Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents

Article abstract of DOI:10.1016/j.bmc.2015.08.043

A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3(2H)-one) was synthesized and tested for their anti

Full text of DOI:10.1016/j.bmc.2015.08.043

Bioorganic & Medicinal Chemistry 23 (2015) 6237–6245
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of five and six-membered heterocycles bearing
an arylpiperazinylalkyl side chain as orally active
antinociceptive agents
Claudia Vergelli a, Giovanna Ciciani a, Agostino Cilibrizzi b, Letizia Crocetti a, Lorenzo Di Cesare Mannelli c,
Carla Ghelardini c, Gabriella Guerrini a, Antonella Iacovone a, Maria Paola Giovannoni a,
⇑
a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy
b Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
c NEUROFARBA, Sezione di Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2015
Revised 31 August 2015
Accepted 31 August 2015
Available online 2 September 2015
A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the pre-
viously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3
(2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many com-
pounds, tested at doses of 20–40 mg/kg po were able to reduce the number of abdominal constrictions
by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and
27c. The analgesia induced by the active compounds was completely prevented by pretreatment with
Keywords:
Synthesis
Antinociception
Adrenergic system
a2-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of
action for these new compounds.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
drugs.7 Recently defined by the International Association for the
Study of Pain (IASP) as ‘pain caused by a lesion or disease of the
somatosensory system’,8 neuropathic pain is a complex phe-
nomenon characterized by burning pain coupled with hyperalgesia
and allodynia involving both the peripheral and central nervous
system.9 At present, first-line drugs recommended for this pathol-
ogy include anticonvulsant, as gabapentin and pregabalin,10,11
antidepressants, as amitriptyline and nortriptyline12,13 and sero-
tonin-norepinephrine reuptake inhibitor antidepressant as dulox-
etine14,15 and milnacipran16 as well as compounds belonging to
different therapeutic classes.17,18
Pain relief continues to be an important medical and
community problem and millions of people worldwide use drugs
for different pain intensity. The identification of new analgesic
agents with limited side effects, as for acute and chronic pain, rep-
resents an important research field for pharmaceutical industry
and academic. In fact the two major classes of analgesic drugs,
the traditional non-steroidal anti-inflammatory drugs (NSAIDs)
and opioids, showed severe side effects.
NSAIDs, primarily used for the treatment of mild to moderate
inflammatory pain1 induce gastrointestinal lesions, such as
ulcerations and perforations, nephrotoxicity and inhibition of pla-
telet aggregation.2 Development of potent and selective COX-2
inhibitors3 only partially solved the problem, since recent studies
correlated the use of these inhibitors with an elevated risk of acute
myocardial infarction.4,5 On the other hand, the clinical use of opi-
oid, for moderate to severe pain, is associated with very strong and
use-limiting side effects, including respiratory depression, consti-
pation, tolerance and physical dependence.6
Our studies in the field of analgesic agents let us to identify a
large number of potent compounds, with pyridazine scaffold19–28
and the most interesting term is ET1 (Fig. 1), belonging to the ser-
ies of arylpyperazinylalkyl pyridazinones.28 It results a potent and
orally active antinociceptive agent showing an ED50 = 0.5 mg/kg in
the hot plate test and a comparable activity in the tail flick test
(ED50 = 0.8 mg/kg). The adrenergic system is involved in the
analgesic activity of ET1 as demonstrated by its ability to act as
a
2AR agonist.28 Recent studies show its activity in a model of
A particular search field regards compounds active on neu-
ropatic pain, which is often resistant to conventional analgesic
peripheral neuropathy (data not shown).
We report here the synthesis and the antinociceptive evaluation
of a series of pyridazinones derivatives as elaboration of the lead
ET1. At the same time, we designed and synthesized new
compounds bearing an arylpiperazinyl moiety linked to different
heterocyclic system through alkyl chains.
⇑
Corresponding author. Tel.: +39 055 4573682.
E-mail address: mariapaola.giovannoni@unifi.it (M.P. Giovannoni).
http://dx.doi.org/10.1016/j.bmc.2015.08.043
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

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C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
Figure 1.
secondary alcohols (4a–g, 4d28), which finally were transformed
2. Chemistry
into the final 4-amino-5-vinyl derivatives 5a–g (5d28) with poly-
phoshoric acid (PPA) (5a–e, 5g) or with sulfuric acid adsorbed on
silica gel (5f). The vinyl group of 5d was further reduced with Parr
instrument to afford compound 6.
All new compounds were synthesized as reported in Schemes
1–4 and the structures were confirmed on the basis of the analyt-
ical and spectral data.
In Schemes 2 and 3 are depicted the synthesis of ET1 analogues
bearing a different N-2 basic side chain with respect to lead compound.
In Scheme 2 compounds 8a–c were obtained from 4-amino-
5-acetylpyridazinone 2d,29 following two different procedures: a
direct alkylation of 2d with 1-(3-bromopropyl)-4-(4-fluo-
rophenyl)piperazine24 in anhydrous DMF and K2CO3 at room tem-
perature, for 8a, or through the synthesis of N-butylbromide 7
followed by condensation with the appropriate R-arylpiperazine
for 8b,c. Final compounds 10a–c were then obtained following
the same synthetic procedure described in Scheme 1.
Scheme 1 shows the synthetic pathway affording the final com-
pounds 5a–g (5d28, alias ET1) and 6, in which we reported modifi-
cations at position 5 or 6 of lead ET1. The 4-amino-5-acyl
derivatives 2a–g (2d–g29,30) were obtained starting from isoxa-
zolo[3,4-d]pyridazinones 1a–g30–32 by reductive cleavage with
ammonium formate and Pd/C and represent the key intermediates
of the reported synthetic pathway. The alkylation of 2a–g with
1-(3-bromopropyl)-4-(p-tolyl)-piperazine28 under standard condi-
tions afforded compounds 3a–g (3d28) which were reduced with
sodium borohydride in methanol to give the corresponding
Scheme 1. Reagents and conditions: (a) 10% Pd/C, HCOONH4, EtOH abs, reflux, 2 h; (b) 1-(3-bromopropyl)-4-(p-tolyl)-piperazine, K2CO3, anhydrous DMF, rt, 16 h; (c) NaBH4,
anhydrous MeOH, rt, 1 h; (d) for 5a–e and 5g: PPA, 90 °C, 5 h; for 5f: H2SO4 on silica gel, anhydrous toluene, 40–50 °C, 5 h, then rt, 16 h; (e) 10% Pd/C, EtOH abs, H2, Parr,
60 PSI, 5 h.

C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
6239
Scheme 2. Reagents and conditions: (a) 1-(3-bromopropyl)-4-(4-fluorophenyl)piperazine, K2CO3, anhydrous DMF, rt, 12 h; (b) 1,4-bromobutane, K2CO3, anhydrous, DMF, rt,
3 h; (c) appropriate R-arylpiperazine, K2CO3, anhydrous DMF, rt, 18 h; (d) NaBH4, anhydrous MeOH, rt, 5–20 min; (e) PPA, 70 °C, 3 h.
Further modifications of the side chain are reported in Scheme 3.
The basic fragment 13, 16 and 18 were prepared by condensing
1,3-dibromopropane or 1-bromo-3-chloro-2-methylpropane with
appropriate substituted-arylpiperazine 12, 15 and 17 in anhydrous
acetone and K2CO3 at room temperature (part 1). Compounds 11,
12, 14 and 15 are commercially available, while compound 17
was synthesized following the procedure reported in leterature.33
Fragment 13, 16 and 18 were then used for the synthesis of the
final compounds 21a–c in the same conditions described in
Scheme 1 (part 2).
Finally, in Scheme 4 is represented the synthetic pathway
affording the final compounds 24a–e, 27a–e and 30a–c,
characterized by a different heterocyclic scaffolds. The starting
compounds 2234, 25, commercially available, and 2835 undergo
to the usual synthetic route to give the desired compounds of type
24, 27 and 30.
presence of a butyl group (5c) unexpectedly determined an inter-
esting antinociceptive effect with an appreciable reduction of con-
striction at 20 and 40 mg/kg.
The effects of the elongation of the vinyl group at position 5 was
also studied: substitution of a hydrogen at b-carbon with a methyl
group (compound 5e) afforded a potent antinociceptive agent able
to reduce for 44% and 63% the abdominal constrictions at 20 and
40 mg/kg, respectively therefore with an activity comparable to
lead ET1. Further lengthening (compounds 5f and 5g) clearly
suggested that position 5 shows specific requirements of steric
hindrance as demonstrated by the progressive decrease of potency
of compounds 5f and 5g.
Finally, the 5-acyl 3a, 3d–g and 5-ethyl derivatives 6 were
synthesized as metabolically more stable homologues of lead
ET1. In any case, these modifications led to compounds less potent
then ET1 and in the series of 4-acyl derivatives, it is possible to
observe a trend similar to vinyl derivatives since antinociceptive
activity decreases moving from 3d (5-COCH3) to 3g (5-COC4H9).
In Table 2 was reported the antinociceptive activity of ET1
derivatives modified at the arylpiperazinylalkyl chain at position
2. All compounds were less active (10a and 21c) or completely
inactive (10c and 21b) than the reference compound. Only deriva-
tives 10b and 21a, at 30 mg/kg per os showed an appreciable
antinociceptive activity reducing by 42% and 47%, respectively,
the number of abdominal constrictions. These data indicated that
the best arrangement for the basic side chain is represented by
3. Biological results and discussion
The antinociceptive activity of the new products was evaluated
per os in the experimental model of the abdominal constriction
test36 and data are reported in Tables 1–3 in comparison with that
of lead, compound ET1.
Starting from the modification at position 6 of ET1 (Table 1,
compounds 5a–c) the replacement of CH3 with C2H5 (5a) or C3H7
(5b) was associated with complete a loss of activity, whereas the

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C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
Scheme 3. Reagents and conditions: (a) K2CO3, anhydrous acetone, rt, 3–16 h; (b) for 19a: K2CO3, anhydrous DMF, 70 °C, 12 h; for 19b,c: K2CO3, anhydrous DMF, rt, 16 h; (c)
NaBH4, anhydrous MeOH, rt, 10 min–1 h; (d) PPA, 70–90 °C, 3–5 h.
the sequence p-tolyl-pyperazinyl-alkyl where the alkyl linker
–(CH2)3– (ET1) is the best, but can be homologated to –(CH2)4–
(10b) or branched (21). All other modifications such as substitution
of the p-CH3 group with a fluorine (10a) or the enlargement of
piperazine to homopiperazine (21c) was detrimental for activity.
Finally, in order to evaluate the role of the pyridazinone scaf-
fold, we synthesized a new series of compounds in which appropri-
ate propylpiperazinylaryl chains were inserted in different
heterocycles (Table 3). In the subseries of pirazoles (24a–e), the
most interesting compounds resulted derivatives 24a and 24e

C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
6241
Scheme 4. Reagents and conditions: (a) 1,3-dibromopropane, K2CO3, anhydrous DMF; for 23, 29: rt, 1–5 h; for 26: rt, 20 h, then 60 °C, 3 h; (b) R-arylpiperazine, K2CO3,
anhydrous DMF, rt–60 °C, 20–24 h.
Table 1
Antinociceptive effect of final compounds in the Writhing Testa
CH3
N
N
N
(H2C)3
N
O
R6
H2N
R5
3a, 3d-g, 5a-c, 5e-g, 6
Compound
CMC
R5
R6
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
30.2 1.3
% rid n° constrictions
23
5a
CH = CH2
C2H5
7
9
5
10
10
20
40
33.4 2.1
32.1 3.1
21.6 3.0*
34.0 2.6
0
0
28
40 + yohimbine
5b
5c
CH = CH2
CH = CH2
C3H7
C4H9
6
7
6
7
10
20
40
29.4 3.5
28.2 3.7
23.6 3.1^
31.9 3.4
3
7
22
40 + yohimbine
6
6
7
8
10
20
40
33.1 2.2
17.9 2.6*
15.6 2.7*
29.8 3.5
0
41
48
20 + yohimbine
(continued on next page)

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C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
Table 1 (continued)
Compound
R5
R6
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
% rid n° constrictions
5e
5f
CH = CH-CH3
CH3
5
6
8
8
10
20
40
33.1 3.3
16.8 2.8*
11.3 2.5*
27.4 3.0
0
44
63
20 + yohimbine
CH = CH-C2H5
CH = CH-C3H7
COCH3
CH3
CH3
C2H5
5
6
6
6
10
20
40
28.8 3.0
19.6 2.8*
16.7 2.6*
30.3 3.0
5
35
45
20 + yohimbine
5g
3a
5
6
6
8
10
20
40
31.6 2.6
25.3 2.3
19.3 2.8*
29.1 3.1§
0
16
36
40 + yohimbine
6
6
6
9
10
20
40
27.3 3.1
17.6 2.5*
17.9 3.1*
28.5 2.3
10
42
41
20 + yohimbine
3d28
3e
COCH3
CH3
CH3
6
6
6
10
30
24.4 3.1^
16.2 2.5*
29.7 2.6
19
46
30 + yohimbine
COC2H5
8
8
8
10
10
20
40
27.5 3.0
18.2 2.7*
21.3 2.5*
31.9 3.3
9
40
29
20 + yohimbine
3f
3g
6
COC3H7
COC4H9
CH2CH3
CH3
CH3
CH3
7
7
6
8
10
20
40
30.3 2.8
22.7 3.3*
20.5 3.1*
28.9 2.0
0
25
32
20 + yohimbine
6
6
8
9
10
20
40
27.9 2.5
23.2 3.0*
25.6 2.9*
31.6 2.2
8
23
15
20 + yohimbine
7
6
6
10
30
23.2 2.9*
16.7 2.3*
30.5 3.1
23
45
30 + yohimbine
6
6
6
6
10
30
40
20.2 3.3^
12.4 3.1*
33
59
65
N
N
(H2C)3
N
CH3
10.6 2.7*
29.1 2.9
N
40 + yohimbine
O
CH3
H2N
CH=CH2
ET1
a
^
*
§
All drugs were administrated per os 30 min before test.
P <0.05.
P <0.05 in comparison with CMC-treated mice.
Versus the corresponding Ai-compound.
Table 2
Antinociceptive effect of final compounds in the Writhing Testa
basic side chain
N
N
O
CH3
H2N
CH=CH2
10a-c, 21a-c
Compound
CMC
Basic side chain
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
30.2 1.3
% rid n° constrictions
23
6
6
6
10
30
30.4 2.5
21.8 2.1*
29.1 2.9
0
28
10a
(H2C)3
N
N
F
30 + yohimbine

C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
6243
Table 2 (continued)
Compound
Basic side chain
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
% rid n° constrictions
7
7
7
10
30
29.3 2.9
17.4 2.8*
28.5 2.6
3
42
10b
10c
(H2C)4
(H2C)4
N
N
CH3
30 + yohimbine
6
6
10
30
NA
NA
N
N
C2H5O
N
5
6
6
10
30
25.1 2.6^
15.9 2.7*
28.8 3.1
17
47
N
CH3
21a
21b
30 + yohimbine
6
6
10
30
NA
NA
Cl
F
(H2C)3
(H2C)3
N
N
N
O
7
8
7
8
10
20
40
31.3 2.3
27.1 2.5
0
10
31
N
CH3
21c
20.8 3.0*
30.5 2.8
40 + yohimbine
6
6
6
6
10
30
40
20.2 3.3^
12.4 3.1*
33
59
65
N
N
(H2C)3
CH3
10.6 2.7*
29.1 2.9
N
N
40 + yohimbine
O
CH3
H2N
CH=CH2
ET1
a
^
*
All drugs were administrated per os 30 min before test.
P <0.05.
P <0.05 in comparison with CMC-treated mice.
Table 3
Antinociceptive effect of final compounds in the Writhing Testa
R3,4
N
N
Het
24a-e, 27a-e, 30a-c
Compound
CMC
Het
R3,4
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
31.5 1.8
% rid n° constrictions
29
7
9
8
10
20
40
28.5 2.5
22.6 2.7*
9
28
51
15.4 3.0*
28.7 3.2§
CN
CH3
24a
24b
24c
4-F
10
40 + yohimbine
N
N
N
N
N
N
7
11
8
20
40
32.5 3.0
24.1 2.7^
0
23
32.6 2.9§
CN
CH3
40 + yohimbine
3-Cl
8
8
8
8
10
20
40
31.6 3.3
24.9 3.2^
0
21
34
20.8 2.5*
27.8 2.1§
CN
CH3
3-OCH3
20 + yohimbine
(continued on next page)

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C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
Table 3 (continued)
Compound
Het
R3,4
N° mice
Treatment (mg kgÀ1
)
Abdominal constrictions
% rid n° constrictions
8
8
8
10
20
40
33.2 3.0
25.8 3.0^
0
8
30
21.9 3.3*
29.3 2.7§
CN
CH3
24d
24e
4-CH3
10
20 + yohimbine
N
N
N
N
8
7
8
10
20
40
32.7 2.5
24.9 3.1
0
21
49
16.2 3.2*
28.2 2.6§
CN
CH3
4-NO2
10
40 + yohimbine
8
7
12
9
10
20
40
32.7 2.6
26.3 2.5
0
16
38
27a
27b
27c
27d
27e
4-F
19.5 2.1*
31.5 2.7§
COCH3
COCH3
COCH3
COCH3
COCH3
Ph
N
40 + yohimbine
8
8
9
10
20
40
30.6 2.7
18.7 2.9*
3
41
54
3-Cl
N
N
N
N
14.5 2.6*
32.1 3.0§
10
20 + yohimbine
9
8
8
9
10
20
40
31.6 2.9
23.4 3.1^
0
26
52
3-OCH3
4-CH3
4-NO2
15.2 2.8*
30.8 2.7§
40 + yohimbine
8
8
8
10
20
40
80
27.8 3.1
29.3 2.5
28.6 2.9
30.2 3.5
12
7
9
4
10
9
8
10
20
40
80
27.9 3.0
33.7 2.5
28.8 2.6
11
0
9
O
8
8
8
8
10
20
40
27.2 3.1
27.8 2.6
14
12
34
20.8 3.0*
33.4 3.5§
30a
30b
4-F
O
O
O
N
N
N
40 + yohimbine
O
O
6
8
8
8
10
20
40
29.4 3.0
21.8 2.6*
7
31
38
19.5 3.5*
29.3 2.7§
3-Cl
Ph
Ph
20 + yohimbine
6
8
8
10
20
40
29.1 2.6
23.5 2.8^
8
25
39
19.3 2.9*
29.6 3.0§
30c
3-OCH3
10
20 + yohimbine
6
6
6
6
10
30
40
20.2 3.3^
12.4 3.1*
33
59
65
N
N
(H2C)3
CH3
10.6 2.7*
29.1 2.9
N
N
40 + yohimbine
O
CH3
H2N
CH=CH2
ET1
a
^
*
§
All drugs were administrated per os 30 min before test.
P <0.05.
P <0.05 in comparison with CMC-treated mice.
Versus the corresponding Ai-compound.
bearing a fluorine and a nitro group in para position of the side
chain: these compounds at 40 mg/kg reduced by 51% and 49%,
respectively, the number of abdominal constriction and retain a
weak antinociceptive activity at 20 mg/kg. On the contrary, the
introduction of a methyl in para position of the basic side chain
(compound 24d) was associated with reduced activity (30% of inhi-
bition at 40 mg/kg). In addition, compounds 24b and 24c, bearing a
chlorine or a methoxy group in meta position, showed a very low
activity.
In the series of pyrrolo derivatives 27a–e, we observe an
opposite trend of activity since the most active compounds
resulted 27b and 27c (54% and 52% of inhibition at 40 mg/kg,
respectively) bearing in the side chain respectively a 3-Cl and a
3-OCH3 group. As in the pyrazole series, the insertion of a methyl
in para position led to the loss of activity (compound 27d) as well
as compounds 27a and 27e.
Finally, the oxazolonic derivatives showed a weak antinocicep-
tive activity (34–39% of inhibition at 40 mg/kg) regardless of the

C. Vergelli et al. / Bioorg. Med. Chem. 23 (2015) 6237–6245
6245
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for activity and only few compounds induced an appreciable
reduction of abdominal constriction (about 50% at 40 mg/kg).
Finally, it’s important to highlight that the antinociception of all
tested compounds was completely prevented by pretreatment
with the a2-antagonist yohimbine, confirming the involvement of
the adrenergic system in the mechanism of action also for these
new products.
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In conclusion, we synthesized new antinociceptive agents with
an appreciable activity in the Writhing Test. The most interesting
terms are able to reduce the abdominal constrictions by more
than 50% when administered per os at the doses of 40 mg/kg
(5e, 24a, 27b and 27c). The chemical manipulation confirmed the
importance of the basic side chain whose requirements seem to
be different depending on the heterocyclic scaffold bearing it. As
regard the heterocyclic nucleus, results demonstrated that the
pyridazinone ring, widely investigated by us, could be replaced
with 5-member nitrogen heterocycles, retaining
a similar
antinociceptive activity. For all new compounds, independently
from the structure, the involvement of the adrenergic system in
the mechanism of antinociception was proved, since the analgesia
of tested products was completely reverted by pretreatment with
a2-antagonist yohimbine.
Supplementary data
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Supplementary data (synthetic routes and spectroscopic data of
all new compounds synthesized and biological procedures) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmc.2015.08.043.
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