Synthesis and Properties of New Fluorine-Containing Thieno[2,3-b]pyridine Derivatives

Article abstract of DOI:10.1134/S1070363219090032

Cyanothioacetamide reacted with 1,1,5,5-tetrafluoroacetylacetone to give 4,6-bis(difluoromethyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile, and alkylation of the latter with α-chloroacetamides afforded 3-amino-4,6-bis(difluoromethyl)thieno[2,3-b]pyridine-2-carboxamides. The structure of the key compounds was proved using two-dimensional NMR techniques. In silico analysis of potential biological activity and bioavailability of the synthesized compounds was performed.

Full text of DOI:10.1134/S1070363219090032

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 9, pp. 1744–1751. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 9, pp. 1327–1336.
Synthesis and Properties of New Fluorine-Containing
Thieno[2,3-b]pyridine Derivatives
D. S. Buryia, V. V. Dotsenkoa,b*, N. A. Aksenovb, and I. V. Aksenovab
a Kuban State University, Krasnodar, 350040 Russia
*e-mail: victor_dotsenko_@mail.ru
b North Caucasian Federal University, Stavropol, Russia
Received March 21, 2019; revised March 21, 2019; accepted March 27, 2019
Abstract—Cyanothioacetamide reacted with 1,1,5,5-tetrafluoroacetylacetone to give 4,6-bis(difluoromethyl)-
2-thioxo-1,2-dihydropyridine-3-carbonitrile, and alkylation of the latter with α-chloroacetamides afforded 3-ami-
no-4,6-bis(difluoromethyl)thieno[2,3-b]pyridine-2-carboxamides. The structure of the key compounds was proved
using two-dimensional NMR techniques. In silico analysis of potential biological activity and bioavailability of
the synthesized compounds was performed.
Keywords: cyanothioacetamide, Guareschi–Thorpe reaction, Thorpe–Ziegler cyclization, thieno[2,3-b]pyridines,
in silico biological activity, organic fluorides
DOI: 10.1134/S1070363219090032
One of the priority problems attracting permanent
attention of chemists is search for compounds with spe-
cific behavior. In this respect, especially promising are
organofluorine compounds due to their relative synthetic
accessibility via standard methods, on the one hand, and
specific properties dtermined by the presence of fluorine
atoms, on the other. Replacement of hydrogen by fluorine
does not lead to an appreciable distortion of geometric
parameters but essentially changes physicochemical
properties and biological activity [1–4]. Owing to a
combination of practically useful properties and specific
features of chemical behavior, fluorinated derivatives of
nitrogen heterocycles have become the subjects of keen
interest (for reviews, see [5–12]).
as unsaturated ketones, β-keto esters, or 1,3-diketones
(Scheme 1).
It should be noted that in most cases, the initial
reactants for the synthesis of 2 were most accessible
compounds with a trifluoroacetyl fragment, so that the
range of the introduced fluorinated fragments (with a
few exceptions [25, 31]) was limited to the trifluoro-
methyl group. The broad spectrum of biological activity
of fluorine-containing thieno[2,3-b]pyridine derivatives
should also be noted. For instance, compounds 4 [22]
and 5 [27] (Scheme 2) showed in vitro activity against
hepatitis C virus. Pyridothienopyrimidine 6 displayed an-
tidiabetic properties [24, 37]. Thienopyridines 7 [38, 39]
and 8 [40] are potent IκB kinase-β inhibitors promising
for the treatment of autoimmune diseases. According to
patent data, amides 9 inhibit cytokine TNF-α with a broad
spectrum of action [41], and tricyclic compounds 10 are
phosphodiesterase-4 inhibitors [42]. The importance of
research in this field is also determined by the quite favor-
able pharmacological profile of the 3-aminothieno[2,3-b]-
pyridine fragment itself [43–45].
In continuation of our studies in the field of function-
ally substituted thieno[2,3-b]pyridine derivatives [13–19],
in the present work we synthesized new fluorine-con-
taining thienopyridines and performed in silico analysis
of their potential biological activity and bioavailability
parameters.
Numerous known examples [20–35] of synthesis of
fluorinated thieno[2,3-b]pyridine derivatives 1 are based
on the tandem C-alkylation/Thorpe–Ziegler cyclization of
fluorinated 3-cyanopyridine-2(1H)-thiones 2. The latter
can be prepared in turn by condensation of cyanothioacet-
amide (3) [36] with fluorinated 1,3-bielectrophiles such
We previously described [46] a procedure for the
synthesis of 4,6-bis(difluoromethyl)-2-thioxo-1,2-dihy-
dropyridine-3-carbonitrile (11), a convenient precursor
to fluorine-containing thienopyridine derivatives, by
the Guareschi–Thorpe reaction of cyanothioacetamide
1744

SYNTHESIS AND PROPERTIES OF NEW FLUORINE-CONTAINING
1745
Scheme 1.
CN
S
CN
CN
S
EWGCH2Hlg,
base
F
F
H2N
N
S
N
EWG
H
2
3
NH2
base
EWG
F
S
N
1
EWG—electron withdrawing substituent,
—fluorine-containing substituent.
F
1
(3) and tetrafluoroacetylacetone. Taking into account
that the yield of 11 according to the reported procedure
[46] was fairly low, we tried to improve the synthesis
of 11 and studied its transformation to thienopyridine
derivatives. By treatment of 11 with chloroacetamides
in the presence of excess alkali we obtained previously
unknown 3-amino-4,6-bis(difluoromethyl)thieno[2,3-b]-
pyridine-2-carboxamides 12a and 12b (Scheme 3).
structure was confirmed by H, 13C (DEPTQ), and 19F
NMR, IR, and high-resolution mass spectra, as well as by
two-dimensional NMR spectra (1H–13C HSQC, 1H–13C
HMBC, 1H–15N HSQC, 1H–15N HMBC) of 3-amino-4,6-
bis(difluoromethyl)thieno[2,3-b]pyridine-2-carboxamide
(12a) (Scheme 4, Table 1). The 1H NMR spectra of 12a
and 12b characteristically showed two triplets in the
region δ 7.07–7.81 ppm (2JHF = 53.6–54.4 Hz) due to pro-
tons of the difluoromethyl groups. The signals of NH2 and
4-CHF2 were shifted downfield (relative to those of the
fluorine-free analog of 12 and the 6-CHF2 signal), which
Compounds 12a and 12b were isolated as yellow pow-
ders readily soluble in acetone and ethyl acetate. Their
Scheme 2.
CF3
N
OMe
NH2
CF3
N
CF3
NH2
H
O
R
N
O
N
Me
S
N
Ph
OMe
NH
S
N
S
S
O
4
5
6
O
O
NH2
H2N
F
NH2
H2N
F
S
S
F3C
Ar
CF3
CH3
N
N
CF3
N
N
NH2
N
S
N
N
O
NH
N
S
N
S
NH2
Ar
O
RO
NR2
H3C
O
10
8
7
9
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1746
BURYI et al.
1
1
Table 1. Principal correlations in the 2D H–13C and H–15N HSQC and HMBC spectra of 3-amino-4,6-bis(difluoromethyl)-
thieno[2,3-b]pyridine-2-carboxamide (12a)a
δC or δN, ppm
δН, ppm
1H–13C HSQC
–
1H–13C HMBC
1H–15N HSQC
64.6 (NH2)
1H–15N HMBC
–
103.3 (С2), 123.7 (С3а),
144.7 (С3)
6.81 s (2Н, NН2)
112.9* (С5),
151.7 (С6)
7.17 t (1Н, С6СНF2)
7.58 br. s (2Н, CONH2)
7.78 t (1Н, С4СНF2)
113.1* (С6СНF2)
–
–
–
–
–
–
107.7 (CONH2)
–
112.9* (С5), 123.7 (С3а),
138.9 (С4)
112.1* (С4СНF2)
112.1* (С4СНF2), 113.1*
(С6СНF2), 123.7 (С3а),
138.9 (С4), 151.7 (С6)
7.87 s (1Н, С5СН)
112.9* (С5)
–
301.3 (NPy)
a Opposite phase signals in the DEPTQ 13C NMR spectrum (CH) are marked with an asterisk.
may be rationalized by intramolecular hydrogen bonding
By using OSIRIS Property Explorer online service
[47] we calculated c LogP [logarithm of the n-octanol–
water partition coefficient, log (co/cw)], solubility (log S),
topological polar surface area (TPSA), toxicological
parameters (i.e., risks of mutagenic, oncogenic, and
reproductive side effects), drug likeness, and drug score
(general pharmacological potential) so that to find out
whether the compounds under study conform to Lipinski’s
“rule of five” (c Log P ≤ 5.0, molecular weight MW ≤
500, TPSA ≤ 140, number of hydrogen bond acceptors ≤
10, number of hydrogen bond donors ≤ 5) [48–50]. The
results are summarized in Table 2.
4-CHF2···H–NH. The 13C NMR spectra of 12a and 12b
2
contained triplets of C4 (δC 138.9–139.0 ppm, JCF
=
22.8–23.5 Hz), C6 (δC 151.7–152.0 ppm, 2JCF = 25.7 Hz),
and CHF2 (δC 112.1–113.1 ppm, 1JCF = 238.4–239.2 Hz)
and a quintet (multiplet) of C5 at δC 112.9–113.2 ppm.
Fluorine nuclei resonated in the 19F NMR spectra as two
doublets at δF –111.7 and –115.6 ppm, which is consistent
with published data for other difluoromethyl-substituted
pyridine derivatives [25]. In the IR spectra of 12a and
12b we observed absorption bands typical of functional
groups present in their molecules, as well as a very strong
C–F stretching band at 1043–1034 cm–1.
It is seen that compounds 12a and 12b should be ap-
preciably more lipophilic than their hydrogen analogs and
that the opposite pattern is observed for compound 11. In
all cases, the c Log P values do not exceed 5.0, indicat-
ing probable good intestinal absorption and permeability
[48–50]. The molecular weights of all compounds are
lower than 400, in keeping with Lipinski’s “rule of five.”
It is known that replacement of hydrogen by fluorine
increases the lipophilicity of a compound and significantly
affects protein–ligand interactions [4]. We performed
in silico analysis of biological activity and bioavailability
parameters of fluorine-containing compounds 11, 12a,
and 12b in comparison with their fluorine-free analogs.
Scheme 3.
F
F
F
F
F
F
NH2
CN
S
CN
S
ClCH2C(O)NHR
KOH, DMF
O
O
+
F
F
F
S
NH
N
O
H2N
N
H
R
F
F
F
ꢀꢁɚ, 12b
R = CONH2 (a), 2-CH3C6H3NHCO (b).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS AND PROPERTIES OF NEW FLUORINE-CONTAINING
1747
Table 2. Toxicity risks and physicochemical parameters of compounds 11, 12a, and 12b and their fluorine-free analogs 11-H,
12a-H, and 12b-H, predicted by OSIRIS Property Explorer
Toxicity riska
Physicochemical parameters
Compound
А
В
С
D
–
сLogP logS MW TPSA drug likeness drug Score
F
F
–
–
–
0.19
0.65
1.64
0.93
4.04
–3.63 236
–2.69 164
–4.54 293
–3.77 221
–6.31 383
67.91
67.91
110.2
110.2
96.25
–7.03
–3.26
–1.6
0.438
0.487
0.445
0.78
CN
F
N
H
S
F
11
CH3
–
–
–
–
–
–
–
–
–
–
–
±
–
–
–
–
CN
S
H3C
N
H
11-H
F
F
NH2
O
F
S
NH2
N
F
12a
CH3
NH2
1.39
O
S
NH2
H3C
N
12a-H
F
F
–0.01
0.28
NH2
O
F
S
NH
N
F
CH3
12b
CH3
NH2
–
–
±
–
3.33
–5.54 311
96.25
3.03
0.47
O
S
NH
H3C
N
CH3
ꢀꢁEꢂɇ
a
“+” stands for high risk, “±” stands for moderate risk, and “–” stands for no toxicity; “A,” “B,” “C,” and “D” denote mutagenicity, car-
cinogenicity, irritant action, and reproductive effects, respectively.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1748
BURYI et al.
Table 3. ADMET parameters and probable biological activities of compounds 11, 12a, and 12b predicted by SwissADME and
SwissTargetPrediction
Cytochrome P450 inhibition
Comp.
no.
Gastrointestinal
absorptiona
Bioavailability
index
BBB penetrationa
Probable targets
0.55
0.55
0.55
11
High
High
Low
+
–
–
+
+
+
–
–
+
–
–
+
–
–
–
–
–
+
–
12a
12b
МАРТ
МАРТ, MBNL1,
MBNL2, MBNL3
a
“+” and “–” denote the presence or absence of effect, respectively.
None of the fluorine-containing compounds showed a
positive drug likeness value or a high drug score (>0.5).
On the other hand, the results of calculations predict
low toxicity of 11, 12a, and 12b. According to the log S
values, the examined compounds are moderately soluble,
and the solubility of compound 12b is the lowest as might
be expected.
protein family are the most probable targets for thieno-
pyridine 12b. The bioavailability index for all compounds
was estimated at 0.55, which indicated consistency with
the Lipinski rule [55].
In summary, the proposed synthetic approach can be
used for the preparation of new thieno[2,3-b]pyridine de-
rivatives containing a difluoromethyl group. The structure
of the synthesized compounds has been studied in detail
using a combination of spectral methods. In silico analy-
sis of biological activity and pharmacological potential
has revealed substantial differences between fluorinated
thienopyridines and their fluorine-free analogs, primar-
ily in their solubilities and lipophilicities, and the results
encourage further research in this field.
The TPSAparameter characterizes the surface area of
polar molecular fragment. Increased TPSA value corre-
sponds to reduced cell membrane or blood–brain barrier
(BBB) permeability, and lower TPSAvalues are generally
more favorable in terms of drug likeness.All compounds
meet the condition TPSA ≤ 140 (Table 2).
Potential biological activity, probable targets, and
ADMET (absorption, distribution, metabolism, excretion,
toxicity) parameters were predicted using SwissADME
[51], SwissTargetPrediction [52], PASS Online [53],
and Molinspiration Property Calculation Service [54].
According to the PASS Online data, compounds 11, 12a,
and 12b could be expected to exhibit anti-arthritic and
anti-allergic activities with a probability of more than
80%, as well as activity in autoimmune disorders. In ad-
dition, compounds 12a and 12b were predicted to show
analgesic effect. Molinspiration Property Calculation
Service predicted kinase inhibitory activity of 12a and
12b with a Molinspiration bioactivity score of –0.32 and
–0.26, respectively.
EXPERIMENTAL
The NMR spectra were recorded on a Bruker Avance
III HD 400 spectrometer at 400.17 (1H), 100.63 (13C),
40.55 (15N), or 376.50 MHz (19F) using DMSO-d6 as
solvent. The chemical shifts were measured relative to
tetramethylsilane or residual proton and carbon signals
of the solvent (1H, 13C), MeNO2 (15N, external), or CFCl3
(19F). The IR spectra were recorded on a Bruker Vertex
70 spectrometer with Fourier transform, equipped with
an diamondATR accessory (spectral resolution ± 4 cm–1).
The high-resolution mass spectra were obtained with a
Bruker maXis time-of-flight spectrometer (electrospray
ionization from solutions in acetonitrile). The purity of
the isolated compounds was checked by TLC on Sorbfil-
A plates using acetone–hexane (1 : 1) as eluent; spots
were visualized by treatment with iodine vapor or under
UV light.
High gastrointestinal absorption was predicted for
compounds 11 and 12a, whereas only compound 11 could
penetrate the BBB (Table 3). According to SwissTarget-
Prediction, microtubule-associated protein tau (MAPT)
is the most probable target for thienopyridine 12a, and
MAPT and muscleblind-like splicing regulator (MBNL)
Cyanothioacetamide (3) was synthesized by passing
gaseous hydrogen sulfide through a solution of malono-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS AND PROPERTIES OF NEW FLUORINE-CONTAINING
1749
2
nitrile in ethanol in the presence of triethylamine [56].
1,1,5,5-Tetrafluoroacetylacetone was provided by PiM
Invest scientific and industrial association (http://fluo-
rine1.ru).
2JHF = 54.5 Hz), –111.7 d (4-CHF2, JHF = 53.1 Hz).
Mass spectrum: m/z 316.0140 [M + Na]+; calculated for
C10H7F4N3NaOS: 316.0138.
3-Amino-4,6-bis(difluoromethyl)-N-(2-methylphe-
nyl)thieno[2,3-b]pyridine-2-carboxamide (12b). Yield
62%, yellow powder. IR spectrum, ν, cm–1: 3445, 3418,
4,6-Bis(difluoromethyl)-2-thioxo-1,2-dihydropyri-
dine-3-carbonitrile (11) was synthesized according to a
modified procedure [46]. Cyanothioacetamide (3, 2.9 g,
29.06 mmol) was added with vigorous stirring in a stream
of nitrogen to a solution of 1,1,5,5-tetrafluoroacetylac-
etone (5.00 g, 29.06 mmol) in 13 mL of ethanol, and a
catalytic amount of morpholine (0.3 mL) was then added
dropwise. When thioamide 3 dissolved completely, the
solution was stirred for 6 h in a nitrogen atmosphere and
was left to stand for 72 h at 4°C. The precipitate was
filtered off and washed with diethyl ether. An additional
amount of the product separated from the mother liquor on
further keeping. Overall yield 4.80 g (70%). The spectral
parameters were identical to those given in [46].
1
3331 br (N–H), 1657 (C=O), 1034 s (C–F). H NMR
spectrum, δ, ppm: 2.22 s (3H, Me), 6.84 br.s (2H, NH2),
7.07–7.34 m (5H, 6-CHF2, Harom), 7.81 t (1H, 4-CHF2,
2JHF = 53.6 Hz), 7.91 s (1H, 5-H), 9.67 br.s (1H, CONH).
13C NMR spectrum (DEPTQ), δC, ppm: 17.9* (Me),
103.2 (C2), 112.2* t (4-CHF2, 1JCF = 238.4 Hz), 113.1*
t (6-CHF2, 1JCF = 239.2 Hz), 113.2* m (C5), 123.6 br.s
(C3a), 126.1* (CHarom), 126.4* (CHarom), 127.2* (CHarom),
130.3* (CHarom), 134.4 (Carom), 135.9 (Carom), 139.0 (C4,
2JCF = 23.5 Hz), 145.2 (C3), 152.0 (C6, 2JCF = 25.7 Hz),
159.3 (C7a), 163.4 (C=O). 19F NMR spectrum, δF, ppm:
2
–115.6 d (6-CHF2, JHF = 54.5 Hz), –111.7 d (4-CHF2,
2JHF = 53.1 Hz). Mass spectrum: m/z 406.0598 [M + Na]+;
3-Amino-4,6-bis(difluoromethyl)thieno[2,3-b]-
pyridines 12a and 12b (general procedure). A 10%
aqueous solution of potassium hydroxide (2.2 mL,
4.25 mmol) was added with stirring to a solution of 1.00 g
of 4,6-bis(difluoromethyl)-2-thioxo-1,2-dihydropyridine-
3-carbonitrile (11, 4.23 mmol) in 4 mL of DMF heated
to 70°C. 2-Chloroacetamide or 2-chloro-N-(2-meth-
ylphenyl)acetamide (4.25 mmol) was then added, and
themixture was stirred for 0.5 h at 70°C. An additional
2.2 mLof 10% aqueous potassium hydroxide was added,
and the mixture was stirred for 0.5 h more at 70°C. The
mixture was cooled, and the precipitate was filtered off,
washed with ethanol, and dried. Compounds 12a and 12b
were thus isolated in an analytically pure form.
calculated for C17H13F4N3NaOS: 406.0608.
FUNDING
This study was performed under financial support
by the Ministry of Science and Higher Education of
the Russian Federation (project no. 4.5547.2017/8.9,
V.V. Dotsenko, I.V.Aksenova; project no. 4.1196.2017/4.6,
N.A. Aksenov) and by the Russian Foundation for Basic
Research (project no. 19-43-230 007 r_a, D.S. Buryi).
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
3-Amino-4,6-bis(difluoromethyl)thieno[2,3-b]-
pyridine-2-carboxamide (12a). Yield 72%, light
yellow powder. IR spectrum, ν, cm–1: 3427, 3392 s, 3346,
1. Fluorine in Medicinal Chemistry and Chemical Biology,
Ojima, I., Ed., Chichester: Wiley, 2009.
1
3294, 3149 br (N–H), 1684 s (C=O), 1043 s (C–F). H
2. Bégué, J.P. and Bonnet-Delpon, D., Bioorganic and Me-
dicinal Chemistry of Fluorine, Hoboken: Wiley, 2008.
NMR spectrum, δ, ppm: 6.81 br.s (2H, NH2), 7.17 t (1H,
6-CHF2, 2JHF = 54.4 Hz), 7.58 br.s (2H, CONH2), 7.78
3. Chambers, R.D., Fluorine in Organic Chemistry, Oxford:
2
t (1H, 4-CHF2, JHF = 53.6 Hz), 7.87 s (1H, 5-H). 13C
Blackwell, 2004.
NMR spectrum (DEPTQ),1 δC, ppm: 103.3 (C2), 112.1*
4. Böhm, H.J., Banner, D., Bendels, S., Kansy, M., Kuhn, B.,
Müller, K., Obst-Sander, U., and Stahl, M.,
ChemBioChem, 2004, vol. 5, no. 5, p. 637.
1
3
t (4-CHF2, JCF = 238.5 Hz), 112.9* quint (C5, JCF
=
4.4 Hz), 113.1* t (6-CHF2, 1JCF = 239.2 Hz), 123.7 br.s
(C3a), 138.9 (C4, 2JCF = 22.8 Hz), 144.7 (C3), 151.7 (C6,
2JCF = 25.7 Hz), 159.0 (C7a), 166.4 (C=O). 15N NMR
spectrum, δN, ppm: 64.6 (NH2), 107.7 (CONH2), 301.3
(N7). 19F NMR spectrum, δF, ppm: –115.6 d (6-CHF2,
https://doi.org/10.1002/cbic.200301023
5. Fluorine in Heterocyclic Chemistry, Nenajdenko, V.,
Ed., Cham: Springer, 2014, vol. 1.
https://doi.org/10.1007/978-3-319-04346-3
6. Fluorine in Heterocyclic Chemistry, Nenajdenko, V., Ed.,
1 Hereinafter, opposite phase signals are marked with an asterisk.
Cham: Springer, 2014, vol. 2.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1750
https://doi.org/10.1007/978-3-319-04435-4
BURYI et al.
21. Bakhite, E.A., Abdel-Rahman, A.E., and Al-Taifi, E.A.,
Arab. J. Chem., 2014, vol. 7, no. 6, p. 936.
https://doi.org/10.1016/j.arabjc.2014.05.035
7. Fluorinated Heterocyclic Compounds: Synthesis, Chem-
istry, and Applications, Petrov, V.A., Ed., Hoboken:
Wiley, 2009.
22. Wang, N.Y., Zuo, W.Q., Xu, Y., Gao, C., Zeng,
X.X., Zhang, L.D., You, X.Y., Peng, C.T., Shen, Y.,
Yang, S.Y., Wei, Y.Q., and Yu, L.T., Bioorg. Med.
Chem. Lett., 2014, vol. 24, no. 6, p. 1581.
8. Nenajdenko,
V.G.
and
Balen-
kova, E.S., Arkivoc, 2011, part (i), p. 246.
https://doi.org/10.3998/ark.5550190.0012.104
9. Nenajdenko, V.G., Sanin, A.V., and Balenkova,
E.S., Molecules, 1997, vol. 2, no. 12, p. 186.
https://doi.org/10.3390/21200186
https://doi.org/10.1016/j.bmcl.2014.01.075
23. H o , Y. W . a n d Y a o , W . H . , D y e s
Pigm., 2006, vol. 70, no. 1, p. 60.
10. F u r i n ,
G . G . ,
C h e m .
H e t e r o -
https://doi.org/10.1016/j.dyepig.2005.04.009
cycl. Compd., 2006, vol. 42, no. 3, p. 285.
24. Ma, F., Liu, J., Zhou, T., Lei, M., Chen, J.,
Wang, X., Zhang, Y., Shen, X., and Hu, L.,
Eur. J. Med. Chem., 2018, vol. 152, p. 307.
https://doi.org/10.1007/s10593-006-0087-1
11. Furin, G.G. and Zhuzhgov, E.L., Chem. Hetero-
cycl. Compd., 2002, vol. 38, no. 2, p. 129.
https://doi.org/10.1016/j.ejmech.2018.04.028
https://doi.org/10.1023/A:1015320822860
25. Rodinovskaya, L.A., Shestopalov, A.M., Gromova, A.V.,
and Shestopalov, A.A., J. Comb. Chem., 2008, vol. 10,
no. 2, p. 313.
12. Elwahy, A.H. and Shaaban, M.R., Curr. Org.
Synth., 2010, vol. 7, no. 5, p. 433.
https://doi.org/10.2174/157017910792246117
13. Dotsenko, V.V., Krivokolysko, S.G., Krivokolysko, B.S.,
and Frolov, K.A., Russ. J. Gen. Chem., 2018, vol. 88,
no. 4, p. 682.
https://doi.org/10.1021/cc7001793
26. Rateb, N.M., J. Sulfur Chem., 2011, vol. 32, no. 6, p. 611.
https://doi.org/10.1080/17415993.2011.628994
27. Zuo, W.Q., Wang, N.Y., Zhu, Y.X., Liu, L., Xiao, K.J.,
Zhang, L.D., Gao, C., Liu, Z.H., You, X.Y., Shi, Y.J.,
Peng, C.T., Ran, K., Tang, H., and Yu, L.T.,
RSC Adv., 2016, vol. 6, no. 46, p. 40 277.
https://doi.org/10.1134/S1070363218040114
14. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov, V.P.,
Mendeleev Commun., 2003, vol. 13, no. 6, p. 267.
https://doi.org/10.1070/MC2003v013n06ABEH001851
15. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov,
V.P., Mendeleev Commun., 2004, vol. 14, no. 1, p. 30.
https://doi.org/10.1070/MC2004v014n01ABEH001882
16. Dotsenko, V.V., Krivokolysko, S.G., Chernega, A.N.,
and Litvinov, V.P., Russ. Chem. Bull., Int. Ed., 2002,
vol. 51, no. 8, p. 1556.
https://doi.org/10.1039/C6RA01179A
28. Dyachenko, V.D., Tkachev, R.P., and Dyachenko, A.D.,
Russ. J. Gen. Chem., 2009, vol. 79, no. 1, p. 121.
https://doi.org/10.1134/S1070363209010186
29. Nikishin, K.G., Kislyi, V.P., Nesterov, V.N., Shesto-
palov, A.M., Struchkov, Yu.T., and Semenov, V.V., Russ.
Chem. Bull., 1998, vol. 47, no. 3, p. 465.
https://doi.org/10.1023/A:1020939712830
https://doi.org/10.1007/BF02495655
17. Dotsenko, V.V., Krivokolysko, S.G., Lit-
vinov, V.P., and Chernega, A.N., Russ. Chem.
Bull., Int. Ed., 2002, vol. 51, no. 2, p. 362.
30. Nikishin, K.G., Nesterov, V.N., Kislyi, V.P., Shesto-
palov, A.M., Struchkov, Y.T., and Semenov, V.V., Russ.
Chem. Bull., 1998, vol. 47, no. 4, p. 698.
https://doi.org/10.1023/A:1015436500899
https://doi.org/10.1007/BF02495978
18. Dotsenko, V.V., Chigorina, E.A., and Krivokolysko, S.G.,
Chem. Heterocycl. Compd., 2017, vol. 53, no. 5, p. 626.
https://doi.org/10.1007/s10593-017-2103-z
31. Rodinovskaya, L.A., Fedorov, A.E., Shestopalov,
A.M., Belyakov, P.A., and Nikishin, K.G., Russ. Chem.
Bull., Int. Ed., 2013, vol. 62, no. 10, p. 2214.
19. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov,
V.P., Monatsh. Chem., 2008, vol. 139, no. 3, p. 271.
https://doi.org/10.1007/s00706-007-0784-1
https://doi.org/10.1007/s11172-013-0321-9
32. Rodinovskaya, L.A., Sharanin, Yu.A., Litvinov, V.P., Shes-
topalov, A.M., Promonenkov, V.K., Zolotarev, B.M., and
Mortikov, V.Yu., J. Org. Chem. USSR, 1985, vol. 21,
no. 11, p. 2230.
20. Kumar, G.S., Poornachandra, Y., Reddy, K.R., Ku-
mar, C.G., and Narsaiah, B., Synth. Com-
mun., 2017, vol. 47, no. 20, p. 1864.
33. A r t y o m o v, V. A . , R o d i n o v s k a y a , L . A . ,
S h e s t o p a l o v, A . M . , a n d L i t v i n o v, V. P. ,
https://doi.org/10.1080/00397911.2017.1354379
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS AND PROPERTIES OF NEW FLUORINE-CONTAINING
1751
Tetrahedron, 1996, vol. 52, no. 3, p. 1011.
https://doi.org/10.1016/0040-4020(95)00935-3
34. Kislyi, V.P., Nikishin, K.G., Kruglova, E.Y., Shestopa-
lov, A.M., Semenov, V.V., Gakh, A.A., and Buchanan, A.C.,
Tetrahedron, 1996, vol. 52, no. 33, p. 10841.
https://doi.org/10.1016/0040-4020(96)00632-1
35. Shestopalov, A.M., Kislyi, V.P., Kruglova, E.Y., Niki-
shin, K.G., Semenov, V.V., Buchanan, A.C., and Gakh, A.A.,
J. Comb. Chem., 2000, vol. 2, no. 1, p. 24.
try of Thienopyridines and Related Systems), Moscow:
Nauka, 2006, p. 6.
46. Buryi, D.S., Aksenov, N.A., and Dotsenko, V.V.,
Fluorine Notes, 2018, no. 4 (119).
https://doi.org/10.17677/fn20714807.2018.04.02
47. Sander, T., OSIRIS Property Explorer, Idorsia Pharma-
ceuticals, Switzerland.
http://www.organic-chemistry.org/prog/peo/
48. Lipinski, C.A., Lombardo, F., Dominy, B.W., and Fee-
ney, P.J., Adv. Drug Delivery Rev., 1997, vol. 23, nos. 1–3,
p. 4.
https://doi.org/10.1016/S0169-409X(96)00423-1
49. Lipinski, C.A., Drug Discovery Today: Technol.,
2004, vol. 1, no. 4, p. 337.
https://doi.org/10.1016/j.ddtec.2004.11.007
50. Lipinski, C.A., Lombardo, F., Dominy, B.W., and Fee-
ney, P.J., Adv. Drug Delivery Rev., 2012, vol. 64,
Suppl., p. 4.
https://doi.org/10.1021/cc990036r
36. Dyachenko, V.D., Dyachenko, I.V., and Nenajden-
ko, V.G., Russ. Chem. Rev., 2018, vol. 87, no. 1, p. 1.
https://doi.org/10.1070/RCR4760
37. Zhou, T.T., Ma, F., Shi, X.F., Xu, X., Du, T., Guo, X.D.,
Wang, G.H., Yu, L., Rukachaisirikul, V., Hu, L.H., Chen, J.,
and Shen, X., J. Mol. Endocrinol., 2017, vol. 59, no. 2,
p. 151.
https://doi.org/10.1530/JME-17-0121
38. Latli, B., Eriksson, M., Hrapchak, M., Busacca, C.A.,
and Senanayake, C.H., J. Labelled Compd. Radiopharm.,
2016, vol. 59, no. 8, p. 300.
https://doi.org/10.1016/j.addr.2012.09.019
51. Daina, A., Michielin, O., and Zoete, V., Sci. Rep.,
2017, vol. 7, article no. 42 717.
https://doi.org/10.1002/jlcr.3398
https://doi.org/10.1038/srep42717
39. Ginn, J.D., Sorcek, R.J., Turner, M.R., and Young, E.R.R.,
US Patent no. 2007 293 533, 2007.
40. Chen, Z., Cirillo, P.F., Disalvo, D., Liu, W., Marshall, D.R.,
Wu, L., and Young, E.R.R., WO Patent no. 2005 056 562,
2005.
41. Reichelt, C., Ludwig, A., and Leistner, S., EP Patent
no. 1 683 799, 2006.
42. Reichelt, C., Ludwig, A., Schulze, A., Daghish, M.,
Leistner, S., Kroedel, A., and Heinicke, J., WO Patent
no. 2006 010 567, 2006.
52. Gfeller, D., Grosdidier, A., Wirth, M., Daina, A.,
Michielin, O., and Zoete, V., Nucleic Acids
Res., 2014, vol. 42, no. W1, p. W32.
https://doi.org/10.1093/nar/gku293
53. PASS Online, Laboratory for Structure-Function Based
Drug Design, Institute of Biomedical Chemistry (IBMC),
Moscow, Russia. http://www.pharmaexpert.ru/passonline/
predict.php
54. Molinspiration Property Calculation Service, Molin-
spiration Cheminformatics, Slovak Republic, 2002.
www.molinspiration.com
43. Litvinov, V.P., Dotsenko, V.V., and Krivokolysko, S.G.,
Russ. Chem. Bull., Int. Ed., 2005, vol. 54, no. 4, p. 864.
https://doi.org/10.1007/s11172-005-0333-1
55. Martin, Y.C., J. Med. Chem., 2005, vol. 48, no. 9,
p. 3164.
44. Litvinov, V.P., Dotsenko, V.V., and Krivokolysko, S.G.,
Adv. Heterocycl. Chem., 2007, vol. 93, p. 117.
https://doi.org/10.1016/S0065-2725(06)93003-7
45. Litvinov, V.P., Dotsenko, V.V., and Krivokolysko, S.G.,
Khimiya tienopiridinov i rodstvennykh sistem (Chemis-
https://doi.org/10.1021/jm0492002
56. Dotsenko, V.V., Krivokolysko, S.G., Polovinko, V.V.,
and Litvinov, V.P., Chem. Heterocycl. Compd., 2012,
vol. 48, no. 2, p. 309.
https://doi.org/10.1007/s10593-012-0991-5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019