Substituted amides and hydrazides of dicarboxylic acids. Part 12. Synthesis and hypoglycemic and hypertensive activity of some pyridylamides and acylhydrazides of maleic and citraconic acid

Full text of DOI:10.1023/A:1019824419554

Pharmaceutical Chemistry Journal
Vol. 36, No. 4, 2002
SEARCH FOR NEW DRUGS
SUBSTITUTED AMIDES AND HYDRAZIDES OF DICARBOXYLIC
1
ACIDS. PART 12. SYNTHESIS AND HYPOGLYCEMIC
AND HYPERTENSIVE ACTIVITY OF SOME PYRIDYLAMIDES
AND ACYLHYDRAZIDES OF MALEIC AND CITRACONIC ACID
A. V. Dolzhenko,2 N. V. Kolotova,2 V. O. Koz’minykh,2 B. Ya. Syropyatov,2
V. P. Kotegov,3 and A. T. Godina3
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 4, pp. 11 – 12, April, 2002.
Original article submitted December 13, 2001.
Previously [1 – 4], we synthesized a series of substituted
amides and hydrazides of dicarboxylic acids and studied
their influence on the blood glucose level and arterial pres-
sure. Some of the synthesized compounds exhibited
hypoglycemic [2 – 4] and hypertensive [1 – 3] effects.
In the search for new biologically active substances
among amides and hydrazides of dicarboxylic acids, we have
synthesized a series of pyridylamides and acylhydrazides of
maleic (Ia – Id) and citraconic (IIa – IId) acids and studied
the relationship between their pharmacological properties
and structure.
The proposed structures of the synthesized compounds
were confirmed by the results of spectroscopic measure-
ments and by comparison to the substituted amides and
hydrazides of dicarboxylic acids, which were synthesized
and studied previously [1 – 4].
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 the reac-
tions was monitored and the purity of the reaction products
was checked by TLC on Silufol UV-254 plates (Czech Re-
public) eluted in an acetone – ethyl acetate – ether (1 : 1 : 1)
system; the spots on the plates were detected by exposure to
iodine vapor.
R
O
R
X
NH2
X
OH
N
H
O
O
O
O
Ià – Id, IIà – IId
R = H (Ià – Id), CH3 (IIà –IId);
The yields, physicochemical characteristics, and parame-
1
ters of the H NMR spectra of the originally synthesized
X =
(Ia, IIa);
N
N (Ib, IIb);
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.
The synthesis, physicochemical properties, and spectro-
scopic characteristics of 3- and 4-pyridylamides (Ia, Ib) of
maleic acid were reported previously [1].
O
O
(Ic, IIc);
(Id, IId).
NH
O
H3C
NH
OH
3- and 4-pyridylamides of citraconic acids (IIa, IIb).
To a suspension of 0.94 g (10 mmole) of 3-aminopyridine in
30 ml of ethyl acetate (for compound IIa) or 0.94 g
(10 mmole) of 4-aminopyridine in 10 ml of water (for IIb)
was added with stirring a solution of 1.12 g (10 mmole) of
citraconic acid anhydride in 30 ml of ethyl acetate (for com-
pound IIa) or in 10 ml of water (for IIb) and the mixture was
allowed to stand at room temperature for 4 – 5 h. The precip-
itated product was separated by filtration and recrystallized
Compounds Ia – Id and IIa – IId were obtained by
acylating the corresponding aminopyridines and hydrazides
of carboxylic acids with maleic or citraconic anhydride under
mild conditions using the well-known procedure described
previously [3].
1
For part 11, see [1].
Perm State Pharmaceutical Academy, Perm, Russia.
2
3
Perm State Medical Academy, Perm, Russia.
174
0091-150X/02/3604-0174$27.00 © 2002 Plenum Publishing Corporation

Substituted Amides and Hydrazides of Dicarboxylic Acids
175
TABLE 1. Yields and Physicochemical Characteristics of New Pyridylamides and Acylhydrazides of Maleic and Citraconic Acids
Compound Yield, %
M.p., °C
Empirical formula
C11H10N2O5
1H NMR spectrum (DMSO-d6): d, ppm
Ic
94
185 – 187
6.38 (s, 2H, CH=CH), 6.78 – 8.18 (m, 4H, C6H4), 10.81 (bs, 2H, NHNH), 11.71 (bs,
1H, COOH)
Id
82
140 – 141
C7H10N2O5
3.25 (s, 3H, OCH3), 3.91 (s, 2H, CH2), 6.28 (s, 2H, CH=CH), 9.98 (s, 2H, NHNH),
11.58 (bs, 1H, COOH)
IIa
IIb
IIc
78
98
95
131 – 133
155 – 157
153 – 155
C10H10N2O3
C10H10N2O3
C12H12N2O5
1.78 (s, 3H, CH3), 6.18 (s, 1H, CH), 6.68 – 8.22 (m, 4H, C5H4N), 7.92 (bs, 1H, NH)
1.98 (s, 3H, CH3), 5.88 (s, 1H, CH), 6.98 – 8.88 (m, 4H, C5H4N), 10.28 (bs, 1H, NH)
1.98 (s, 3H, CH3), 6.08 (s, 1H, CH), 6.68 – 8.18 (m, 4H, C6H4), 10.78 (bs, 2H,
NHNH), 11.88 (bs, 1H, COOH)
IId
67
91 – 93
C8H12N2O5
1.85 (s, 3H, CH3), 3.22 (s, 3H, OCH3), 3.45 (s, 2H, CH2), 5.82 (s, 1H, CH), 9.75,
10.38 (2s, 2H, NHNH), 11.12 (bs, 1H, COOH)
TABLE 3. Effect of Substituted Amides and Hydrazides of Maleic
(Ia – Id) and citraconic (IIa – IId) Acids on Blood Glucose Level in
Intact Rats
TABLE 2. Hypertensive Activity of 4-Pyridylamides of Maleic
(Ib) and Citraconic (IIb) Acids
Hypertensive
effect duration,
min
Dose,
mg/kg (i.v.)
Blood pressure
increase, Torr
Compound
Number
of rats
in test
group
Blood glucose level change,
% of initial
Dose, Initial blood
Compound
mg/kg
glucose
Ib
5
5
30
60
90
(i.p.)
level, mM
54.0 ± 18.91*
49.6 ± 11.09**
26.4 ± 5.81**
after 3 h
after 5 h
IIb
Ia
5
6
5
6
6
6
7
6
5
6
5
6
6
6
5
6
6
6
50
–
5.4 ± 0.2
5.4 ± 0.2
+5.6 ± 4.8*
–8.5 ± 1.6
+1.9 ± 5.6
–7.8 ± 2.2
Midodrine
2.5
Control
Ib
Notes. 1 Compounds Ia, Ic, Id, IIa, IIc, IId do not affect blood pres-
sure; differences from control are reliable for * p < 0.05,
** p < 0.01.
5
4.0 ± 0.4 –25.0 ± 5.1** –22.5 ± 3.1**
Control
Ic
–
4.1 ± 0.2
5.6 ± 0.1 –11.7 ± 3.1
5.4 ± 0.2 –8.5 ± 1.6
5.0 ± 0.1 –16.0 ± 6.8
–3.7 ± 3.3
–13.5 ± 4.3
–9.9 ± 7.2
–7.8 ± 2.2
–14.0 ± 3.2
–8.9 ± 2.8
–18.8 ± 3.0*
–8.9 ± 2.8
50
–
Control
Id
50
–
Control
IIa
4.7 ± 0.2
4.8 ± 0.4
4.7 ± 0.2
–4.2 ± 1.2
–6.3 ± 4.9
–4.2 ± 1.2
from ethanol (for compound IIb) or ethanol – DMSO 4 : 1
mixture (for IIa).
50
–
Control
IIb
Acylhydrazides of maleic (Ic, Id) and citraconic (IIc,
IId) acid. To a solution of 1.52 g (10 mmole) of salicylic
acid hydrazide or 1.04 g (10 mmole) of methoxyacetic acid
hydrazide in 30 – 50 ml of ethyl acetate was added with stir-
ring a solution of maleic anhydride (0.98 g, 10 mmole) or
citraconic anhydride (1.12 g, 10 mmole) in 40 – 50 ml of
ethyl acetate. The precipitated product was separated by fil-
tration and recrystallized from ethanol – DMSO (for Ic), eth-
anol – DMF (2 : 1) mixture (for IIc), or ethyl acetate – etha-
nol (10 : 1) mixture (for Id, IId).
5
3.8 ± 0.3 –28.3 ± 6.0** –31.6 ± 2.6**
4.1 ± 0.2 –3.7 ± 3.3 –13.5 ± 4.3
4.7 ± 0.5 +66.1 ± 33.7 +82.0 ± 41.3
Control
IIc
–
50
–
Control
IId
4.7 ± 0.2
5.0 ± 0.2 –12.0 ± 3.3
4.7 ± 0.2 –4.2 ± 1.2
–4.2 ± 1.2
–8.9 ± 2.8
+6.0 ± 3.3**
–8.9 ± 2.8
50
–
Control
Glipizide
Control
50
–
5.4 ± 0.2 –28.5 ± 5.6** –31.9 ± 6.4**
5.4 ± 0.2 –8.5 ± 1.6 –7.8 ± 2.2
Note. Differences from control are reliable for * p < 0.05 and
** p < 0.01.
EXPERIMENTAL BIOLOGICAL PART
The effect of the synthesized compounds on the systemic
arterial pressure was studied in cats narcotized with
pentobarbital sodium (400 mg/kg, i.p.). The arterial pressure
was 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) administered intrave-
nously in a dose of 2.5 mg/kg. Each compound was tested in
five experiments.
The hypoglycemic activity was studied on intact white
mongrel rats weighing 200 – 250 g. The compounds studied
and the reference drug glipizide (Glucotrol, Pfizer, France)
were intraperitoneally injected in a dose of 50 mg/kg (the
doses of toxic 4-pyridylamide maleate and citraconate were
reduced to 5 mg/kg). The blood glucose level was deter-
mined by the glucose oxidase technique [6]. The analyses

176
A. V. Dolzhenko et al.
were taken before and after (3 and 5 h) drug injections; ani-
mals in the control groups received an equivalent volume of
pure 1% starch jelly. The animals were deprived of food 14 h
before and during the experiment, while receiving water ad
libitum.
Thus, our investigation showed that 4-pyridylamides of
the maleic and citraconic acids studied possess hypertensive
and hypoglycemic properties.
REFERENCES
It was established that, among all the tested compounds,
only 4-pyridylamides of succinic (Ib) [1] and citraconic (IIb)
acids exhibited a significant hypertensive action (Table 2),
their effects being more pronounced but not as prolonged as
that of midodrine.
Hypoglycemic activity was observed only for the 4-pyri-
dylamide of maleic acid (Ib) and 3- and 4-pyridylamides of
citraconic acid (IIa, IIb). At the same time, the 3-pyridyl-
amide of maleic acid (Ia) and methoxyacetylhydrazide of
citraconic acid (IId) produced a weak hyperglycemic effect
(Table 3). A certain tendency to hyperglycemic action was
also observed for 2–hydroxybenzoylhydrazide of citraconic
acid (IIc).
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Khim.-Farm. Zh., 36(3), 17 – 19 (2002).
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Khim.-Farm. Zh., 35(3), 26 – 30 (2001).
4. N. V. Kolotova, A. V. Dolzhenko, V. O. Koz’minykh, et al.,
Khim.-Farm. Zh., 33(12), 9 – 11 (1999).
5. L. L. Vasil’eva and I. A. Vetyukova (eds.), Comprehensive Prac-
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Vysshaya Shkola, Moscow (1961), pp. 164 – 166.
6. Z. I. Tsyukhno, V. N. Slavnov, N. I. Panchenko, et al., Func-
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