Substituted amides and hydrazides of dicarboxylic acids. Part 11. Synthesis and pharmacological activity of a series of pyridylamides of dicarboxylic acids

Full text of DOI:10.1023/A:1019674109829

Pharmaceutical Chemistry Journal
Vol. 36, No. 3, 2002
SEARCH FOR NEW DRUGS
SUBSTITUTED AMIDES AND HYDRAZIDES
1
OF DICARBOXYLIC ACIDS. PART 11. SYNTHESIS
AND PHARMACOLOGICAL ACTIVITY OF A SERIES
OF PYRIDYLAMIDES OF DICARBOXYLIC ACIDS
A. V. Dolzhenko,2 N. V. Kolotova,2 V. O. Koz’minykh,2 and B. Ya. Syropyatov2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 3, pp. 17 – 19, March, 2002.
Original article submitted September 25, 2001.
Previously [1, 2], we have found compounds producing a
hypertensive effect in pyridylamides of some dicarboxylic
acids. Below we report on the synthesis of a series of new
pyridylamides of succinic (Ia – IIIa), maleic (Ib – IIIb), and
phthalic (Ic – IIIc) acids and attempts at establishing a rela-
tionship between the hypertensive activity and structure of
these compounds.
Amides I – III were obtained by acylating the corre-
sponding 2-, 3-, and 4-aminopyridines with succinic, maleic,
and phthalic acid anhydrides under mild conditions using the
well-known procedure described previously [2].
EXPERIMENTAL CHEMICAL PART
1
The H NMR spectra were recorded on a RYa-2310
(60 MHz) instrument (Russia) using DMSO-d6 as the solvent
and HMDS as the internal standard. The course of reactions
was monitored and the purity of the reaction products was
checked by TLC on Silufol UV-254 plates (Czech Republic)
eluted in an acetone – ethyl acetate – ether (1 : 1 : 1) system;
the spots on the plates were detected by exposure to iodine
vapor.
The yields, physicochemical characteristics, and parame-
1
ters of the H NMR spectra of the originally synthesized
compounds are listed in Table 1. The data of elemental anal-
ysis coincide with the values obtained by analytical calcula-
tions according to the empirical formulas.
2-Pyridylamides of maleic and phthalic acids (IIb,
IIc, IIIb, IIIc). To a solution of 0.94 g (10 mmole) of 3- or
NH2
OH
N
NH
X
X
X
O
N
NH2
NH2
O
Ia – Ic
X
X
OH
N
NH
O
O
O
O
X
O
N
N
AP, Torr
IIa – IIc
OH
70
N
NH
O
60
50
40
30
X
X
O
IIIa – IIIc
I – III: (X – X) = CH2–CH2 (a); CH=CH (b); 1,2-C6H4 (c)
20
IIIa
The proposed structures of the synthesized compounds
were confirmed by the results of spectroscopic measure-
ments (Table 1) and by comparison with the spectra of sub-
stituted dicarboxylic acid amides synthesized and studied
previously [1 – 4].
10
0
Ia
50
100
150
200
250
–10
Time, min
Fig. 1. Arterial pressure (AP) variation in narcotized cats treated
with 2- and 4-pyridylamides of succinic acid (Ia, IIIa) in a dose of
5 mg/kg (i.v.).
1
For part 10, see [1].
State Pharmaceutical Academy, Perm, Russia.
2
125
0091-150X/02/3603-0125$27.00 © 2002 Plenum Publishing Corporation

126
A. V. Dolzhenko et al.
AP, Torr
AP, Torr
50
80
70
60
50
40
30
20
10
0
40
30
20
IIIb
50
IIIc
10
0
Ib
30
10
20
40
60
70
80
90
50
100
Time, min
150
200
250
–10
–20
–10
–20
Time, min
Fig. 2. Arterial pressure (AP) variation in narcotized cats treated
with 2- and 4-pyridylamides of maleic acid (Ib, IIIb) in a dose of
5 mg/kg (i.v.).
Fig. 3. Arterial pressure (AP) variation in narcotized cats treated
with 4-pyridylamide of phthalic acid (IIIc) in a dose of 5 mg/kg
(i.v.).
4-aminopyridine in 40 – 50 ml of ethyl acetate (for com-
pound IIc), diethyl ether (for (IIb), or dioxane (IIIb, IIIc) was
added with stirring a solution of maleic or phthalic anhy-
drides (10 mmole) in 50 – 60 ml of ethyl acetate (for com-
pounds IIc and IIIc), diethyl ether (for (IIb), or dioxane (IIIb)
and the mixture was allowed to stand at room temperature
for 1 – 2 h. The precipitated product was separated by filtra-
tion and recrystallized from ethanol (for compound IIIb), wa-
ter (IIb), ethanol – DMSO (1 : 1, IIc), or acetonitrile – water
(5 : 1, IIIc) mixtures.
measured in the carotid artery by a direct method using a
mercury manometer [5]. Each compound to be tested was
dissolved in 3 ml of an isotonic sodium chloride solution and
infused in a dose of 5 mg/kg over 2 min into the femoral
vein. The reference hypertensive drug was midodrine hydro-
chloride (gutron, Nicomed, Austria) [6] administered intra-
venously in a dose of 2.5 mg/kg. Each compound was tested
in a group of 5 – 7 animals.
In order to check for the role of antagonism between the
most active hypertensive derivative (IIIa) [6] and NO in the
hypertensive effect, we have compared the effects of sodium
nitroprusside (10 mg/kg, i.v.) on the systemic arterial pres-
sure in intact animals and 20 min after injection of com-
pound IIIa (5 mg/kg). The results were averaged over six ex-
periments in the test and control groups.
The synthesis, physicochemical properties, and spectro-
scopic characteristics of succinic acid pyridylamides (Ia, IIa,
IIIa), maleic acid 2-pyridylamide (Ib), and phthalic acid
pyridylamide (Ic) were reported previously [1 – 3].
EXPERIMENTAL BIOLOGICAL PART
It was established that, among all the tested compounds,
only 2- and 4-pyridylamides Ia, Ib, and IIIa – IIIc produced a
significant hypertensive action (Table 2). Among the
phthalic acid derivatives, only 4-pyridylamide IIIc was stud-
ied because the other compounds in this series were insolu-
ble in water.
The effect of the synthesized compounds on the systemic
arterial pressure was studied in cats narcotized with pheno-
barbital sodium (400 mg/kg, i.p.). The arterial pressure was
As can be seen from Fig. 1, succinic acid 4-pyridylamide
IIIa more significantly increases the arterial pressure than
does 2-pyridylamide (Ia) of the same acid. Figure 2 shows
that generally the same relationship is observed for the series
of maleic acid derivatives studied, where 4-pyridylamide
(IIIb) is more active than 2-pyridylamide (Ib). Figure 3
shows comparative data on the hypertensive activity of
4-pyridylamides, from which it is seen that the action of
phthalic acid derivative (IIIc) is shorter than that of succinic
acid 4-pyridylamide (IIIa), but longer than the effect of the
analogous maleic acid derivative (IIIb).
The results of our investigation of the effect of
pyridylamides of dicarboxylic acids show that these com-
pounds are comparable in activity with midodrine, while
some of the tested substances are even superior to the refer-
ence drug. Irrespective of the anhydride used for acylation,
4-pyridylamides (IIIa, IIIb) exhibit more pronounced and
TABLE 1. Yields and Physicochemical Characteristics of Pyridyl-
amides of Some Dicarboxylic Acids
Com- Yield,
M.p.,
°C
Empirical
formula
1H NMR spectrum
(DMSO-d6): d, ppm
pound
%
IIb
91 183 – 185
C9H8N2O3 6.28, 6.58 (dd, 2 H,
CH=CH), 7.15 – 9.25 (m,
4 H, C5H4N), 9.28 (s, 1,
NH), 10.58 (bs, 1 H, NH)
IIc
86 222 – 223 C13H10N2O3 7.05 – 9.13 (m, 8 H, C6H4,
C5H4N), 10.55 (s, 1 H, NH)
IIIb
99 203 – 204
C9H8N2O3 2.52 (s, 3H, CH3), 2.58 (s,
4H, CH2–CH2), 7.42 – 8.05
(m, 4H, C6H4), 10.28 (bs,
1 H, NH), 13.32 (bs, 1 H,
COOH)
IIIc
75 161 – 163 C13H10N2O3 6.45 – 8.58 (m, 8H, C6H4,
C5H4N), 11.18 (bs, 1 H, NH)

Substituted Amides and Hydrazides of Dicarboxylic Acids
127
TABLE 2. Hypertensive Activity of Pyridylamides of Some Dicar-
boxylic Acids*
control group and by 23.7 ± 2.03 Torr against the back-
ground of succinic acid 4-pyridylamide IIIa. This effect can
be related to the well-known antagonism between the
unsubstituted 4-pyridylamide and NO [7, 8] and is probably
mediated by potential-dependent potassium channels [8].
Thus, the investigation showed that it would be expedi-
ent to continue the search for hypertensive agents among
2-and 4-pyridylamides of dicarboxylic acids. The mecha-
nism of the hypertensive action of these compounds is appar-
ently related to blocking the potential-dependent potassium
channels in the smooth muscles of blood vessels.
Hypertensive
effect duration,
min
Dose,
mg/kg (i.v.)
Blood pressure
increase, Torr
Compound
21.2 ± 2.941
35.6 ± 4.451
53.0 ± 9.961
54.0 ± 18.912
39.6 ± 7.101
26.4 ± 5.813
Ia
5
45
15
Ib
5
IIIa
IIIb
IIIc
5
240
30
5
5
45
Midodrine
2.5
90
*
Compounds IIa and IIb are inactive; compounds Ic and IIc are in-
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prolonged action as compared to that of 2-pyridylamides (Ia,
Ib). With respect to duration of the effect, succinic acid de-
rivatives (Ia, IIIa) are superior to their counterparts with un-
saturated acid fragments (Ib, IIIb). This can be related to dif-
ferences both in the pharmacokinetics of the compounds
studied and in the degree of their binding to the correspond-
ing structures.
Investigation of the effect of the most active derivative
(IIIa) on the hypotensive activity of sodium nitroprusside
showed that the former substance significantly (by 41.8%)
reduced the vasodilatory action of the latter compound: the
arterial pressure decreased by 40.7 ± 5.33 Torr in the intact