Synthesis and Hypoglycemic Activity of Aryl(Hetaryl)Propenoic Cyanopyrrolidine Amides

Article abstract of DOI:10.1134/S1068162019050078

Abstract: A series of amides based on (2S)-cyanopyrrolidine and α, β-unsaturated aryl- and hetarylcarboxylic acids have been synthesized. The dependence of the hypoglycemic activity of compounds on the structure of the aromatic fragment has been studied in the oral glucose tolerance test in mice. Amides based on (E)-3-phenylprop-2-enoic and (E)-3-(4-methoxyphenyl)prop-2-enoic acids and (2S)-cyanopyrrolidine have been shown to significantly reduce blood glucose levels in mice. The observed hypoglycemic effect at a dose of 10 mg/kg is comparable to the effect of hypoglycemic drug vildagliptin.

Full text of DOI:10.1134/S1068162019050078

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, No. 5, pp. 374–380. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Bioorganicheskaya Khimiya, 2019, Vol. 45, No. 5, pp. 534–541.
Synthesis and Hypoglycemic Activity
of Aryl(Hetaryl)Propenoic Cyanopyrrolidine Amides
a, 1
a, b
a
a, b
S. O. Kuranov , M. E. Blokhin , S. A. Borisov , M. V. Khvostov ,
a
a, b
O. A. Luzina , and N. F. Salakhutdinov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
a
Novosibirsk, 630090 Russia
b
Novosibirsk State University, Novosibirsk, 630090 Russia
Received February 22, 2019; revised March 18, 2019; accepted April 2, 2019
Abstract—A series of amides based on (2S)-cyanopyrrolidine and α, β-unsaturated aryl- and hetarylcarbox-
ylic acids have been synthesized. The dependence of the hypoglycemic activity of compounds on the struc-
ture of the aromatic fragment has been studied in the oral glucose tolerance test in mice. Amides based on
(
E)-3-phenylprop-2-enoic and (E)-3-(4-methoxyphenyl)prop-2-enoic acids and (2S)-cyanopyrrolidine
have been shown to significantly reduce blood glucose levels in mice. The observed hypoglycemic effect at a
dose of 10 mg/kg is comparable to the effect of hypoglycemic drug vildagliptin.
Keywords: diabetes mellitus type 2, cyanopyrrolidine, oral glucose tolerance test, hypoglycemic activity
DOI: 10.1134/S1068162019050078
INTRODUCTION
agents, which act by the same mechanism, is still rele-
vant [4–6].
Type 2 diabetes mellitus (DM-2) is a metabolic
disease characterized by chronic hyperglycemia asso-
ciated with insulin resistance of tissues. The WHO
estimates that the number of patients suffering from
DM-2 in 2015 had exceeded 392 million people,
which is about 90% of all cases of DM [1].
An important area of medicinal chemistry for
obtaining new drugs is the synthetic transformation of
natural compounds [7]. The DPP-4 inhibitors of nat-
ural origin include, in particular, compounds that
contain the α,β-unsaturated styrene fragment. These
compounds, i.e., caffeic acid (III) and resveratrol (IV)
inhibit DPP-4 in vitro at nanomolar concentrations [8].
The main disadvantage of these compounds is the
nonselective action, which complicates their targeted
use as hypoglycemic agents. For example, cinnamon
acids exhibit antioxidant, antihypoxic, cerebroprotec-
tive, hepatoprotective, choleretic, antiinflammatory,
cytostatic, lipid-lowering, anticoagulant, antiallergic,
antibacterial, antiviral, fungicidal, and other activities
in addition to hypoglycemic effects [9–12]. The mod-
ification of a molecule with broad pharmacophore
coverage can lead to the desired increase in the speci-
ficity of its action [13]. In our case, it seems promising
to combine fragments that specifically bind to the
active center of DPP-4 with molecules that have a cer-
tain affinity to the enzyme.
Dipeptidyl peptidase-4 (DPP-4), an enzyme that
cleaves peptides from the N-terminus of proline, plays
an important role in glucose metabolism. After a meal,
glucagon-like peptide-1 (GLP-1) and glucose-depen-
dent insulinotropic polypeptide (GIP) are produced,
which leads to a glucose-dependent increase in insulin
secretion and inhibition of glucagon secretion. How-
ever, the lifetime of these incretins is extremely short
because they quickly deactivate DPP-4 [2], thus lead-
ing to the prolongation of beneficial effects of GLP-1
and HIP, which is used in the treatment of DM-2.
Compounds that contain the cyanopyrrolidine frag-
ment, which has been shown [3] to bind to the active
center of the enzyme, are a substantial proportion
among the DPP-4 inhibitors, also called gliptins, e.g.,
vildagliptin (I) and saxagliptin (II) (Fig. 1). Despite
the fact that presently known gliptins are used in ther-
apeutic practice, the search for new hypoglycemic
According to the results of molecular docking [14],
resveratrol binds to the same DPP-4 site as the com-
mercially available gliptins. In this case, one of its aro-
matic rings plays the role of the cyanopyrrolidine frag-
ment and occupies the S1 pocket in the enzyme, and
the remaining styrene fragment is involved in the
binding to the protein due to the π–π stacking. It can
be assumed that the combination of the styrene moiety
Abbreviations: GTT, glucose tolerance test; DPP-4, dipeptidyl
peptidase-4; DM-2, type 2 diabetes mellitus; GLP-1, glucagon-like
peptide-1; GIP, glucose-dependent insulinotropic polypeptide.
1
Corresponding author: fax: (383) 330 9752; e-mail:
s.o.kuranov@chemomsu.ru.
374

SYNTHESIS AND HYPOGLYCEMIC ACTIVITY
375
OH
OH
O
N
N
N
H
NH2
N
O
N
Vildagliptin (I)
Saxagliptin (II)
OH
O
HO
OH
HO
OH
Caffeic acid (III)
OH
Resveratrol (IV)
Fig. 1. Inhibitors of DPP-4.
of caffeic acid with resveratrol that contains the corre- the interaction of corresponding aldehyde with malo-
sponding cyanopyrrolidine amide moiety will result in nic acid in pyridine in the presence of catalytic
the compounds, which will also exhibit the hypoglyce- amount of piperidine (method B) because method A
mic activity
led to either poor yields of compounds (XIe, f) or the
formation of corresponding dicarbonic acids in the case
of compounds (XIj–m). The yields of acids (XIa–m)
were 45–95%.
The goal of this work was to synthesize new com-
pounds by combining the fragment of α,β-unsatu-
rated aromatic acids that contained the structural
block of synthetic inhibitors of DPP-4 (2-cyanopyrro-
Target (2S)-cyanopyrrolidine amides of (Е)-3-((het-
lidine) and to study the hypoglycemic activity of the aryl)-2-propenoic acids (XIIa–m) were synthesized by
resulting compounds.
the condensation of corresponding propenoic acids
(
(
XIa–m) with 2-cyanopyrrolidine tosylate (IX)
Scheme 2) in the presence of hexafluorophosphate of
RESULTS AND DISCUSSION
(
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
(
HBTU) and trimethylamine in DMF. Amides (XIIa–m)
Cyanopyrrolidine tosylate (IX) was synthesized
from commercially available L-proline (V) (Scheme 1).
were isolated in yields of 41–94%. Amide (XIIa) was
described in the patent [21] (however, without any
spectral data).
The amino group of L-proline was protected by Boc O
2
in aqueous dioxane in the presence of sodium bicarbon-
ate with the formation of acid (VI) [15]. Amide (VII)
It should be noted that resulting amides (XIIa–m)
was synthesized by the reaction of N-Boc-protected exist in solution as a mixture of rotamers because of hin-
acid (VI) with Boc O and NH HCO in the presence of dered rotation around the amide bond C–N, which
2
4
3
1
pyridine in dioxane [16]. Amide (VII) was dehydrated leads to doubling of some signals in the H NMR spec-
by trifluoroacetic acid anhydride in the presence of tra [22].
trimethylamine in methylene chloride with the for-
mation of nitrile (VIII) [17]. The treatment of com-
Hypoglycemic Activity
Amides (XIIa–m) were studied for their hypogly-
pound (VIII) with p-toluolsulfonic acid led to the
removal of the Boc-protective group. (2S)-Pyrrolidine
carbonitrile was isolated from the solution in the form cemic activity in oral glucose tolerance test (GTT) on
of cyanopyrrolidine tosylate (IX) [18].
male CD-1 mice. The results of this test 30 and 60 min
after glucose administration are presented in Fig 2. In
The series of α,β-unsaturated acids (XIa–m) was
synthesized from aromatic and heteroaromatic alde-
hydes (Xa–m) (Scheme 2). Compounds (XIa–d, g–i)
were prepared by the method described in [19] by the
interaction of the corresponding aldehyde with malonic
acid in toluol under reflux in the presence of piperidine
and trimethylamine (method A). Compounds (XIe, f,
9
0 min, the glucose level was equal in mice of all
groups. Vildagliptin (I) was used as the reference prepa-
ration. The results showed that compounds (XIIa) and
(
XIIb) exhibited the hypoglycemic effect comparable
to that of vildagliptin.
The replacement of the methoxy group by
j–m) were prepared according to the method [20] by another substituent (fluoro (XIIc), nitro (XIId),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 5 2019

3
76
KURANOV et al.
hydroxy (XIIf)), an increase in the number of the mic effect in the experiment. In some cases, these
methoxy groups in the aromatic fragment (XIIg, h, i), transformations led to an increase in the glucose level
and the introduction of the thiophene cycle instead in blood compared to the control group (compounds
of benzene ring (XIIl) led to a loss of the hypoglyce- (XIIe, g, j, k, m)).
O
O
O
Boc2O, NaHCO3
Dioxane, H2O
Boc2O, NH4HCO3
Py, Dioxane
N
H
OH
N
OH
N
NH2
Boc
Boc
(
V)
(VI)
(VII)
TFAA
Et3N
CH2Cl2
pTsOH · H2O
MeCN
N
N
N
N
H TosOH
Boc
(IX)
(VIII)
Scheme 1. Synthesis of cyanopyrrolidine fragment (IX).
O
(IX), HBTU
O
Et3N
R
N
R
O
A or B
R
OH
(XIa−m)
DMF
N
(Xa−m)
(XIIa−m)
a. R = phenylA
h. R = 3,4-dimethylphenylA
i. R = 2,3,4-trimethylphenylA
j. R = 2-thienylB
b. R = 4-methylphenylA
c. R = 4-fluorophenylA
d. R = 4-nitrophenylA
k. R = 3-thienylB
B
e. R = 3-hydroxyphenyl
l. R = 5-methyl-2-thienylB
B
f. R = 4-hydroxyphenyl
g. R = 2,3-dimethylphenylA
m. R = 4-pyridylB
Scheme 2. Synthesis of (2S)-cyanopyrrolidine amides of (Е)-3-((hetaryl)-2-propenoic acids (XIIa
–m). Method A:
CH (COOH) , piperidine, Et N, PhCH , Δ; method B: CH (COOH) , piperidine, pyridine, 67°С.
2
2
3
3
2
2
Clarification of the mechanism of hyperglycemia been synthesized. (2S)-Cyanopyrrolidine amide of
requires further research. One of the possible options (Е)-3-phenyl-2-propeonic acid (XIIa) and (2S)-
may be an insufficient increase in insulin secretion in cyanopyrrolidine amide of (Е)-3-(4-methoxyphe-
response to oral glucose administration, which is usu- nyl)-2-propenoic acid (XIIb) exhibited the hypogly-
ally mediated by the activation of incretins (GPP-1) cemic activity in GTT on mice at a dose of 10 mg/kg,
and (GIP) [23]. It can be assumed that compounds which was comparable with the effect of vildagliptin (I).
(
XIIe, g, j, k, m) reduce the production of these poly- The hyperglycemic effect was observed for com-
peptide hormones for example by blocking the pounds (XIIe, g, j, k, m).
sodium-dependent glucose cotransporter (SGLT),
which is important for glucose-induced secretion of
GPP-1 [24].
EXPERIMENTAL
The Н and С spectra were recorded in CDCl
1
13
3
(
where it is not specified) on AV-400 and AV-300
spectrometers (Brukеr, United States), (δ, ppm; SSIC,
Amides of α, β-unsaturated aryl and hetarylcar- Hz). Signals of residual protons of CDCl were used as an
boxylic acids and (2S)-pyrrolidine carbonitrile have internal standard (δH 7.26 ppm; δC 77.00 ppm). The IR
CONCLUSIONS
3
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
No. 5
2019

SYNTHESIS AND HYPOGLYCEMIC ACTIVITY
377
2
5
0
0
30 min
60 min
*
*
2
*
*
*
1
5
*
*
*
*
*
10
*
5
0
C
(I) (XIIa)(XIIb) (XIc) (XIId) (XIIe) (XIIf) (XIIg)(XIIh) (XIIi) (XIIj) (XIIk) (XIIl)(XIIm)
Fig. 2. Results of the glucose tolerance test. The glucose content in the plasma was measured at the beginning of the experiment
and 30 and 60 minutes after its administration; the values are presented as the mean ± standard error of the mean (n = 5).
C, control group. * p < 0.05 relative to the control.
spectra were recorded on a Bruker Tensor 27 instru- m, CH CH N), 4.79 (0.2 H, d, J 6.9, CHCN), 4.87
2
2
–
1
ment in KBr tablets (ν, cm ). The reactions were (0.8 H, d, J 5.9, CHCN), 6.66 (1 H, d, J 15.4, ArCH-
monitored by TLC on Merck silica gel 60 F254 plates CHCO), 6.77 (1 H, d, J 15.6, ArCHCHCO), 7.35–
in a chloroform–methanol system (10 : 1). Com- 7.44 (3 H, m, Ph-3,4,5), 7.50–7.60 (2 H, m, Ph-2,6), 7.79
1
3
pounds were visualized in the iodine chamber or by (1 H, d, J15.4, ArCHCHCO). С NMR (126 MHz): 25.1
UV irradiation. The column chromatography was per- (CH CH CH CHCN), 30.0 (CH CH CH CHCN),
2
2
2
2
2
2
formed on Merck silica gel (70–230 μm). The melting
temperatures of the compounds were determined on a
Mettler Toledo FP90 instrument and Koffler table.
Initial aldehydes L-proline (Sigma-Aldrich, ≥98.5%),
reactants, and solvents were obtained from commer-
cial sources. The solvents were purified before use
according to the indicated methods [25]. Compounds
4
6.3 (CH CH N), 46.6 (CHCN), 116.8 (ArCHCHCO),
2 2
1
18.4 (CN), 128.0 (Ph-3,5), 128.8 (Ph-2,6), 130.2
(
(
Ph-4), 134.6 (Ph-1), 144.3 (ArCHCH), 164.9
+
ArCHCHCO). Found: m/z 226.1109 [M] . С H N O.
14 14 2
Calc.,M 226.1106. Found, %: С 74.46; Н 6.27; N 12.35.
С Н N O. Calc., %: С 74.31; Н 6.24; N 12.38.
1
4
14
2
(
VIа–m) and (VII–XI) were synthesized by the litera-
(
2S)-Cyanopyrrolidine amide of (Е)-3-(4-methoxy-
1
ture methods [15–20] and identified by the Н spectra. phenyl)- 2-propenoic acid (XIIb). White powder; yield,
General method of the synthesis of amides (XIIa–m).
The mixture of corresponding acid (XIa–m) (1 mmol),
cyanopyrrolidine tosylate (IX) (0.27 g, 1 mmol), and
27.4
6
5%; mp, 107.2°С, decomp.
[
α
]
–114 (c 0.18, CHCl3).
D
1
IR spectrum: 2235 (–С≡N). Н NMR (400 MHz):
2
(
.09–2.45 (4 H, m, CH CH CH CHCN), 3.57–3.65
2 2 2
Et N (0.28 mL, 2 mmol) in DMF (10 mL) were stirred
3
1 H, m, CH CH N), 3.77–3.85 (4 H, m, CH CH N,
2 2 2 2
in an inert atmosphere at room temperature for 24 h.
The reaction mixture was poured into 40 mL of water,
and the product was extracted with ethyl acetate (3 ×
Ph-4-OCH ), 4.85 (1 H, d, J 5.6, CHCN), 6.51 (1 H,
3
d, J 15.4, ArCHCHCO), 6.62 (1 H, d, J 14.9, ArCH-
CHCO), 6.89 (2 H, d, J 8.7, Ph-3,5), 7.48 (2 H, d,
1
0 mL). The combined organic layers were washed
13
J 8.6, Ph-2,6), 7.73 (1 H, d, J 15.4, ArCHCHCO). С
successively by water (10 mL) and saturated sodium
NMR (101 MHz): 25.1 (CH CH CH CHCN), 29.9
chloride (10 mL) and dried over MgSO . The precipi-
2
2
2
4
(
CH CH CH CHCN), 46.2 (CH CH N), 46.6
2 2 2 2 2
tate was filtered off, and the solution was evaporated
under reduced pressure. The residue was purified by (CHCN), 55.3 (Ph-6-OCH ), 114.2 (Ph-3,5), 114.3
3
column chromatography using a chloroform-metha- (ArCHCHCO), 118.5 (CN), 127.3 (Ph-1), 129.7 (Ph-2,6),
nol mixture (10 : 1) as an eluent.
143.8 (ArCHCH), 161.2 (Ph-4), 165.2 (ArCHCHCO).
2S)-Cyanopyrrolidine amide of (Е)-3-phenyl-2- Found: m/z 256.1217 [M] . С15
propenoic acid (XIIa). White powder; yield, 43%; mp, 256.1212. Found, %: С 70.27; Н 6.31; N 10.95.
С Н N O . Calc., %: С 70.29; Н 6.29; N 10.93.
+
(
H N O . Calc.: M
16 2 2
2
7.4
1
5
16
2
2
1
31.8°С, decomp. [α]
–129 (c 0.24, CHCl ). IR
3
D
1
spectrum: 2241 (–С≡N). Н NMR (400 MHz): 2.10–
(2S)-Cyanopyrrolidine amide of (Е)-3-(4-fluoro-
2
.49 (4 H, m, CH CH CH CHCN), 3.57–3.88 (2 H, phenyl)- 2-propenoic acid (XIIc). White powder; yield,
2
2
2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 5 2019

3
78
KURANOV et al.
2
7.4
9
4%; mp, 125.0°С, decomp.
[
α
]
–111 (c 0.19,
(2S)-Cyanopyrrolidine amide of (Е)-3-(4-hydroxy-
phenyl)-2-propenoic acid (XIIf). White powder; yield,
D
1
CHCl ). IR spectrum: 2237 (–С≡N). Н NMR (400
3
2
7.4
MHz): 2.05–2.53 (4 H, m, CH CH CH CHCN),
2
2
2
44%, mp, 137.6°С, decomp.
[
α
]
–72 (c 0.2,
D
1
3
.54–3.92 (2 H, m, CH CH N), 4.79 (0.2 H, d, J 6.4,
2 2
CHCl ). IR spectrum: 2240 (–С≡N). Н NMR (400
3
CHCN), 4.87 (0.8 H, d, J 5.6, CHCN), 6.58 (0.8 H,
d, J 15.4, ArCHCHCO), 6.64–6.74 (0.2 H, m, ArCH-
CHCO), 7.07 (2 H, t, J 8.5, Ph-3,5), 7.46–7.61 (2 H, m,
MHz): 2.05–2.42 (4 H, m, CH CH CH CHCN),
2
2
2
3
.51–3.76 (2 H, dt, J 7.9, CH CH N), 4.76–4.87 (1
2 2
H, m, CHCN), 6.44 (0.8 H, d, J 15.4, ArCHCHCO),
.57 (0.2 H, d, J 15.2, ArCHCHCO), 6.90 (2 H, d, J
13
Ph-2,6), 7.75 (1 H, d, J 15.4, ArCHCHCO). С NMR
6
(
75 MHz): 25.0 (CH CH CH CHCN), 29.9
2
2
2
8.5, Ph-3,5), 7.36 (2 H, d, J 8.5, Ph-2,6), 7.66 (1 H, d, J
(
(
(
(
CH CH CH CHCN), 46.2 (CH CH N), 46.6
13
2
2
2
2
2
15.3, ArCHCHCO), 8.67 (1 H, br.s, Ph-4-OH). С
NMR (101 MHz): 24.8 (CH CH CH CHCN), 29.6
CHCN), 115.9 (Ph-3,5), 116.6 (ArCHCHCO), 118.4
CN), 129.8 (Ph-2,6), 130.8 (Ph-1), 142.8
2
2
2
(
CH CH CH CHCN), 46.1 (CH CH N), 46.3
2 2 2 2 2
ArCHCH), 163.7 (Ph-4), 164.7 (ArCHCHCO).
(
CHCN), 114.8 (ArCHCHCO), 115.7 (Ph-3,5), 119.5
(CN), 125.7 (Ph-1), 130.1 (Ph-2,6), 142.4 (ArCHCH),
59.4 (Ph-4), 164.6 (ArCHCHCO). Found: m/z
+
Found: m/z 244.1008 [M] . С H FN O. Calc., M
14
14
2
2
44.1012. Found, %: С 68.90; Н 5.37; N 11.49.
1
С Н N OF. Calc., %: С 68.84; Н 5.36; N 11.47.
+
14
13
2
242.1051 [M] . С H N O . Calc., M 242.1055.
14 14 2 2
(
2S)-Cyanopyrrolidine amide of (Е)-3-(4-nitrophe- Found, %: С 69.50; Н 5.84; N 11.58. С Н N O .
14 14 2 2
nyl)-2-propenoic acid (XIId). Light yellow powder; Calc., %: С 69.41; Н 5.82; N 11.56.
2
4.3
D
Yield, 56%; mp, 166.9°С, decomp.
[
α
]
–129 (c 0.4,
(2S)-Cyanopyrrolidine amide of (Е)-3-(2,3-dime-
thoxyphenyl)-2-propenoic acid (XIIg). White powder;
CHCl ). IR spectrum: 1400 (NO ), 1537 (NO ), 2239
3
2
2
1
(
–С≡N). Н NMR (400 MHz): 2–2.51 (4 H, m,
27.4
yield, 69%; mp, 134–136°С;
[
α
]
–31 (c 0.26, CHCl3).
D
CH CH CH CHCN), 3.56–3.94 (2 H, m,
2
2
2
1
IR spectrum: 2237 (–С≡N). Н NMR (400 MHz):
CH CH N), 4.82 (0.2 H, d, J 7.3, CHCN), 4.88
2
2
2
(
.10–2.44 (4 H, m, CH CH CH CHCN), 3.58–3.67
2
2
2
(
0.8 H, d J 6.4, CHCN), 6.79 (0.8 H, d, J 15.6,
ArCHCHCO), 6.89 (0.2 H, d J 15.2, ArCHCHCO),
.68 (2 H, d, J 8.7, Ph-2,6), 7.81 (1 H, d, J 15.6,
1 H, m, CH CH N), 3.78 - 3.90 (7 H, m, CH CH N,
2 2 2 2
Ph-2,3-OCH ), 4.77 (0.2 H, d, J 7.7, CHCN), 4.87
3
7
13
(0.8 H, d, J 5.9, CHCN), 6.77 (0.9 H, d, J 15.7,
ArCHCHCO), 6.93 (1.1 H, d, J 7.9, ArCHCHCO,
Ph-6), 7.03–7.09 (1 H, m, Ph-5), 7.12 (1 H, d, J 7.1,
ArCHCHCO), 8.24 (2 H, d, J 8.7, Ph-3,5). С NMR
(
(
(
(
(
126 MHz): 25.1 (CH CH CH CHCN), 30.0
2 2 2
CH CH CH CHCN), 46.4 (CH CH N), 46.8
2
2
2
2
2
13
Ph-4), 8.02 (1 H, d, J 15.7, ArCHCHCO). С NMR
CHCN), 118.1 (CN), 121.0 (ArCHCHCO), 124.1
Ph-2,6), 128.6 (Ph-3,5), 140.7 (Ph-1), 141.4
(
101 MHz): 25.1 (CH CH CH CHCN), 30.0
2 2 2
(
CH CH CH CHCN), 46.3 (CH CH N), 46.6
2
2
2
2
2
ArCHCH), 148.3 (Ph-4), 163.9 (ArCHCHCO).
+
(CHCN), 55.8 (Ph-3-OCH ), 61.1 (Ph-2-OCH ),
3
3
Found: m/z 244.1008 [M] . С H N O . Calc.: M
14
13
3
3
1
(
13.7 (ArCHCHCO), 118.5 (CN), 118.6 (Ph-4), 119.8
Ph-5), 124.1 (Ph-6), 128.8 (Ph-1), 139.2 (ArCHCH),
48.5 (Ph-3), 153.2 (Ph-2), 165.2 (ArCHCHCO).
2
71.0957. Found, %: С 62.11; Н 4.84; N 15.50.
С Н N O . Calc., %: С 61.99; Н 4.83; N 15.49.
14
13
3
3
1
(
2S)-Cyanopyrrolidine amide of (Е)-3-(3-hydroxy-
phenyl)-2-propenoic acid (XIIe). Light beige powder;
+
Found: m/z 286.1315 [M] . С H N O . Calc.: M
17
20
2
4
2
86.1317. Found, %: С 67.05; Н 6.36; N 9.79.
2
7.4
yield, 41%; mp, 143.2°С, decomp. [α] –85 (c 0.19, С Н N O . Calc., %: С 67.12; Н 6.34; N 9.78.
D
16 18
2
3
1
CHCl ). IR spectrum: 2239 (–С≡N). Н NMR (400
3
(
2S)-Cyanopyrrolidine amide of (Е)-3-(3,4-dime-
MHz, CDCl /DMSO-d :1/2): 2.01–2.34 (4 H, m,
3
6
thoxyphenyl)-2-propenoic acid (XIIh). White powder;
CH CH CH CHCN), 3.57–3.85 (2 H, m, CH CH N),
2
2
2
2
2
2
7.4
yield, 48%; mp,, 139–140°С;[α]
D
–98 (c 0.22, CHCl3).
4
.77 (1 H, t, J 5.2, CHCN), 5.22 (0.2 H, dd, J 6.6, 2.6,
Ph-3-OH), 6.68 (0.8 H, d, J 15.4, ArCHCHCO), IR spectrum: 2235 (–С≡N). Н NMR (400 MHz): 2.10–
.74–6.79 (1 H, m, Ph-4), 6.84 (0.2 H, d, J 15.2, 2.47 (4 H, m, CH CH CH CHCN), 3.57–3.71 (1 H,
ArCHCHCO), 6.93–7.00 (2 H, m, Ph-2,6), 7.09– m, CH CH N), 3.79–3.98 (7 H, m, CH CH N,
1
6
2
2
2
2
2
2
2
7
9
.16 (1 H, m, Ph-3), 7.49 (1 H, d, J 15.4, ArCHCHCO), Ph-3,4-OCH ), 4.76–4.83 (0.2 H, m, CHCN), 4.87
3
13
.25 (0.8 H, s, Ph-3-OH). С NMR (75 MHz, (0.8 H, d, J 5.5, CHCN), 6.50 (0.8 H, d, J 15.4,
CDCl /DMSO-d :1/2): 24.9 (CH CH CH CHCN), ArCHCHCO), 6.55–6.63 (0.2 H, m, ArCHCHCO),
3
6
2
2
2
2
9.6 (CH CH CH CHCN), 45.8 (CH CH N), 46.4 6.86 (1 H, d, J 8.3, Ph-5), 7.02 (1 H, s, Ph-2), 7.13
2 2 2 2 2
(
(
(
CHCN), 114.7 (Ph-2), 117.3 (ArCHCHCO), 118.4 (1 H, d, J 7.9, Ph-6), 7.72 (1 H, d, J 15.4, ArCHCHCO).
13
Ph-4), 119.3 (Ph-6), 119.4 (CN), 129.9 (Ph-5), 136.0
С NMR (75 MHz): 25.1 (CH CH CH CHCN),
2 2 2
Ph-1), 142.5 (ArCHCH), 157.8 (Ph-2), 164.3 30.0 (CH CH CH CHCN), 46.2 (CH CH N), 46.6
2
2
2
2
2
+
(
ArCHCHCO). Found: m/z 242.1053 [M] . С H N O . (CHCN), 55.9 (Ph-3,4-OCH ), 110.1 (ArCHCHCO),
14
14
2
2
3
Calc.: M 242.1055. Found, %: С 69.63; Н 5.85; N 111.1 (Ph-5), 114.5 (Ph-2), 118.5 (CN), 122.3 (Ph-6),
1
1.58. С Н N O . Calc., %: С 69.41; Н 5.82; N 11.56. 127.6 (Ph-1), 144.2 (ArCHCH), 149.1 (Ph-3), 151.0
14
14
2
2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
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2019

SYNTHESIS AND HYPOGLYCEMIC ACTIVITY
379
(
Ph-4), 165.1 (ArCHCHCO). Found: m/z 286.1320 (CHCN), 114.1 (ArCHCHCO), 118.5 (CN), 126.5
+
[
M] . С H N O . Calc.: M 286.1317. Found, %: С (Th-3), 132.0 (Th-2), 137.0 (ArCHCH), 137.7 (Th-4),
1
7
20
2
4
1
43.6 (Th-1), 164.9 (ArCHCHCO). Found: m/z
6
7.14; Н 6.37; N 9.77. С Н N O . Calc., %: С 67.12;
16 18 2 3
+
2
46.0831 [M] . С H N OS. Calc.: M 246.0827.
Н 6.34; N 9.78.
13 14 2
Found, %: С 63.38; Н 5.73; N 11.39. С Н N OS.
Calc., %: С 63.39; Н 5.73; N 11.37.
13
14
2
(
2S)-Cyanopyrrolidine amide of (Е)-3-(2,3,4-tri-
methoxyphenyl)-2-propenoic acid (XIIi). Light yellow
oil; yield, 66%; mp, 87°С, decomp.
CHCl ). IR spectrum: 2243 (–С≡N). Н NMR
(
2S)-Cyanopyrrolidine amide of (Е)-3-(3-thienyl)-
2
7.4
[
α
]
–23 (c 0.24,
D
2
-propenoic acid (XIIl). Gray powder; yield, 62%; mp,
1
3
27.4
1
51.2°С, decomp. [α]D –250 (c 0.19, CHCl ). IR
3
(
400 MHz): 2.11–2.45 (4 H, m, CH CH CH CHCN),
2
2
2
1
spectrum: 2240 (–С≡N). Н NMR (400 MHz): 2.04–
3
.55–3.67 (1 H, m, CH CH N), 3.75–3.95 (10 H, m,
2 2
2
.45 (4 H, m, CH CH CH CHCN), 3.50–3.85 (1 H,
2
2
2
CH CH N, Ph-2,3,4-OCH ), 4.77 (0.2 H, d, J 7.4,
2
2
3
m, CH CH N), 4.74–4.90 (1 H, m, CHCN), 6.46 (0.2
2
2
CHCN), 4.88 (0.8 H, d, J 5.4, CHCN), 6.63-6.76
1.8 H, m, ArCHCHCO,Ph-5), 6.89 (0.2 H, d, J 15.3,
ArCHCHCO), 7.21 (1 H, d, J 8.7, Ph-6), 7.88 (1 H, d,
H, d, J 15.4, ArCHCHCO), 6.58 (0.8 H, d, J 15.2,
ArCHCHCO), 7.22–7.37 (2 H, m, Th-4,5), 7.48 (1 H,
d, J 1.5, Th-2), 7.73 (1 H, d, J 15.3, ArCHCHCO).
(
1
3
J 15.6, ArCHCHCO). С NMR (101 MHz): 25.1
(
4
13
С NMR (126 MHz): 25.0 (CH CH CH CHCN),
CH CH CH CHCN), 30.0 (CH CH CH CHCN),
2
2
2
2
2
2
2
2
2
2
9.9 (CH CH CH CHCN), 46.2 (CH CH N), 46.5
2 2 2 2 2
6.2 (CH CH N), 46.6 (CHCN), 56.0 (Ph-2-OCH ),
2
2
3
(
(
CHCN), 116.5 (ArCHCHCO), 118.4 (CN), 125.0
Th-2), 126.8 (Th-3), 128.0 (Th-4), 137.5 (ArCHCH),
6
0.8 (Ph-3-OCH ), 61.1 (Ph-4-OCH ), 107.4 (ArCH-
3
3
CHCO), 116.1 (Ph-5), 118.5 (CN), 121.6 (Ph-1), 124.1
1
37.6 (Th-2), 165.0 (ArCHCHCO). Found: m/z
(
Ph-6), 139.6 (ArCHCH), 142.4 (Ph-3), 153.4 (Ph-4),
+
2
32.0673 [M] . С H N OS. Calc.: M 232.0670.
1
55.3 (Ph-2), 165.6 (ArCHCHCO). Found: m/z
12 12 2
+
Found, %: С 62.08; Н 5.23; N 12.07. С Н N OS.
12 12 2
3
16.1424 [M] . С H N O . Calc.: M 316.1423.
17
20
2
4
Calc., %: С 62.04; Н 5.21; N 12.06.
2S)-Cyanopyrrolidine amide of (Е)-3-(4-pyridyl)-
-propenoic acid (XIIm). Gray powder; yield, 62%;
Found, %: С 64.71; Н 6.38; N 8.88. С Н N O .
1
7
20
2
4
(
Calc., %: С 64.54; Н 6.37; N 8.86.
2S)-Cyanopyrrolidine amide of (Е)-3-(2-thienyl)-
2
2
(
2
7.4
-propenoic acid (XIIj). Beige powder; yield, 59%; mp, 158.7°С, decomp.
[
α
]
–93 (c 0.21, CHCl
spectrum: 2238 (–С≡N). Н NMR (300 MHz): 2.06–
.50 (4 H, m, CH CH CH CHCN), 3.53–3.89 (2 H,
). IR
D
3
1
2
D
7.4
mp, 123.2°С, decomp. [α]
IR spectrum: 2236 (–С≡N). Н-NMR (400 MHz):
–160 (c 0.21, CHCl ).
3
2
1
2
2
2
m, CH CH N), 4.77–4.89 (1 H, m, CHCN), 6.80 (0.2
2
2
2
.09–2.45 (4 H, m, CH CH CH CHCN), 3.55–3.85
2 2 2
H, d, J 15.4, ArCHCHCO), 6.92 (0.8 H, d, J 15.4,
ArCHCHCO), 7.34 (2 H, d, J 6.0, Py-3,5), 7.66 (1 H,
d, J 15.5, ArCHCHCO), 8.62 (2 H, d, J 6.0, Py-2,6).
(
2 H, m, CH CH N), 4.77 (0.8 H, d, J 6.3, CHCN),
2 2
4
.85 (0.2 H, d, J 5.4, CHCN), 6.43 (0.8 H, d, J 15.0,
ArCHCHCO), 6.53 (0.2 H, d, J 14.6, ArCHCHCO),
1
3
С NMR (101 MHz): 24.9 (CH CH CH CHCN),
2
2
2
7
.04 (1 H, dd, J 5.0, 3.6, Th-3), 7.25 (1 H, br.s, Th-2), 7.35
2
9.7 (CH CH CH CHCN), 46.2 (CH CH N), 46.5
2 2 2 2 2
(
1 H, d, J 5.0, Th-4), 7.88 (1 H, d, J 15.0, ArCHCHCO).
13
(CHCN), 118.0 (CN), 121.2 (ArCHCHCO), 121.6
С NMR (126 MHz): 25.2 (CH CH CH CHCN),
2
2
2
(
Py-3,5), 141.0 (ArCHCH), 141.5 (Py-4), 150.3 (Py-2,6),
63.7 (ArCHCHCO). Found: m/z 227.1055 [M] .
3
0.3 (CH CH CH CHCN), 46.1 (CH CH N), 46.4
2 2 2 2 2
+
1
(
CHCN), 113.9 (ArCHCHCO), 118.2 (CN), 128.5
Th-3), 129.0 (Th-2), 137.2 (ArCHCH), 130.5 (Th-4),
40.3 (Th-1), 164.8 (ArCHCHCO). Found: m/z
С H N O. Calc.: M 227.1059. Found, %: С 68.74;
13
13
3
(
Н 5.75; N 18.54. С Н N OS. Calc., %: С 68.70;
12
12
2
1
+
Н 5.77; N 18.49.
2
32.0674 [M] . С H N OS. Calc.: M 232.0670.
12 12 2
Found, %: С 62.14; Н 5.23; N 12.01. С Н N OS.
12
12
2
Calc., %: С 62.04; Н 5.21; N 12.06.
2S)-Cyanopyrrolidine amide of (Е)-3-(5-methyl-
-thienyl)-2-propenoic acid (XIIk). Yellow powder; yield, were obtained from the vivarium of the Institute of
Biological Tests
(
We used male CD-1 mice (25–30 g). The animals
2
2
7.4
Cytology and Genetics of the Siberian Branch of the
Russian Academy of Sciences and were kept in stan-
dard conditions with free access to food and water. All
experiments were conducted in accordance with the
European Convention for the Protection of Animals
used for Experimental and Other Scientific Purposes,
5
6%; mp, 137.1°С, decomp. [α] –195 (c 0.17, CHCl3).
D
1
IR spectrum: 2237 (–С≡N). Н NMR (300 MHz): 2.09–
2
.42 (4 H, m, CH CH CH CHCN), 2.49 (3 H, s, Th-4-
2 2 2
CH ), 3.53–3.84 (2 H, m, CH CH N), 4.85 (1 H, d,
3
2
2
J 7.3, CHCN), 6.29 (0.8 H, d, J 15.0, ArCHCHCO),
.38 (0.2 H, d, J 15.4, ArCHCHCO), 6.67 - 6.75 (1 H,
m, Th-3), 7.06 (1 H, d, J 3.5, Th-2), 7.80 (1 H, d,
6
1
986. After quarantine, the animals were randomized
by weight and divided into groups of five mice each.
All test compounds were mixed with a few drops of
Tween 80 or DMSO, dissolved in distilled water, and
13
J 15.0, ArCHCHCO). С NMR (126 MHz): 15.8
Th-4-OCH ), 25.0 (CH CH CH CHCN), 30.0
CH CH CH CHCN), 46.2 (CH CH N), 46.6 orally administered in mice on an empty stomach (hun-
(
(
3 2 2 2
2
2
2
2
2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 5 2019

3
80
KURANOV et al.
ger for 12 h) 5 h before oral glucose load (2.5 g/kg).
Control animals received only water with Tween 80 or
DMSO. The blood glucose level was measured using
the ONE TOUCH Select glucometer (LIFESCAN
Inc., United States) before dosing (0) and 30, 60,
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pp. 2131–2135.
7. Newman, D.J. and Cragg, G.M., J. Nat. Prod., 2007,
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8. Gao, Y., Zhang, Y., Zhu, J., Li, B., Li, Z., Zhu, W.,
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9
0 minutes after glucose administration. Vildagliptin
(
Galvus, Novartis) was used as a positive control. Sta-
9
tistical analysis was performed using the Mann–Whit-
ney U-test. The value P < 0.05 was considered statisti-
cally significant.
1
0. Kepa, M., Miklasinska-Majdanik, M., Wojtyczka, R.D.,
Idzik, D., Korzeniowski, K., Smolen-Dzirba, J., and
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ACKNOWLEDGMENTS
1
1. Da, Cunha F.M., Duma, D., Assreuy, J., Buzzi, F.C.,
Niero, R., Campos, M.M., and Calixto, J.B., Free Rad-
ic. Res., 2004, vol. 38, pp. 1241–1253.
The authors thank the Chemical Research Center for
Collective Use of the Siberian Branch of the Russian Acad-
emy of Sciences for carrying out spectral and analytical
measurements.
1
2. Avanesyan, A.A., Pashkov, A.N., Simonyan, N.A., Si-
monyan, A.V., and Myachina, O.V., Pharm. Chem. J.,
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5. Patent WO 2014/105926 A1, 2014.
6. Pace, P., Francesco, E.D., Gardelli, C., Harper, S.,
COMPLIANCE WITH ETHICAL STANDARDS
Conflict of Interest
1
2
The authors state that there is no conflict of interests.
1
1
Statement on the Welfare of Animals
Muraglia, E., Nizi, E., Orvieto, F., Petrocchi, A., Po-
ma, M., Rowley, M., Scarpelli, R., Laufer, R.,
Paz, O.G., Monteagudo, E., Bonelli, F., Hazuda, D.,
Stillmock, K.A., and Summa, V., J. Med. Chem. Am.
Chem. Soc., 2007, vol. 50, pp. 2225–2239.
All applicable international, national and institutional
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Translated by A. Levina
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
No. 5
2019