Synthesis and Antidiabetic Activity of Thiazolo[2,3-f]Purine Derivatives and Their Analogs

Article abstract of DOI:10.1007/s11094-017-1649-5

Thiazolo[2, 3-f]purine derivatives and their analogs – dihydrothiazolo[2, 3-f]purine, 7-(thietan-3-yl)purine, and 8-(2-hydroxypropylthio)purine derivatives – were synthesized. The compounds synthesized here had no effects on protein glycation reactions us

Full text of DOI:10.1007/s11094-017-1649-5

DOI 10.1007/s11094-017-1649-5
Pharmaceutical Chemistry Journal, Vol. 51, No. 7, October, 2017 (Russian Original Vol. 51, No. 7, July, 2017)
SEARCH FOR NEW DRUGS
SYNTHESIS AND ANTIDIABETIC ACTIVITY
OF THIAZOLO[2,3-f]PURINE DERIVATIVES AND THEIR ANALOGS
A. A. Spasov,1 F. A. Khaliullin,2 D. A. Babkov,1 G. A. Timirkhanova,2
V. A. Kuznetsova,1 L. V. Naumenko,1 D. R. Muleeva,1
O. Yu. Maika,1 T. Yu. Prokhorova,1 and E. A. Sturova1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 51, No. 7, pp. 13 – 19, July, 2017.
Original article submitted May 11, 2017.
Thiazolo[2, 3-f]purine derivatives and their analogs – dihydrothiazolo[2, 3-f]purine, 7-(thietan-3-yl)purine,
and 8-(2-hydroxypropylthio)purine derivatives – were synthesized. The compounds synthesized here had no
effects on protein glycation reactions using glucose; they gave weak inhibition of glycogen phosphorylase;
they had no hemorheological activity. Substances with hypotensive activity greater than that of Dibazol were
found. A number of substances had hypoglycemic effects greater than those of chlorpropamide and Adebit.
Two compounds inhibited dipeptidylpeptidase-4, but were less active than reference agent vildagliptin.
Keywords: thietanes, purine, antidiabetic activity.
Data from the International Diabetes Federation (IDF)
indicate that there are now around 415 million patients with
diabetes mellitus and that by 2040 the number may reach
642 million [1]. The current arsenal of agents for the phar-
macological correction of metabolic anomalies in diabetes
mellitus generally do not allow adequate glycemic control to
be attained or the development of micro- and macrovascular
complications to be prevented [2 – 4]. Thus, the develop-
ment of novel antidiabetic substances is a relevant and neces-
sary objective.
In our previous work [6] we demonstrated the hypogly-
cemic activity of dihydrothiazolo[2, 3-f]purine derivatives.
The aims of the present work were to study the biological ac-
tivity of thiazolo[2,3-f]purine derivatives and their structural
analogs in relation to a series of antidiabetic targets - type 4
dipeptidylpeptidase, glycogen phosphorylase, and the forma-
tion of glycation end products - and to evaluate their effects
on arterial blood pressure and the rheological properties of
the blood.
Reaction of 1,3-dimethyl-6-chloromethylthiazolo[2,3-f]-
purin-2,4-(1H,3H)-dione (I) with cyclohexylamine or imida-
zole in ethanol was used to synthesize 6-substituted
1,3-dimethylthiazolo[2,3-f]purin-2,4-(1H,3H)-diones (IIa, b).
Gaseous hydrogen chloride was passed through chloroform
solutions of compounds IIa, b to obtain the hydrochlorides
(IIIa, b) (scheme 1). The structure of compound IIb was con-
Type 2 diabetes mellitus is generally a manifestation of
metabolic syndrome, which along with impaired glucose tol-
erance and dysfunction of the islet apparatus of the pancreas
includes the following main components: arterial hyperten-
sion, abdominal-type obesity, hyperlipidemia, and hypercho-
lesterolemia. The combination of these factors increases the
probability of developing serious cardiovascular complica-
tions – atherosclerosis, myocardial infarction, cerebral
stroke, and sudden death [5].
firmed by 1H NMR spectroscopy, where signals from NCH ,
3
NCH , and SCH group protons was accompanied by singlets
2
from protons in the imidazole ring at 7.3, 7.5, and 7.9 ppm.
Dihydrogenated thiazolopurine derivatives were synthe-
sized from 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-
1H-purin-2,6-(3H,7H)-dione (IV). Reaction of compound IV
with piperidine or piperazine hexahydrate in ethanol yielded
7-substituted
1
Volgograd State Medical University, Ministry of Health of the Russian
Federation, 400131 Volgograd, Russia.
2
Bashkir State Medical University, Ministry of Health of the Russian Fed-
eration, 450008, Ufa, Russia.
533
0091-150X/17/5107-0533 © 2017 Springer Science+Business Media New York

534
A. A. Spasov et al.
Scheme 1
IIa, b
IIIa, b
IIa, IIIa;
IIb, IIIb;
Scheme 2
Va, b
VIa, b
(Vb, VIb);
n = 1(VIa), 2 (VIb)
(Va, VIa);
1,3-dimethyl-6,7-dihydrothiazolo[2,3-f]purin-2,4-(1H,3H)-d
iones (Va, b). Treatment of compounds Va, b with ethanolic
hydrogen chloride in dioxane yielded the corresponding hy-
drochlorides (VIa, b). Reaction of compound Va with methyl
iodide in dioxane yielded 1-[1,3-dimethyl-2,4-dioxo-
1,2,3,4,6,7-hexahydrothiazolo[2,3-f]purin-7-yl)-methyl]meth
ylpiperidin-1-ium iodide (VII) (scheme 2). The structure of
compound Vb was confirmed by 1H and 13C NMR spectros-
copy. Along with singlets from the two NCH groups and
3
1
multiplets from the piperazinomethyl residue, the H NMR
spectrum contained a multiplet from the dihydrothiazole ring
at 4.17 – 4.77 ppm. Formation of the dihydrothiazole ring
was also confirmed by carbon signals at 49.59 (C ) and 51.54
(C ) ppm in the 13C NMR spectrum.
3
2

Synthesis and Antidiabetic Activity
535
Scheme 3
VIII
IXa, b
Xa, b
(IXb, Xb)
(IXa, Xa);
Scheme 4
Thietane-containing analogs of dihydrothiazolopurines
were synthesized from 8-bromo-1,3-dimethyl-7-(thietan-3-yl)-
1H-purine-2,6-(3H,7H)-dione (VIII). Reaction of compound
VIII with N,N-dimethylethylenediamine or piperazine in eth-
anol yielded 8-substituted 1,3-dimethyl-7-(thietan-3-yl)-pu-
rine-2,6-(3H,7H)-diones (IXa, b). Treatment of compounds
IXa, b with ethanolic hydrochloride solution in dioxane was
used to synthesize their hydrochlorides (Xa, b) (scheme 3).
The 1H NMR spectra of compounds IXa, b confirmed preser-
vation of the thietane ring, for example the multiplet from the
NCH group at 5.3 – 5.7 ppm. Spectra also contained signals
thio]-1,3-dimethyl-1H-purine-2,6-(3H,7H)-dione
1
(scheme 4). The H NMR spectrum of compound XIII con-
firmed the presence of a morpholine residue, for example the
(XIII)
triplet from the O(CH ) group centered at 3.76 ppm. The
2 2
spectrum also contained signals from the NCH group and
3
protons from the propyl residue as broad singlets at 4.16 and
7.86 ppm, from protons of the OH and NH groups respec-
tively. The IR spectrum of compound XIII contained stretch
vibration absorption bands from NH and OH bonds at
3090 – 3130 and 3415 cm-1 respectively.
from NCH group protons and protons from the correspond-
EXPERIMENTAL CHEMICAL SECTION
3
ing amine residues. The IR spectra of compound IXb con-
tained an N-H bond stretch vibration absorption band at
3340 cm-1.
1H NMR spectra were recorded on a Tesla BS 567 instru-
ment with a working frequency of 100 MHz in CDCl (inter-
3
Reaction of 8-mercapto-1,3-dimethyl-1H-purine-2,6-
(3H,7H)-dione (XI) with 2-(morpholinomethyl)oxirane (XII)
in n-propanol was used to synthesize the acyclic dihydro-
thiazolopurine analog 8-[2-hydroxy-3-morpholinopropyl)-
nal standard TMS, compounds Vb, IXb, and XIII) and
trifluoroacetic acid (internal standard HMDS, compounds
IIb, IXa. The 13C NMR spectrum of compound Vb was re-
corded on a JEOL FX-90 Q instrument with a working fre-

536
A. A. Spasov et al.
quency of 22.5 MHz in CDCl (internal standard TMS). IR
1-[((1,3-Dimethyl-2,4-dioxo-1,2,3,4,6,7-hexahydrothia
zolo[2,3-f]purine)-7-yl)methyl]-1-methylpiperidin-1-iumi-
odide (VII). A solution of 3.56 g (10 mmol) of compound Va
and 4.26 g (30 mmol) of methyl iodide in 100 ml of dioxane
was boiled for 3 h. The reaction was cooled and the resulting
precipitate was collected by filtration, washed with dioxane,
and dried. This yielded compound VII.
3
spectra of compounds as suspensions in Vaseline grease were
recorded on a UR-20 instrument. Melting temperatures were
measured on an SMP 11 instrument. Elemental analysis re-
sults for C, H, and N were consistent with calculated values.
The yields and properties of the compounds synthesized
here are presented in Table 1. Starting compounds were syn-
thesized by known methods: compounds I [7], IV [8], VIII
[9], XI [10], and XII [11]. We described the synthesis of
compounds IIa and IIIa in [12] and that of compounds Va-c
in [6].
1,3-Dimethyl-8-[(2-dimethylaminoethyl)amino]-7-(thi-
etan-3-yl)-1H-purine-2,6-(3H,7H)dione (IXa). A mixture
of 3.31 g (10 mmol) of compound VIII and 1.68 g (20 mmol)
of N,N-dimethylethylenediamine in 50 ml of ethanol was
boiled for 5 h. The reaction was cooled and the resulting pre-
cipitate was collected by filtration, washed with water, and
6-[(1H-Imidazol-1-yl)methyl]-1,3-dimethylthiazolo[2,3-f]-
purine-2,4-(1H,3H)-dione (IIb). Metallic sodium (0.28 g,
12 mmol) was carefully dissolved in 10 ml of absolute etha-
nol; when gas bubbles stopped forming, 0.82 g (12 mmol) of
imidazole was added. The resulting solution was supple-
mented with 60 ml of dimethylformamide and ethanol was
removed by evaporation using a water bath. Compounds I
(2.85 g, 10 mmol) was added to the resulting solution and the
mixture was boiled for 8 h. On cooling, the resulting precipi-
tate was collected by filtration, washed with water, and dried.
This yielded compound IIb. The 1H NMR spectrum, d, ppm,
was: 3.1 (s, 3H, 3-CH ); 3.3 (s, 3H, 1-CH ); 4.3 (broad s, 2H,
1
dried. This yielded compound IXa. The H NMR spectrum,
d, ppm, was: 2.65 (d, 6H, J 5 Hz, N(CH ) ); 2.88 – 3.26 (m,
3 2
10H, 1- and 3-CH , S(CH) , NCH ); 3.50 – 3.84 (m, 4H,
3
2
2
S(CH) , 8-NCH ); 5.30 – 5.68 (m, 1H, NCH).
2
2
1,3-Dimethyl-8-(piperazin-1-yl)-7-(thietan-3-yl)-1H-
purine-2,6-(3H,7H)-dione (IXb). A mixture of 3.31 g
(10 mmol) of compound VIII and 9.70 g (50 mmol) of
piperazine hexahydrate in 50 ml of ethanol was boiled for
3 h. The reaction was filtered hot. The filtrate was cooled and
the resulting precipitate was collected by filtration, washed
with water, and dried. This yielded compound IXb. The IR
spectrum, nmax, cm-1, was: 1610, 1655, 1690 (C=O, C=N,
3
3
6-CH ); 7.1 (s, 1H, 7-H); 7.3 (broad s, 1H, 4’-H); 7.5 (broad
2
s, 1H, 5’-H); 7.9 (s, 1H, 2’-H).
1
C=C); 3340 (N-H). The H NMR spectrum, d, ppm, was:
6-[(1H-Imidazol-1-yl)methyl]-1,3-dimethylthiazolo[2,3-f]-
purine-2,4-(1H,3H)-dione hydrochloride (IIIb). Gaseous
hydrochloride was passed through a solution of 1.58 g
(5 mmol) of compound IIb in 20 ml of chloroform for
5 – 10 min to pH 2. The resulting precipitate was collected
by filtration, washed with chloroform, and dried. This
yielded compound IIIb.
2.92 – 3.32 (m, 10H, S(CH) , 2 N(CH ) ); 3.40 (s, 3H,
2
2 2
1-CH ); 3.48 (s, 3H, 3-CH ); 4.20 – 4.44 (m, 2H, S(CH) );
3
3
2
5.26 – 5.70 (m, 1H, NCH).
1,3-Dimethyl-8-[(2-dimethylaminoethyl)amino]-7-(thi
etan-3-yl)-1H-purin-2,6-(3H,7H)-dione hydrochloride (Xa).
This was prepared in the same way as compound VIa.
1,3-Dimethyl-8-(piperazin-1-yl)-7-(thietan-3-yl)-1H-
purin-2,6-(3H,7H)-dione hydrochloride (Xb). This was
prepared in the same way as compound VIa.
1,3-Dimethyl-7-(piperazin-1-ylmethyl)-6,7-dihydrothi-
azolo[2,3-f]purine-2,4-(1H,3H)-dione (Vb). A mixture of
3.31 g (10 mmol) of compound IV and 9.70 g (50 mmol) of
piperazine hexahydrate in 100 ml of ethanol was boiled for
5 h. The mixture was cooled and the resulting precipitate was
collected by filtration, washed with water, and dried. This
yielded compound Vb. The 1H NMR spectrum, d, ppm, was:
8-[(2-Hydroxy-3-morpholinopropyl)thio]-1,3-dimethyl-
1H-purin-2,6-(3H,7H)-dione (XIII). A mixture of 2.12 g
(10 mmol) of compounds XI and 1.72 g (12 mmol) of com-
pound XII in 50 ml of n-propanol was boiled for 3 h. The re-
action was cooled, and 150 ml of diethyl ether was added;
the resulting precipitate was decrease collected by filtration,
washed with diethyl ether, and dried. This produced com-
pound XIII. The IR spectrum, nmax, cm-1, was: 1120 (C=O);
1610, 1650, 1715 (C=O, C=N, C=C); 3090 – 3130(N-H);
3415 (O-H). The 1H NMR spectrum, d, ppm, was:
2.33 – 2.78 (m, 8N, SCH , N(CH ) ); 3.06 – 3.60 (m, 7H, 1-
2.47 – 2.65 (m, 4H, N(CH ) ); 2.75 – 3.00 (m, 6H,
2 2
N(CH ) ); 3.35 (s, 3H, 3-CH ); 3.51 (s, 3H, 1-CH );
2 3
3
3
4.17 – 4.77 (m, 3H, SCH-NCH ). The 13C NMR spectrum, d,
2
ppm, was: 27.91 (3-CH ); 29.91 (1-CH ); 45.86 (HN(CH ) );
3
3
2 2
49.59 (C ); 51.54 (C ); 54.48 (N(CH ) ); 61.90 (7-CH );
6
7
2 2
2
106.98; 151.27; 152.35; 153.57; 156.60 (purine carbons).
1,3-Dimethyl-7-(piperidin-1-ylmethyl)-6,7-dihydrothi-
azolo[2,3-f]purine-2,4-(1H,3H)-dione hydrochloride (VIa).
Hydrogen chloride solution (5%) in ethanol was added
dropwise with mixing to compound Va (1.78 g, 5 mmol) in
50 ml of dioxane to pH 2. The resulting precipitate was col-
lected by filtration, washed with dioxane, and dried. This
produced compound VIa.
2
2 3
and 3- CH , CH); 3.76 (4H, t, J 5 Hz, O(CH ) ); 4.16 (broad
3
2 2
s, 1H, OH); 7.86 (broad s, 1H, NH).
EXPERIMENTAL BIOLOGICAL SECTION
In vitro dipeptidylpeptidase-4 activity. The inhibitory
activity of compounds against plasma dipeptidylpeptidase-4
was assessed by adding 40 ml of plasma from healthy volun-
teers to 50 ml of 0.1 M tris-HCl buffer pH 8.0. The mixture
1,3-Dimethyl-7-(piperazin-1-ylmethyl)-6,7-dihydrothi
azolo[2,3-f]purine-2,4-(1H,3H)-dione
dihydrochloride
(VIb). This was prepared in the same way as compound VIa.

Synthesis and Antidiabetic Activity
537
end of the incubation period, the specific fluorescence of
glycated BSA was measured using an F-7000 spectroflu-
was supplemented with 10 ml of test substance solution at the
required concentration in tris buffer and preincubated at
37°C for 5 min. Dipeptidylpeptidase-4 substrate gly-pro-p-
nitroanilide (Sigma, USA) (1 mM, 100 ml) was then added to
the reaction mix. Reactions were incubated at 37°C for
15 min and the formation of p-nitroanilide was measured in
terms of optical density at 405 nm [13] using an Infinite
M200 PRO microplate reader (Tecan, Austria). Vildagliptin
(Sigma, USA) was used as positive control [14].
orimeter (Hitachi, Japan) at lex = 370 nM and lem = 440 nm.
Antiglycation activity was recorded as the ratio with fluores-
cence in control samples. The reference substance was the
known inhibitor of the nonenzymatic glycosylation amino-
guanidine [18].
Hemorheological activity was assessed in terms of
changes in blood viscosity in rabbits in an in vitro model of
altered blood rheological properties – blood was incubated at
42.5°C for 60 min. Blood samples were standardized to a
hematocrit of 45 U. Test substances were added to blood
In vitro glycogen phosphorylase activity. The inhibi-
tory activity of compounds against glycogen phosphorylase
was assessed in reactions consisting of 100 ml of 50 mM
HEPES buffer pH 7.2 containing 100 mM KCl, 2.5 mM
samples to a final concentration of 10 mM. The reference
agent was pentoxifylline (Aventis, Germany). Blood viscos-
ity was measured on an AKR-2 viscometer (Russia). The ef-
fects of substances on measures of blood viscosity were eval-
uated in terms of changes in the index of erythrocyte aggre-
gation, which was calculated as the ratio of blood viscosity at
a shear rate of 3 sec-1 to blood viscosity at 100 sec-1.
MgCl , 0.5 mM glucose-1-phosphate (Sigma #G6875,
2
USA), and 1 mg/ml glycogen; reactions were incubated with
0.2 U/ml rabbit muscle glycogen phosphorylase (Sigma
#P1261, USA) and 5 ml of test substance solution at the re-
quired concentration at 30°C for 30 min. Reactions were
then supplemented with 150 ml of a solution containing
1.05% (NH ) MoO and 0.034% malachite green. The quan-
4 2
4
tity of phosphate anion released in 20 min at 30°C was as-
sessed in terms of optical density at 620 nm [15] using an In-
finite M200 PRO microplate reader (Tecan, Austria). Posi-
tive controls consisted of the experimental glycogen
phosphorylase inhibitor CP-316819 (Sigma #PZ0189, USA)
[16].
Hypoglycemic Activity was assessed by i.p. administra-
tion of test substances to adult male albino rats at a dose of
50 mg/kg. Samples of venous blood were collected from the
tail vein and the glucose concentration was measured using a
Biosen C Line analyzer (EKF Diagnostics, Germany) at 0.2
and 4 h. Reference agents were chlorpropamide and Adebit.
Hypotensive activity was studied in acute experiments
in white rats anesthetized with ethaminal sodium (50 mg/kg,
i.p.) with i.v. administration of test substances. Arterial blood
pressure was measured in the carotid artery with a mercury
manometer over 1 h. The measure of hypotensive activity
The protein glycation reaction with glucose was mod-
eled in a reaction mix containing glucose (500 mM) and bo-
vine serum albumin (BSA) (1 mg/ml) dissolved in phosphate
buffer pH 7.4 and 0.02% sodium azide to prevent bacterial
growth [17]. All substances were dissolved in DMSO. Ex-
perimental samples were supplemented with test substances
at final concentrations of 10–3 and 10–4 M; control samples
were supplemented with the same volume of solvent. All ex-
perimental samples were incubated for 24 h at 60°C. At the
was expressed as the ED – the dose of compound decreas-
20
ing arterial blood pressure by 20% at 30 – 60 min. The refer-
ence agent was Dibazol.
TABLE 1. Yields and Properties of Compounds Synthesized Here
Compound
IIb
Yield, %
33
Tm, °C (solvent)
237 – 239 (isopropanol)
283 – 285 (ethanol)
218 – 220 (ethanol)
252 – 254 (ethanol)
246 – 248 (ethanol)
253 – 254 (ethanol)
199 – 200 (ethanol)
223 – 224 (ethanol)
263 – 264 (ethanol)
239 – 241 (ethanol)
170 – 171*
Atomic formula
C13H12N6O2S
IIIb
Vb
42
C13H13ClN6O2S
C14H20N6O2S
79
VIa
VIb
VII
88
C15H22ClN5O2S
C14H22Cl2N6O2S
C16H24JN5O2S
C14H22N6O2S
98
88
IXa
IXb
Xa
57
70
C14H20N6O2S
91
C14H23ClN6O2S
C14H21ClN6O2S
C14H21N5O4S
Xb
91
XIII
96
* Ethanol/diethyl ether, ratio 1:3

538
A. A. Spasov et al.
RESULTS AND DISCUSSION
the absolute value of the erythrocyte aggregation index.
Overall, the absence of any change in the erythrocyte aggre-
gation index is evidence that compounds of this series had no
effect on erythrocyte deformability or blood viscosity.
The thiazolo[2,3-f]purine derivatives and their structural
analogs prepared here were tested for hypotensive, hemo-
rheological, and antidiabetic activities. The results are pre-
sented in Table 2. In particular, studies of activity in whole
animals showed that the substances of this series had marked
hypotensive properties. Compounds VIa, Xa, Xb, and XIII
The antidiabetic properties of the thiazolo[2,3-f]purine
derivatives and their structural analogs synthesized here
were studied in vitro. Their influences on dipeptidylpepti-
dase type 4 (DPP4) and glycogen phosphorylase (GP) activi-
ties and on the formation of glycation end products were de-
termined. Test compounds at concentrations of 0.1 – 1.0 mM
had no statistically significant antiglycation activity. Weak
glycogen phosphorylase-inhibiting properties were noted
with compounds VIa and XIII, containing piperidine and
morpholine radicals in the side chain respectively, though
their activity levels were significantly lower than that of ref-
erence agent CP-316819. At the same time, two compounds
(IIIa and VII, containing a cyclohexylamine and an N-me-
thylpiperidine residue respectively) were dipeptidylpeptidase
type 4 inhibitors, but were less active than reference agent
had greater activity than Dibazol in terms of the ED value.
20
Imidazole-substituted derivative IIIb and compound VII,
containing a quaternary nitrogen atom in the side chain, had
levels of activity which were 10 – 15 times lower than the
most active compound of the series, VIa. This leads to the
conclusion that the hypotensive activity is associated with
the lipophilic radical in the side chain (the piperidine,
piperazine, morpholine, or akylamine residues) and de-
creases in the presence of an aromatic substituent or quater-
nary nitrogen atom.
In terms of effects on erythrocyte aggregation, virtually
all test purine derivatives were inactive and even had
proaggregant properties, as in the case of imidazolylmethyl
derivative IIIb. The exception was compound IIIa, character-
ized by having a cyclohexylaminomethyl radical, though this
substance was also less active than pentoxifylline in terms of
vildagliptin at a concentration of 100 mM. The most active
compound, IIIa, had an IC of 39.14 mM (the IC for
50
50
vildagliptin was 0.034 mM in a parallel experiment). Among
purine analogs, structurally similar nanomolar inhibitors of
TABLE 2. Biological Activities of Test Compounds
Hypoglycemic properties (50 mg/kg,
Change in eryth-
Antiglycation activity,
Hypotensi
DPP4-inhibiting GP inhibiting ac-
i.p.), blood glucose compared
activity (10 4 M), tivity (10 4 M), %
rocyte aggrega-
% (m SEM)
Compound
ve, ED20,
mg/kg
with baseline, D% (m SEM)
tion index, D%
(m ± SEM)
% (m SEM)
(m SEM)
10 – 3 M
10 – 4
M
at 2 h
– 38.76 ± 4.7* – 32.40 ± 5.7*
– 9.98 ± 4.8 0 ± 5
at 4 h
1
IIIa
IIIb
–
– 12.2 ± 0.9*
30.0 ± 6.3*
4.19 ± 0.3*
9.0 ± 1.2
14.54 ± 9.19
– 3.79 ± 3.72
15.59 ± 6.29
11.80 ± 5.91
– 12.43 ± 4.10 83.32 ± 1.93*
8.84 ± 10.88
2.72 ± 3.24
31.6
3.1
– 0.18 ± 1.89
– 0.83 ± 7.16
0.75 ± 6.70
-5.78 ± 1.68
4.36 ± 2.17
7.95 ± 2.09
VIa
17.32 ± 2.65* – 22.80 ± 3.36* – 18.69 ± 5.30
12.29 ± 10.52 – 34.79 ± 5.1* – 22.30 ± 2.8*
2
VIb
–
VII
46.8
3.5
3.1 ± 0.2
– 0.50 ± 2.39 – 16.98 ± 1.60 67.11 ± 3.12*
12.92 ± 5.75
7.91 ± 9.02
9.51 ± 6.85
– 35.04 ± 16.2 – 33.7 ± 3.1*
– 27.16 ± 7.6 – 22.98 ± 2.1*
Xa
– 0.7 ± 0.9
5.69 ± 1.0
5.8 ± 0.2
16.98 ± 4.41
3.87 ± 3.79
5.07 ± 4.39
6.38 ± 0.98
9.3 ± 0.84*
5.50 ± 0.36*
3
3
Xb
7.1
–
–
– 3.30 ± 5.11
XIII
7.1
– 20.33 ± 11.72 – 0.72 ± 6.92
23.09 ± 1.71* – 8.61 ± 1.09* – 15.41 ± 9.31
Dibazol
Pentoxifylline
Aminoguanidine
Vildagliptin
CP-316819
Chlorpropamide
Adebit
22.1
– 18.6 ± 2.5*
57.83 ± 0.58*
6.01 ± 2.12
99.65 ± 1.16*
94.54 ± 1.52*
– 11.0 ± 0.01* – 12.0 ± 0.015*
– 24.0 ± 2.01* – 23.0 ± 0.1*
* Data statistically significant compared with controls (Mann-Whitney U test, p < 0.05)
1
Insoluble in water
2
Dose of 5 mg – death.
3
Not studied

Synthesis and Antidiabetic Activity
539
Clinical Features [in Russian], Volgograd State Medical Uni-
versity Press, Volgograd (2016).
DPP4 containing a 3-aminopiperidine fragment have been
described [19]. This suggests that administration of an amino
group at position 3 of the cyclohexylamine residue of com-
pound IIIa increases its affinity for the active center of the
enzyme and strengthens its inhibitory activity.
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The hypoglycemic activity of the derivatives was then
studied by single-dose administration to experimental ani-
mals. Compounds IIIa, VIb, and VII were found to be more
active than reference agents chlorpropamide and Adebit,
while compounds VIa and Xa had activity comparable with
these agents. Thus, hypoglycemic activity was greater for de-
rivatives containing an aminomethyl group in an aliphatic or
alicyclic fragment in the side chain. While the likely target of
the hypoglycemic action of compound IIIa is dipeptidylpep-
tidase type 4, identification of the mechanism of the hypo-
glycemic actions of the other compounds requires further
study.
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and Preclinical Study of Novel Biologically Active Compounds
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This work was supported by the Russian Scientific Foun-
dation (project No. 14-25-00139).
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