Synthesis and antimicrobial activity of acridine carboxylic acid derivatives containing a piperazine moiety

Article abstract of DOI:10.1007/s11172-017-1709-8

A convenient method for the synthesis of new acridine derivatives containing a piperazine moiety was developed. Antimicrobial activity against some pathogenic microorganisms was established for a series of the synthesized compounds.

Full text of DOI:10.1007/s11172-017-1709-8

Russian Chemical Bulletin, International Edition, Vol. 66, No.1, pp. 123—128, January, 2017
123
Synthesis and antimicrobial activity of acridine carboxylic acid derivatives
containing a piperazine moiety
T. N. Kudryavtseva,a A. Yu. Lamanov, L. G. Klimova, and G. V. Nazarov
a
b
a
aKursk State University,
3
3 ul. Radishcheva, 305000 Kursk, Russian Federation.
Eꢀmail: labos.kgu@mail.ru
b
Kursk State Medical University,
3
ul. Karla Marksa, 305041 Kursk, Russian Federation
A convenient method for the synthesis of new acridine derivatives containing a piperazine
moiety was developed. Antimicrobial activity against some pathogenic microorganisms was
established for a series of the synthesized compounds.
Key words: acridine, piperazine, nitrofuran, antibacterial activity.
Biological activity of 9ꢀoxoacridines is presently being
studied actively. The antibacterial properties characterisꢀ
tic of compounds of this class are attributed to the intercaꢀ
lating abilities of the acridine cycle. At the same time, the
cyclohexyl carbodiimide) the byꢀproduct (imidazole) is
easily washed off with water to give the pure product withꢀ
out additional purification stages. Intermediates products
3 and 4 were thus synthesized and then subjected to quatꢀ
ernization to the corresponding quaternary salts 5a,b and
6a,b (Scheme 1).
1
9
ꢀoxoacridine derivatives exhibit antitumor, antiviral, and
2
—7
other types of biological activity.
Search for novel drugs performed by the modification of
known pharmaceuticals is one of trends aimed at improving
drugs, enhancing therapeutical efficiency, and diminishing
However, we failed to activate acridineꢀ9ꢀcarboxylic (7)
and 9ꢀoxoꢀ9,10ꢀdihydroacridineꢀ2ꢀcarboxylic (2ꢀcarboxyꢀ
acridone) (8) acids with CDI and, hence, derivatives 9
and 10 of these acids were obtained via the corresponding
acid chlorides, which were further transformed into the
corresponding quaternary salts 11a,b and 12a,b (Scheme 2).
Note that an excess of thionyl chloride is needed for
the synthesis of acridineꢀ9ꢀcarboxylic acid chloride. At
the same time, 9ꢀchloroacridineꢀ2ꢀcarbonyl chloride is
formed by the treatment of 2ꢀcarboxyacridone with thionyl
chloride excess and, therefore, equivalent amounts of thioꢀ
nyl chloride and 2ꢀcarboxyacridone should be used to obꢀ
tain acridoneꢀ2ꢀcarbonyl chloride. Since the starting comꢀ
pounds 3, 4, 9, and 10 are highly soluble in acetonitrile,
quaternization proceeds almost quantitatively and the quaꢀ
ternary salts formed in the reaction precipitate. As a result,
high yields and purity of the products can be achieved.
For the synthesis of the acridine derivatives containing
the 5ꢀnitrofuranꢀ2ꢀcarboxylic acid and 2ꢀmethylꢀ5ꢀnitroꢀ
furan moiety, the studied acridinecarboxylic acids were
amidated with 1ꢀ(tertꢀbutoxycarbonyl)piperazine. Then
the tertꢀbutoxycarbonyl group (Boc) was removed using
trifluoroacetic acid (TFA). As a result, the synthetic blocks
(13a—c) bearing the highly reactive secondary amino
group were obtained in good yields. Unlike the NH group
of acridone, the secondary amino group was easily both
acylated by 5ꢀnitrofuranecarboxylic acid and alkylated by
2ꢀbromomethylꢀ5ꢀnitrofuran (Scheme 3).
8
possible side effects. In continuation of our studies on the
synthesis and investigation of antibacterial activity of new
compounds in the series of 9ꢀoxoacridines, we obtained new
derivatives of acridoneacetic acid (AАА), 9ꢀoxoꢀ9,10ꢀdiꢀ
hydroacridineꢀ2ꢀcarboxylic acid, 9ꢀoxoꢀ9,10ꢀdihydroꢀ
acridineꢀ4ꢀcarboxylic acid, and acridineꢀ9ꢀcarboxylic acid
containing the pharmacophoric moiety of 5ꢀnitrofuran.
It is known that the 5ꢀnitrofuran derivatives possess
a wide range of biological activity against bacterial, viruses,
and protozoa and can act on strains resistant to many
9
—11
antibiotics.
For example, Furacilin (nitrofural, semiꢀ
carbazoneꢀ5ꢀnitrofurfural) is among widely used pharmaꢀ
ceuticals of this series.
An important task in the synthesis of target compounds
is to choose the unit connecting the acridine and 5ꢀnitroꢀ
furan moieties. We chose the piperazine cycle, which is
makes it possible, being fairly convenient moiety for the conꢀ
struction of organic molecules, to functionalize the moleꢀ
cule of acridinecarboxylic acids for further procedures.
It was found that AAA (1) and acridineꢀ9(10Н)ꢀoneꢀ4ꢀ
carboxylic acid (4ꢀcarboxyacridone, 2) rapidly react with
1
,1´ꢀcarbonyldiimidazole (CDI) in dimethylformamide
(
DMF) to form imidazolide, which reacts readily with
aliphatic and aromatic amines and alcohols. Unlike other
methods of carboxyl group activation (for example, using diꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0123—0128, January, 2017.
066ꢀ5285/17/6601ꢀ0123 © 2017 Springer Science+Business Media, Inc.
1

1
24
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
Kudryavtseva et al.
Scheme 1
Scheme 2
Byꢀproducts were formed in the alkylation and acylaꢀ
multiple test strains E. Coli, Ps. Aeruginosa, Pr. Vulgaris,
S. Aureus, B. Subtilis, and Candida albicans using lactate
ethacridine (Rivanol) as a standard. Rivanol is applied in
medicine as an antibacterial pharmaceutical. The data obꢀ
tained are presented in Table 1.
tion reactions of derivatives 13а—с. Therefore, the final
compounds were purified using preparative chromatograꢀ
phy, which made it possible to achieve maximum yields of
the compounds.
2
The antimicrobial activity was tested in vitro for hetꢀ
erocyclic derivatives 5b, 6a,b, 12b, 14b, and 15c against
The antimicrobial activity of compounds 5b and 12b is
comparable with that of Rivanol (pharmaceutical of the

Acridine carboxylic acid derivatives
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
125
Scheme 3
acridine series), and compound 5b is characterized by
a higher inhibition effect relative to the chosen test strains
of microorganisms compared to the standard. Comꢀ
pounds 14b and 15c showed moderate activity. Compound 6a
bearing no 5ꢀnitrofuran moiety, as it was assumed, deꢀ
monstrated the lowest activity among the samples studied.
To conclude, new series of acridine derivatives conꢀ
taining piperazine and nitrofuryl moieties were syntheꢀ
sized, and the possibility to functionalize acridinecarbꢀ
oxylic acids and use them as blocks for further synthetic
procedures was shown. The antimicrobial activity of the
acridine derivatives was tested. It was found that comꢀ
pound 5b exerts a higher inhibition effect against the
microorganisms than the standard. It follows from this
that the 9ꢀoxoacridine derivatives are promising for the
synthesis of biologically active compounds.
Experimental
Acridinecarboxylic acids were synthesized according to earꢀ
7,12—14
lier described procedures.
The 1Н and 13С NMR spectra of solutions of the tested
compounds in DMSOꢀd were recorded on a Bruker АМꢀ600
6
spectrometer at a working frequency of 600.13 MHz using Me Si
4
as an internal standard. Elemental analysis was carried out on
a Thermo Element 2 instrument. Preparative chromatography
was conducted on a puriFlash 450 instrument (column 120 g,
silica gel 15 μm, eluent MeCl → MeCl —MeOH (95 : 5), flow
2
2
rate 50 mL min– ).
1
Synthesis of compounds 3 and 4 (general procedure). Acid 1
or 2 (0.01 mol) was dispersed in DMF (20 mL), CDI (0.01 mol)
was added by portions, the mixture was stirred until CO stopped
evolving (~20 min), and amine (0.01 mol) was added. The reacꢀ
tion mixture was stirred for 24 h, poured into water (150 mL),
2
Table 1. Antimicrobial activity of compounds 5b, 6a,b, 12b, 14b, and 15c
Tested
compound*
Size of bacteriostasis zone/mm
Pr. vulgaris S. aureus
Е. coli
Ps. Aeruginosa
B. subtilis
Candida albicans
(
АТСС 25922) (АТСС 27853) (АТСС 4636) (АТСС 25923) (АТСС 6633)
(NCTC2625)
5
6
6
1
1
1
b
a
b
2b
4b
5c
20±1.1
11.5±0.5
10.5±0.5
14±0.5
9.5±0.5
10±0.4
11.5±1.1
11±0.4
13.5±0.5
16.5±1.2
9±0.3
18.5±1.5
10.5±0.5
13
18.5±1.5
12.5±0.5
13±0.5
15±0.5
20±1.1
9.5±0.5
12.5±0.5
12.5±0.5
11±0.6
19.5±1.5
8.5±0.5
15
18±0.7
18±1.0
18±0.7
15±0.6
20±1.3
11±0.6
12.5±0.5
11±1.0
11.5±0.5
12.5±0.5
15±0.5
16.5±1.5
15±0.4
12.5±0.5
20±0.7
Rivanol
14±0.5
*
Concentration 2%.

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Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
Kudryavtseva et al.
and cooled down. The precipitated product was filtered off,
washed with water, and dried.
for 24 h, the solvent was distilled off, water (20 mL) was added,
and the mixture was triturated. The precipitate was filtered off
and dried. The yield was 77%, yellow crystals, m.p. 187—189 °С.
Found (%): C, 71.49; H, 6.16; N, 13.47. C H N O . Calculatꢀ
4
ꢀ(4ꢀMethylpiperazineꢀ1ꢀcarbonyl)acridinꢀ9(10H)ꢀone (3).
The yield was 85%, yellow crystals, m.p. 144—146 °С. Found (%):
19
19
3
2
1
С, 71.52; Н, 5.64; N, 12.78. C H N O . Calculated (%):
ed (%): C, 71.01; H, 5.96; N, 13.08. H NMR, δ: 2.22 (s, 3 Н,
1
9
19
3
2
1
C, 71.01; H, 5.96; N, 13.08. Н NMR, δ: 2.12—2.36 (m, 5 H,
С(12)H ); 2.28—2.42 (m, 4 Н, C(11)H , C(11а)H); 3.44—3.73
3
2
C(11)H , С(12)Н ); 2.39—2.61 (m, 2 H, C(11a)H ); 3.09—3.31
(m, 4 Н, C(10)H , C(10а)H); 7.29—7.32 (m, 1 Н, C(7)H); 7.55—7.61
2
3
2
2
(
(
m, 2 H, C(10)H ); 3.64—3.68 (m, 2 H, C(10a)H ); 7.28—7.34
(m, 2 Н, C(5)H, C(6)H); 7.74—7.8 (m, 2 Н, C(3)H, C(4)H);
2
2
13
m, 2 Н, С(2)Н, С(6)H); 7,66 (dd, 1 Н, С(5)Н, J = 7.2 Hz,
8.21—8.26 (m, 2 Н, C(1)H, C(8)H); 11.95 (s, NH). С NMR,
δ: 40.5 (С(10), C(10а)); 46.1 (С(12)); 55.04 (С(11), C(11а));
118.01 (С(5)); 118.08 (С(4)); 120.02 (С(8а)); 121.12 (С(1а));
122.07 (С(7)); 125.71 (С8)); 126.51 (С(1); 128.46 (С(2)); 132.93
(С(6)); 134.3 (С(3)); 141.31 (С(5а)); 141.94 (С(4а)); 168.99
(С(2а)); 177.07 (С(9)).
1
J = 1.6 Hz); 7.75 (ddd, 1 H, С(7)H, J = 8.4 Hz, J = 6.9 Hz,
J3 = 1.6 Hz); 7.9 (d, 1 Н, С(3)Н, J = 8.5 Hz); 8.24 (dd, 1 Н,
С(8)Н, J1 = 8.0 Hz, J2 = 1.5 Hz); 8.34 (dd, 1 Н, С(1)Н,
J = 8.0 Hz, J = 1.5 Hz); 10.83 (s, 1 Н, NH). С NMR, δ:
4
2
1
2
13
1
2
2.07 (С(10)); 46.09 (С(12)); 47.2 (С(10a)); 54.26 (С(11a)); 55.1
(
(
(
(
С(11)); 118.63 (С(8а)); 120.94 (С(5)); 121.1 (С(2)); 121.57
С(1а)); 122.11 (С(7)); 125.01 (С(4)); 126.26 (С(8)); 127.82
С(3)); 132.54 (С(6)); 134.16 (С(1)); 137.72 (С(5а)); 141.5
С(4а)); 166.59 (С(4b)); 177.08 (С(9)).
Synthesis of compounds 5a,b, 6a,b, 11a,b, and 12a,b (general
procedure). A quaternizing agent (3 mmol) was added to a soluꢀ
tion of compound 3, 4, 9, or 10 (2 mmol) in acetonitrile (7 mL).
The reaction mixture was stirred for 24 h. As a result, the product
precipitated, filtered off, washed with acetonitrile and diethyl
ether, and dried in vacuo.
1
0ꢀ[2ꢀ(4ꢀMethylpiperazinꢀ1ꢀyl)ꢀ2ꢀoxoethyl]acridinꢀ9(10H)ꢀ
one (4). The yield was 90%, white powder, m.p. 247—249 °С.
Found (%): C, 71.95; H, 6.71; N, 12.84. C H N O . Calculatꢀ
ed (%): C, 71.62; H, 6.31; N, 12.53. H NMR, δ: 2.27 (s, 3 H,
1ꢀMethylꢀ1ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀ(9ꢀoxoꢀ9,10ꢀdihydroꢀ
acridineꢀ4ꢀcarbonyl)piperazinꢀ1ꢀium bromide (5a). The yield was
93%, white crystals, m.p. 190—192 °С. Found (%): C, 56.97;
H, 5.66; N, 8.93. C H BrN O . Calculated (%): C, 56.56;
2
0
21
3
2
1
С(12)H ); 2.32—2.37 (m, 2 H, C(11a)H ); 2.49—2.55 (m, 2 H,
3
2
C(11)H ); 3.48—3.54 (m, 2 H, C(10a)H ); 3.7—3.76 (m, 2 H,
2
2
23 26
3
4
1
C(10)H ); 5.50 (s, 2 H, C(4b)H); 7.34 (t, 2 H, C(2)H, C(7)H,
H, 5.37; N, 8.60. H NMR, δ: 1.26 (t, 3 Н, С(16)Н , J = 7.2 Hz);
2
3
J = 7.4 Hz); 7.53 (d, 2 H, C(4)H, C(5)H, J = 8.7 Hz); 7.77—7.81
3.38 (s, 3 Н, С(12)Н ); 3.52—4.09 (m, 8 Н, С(10)Н , С(10а)Н ,
3
2
2
(
m, 2 H, C(3)H, C(6)H); 8.36 (dd, 2 H, C(1)H, C(8)H,
С(11)Н , С(11а)Н ); 4.25 (q, 2 Н, С(15)Н , J = 7.2 Hz); 4.66
2 2 2
(br.s, 2 Н, С(13)Н ); 7.31 (ddd, 1 Н, С(7)H, J = 8.1 Hz,
2 1
13
J = 8.0 Hz, J = 1.7 Hz). C NMR, δ: 42.08 (С(10)); 44.73
1
2
(
(
С(10a)); 46.21 (С(12)); 47.81 (С(4b)); 54.81 (С(11a)); 55.27
C(11)); 116.54 (C(4), C(5)); 121.78 (C(2), C(7)); 122.02 (C(1а),
J = 7.0 Hz, J = 1.1 Hz); 7.36 (dd, 1 Н, C(6)H, J = 8.5 Hz,
2 3 1
J2 = 7.2 Hz); 7.73—7.79 (m, 2 Н, C(2)H, C(5)H); 7.95 (d, 1 Н,
C(3)H, J = 8.5 Hz); 8.24 (dd, 1 Н, C(8)H, J1 = 8.1 Hz,
J = 1.5 Hz); 8.38 (dd, 1 Н, C(1)H, J = 8.0 Hz, J = 1.1 Hz);
C(8а)); 126.92 (С(1), (8)); 134.42 (С(3), C(6)); 142.94 (С(4а),
C(5а)); 165.2 (С(4с)); 177.2 (С(9)).
2
1
2
13
Acridinꢀ9ꢀyl(4ꢀmethylpiperazinꢀ1ꢀyl)methanone (9). A mixꢀ
ture of acid 7 (10 mmol) and thionyl chloride (10 mL) was reꢀ
fluxed for 4 h. Thionyl chloride excess was distilled off in vacuo,
benzene (10 mL) was added to the residue, and the solvent was
distilled off again. A solution of triethylamine (20 mmol) and
Nꢀmethylpiperazine (10 mmol) in dichloromethane (5 mL) was
added to a mixture (cooled to 0 °С) of the acid chloride dried
in vacuo and dichloromethane (15 mL). The mixture was stirred
for 24 h, the solvent was distilled off, water (20 mL) was added,
and the mixture was triturated. The precipitate was filtered off
and dried. The yield was 95%, yellow crystals, m.p. 167—169 °С.
Found (%): C, 75.12; H, 6.56; N, 14.12. C H N O. Calculatꢀ
10.88 (s, 1 Н, NH). С NMR, δ: 14.29 (С(16)); 47.89 (С(10),
C(10а)); 60.25 (С(12)); 61.14 (С(11), C(11а)); 62,62 (С(13));
65.4 (С(15)); 118.75 (С(8а)); 121.02 (С(5)); 121.12 (С(2));
121.75 (С(1а)); 122.25 (С(7)); 123.45 (С(4)); 126.26 (С(8));
128.5 (С(6)); 132.8 (С(1)); 134.16 (С(3)); 137.81 (С(5а)); 141.46
(С(4а)); 164.89 (С(14)); 167 (С(4b)); 177.06 (С(9)).
1ꢀMethylꢀ1ꢀ[(5ꢀnitrofuranꢀ2ꢀyl)methyl]ꢀ4ꢀ(9ꢀoxoꢀ9,10ꢀdiꢀ
hydroacridineꢀ4ꢀcarbonyl)piperazinꢀ1ꢀium bromide (5b). The yield
was 83%, yellow crystals, m.p. 213—215 °С. Found (%): C, 55.21;
H, 4.57; N, 10.73. C H BrN O . Calculated (%): C, 54.66; H,
2
4
23
4
5
1
4.40; N, 10.62. H NMR, δ: 3.29 (s, 3 Н, С(12)Н ); 3.40—4.55
3
(m, 8 Н, С(10)Н , С(10а)Н , С(11)Н , С(11b)Н ); 5.11 (s, 2 Н,
19
19
3
2
2
2
2
1
ed (%): C, 74.73; H, 6.27; N, 13.76. H NMR, δ: 2.07—2.12
m, 2 Н, С(11)H ); 2.19 (s, 3 H, С(12)H ); 2.54—2.59 (m, 2 Н,
С(12a)Н ); 7.28 (d, 1 H, C(14)H, J = 3.8 Hz); 7.34—7.39 (m, 2 Н,
2
(
С(5)H, C(7)H); 7.73—7.79 (m, 2 Н, C(2)H, C(6)H); 7.83 (d, 1 H,
C(15)H, J = 3.8 Hz); 7.9 (d, 1 Н, C(3)H, J = 8.4 Hz); 8.24
(dd, 1 Н, C(8)H, J = 8.1 Hz, J = 1.5 Hz); 8.37 (dd, 1 Н,
2
3
С(11a)H ); 2.94—2.99 (m, 2 Н, С(10)H ); 3.94—4.01 (m, 2 Н,
С(10a)H ); 7.71(ddd, 2 H, С(3)Р, С(6)Р, J = 8.33 Hz, J =
=
C(5)H, C(7)H); 8.21—8.24 (m, 2 H, C(1)H, C(8)H). С NMR,
δ: 42.08 (С(12)); 44.73 (С(10)); 46.65 (С(10a)); 53.34 (С(11));
2
2
2
1
2
1
2
13
6.89 Hz, J = 1.14 Hz); 7.89—7.94 (m, 4 H, С(2)H, C(4)H,
C(1)H, J = 8.01 Hz, J = 1.14 Hz); 10.84 (s, 1 Н, NH). С NMR,
3
1 2
13
δ: 45.3 (C(10), C(10а)); 46.88 (C(12)); 49.05 (C(12a)); 58.96
(С(11), C(11)a); 113.72 (С(14)); 118.62 (С(15)); 120.81 (С(8а));
121.04 (С(5)); 121.15 (C(2)); 121.76 (С(1а)); 122.23 (С(7));
123.55 (С(4)); 126.26 (С(8)); 128.45 (С(6)); 132.82 (С(1));
134.09 (С(3)); 137.76 (С(5а)); 141.46 (С(4а)); 145.96 (С(13));
153.41 (С(16)); 167.02 (С(4b)); 177.07 (С(9)).
5
(
4.8 (С(11a)); 121.88 (C(1а), C(8а)); 125.61 (C(2), C(7)); 127.68
C(1), C(8)); 130.00 (С(3), C(6)); 131.3 (С(9)); 141.14 (С(4),
C(5)); 148.59 (С(4а), C(5а)); 165.24 (С(9а)).
ꢀ(4ꢀMethylpiperazineꢀ1ꢀcarbonyl)acridinꢀ9(10H)ꢀone (10).
2
A mixture of acid 8 (10 mmol) and thionyl chloride (11 mmol) in
dichloromethane (20 mL) was refluxed for 9 h. The solvent was
distilled off in vacuo, benzene (10 mL) was added, and the solꢀ
vent was distilled off again. A solution of triethylamine (20 mmol)
and Nꢀmethylpiperazine (10 mmol) in dichloromethane (5 mL)
was added to a mixture (cooled to 0 °С) of the acid chloride dried
in vacuo and dichloromethane (15 mL). The mixture was stirred
1ꢀMethylꢀ1ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀ[2ꢀ(9ꢀoxoacridinꢀ
10(9H)ꢀyl)acetyl]piperazinꢀ1ꢀium bromide (6a). The yield was
88%, white crystals, m.p. 221—223 °С. Found (%): C, 57.69; H,
5.73; N, 8.56. C H BrN O . Calculated (%): C, 57.38; H,
2
4
28
3
4
1
5.62; N, 8.36. H NMR, δ: 1.29—1.32 (m, 3 H, C(16)Н ); 3.44
3
(s, 3 H, C(12)Н ); 3.71—4.27 (m, 8 H, C(10)Н , C(10а)Н ,
3
2
2
C(11)Н , C(11а)Н ); 4.30 (q, 2 Н, C(15)Н , J = 7.1 Hz); 4.72
2
2
2

Acridine carboxylic acid derivatives
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
127
(
s, 2 Н, C(13)Н ); 5.56—5.70 (m, 2 Н, C(4b)Н ); 7.36 (td, 2 H,
С(13)Н ); 7.29—7.33 (m, 1 Н, C(7)H); 7.64 (d, 1 Н, C(5)H,
2
2
2
C(2)H, C(7)H, J = 7.5 Hz, J = 0.7 Hz); 7.59 (d, 2 H, C(4)H,
J = 8.4 Hz); 7.69 (dd, 1 Н, C(4)H, J = 8.58 Hz, J = 1.72 Hz);
1
2
1
2
C(5)H, J = 8.7 Hz); 7.8 (ddd, 2 H, C(3)H, C(6)H, J = 8.7 Hz,
7.76—7.80 (m, 1 Н, C(6)H); 7.82 (dd, 1 Н, C(3)H, J = 8.58 Hz,
1
1
J = 6.9 Hz, J = 1.7 Hz); 8.36 (dd, 2 H, C(1)H, C(8)H, J = 7.9 Hz,
J2 = 1.7 Hz). С NMR, δ: 36.03 (С(16)); 38.8 (С(10), C(10а));
J = 2.06 Hz); 8.24 (dd, 1 Н, C(8)H, J = 8.0 Hz, J = 0.8 Hz);
2
3
1
1
2
1
2
13
3
8.33 (d, 1 Н, C(1)H, J = 1.94 Hz); 12.14 (s, NH). С NMR, δ:
14.29 (С(16)); 47.86 (С(10), C(10а)); 60.25 (С(12)); 60.80
(С(11), C(11а)); 62.62 (С(13)); 65.38 (С(15)); 118.05 (С(5));
118.26 (С(4)); 120.04 (С(8а)); 121.15 (С(1а)); 122.19 (С(7));
126.25 (С(8)); 126.45 (С(1)); 126.95 (С(2)); 132.86 (С(6));
134.36 (С(3)); 141.29 (С(5а)); 142.29 (С(4а)); 164.96 (С(14));
169.30 (С(2а)); 177.08 (С(9)).
4
6
7.84 (С(12)); 60.09 (С(4b)); 60.38 (С(11), C(11а)); 61.11 (С(13));
2.69 (С(15)); 116.59 (С(4), C(5)); 121.93 (С(2), C(7)); 122.06
(
(
С(1а), C(8а)); 127.00 (C(1), C(8)); 134.42 (С(3), C(6)); 142.85
С(4а), C(5а)); 164.98 (С(14)); 165.93 (С(4с)); 177.2 (С(9)).
1
ꢀMethylꢀ1ꢀ[(5ꢀnitrofuranꢀ2ꢀyl)methyl]ꢀ4ꢀ[2ꢀ(9ꢀoxoacriꢀ
dinꢀ10(9H)ꢀyl)acetyl]piperazinꢀ1ꢀium bromide (6b). The yield was
3%, yellow crystals, m.p. 230—232 °С. Found (%): C, 55.89;
H, 4.75; N, 10.56. C H BrN O . Calculated (%): C, 55.46;
9
1ꢀMethylꢀ1ꢀ[(5ꢀnitrofuranꢀ2ꢀyl)methyl]ꢀ4ꢀ(9ꢀoxoꢀ9,10ꢀdiꢀ
hydroacridineꢀ2ꢀcarbonyl)piperazinꢀ1ꢀium bromide (12b). The
yield was 91%, yellow crystals, m.p. 217—219 °С. Found (%): C, 54.15;
H, 4.35; N, 10.57. C H BrN O . Calculated (%): C, 54.66;
2
5
25
4
5
1
H, 4.65; N, 10.35. H NMR, δ: 3.29 (s, 3 H, C(12)H ); 3.57—4.38
3
(
(
m, 8 Н, C(10)H , C(10a)H , C(11)H , C(11a)H ); 5.09—5.12
2 2 2 2
24 23
4
5
1
m, 2 Н, C(4b)H ); 5.57—5.76 (m, 2 Н, C(12a)H ); 7.31 (d, 1 Н,
H, 4.40; N, 10.62. H NMR, δ: 3.24 (s, 3 Н, С(12)Н ); 3.45—4.40
2
2
3
C(14)H, J = 3.8 Hz); 7.36 (t, 2 H, C(2)H, C(7)H, J = 7.4 Hz);
.6 (d, 2 H, C(4)H, C(5)H, J = 8.8 Hz); 7.78—7.82 (m, 2 H,
C(3)H, C(6)H); 7.83 (d, 1 Н, C(15)H, J = 3.8 Hz); 8.37 (dd, 2 H,
(m, 8 Н, C(10)Н , C(10а)Н , C(11)Н , C(11а)Н ); 5.02 (s, 2 Н,
2
2
2
2
7
C(12а)Н ); 7.25 (d, 1 Н, C(14)H, J = 3.8 Hz); 7.32 (m, 1 Н,
2
C(7)H); 7.61 (d, 1 Н, C(5)H, J = 8.35 Hz); 7.67 (d, 1 Н, C(4)H,
J = 8.6 Hz); 7.76—7.84 (m, 3 Н, C(3)H, C(6)H, C(15)H); 8.25
(dd, 1 Н, C(8)H, J = 8.0 Hz, J = 0.8 Hz); 8.36 (d, 1 Н, C(1)H,
13
C(1)H, C(8)H, J = 8.0 Hz, J = 1.7 Hz). С NMR, δ: 36.04
1
2
(
5
С(10)); 36.25 (С(10а)); 38.86 (С(12)); 46.44 (С(11)); 47.86 (С(4b));
8.85 (C(12а)); 59.29 (C(11а)); 113.71 (C(15)); 116.6 (C(4),
C(5)); 120.67 (С(14)); 121.93 (С(2), C(7)); 122.06 (С(1а), C(8а));
1
2
13
J = 1.8 Hz); 12.06 (s, NH). С NMR, δ: 31.16 (С(10), (10а));
36.07 (С(12)); 46.63 (С(12а)); 59.14 (С(11), C(11а)); 113.66
(С(14)); 118.07 (С(5)); 118.31 (С(4)); 120.02 (С(8а)); 120.61
(С(15)); 121.17 (С(1а)); 122.22 (С(7)); 126.29 (С(8)); 126.49
(С(1)); 126.97 (С(2)); 132.91 (С(6)); 134.64 (С(3)); 141.29
(С(5а)); 142.32 (С(4а)); 145.95 (С(13)); 162.77 (С(16)); 169.41
(С(2а)); 177.10 (С(9)).
1
1
27.01 (С(1), C(8)); 134.42 (C(3), C(6)); 142.87 (С(4а), C(5а));
46.02 (С(13)); 162.78 (С(16)); 165.92 (С(4с)); 177.20 (С(9)).
4
ꢀ(Acridineꢀ9ꢀcarbonyl)ꢀ1ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ1ꢀmethꢀ
ylpiperazinꢀ1ꢀium bromide (11a). The yield was 90%, white crysꢀ
tals, m.p. 203—205 °С. Found (%): C, 58.96; H, 5.65; N, 8.98.
C H BrN O . Calculated (%): C, 58.48; H, 5.55; N, 8.90.
Synthesis of compounds 14a,b (general procedure). 1,1´ꢀCarbꢀ
onyldiimidazole (10 mmol) was added by portions to a suspension
of acid 1 or 2 (10 mmol) in DMF (20 mL), and the mixture was
2
3
26
3
3
1
H NMR, δ: 1.25 (t, 3 H, C(16)Н ); 3.37—3.56 (m, 7 Н, C(11а)Н ,
3
2
C(15)Н , C(12)Н ); 3.91—4.05 (m, 2 Н, C(11)Н ); 4.20—4.26
2
3
2
(
(
(
7
m, 2 H, C(13)Н ); 4.27—4.51 (m, 2 Н, C(10)Н ); 4.63—4.76
stirred until CO stopped evolving. Then 1ꢀ(tertꢀbutoxycarbonyl)ꢀ
2
2
2
m, 2 Н, C(10a)H ); 7.71—7.75 (m, 2 H, C(4)H, C(5)H); 7.94
piperazine (10 mmol) was added. The reaction mixture was stirred
for 24 h and poured into water (150 mL). The precipitated product
was filtered off, washed with water, and dried. Trifluoroacetic
acid was added (1 : 1), the mixture was kept for 24 h and evaporatꢀ
2
ddd, 2 Н, C(3)H, C(6)H, J = 8.7 Hz, J = 6.7 Hz, J = 1.3 Hz);
1
2
3
.99—8.05 (m, 2 H, C(2)H, C(7)H); 8.25 (d, 2 H, C(1)H,
13
C(8)H). С NMR, δ: 14.28 (С(16)); 35.4 (С(10), C(10а)); 47.96
(
(
(
С(12)); 59.96 (С(11)); 60.22 (С(11а)); 60.45 (C(13)); 62.63
С(15)); 122.03 (С(1а), C(8а)); 125.29 (С(2), C(7)); 127.88
С(1), C(8)); 130.04 (C(3), C(6)); 131.37 (С(9)); 139.58 (С(4),
ed. The residue was neutralized with a solution of NaHCO . The
3
precipitate was filtered off, washed with water, dried, and disꢀ
persed in dichloromethane (15 mL). Triethylamine (10 mmol)
and 5ꢀnitrofuranꢀ2ꢀcarboxylic acid chloride (10 mmol) in dichloꢀ
romethane (5 mL) were added. The solution was stirred for 6 h
and washed with water. The organic layer was concentrated and
purified by preparative chromatography.
C(5)); 148.58 (С(4а), (5а)); 164.63 (С(14)); 165.87 (С(9а)).
ꢀ(Acridineꢀ9ꢀcarbonyl)ꢀ1ꢀmethylꢀ1ꢀ[(5ꢀnitrofuranꢀ2ꢀyl)ꢀ
4
methyl]piperazinꢀ1ꢀium bromide (11b). The yield was 75%, yellow
crystals, m.p. 167—170 °С. Found (%): C, 55.98; H, 4.43; N, 10.74.
C H BrN O . Calculated (%): C, 56.37; H, 4.53; N, 10.96.
4ꢀ[4ꢀ(5ꢀNitrofuranꢀ2ꢀcarbonyl)piperazineꢀ1ꢀcarbonyl]acridꢀ
inꢀ9(10H)ꢀone (14a). The yield was 54%, yellow crystals, m.p.
206—208 °С. Found (%): C, 62.97; H, 4.43; N, 12.36. C H N O .
2
4
23
4
4
1
H NMR, δ: 3.23 (s, 3 Н, C(12)Н ); 3.42—3.59 (m, 2 Н, C(11а)Н );
3
2
3
4
.74—3.92 (m, 2 Н, C(11)H ); 4.13—4.21 (m, 2 Н, C(10)H);
2
23 18
4 6
1
.60—4.67 (m, 2 Н, C(10а)H); 4.98—5.09 (m, 2 H, C(12а)Н ); 7.22
Calculated (%): C, 62.60; H, 4.38; N, 12.17. H NMR, δ: 4.01—4.54
2
(
7
d, 1 H, С(14)H, J = 3.8 Hz); 7.69—7.76 (m, 2 H, C(4)H, C(5)H);
.78 (d, 1 Н, C(15)H, J = 3.8 Hz); 7.92—8.11 (m, 4 H, C(2)H,
(m, 8 H, C(10)H , C(10a)H , C(11)H , C(11а)H ); 7.25—7.39
2
2
2
2
(m, 3 Н, C(2)H, C(6)H, C(14)H); 7.70—7.81 (m, 3 H, C(5)H,
C(7)H, C(15)H); 7.88 (d, 1 Н, C(3)H, J = 8.4 Hz); 8.24 (dd, 1 Н,
C(8)H, J = 7.3 Hz); 8.33—8.38 (m, 1 Н, C(1)H); 10.91 (s, 1 Н,
C(3)H, C(6)H, C(7)H); 8.28—8.23 (m, 2 H, C(1)H, C(8)H).
1
3
С NMR, δ: 41.55 (С(12)); 46.65 (С(10), C(10а)); 58.91
С(12а)); 59.37 (С(11), C(11а)); 120.62 (С(14)); 121.99 (С(15));
13
(
1
1
NH). С NMR, δ: 55.38 (С(10), C(10а)); 60.19 (С(11), C11а));
113.26 (С(14)); 117.66 (С(8а)); 118.56 (С(5)); 121.00 (С(2));
121.15 (С(1а)); 121.62 (С(15)); 122.15 (С(7)); 124.65 (С(4));
126.3 (С(8)); 128.06 (С(6)); 132.77 (С(3)); 134.19 (С(1)); 137.72
(С(5а)); 141.59 (С(4а)); 147.76 (С(12)); 151.70 (С(13)); 157.42
(С(16)); 166.92 (С(4b)); 177.08 (С(9)).
22.12 (С(1а), C(8а)); 125.72 (С(2), C(7)); 127.88 (С(1), C(8));
30.07 (С(3), C(6)); 131.35 (С(9)); 139.63 (С(4), C(5)); 148.62
(
С(4а), C(5а)); 148.87 (С(13)); 153.42 (С(16)); 165.89 (С(9а)).
ꢀMethylꢀ1ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀ(9ꢀoxoꢀ9,10ꢀdihydroꢀ
acridineꢀ2ꢀcarbonyl)piperazinꢀ1ꢀium bromide (12a). The yield was
3%, white crystals, m.p. 225—227 °С. Found (%): C, 56.94; H, 5.42;
N, 8.71. C H BrN O . Calculated (%): C, 56.56; H, 5.37; N, 8.60.
1
9
10ꢀ{2ꢀ[4ꢀ(5ꢀNitrofuranꢀ2ꢀcarbonyl)piperazinꢀ1ꢀyl]ꢀ2ꢀoxoꢀ
ethyl}acridinꢀ9(10H)ꢀone (14b). The yield was 67%, yellow crysꢀ
tals, m.p. 229—231 °С. Found (%): C, 62.10; H, 4.32; N, 12.06.
C H N O . Calculated (%): C, 62.60; H, 4.38; N, 12.17.
23
26
3 4
1
H NMR, δ: 1.26 (td, 3 Н, С(16)Н , J = 7.2, J = 0.8); 3.40 (s, 3 Н,
3
1
2
С(12)Н ); 3.65—4.15 (m, 8 Н, С(10)Н , С(10а)Н , С(11)Н ,
С(11а)Н ); 4.25 (q, 2 Н, С(15)Н , J = 7.2 Hz); 4.69 (br.s, 2 Н,
3
2
2
2
24 20
4
6
1
H NMR, δ: 3.58—4.09 (m, 8 H, C(10)Н , C(10а)Н , C(11)Н ,
2 2 2
2
2

1
28
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
Kudryavtseva et al.
C(11а)Н ); 5.57 (s, 2 H, C(4b)Н ); 7.29—7.41 (m, 3 H, C(2)H,
Determination of antimicrobial activity.15 Glass Petri dishes
mounted in stages with the rigidly horizontal surface were poured
with melted agar medium preꢀseeded with test strains of microꢀ
organisms.
2
2
C(7)H, C(14)H); 7.61 (dd, 2 H, C(4)H, C(5)H, J = 8.7 Hz);
.73—7.86 (m, 3 H, C(3)H, C(6)H, C(15)H); 8.36 (dd, 2 H,
7
13
C(1)H, C(8)H, J = 7.9 Hz, J = 1.4 Hz). С NMR, δ: 42.77
1
2
(
(
1
1
1
С(11)); 44.28 (С(11а)); 44.83 (С(10)); 46.58 (С(10а)); 47.94
С(4b)); 113.40 (С(14)); 116.67 (С(4), C(5)); 117.90 (С(15));
21.84 (С(2), C(7)); 122.02 (С(1а), C(8а)); 126.92 (С(1), C(8));
34.45 (С(3), C(6)); 142.94 (С(4а), C(5а)); 148.00 (С(12));
51.78 (С(16)); 157.49 (С(13)); 165.66 (С(4с)); 177.22 (С(9)).
Synthesis of compounds 15a—c (general procedure). Potassium
A suspension of test microbes for seeding on Petri dishes was
prepared according to a turbidity standard of 10 EU. Daily culꢀ
tures were used as inoculum. A suspension of each type of miꢀ
croorganism was seeded on a Petri dish. The microbial load was
1 000 000 microbial cells per 1 mL.
To determine the antimicrobial activity of the tested subꢀ
stances, their solutions with concentrations of 0.5, 1.0, and 2.0%
were placed at the center of a cylinder (0.1 mL). Then the dishes
were incubated for 18—20 h at 37±1 °С. Standard solutions of
Rivanol in the same concentrations were used as reference samples.
The diameter of the bacteriostasis zones for test microbes
was measured with a microruler with the accuracy to 1 mm.
bicarbonate (1.1 mmol) was added to compound 13а—с (1 mmol)
in DMF (10 mL). Then 2ꢀbromomethylꢀ5ꢀnitrofuran (1.1 mmol)
was added. The reaction mixture was stirred for 24 h, poured
into water, and filtered. The precipitate was washed with water,
dried, and purified by preparative chromatography.
4
ꢀ{4ꢀ[(5ꢀNitrofuranꢀ2ꢀyl)methyl]piperazinꢀ1ꢀcarbonyl]acridꢀ
inꢀ9(10H)ꢀone (15a). The yield was 77%, yellow crystals, m.p.
09—211 °С. Found (%): C, 63.16; H, 4.61; N, 12.86. C H N O .
2
References
23
20
4 5
1
Calculated (%): C, 63.88; H, 4.66; N, 12.96. H NMR, δ: 2.46—2.34
(
(
m, 2 Н, C(11a)Н ); 2.59—2.77 (m, 2 Н, C(11)Н ); 3.18—3.30
1. T. N. Kudryavtseva, P. I. Sysoev, S. V. Popkov, G. V. Nazꢀ
arov, L. G. Klimova, Russ. Chem. Bull. (Int. Ed.), 2015, 64,
445 [Izv. Akad. Nauk, Ser. Khim., 2015, 445].
2
2
m, 2 Н, C(10а)Н ); 3.72 (s, 2 Н, C(12)Н ); 3.75—3.89 (m, 2 Н,
2
2
C(10)Н ); 6.78 (d, 1 Н, C(14)H, J = 3.7 Hz); 7.26—7.33 (m, 2 Н,
2
C(6)H, C(7)H); 7.66 (dd, 1 Н, C(5)H, J = 7.7 Hz, J = 1.5 Hz);
2. A. Kleemann, J. Engel, Pharmaceutical Substances, Thieme,
Stuttgart—New York, 2001, 2409 pp.
1
2
7
7
.68 (d, 1 Н, C(15)H, J = 3.7 Hz); 7.70—7.76 (m, 1 Н, C(2)H);
.84 (d, 1 Н, C(3)H, J = 8.4 Hz); 8.23 (dd, 1 Н, C(8)H, J = 8.1 Hz,
1
3. F. I. Ershov, M. G. Romantsov, A. L. Kovalenko, V. A.
Isakov, Yu. V. Aspel´, Tsikloferon 12.5% dlya in"ektsii: itogi i
perspektivy klinicheskogo primeneniya [Cycloferon 12.5% for
Injections: Results and Propspects of Clinical Application],
NTFF Polisan, St. Petersburg, 1999, 80 pp. (in Russian).
4. O. Tabarrini, V. Cecchetti, A. Fravolini, G. Nocentini,
A. Barzi, S. Sabatini, Hua Miao, C. Sissi, J. Med. Chem.,
J = 1.3 Hz); 8.33 (dd, 1 Н, C(1)H, J = 8.0 Hz, J = 1.5 Hz);
2
1
2
1
(
0.83 (s, 1 Н, NH). 13С NMR, δ: 53.87 (С10), C(10а)); 55.24
С(12)); 60.11 (С(11), C(11а)); 113.73 (С(14)); 114.38 (С(15));
1
1
1
1
18.59 (С(5)); 120.95 (С(2)); 121.11 (С(8а)); 121.54 (С(1а));
22.11 (С(7)); 124.96 (С(4)); 126.26 (С(8)); 127.85 (С(6));
32.60 (С(1)); 134.10 (С(3)); 137.66 (С(5а)); 141.47 (С(4а));
51.84 (С(13)); 156.84 (С(16)); 166.54 (С(4b)); 177.07 (С(9)).
1
999, 42, 2136.
1
0ꢀ(2ꢀ{4ꢀ[(5ꢀNitrofuranꢀ2ꢀyl)methyl]piperazinꢀ1ꢀyl}ꢀ2ꢀoxoꢀ
5. A. StankiewiczꢀDrogon, L. G. Palchykovska, V. G. Kostina,
I. V. Alexeeva, A. D. Shved, A. M. BoguszewskaꢀChachulsꢀ
ka, J. Bioorg. Med. Chem. Lett., 2008, 16, 8846.
6. M. Fujiwara, M. Okamoto, M. Okamoto, M. Watanabe,
H. Machida, Sh. Shigeta, K. Konno, T. Yokota, M. Baba,
Antiviral Res., 1999, 43, 179.
7. M. Wainwright, J. Antimicrob. Chemother., 2001, 47, 1.
8. T. N. Kudryavtseva, K. V. Bogatyrev, L. G. Klimova, E. A. Baꢀ
tuev, Fluorine Notes: Online Journal, 2014, № 3, 94; URL: http:
//notes.fluorine1.ru/public/2014/3_2014/letters/index.html.
9. V. C. Jones, A. J. Lenaerts, M. R. McNeil, Yuehong Wang,
S. Franzblau, R. E. Lee, J. Med. Chem., 2004, 47, 5276.
10. J. G. Hurdle, R. B. Lee, N. R. Budha, E. I. Carson, J. Qi, M. S.
Scherman, Sang Hyun Cho, M. R. McNeil, A. J. Lenaerts,
S. G. Franzblau, B. Meibohm, R. E. Lee, J. Antimicrob.
Chemother., 2008, 62, 1037.
1. S. Emami, N. Shahrokhirad, A. Foroumadi, M. A. Faramarzi,
N. Samadi, N. SoltaniꢀGhofrani, Med. Chem. Res., 2013,
22, 5940.
2. P. Singh, J. Kaur, B. Yadav, S. S. Komath, Bioorg. Med.
Chem., 2009, 17, 3973.
13. Z. Szuls, J. Mlochowski, J. Palus, J. Prakt. Chem., 1988,
330, 1023.
4. S. Samai, G. C. Nandi, P. Singh, A. Gupta, M. S. Singh,
Ind. J. Chem., Sect B, 2011, 50, 580.
ethyl)acridinꢀ9(10H)ꢀone (15b). The yield was 87%, yellow crysꢀ
tals, m.p. 235—237 °С. Found (%): C, 64.96; H, 5.03; N, 12.65.
C H N O . Calculated (%): C, 64.57; H, 4.97; N, 12.55. H NMR,
δ: 2.47—2.54 (m, 2 H, С(11а)H ); 2.66—2.71 (m, 2 H, C(11)H );
.5—3.57 (m, 2 H, C(10)H ); 3.74—3.80 (m, 4 H, C(10a)H ,
2 2
C(12)H ); 5.5 (s, 2 Н, C(4b)H ); 6.83 (d, 1 Н, C(14)H, J = 3.7 Hz);
.33 (ddd, 2 H, C(2)H, C(7)H, J = 8.0 Hz, J = 7.1 Hz, J = 0.5 Hz);
.53 (d, 1 Н, C(4)H, C(5)H, J = 8.8 Hz); 7.71 (d, 1 Н, C(15)H,
J = 3.7 Hz); 7.77 (ddd, 2 H, C(3)H, C(6)H, J = 8.7 Hz, J = 6.9 Hz,
1
2
4
22
4 5
2
2
3
2
2
7
7
1 2 3
1
2
J = 1.8 Hz); 8.35 (dd, 2 H, C(1)H, C(8)H, J = 8.1 Hz, J = 1.7 Hz).
3
3
1
2
1
С NMR, δ: 42.08 (С(10)); 44.76 (С(10а)); 47.8 (С(11)); 52.36
С(4b)); 52.87 (С(12)); 54.01 (С(11а)); 113.7 (С(15)); 114.44
С(14)); 116.54 (С(4), C(5)); 121.78 (С(2), C(7)); 122.01 (С(1а),
C(8а)); 126.92 (С(1), C(8)); 134.39 (С(3), C(6)); 142.92 (С(4а),
C(5а)); 151.92 (С(16)); 156.98 (С(13)); 165.26 (С(4c)); 177.2 (С(9)).
Acridinꢀ9ꢀylꢀ{4ꢀ[(5ꢀnitrofuranꢀ2ꢀyl)methyl]piperazinꢀ1ꢀyl}ꢀ
methanone (15c). The yield was 90%, yellow crystals, m.p.
01—303 °С. Found (%): C, 66.85; H, 4.89; N, 13.57. C H N O .
Calculated (%): C, 66.34; H, 4.84; N, 13.45. H NMR, δ: 2.23—2.31
m, 2 H, C(11а)Н ); 2.69—2.77 (m, 2 H, C(11)Н ); 2.97—3.04
m, 2 H, C(10а)Н ); 3.71 (s, 2 Н, C(12)Н ); 3.95—4.04 (m, 2 H,
C(10)Н ); 6.76 (d, 1 H, C(14)H, J = 3.7 Hz); 7.64—7.73 (m, 3 H,
C(2)H, C(7)H, C(15)H); 7.87—7.97(m, 4 H, C(3)H, C(4)H,
C(5)H, C(6)H); 8.22 (d, 2 H, C(1)H, C(8)H, J = 8.7 Hz). С NMR,
δ: 41.55 (С(12)); 46.65 (С(10)); 52.41 (С(10а)); 52.99 (С(11));
3.84 (С(11а)); 113.62 (С(14)); 114.36 (С(15)); 121.87 (С(1а),
(
(
1
3
23 20 4 4
1
1
(
(
2
2
2
2
2
1
13
1
5. Gosudarstvennaya farmakopeya SSSR [State Pharmacopoeia
of the USSR], Meditsina, Moscow, 1990, 11 (in Russian).
5
C(8а)); 125.62 (С(2), C(7)); 127.64 (С(1), C(8)); 130.01 (С(3),
C(6)); 131.29 (С(9)); 141 (С(4), C(5)); 148.58 (С(4а), C(5а));
Received March 22, 2016;
1
51.79 (С(13)); 156.85 (С(16)); 165.24 (С(9а)).
in revised form September 8, 2016