 50%.
Ta ble 3. Binding Affinity for 5HT2A and R1 Receptors of
Compounds 1 and 2a -e
IC50 (µM)a
compd
5HT2A [3H]ketanserin
R1 [3H]prazosin
1
0.017 (0.015-0.020)b
0.094 (0.060-0.147)b
0.017 (0.014-0.021)b
0.031 (0.023-0.042)b
0.169 (0.152-0.187)b
0.281 (0.174-0.455)b
0.531 (0.286-0.985)b
0.627 (0.454-0.866)b
0.471 (0.338-0.655)b
0.493 (0.372-0.653)b
2a
2b
2c
2e
a
IC50 values were determined, using six concentrations in
b
triplicate, as described in the Experimental Section. The data
in parentheses are 95% confidence intervals.
The results summarized in Table 4 show similar
functional effects on the serotoninergic system for the
two enantiomers (pA2 values), while (S)-2c shows the
lowest adrenolytic activity.
(2) Com p u t er -Assist ed Molecu la r Mod elin g.
Three-dimensional molecular models were generated for
trazodone (1) and the monomethyl derivatives 2a -d .
Conformational searches were carried out using the
MM2 force field as implemented in SPARTAN18 to
assess the effect of the introduction of one methyl group
pounds 2d ,f,g, all bearing at least one methyl group on
the piperazine ring in the position â to N1. For com-
pounds 2a -c,e, which showed an inhibition of more
than 50% at 10-7 M for the 5HT2 or R1 receptors, the
IC50 values were also determined for the same receptors.
The results are shown in Table 3.
Upon this further investigation, all compounds showed
a reduction of binding affinity to the R1 receptor as
compared to trazodone. With regard to the 5HT2A

340 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Giannangeli et al.
on the propyl chain (compounds 2a ,b) and, respectively,
on the piperazine ring (compounds 2c,d ) with respect
to trazodone.
as a metabolite, contrary to trazodone and nefazodone.
However it is worth noting that there are conflicting
opinions, which have not yet been completely clarified,
about the relevance of this metabolite in the therapeutic
activity of trazodone.19 Therefore, (S)-2-[3-[4-(3-chlo-
rophenyl)-2-methyl-1-piperazinyl]propyl]-1,2,4-triazolo-
[4,3-a]pyridin-3-one tartrate ((S)-2c) and its potential
metabolite methyl-MCPP ((S)-5c) have been selected for
additional studies that will be reported in future papers.
By comparing the total number and relative energy
values for all conformers of compounds 1, and 2a ,b,
respectively, it appears that compound 2a is conforma-
tionally restricted when compared to the other two
molecules. Therefore, the partial loss of affinity for
5HT2A receptors (Table 3) can be explained by stating
that the “active” conformation for that receptor is
energetically less accessible to 2a than to 1 and 2b.
Conformational analyses on compounds 2c,d indicate
that the methyl substituent on the piperazine ring does
not significantly alter the overall conformational space
of these compounds compared to trazodone. Compound
2d , in which the methyl group is â to N1, shows a loss
of affinity for the 5HT2A receptor (Table 2), while 1 and
2c show very similar binding affinities toward the same
receptor. To rationalize these facts, ab initio 3-21G*
calculations were performed on compound 2d using
SPARTAN. The results indicate that the additional
methyl group on the piperazine ring of 2d prefers an
axial geometry by about 0.5 kcal/mol instead of the
equatorial geometry found in 2c. Therefore, based on
these results, there are two alternative hypotheses to
explain the loss of affinity of 2d toward the 5HT2A
receptor. If the additional methyl group is axial, it may
be responsible for steric hindrance inside the binding
site cavity; however, if the same methyl group is
equatorial either it or the phenyl ringsforced into an
orthogonal conformationscould clash with the amino
acid residues in the binding cleft.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Buchi
apparatus and are uncorrected. 1H NMR spectra were recorded
on a Bruker AC 100 spectrometer. Chemical shifts (δ) are
expressed in parts per million (ppm) relative to the internal
standard tetramethylsilane (TMS). IR spectra were deter-
mined with a Perkin-Elmer FT-IR System 2000 spectrometer.
UV spectra were obtained on a Perkin-Elmer Lamba 38
spectroemter. Elemental analyses for carbon, hydrogen, and
nitrogen were determined on a Carlo Erba EA1108 elemental
analyzer. The optical purity of enantiomers was determined
by an HPLC method using a Chiralcel OD-R (J .T. Baker)
analytical column. Optical rotation (R) of pure enantiomers
was measured by a Perkin-Elmer 241 polarimeter. Silica gel
flash chromatography was performed with Kieselgel 60 (230-
400 mesh). Extraction solvents were dried over sodium sulfate.
Gen er a l P r oced u r e for th e Alk yla tion of 1,2,4-Tr ia -
zolo[4,3-a ]p yr id in -3(2H)-on e (3): Com p ou n d s 2a -c,e-g.
This procedure is described for the synthesis of 2a .
2-{3-[4-(Ch lor oph en yl)-1-piper azin yl]-2-m eth ylpr opyl}-
1,2,4-tr iazolo[4,3-a ]pyr idin -3(2H)-on e Hydr och lor ide (2a).
1-(3-Chlorophenyl)-4-(2-methyl-3-chloropropyl)piperazine (4a )
(43 g, 0.24 mol) was added to a stirred suspension of 1,2,4-
triazolo[4,3-a]pyridin-3(2H)-one9 (3) sodium salt (22,5 g, 0.16
mol) in a solution of 10:1 xylene-isobutyl alcohol (330 mL), and
the reaction mixture was heated at reflux temperature for 8
h. After cooling, the solution was washed with water and
evaporated under reduced pressure. The residue was solidified
with a solution of 2 N HCl, then filtered, and recrystallized
from water to obtain 2a (35 g, 58% yield). Mp 196-198 °C. IR
(KBr, νCdO): 1710 cm-1. UV (EtOH, λmax): 246 (ꢀ ) 11 400),
310 (ꢀ ) 3600) nm. Anal. (C20H25Cl2N5O) C, H, N, Cl-. As free
base, 1H NMR (CDCl3): δ 1.1 (d, J ) 7 Hz, 3H, CH3-CH), 2.5
(m, 7H, CH- and 3CH2), 3.1 (t, J ) 5.5 Hz, 4H, 2CH2), 4.0 (dd,
2H, CH2), 6.3-7.3 (m, 7H, ArH), 7.7 (d, 1H, CH triazolopyri-
dine).
Con clu sion s
Simple chemical modifications on the piperazine ring
of trazodone (1), such as substitution with an ethylene-
diamine moiety or introduction of an oxo function, cause
a loss of affinity toward the R1 and 5HT2 receptors, as
shown for compounds 2h -l in preliminary binding tests.
Of all compounds (2a -g) characterized by the introduc-
tion of alkyl substituents on the carbon atoms of
fragment A, only 2b,c retain an affinity similar to that
of trazodone for the 5HT2A receptor and a slightly
reduced affinity for R1. All the other compounds show a
lower affinity for both receptors.
In general, the position of the carbon to which the
methyl group is attached is the most relevant effect of
chemical modifications on the binding affinity for the
two selected receptors. A methyl group on a carbon atom
in the â position to N1, either on a ring (compounds
2d ,f,g) or on a linear chain (compounds 2e,a ), reduces
the affinity particularly for the 5HT2A receptor. How-
ever, a methyl group on a carbon atom in the R position
to N1 (compounds 2b,c), although having a minor impact
on receptor binding, decreases the affinity, especially
for the R1 receptor.
Using the procedure described for compound 2a , the follow-
ing compounds were obtained (yield 40-70%) from the ap-
propriate 4b,c,e-g halo derivatives.
2-{3-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]-1-m et h ylp r o-
p yl}-1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Dih yd r och lor id e
Mon oh yd r a te (2b). Mp: 196-199 °C. IR (KBr, νCdO): 1710
cm-1. UV (EtOH, λmax): 245 (ꢀ ) 11 600), 310 (ꢀ ) 3690) nm.
Anal. (C20H28Cl3N5O2) C, H, N, Cl-. As free base, 1H NMR
(CDCl3): δ 1.1 (d, J ) 7 Hz, 3H, CH3-CH), 1.9 (m, 2H, CH2-
CH), 2.6 (m, 5H, CH- and 2CH2), 3.1 (t, 4H, 2CH2), 4.1 (t, J )
7 Hz, 2H, CH2), 6.3-7.2 (m, 7H, ArH), 7.8 (d, J ) 6.5 Hz, 1H,
CH triazolopyridine).
2-{3-[4-(3-Ch lor op h en yl)-2-m et h yl-1-p ip er a zin yl]p r o-
pyl}-1,2,4-tr iazolo[4,3-a ]pyr idin -3-on e Hydr och lor ide (2c).
Mp: 191-192 °C. IR (KBr, νCdO): 1710 cm-1. UV (EtOH,
λ
max): 312 (ꢀ ) 3540), 246 (ꢀ ) 10 970) nm. Anal. (C20H25
-
+
Cl2N5O) C, H, N, Cl-. As free base, 1H NMR (CDCl3
DMSO): δ 1.1 (d, J ) 7 Hz, 3H, CH3-CH), 1.9-3.5 (m, 11H,
aliphatic CH2 and CH), 4.0 (t, J ) 7 Hz, 2H, CH2), 6.4-7.2
(m, 7H, ArH), 7.8 (d, J ) 7 Hz, 1H, CH triazolopyridine).
2-{3-[4-(3-Ch lor oph en yl)-2-eth yl-1-piper azin yl]pr opyl}-
1,2,4-t r ia zolo[4,3-a ]p yr id in -3-on e H yd r och lor id e (2e).
Mp: 180-182 °C. IR (KBr, νCdO): 1710 cm-1. UV (EtOH,
The (S)-enantiomer of 2c exhibits an interesting
balance between adrenergic and serotoninergic activity,
showing a reduced adrenolytic activity in comparison
to trazodone (1) while retaining functional effects on the
serotoninergic system. Furthermore, (S)-2c, although
structurally similar to 1, includes a 2-methyl-4-(3-
chlorophenyl)piperazine moiety, and as a consequence,
it cannot give rise to 4-(3-chlorophenyl)piperazine (MCPP)
λ
max): 323 (ꢀ ) 3450), 252 (ꢀ ) 14000) nm. Anal. (C21H27Cl2N5O)
C, H, N, Cl-. As free base, 1H NMR (D2O): δ 1.1 (t, J ) 6.5
Hz, 3H, CH3-CH2), 1.6-3.9 (m, 13H, CH2 and CH), 4.2 (t, J

Effect of Modifications of Trazodone
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 341
) 7 Hz, 2H, CH2), 6.6-7.5 (m, 7H, ArH), 7.9 (d, J ) 7 Hz, 1H,
CH triazolopyridine).
ylp ip er a zin e (4g). As a colorless oil. Bp: 200 °C (0.4 mmHg),
43% yield. 1H NMR (CDCl3): δ 1.08 (d, s, s, 9H, J ) 6.5, CH3-
CH and 2CH3-C), 1.75-2.9 (m, 6H, 3CH2), 2.9 (s, 2H, CH2),
3.6 (t, 2H, J ) 6.9 Hz, CH2-Cl), 3.9 (m, 1H, CH-CH3), 6.7
(m, 3H, ArH), 7.1 (t, 1H, J ) 8 Hz, ArH). Anal. (C16H24Cl2N2)
C, H, N.
4-(3-Ch lor op h en yl)-1-(3-ch lor o-2-m eth ylp r op yl)p ip er -
a zin e (4a ). As a colorless oil, purified by flash chromatography
(1:1 hexane/EtOAc) in 57% yield. 1H NMR (CDCl3): δ 1.02 (d,
3H, J ) 7 Hz, CH3-CH), 1.75-2.65 (m, 7H, CH2 and CH),
3.15 (t, 4H, J ) 6.5 Hz, 2CH2), 3.6 (m, 2H, CH2-Cl), 6.7 (m,
3H, ArH), 7.1 (t, 1H, J ) 8 Hz, ArH). Anal. (C14H20Cl2N2) C,
H, N. As HCl salt, mp: 178-179 °C.
2-{3-[4-(3-Ch lor op h e n yl)-2-m e t h yl-1-p ip e r a zin yl]-2-
m eth ylp r op yl}-1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e m a lea te
(2f). The reaction mixture from the alkylation of 3 sodium salt
with 4f was worked up as usual, and the raw residue was
purified by flash chromatography, eluting with 1:1 hexane/
EtOAc. The base thus obtained was dissolved in absolute
ethanol, and a solution of equimolar maleic acid was then
added to obtain 2f, which was recrystallized from absolute
ethanol. Mp 148-149 °C. UV (EtOH, λmax): 308 (ꢀ ) 3550),
257 (ꢀ ) 16 300) nm. Anal. (C25H30ClN5O5) C, H, N. As free
base 1H NMR (CDCl3): due to the presence of two chiral
centers, the compound shows all superimposed figures at δ
1.05 (6H, 2CH3-CH), 2.1-3.2, (9H, aliphatic), 3.6-4.3 (3H,
CH and CH2), 6.4-7.3 (7H, ArH), 7.8 (1H, CH triazolopyri-
dine).
2-{3-[4-(3-Ch lor op h en yl)-2,2,3-tr im eth yl-1-p ip er a zin yl]-
p r op yl}-1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e
Mon oh yd r a te (2g). Mp: 205-206 °C. IR (KBr, νCdO) 1710
cm-1. UV (EtOH, λmax): 312 (ꢀ ) 3470), 259 (ꢀ ) 14 900) nm.
Anal. (C22H31Cl2N5O2) C, H, N, Cl-. As free base, 1H NMR
(CDCl3): δ 1.0 (d, 3H, J ) 6.5 Hz, CH3-CH), 1.6 (d, J ) 7 Hz,
6H, 2CH3-C), 2.3-4.4 (m, 11H, aliphatic), 6.5-7.4 (m, 7H,
Ar-H), 7.7 (d, J ) 7 Hz, 1H, CH triazolopyridine). UV (EtOH,
4-(3-Ch lor op h en yl)-1-(3-ch lor op r op yl)-2-m eth ylp ip er -
1
a zin e (4c). As a colorless oil, in 87% yield. H NMR (CDCl3):
δ 1.1 (d, 3H, J ) 7 Hz, CH3-CH), 1.9 (q, 2H, J ) 7.1 Hz, CH2),
2.1-3.4 (m, 9H, CH and 4CH2), 3.4 (m, 2H, CH2), 3.6 (t, 2H, J
) 7.1 Hz, CH2-Cl), 6.7 (m, 3H, ArH), 7.1 (m, 1H, ArH). Anal.
(C14H20Cl2N2) C, H, N. As 2HCl salt, mp: 174-176 °C dec.
4-(3-Ch lor op h en yl)-1-(3-ch lor o-1-m eth ylp r op yl)p ip er -
a zin e (4b). A solution of SOCl2 (15 mL, 0.20 mol) in CHCl3
(50 mL) was added dropwise, under stirring and at reflux
temperature, to a solution of 4-(3-chlorophenyl)-1-(3-hydroxy-
1-methylpropyl)piperazine (11b) (45 g, 0.17 mol) in CHCl3 (200
mL). After 1 h at reflux temperature, the reaction was
evaporated under reduced pressure, and the residue was
suspended in 2 N NaOH (150 mL) and extracted with diethyl
ether. After evaporation of the solvent, the colorless oil
obtained (39 g, 82% yield) was used in the following step
λ
max): 312 (ꢀ ) 3470), 259 (ꢀ ) 14 900) nm. IR (KBr, νCdO):
1710 cm-1
Compound 2d was prepared in an alternative procedure as
follows.
.
1
without further purification. H NMR (CDCl3): δ 1.0 (d, 3H,
2-{3-[4-(3-Ch lor op h en yl)-3-m et h yl-1-p ip er a zin yl]p r o-
pyl}-1,2,4-tr iazolo[4,3-a ]pyr idin -3-on e Hydr och lor ide (2d).
A solution of 1-(3-chlorophenyl)-2-methylpiperazine (5d )20 (6.1
g, 0.029 mol), 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-
3-one (6.1 g, 0.029 mol), and triethylamine (2.9 g, 0.029 mol)
in toluene (100 mL) was refluxed for 18 h. The reaction
mixture was washed with water and evaporated under reduced
pressure. The remaining residue was purified by flash chro-
matography (8:2 hexane/EtOAc). The obtained base was
transformed into the corresponding hydrochloride which was
recrystallized from absolute ethanol to obtain 2d (5 g, 41%
yield). Mp: 179-180 °C. IR (KBr, νCdO): 1705 cm-1. UV (H2O,
J ) 7 Hz, CH3-CH), 1.8 (m, 2H, CH2), 2.4-3.1 (m, 5H, CH
and 2CH2), 3.15 (m, 4H, 2CH2), 3.6 (m, 2H, CH2-Cl), 6.7 (m,
3H, ArH), 7.1 (t, 1H, J ) 8 Hz, ArH). Anal. (C14H20Cl2N2) C,
H, N. As 2HCl salt, mp: 160-162 °C dec.
4-(3-Ch lor op h en yl)-1-(3-h yd r oxy-1-m eth ylp r op yl)p ip -
er a zin e (11b). A solution of the ethyl ester of 3-[4-(3-
chlorophenyl)-1-piperazinyl]-3-methylbutanoic acid (10b) (49
g, 0.16 mol) in diethyl ether (200 mL) was added dropwise at
room temperature to a stirred solution of Red-Al (65 wt %
solution of sodium bis(2-methoxyethoxy)aluminum hydride in
toluene) (60 mL) in diethyl ether (300 mL). After 2 h at room
temperature, the reaction mixture was cooled with ice, and 2
N NaOH solution (80 mL) was added. The organic layer was
separated, washed with water, and dried, and the solvent was
evaporated under reduced pressure. The residue was recrys-
tallized from hexane to obtain 11b (40 g, 95% yield). Mp: 86-
λ
max): 249 (ꢀ ) 8800), 311 (ꢀ ) 3800) nm. Anal. (C20H25Cl2N5O)
1
C, H, N, Cl-. As free base, H NMR (CDCl3): δ 1.04 (d, 3H, J
) 7 Hz, CH3-CH), 1.8-3.2 (m, 10H, CH2), 3.4-3.9 (m, 1H,
CH), 4.1 (t, J ) 6 Hz, 2H, CH2), 6.4-7.3 (m, 7H, ArH), 7.7 (d,
J ) 7 Hz, 1H, CH triazolopyridine).
1
87 °C. H NMR (CDCl3): δ 1.02 (d, 3H, J ) 8 Hz, CH3-CH),
Gen er a l P r oced u r e for th e Syn th esis of In ter m ed ia tes
(Ha loa lk yl)-3-(ch lor op h en yl)p ip er a zin es 4a ,c,e-g. The
compounds 4a ,c,f,g were prepared, starting with appropriate
dihalopropanes and piperazines, utilizing the same procedure
described for 4e.
1.3-2.15 (m, 2H, CH2), 2.4-3.4 (m, 9H, 4CH2 and CH), 3.82
(m, 2H, CH2-OH), 6.7 (m, 3H, ArH), 7.1 (t, 1H, J ) 8 Hz,
ArH). Anal. (C14H21ClN2O) C, H, N.
Eth yl Ester of 3-[4-(3-ch lor op h en yl)-1-p ip er a zin yl]-3-
m eth ylbu ta n oic Acid Hyd r och lor id e (10b). 1-(3-Chlo-
rophenyl)piperazine (5a ) (100 g, 0.5 mol) and ethyl crotonate
(60.6 g, 0.53 mol) were added at 60 °C to a stirred 0.04 M
solution of EtONa in EtOH (100 mL). After 2 h the reaction
mixture was poured into cooled water and extracted with
diethyl ether, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography
(1:1 hexane/EtOAc) to give 10b (70 g, 43% yield). As HCl salt,
4-(3-Ch lor op h en yl)-1-(3-ch lor op r op yl)-2-et h ylp ip er a -
zin e (4e). 1-(3-Chlorophenyl)-3-ethylpiperazine (5e) (6.3 g,
0.028 mol) and 1-bromo-3-chloropropane (6.6 g, 0.042 mol)
were added dropwise to a stirred solution of 0.6 N NaOH (10
mL) and acetone (25 mL) at 0 °C. After 48 h at room
temperature, under stirring, and 1 h at 50 °C, the reaction
mixture was diluted with toluene (30 mL), washed with
aqueous 1% HCl (2 × 10 mL), and dried, and the solvent was
evaporated under reduced pressure. After purification by flash
chromatography eluting with EtOAc, the obtained colorless oil
1
mp: 179-180 °C. H NMR (D2O): δ 1.4 (m, 6H, 2CH3), 2.7-
4.1 (m, 11H, CH and 5CH2), 4.3 (q, 2H, CH2-CH3), 6.9-7.5
(m, 4H, ArH). Anal. (C16H24Cl2N2O2) C, H, N, Cl-.
1
(3.6 g, 45% yield) was used directly in the following step. H
NMR (CDCl3): δ 1.0 (t, 3H, J ) 7.2 Hz, CH3), 1.1-2.1 (m, 4H,
2CH2 ), 2.3-3.4 (m, 9H, 4CH2 and CH), 3.6 (t, 2H, J ) 6.5 Hz,
CH2-Cl), 6.7 (m, 3H, ArH), 7.1 (t, 1H, J ) 8 Hz, ArH). Anal.
(C15H22Cl2N2) C, H, N.
4-(3-Ch lor op h e n yl)-1-(3-ch lor o-2-m e t h ylp r op yl)-3-
m eth ylp ip er a zin e (4f). As a colorless oil, purified by flash
chromatography eluting with EtOAc in 77% yield. 1H NMR
(CDCl3): δ 1.05 (d, d, 6H, J ) 7.4, 7.3 Hz, 2CH3-CH), 1.9-
3.4 (m, 9H, CH2 and CH), 3.6 (m, 2H, CH2-Cl), 3.9 (m, 1H,
CH-CH3), 6.7 (m, 3H, ArH), 7.1 (t, 1H, J ) 8 Hz, ArH). Anal.
(C15H22Cl2N2) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 1-(3-Ch lor o-
p h en yl)p ip er a zin es 5c,d ,e,g. The compounds 5d ,e,g were
prepared with the same procedure as described for 5c, starting
with the corresponding piperazinones 9c,d ,e,g as free bases.
1-(3-Ch lor op h en yl)-3-m eth ylp ip er a zin e h yd r och lor id e
(5c). (a) A solution of piperazinone 9c as free base (33.7 g,
0.15 mol) in 450 mL of diethyl ether was added dropwise, to
keep a light reflux (2.5 h), to a suspension of LiAlH4 (11 g, 0.3
mol) in diethyl ether (470 mL). After 3 h at reflux temperature,
the reaction mixture was cooled with ice and the metal hydride
excess was decomposed by adding dropwise: H2O (15 mL), 2
N NaOH (15 mL), and H2O (30 mL). After stirring for 30 min
4-(3-Ch lor op h en yl)-1-(3-ch lor op r op yl)-2,2,3-t r im et h -

342 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Giannangeli et al.
at room temperature, the filtered solution was evaporated
(CDCl3): δ 1.05 (d, J ) 7 Hz, 3H, CH3-CH), 1.42 (s, 3H, CH3),
1.46 (s, 3H, CH3), 1.75 (s, 1H, NH), 2.8-3.5 (m, 2H, CH2), 3.7-
4.0 (m, 1H, CH), 6.9-7.4 (m, 4H, ArH). Anal. (C13H17ClN2O)
C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 1-(3-Ch lor o-
p h en yl)eth a n ed ia m in o Ester s or Acid s (8c-e,g). The
compounds were prepared by alkylation with a halo ester, of
the suitable benzene ethanediamines 7a ,b, as described for
8c. For 8e,g, the corresponding acids were isolated by hy-
drolysis of the reaction mixture.
Eth yl Ester of N-[2-(3-Ch lor oben za m in o)eth yl]a la n in e
Hyd r och lor id e (8c). At room temperature, ethyl 2-bromopro-
pionate (52.17 g, 0.29 mol) was added dropwise to a solution
of N-(3-chlorophenyl)ethanediamine (7a ) (35.4 g, 0.21 mol) and
triethylamine (31.5 g, 0.31 mol) in toluene (250 mL). The
reaction mixture was then heated at reflux temperature for 6
h, cooled, and washed with water (2 × 100 mL), and the
organic phase was separated. After extraction with 2 N HCl
(3 × 80 mL), KOH (40 g) was added to the aqueous solution
and the oil was extracted with toluene (3 × 75 mL) to obtain
8c as free base (44 g, 70% yield). 1H NMR (CDCl3): δ 1.25 (m,
6H, 2CH3), 2.74-3.36 (m, 5H, 2CH2 and CH), 4.15 (q, J ) 7
Hz, 2H, CH2), 6.35-7.2 (m, 4H, ArH). Anal. (C13H19ClN2O2)
C, H, N. As HCl salt, mp: 108-110 °C.
Eth yl Ester of N-[2-(3-ch lor oben za m in o)p r op yl]gly-
cin e (8d ). From 7b, as an oil, in 75% yield. 1H NMR (CDCl3):
δ 1.20 (m, 6H, 2CH3), 1.85 (s,1H, NH), 2.70 (d, J ) 7 Hz, 2H,
CH2), 3.42 (s, 2H, CH2-CO), 3.5 (m, 1H, CH), 4.22 (q, J ) 7
Hz, 2H, CH2), 6.4-7.4 (m, 4H, ArH). Anal. (C13H19ClN2O2) C,
H, N.
under reduced pressure to obtain 5c as free base (25.8 g, 82%
1
yield). Bp: 152-153 °C (0.9 mmHg). H NMR (CDCl3): δ 1.1
(d, J ) 6 Hz, 3H, CH3-CH), 1.5 (s, 1H, NH), 2.2-3.6 (m, 7H,
CH2 and CH), 6.6-7.2 (m, 4H, ArH). As HCl salt, mp: 181-
1
182 °C. H NMR (D2O): δ 1.36 (d, J ) 6 Hz, 3H, CH3), 2.8-
3.8 (m, 7H, CH and CH2), 6.8-7.4 (m, 4H, ArH). Anal.
(C11H16Cl2N2) C, H, N, Cl-.
(b) While mantaining a nitrogen atmosphere and keeping
the reaction temperature under 50 °C, a solution of 9c free
base (4.9 g, 0.022 mol) and NaBH4 (2.5 g, 0.066 mol) in diglyme
(70 mL) was added dropwise to a suspension of AlCl3 (2.9 g,
0.022 mol) in diglyme (10 mL). The reaction mixture was
stirred for 1 h at room temperature, then poured into a mixture
of ice (150 g) and 37% HCl solution (32 mL), and stirred for
an additional 12 h. After being washed with diethyl ether (100
mL), the aqueous solution was basified with 5 N NaOH and
then extracted with diethyl ether. The organic solution was
evaporated to obtain pure 5c as free base (3.25 g, 72% yield).
1-(3-Ch lor op h en yl)-2-m et h ylp ip er a zin e H yd r och lo-
r id e (5d ).20 The free base was obtained in 58% yield, as an
1
oil. Bp: 112-113 °C (0.4 mmHg). H NMR (CDCl3): δ 1.1 (d,
J ) 6 Hz, 3H, CH3-CH), 1.6 (s, 1H, NH), 2.7-3.2 (m, 6H,
3CH2), 3.7 (m, 1H, CH), 6.7-7.2 (m, 4H, ArH). As HCl salt,
mp: 172-174 °C. 1H NMR (D2O): δ 1.2 (d, J ) 7 Hz, 3H, CH3),
3.4-4.0 (m, 6H, 3CH2), 4.1-4.4 (m, 1H, CH), 7.4-7.7 (m, 4H,
ArH). Anal. (C11H16Cl2N2) Cl-.
1-(3-Ch lor op h en yl)-3-eth ylp ip er a zin e Hyd r och lor id e
(5e). Yield: 40%. Mp: 183-184 °C. 1H NMR (D2O): δ 1.03 (t,
J ) 7 Hz, 3H, CH3-CH2), 1.64-1.79 (m, 2H, CH2), 2.76-3.75
(m, 7H, 3CH2 and CH), 6.90-7.37 (m, 4H, ArH). Anal. (C12H18
-
N-[2-(3-Ch lor oben zam in o)eth yl]am in obu tyr ic Acid (8e).
From 7a , in 53% yield. Mp: 207-208 °C. 1H NMR (DMSO):
δ 1.0 (t, J ) 7 Hz, 3H, CH3-CH2), 1.92 (m, 2H, CH2), 2.90-
3.60 (m, 4H, 2CH2), 3.70 (t, J ) 6 Hz, 1H, CH), 6.42-7.18 (m,
4H, ArH), 9.8 (s broad, 1H, COOH). Anal. (C12H17ClN2O2) C,
H, N.
Cl2N2) C, H, N, Cl-.
1-(3-Ch lor op h en yl)-2,5,5-tr im eth ylp ip er a zin e Hyd r o-
ch lor id e (5g). Yield: 45%. Mp: 181-183 °C. 1H NMR (D2O):
δ 1.06 (d, J ) 6 Hz, 3H, CH3-CH), 1.37 (s, 3H, CH3-C), 1.50
(s, 3H, CH3-C), 3.01-3.42 (m, 4H, 2CH2), 3.90 (m, 1H, CH),
6.67-7.34 (m, 4H, ArH). Anal. (C13H20Cl2N2) C, H, N, Cl-.
Gen er a l P r oced u r e for th e Syn th esis of 1-(3-Ch lor o-
p h en yl)p ip er a zin on es 9c-e,g. The compounds 9c,d were
prepared by cyclocondensation of suitable amino esters 8c,d .
Compounds 9e,g were prepared from amino acids 8e,g by
cyclocondensation of the corresponding acid chlorides.
N-[2-(3-Ch lor ob en zen a m in o)p r op yl]a m in oisob u t yr ic
1
Acid (8g). From 7b, in 40% yield. Mp: 205-210 °C. H NMR
(CD3COOD): δ 1.22 (d, J ) 6 Hz, 3H, CH3-CH), 1.49 (s, 6H,
2CH3), 2.90-3.22 (m, 2H, CH2), 3.62-4.03 (m, 1H, CH), 6.5-
7.2 (m, 4H, ArH). Anal. (C13H19ClN2O2) C, H, N.
N-(3-Ch lor op h en yl)-1,2-eth a n ed ia m in e (7a ).11 At room
temperature and with stirring, a 47% HBr solution (101.5 mL,
0.88 mol) was added dropwise to a mixture of 3-chloroaniline
(56 g, 0.44 mol) and ethanolamine (26.6 g, 0.44 mol). Water
was removed by heating the solution to 168-171 °C (1 h). The
reaction mixture was then kept at this temperature for 6 h,
cooled, diluted with H2O (100 mL), basified with 6 N NaOH
solution (180 mL) and stirred at room temperature for an
additional 8 h. The oil was extracted with toluene (3 × 90 mL),
the organic phase evaporated, and the residue distilled to give
7a (40.5 g, 54.5% yield). Bp 116-121 °C (0.1 mmHg) (lit.11 bp
118-125 °C, 0.1 mmHg).
1-(3-Ch lor op h en yl)-3-m et h ylp ip er a zin -2-on e H yd r o-
ch lor id e (9c). A suspension of the ethyl ester of N-[2-(3-
chlorobenzenamino)ethyl]alanine (8c) (55.2 g, 0.2 mol) in 2 N
HCl solution was heated at reflux temperature for 5 h. After
cooling, K2CO3 (110.4 g, 0.8 mol) was added and the oil was
extracted with dichloromethane (3 × 100 mL) to obtain 9c as
free base (33.1 g, 73% yield). Bp: 180-182 °C (0.4 mmHg).
1H NMR (CDCl3): δ 1.40 (d, J ) 6 Hz, 3H, CH3-CH), 1.90 (s,
1H, NH), 3.0-3.95 (m, 5H, 2CH2 and CH), 7.1-7.5 (m, 4H,
ArH). As HCl salt, mp: 181-183 °C. Anal. (C11H14Cl2N2O) Cl-.
1-(3-Ch lor op h en yl)-2-m eth ylp ip er a zin -6-on e (9d ). Fol-
lowing the same procedure described for 9c, an oil was
Eth yl Ester of 2-(3-Ch lor oben za m in o)p r op a n oic Acid
(13). While stirring, the ethyl ester of 2-bromopropanoic acid
(25 g, 0.14 mol) was added dropwise into a mixture of
3-chloroaniline (15.8 g, 0.13 mol) and triethylamine (10.1 mL,
0.25 mol). The reaction mixture was heated at 100 °C for 12
h, cooled, diluted with toluene (100 mL), and washed with H2O.
The organic phase was then evaporated at reduced pressure
to obtain a residue which was distilled to give 1321 (24.5 g,
1
obtained in 52% yield. H NMR (CDCl3): δ 1.09 (d, J ) 6 Hz,
3H, CH3-CH), 2.09 (s, 1H, NH), 2.94-3.28 (m, 2H, CH2), 3.65
(s, 2H, CH2-CO), 3.75-4.05 (m, 1H, CH), 7.02-7.45 (m, 4H,
ArH). Anal. (C11H13ClN2O) C, H, N.
1-(3-Ch lor op h en yl)-3-eth ylp ip er a zin -2-on e Hyd r och lo-
r id e (9e). SOCl2 (4.2 mL, 0.058 mol) was added to a solution
of N-[2-(3-chlorobenzamino)ethyl]aminobutyric acid (8e) (10
g, 0.039 mol) in CHCl3 (100 mL). The reaction mixture was
heated at reflux temperature for 2 h, then cooled, and
evaporated. A solution of the residue in toluene (100 mL) and
triethylamine (10.8 mL, 0.078 mol) was heated at 60 °C for 4
h, then cooled, and filtered; the solution evaporated to obtain
9e as free base (6.6 g, 83.4% yield). Bp: 195-200 °C (0.3
1
87% yield). Bp: 132-135 °C (0.7 mmHg). Mp: 37-38 °C. H
NMR (CDCl3): δ 1.1-1.5 (m, 6H, 2CH3), 3.9-4.4 (m, 4H, CH,
CH2 and NH), 6.4-7.2 (m, 4H, ArH).
2-(3-Ch lor ob en za m in o)p r op a n a m id e (14). NH3 was
bubbled for 8 h into a cooled (ice-water bath) 0.05 M solution
of MeONa in MeOH (200 mL) in which 13 (32 g, 0.14 mol)
was dissolved. After standing at room temperature for 12 h,
the reaction mixture was concentrated to one-half volume and
poured into H2O (200 mL). The precipitate was filtered and
recrystallized to obtain 14 (24 g, 89% yield). Mp: 121-122
°C. 1H NMR (CDCl3 + DMSO): δ 1.46 (d, J ) 7 Hz, 3H, CH3),
3.79 (m, 1H, CH), 5.12 (d, J ) 5 Hz, 1H, NH), 6.4-7.2 (m, 6H,
ArH and NH2).
1
mmHg). As HCl salt, Mp: 149-152 °C. H NMR (DMSO): δ
1.07 (t, J ) 7 Hz, 3H, CH3), 1.67-2.30 (m, 2H, CH2), 3.32-4.8
(m, 5H, 2CH2 and CH), 7.2-7.6 (m, 4H, ArH), 10.3 (s, 1H, NH).
Anal. (C12H16Cl2N2O) C, H, N, Cl-.
1-(3-Ch lor oph en yl)-2,5,5-tr im eth ylpiper azin -6-on e (9g).
Following the same procedure described for 9e, an oil was
obtained. Bp: 160-162 °C (0.2 mmHg), 65% yield. 1H NMR

Effect of Modifications of Trazodone
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 343
2-(3-Ch lor oben za m in o)p r op a n a m in e (7b). At room tem-
perature, a solution of 14 (10 g, 0.05 mol) in THF (100 mL)
was added dropwise to a suspension of LiAlH4 (6.8 g, 0.18 mol)
in diethyl ether (150 mL). The reaction mixture was heated
to reflux temperature and then cooled. The excess of LiAlH4
was decomposed as previously described. After filtration, the
organic phase was evaporated and the residue was distilled
to obtain 7b (6.7 g, 73% yield). Bp: 125-130 °C (0.5 mmHg).
1H NMR (CDCl3): δ 1.1 (d, s, J ) 6 Hz, 5H, CH3 and NH2),
2.52-2.95 (m, 2H, CH2), 3.3-3.55 (m, 1H, CH), 3.8 (br s, 1H,
NH), 6.4-7.2 (m, 4H, ArH). Anal. (C9H13ClN2) C, H, N.
triethylamine (64 g, 0.63 mol) was heated at 90 °C for 18 h.
The reaction mixture was diluted with water and extracted
with diethyl ether to give, after removal of the solvent, a
residue which was purified by flash chromatography (9:1
CHCl3/MeOH). The obtained 2j base (7.3 g, 35% yield) was
converted to the hydrochloride salt. Mp 185-186 °C. 1H NMR
(DMSO): δ 2.0-2.35 (m, 2H, CH2), 2.7-3.35 (m, 11H, 4CH2
and CH3), 4.05 (t, J ) 6 Hz, 2H, CH2), 6.5-7.3 (m, 7H, ArH),
7.8 (d, J ) 7 Hz, 1H, CH triazolopyridine), 9.3 (broad s, 1H,
NH). IR (KBr, νmax): 1720, 3460 cm-1. UV (H2O, λmax): 246 (ꢀ
) 15 000), 305 (ꢀ ) 4800) nm. Anal. (C18H23Cl2N5O‚1/2H2O) C,
H, N.
2-{3-[4-(3-Ch lor op h en yl)-3-oxo-1-p ip er a zin yl]p r op yl}-
1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e (2k ). At
90 °C and with stirring, ethyl chloroacetate (1.46 g, 0.11 mol)
was added dropwise to a mixture of 2h as freebase (3.75 g,
0.011 mol) and triethylamine (2.2 g, 0.02 mol). After 2 h, the
reaction mixture was poured into water and the resultant oil
was extracted with diethyl ether. Removal of the solvent left
a residue which was then dissolved in toluene (30 mL) in the
presence of NaH (0.2 mg), and the reaction mixture was
refluxed for 1 h. After being washed with water and evapora-
tion of the organic solvent, the residue was dissolved in ethanol
and converted to the hydrochloride salt (2.6 g, 62% yield). Mp
210-212 °C. 1H NMR (D2O): δ 2.3-2.7 (m, 2H, CH2), 3.4-4.4
(m, 10H, 5CH2), 6.9-7.6 (m, 7H, ArH), 7.8 (d, 1H, CH
triazolopyridine). IR (KBr, νCdO): 1690 cm-1. UV (H2O, λmax):
264 (ꢀ ) 3780), 316 (ꢀ ) 3430) nm. Anal. (C19H21Cl2N5O2 ) C,
H, N.
2-(3-{[2-(3-Ch lor oa n ilin o)et h yl]a m in o}p r op yl)-1,2,4-
tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e (2h ). A mix-
ture of 7a (3.4 g, 0.02 mol), 2-(3-chloropropyl)triazolo[4,3-
a]pyridin-3-one9 (4.2 g, 0.02 mol), and triethylamine (20.2 g,
0.2 mol) was heated at 90 °C for 20 h, then diluted with water
(10 mL), and extracted with diethyl ether (2 × 10 mL). The
residue of the combined organic layers (6.9 g) was purified by
flash chromatography (9:1 CHCl3/MeOH) to obtain 2i as free
base (4.2 g, 61% yield). As HCl salt, mp: 189-191 °C. 1H NMR
(DMSO): δ 2.2-2.4 (m, 2H, CH2), 2.9-3.2 (m, 4H, 2CH2), 3.2-
3.6 (m, 2H, CH2), 4.05 (t, J ) 7 Hz, 2H, CH2), 6.4 (m, 1H, NH),
6.5-7.3 (m, 7H, ArH), 7.9 (d, J ) 7 Hz, 1H, CH triazolopyri-
dine), 9.3 (broad s, 1H, NH). IR (KBr, νmax): 1700, 3320 cm-1
.
UV (H2O, λmax): 246 (ꢀ ) 13360), 305 (ꢀ ) 4700) nm. Anal.
(C17H21Cl2N5O) C, H, N, Cl-.
2-(3-{[2-(3-Ch lor oa n ilin o)eth yl]m eth yla m in o}p r op yl)-
1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e (2i). At
room temperature, compound 2h (1.53 g, 0.004 mol) was added
to a stirred mixture of benzene (10 mL) and 1.07 N NaOH (15
mL). Dimethyl sulfate (1 g, 0.008 mol) was then added
dropwise; and, after 20 h at room temperature, the organic
phase was separated, washed with water, and evaporated
under reduced pressure. The residue (1.6 g) was purified by
flash chromatography (9:1 CHCl3/MeOH), and the obtained
base was transformed into the corresponding hydrochloride
2i (1.3 g, 82% yield). Mp: 160-162 °C. 1H NMR (D2O): δ 2.2-
2.4 (m, 2H, CH2), 3.1 (s, 3H, CH3), 3.2-3.7 (m, 6H, 3CH2), 4.1
(t, J ) 7 Hz, 2H, CH2), 6.5-7.5 (m, 7H, ArH), 7.7 (d, J ) 7 Hz,
1H, CH triazolopyridine). IR (KBr, νmax): 1700, 3320 cm-1. UV
2-{3-[4-(3-Ch lor op h en yl)-2-m eth yl-3-oxo-1-p ip er a zin yl]-
p r op yl}-1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e
(2l). Following the same procedure described for 2k , but
starting with 2h (3.1 g, 0.009 mol) and ethyl 2-bromopropi-
onate (2.44 g, 0.009 mol), 2l (1.9 g, 49% yield) was obtained.
Mp: 243-245 °C. 1H NMR (D2O): δ 1.7 (d, J ) 8 Hz, 3H, CH3),
2.3-2.7 (m, 2H, CH2), 3.4-4.5 (m, 9H, 4CH2 and CH), 6.7-
7.6 (m, 7H, ArH), 7.85 (d, 1H, CH triazolopyridine). IR (KBr,
ν
CdO): 1680, 1720 cm-1. UV (H2O, λmax): 264 (ꢀ ) 3840), 316
(ꢀ ) 3600) nm. Anal. (C20H23Cl2N5O2 ) C, H, N.
Op tica l Resolu tion of 2-{3-[4-(3-Ch lor op h en yl)-2-m eth -
yl-1-p ip er a zin yl]p r op yl}-1,2,4-t r ia zolo[4,3-a ]p yr id in -3-
on e (2c). (a ) A suspension of 2c as free base (12.5 g, 0.032
mol) and naturally occurring (+)-tartaric acid (4.8 g, 0.032 mol)
in ethanol (125 mL) was heated at 60 °C until dissolution and
then slowly cooled at room temperature. The precipitate was
filtered and recrystallized twice from ethanol (3 × 50 mL) to
(H2O, λmax): 246 (ꢀ ) 13 000), 305 (ꢀ ) 4650) nm. Anal. (C18H23
-
Cl2N5O) C, H, N, Cl-
.
N1-(3-Ch lor op h en yl)-N1-m eth yl-1,2-eth a n ed ia m in e Di-
h yd r och lor id e (7c). (a ) N-methyl-3-chloroaniline (7.01 g,
0.05 mol) was heated in 1,2-dibromoethane (46.5 g, 0.25 mol)
at 120 °C for 18 h. The reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in
water (20 mL), basified with 6 N NaOH, and extracted with
diethyl ether. The obtained oil was distilled to yield 4.4 g of
N-(2-bromoethyl)-N-methyl-3-chloroaniline, bp: 120-125 °C
(0.5 mmHg), which was reacted with equimolar 1,3-isoindo-
linedione potassium salt (3.28 g) in DMF solution (30 mL).
After 5 h at 80 °C, the stirred reaction mixture was poured
into water and the oil was extracted with diethyl ether. The
solvent was evaporated, and the residue was purified by flash
chromatography (2:1 hexane/EtOAc) to yield 2.6 g of 2-[2-(N-
methyl-3-chloroanilino)ethyl]-1,3-isoindolinedione. Mp: 86-
88 °C. 1H NMR (CDCl3): δ 2.95 (s, 3H, CH3), 3.5-3.95 (m,
4H, 2CH2), 6.4-7.1 (m, 4H, ArH), 7.55-7.9 (m, 4H, ArH).
yield 4.7 g of (S)-2c (+)-tartrate salt. Mp: 151-152 °C. [R]25
D
+14.2° (c ) 1, methanol). Anal. (C24H30ClN5O7) C, H, N. After
the salt was partitioned between 5% K2CO3 solution and
CHCl3, the organic layer was washed with water and evapo-
rated to obtain (S)-2c free base (3.1 g). Mp: 63-65 °C. [R]25
D
+32° (c ) 1, ethanol). As HCl salt, mp: 122-124 °C (hygro-
scopic).
(b) The mother liquor from the isolation of (S)-2c was
concentrated to dryness and the solid partitioned between 5%
K2CO3 solution and CHCl3. The residue (5.7 g) from the organic
layer was added to equimolar (-)-tartaric acid in ethanol (80
mL), and the suspension was heated at reflux temperature
for 10 min. After cooling, the salt was filtered, recrystallized
from water, and then recrystallized from ethanol, to yield, after
(b) A suspension of the above-described product (10.6 g,
0.034 mol) in concentrated HCl (40 mL) and water (6 mL) was
heated at reflux temperature for 10 h. The reaction mixture
was cooled then filtered. The resultant aqueous solution was
basified to obtain an oil which was extracted with diethyl
ether. The organic phase was washed with NaHCO3 solution
and then evaporated to give a residue which was distilled. The
fraction (3.6 g) at bp 93-95 °C was converted to the dihydro-
chloride salt 7c. Mp 232-234 °C dec. Anal. (C9H15Cl3N2) Cl-.
decomposition of the tartrate, 3.2 g of (R)-2c free base. [R]25
- 28° (c ) 1, ethanol).
D
En a n tiosp ecific Syn th esis of (S)-2-{3-[4-(3-Ch lor o-
p h en yl)-2-m et h yl-1-p ip er a zin yl]p r op yl}1,2,4-t r ia zolo-
[4,3-a ]p yr id in -3-on e (+)-ta r tr a te ((S)-2c). Following the
procedure described for the racemic 2c, but starting with the
enantiomer (S)-4c (3.5 g, 0.012 mol), (S)-2c free base (4.2 g,
89% yield) was obtained. Mp: 65-66 °C. [R]25 +32° (c ) 1,
D
1
As free base, H NMR (CDCl3): δ 1.1 (s, 2H, NH2), 2.7-2.95
ethanol). To a solution of the described free base (4.2 g, 0.011
mol) in ethanol (50 mL) was added (+)-tartaric acid (1.63 g,
0.011 mol), and the suspension was heated at reflux temper-
ature for 10 min. After cooling and dilution with ethanol (20
mL), the precipitate was filtered to obtain 5.4 g of (S)-2c (+)-
(m, 7H, 2CH2 and CH3), 6.4-7.2 (m, 4H, ArH).
2-(3-{[2-(3-Ch lor o(m eth yl)an ilin o)eth yl]am in o}pr opyl)-
1,2,4-tr ia zolo[4,3-a ]p yr id in -3-on e Hyd r och lor id e (2j). A
mixture of 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-3-one9
(13.4 g, 0.063 mol) and 7c as free base (11.7 g, 0.063 mol) in
tartrate. Mp 151-152 °C. [R]25 +14.2° (c ) 1, methanol).
D

344 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Giannangeli et al.
(S)-4-(3-Ch lor oph en yl)-1-(3-ch lor opr opyl)-2-m eth ylpip-
er a zin e ((S)-4c). To a stirred solution of 6 N NaOH (20 mL)
and acetone (44 mL) cooled at 5 °C were added dropwise
1-bromo-3-chloropropane (8.4 g, 0.054 mol) and, afterward, (S)-
5c (9.4 g, 0.045 mol). After 12 h at room temperature, the
reaction mixture was diluted with toluene (50 mL) and the
aqueous phase was separated. After extraction of the organic
phase with 6 N HCl, the aqueous solution was basified and
the oil extracted with EtOAc. The residue of the organic solvent
was purified by flash chromatography eluting with EtOAc to
obtain an oil (10.5 g, 83% yield), [R]25D +47.6° (c ) 1, ethanol).
Molecu la r Mod elin g. All molecular mechanics and quan-
tum mechanics calculations were carried out under vacuum
and on neutral species, on a Silicon Graphics Indigo R4000
workstation using the software package SPARTAN.18 In
particular, each 3D structure was optimized using the MM2
force field as implemented in the above-mentioned software
package. Since corrections for conjugated systems are currently
not included in this implementation, the TYPE50 keyword was
invoked to assign appropriate atom types and parameters to
aromatic carbons. Default values were used for all other
keywords. Each time the energy convergence criterion (i.e.,
0.00001 kcal/mol) was first met, a second minimization was
automatically started to ensure proper convergence. Only one
of two enantiomeric forms was arbitrarily chosen for molecules
with one asymmetric carbon atom.
Biology: Recep tor Bin d in g. The receptors affinity was
estimated at Nova Screen Laboratories22 by the ability of the
tested compounds to displace selective radioligands. The
assays were carried out using the following: for 5HT2Asrat
cortical membranes, [3H]ketanserin (1.0 nM) as radioligand
and methysergide as reference compound; for R1srat cortical
membranes, [3H]prazosin (0.5 nM) and prazosin; for 5HT-Rs
rat forebrain membranes, [3H]citalopram (0.7 nM) and imi-
pramine; for D2srat striatal membranes, [3H]sulpiride (3.0
nM) and sulpiride; for NE-Rsrat cortical membranes, [3H]-
desmethylimipramine (3.0 nM) and desipramine; for H1s
bovine cerebellar membranes, [3H]pyrilamine (2.0 nM) and
triprolidine; for σ1spig brain membranes, [3H]-(+)-pentazocine
(3.0 nM) and (+)-3-PPP.
In the preliminary binding assay, the results are expressed
as inhibition percentage compared to results without drug
(Table 2) and represent the average of duplicate tubes at each
tested concentration in a single experiment. For the selected
compounds (inhibition > 50% at 10-7 M) the binding affinities
for 5HT2A and R1 are expressed as IC50 values (Tables 3 and
4), which were calculated based on three replicates at six
different concentrations of the tested compounds in a single
experiment.
Ra t Va s Defer en s. Male Sprague-Dawley rats weighing
200-300 g were used. According to Bonaccorsi23and Tayo,24
isometric contractions of 3-4 different preparations of vas
deferens were recorded with a Ugo Basile microdynamometer
recorder. Cumulative contractile dose-response curves were
obtained by a stepwise increase in concentrations of agonist
(L-noradrenaline HCl; Fluka) as soon as a steady response to
the preceding dose was obtained. Tested compounds were
added 2 min before agonist. The pA2 of the curves was
calculated by the Schild Plot analysis.25
(S)-1-(3-Ch lor op h en yl)-3-m eth ylp ip er a zin e ((S)-5c). (a )
By Op tica l Resolu tion of Ra cem ic P ip er a zin e 5c. A
suspension of 5c (29.1 g, 0.138 mol) and (+)-tartaric acid (21
g, 0.140 mol) in H2O (175 mL) was heated at 60 °C until
dissolution. After spontaneous cooling at room temperature
for 12 h, the solid which precipitated was filtered and
recrystallized from H2O (130 mL) to obtain (S)-5c (+)-tartrate
(12 g, 48% yield). Mp: 150-152 °C. The salt was suspended
in 10% NaOH (30 mL) with stirring for 30 min, and the oil
was extracted with dichloromethane (3 × 15 mL). The com-
bined organic layers were evaporated to obtain (S)-5c free base
as an oil (6.9 g, 98.5% yield). [R]25 -14.7° (c ) 1, ethanol).
D
(b) By Ster eosp ecific Syn th esis. Under a nitrogen at-
mosphere, while stirring and mantaining a reaction temper-
ature of less than 45 °C, a solution of NaBH4 (3.42 g, 0.09 mol)
and piperazinone (S)-9c (6.8 g, 0.03 mol) in diglyme (100 mL)
was added dropwise to a suspension of AlCl3 (3.99 g, 0.03 mol)
in diglyme (14 mL). After 1 h, the reaction mixture was poured
into ice (210 g) and concentrated HCl (45 mL), stirred for 14
h at room temperature, and then heated for 2 h at 50 °C; 5 N
NaOH (95 mL) was added, and the oil was extracted with
dichloromethane (2 × 50 mL). The residue of the combined
organic layers was distilled to obtain (S)-5c as free base (4.2
g). Bp: 143-145 °C (0.4 mmHg). [R]25D - 14.1° (c ) 1, ethanol).
(R)-1-(3-Ch lor oph en yl)-3-m eth ylpiper azin e ((R)-5c). The
mother liquor from the isolation of enantiomer (S)-5c, de-
scribed above, was basified with 5% K2CO3, and the oil was
extracted with dichloromethane. Evaporation of the solvent
afforded a residue (3.6 g) which was suspended in water (25
mL). Then (-)-tartaric acid (2.55 g) was added. The mixture
was refluxed until dissolution and then cooled, and the salt
was filtered and recrystallized from ethanol to obtain (R)-5c
(-) tartrate (5.5 g). Mp 149-150 °C. The corresponding base
showed [R]25 +14.5° (c ) 1, ethanol).
D
(R)-2-{3-[4-(3-Ch lor op h en yl)-2-m et h yl-1-p ip er a zin yl]-
pr opyl}-1,2,4-tr iazolo[4,3-a ]pyr idin -3-on e (+)-tar tr ate ((R)-
2c). The compound was prepared following the same procedure
described for the enantiomer (S)-2c, with retention of config-
uration and starting from the enantiomer (R)-5c. The (R)-2c
(+)-tartrate was decomposed to give the corresponding base.
Ra t Aor ta Str ip s. Male Sprague-Dawley rats weighing
200-300 g were used. In agreement with Patil et al.,26
isometric contractions of 3-7 different preparations of aorta
strips were recorded with a Ugo Basile microdynamometer
recorder. Cumulative contractile dose-response curves were
obtained by stepwise increase in concentration of the agonist
(serotonin creatinin sulfate; Sigma), as soon as a steady
response to the preceding dose was obtained. Tested com-
pounds were added 2 min before agonist. The pA2 of the curves
were calculated by the Schild plot analysis.24
[R]25 -25.2° (c ) 1, toluene).
D
(S)-Eth yl Ester of N-[2-(3-Ch lor oben zen a m in o)eth yl]-
a la n in e Ma lea te ((S)-8c). Triethylamine (10.7 mL, 0.077 mol)
was added dropwise to a stirred solution of 7a (8.7 g, 0.051
mol) and (R)-ethyl 2-bromopropionate (16)15 (9.26 g, 0.051 mol;
[R]20 +44.3°, neat) in toluene (90 mL) at 60 °C. The reaction
D
mixture was then refluxed for 11 h, cooled, and extracted with
2 N HCl solution. The aqueous layer was basified, and the oil
was extracted with dichloromethane to yield 10 g of residue
after evaporation of the solvent. Equimolar maleic acid was
added to the solution of the raw (S)-8c free base (10 g) in
2-propanol (100 mL) and the mixture was heated at reflux
temperature for 10 min. After cooling, the solid was filtered
and recrystallized twice from 2-propanol to yield 2.5 g of (S)-
Ack n ow led gm en t. We thank Franco Della Guardia,
Francesco Damasco, and Giancarlo Ciocci for their
technical assistance and Dr. Mario Pinza and Prof.
Mario Brufani for helpful discussions.
Refer en ces
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D
(S)-1-(3-Ch lor op h en yl)-3-m et h ylp ip er a zin -2-on e H y-
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of the organic phase was purified by flash chromatography
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Effect of Modifications of Trazodone
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