Substituted amides and hydrazides of dicarboxylic acids. Part 9. Pharmacological activity of the products of interaction of 2-aminopyridines and 2-aminopyrimidine with dicarboxylic acid anhydrides

Full text of DOI:10.1023/A:1010405928810

Pharmaceutical Chemistry Journal
Vol. 35, No. 3, 2001
SUBSTITUTED AMIDES AND HYDRAZIDES OF DICARBOXYLIC
1
ACIDS. PART 9. PHARMACOLOGICAL ACTIVITY
OF THE PRODUCTS OF INTERACTION OF 2-AMINOPYRIDINES
AND 2-AMINOPYRIMIDINE WITH DICARBOXYLIC
ACID ANHYDRIDES
N. V. Kolotova,2 V. O. Koz’minykh,2 A. V. Dolzhenko,2 E. N. Koz’minykh,2
V. P. Kotegov,3 A. T. Godina,3 B. Ya. Syropyatov,2 and G. N. Novoselova2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 3, pp. 26 – 30, March, 2001.
Original article submitted October 19, 2000.
Schåme 1
There is evidence that some heterylamides of maleic,
citraconic, succinic, and phthalic acids, obtained by acylating
certain heterocyclic amines with the corresponding acid an-
hydrides, possess hypo- and hypertensive, hypo- and
CH3
R2
CH3
R2
OH
N
N
+
hyperglycemic, analgesic, antiinflammatory, and antibacte-
R1
NH2
O
R1
N
O
O
O
O
rial properties [1 – 10]. At the same time, the pharmacologi-
cal activity of pyridyl- and pyrimidylamides of dicarboxylic
acids was insufficiently studied.
H
III
It was reported almost half a century ago [11] that the in-
teraction of 2-aminopyridine with citraconic acid anhydride
yields the corresponding 2-pyridylamide, but this structure
was not confirmed by spectroscopic data. Later [12 – 15], it
was unambiguously established that 2-aminopyridines can be
acylated by interaction with esters and chloroanhydrides of
unsaturated carboxylic acids, leading to the formation of oxo
derivatives of pyrido[1,2-a]pyrimidine. The reactions of
2-aminopyrimidine and its derivatives with electron-defi-
cient alkenes (in particular, with dicarboxylic acid anhy-
drides) possessing two vicinal carbonyl groups were not
studied in detail (only the aforementioned paper [11] is avail-
able, which presented insufficiently convincing data).
In this context, we studied the interaction of 2-aminopy-
ridine, 2-amino-5-bromopyridine, and 2-amino-4-picoline
with citraconic anhydride (see Scheme 1). The reaction pro-
ceeded in ethyl acetate at room temperature and was accom-
panied by instantaneous crystallization of the products
(Ia – Ic). The structures of these compounds were established
based on spectroscopic data.
O
O
OH
H3C
R2
OH
R2
R1
CH3
4
6
N
N
3
7
8
5
2
`
1
9
R1
N
O
N
O
Ia – Ic
II
I – III: R1 = R2 = H (a); R1 = H, R2 = Br (b); R1 = CH3, R2 = H (c).
1
The H NMR spectra of the reaction products contained
a clear signal due to diastereotopic geminal protons of the
3-CH2 methylene group, representing two doublets of the
AB-system in the regions of 2.89 – 2.97 and 3.21 – 3.27 ppm
(J2 = 18.0 – 19.0 Hz). This fact, in the absence of a signal
due to amide NH groups, was indicative of the formation of
4-methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine-4-carbo-
xylic acids (Ia – Ic) rather than pyridylamides of citraconic
acid (which could be expected based on the data from [11]).
Moreover, the presence of the characteristic signal due to the
3-CH2 group allowed us to reject the possible isomer struc-
ture of 3-methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine-
4-carboxylic acids (II, Scheme 1).
The structure of compounds Ia – Ic indicates that the
acylation reaction (proceeding at the amino group of
2-aminopyridine) involves the lactone carbonyl group re-
1
For part 8, see [1].
State Pharmaceutical Academy, Perm, Russia.
State Medical Academy, Perm, Russia.
2
3
146
0091-150X/01/3503-0146$25.00 © 2001 Plenum Publishing Corporation

Substituted Amides and Hydrazides of Dicarboxylic Acids
147
Scheme 2
mote from the methyl substituent. The intermediate
compound probably has a structure of the corresponding
2¢-pyridylamide of (Z)-2-methyl-1,4-butenedioic acid
(III). Indeed, the reaction of 2-amino-4-picoline with
citraconic anhydride led initially to a mixture of
cocrystallizing products: 4¢-methyl-2¢-pyridylamide of
(Z)-2-methyl-1,4-butenedioic acid (IIIa: R1 = CH3,
H
a
H
O
OH
b
O
O
O
X
O
(X = CH, N; R1 = H)
CH3
H
N
N
H
a
IVa, IVb
1
R2 = H) with a relative content of 41% (the H NMR
O
O
OH
O
O
O
N
R1
N
spectrum contains a characteristic signal at 6.02 ppm
due to a CH methine group of the citraconoyl fragment4)
(X = N; R1 = H)
N
N
H
CH3
X
and
rimidine-4-carboxylic acid (Ic) with a relative content of
4,8-dimethyl-2-oxo-3,4-dihydropyrido[1,2-a]py-
V
NH2
1
59% (the H NMR spectrum contains two doublets of
O
O
O
X
O
OH
(X = CH, N; R1 = H)
the AB-system at 2.97 and 3.24 ppm with J2 = 19.0 Hz).
Subsequent recrystallizations allowed us to isolate pure
acid Ic from this mixture.
N
N
H
R2
O
O
VIa, VIb
R3
The IR spectra of pyrido[1,2-a]pyrimidines I exhibit
a relatively high-frequency absorption band due to
stretching vibrations of the carboxy group
(1755 – 1760 cm – 1) and a band due to the C(2)=O car-
bonyl group (1650 – 1658 cm – 1). These signals are
consistent with the proposed structure and agree with
the published data [13].
R1
O
O
O
OH
R3
X
R3
O
R3
N
N
(X = CH, N)
H
R2
R3
R3
VIIa – VIIf
In view of the unusual course of acylation of
2-aminopyridines by citraconic acid anhydride, it should
be pointed out that the reactions of 2-aminopyridines
with maleic, succinic, phthalic, 3-nitrophthalic, and tet-
rachlorophthalic anhydrides under mild conditions
(ethyl acetate, room temperature) lead to the predicted
2-pyridylamides of the corresponding acids (IVa, VIa,
and VIIa – VIId, Scheme 2). We have also established
that, under analogous conditions, 2-aminopyrimidine is
readily acylated by the above dicarboxylic acid anhy-
drides, as well as by citraconic acid anhydride, with the
formation of monosubstituted 2-pyridylamides of the
corresponding acids (IVb, V, VIb, VIIe, and VIIf,
Scheme 2).
Compound
IVa
X
R1
R2
R3
CH
–
–
–
IVb
N
–
–
–
VIa
CH
N
–
–
–
VIb
–
–
–
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
CH
CH
CH
CH
N
H
CH3
H
H
H
H
H
H
H
H
H
NO2
Cl
Cl
H
H
N
NO2
H
The structures of newly synthesized compounds
(IV – VII) were confirmed by spectroscopic data (Ta-
ble 1) in comparison with the known dicarboxylic acid
EXPERIMENTAL CHEMICAL PART
1
heterylamides [1]. The H NMR spectra of amides IV – VII
contain a group of signals due to protons of the correspond-
ing heterocyclic azine fragments in the region of
6.72 – 11.30 ppm. The signal from two methine protons in
the spectra of maleamides IVa and IVb appears as a singlet at
6.14 and 6.25 ppm, respectively. The protons of two methy-
lene groups in compounds VIa and VIb also give singlet sig-
nals observed at 2.35 and 2.42 ppm, respectively.
The IR absorption spectra of the synthesized compounds
were measured on UR-20 and Specord M-80 spectrophotom-
eters (Germany) using samples prepared as nujol mulls. The
1H NMR spectra were recorded with RYa-2310 (60 MHz)
(Russia) and Bruker AS-300 (300.13 MHz) (Germany) in-
struments using DMSO-d6 as the solvent and HMDS or TMS
as the internal standard. The mass spectra were obtained with
an MS-30 mass spectrometer (Kratos, Great Britain) using
direct sample introduction into the ion source (emission cur-
rent, 1000 mA; electron-impact ionization energy, 70 eV;
evaporator temperature, 100 – 150°C).
4
According to the results of our 1H NMR measurements, a relatively
The course of reactions was monitored and purity of the
reaction products was checked by TLC on Silufol UV-254
plates (Czech Republic) eluted in an acetone – ethyl ace-
high-field signal of the methine proton in the spectra of citraconic acid
heterylamides (in DMSO-d6) occurs in the region of 5.88 – 6.15 ppm.

148
N. V. Kolotova et al.
1658 (C2=O); 1H NMR spectrum in DMSO-d6 (d, ppm): 1.45
(s, 3H, CH3), 2.89, 3.27 (dd, 2H, AB-system J2 18.0 Hz,
CH2), 7.02 (d, 1H, C9H, for notations see Scheme 1), 7.81 (d,
1H, C8H), 8.70 (s, 1H, C6H); C10H9BrN2O3; m.w., 285.10.
Compound Ic. The first crystallization yields 2.0 g of a
mixture of IIIa (III: R1 = CH3, R2 = H) and Ic: m.p.,
206 – 207°C (with decomp.); IR spectrum (nmax, cm – 1):
3328 (COOH), 3142 (NH), 1678 (COOH, C=C), 1637
(COamide). Compound IIIa probably occurs in a 2-imide form,
as evidenced by the relatively low frequency of the NH
(amidine group) stretching vibrations in the IR spectrum and
by the absence of a signal due to the amide proton in the re-
gion above 8 ppm. We failed to isolate product IIIa in pure
form because repeated crystallization is accompanied by
heterocyclization with the formation of pyridopyrimidine Ic.
1H NMR spectrum of IIIa + Ic in DMSO-d6 (d, ppm):
1.42 (s, 3H, C4-CH3, Ic, 59%), 1.89 (s, 3H, –CH=C–CH3,
tate – ether (1 : 1 : 1) system; the spots on the plates were de-
tected by exposure to iodine vapor. The yields, physicoche-
mical characteristics, and spectral parameters of
pyrido[1,2-a]pyrimidines (Ia – Ic) and amide IVa are pre-
sented with comments in the description of synthesis below.
The data for compounds IV – VII are summarized in Table 1.
The data of elemental analysis coincide with the values ob-
tained by analytical calculations according to the empirical
formulas.
4-Methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine-
4-carboxylic acids (Ia – Ic). To a solution of 10 mmole of
2-aminopyridine, 2-amino-5-bromopyridine, or 2-amino-4-
picoline in 40 – 50 ml of ethyl acetate was added with stir-
ring a solution of citraconic anhydride (1.12 g, 10 mmole) in
30 ml of ethyl acetate and the mixture was allowed to stand
at room temperature for 2 – 3 h. The precipitated product
was separated by filtration and multiply recrystallized (until
reaching the desired purity) from a 70% (compound Ia) or
96% (Ib and Ic) aqueous ethanol solution.
IIIa, 41%), 2.25 (s, 3H, 4¢-CH3, IIIa), 2.38 (s, 3H, C8–CH3,
Ic), 2.97, 3.24 (dd, 2H, CH2, AB-system J2 19.0 Hz, Ic), 6.02
(s, 1H, CH, IIIa), 6.56, 6.58, 6.80, 6.83, 7.00, 7.79, 8.33
(group of signals, 7H, 2C5H3N, NH, Ic + IIIa).
Compound Ia. Yield, 1.80 g (82%); m.p., 233 – 234°C
(with decomp.); IR spectrum (nmax, cm – 1): 1758 (COOH),
1650 (C2=O); 1H NMR spectrum in DMSO-d6 (d, ppm): 1.40
(s, 3H, CH3), 2.92, 3.21 (dd, 2H, AB-system J2 18.0 Hz,
CH2), 6.81 (t, 1H, C7H, for notations see Scheme 1), 7.07 (d,
1H, C9H), 7.75 (t, 1H, C8H), 8.32 (d, 1H, C6H); mass spec-
trum m/z (Irel, %; only peaks with Irel > 5% are listed):
206(40) [M]+, 189(5) [M–OH]+, 188 [M–H2O]+, 162(16)
[M–CO2]+, 161(100) [M–CO2–H]+, 160(28) [M–CO2–2H]+,
133(6) [M–CO2–H–CO]+, 132(23) [M–CO2–2H–CO]+,
131(21), 121(57), 120(27), 94(31) [C5H4N–NH2]+, 92(12),
79(8), 78(54), 69(9), 68(15), 67(18); C10H10N2O3; m.w.,
206.20.
Triple recrystallization (repeated synthesis) yields pure
Ic: yield, 1.75 g (80%); m.p., 211 – 212°C (with decomp.);
1
IR spectrum (nmax, cm – 1): 1755 (COOH), 1652 (C2=O); H
NMR spectrum in DMSO-d6 (d, ppm): 1.42 (s, 3H, C4-CH3),
2.38 (s, 3H, C8-CH3), 2.97, 3.24 (dd, 2H, AB-system, J2
19.0 Hz, CH2), 6.83 (d, 1H, C7H, for notations see Scheme
1), 7.00 (t, 1H, C9H), 8.33 (d, 1H, C6H); mass spectrum m/z
(Irel, %; only peaks with Irel > 5% are listed): 220(24) [M]+,
203(5) [M–OH]+, 202(32) [M–H2O]+, 176(19) [M–CO2]+,
175(97) [M–CO2–H]+, 174(23) [M–CO2–2H]+, 161(10)
[M–CO2–CH3]+, 160(5) [M–CO2–H–CH3]+, 147(10)
[M–CO2–H–CO]+, 146(28) [M–CO2–2H–CO]+, 145(17),
135(62), 134(29), 131(11), 120(5), 119(6), 108(12),
Compound Ib. Yield, 2.10 g (74%); m.p., 199 – 200°C
(with decomp.); IR spectrum (nmax, cm – 1): 1760 (COOH),
TABLE 1. Physicochemical Characteristics of 2-Pyridylamides and 2-Pyrimidylamides of Dicarboxylic Acids (IV – VII)
M.p., °C
Com- Yield,
pound
Empirical
formula
1H NMR spectrum (DMSO-d6): d, ppm*
(with
%
decomp.)
IVa
83
132 – 133 C9H8N2O3
161 – 162 C8H7N3O3
122 – 123 C9H9N3O3
142 – 143 C9H10N2O3
148 – 149 C8H9N3O3
6.14 (s, 2H, CH=CH), 6.58 – 8.05 (m, 4H, C5H4N), 8.82 (bs, 1H, NH)
IVb
V
93
88
80
62
70
65
84
82
86
91
6.25 (s, 2H, CH=CH), 6.59 (t, 1H, Hb in C4H3N2), 8.25 (d, 2H, Ha), 8.30 (s, 1H, NH)
1.98 (s, 3H, CH3), 5.88 (s, 1H, CH=), 6.55 (t, 1H, Hb in C4H3N2), 8.28 (d, 2H, Ha), 9.28 (bs, 1H, NH)
2.35 (s, 4H, CH2–CH2), 6.25 – 8.45 (m, 4H, C5H4N), 10.52 (bs, 1H, NH)
VIa*
VIb
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
2.42 (s, 4H, CH2–CH2), 6.53 (t, 1H, Hb in C4H3N2), 8.30 (d, 2H, Ha), 8.45 (bs, 1H, NH)
226 – 227 C13H10N2O3 6.55 – 8.88 (m, 8H, C6H4, C5H4N), 10.88 (bs, 1H, NH)
132 – 133 C14H12N2O3 2.08 (s, 3H, CH3), 6.08 – 8.55 (m, 7H, C6H4, C5H3N), 10.85 (bs, 1H, NH)
161 – 162 C13H9N3O5
6.68 – 8.95 (m, 8H, C6H3, C5H4N, NH)
172 – 173 C13H6Cl4N2O3 6.48 – 9.00 (m, 4H, C5H4N), 11.30 (bs, 1H, NH)
125 – 126 C12H9N3O3
177 – 178 C12H8N4O5
6.58 (t, 1H, Hb in C4H3N2), 6.72 – 8.05 (m, 4H, C6H4), 8.23 (d, 2H, Ha), 8.42 (bs, 1H, NH)
6.68 (t, 1H, Hb in C4H3N2), 8.28 (d, 2H, Ha), 7.78 – 8.62 (m, 3H, C6H3), 9.05 (bs, 1H, NH),
12.18 (bs, 1H, COOH)
*
See Scheme 2 for Ha and Hb proton localization.

Substituted Amides and Hydrazides of Dicarboxylic Acids
149
107(100) [C5H3(CH3)–NH]+, 106(7), 105(6), 93(15), 92(45),
91(9), 81(20), 80(39), 79(6); C11H12N2O3; m.w., 220.22.
Dicarboxylic acid 2-pyridylamides (IVa, VIa,
VIIa – VIId). To a solution of 10 mmole of 2-aminopyridine
or 2-amino-4-picoline in 40 – 50 ml of ethyl acetate was
added with stirring a solution of maleic, succinic, phthalic,
EXPERIMENTAL BIOLOGICAL PART
The antimicrobial activity of the synthesized compounds
with respect to the standard strains of Escherichia coli M17
and Staphylococcus aureus P-209 was determined by a con-
ventional method of double serial dilutions in a beef-infusion
broth for a bacterial load from 2.50 ´ 105 to 5 ´ 106 micro-
bial cells per ml solution [16]. The active dose was character-
ized by the minimum inhibiting concentration (MIC) of each
compound, that is, by the maximum dilution ensuring com-
plete suppression of bacterial test culture growth. The
bacteriostatic effect of the compounds studied was compared
to that of several reference compounds including ethacridine
lactate [17] and three modern antibacterial drugs represent-
ing the group of 4-oxoquinoline-3-carboxylic acids (oxolinic
and nalidixic acids and flumequine) [18, 19 (Table 2)].
The hypoglycemic activity was studied on intact white
mongrel rats weighing 220 – 250 g. The compounds studied
and the reference drugs (glipizide and glibenclamide) were
intraperitoneally injected in a dose of 5 or 50 mg/kg. The
blood glucose level was determined by the glucose oxidase
technique. The analyses were taken before and after (3 and
5 h) injections; animals 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 [20].
3-nitrophthalic,
or
tetrachlorophthalic
anhydrides
(10 mmole) in 50 – 60 ml of ethyl acetate or dioxane and the
mixture was allowed to stand at room temperature for
3 – 4 h. The precipitated product was separated by filtration
and recrystallized from ethanol (for compounds IVa, VIa,
VIIc), ethyl acetate – dioxane (1 : 1) mixture (compound
VIIb), or ethanol – DMSO (4 : 1) mixture (compounds VIIa
and VIId).
Compound IVa. Yield, 1.59 g (83%); m.p., 132 – 133°C
(with decomp.); IR spectrum (nmax, cm – 1): 3316 (COOH),
3240 (NHCO), 1710 (COOH), 1684 (C=C), 1636 (CONH);
mass spectrum, m/z (Irel, %; only peaks with Irel > 5% are
listed): molecular ion signal is missing, 99(5)
[M–2NH–C5H4N]+, 94(100) [2NH2–C5H4N]+, 91(10),
72(25)
[CH2=CH–COOH]+,
67(65),
55(10)
[CH2=CH–CºO]+, 54(8), 50(15), 41(18); C9H8N2O3; m.w.,
192.18.
Dicarboxylic acid 2-pyrimidylamides (IVb, V, VIb,
VIIe, VIIf). To a solution of 0.95 g (10 mmole) of
2-aminopyridine in 30 ml of ethyl acetate was added with
stirring a solution of maleic, citraconic, succinic, phthalic, or
3-nitrophthalic anhydride (10 mmole) in 50 – 60 ml of ethyl
acetate. The solvent was evaporated and the residue was
crystallized from ethanol.
The effect of the synthesized compounds on the systemic
arterial pressure was studied in cats narcotized with medinal
(400 mg/kg). 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 a femoral vein. The arterial
pressure was measured in a carotid artery by a direct method
using a mercury manometer.
TABLE 2. Bacteriostatic Activity of the Synthesized Compounds
MIC, mg/ml
Compound
Escherichia coli
Staphylococcus
TABLE 3. Effect of Some 2-Pyridylamides and 2-Pyrimidylamides
of Dicarboxylic Acids (IV – VII) on Blood Glucose Level in Intact
Rats*
M17
aureus P-209
Ia
3.9
> 1000
1000
7.8
> 1000
1000
Ib
Blood glucose level
Dose,
Ic
Compound
mg/kg
(i.p.)
initial,
mM
after 3 h,
after 5 h,
IVa
> 1000
1000
1000
% of initial
% of initial
IVb
1000
IVb
50
“
5.1 ± 0.2 – 10.4 ± 3.0
– 12.5 ± 2.9
– 13.2 ± 2.8
V
1000
1000
V
3.7 ± 0.2
4.7 ± 0.1
5.0 ± 0.2
– 6.6 ± 2.7
VIa
1000
1000
VIa [1]
VIIa
“
+ 9.4 ± 2.2** + 0.6 ± 3.6**
VIIa
1000
1000
“
– 8.0 ± 3.1
– 24.0 ± 4.0**
– 9.6 ± 2.2
VIIb
> 1000
1000
1000
VIIb
5
5.2 ± 0.2 – 11.5 ± 3.1
VIIc
1000
VIIc
50
“
5.2 ± 0.2 – 15.4 ± 3.4** – 9.6 ± 1.9
4.5 ± 0.1 – 17.8 ± 6.0** – 28.9 ± 5.4**
5.4 ± 0.2 – 28.5 ± 5.6** – 31.9 ± 6.4**
4.5 ± 0.3 – 43.7 ± 0.8** – 28.6 ± 6.7**
VIId
500
500
VIId
VIIe
500
500
Glipizide
Glibenclamide
Control
“
Ethacridine lactate
Oxolinic acid
Nalidixic acid
Flumequine
2000
500
5
0.5 – 16*
0.5 – 8*
0.5 – 16*
12.5 – > 256*
12.5 – > 256*
12.5 – > 256*
–
4.7 ± 0.2
– 4.2 ± 1.2
– 8.9 ± 2.8
*
Number of experimental animals in all tests n = 6.
Differences from control are reliable for p < 0.05.
**
* MIC interval [20, 21].

150
N. V. Kolotova et al.
TABLE 4. Effect of Some 2-Pyridylamides and 2-Pyrimidylamides of Dicarboxylic Acids (IV – VII) on Systemic Arterial Pressure in
Narcotized Cats
Arterial pressure, Torr
10 min
Compound
Initial
1 min
2 min
5 min
15 min
30 min
45 min
60 min
VIa (n = 5)
VIIc (n = 6)
136.4
124.7
148.8 ± 2.1* 157.6 ± 2.9* 152.0 ± 3.3* 151.6 ± 3.3* 150.0 ± 4.1* 154.8 ± 3.8* 148.8 ± 2.0* 143.6 ± 4.8
146.7 ± 4.3* 162.2 ± 9.9* 161.3 ± 12.7* 153.3 ± 10.6* 147.3 ± 9.0* 143.7 ± 6.4* 136.0 ± 6.0 131.7 ± 6.2
* Differences from the initial level are reliable for p < 0.05.
5. A. V. Dolzhenko, B. Ya. Syropyatov, N. V. Kolotova, and
V. O. Koz’minykh, in: Current Problems in Pharmaceutical
Science and Education: Developments and Prospects [in Rus-
sian], Perm State Pharmaceutical Academy, Perm (2000),
pp. 96 – 97.
It was established that most of the tested compounds (I,
IV – VII) exhibit a weakly pronounced antimicrobial activity
with MIC = 500 – 1000 mg/ml (Table 2). A significant bac-
teriostatic effect was observed for 4-methyl-2-oxo-3,4-di-
hydropyrido[1,2-a]pyrimidine-4-carboxylic acid Ia, which
effectively inhibited the growth of both E. coli
(MIC = 3.9 mg/ml) and St. aureus (MIC = 7.8 mg/ml), being
comparable in activity with the reference antibacterial drugs.
Some of the phthalic acid 2-pyridylamides (VIIa, VIIc,
VIId) exhibited hypoglycemic activity (Table 3). Note that
succinic acid 2-pyridylamide (VIa), which is structurally
close to compounds VII but contains no benzene ring, exhib-
ited the opposite effect – increased blood glucose level [1].
In the series of substituted dicarboxylic acid amides stud-
ied, 2-pyridylamides of succinic acid (VIa) and
3-nitrophthalic acid (VIIc) produced a hypertensive action in
a dose of 5 mg/kg (Table 4). A very weak hypertensive ef-
fect was observed for phthalic acid 2-pyridylamide VIIa and
acid Ia. Compound VIId was not studied because of poor sol-
ubility in water.
6. B. Ya. Syropyatov, A. V. Dolzhenko, N. V. Kolotova, and
V. O. Koz’minykh, Abstracts of Papers. The 7th All-Russia
Congr. “Humans and Drugs” [in Russian], GEOTAR Medi-
cine, Moscow (2000), p. 551.
7. V. P. Kotegov, A. T. Godina, A. P. Dolzhenko, et al., in: Current
Problems in Endocrinology [in Russian], Perm State Pharma-
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This study was supported by the Federal Targeted Pro-
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