Synthesis and local anesthetic activity of fluoro-substituted imipramine and its analogues

Article abstract of DOI:10.1016/j.bmcl.2007.04.025

A series of fluoro-substituted imipramines and its analogues, 6a-6e, were synthesized and evaluated for their in vitro local anesthetic activity. Compound 6b was found to have potency, onset, and duration of action comparable to those of lidocaine (lidocaine hydrochloride, CAS:6108-05-0). Dissociation constants (pK_a) of these compounds have been determined to be 7.6-7.9.

Full text of DOI:10.1016/j.bmcl.2007.04.025

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3733–3735
Synthesis and local anesthetic activity of
fluoro-substituted imipramine and its analogues
a,b
Wen Li and Qidong You
a,
*
a
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
b
School of Chemical Engineering, Zhengzhou University, Zhengzhou 450002, PR China
Received 2 December 2006; revised 23 March 2007; accepted 6 April 2007
Available online 10 April 2007
Abstract—A series of fluoro-substituted imipramines and its analogues, 6a–6e, were synthesized and evaluated for their in vitro local
anesthetic activity. Compound 6b was found to have potency, onset, and duration of action comparable to those of lidocaine (lido-
caine hydrochloride, CAS:6108-05-0). Dissociation constants (pK
Ó 2007 Elsevier Ltd. All rights reserved.
a
) of these compounds have been determined to be 7.6–7.9.
Local anesthetics interrupt conduction of neural mes-
sages in sensory, motor, and autonomic nerves. They
prevent both the generation and conduction of the nerve
impulse in a circumscribed area by binding to the so-
dium channel and blocking sodium entry into neuron.
Five fluoro-substituted imipramines and its analogues
which were mainly modified at positions 3 and 7 with
two fluorines on phenyl ring and different substitutions
on the amines were designed and synthesized. Their
in vitro local anesthetic activity was evaluated by sciatic
nerve block.
Tri-cyclic antidepressants (TCAs) have been widely used
in treating major depressive disorders. Recent studies
further demonstrated that TCAs have potent sodium
The target compounds 6a–6e were prepared as shown in
Scheme 1.
1
–6
channel blocking effect.
5
than that of bupivacaine at 15.4 mM (0.5%). About
0 new substituted local anesthetics where the benzene
For example, imipramine at
mM elicited a longer complete sciatic nerve blockade
4-Fluoro-2-nitro-toluene was condensed with each other
in the presence of sodium methoxide in petroleum ether
7
0
5
at 5–15 °C to give the 4,4 -difluoro-dinitrodibenzyl (2) in
ring is substituted by fluorine in the o-, m-, and p-posi-
tions were synthesized in our previous work. Some of
these compounds exhibited infiltration and surface local
anesthetic actions, and the potency was higher than that
of lidocaine. When fluorine is at position 1 of the phenyl
ring, amitriptyline exhibits substantially increased anti-
depressant activity and significantly decreased anticho-
a yield of 72%. It was reduced to give compound 3 in
ethanol at 60 °C by Fe powder as reductive agent under
acidic condition in a yield of 76%. The compound 3 was
condensed at 290 °C for 1 h to obtain compound 4 in a
yield of 5%. Other resultants were removed by tritur-
ation of the reaction mixture between petroleum ether
and water. Treatment of 4 with NaNH in refluxing tol-
2
8
linergic toxicity. So far, there were no reports about
uene, followed by the addition of N,N-dimethyl-3-chlo-
ride propylamine with further refluxing, gave compound
5 in a yield of 67%. An excess of reactant was removed
using column chromatography on silica gel. Compound
5 was dissolved in anhydrous ether and dried gas of
hydrogen chloride was added at rt for 5 min, 5 was
the change of the sodium channel blocking effect of fluo-
rine substituted amitriptyline. The biological properties
of fluoro-TCAs raised our interest to focus on their der-
ivations as potential long-acting local anesthetics.
9
10
transformed into 6a. Compounds 6b–6e were pre-
pared by following the same procedure as shown in
Scheme 1.
Keywords: Fluoro-substituted imipramine; Local anesthetic activity;
Synthesis; Dissociation constants; Lidocaine.
3,7-Difluoro-10,11-dihydro-5H-dibenz[b,f]azepine (com-
pound 4) was the key intermediate. The parent 10,11-
dihydro-5H-dibenz[b,f]azepine was first synthesized in
*
Corresponding author. Tel./fax: +86 25 83271351; e-mail addresses:
liwen@zzu.edu.cn; youqidong@gmail.com
0
960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.025

3734
W. Li, Q. You / Bioorg. Med. Chem. Lett. 17 (2007) 3733–3735
CH
3
i
ii
iii
iv
NO
2
F
F
F
F
N
H
F
F
N
F
F
F
NH2
NO
2
NH2
NO
2
X
1
2
3
4
5
a-5e
5
e
5
a
5b
5c
5d
v
F
N
F
X
.HCl
CH
3
2 5
C H
X=
N
N
N
N
N
O
CH
3
2 5
C H
6
a-6e
Scheme 1. Synthesis procedure for compounds 5a–5e. Reagents and conditions: (i) CH
1
3
ONa, 5–15 °C, 4–5 h; (ii) Fe/HCl, 60–70 °C, 3 h; (iii) 290 °C,
2 2 2 2 1 2
h; (iv) NaNH /ClCH CH CH NR R , 110 °C, 12 h; (v) HCl, rt, 5 min.
1
1
1899 by Thiele and Holzinger and since then many
substituted 10,11-dihydro-5H-dibenz[b,f]azepines have
All target compounds 6a–6e were evaluated for their lo-
1
cal anesthetic effects of sciatic nerve block in toads.
8–20
1
2
been prepared. The derivatives have been made either
directly by substitution reactions on the parent unsubsti-
tuted tricycle or by ring synthesis starting from substi-
tuted synthons. Most direct substitution reactions, for
Electrophysiological experimental data were obtained
on Doctor-95 Super Lab (Jingsu Medicine technological
institute). All of the experiments were performed with
wild adult toads (two available isolated sciatic nerves
of one toad). Lidocaine (lidocaine hydrochloride,
CAS: 6108-05-0) was obtained from Shanghai Xidi Bio-
tech. Co., Ltd and was used after dissolving in Ringer’s
1
3
14
example, nitration, bromination and Friedel-Crafts
1
5
acylation, are possible, but in general proceed in low
yields and either give mixtures of regioisomers or limit
to only one accessible position on the ring system. Ring
synthesis of 10,11-dihydro-5H-dibenz[b,f]azepines has
2
1
solutions. Experimental data and results are summa-
rized in Table 1.
1
6
been approached in a few different ways. All methods
require relatively harsh conditions or inconvenient mul-
ti-steps with very low yields. We obtained compound 4
by only three steps from 4-fluoro-2-nitro-toluene
through the ring synthesis method which differs from
the methods mentioned above. The yield of the key step
is only 5% because the great mass of reactant was car-
bonized at the reactive temperature. Compound 4 was
dissolved in petroleum ether while the carbonizations
did not, so carbonizations could be easily removed by
the trituration of the reaction mixture between petro-
leum ether and water conveniently. A facile, flexible,
and easily accessible synthetic route toward 3,7-diflu-
oro-10,11-dihydro-5H-dibenz[b,f]azepine is still under
investigation.
The new compounds increased the ED50 (%) to the
electric stimuli applied on the injected area with value
ranging between 0.018 and 0.094. Under the same
conditions lidocaine had an effect equal to 0.019.
The analysis of the results showed that the most active
compound which produced an effect versus lidocaine
hydrochloride was 6b with 105.5. Its analogues 6d,
6e also exhibited significant efficacy with 48.7 and
65.5, respectively. Compounds 6a and 6c (20.2,27.5)
were less effective than lidocaine. The latent period
of these compounds was 30.7–40.6 min, which were
very close to that of lidocaine (37.2 min) at the same
test conditions.
Structurally, the most active compound was character-
ized by the presence of the diethyl amine group on the
side chain. The least active compound 6a had 20.2 of
the lidocaine action, which possesses the dimethyl amine
group. The side chain of compounds 6c, 6d, and 6e was
tetrahydropyrrolyl, piperidino, and morpholine group,
respectively.
Dissociation constant (pK ) is an important physico-
a
chemical parameter for local anesthetic. Most of the
clinically useful local anesthetics have pKa values of
7
.5–9.0. This implies that compounds with pK values
a
below 7.0 are not sufficiently ionized at physiological
pH to be effective in bringing about anesthesia even
though they can penetrate the axon. In contrast, drugs
with pK values above 9.5 are almost fully ionized at
a
To summarize, a series of fluoro-substituted imipram-
ines and its analogues, 6a–6e, were synthesized and eval-
physiological pH. Consequently, these drugs are less
effective because they have difficulty in penetrating the
cell membrane. The pKa values of these compounds
have been determined by potentiometric titration meth-
Table 1. Sciatic nerve block activities of compounds 6a–6e
1
7
Compound ED50 (%) Latent Effect versus
period (min) lidocaine 0.019 = 100
od. A graph was plotted for volume of hydrochloric
acid added versus pH of the solution. The dissociation
constant (pK ) values were obtained from the pH at half
a
6a
6b
6c
0.094
0.018
0.069
0.039
0.029
0.019
30.7
38.2
40.6
39.8
37.3
37.2
20.2
105.5
27.5
48.7
65.5
100
neutralization point of the titration curves. The pK of
a
compounds 5a–5e obtained from this method were 7.7,
6
d
7.7, 7.9, 7.6, and 7.6, respectively. This means com-
pounds 5a–5e have the appropriate pK values for use
as potent Na-channel blockader.
6e
Lidocaine
a

W. Li, Q. You / Bioorg. Med. Chem. Lett. 17 (2007) 3733–3735
3735
uated for their in vitro local anesthetic activity. The
compounds 6a–6e were obtained starting from 4-flu-
oro-2-nitro-toluene. The in vitro local anesthetic activity
was evaluated by sciatic nerve block. Dissociation con-
J = 6.5 Hz, 1-NCH
ArH), 7.18 (2H, m, ArH). Compound 6c: (CD
2
), 6.76 (2H, m, ArH), 6.99 (2H, m,
3
OD) d 2.02
0
0
(
CH
2H, m, 2-CH ), 2.06 (2H, m, 2 -CH ), 2.15 (2H, m, 3 -
2
2
0
2
), 3.16 (2H, m, 4 -CH
2
N), 3.28 (4H, m, ArCH
0
2
–), 3.35
), 3.86 (2H, t,
(2H, m, 3-CH
J = 7 Hz, 1-NCH
2
N), 3.36 (2H, m, 1 -NCH
2
stants (pK ) of these compounds have been determined
a
2
), 6.76 (2H, m, ArH), 6.97 (2H, m,
to be 7.6–7.9. These compounds have different degrees
of local anesthetic action. Compound 6b was found to
have potency, onset, and duration of action comparable
to those of lidocaine. The new compound 6b may de-
serve further evaluation as potential local anesthetic.
ArH), 7.16 (2H, m, ArH). Compound 6d: (CD OD) d 1.22
3
0
0
0
(
2H, m, 3 -CH
CH ), 2.07 (2H, m, 2-CH
2
), 1.77 (2H, m, 2 -CH
2
), 1.91 (2H, m, 4 -
0
2
2
), 2.90 (2H, m, 5 -CH
2
N), 3.10
0
(2H, m, 1 -CH N), 3.18 (4H, m, ArCH –), 3.35 (2H, m, 3-
2
2
CH N), 3.86 (2H, t, J = 7 Hz, 1-NCH ), 6.76 (2H, m,
2
2
ArH), 6.97 (2H, m, ArH), 7.16 (2H, m, ArH). Compound
e: (CD OD) d 2.00 (2H, m, 2-CH ), 3.05 (6H, m, 3-
CH N, 1 -NCH , 5 -CH N), 3.18 (4H, m, ArCH ), 3.65
6
3
2
0
0
Acknowledgments
2
2
2
2
0
(
2H, m, 2 -CH
0
2
O–), 3.80 (2H, t, J = 7 Hz, 1-NCH
2
), 3.97
(
ArH), 7.10 (2H, m, ArH).
2H, m, 4 -CH
2
O–), 6.70 (2H, m, ArH), 6.90 (2H, m,
This work was supported by a grant from Jiangsu Hen-
grui Pharmaceutical Com. Ltd. The authors are grateful
to Dr. J. H. Fu (Pharmaceutical School, China Pharma-
ceutical University) for the determination of biological
activity.
1
1
1
1. Thiele, J.; Holzinger, O. Liebigs Ann. Chem. 1899, 305, 96.
2. Kricka, L. J.; Ledwith, A. Chem. Rev. 1974, 74, 102.
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4
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002, 96, 109.
2
2
0. Lee-Son, S.; Wang, H. K.; Concus, A. Anesthesiology
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992, 77, 324.
1. The regress equation of AP decreasing extent (%) and
compound concentration was y = blogx + a (y: AP
decreasing extent (%); x: drug concentration; a, b: regress
coefficient). The regress equation of latent period and
compound concentration was y = blogx + a (y: latent
period; x:drug concentration; a and b: regress coefficient).
The ED50 and latent time were calculated by these
equations.
. Compound 6a: (CD
0
3
OD) d 2.02 (2H, m, 2-CH
2
), 2.82 (6H,
s, 1 -NCH
CH N), 3.82 (2H, t, J = 7 Hz, 1-NCH ), 6.72 (2H, m,
3
), 3.18 (4H, m, ArCH
2
–), 3.32 (2H, m, 3-
2
2
ArH), 6.94 (2H, m, ArH), 7.13 (2H, m, ArH).
0
1
3
0. Compound 6b: (CD OD) d 1.22 (6H, t, J = 6.5 Hz, 2 -
0
CH ), 2.03 (2H, m, 2-CH ), 3.14 (4H, m, 1 -NCH ), 3.18
3
2
2
(
4H, m, ArCH
2
–), 3.32 (2H, m, 3-CH
2
N), 3.88 (2H, t,