Synthesis of cyclic D-(+)-camphoric acid imides and study of their antiviral activity

Article abstract of DOI:10.1007/s10593-020-02728-y

[Figure not available: see fulltext.] Several D-(+)-camphoric acid imides, not previously described in the literature, were synthesized with good yields. The synthesis of previously known imides was improved. The cytotoxicity and antiviral activity of all synthesized imides were studied.

Full text of DOI:10.1007/s10593-020-02728-y

DOI 10.1007/s10593-020-02728-y
Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
Synthesis of cyclic D-(+)-camphoric acid imides
and study of their antiviral activity
1
,2
1,2
Vladimir V. Chernyshov *, Olga I. Yarovaya ,
2
1,2
Roman Yu. Peshkov , Nariman F. Salakhutdinov
1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of Russian Academy of Sciences, ,
9
Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
2
Novosibirsk State University,
Pirogova St., Novosibirsk 630090, Russia
е-mail: vladimir.chernyshov2012@yandex.ru
2
Published in Khimiya Geterotsiklicheskikh Soedinenii,
020, 56(6), 763–768
Submitted March 19, 2020
Accepted April 13, 2020
2
Several D-(+)-camphoric acid imides, not previously described in the literature, were synthesized with good yields. The synthesis of
previously known imides was improved. The cytotoxicity and antiviral activity of all synthesized imides were studied.
Keywords: D-(+)-camphoric acid, D-(+)-camphoric acid anhydride, imides, antiviral activity, cytotoxicity.
Monoterpenoids are found in abundance in nature and
have been of keen interest among researchers during all the
periods of the development of organic chemistry. This
interest is still high in the 21st century when the problem of
using monoterpenoids as a renewable source for the
synthesis of biologically active compounds is among the
example, Komissarov et al. found that some camphoric
acid imides display pronounced tranquilizing, neuroleptic,
12
and antiemetic activities and low toxicity. One should
also note the work of Takeda et al. where imides 4 were
used in peptide synthesis.13 Some examples of imides 4
found in the literature, synthesized in the first half of the
20th century, were not characterized by a set of physico-
1
high-priority ones. Earlier, a library of (+)-camphor and
2
14–17
borneol derivatives was synthesized in our laboratory,
chemical data and were not tested for biological activity.
3,4
which showed a wide range of antiviral activity. Thus,
the task was set to study the biological activity of hetero-
cyclic derivatives of D-(+)-camphoric acid 1, a product of
There are few recent works, in which D-(+)-camphoric acid
1 and its anhydride 2 appear as starting compounds for the
18
19,20
synthesis of amino acids, chiral ligands,
and other
21
(
+)-camphor oxidation. It was shown that it is possible to
derivatives. Based on the above, we can say that at the
moment in the literature there are practically no studies
aimed for the synthesis of camphoric acid imides and their
biological activity. Herein, we report a synthetic pathway
that allows obtaining imides 4a–t from anhydride 2 and
different amines or hydrazides 3a–t with good yields.
In the first stage, anhydride 2 was synthesized with good
synthesize new heterocyclic compounds, analogs of
alkaloids, from compound 1 and diamines of various
5
structures. However, it was found that their antiviral
activity is much lower than that of (+)-camphor derivatives.
Thus, the next step in our work was the study of the
biological activity of another class of D-(+)-camphoric acid
derivatives – D-(+)-camphoric acid imides 4. As it is known,
amides and imides containing heterocyclic fragment often
22
yield by a known method (Scheme 1). Then, various
amines and hydrazides were acylated with the obtained
anhydride 2. Thus, refluxing a mixture of anhydride 2 with
the corresponding amines or hydrazides 3m,n,q–t in EtOH
allows us to obtain compounds 4m,n,q–t in good yields.
Unfortunately, under these conditions, no interaction was
6
–11
have diverse biological activity.
An analysis of the literature data showed that there are
few works devoted to the synthesis and study of the
biological activity of D-(+)-camphoric acid imides. For
0
009-3122/20/56(6)-0763©2020 Springer Science+Business Media, LLC
763

Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
Scheme 1. Synthesis of camphoric acid anhydride and imides
observed between anhydride 2 and amines containing an
aromatic substituent, since the reaction was slow with a
low conversion of anhydride 2. Thus, compounds 4k,l,o,p
were synthesized by refluxing a mixture of anhydride 2
with amines 3k,l,o,p in o-xylene. A low yield of the
reaction product was observed during synthesis of
compound 4o. We decided to conduct the reaction between
anhydride 2 and amine 3o under the conditions that we had
activity of different classes of compounds, among which
several leaders can be distinguished: benzavir-2 (against
24
Zika virus, EC50 0.8 ± 0.1 µM), benzothiazole derivatives
(against yellow fever virus, EC50 up to 0.9 ± 0.1 µM),25
imidazole-4,5-dicarboxamide derivative I45DC (against
26
yellow fever virus, EC50 1.8 ± 0.1 µM), N,N'-carbazoylaryl-
27
urea derivatives (against Zika virus, EC50 up to 1.6 ± 0.1 µM).
Thus, compound 4l is not less promising for further studies
of this type of activity than the presented leader compounds.
The Zika virus and the yellow fever virus belong to the
Flaviviridae family. Flaviviruses include 53 species of
viruses, including viruses that are well known to be
dangerous for humans: yellow fever virus, distinguished by
its high pathogenicity, West Nile virus, dengue virus, tick-
borne encephalitis virus, and Zika virus. The increasing
complexity of the epidemiological situation requires a rapid
search for the compounds against a wide range of viruses,
from at least one or more families. The ability of viruses to
mutate quickly and to develop resistance to the few
antiviral drugs available is also a serious problem.
5
previously developed. Conditions included heating the
mixture of reagents under reflux without solvent. To our
surprise, the reaction was completed in 30 min with the
formation of the single product 4o with a yield of 98%
according to GC-MS. We also tried to carry out the
reaction of anhydride 2 with aliphatic linear amines 3a–g
and amino alcohols 3h–j under different conditions and
always observed the absence of the products (in case of
amines 3a–g) and a complex mixture of products (in case
of amino alcohols 3h–j). However, the corresponding
products 4a–j can be synthesized with excellent yields by
heating the mixture of anhydride 2 and amines 3a–j
without any solvent under reflux.
Preliminary data on the activity of camphoric acid
derivatives presented in this paper allows us to conclude
that a more in-depth study of the antiviral activity of this
class of compounds is required.
We have previously shown that monoterpene derivatives
containing the 1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-
2
,4-dione fragment are effective inhibitors of the influenza
23
virus and are specifically active for the Marburg virus.
Experimental
Almost all new compounds synthesized in this paper have
been tested as influenza virus inhibitors, but unfortunately,
they were not active. Further, compounds were tested
against yellow fever virus, Zika virus, and Chikungunya
virus. Among all the compounds tested, only compounds 4k,l
containing the 2,6-di-tert-butylphenol fragment showed
significant activity against the Zika virus and yellow fever
virus. Compound 4k showed antiviral activity against the
Zika virus with EC50 14 ± 6 µM, whereas compound 4l was
more potent in inhibiting Zika virus in cell culture
The IR spectra were recorded on a Bruker Vector 22 FT-IR
1
13
spectrometer in KBr pellets. Н and С NMR spectra were
acquired on a Bruker DRX-500 spectrometer (500 and
125 MHz, respectively) in CDCl , with residual solvent
3
1
signals used as internal standards (7.24 ppm for H nuclei,
13
13
76.9 ppm for C nuclei). Assignments in С NMR spectra
were made based on the COSY, NOESY, as well as two-
1
13
1
13
dimensional heteronuclear H– C HSQC and H– C HMBC
experiments. High-resolution mass spectra were recorded
on a Thermo Scientific DFS instrument in full scan mode
over the m/z range of 0–500, ionization by electron impact
at 70 eV, and direct introduction of samples. The reaction
products were separated by column chromatography (60–
200 μm silica gel, Macherey-Nagel). GC-MS analysis was
performed on an Agilent 7890 A gas chromatograph with
(
EC50 1.1 ± 0.01 µM). Compound 4l also exhibited
antiviral activity against the yellow fever virus with
EC50 1.6 ± 0.3 µM. Toxicity of the tested compounds
(
СС50) was over 100 µM. At the moment, there are no
drugs against Zika virus and yellow fever virus. However,
there are some works devoted to the study of the antiviral
7
64

Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
an Agilent 5975C quadrupole mass spectrometer as a
detector, НР-5MS (30000 × 0.25) mm fused silica column,
carrier gas – helium. The identification of compounds was
performed by comparing the retention times with a series
of authentic samples and comparing the complete experi-
mentally obtained mass spectra with the mass spectral
database. Melting points were determined on a Kofler
bench. Optical rotation was measured on a PolAAr 3005
m, 12-CH
3-CH ); 2.13–2.19 (1H, m, 2-CH
1-CH); 3.58–3.65 (2H, m, 11-CH
2
); 1.69–1.74 (1H, m, 2-CH
2
); 1.83–1.91 (2H, m,
2
2
); 2.66 (1H, d, J = 6.9,
13
2
). C NMR spectrum,
δ, ppm: 13.8 (C-15); 13.9 (C-8); 19.0 (C-7); 21.8 (C-6);
22.2 (C-14); 25.2 (C-2); 27.1 (C-12); 29.0 (C-13); 34.1
(C-3); 39.2 (C-11); 44.0 (C-5); 54.3 (C-4); 56.5 (C-1);
+
176.2 (C-9); 178.2 (C-10). Found, m/z: 251.1884 [M] .
C
15
H
25NO . Calculated, m/z: 251.1880.
2
spectrometer (CHCl
3
solution). Specific rotation is expressed
(1R,5S)-3-Hexyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4b). Yield 1.24 g (85%), colorless amor-
as (°)/[(g/ml)(dm)] and concentration is expressed as g per
25.5
1
00 ml.
phous solid, [α]
D
+7.8 (c 0.51, MeOH). IR spectrum,
–1
The atom numbering in the compounds is intended for
ν, cm : 2958 (C–H st), 1728 (C=O st as), 1678 (C=O st),
1
the assignment of the NMR signals and does not necessarily
match the IUPAC nomenclature, the atom numbering is
presented in the supplementary information file.
1352 (CH δ sy), 1088 (CH γ). H NMR spectrum, δ, ppm
3
3
(J, Hz): 0.83 (3H, t, J = 6.9, 16-CH
3
); 0.92 (3H, s, 6-CH
3
);
); 1.23–1.27 (6H,
); 1.40–1.44 (2H, m, 12-CH ); 1.68–1.73
); 1.82–1.91 (2H, m, 3-CH ); 2.13–2.19 (1H,
); 2.66 (1H, d, J = 6.9, 1-CH); 3.60–3.62 (2H, m,
0.93 (3H, s, 7-CH
m, 13,14,15-CH
(1H, m, 2-CH
m, 2-CH
3
); 1.16 (3H, s, 8-CH
3
(
1R,5S)-1,8,8-Trimethyl-3-oxabicyclo[3.2.1]octane-
2
2
22
2
,4-dione (2) was synthesized by a known method. Finely
powdered Na CO (4.24 g, 40 mmol,) was mixed with the
freshly distilled SOCl (3 ml, 40 mmol, ρ 1.63 g/ml) in a
50-ml round-bottom flask at room temperature. To the
resulting powder, a solution of carboxylic acid 1 (8.00 g,
0 mmol,) in a 1:1 mixture of anhydrous CH Cl /dioxane
150 ml) was slowly added. The resulting solution was
2
2
2
3
2
13
2
11-CH ). C NMR spectrum, δ, ppm: 13.9 (C-16); 14.0
2
2
(C-8); 19.0 (C-7); 21.8 (C-6); 22.4 (C-15); 25.2 (C-2); 26.5
(C-13); 27.4 (C-12); 31.3 (C-14); 34.1 (C-3); 39.2 (C-11);
4
2
2
44.0 (C-5); 54.2 (C-4); 56.5 (C-1); 176.2 (C-9); 178.2
+
(
(C-10). Found, m/z: 265.2035 [M] . C16
lated, m/z: 265.2036.
H
27NO . Calcu-
2
refluxed. The progress of the reaction was followed by TLC
until no starting material could be detected. After cooling
to ambient temperature, the product was then filtered and
(1R,5S)-3-Heptyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4c). Yield 1.15 g (75%), colorless amor-
24.5
the residue was washed thoroughly with CH
2
Cl
2
(100 ml).
phous solid, [α]
D
+12.3 (c 1.15, EtOH). IR spectrum,
–1
Evaporation of the solvent under reduced pressure
furnished the desired anhydride, yield 6.92 g (95%).
Synthesis of compounds 4a–j,o by acylation of amines
ν, cm : 2958 (C–H st), 1728 (C=O st as), 1678 (C=O st),
1
1352 (CH
(J, Hz): 0.83 (3H, t, J = 7.0, 17-CH
0.93 (3H, s, 7-CH ); 1.16 (3H, s, 8-CH
m, 13–16-CH ); 1.41–1.46 (2H, m, 12-CH
(1H, m, 2-CH ); 1.82–1.91 (2H, m, 3-CH ); 2.13–2.19 (1H,
m, 2-CH ); 2.65 (1H, d, J = 6.9, 1-CH); 3.58–3.65 (2H, m,
3
δ sy), 1090 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.92 (3H, s, 6-CH );
); 1.18–1.28 (8H,
); 1.68–1.73
3
3
3
a–j,o. Anhydride 2 (1.00 g, 5.5 mmol,) was mixed in a round-
3
3
bottom flask with the corresponding amine 3a–j,o
2
2
(
5.5 mmol), the mixture was heated under reflux for 0.5–1 h
2
2
and then evaporated under reduced pressure. The residue
was purified by silica gel column chromatography, eluent
hexane–EtOAc, 19:1.
2
13
11-CH ). C NMR spectrum, δ, ppm: 13.9 (C-8,17); 19.0
2
(C-7); 21.8 (C-6); 22.4 (C-16); 25.2 (C-2); 26.8 (C-13);
27.4 (C-12); 28.8 (C-14); 31.6 (C-15); 34.1 (C-3); 39.2
Synthesis of compounds 4k–l,p by acylation of amines
3k,l,p. Anhydride 2 (1.00 g, 5.5 mmol) was mixed in a round-
(C-11); 44.0 (C-5); 54.3 (C-4); 56.5 (C-1); 176.2 (C-9);
+
bottom flask with the corresponding amine 3k,l,p (5.5 mmol),
the mixture was dissolved in o-xylene (50 ml). The
resulting solution was refluxed for 10–15 h and then
evaporated under reduced pressure. The residue was
purified by silica gel column chromatography, eluent
178.2 (C-10). Found, m/z: 279.2191 [M] . C17
Calculated, m/z: 279.2193.
H
29NO .
2
(1R,5S)-1,8,8-Trimethyl-3-octyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4d). Yield 1.13 g (70%), colorless amor-
25.0
–1
phous solid, [α]
D
+9.3 (c 1.5, EtOH). IR spectrum, ν, cm :
3
hexane–CHCl , 3:1.
2958 (C–H st), 1728 (C=O st as), 1678 (C=O st), 1352
1
Synthesis of compounds 4m,n,q–t by acylation of
amines 3m,n,q–t. Anhydride 2 (1.00 g, 5.5 mmol) was
mixed in a round-bottom flask with the corresponding
amine 3m,n,q–t (5.5 mmol), the mixture was dissolved in
EtOH (50 ml). The resulting solution was refluxed for 2–6 h
and then evaporated under reduced pressure. The residue
was purified by silica gel column chromatography, eluent
hexane–EtOAc, 19:1.
(CH
(J, Hz): 0.83 (3H, t, J = 7.0, 18-CH
0.93 (3H, s, 7-CH ); 1.16 (3H, s, 8-CH
3
δ sy), 1088 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.91 (3H, s, 6-CH );
); 1.21–1.26 (10H,
3
3
3
3
m, 13–17-CH ); 1.42–1.45 (2H, m, 12-CH ); 1.68–1.73
2
2
(1H, m, 2-CH
m, 2-CH
2
); 1.82–1.90 (2H, m, 3-CH
2
); 2.12–2.19 (1H,
2
); 2.65 (1H, d, J = 6.9, 1-CH); 3.57–3.64 (2H, m,
13
11-CH ). C NMR spectrum, δ, ppm: 13.9 (C-18); 14.0
2
(C-8); 19.1 (C-7); 21.9 (C-6); 22.5 (C-17); 25.2 (C-2); 26.9
(C-13); 27.4 (C-12); 29.0 (C-14); 29.1 (C-15); 31.6 (C-16);
34.1 (C-3); 39.2 (C-11); 44.0 (C-5); 54.2 (C-4); 56.5 (C-1);
(
1R,5S)-1,8,8-Trimethyl-3-pentyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4a). Yield 1.10 g (80%), colorless amor-
26.2
+
phous solid, [α]
D
+8.5 (c 1.4, CHCl
3
). IR spectrum,
176.2 (C-9); 178.2 (C-10). Found, m/z: 293.2351 [M] .
–1
ν, cm : 2960 (C–H st), 1728 (C=O st as), 1676 (C=O st),
C
18
H
31NO . Calculated, m/z: 293.2349.
2
1
1
354 (CH
3
δ sy), 1086 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.92 (3H, s, 6-CH );
); 1.16 (3H, s, 8-CH ); 1.20–1.26 (2H,
); 1.26–1.31 (2H, m, 14-CH ); 1.42–1.47 (2H,
(1R,5S)-3-Decyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4e). Yield 1.24 g (70%), colorless amor-
(
J, Hz): 0.84 (3H, t, J = 7.2, 15-CH
3
3
19.5
0
.93 (3H, s, 7-CH
3
3
phous solid, [α]
D
+4.5 (c 1.16, CHCl
3
). IR spectrum,
–1
m, 13-CH
2
2
ν, cm : 2958 (C–H st), 1730 (C=O st as), 1678 (C=O st),
7
65

Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
1
1
354 (CH
3
δ sy), 1092 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.95 (3H, s, 6-CH );
); 1.25–1.30 (14H,
); 1.68–1.77
(1R,5S)-3-(2-Hydroxypropyl)-1,8,8-trimethyl-3-aza-
bicyclo[3.2.1]octane-2,4-dione (4i). Yield 1.12 g (85%),
(
J, Hz): 0.87 (3H, t, J = 6.9, 20-CH
3
3
28.0
0
.96 (3H, s, 7-CH
3
); 1.19 (3H, s, 8-CH
3
colorless amorphous solid, [α]
D
+5.5 (c 2, CHCl ).
3
–1
m, 13–19-CH
2
); 1.45–1.49 (2H, m, 12-CH
); 1.85–1.95 (2H, m, 3-CH ); 2.15–2.23 (1H,
); 2.69 (1H, d, J = 6.9, 1-CH); 3.65 (2H, t, J = 7.6,
2
IR spectrum, ν, cm : 3495 (O–H st), 2966 (C–H st), 1726
(C=O st as), 1674 (C=O st), 1350 (CH δ sy), 1176 (CH γ).
H NMR spectrum, δ, ppm (J, Hz): 0.93 (3H, s, 6-CH );
0.94 (3H, s, 7-CH ); 1.16 (3H, s, 8-CH ); 1.68–1.74 (3H,
m, 12-CH , 2-CH ); 1.84–1.94 (2H, m, 3-CH ); 2.16–2.22
(1H, m, 2-CH ); 2.69 (1H, d, J = 6.9, 1-CH); 3.45 (2H, t,
J = 5.8, 13-CH
(
1H, m, 2-CH
2
2
3
3
1
m, 2-CH
2
3
1
3
1
1-CH
2
). C NMR spectrum, δ, ppm: 14.2 (C-8,20); 19.3
3
3
(
C-7); 22.1 (C-6); 22.7 (C-19); 25.4 (C-2); 27.1 (C-13);
2
2
2
2
3
1
7.7 (C-12); 29.4 (C-14,17); 29.6 (C-15,16); 32.0 (C-18);
4.4 (C-3); 39.5 (C-11); 44.2 (C-5); 54.5 (C-4); 56.8 (C-1);
2
1
3
2
); 3.75–3.81 (2H, m, 11-CH ). C NMR
2
+
76.4 (C-9); 178.4 (C-10). Found, m/z: 321.2670 [M] .
spectrum, δ, ppm: 13.9 (C-8); 19.2 (C-7); 21.8 (C-6); 25.3
C
20
(
H
35NO
2
. Calculated, m/z: 321.2662.
(C-2); 30.7 (C-12); 34.2 (C-3); 35.5 (C-11); 44.1 (C-5);
1R,5S)-3-Dodecyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4f). Yield 1.34 g (70%), colorless amor-
54.4 (C-4); 56.4 (C-1); 58.9 (C-13); 177.1 (C-9); 179.0 (C-10).
+
Found, m/z: 239.1522 [M] . C13
H
21NO . Calculated, m/z:
3
19.4
–1
phous solid, [α]
2
D
+6.2 (c 1.4, CHCl
3
). IR spectrum, ν, cm :
239.1516.
956 (C–H st), 1730 (C=O st as), 1678 (C=O st), 1352
(1R,5S)-3-(2-Hydroxypentyl)-1,8,8-trimethyl-3-aza-
bicyclo[3.2.1]octane-2,4-dione (4j). Yield 1.25 g (85%),
colorless amorphous solid, [α]
1
(
(
CH
3
δ sy), 1082 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.96 (3H, s, 6-CH );
); 1.20 (3H, s, 8-CH ); 1.25–1.29 (18H,
); 1.46–1.49 (2H, m, 12-CH ); 1.72–1.78
); 1.86–1.95 (2H, m, 3-CH ); 2.16–2.23 (1H,
); 2.70 (1H, d, J = 6.9, 1-CH); 3.65 (2H, t, J = 7.6,
28.0
J, Hz): 0.88 (3H, t, J = 6.9, 22-CH
3
3
D
+3.6 (c 2, CHCl ).
3
–1
0
.97 (3H, s, 7-CH
3
3
IR spectrum, ν, cm : 3470 (O–H st), 2939 (C–H st), 1726
(C=O st as), 1674 (C=O st), 1352 (CH δ sy), 1080 (CH γ).
H NMR spectrum, δ, ppm (J, Hz): 0.92 (3H, s, 6-CH );
0.92 (3H, s, 7-CH ); 1.15 (3H, s, 8-CH ); 1.29–1.34 (2H,
m, 13-CH ); 1.45–1.50 (2H, m, 14-CH ); 1.52–1.57 (2H,
m, 12-CH ); 1.68–1.73 (1H, m, 2-CH ); 1.82–1.91 (2H, m,
3-CH ); 2.13–2.18 (1H, m, 2-CH ); 2.66 (1H, d, J = 6.9,
1-CH); 3.59 (2H, t, J = 6.5, 13-CH ); 3.61–3.64 (2H, m,
m, 13–21-CH
2
2
3
3
1
(
1H, m, 2-CH
2
2
3
m, 2-CH
2
3
3
1
3
1
1-CH
2
). C NMR spectrum, δ, ppm: 14.2 (C-8,22); 19.3
2
2
(
C-7); 22.1 (C-6); 22.8 (C-21); 25.4 (C-2); 27.1 (C-13);
2
2
2
7.7 (C-12); 29.4 (C-14,17); 29.6 (C-15,16); 29.7
2
2
(
(
C-19,20); 32.0 (C-18); 34.4 (C-3); 39.5 (C-11); 44.2
2
1
3
C-5); 54.5 (C-4); 56.8 (C-1); 176.4 (C-9); 178.4 (C-10).
11-CH ). C NMR spectrum, δ, ppm: 13.9 (C-8); 19.0
2
+
Found, m/z: 349.2974 [M] . C22
H
39NO
2
. Calculated, m/z:
(C-7); 21.8 (C-6); 23.0 (C-13); 25.2 (C-2); 27.1 (C-14);
32.1 (C-12); 34.1 (C-3); 39.0 (C-11); 44.0 (C-5); 54.3
3
49.2975.
1R,5S)-1,8,8-Trimethyl-3-octadecyl-3-azabicyclo[3.2.1]-
octane-2,4-dione (4g). Yield 1.67 g (70%), colorless amor-
(
(C-4); 56.5 (C-1); 62.5 (C-15); 176.3 (C-9); 178.3 (C-10).
+
Found, m/z: 267.1830 [M] . C15
267.1829.
H
25NO . Calculated, m/z:
3
23.0
phous solid, [α]
D
+5.8 (c 1.55, CHCl
3
). IR spectrum,
–1
ν, cm : 2924 (C–H st), 1730 (C=O st as), 1678 (C=O st),
(1R,5S)-3-(3,5-Di-tert-butyl-4-hydroxyphenethyl)-
1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-dione (4k).
1
1
354 (CH
3
δ sy), 1086 (CH
3
γ). H NMR spectrum, δ, ppm
); 0.97 (3H, s, 6-CH );
); 1.21 (3H, s, 8-CH ); 1.26–1.31 (30H,
); 1.47–1.51 (2H, m, 12-CH ); 1.73–1.78
); 1.87–1.96 (2H, m, 3-CH ); 2.17–2.24 (1H,
); 2.70 (1H, d, J = 6.9, 1-CH); 3.66 (2H, t, J = 7.6,
1
9
(
J, Hz): 0.89 (3H, t, J = 6.9, 28-CH
3
3
Yield 1.25 g (55%), red amorphous solid, [α]
D
+3.93
–1
0
.98 (3H, s, 7-CH
3
3
(c 1.375, CHCl
2958 (C–H st), 1728 (C=O st as), 1674 (C=O st), 1356
(CH δ sy), 1109 (CH γ), 1018 (C–H δ ip), 922 (C=C).
H NMR spectrum, δ, ppm (J, Hz): 0.89 (3H, s, 6-CH );
0.89 (3H, s, 7-CH ); 1.13 (3H, s, 8-CH ); 1.40 (18H, s, 20–
22,24–26-CH ); 1.41–1.46 (1H, m, 2-CH ); 1.50–1.55 (1H,
m, 3-CH ); 1.73–1.78 (1H, m, 3-CH ); 2.02–2.08 (1H, m,
2-CH ); 2.60 (1H, d, J = 6.9, 1-CH); 2.74 (2H, t, J = 7.6,
12-CH ); 3.92–3.95 (2H, m, 11-CH ); 5.05 (1H, s, OH);
3
). IR spectrum, ν, cm : 3643 (O–H st),
m, 13–27-CH
2
2
(
1H, m, 2-CH
2
2
3
3
1
m, 2-CH
2
3
1
3
1
1-CH
C-7); 22.1 (C-6); 22.8 (C-27); 25.5 (C-2); 27.1 (C-13);
7.7 (C-12); 29.4 (C-14); 29.5 (C-25); 29.6 (C-15); 29.7
C-16–24); 32.0 (C-26); 34.4 (C-3); 39.5 (C-11); 44.3 (C-
); 54.6 (C-4); 56.8 (C-1); 176.5 (C-9); 178.4 (C-10).
2
). C NMR spectrum, δ, ppm: 14.2 (C-8,28); 19.4
3
3
(
3
2
2
2
2
(
2
5
2
2
+
13
Found, m/z: 433.3914 [M] . C28
33.3914.
1R,5S)-3-(2-Hydroxyethyl)-1,8,8-trimethyl-3-azabicyclo-
3.2.1]octane-2,4-dione (4h). Yield 1.11 g (90%), colorless
H
51NO
2
. Calculated, m/z:
7.00 (2H, s, H-14,18). C NMR spectrum, δ, ppm: 13.9 (C-8);
19.1 (C-7); 21.8 (C-6); 25.0 (C-2); 30.1 (C-20–22,24–26);
33.1 (C-12); 33.9 (C-3); 34.1 (C-19,23); 39.7 (C-11); 44.0
(C-5); 54.2 (C-4); 56.5 (C-1); 125.5 (C-14,18); 128.6
4
(
[
22.0
amorphous solid, [α]
D
+1.5 (c 0.55, CHCl
3
). IR spectrum,
(C-13); 135.5 (C-15,17); 152.2 (C-16); 176.2 (C-9); 178.1
–1
+
ν, cm : 3483 (O–H st), 2968 (C–H st), 1728 (C=O st as),
(C-10). Found, m/z: 413.2920 [M] . C26
lated, m/z: 413.2925.
H
39NO . Calcu-
3
1
1
674 (C=O st), 1343 (CH
3
δ sy), 1036 (CH
3
γ). H NMR
); 0.98 (3H, s,
); 1.73–1.78 (1H, m, 2-CH );
); 2.15–2.21 (1H, m, 2-CH ); 2.70
); 3.88–
spectrum, δ, ppm (J, Hz): 0.93 (3H, s, 6-CH
3
(1R,5S)-3-[3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-
propyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-
dione (4l). Yield 1.17 g (50%), red amorphous solid,
7
-CH
3
); 1.17 (3H, s, 8-CH
3
2
1
.89–1.92 (2H, m, 3-CH
2
2
28
–1
(
1H, d, J = 6.9, 1-CH); 3.68–3.71 (2H, m, 12-CH
2
[α]
D
+9.29 (c 1.83, CHCl
3
). IR spectrum, ν, cm : 3639
1
3
3
.90 (2H, m, 11-CH
2
). C NMR spectrum, δ, ppm: 13.9
(O–H st), 2960 (C–H st), 1728 (C=O st as), 1676 (C=O st),
(
(
C-8); 19.1 (C-7); 21.9 (C-6); 25.1 (C-2); 34.1 (C-3); 41.5
1358 (CH
3
δ sy), 1173 (CH
(C=C). H NMR spectrum, δ, ppm (J, Hz): 0.94 (3H, s,
6-CH ); 0.95 (3H, s, 7-CH ); 1.19 (3H, s, 8-CH ); 1.41
(18H, s, 21–23,25–27-CH ); 1.70–1.79 (3H, m, 2,12-CH );
3
γ), 1040 (C–H δ ip), 887
1
C-11); 44.2 (C-5); 54.4 (C-4); 56.4 (C-1); 61.2 (C-12);
+
1
77.3 (C-9); 179.2 (C-10). Found, m/z: 226.1440 [M] .
3
3
3
C
12
H
19NO
3
. Calculated, m/z: 225.1359.
3
2
7
66

Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
+
1
.84–1.92 (2H, m, 3-CH
.53 (2H, m, 13-CH ); 2.69 (1H, d, J = 6.9, 1-CH); 3.71–3.74
); 5.02 (1H, s, OH); 6.96 (2H, s, H-15,19).
C NMR spectrum, δ, ppm: 14.0 (C-8); 19.2 (C-7); 21.8
2
); 2.15–2.21 (1H, m, 2-CH
2
); 2.50–
(C-10). Found, m/z: 301.1669 [M] . C18
lated, m/z: 301.1673.
H
23NO . Calcu-
3
2
2
(
2H, m, 11-CH
2
(1R,5S)-3-[2-(1H-Indol-2-yl)ethyl]-1,8,8-trimethyl-3-aza-
bicyclo[3.2.1]octane-2,4-dione (4p). Yield 890 mg (50%),
1
3
18.5
(
(
(
(
(
C-6); 25.2 (C-2); 29.8 (C-12); 30.2 (C-21–23,25–27); 33.3
C-13); 34.1 (C-20,24); 34.2 (C-3); 39.3 (C-11); 44.0
C-5); 54.3 (C-4); 56.5 (C-1); 124.7 (C-15,19); 132.0
yellow solid, mp 167.9°С, [α]
D
+15 (c 0.28, CHCl ).
3
–1
IR spectrum, ν, cm : 3356 (N–H st), 2962 (C–H st), 1724
(C=O st as), 1670 (C=O st), 1350 (CH δ sy), 743 (C=C).
H NMR spectrum, δ, ppm (J, Hz): 0.94 (3H, s, 6-CH );
0.97 (3H, s, 7-CH ); 1.20 (3H, s, 8-CH ); 1.59–1.63 (1H,
m, 2-CH ); 1.75–1.79 (1H, m, 3-CH ); 1.83–1.88 (1H, m,
3-CH ); 2.10–2.16 (1H, m, 2-CH ); 2.69 (1H, d, J = 6.9,
1-CH); 2.94 (2H, t, J = 7.9, 12-CH ); 3.94–4.02 (2H, m,
3
1
C-14); 135.6 (C-16,18); 151.8 (C-17); 176.2 (C-9); 178.2
3
+
C-10). Found, m/z: 427.3084 [M] . C27
H
41NO
3
. Calcu-
3
3
lated, m/z: 427.3081.
1R,5S)-3-[3-(Diethylamino)propyl]-1,8,8-trimethyl-3-
azabicyclo[3.2.1]octane-2,4-dione (4m). Yield 1.21 g (75%),
2
2
(
2
2
2
2
5.2
yellow amorphous solid, [α]
D
+10.3 (c 0.56, EtOH).
11-CH ); 7.02–7.03 (1H, m, H-16); 7.10–7.13 (1H, m,
2
–
1
IR spectrum, ν, cm : 2966 (C–H st), 1726 (C=O st as),
H-17); 7.15–7.18 (1H, m, H-18); 7.32–7.33 (1H, m, H-14);
1
13
1
678 (C=O st), 1356 (CH
3
δ sy), 1113 (CH
3
γ). H NMR
); 0.90 (3H, s,
); 1.14 (3H, s,
7.78–7.80 (1H, m, H-19); 8.03 (1H, s, NH). C NMR
spectrum, δ, ppm (J, Hz): 0.90 (3H, s, 6-CH
3
spectrum, δ, ppm: 14.0 (C-8); 19.2 (C-7); 21.9 (C-6); 23.2
(C-12); 25.1 (C-2); 34.0 (C-3); 39.7 (C-11); 44.1 (C-5);
54.3 (C-4); 56.5 (C-1); 110.8 (C-14); 112.6 (C-13); 119.1
(C-19); 119.3 (C-17); 121.9 (C-16,18); 127.5 (C-15); 136.0
7
8
2
2
1
-CH
-CH
-CH
-CH
3
3
2
2
); 0.97 (6H, t, J = 7.2, 16,17-CH
3
); 1.59–1.64 (2H, m, 12-CH ); 1.67–1.71 (1H, m,
2
); 1.81–1.89 (2H, m, 3-CH
2
); 2.11–2.17 (1H, m,
); 2.43 (2H, t, J = 7.3, 13-CH
2
); 2.50 (4H, q, J = 7.2,
(C-20); 176.3 (C-9); 178.3 (C-10). Found, m/z: 324.1831
+
4,15-CH
2
); 2.64 (1H, d, J = 6.9, 1-CH); 3.61–3.64 (2H,
[M] . C20
H
24
N
2
O . Calculated, m/z: 324.1832.
2
13
m, 11-CH
2
). C NMR spectrum, δ, ppm: 11.1 (C-16,17);
3.9 (C-8); 19.1 (C-7); 21.8 (C-6); 24.5 (C-12); 25.1 (C-2);
4.1 (C-3); 37.6 (C-11); 44.0 (C-5); 46.4 (C-14,15); 49.7
(1R,5S)-1,8,8-Trimethyl-3-[3-(morpholin-4-yl)propyl]-
3-azabicyclo[3.2.1]octane-2,4-dione (4q). Yield 340 mg
1
3
26.0
(20%), yellow amorphous solid, [α]
D
+9.4 (c 1.0, EtOH).
–1
(
C-13); 54.2 (C-4); 56.4 (C-1); 176.1 (C-9); 178.1 (C-10).
IR spectrum, ν, cm : 2960 (C–H st), 1726 (C=O st as),
+
1
Found, m/z: 294.2298 [M] . C17
94.2302.
1R,5S)-3-[3-(Dibutylamino)propyl]-1,8,8-trimethyl-
H
30
N
2
O
2
. Calculated, m/z:
1676 (C=O st), 1354 (CH
spectrum, δ, ppm (J, Hz): 0.92 (3H, s, 6-CH
7-CH ); 1.15 (3H, s, 8-CH ); 1.61–1.66 (2H, m, 12-CH
1.68–1.72 (1H, m, 2-CH ); 1.82–1.91 (2H, m, 3-CH ); 2.13–
); 2.31 (2H, t, J = 7.3, 13-CH ); 2.36–
3
δ sy), 1119 (C–O st). H NMR
); 0.92 (3H, s,
);
2
3
(
3
3
2
3
-azabicyclo[3.2.1]octane-2,4-dione (4n). Yield 1.35 g (70%),
2
2
2
5.2
yellow amorphous solid, [α]
D
+28.8 (c 0.66, CHCl
3
).
2.19 (1H, m, 2-CH
2
2
–
1
IR spectrum, ν, cm : 2958 (C–H st), 1730 (C=O st as),
2.43 (4H, m, 14,15-CH
2
); 2.65 (1H, d, J = 6.9, 1-CH); 3.65–
1
13
1
678 (C=O st), 1354 (CH
3
δ sy), 1074 (CH
3
γ). H NMR
);
); 1.16 (3H, s,
); 1.33–1.38 (4H, m,
); 1.56–1.61 (2H, m, 12-CH ); 1.69–1.73 (1H,
); 1.83–1.91 (2H, m, 3-CH ); 2.13–2.19 (1H, m,
); 2.33 (4H, q, J = 7.3, 14,15-CH ); 2.38 (2H, t, J = 7.3,
); 2.66 (1H, d, J = 6.9, 1-CH); 3.64 (2H, t, J = 7.5,
3.69 (6H, m, 11,16,17-CH
2
). C NMR spectrum, δ, ppm:
spectrum, δ, ppm (J, Hz): 0.86 (6H, t, J = 7.3, 20,21-CH
3
13.9 (C-8); 19.0 (C-7); 21.8 (C-6); 24.4 (C-12); 25.1 (C-2);
34.1 (C-3); 37.5 (C-11); 44.0 (C-5); 53.4 (C-14,15); 54.2
0
8
1
.92 (3H, s, 6-CH
-CH ); 1.22–1.28 (4H, m, 18,19-CH
6,17-CH
3
); 0.93 (3H, s, 7-CH
3
3
2
(C-4); 56.2 (C-13); 56.4 (C-1); 66.9 (C-16,17); 176.2 (C-9);
+
2
2
178.2 (C-10). Found, m/z: 308.2100 [M] . C17
H N O .
28 2 3
m, 2-CH
2
2
Calculated, m/z: 308.2094.
2
-CH
3-CH
1-CH
2
2
(1R,5S)-1,8,8-Trimethyl-3-[2-(piperazin-1-yl)ethyl]-3-
1
1
2
2
azabicyclo[3.2.1]octane-2,4-dione (4r). Yield 320 mg
13
25.2
). C NMR spectrum, δ, ppm: 13.9 (C-8); 14.0
(20%), yellow amorphous solid, [α]
D
+1.9 (c 1.5, CHCl ).
3
–1
(
(
(
(
C-20,21); 19.1 (C-7); 20.6 (C-18,19); 21.8 (C-6); 25.1
C-12); 25.2 (C-2); 29.2 (C-16,17); 34.1 (C-3); 37.8
C-11); 44.0 (C-5); 51.5 (C-13); 53.6 (C-14,15); 54.3
IR spectrum, ν, cm : 3340 (N–H st), 2960 (C–H st), 1728
(C=O st as), 1674 (C=O st), 1346 (CH δ sy), 1106 (C–N
st), 1013 (C–Br st). H NMR spectrum, δ, ppm (J, Hz):
3
1
C-4); 56.5 (C-1); 176.2 (C-9); 178.1 (C-10). Found, m/z:
0.91 (3H, s, 6-CH
3
); 0.98 (3H, s, 7-CH ); 1.15 (3H, s,
3
+
3
50.2930 [M] . C21
H
38
N
2
O
2
. Calculated, m/z: 350.2928.
8-CH
3-CH
3
); 1.72–1.77 (1H, m, 2-CH
2
); 1.84–1.92 (2H, m,
); 2.39–2.46 (6H, m,
(
1R,5S)-3-(4-Methoxybenzyl)-1,8,8-trimethyl-3-aza-
bicyclo[3.2.1]octane-2,4-dione (4o). Yield 1.10 g (65%),
2
); 2.12–2.18 (1H, m, 2-CH
2
12–14-CH
2
); 2.65 (1H, d, J = 6.9, 1-CH); 2.76–2.78 (4H,
2
4.5
13
colorless amorphous solid, [α]
D
+0.74 (c 1.35, CHCl
3
).
m, 15,16-CH
2
); 3.74–3.82 (2H, m, 11-CH
2
). C NMR
–
1
IR spectrum, ν, cm : 2966 (C–H st), 1726 (C=O st as),
spectrum, δ, ppm: 13.9 (C-8); 19.1 (C-6); 21.8 (C-7); 25.2
1
(
(
676 (C=O st), 1514 (C–O–C st as), 1346 (CH
3
δ sy), 1248
C–O–C st sy), 984 (=CH δ). H NMR spectrum, δ, ppm
J, Hz): 0.82 (3H, s, 6-CH ); 0.90 (3H, s, 7-CH ); 1.15 (3H,
); 1.65–1.69 (1H, m, 2-CH ); 1.78–1.88 (2H, m,
); 2.11–2.18 (1H, m, 2-CH ); 2.68 (1H, d, J = 6.9,
-CH); 3.74 (3H, s, 18-CH ); 4.76 (2H, s, 11-CH ); 6.76–
(C-2); 34.2 (C-3); 35.8 (C-11); 44.0 (C-5); 45.9 (C-15,16);
1
54.2 (C-4); 54.3 (C-12); 55.5 (C-13,14); 56.6 (C-1); 176.3
+
3
3
(C-9); 178.2 (C-10). Found, m/z: 293.2095 [M] . C16
H
27
N
3
O .
2
s, 8-CH
3
2
Calculated, m/z: 293.2098.
3
1
6
-CH
2
2
4-Bromo-N-((1R,5S)-1,8,8-trimethyl-2,4-dioxo-3-aza-
bicyclo[3.2.1]octan-3-yl)benzamide (4s). Yield 1.56 g (75%),
3
2
23.3
.77 (2H, m, H-15,16); 7.26–7.27 (2H, m, H-13,14).
C NMR spectrum, δ, ppm: 13.9 (C-8); 19.0 (C-7); 21.9
C-6); 25.1 (C-2); 34.0 (C-3); 41.8 (C-11); 44.1 (C-5); 54.3
C-4); 55.0 (C-18); 56.4 (C-1); 113.5 (C-15,16); 129.4
C-12); 130.1 (C-13,14); 158.6 (C-17); 176.1 (C-9); 178.1
white solid, mp 149.9°С, [α]
D
+38.6 (c 0.83, CHCl ).
3
1
3
–1
IR spectrum, ν, cm : 3259 (N–H st), 2973 (C–H st), 1709
(C=O st as), 1637 (C=O st), 1265 (CH δ sy), 841 (C=C).
H NMR spectrum, δ, ppm (J, Hz): 1.45 (3H, s, 6-CH );
1.79 (3H, s, 7-CH ); 1.87 (3H, s, 8-CH ); 1.99–2.07 (1H,
(
(
(
3
1
3
3
3
7
67

Chemistry of Heterocyclic Compounds 2020, 56(6), 763–768
m, 3-CH
2
); 2.30–2.39 (1H, m, 2-CH
); 3.02–3.14 (1H, m, 3-CH ); 3.32–3.36 (1H, m,
-CH); 8.11–8.12 (2H, m, H-13,14); 8.27–8.29 (2H, m,
2
); 2.68–2.77 (1H, m,
Sinegubova, K. O.; Zarubaev, V. V.; Salakhutdinov, N. F.
Mol. Diversity 2020, 24, 61.
2-CH
2
2
6
7
8
.
.
.
Firstova, A. A.; Kofanov, E. R.; Zakshevskaya, V. M.;
Kovaleva, M. I. Russ. J. Bioorg. Chem. 2019, 45, 204.
1
13
H-15,16). C NMR spectrum, δ, ppm: 21.2 (C-7); 21.9
[
Bioorg. Khim. 2019, 45, 430.]
(
(
(
(
C-6); 22.7 (C-8); 23.0 (C-2); 33.0 (C-3); 46.9 (C-5); 52.2
C-1); 56.6 (C-4); 127.1 (C-17); 129.6 (C-15,16); 131.5
Xu, M.; Wang, Y.; Yang, F.; Wu, C.; Wang, Z.; Ye, B.; Jiang, X.;
Zhao, Q.; Li, J.; Liu, Y.; Zhang, J.; Tian, G.; He, Y.; Shen, J.;
Jiang, H. Eur. J. Med. Chem. 2018, 145, 74.
C-12); 132.1 (C-13,14); 166.9 (C-11); 173.7 (C-9); 178.9
+
C-10). Found, m/z: 378.0575 [M] . C17
H
19BrN
2
3
O . Calcu-
Köse, A.; Kaya, M.; Kishalı, N. H.; Akdemir, A.; Şahin, E.;
Kara, Y.; Şanlı-Mohamed, G. Bioorg. Chem. 2020, 94, 103421.
lated, m/z: 378.0574.
N-((1R,5S)-1,8,8-Trimethyl-2,4-dioxo-3-azabicyclo-
3.2.1]oct-3-yl)pyridine-4-carboxamide (4t). Yield 1.49 g
9. Chen, H.; Song, W.; Huang, S. Chem. Heterocycl. Compd.
2006, 42, 726. [Khim. Geterotsikl. Soedin. 2006, 832.]
[
(
(
(
8
(
2
5.2
1
0. Novakov, I. A.; Sheikin, D. S.; Chapurkin, V. V.;
Nawrozkij, M. B.; Babushkin, A. S.; Kuznetsov, Y. P.;
Ruchko, E. A.; Kachala, V. V.; Maryshev, A. Yu.; Schols, D.
Chem. Heterocycl. Compd. 2020, 56, 67. [Khim. Geterotsikl.
Soedin. 2020, 56, 67.]
90%), white solid, mp 169.7–171.2°С, [α]
D
+73.6
–
1
c 1.0, EtOH). IR spectrum, ν, cm : 3265 (N–H st), 2974
C–H st), 1670 (C=O st), 1535 (C=N st), 1276 (CH δ sy),
OD), δ, ppm
); 1.22 (3H, s, 7-CH ); 1.30 (3H,
); 1.46–1.58 (1H, m, 3-CH ); 1.76–1.89 (1H, m,
); 2.46–2.57 (1H, m,
); 2.76–2.81 (1H, m, 1-CH); 7.75–7.77 (2H, m,
3
1
46 (C=C). H NMR spectrum (CDCl
3
+ CD
3
J, Hz): 0.88 (3H, s, 6-CH
3
3
1
1
1. El-Etrawy, A. Sh.; Abdel-Rahman, A. A.-H. Chem.
Heterocycl. Compd. 2010, 46, 1105. [Khim. Geterotsikl.
Soedin. 2010, 1372.]
s, 8-CH
2
3
2
-CH
-CH
2
); 2.11–2.21 (1H, m, 2-CH
2
2
3
2. Komissarov, I. V.; Dulenko, V. I.; Voshchula, V. N.; Kharin,
N. A.; Naletov, S. V.; Mamonov, A. B. Pharm. Chem. J.
1994, 28, 638. [Khim.-Farm. Zh. 1994, 28(9), 27.]
1
3
H-13,16); 8.65–8.71 (2H, m, H-14,15). C NMR spectrum
(
(
(
CDCl
3
+ CD OD), δ, ppm: 21.4 (C-7); 22.1 (C-6); 22.9
3
C-8); 23.2 (C-2); 33.1 (C-3); 47.1 (C-5); 52.4 (C-1); 56.8
C-4); 122.5 (C-13,15); 141.0 (C-12); 150.3 (C-14,15);
13. Takeda, K.; Tsuboyama, K.; Suzuki, A.; Ogura, H. Chem.
Pharm. Bull. 1985, 33, 2545.
1
4. Wanner, K. T. J. Chem. Inf. Model. 1988, 321, 353.
1
3
65.7 (C-11); 173.9 (C-9); 179.1 (C-10). Found, m/z:
+
15. Bell, K. H. Aust. J. Chem. 1981, 34, 665.
01.1424 [M] . C16
H
19
N
3
O . Calculated, m/z: 301.1421.
3
1
1
6. Rice, L. M.; Grogan, C. H. Hypotens. Agents 1957, 185.
7. Merzlikin, S. I.; Sal'nikova, S. I.; Yaremenko, F. G. Pharm.
Chem. J. 2001, 35, 139.
Study of the antiviral activity of the synthesized
compounds. Antiviral assays for the yellow fever virus,
Chikungunya virus, and the Zika virus were performed as
described earlier.2
1
8. Eagles, J. B.; Hitchcock, S. R. Tetrahedron: Asymmetry 2010,
6,28–30
2
1, 519.
1
9. Moloney, M. G.; Paul, D. R.; Thompson, R. M.; Wright, E.
1
Supplementary information file containing H and
Tetrahedron: Asymmetry 1996, 7, 2551.
1
3
C NMR spectra, IR spectra, and HRMS of all synthesized
20. Hintermann, L.; Broggini, D.; Togni, A. Helv. Chim. Acta
2
002, 85, 1597.
compounds is available at the journal website at http://
link.springer.com/journal/10593.
2
2
2
1. Boeckman, R. K., Jr.; Miller, Y.; Savage, D.; Summerton, J.
E. Tetrahedron Lett. 2011, 52, 2243.
2. Kazemi, F.; Kiasat, A. R.; Mombaini, B. Synth. Commun.
The authors would like to express their gratitude to the
Collective Use Chemical Service Center of the Siberian
Branch of Russian Academy of Sciences, for the obtained
spectra and analytical data, as well as Dr. D. S. Fadeev for
the obtained NMR spectra data. The authors also would
like to thank Prof. J. Neyts, Dr. D. Jochmans, and C. Collard
2
007, 37, 3219.
3. Kononova, A. A.; Sokolova, A. S.; Cheresiz, S. V.;
Yarovaya, O. I.; Nikitina, R. A.; Chepurnov, A. A.;
Pokrovsky, A. G.; Salakhutdinov, N. F. MedChemComm
2017, 8, 2233.
24. Gwon, Y.-D.; Strand, M.; Lindqvist, R.; Nilsson, E.; Saleeb, M.;
(
Rega Institute for Medical Research, KU Leuven) for the
Elofsson, M.; Överby, A. K.; Evander, M. Viruses 2020, 12, 351.
2
2
5. Singh, I. P.; Gupta, S.; Kumar, S. Med. Chem. 2020, 16, 4.
6. Saudi, M.; Zmurko, J.; Kaptein, S.; Rozenski, J.; Neyts, J.;
Van Aerschot, A. Eur. J. Med. Chem. 2014, 87, 529.
obtained data on the antiviral activity.
References
2
7. Spizzichino, S.; Mattedi, G.; Lauder, K.; Valle, C.; Aouadi, W.;
Canard, B.; Decroly, E.; Kaptein, S. J. F.; Neyts, J.; Graham, C.;
Sule, Z.; Barlow, D. J.; Silvestri, R.; Castagnolo, D.
ChemMedChem 2020, 15, 385.
1
.
.
Salakhutdinov, N. F.; Volcho, K. P.; Yarovaya, O. I. Pure
Appl. Chem. 2017, 89, 1105.
2
Sokolova, A. S.; Yarovaya, О. I.; Shtro, A. A.; Borisova, M. S.;
Morozova, E. A.; Tolstikova, T. G.; Zarubaev, V. V;
Salakhutdinov, N. F. Chem. Heterocycl. Compd. 2017, 53,
2
8. Delang, L.; Li, C.; Tas, A.; Quérat, G.; Albulescu, I. C.; De
Burghgraeve, T.; Segura Guerrero, N. A.; Gigante, A.;
Piorkowski, G.; Decroly, E.; Jochmans, D.; Canard, B.;
Snijder, E. J.; Pérez-Pérez, M. J.; van Hemert, M. J.; Coutard, B.;
Leyssen, P.; Neyts, J. Sci. Rep. 2016, 6, 31819.
9. Lacroix, C.; Querol-Audí, J.; Roche, M.; Franco, D.; Froeyen, M.;
Guerra, P.; Terme, T.; Vanelle, P.; Verdaguer, N.; Neyts, J.;
Leyssen, P. J. Antimicrob. Chemother. 2014, 69, 2723.
0. Tănase, C. I.; Drăghici, C.; Hanganu, A.; Pintilie, L.; Maganu, M.;
Volobueva, A.; Sinegubova, E.; Zarubaev, V. V.; Neyts, J.;
Jochmans, D.; Slita, A. V. Molecules 2019, 24, 2446.
3
71. [Khim. Geterotsikl. Soedin. 2017, 53, 371.]
3.
Sokolova, A. S.; Yarovaya, O. I.; Shernyukov, A. V.;
Gatilov, Y. V.; Razumova, Y. V.; Zarubaev, V. V.; Tretiak, T. S.;
Pokrovsky, A. G.; Kiselev, O. I.; Salakhutdinov, N. F. Eur. J.
Med. Chem. 2015, 105, 263.
2
4
.
.
Sokolova, A. S.; Yarovaya, O. I.; Bormotov, N. I.; Shishkina, L. N.;
Salakhutdinov, N. F. MedChemComm 2018, 9, 1746.
Chernyshov, V. V.; Yarovaya, O. I.; Fadeev, D. S.;
Gatilov, Y. V.; Esaulkova, Y. L.; Muryleva, A. S.;
3
5
7
68