Antiarrhythmic agents based on diterpenoid alkaloid lappaconitine. Protonation of N-deacethyllappaconitine in methanol solutions

Article abstract of DOI:10.1007/s11172-020-2800-0

The data on antiarrhythmic drugs based on diterpene alkaloid lappaconitine are summarized. N-Deacetyllappaconitine is the main metabolite of allapinin and a potential antiarrhythmics for intravenous use. The basicity of two nitrogen atoms of this compound and the possibility of obtaining mono- and di-salts with the example of hydrochlorides and hydrobromides having good solubility in water have been studied. It was shown using NMR spectroscopy and potentiometric titration that in the methanolic solutions the atom N(20) is protonated at the first step (pK_b1 = 6.77, 25 °C) in the pH range of 6—7. The nitrogen of the primary aromatic amino group is protonated in the pH range of 2—3 (pK_b2 = 2.18, 25 °C).

Full text of DOI:10.1007/s11172-020-2800-0

Russian Chemical Bulletin, International Edition, Vol. 69, No. 3, pp. 567—571, March, 2020
567
Antiarrhythmic agents based on diterpenoid alkaloid lappaconitine.
Protonation of N-deacethyllappaconitine in methanol solutions
a
a
a
a
a
A. A. Akhiyarov, A. N. Lobov, S. P. Ivanov, L. V. Spirikhin, T. M. Gabbasov,
a
b
b
b
a
E. M. Tsyrlina, N. V. Valiev, A. Z. Sadikov, Sh. Sh. Sagdullaev, and M. S. Yunusov
aUfa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences,
7
1 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6066. Е-mail: msyunusov@anrb.ru
b
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan,
7
7 M. Ulugbek ul., 700170 Tashkent, Republic of Uzbekistan.
Fax: +9 (9871) 120 6475
The data on antiarrhythmic drugs based on diterpene alkaloid lappaconitine are summarized.
N-Deacetyllappaconitine is the main metabolite of allapinin and a potential antiarrhythmics
for intravenous use. The basicity of two nitrogen atoms of this compound and the possibility
of obtaining mono- and di-salts with the example of hydrochlorides and hydrobromides having
good solubility in water have been studied. It was shown using NMR spectroscopy and poten-
tiometric titration that in the methanolic solutions the atom N(20) is protonated at the first step
(
pKb1 = 6.77, 25 C) in the pH range of 6—7. The nitrogen of the primary aromatic amino group
is protonated in the pH range of 2—3 (pKb2 = 2.18, 25 C).
Key words: diterpene alkaloids, lappaconitine, antiarrhythmics, N-deacetyllappaconitine,
drug, stepwise protonation, salt formation.
Alkaloid lappaconitine (1) was isolated from the plant
1
Aconitum septentrionale in 1895 by Rosendahl. Its struc-
ture was established at the beginning of the 70th of the
past century.2 It was established in the course of the
study of the pharmaco-toxicological properties of com-
—6
7
,8
pound 1 that it possesses arrhythmogenic, analgesic,
9
and locally anesthetizing properties. Its antiarrhythmic
action was revealed in the late 70th.10
Hydrobromide of lappaconitine is introduced into
medical practice as an antiarrhythmic agent under the
name of allapinin in 1987.1
0—13
The drug is included in
the list of the most vitally important medicines ap-
proved by the Ministry of Health of the Russian Fede-
ration. It is one of the most effective in the treatment of
life-threatening forms of arrhythmias, namely, atrial fibrilla-
tion (AF) and ventricle rhythm disorders.14 The substance
of the allapinin drug is fabricated at the experimental
production plant of the S. Yu. Yunusov Institute of the
Chemistry of Plant Substances, Academy of Sciences of
the Republic of Uzbekistan (Tashkent), and the pharma-
ceutical form (pills) is manufactured by VILAR Pharm-
center (Moscow). The prolonged pharmaceutical form is
also produced by VILAR Pharmcenter under the name of
allaforte.1 The medication aklezin, namely, the mixture
of alkaloids from the overground part of the plant Aconitum
Leucostomum Worosch, is also authorized for use as the
antiarrhythmic agent.16 The main component of aklezin
is lappaconitine.
R = COMe (1), H (2)
Revealed dependence of antiarrhythmic activity on the
peculiarities of the structure allowed to carry out a directed
synthesis of a series of new active compounds on the basis
1
7,18
of diterpene alkaloids.
At present, antiarrhythmic drugs amiodarone, diso-
pyramide, flecainide, propafenone, and sotalol are used
to control the heart rhythm in patients with AF in Europe.
Dofetilide is used for these purposes in the United States.
The medications of 1C class, namely, ethacizine, niferidil,
and allapinin, are available in Russia in addition to amio-
5
1
9,20
darone, sotalol, and propafenone.
The use of allapinin is often complicated by a number
of side effects limiting its application. It is established that
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0567—0571, March, 2020.
066-5285/20/6903-0567 © 2020 Springer Science+Business Media LLC
1

5
68
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 3, March, 2020
Akhiyarov et al.
these symptoms are caused by high concentrations of al-
lapinin in the blood plasma.21
which should be used, was not discussed, and physico-
chemical characterization has not been reported. To solve
this problem, we studied the basicity of two nitrogen atoms
and the possibility of obtaining mono- and di-salts.
A new drug based on lappaconitine was developed.
Its preclinical investigations were completed in the
course of the implementation of the State Contract
No. 14.N08.11.0068. Established concentration depen-
dencies of the action (dose-effect) of allapinin and the
new preparation on the sodium current and their efficiency
in the treatment of the heart arrhythmias testify that the
effective dose of the studied agent is in all cases lower by
a factor of 3—4 compared to lappaconitine hydrobromide.
In addition, the new drug does not possess the side effects
inherent to allapinin. Unlike the allapinin, the new agent
blocks not only sodium channels, but, in part, also potas-
Results and Discussion
The UV spectra of the methanolic solutions of com-
pound 2 at different pH were registered for the study of its
protonation. Three absorption maxima in the 220, 250,
3
2
and 340 nm regions, caused by the —*-transitions in
the anthranilic fragment, are observed in the UV spectra
at pH 7. The decrease in pH results in a batochromic shift
of maxima at 220 and 340 nm by 7—8 nm, which is prob-
ably caused by the redistribution of the electronic density
at protonation of the primary amino group of the anthra-
2
2—25
sium channels.
Allapinin is authorized for use in both pills and ampoule
injectable) form. However, intravenous application of
(
3
2,33
this drug did not find wide use because of the late appear-
nilic fragment of compound 2.
The most informative for the study of the protonation
2
6
ance of therapeutic effect and side cardiac effects.
1
13
15
N-Deacethyllappaconitine (2), the main metabolite of the
allapinin drug,2 is not inferior to allapinin by activity in
most types of arrhythmias, but it is less toxic, has greater
therapeutic breadth, and exceeds allapinin by the rapid
development of antiarrhythmic effect. However, it is in-
ferior to allapinin by prolongation of action.21 These data
allow us to suppose that compound 2 can serve as the
basis for the creation of a new effective antiarrhythmic
agent in an injectable form. The arsenal of such drugs in
medical practice is very limited.
process of compound 2 are the H, C, and N NMR
spectra obtained by the addition to the solution of 2 in
7
CD OD of one (3a) or two (4a) moles of HCl. Similar
spectra were recorded for the salts with HBr (3b and 4b,
3
respectively).
The most pronounced effect is observed in the 13C,
and 1 N NMR spectra. Thus, an addition of 1 mole of
acid leads to a high-field shift of N(20) atom signal
(N = +16.97 for 3a and N = +16.93 for 3b). A high-
field shift of the nitrogen atom signal of the aromatic amino
group (N = –9.30 for 4a and N = –11.84 for 4b) oc-
curs on the addition of another mole of the protonating
agent (HCl or HBr). At that the position of N(20) atom
5
N-Deacethyllappaconitine is rarely found in nature,
its reserves are very limited and completely insufficient for
the development of the drug. The lappaconitine (1) can
be the main source of compound 2. The lappaconitine is
widespread in nature, and compound 2 can be obtained
from compound 1 by acid hydrolysis. At the same time,
there are secondary products of the manufacture of the
drug allapinin, which can serve as the source of noticeable
amounts of compound 2. The work is already underway
in Uzbekistan to prepare compound 2 from the secondary
products of the preparation of the drug allapinin, and also
to create the intravenous form of this drug.28
3
4
signals is the same as for the salts 3a and 3b (Table 1,
Fig. 1). The observed change in the spectral pattern indi-
cates a significant difference in the basicity of the two
nitrogen atoms in compound 2 and stepwise protonation
of nitrogen atoms. Namely, at the first step, N(20) nitro-
gen is protonated, while at the second step, the nitrogen
of aromatic amino group С(2ʺ)—N is protonated.
The stepwise protonation of nitrogen atoms is also
13
confirmed by C NMR spectroscopy. At the first step,
A stable, water-soluble form of the medication, for
example, in the form of a salt, is necessary for the develop-
ment of a medicament for intravenous administration on
the basis of compound 2.
significant signal shifts are observed for the C(17), С(19),
3
4
С(21), and С(22) atoms. At the second step of proton-
ation, significant shifts of the atoms of the aromatic cycle
С(1ʺ—3ʺ), С(5ʺ) and ОСО-group (see Table 1, Figs 1, 2)
take place, which indicates the protonation of the primary
It should be noted that compound 2 in contrast to
lappaconitine contains in its structure two nitrogen atoms
having a basic character. One of them is represented by
a primary amino group in the anthranilic acid residue,
while the second one is a part of the piperidine cycle and
alkylated by an ethyl group. Accordingly, compound 2 is
capable of forming both mono- and di-salts. The possibil-
ity of using salts of N-deacethyllappaconitine for the
3
4
amino groups of the anthranil fragment.
The constants and thermodynamic characteristics of
the protonation of compound 2 in methanol were deter-
3
5
mined using a standard methodology (Table 2).
According to the results obtained, the protonation
constant (рК ) is 6.77 at 25 C, i.e. in methanol at this
b1
value of pH, a half of the molecules of compound 2 are in
the protonated form. The proton addition occurs at N(20)
atom according to NMR spectroscopy.
creation of medicines is declared in a number of publica-
tions.2
9—31
However, the nature of the salt, mono- or di-,

Antiarrhythmic agents
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 3, March, 2020
569
Table 1. Values of chemical shifts in 13C and 15N spectra of studied compounds (, СD OD)*
3
Atom
2
3а
3b
4а
4b









N(20)
C(2)—N
С(4)
41.05
61.53
58.02
62.91
+16.97
+1.38
+0.07
–0.35
+1.35
+1.16
+0.67
–2.82
–0.72
–0.68
–0.95
+0.67
+0.77
+1.04
–0.05
57.98
63.62
+16.93
+2.09
+0.05
–0.29
+1.56
+1.23
+0.71
–2.75
–0.48
–1.67
+0.53
+0.03
+0.70
–0.01
–0.11
58.09
52.23
+17.04
–9.30
+0.05
–0.30
+1.26
+0.82
+0.76
–2.81
–2.41
+7.79
–12.99
+5.71
+1.12
+9.56
+0.64
57.86
49.69
+16.81
–11.84
+0.03
–0.13
+1.53
+0.87
+0.83
–2.72
–2.56
+8.89
–14.26
+6.21
+1.22
+10.62
+0.88
83.80
83.87
83.85
83.85
83.83
C(11)
С(17)
С(19)
С(21)
C(22)
ОС(О)
С(1)
С(2)
С(3)
С(4)
С(5)
С(6)
52.29
51.94
52.00
51.99
52.16
62.33
63.68
63.89
63.59
63.86
57.15
58.31
58.38
57.97
58.02
49.96
50.63
50.67
50.72
50.79
13.66
10.84
10.91
10.85
10.94
168.71
112.37
152.68
117.84
134.87
116.56
132.19
167.99
111.69
151.73
118.51
135.64
117.60
132.14
168.23
110.70
153.21
117.87
135.57
116.55
132.08
166.30
120.16
139.69
123.55
135.99
126.12
132.83
166.15
121.26
138.42
124.05
136.09
127.18
133.07
*
 values correspond to the shifts of atom signals in compounds 3а,b and 4a,b relative to compound 2.
N(20)
N(20)
C(2)—N
C(2)—N
4
3
2
a
a
4b
N(20)
N(20)
C(2)—N
C(2)—N
3
2
b
N(20)
N(20)
C(2)—N
C(2)—N
6
5
60
55
50
45
40
35 30

65
60
55
50
45
40
35
30

Fig. 1. 15N-Projection of NMR spectra { H,15N} in HMBC experiment of compounds 2, 3а, 4а, 3b, and 4b in СD OD solution.
1
3
Figure 3 shows a plot of the change of pH of solution on
the ratio of molar concentrations of compound 2 and HCl.
It is evident that the protonation at the first step (at
the heterocyclic nitrogen) occurs at рН 6—7, while at the
second step (at the primary aromatic amino group) begins
at pH below 3.0, рKb2 consists of 2.18 at 25 C. Identical
value of рKb2 was obtained for aqueous solutions of an-
3
6
thranilic acid by spectrophotometric method.
Thermodynamic characteristics of the acid-base equi-
librium (see Table 2) show the energy disadvantage of
Fig. 2. Change of chemical shift in 13C and 15N spectra of compounds 3a and 4а in CD OD solution.
3

570
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 3, March, 2020
Akhiyarov et al.
Table 2. Constants and thermodynamic characteristics of protonation of compound 2 in CH O
3
Protonation step
I
Т/C
рКb
G298/kJ mol–1
H/kJ mol–1
S298/J (mol K)–1
15
6.92±0.11
6.77±0.07
6.59±0.06
6.30±0.08
38.6±0.8
35.6±0.9
–10.0±1.0
36.0±2.0
2
3
4
5
5
5
II
15
2.40±0.11
2.18±0.10
2.13±0.11
1.46±0.10
12.4±0.6
23.1±0.7
2
3
4
5
5
5
pH
Experimental
7
N-Deacethyllappaconitine (2) was prepared by hydrolysis of
6
5
4
3
2
1
37
lappaconitine according to a known procedure. M.p. 213—214 C,
20
[
]D +29.2 (c 0.9, CHCl ), physico-chemical characteris-
3
tics of the sample were identical to those described in the lit-
erature.
The value of рK of compound 2 was determined according
to the standard methodology by potentiometric titration in
a one-necked thermostated reactor (25 mL volume) with a reflux
condenser at four temperatures, namely, 15, 25, 35, and 45 C.
The temperature was maintained to within ± 0.1 C using
a LOIP LT-205 thermostate. The titration was carried out using
a pH-150MI pH-meter with a combined glass electrode ESK-
3
7,38
b
3
5
0
.4
0.8
1.2
1.6
CHCl/C2
Fig. 3. Dependence of change of pH in methanolic solution of
compound 2 on ratio CHCl/C2.
1
0307. The calibration of the electrode was carried out with the
help of standard buffer solutions. The ionic force was not taken
into account at the titrationic in methanol solutions. Methanol
for the gradient HPLC (99%, Akvametriya, Russia) was used as
a solvent. Due to low solubility of compound 2 in water, its solu-
tions for potentiometric titration were prepared in methanol
protonation of compound 2 in methanolic solutions.
+
Therefore, it is necessary to increase H concentration,
i.e. decrease a pH value for a shift of equilibrium to the
protonated form.
Thus, it was shown by NMR spectroscopy and poten-
tiometric titration that a stepwise protonation of nitrogen
atoms occurs in the interaction with strong acids (HCl
and HBr) in methanolic solutions of N-deacethyllappa-
conitine (2). At the first step, N(20) atom (рКb1 = 6.77,
–
1
with a concentration of 0.01 mol L as follows. Compound 2
0.2713 g) was placed in a 500 mL volumetric flask, then meth-
(
anol (100 mL) was added and the mixture was stirred until
complete dissolution. Afterwards, the methanol was added to
the label.
UV spectra of methanolic solutions of compound 2
–1
(
10–4 mol L ) at different pH were recorded using a Shimadzu
2
5 C) is protonated in methanolic solutions at рН 6—7,
while nitrogen of the aromatic primary amino group
рКb2 = 2.18, 25 C) is protonated at pH 2—3. Consequently,
UV-1800 spectrophotometer in a wavelength range of 200—400 nm.
The pH values were maintained by the small addition of HCl to
the initial methanol solution of compound 2. The dilution was
(
it is possible to obtain both mono- and di-salts by tuning
the pH value. Obtained results are undoubtedly important
for the creation of a medication on the basis of N-de-
acethyllappaconitine, since the antiarrhythmic action of
mono- and di-salts can be rather different.
It is known that the diterpene alkaloid lappaconitine
and the compounds obtained on its basis are included
in many drug formulations. Considering the availabil-
ity of lappaconitine and the widespread growth of Aconi-
tum leucostomum Worosch, A. septentrionale Koelle, and
A. sinomontanum Nakai plants, the basic sources of its
production, it is possible to consider the studies on the
creation of new drug agents based on lappaconitine as
promising.
<
5%. Pure methanol served as the comparison solution. Quartz
cuvettes with optical pathlength of 1 cm were used.
1
13
Н and С NMR spectra were obtained using a Bruker
Avance III impulse spectrometer with an operating frequency of
500.13 MHz ( H), 125.47 MHz ( C), and 50.67 MHz ( N)
equipped with a Z-axis gradient unit and operated with a 5 mm
PABBO probe at a sample constant temperature of 298 K. The
chemical shifts in the Н and С NMR spectra are presented
relative to the signal of the tetramethylsilane (Me Si) internal
1
13
15
1
13
4
1
5
standard, and in the N NMR spectra to the signal of the exter-
nal standard of liquid ammonia. The delay between impulse
sequences was established to achieve complete relaxation. For
the sake of increasing the digital resolution, zero-filling and
Fourier-image multiplication of the spectrum by an exponential
1
13
function (0.1 Hz for H and 1 Hz for C) were used.

Antiarrhythmic agents
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 3, March, 2020
571
The spectra were recorded using the equipment of the
Center for Collective Use "Chemistry" of the Ufa Institute
of Chemistry of the UFRC RAS and RCCU "Agidel" of
the UFRC RAS.
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(
The work was financially supported by the Russian
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Received September 27, 2019;
in revised form December 3, 2019;
accepted January 13, 2020
2
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Sokolov, S. P. Golizin, L. V. Rosenshtraukh, Е. I. Chazov,