Modification of biologically active amides and amines with fluorine-containing heterocycles 7. Fluorine-containing heterocyclic derivatives of the acetazolamide

Article abstract of DOI:10.1007/s11172-012-0297-x

An approach is proposed to modification of a medical product acetazolamide (N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide) by interaction of 2-(5-acetylamino-1,3,4-thiadiazole-2-yl)sulfonyl imine methyl trifluoropyruvate, which is in-situ generated from

Full text of DOI:10.1007/s11172-012-0297-x

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2124—2128, November, 2012
2124
УДК 542.91
Modification of biologically active amides and amines
with fluorineꢀcontaining heterocycles
7.* Fluorineꢀcontaining heterocyclic derivatives of the acetazolamide
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Substances, Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
An approach is proposed to modification of a medical product acetazolamide (Nꢀ(5ꢀsulfaꢀ
moylꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)acetamide) by interaction of 2ꢀ(5ꢀacetylaminoꢀ1,3,4ꢀthiadiazoleꢀ
2ꢀyl)sulfonyl imine methyl trifluoropyruvate, which is inꢀsitu generated from acetazolamide,
with 1,3ꢀbinucleophiles: 6ꢀaminouracils, 6ꢀaminothiouracils, and Nꢀsubstituted ureas, to yield
heterocyclic compounds with the CF3 substituent in the nitrogenꢀcontaining monoꢀ or bicycle.
Key words: acetazolamide, methyl trifluoropyruvate, 6ꢀaminouracils, 6ꢀaminothiouracils,
Nꢀsubstituted ureas, fluorineꢀcontaining hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidines, 2,5ꢀdioxoꢀ
imidazolidines, cyclocondensation.
Acetazolamide — Nꢀ(5ꢀsulfamoylꢀ1,3,4ꢀthiadiazolꢀ2ꢀ
of the binucleophile to the highly reactive C=Nꢀgroup
yl)acetamide (1), or "diacarb", is one of the effective inꢀ
hibitors of the carboanhydrase, which is used for conserꢀ
vative management of intracranial hypertension and hyꢀ
with the following heterocyclization with methanol elimiꢀ
nation in the presence of catalytic amount of Et3N. In
these intractions 6ꢀaminouracils 4а—с, 6ꢀaminothiouraꢀ
cyls 6а—с, and Nꢀsubstituted ureas 8а—с were used as
1,3ꢀbinucleophyles. Cyclocondensation of the imine 3 with
4a—c, 6а—с, and 8а—с resulted in formation of the correꢀ
sponding heterocyclic derivatives of the acetazolamide:
2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ
1Нꢀpyrrolo[2,3ꢀd]pyrimidines 5а—с, 4,6ꢀdioxoꢀ2ꢀthioxoꢀ
5ꢀtrifluoromethylꢀ1ꢀarylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrꢀ
rolo[2,3ꢀd]pyrimidines 7а—с, and 2,5ꢀdioxoꢀ4ꢀtrifluoroꢀ
methylimidazolidines 9а—с. NꢀAcetylated heterocyclic
derivatives of acetazolamide 5а,с, 7а, and 9а—с are transꢀ
formed to corresponding trifluoromethylꢀcontaining heteroꢀ
cyclic derivatives of 5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀsulfonic
acid 10а,b, 11, and 12а—с under reflux in 10% HCl for 1 h.
Fluorineꢀcontaining heterocyclic derivatives of acetꢀ
azolamide 5а—с, 7а—с, 9а—с, 10а,b, 11, and 12а—с are
solid crystalline compounds, their composition and strucꢀ
ture were confirmed with the elemental analysis data and
1Н and 19F NMR spectroscopy data (Tables 1 and 2).
In 19F NMR spectra, characteristic signals are obꢀ
served at  4—5 ppm for 5а—с, 7а—с, 10а,b, 11, and at
0.1—0.6 ppm for 9а—с and 12а—с.
drocefalus2—4
.
The aim of the present research is to expand the reperꢀ
toire of actazolamide derivatives, which are furnished with
trifluoromethylꢀcontaining fiveꢀmembered ring heteroꢀ
cycles using the multicomponent reaction of 1 with methꢀ
yl trifluoropyruvate (MTFP) (2) and 1,3ꢀbinucleophiles,
with a view to biological studies. The prerequisites for this
work were the results of the research on the behavior of
Nꢀsubstituted imines of MTFP in cyclocondensation reꢀ
actions with 1,3ꢀbinucleophiles. which lead to formation
of trifluoromethylꢀcontaining fiveꢀmembered ring heteroꢀ
cycles5—9, and the data on modification of biologically
active amides with fluorineꢀcontaining heterocycles10,11
.
As the attempts to obtain the starting biselectrophilic
synthon sulfonylimine of MTFP 3 in its pure state using
the known methods of synthesis of Nꢀsubstituted imines
of MTFP failed, the imine 3 was generated inꢀsitu by sucꢀ
cessive addition of pyridine, MTFP (2), and SOCl2 to the
solution of sulfonamide 1 in DMF with the following inꢀ
volvement of the compound 3 in cyclocondensation with
1,3ꢀbinucleophiles (Scheme 1). Interaction of the imine 3
with 1,3ꢀbinucleophiles is performed according to the
mechanism of the cyclocondensation reaction: addition
For fluorineꢀcontaining heterocyclic derivatives of
5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀsulfonic acid 10а,b, 11, and
12а—с bactericidal and fungicidal activity against
S. aureus, S. enteritidis, B. Anthracis, Cand. and E. Coli. was
* Report 6 see lit1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2108—2111, November, 2012.
1066ꢀ5285/12/6111ꢀ2124 © 2012 Springer Science+Business Media, Inc.

Fluorinated derivatives of acetazolamide
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2125
Scheme 1
5: R = Bu (a), 2ꢀMeꢀC6H4 (b), 3,4ꢀ(MeO)2С6Н3CH2CH2 (c); 7: R = Ph (a), 3ꢀMeꢀC6H4 (b), 4ꢀMeꢀC6H4 (c); 9: R = Me (a), cycloꢀC5H9 (b),
PhCH2 (c); 10: R = Bun (a), 3,4ꢀ(MeO)2С6Н3CH2CH2 (b); 12: R = Me (a), cycloꢀC5H9 (b), PhCH2 (c)
Table 1. Yields, melting points and elemental analysis data for compounds 5, 7, 9, 10—12
Comꢀ Yield
pound (%)
M.p.
Molecular
formula
Found
Comꢀ Yield M.p.
pound (%) /С
Molecular
formula
Found
(%)
N
(%)
N
/С
Calculated
Calculated
C
H
C
H
5b
5c
7a
7b
7c
9a
9b
73 243—245 C18H14F3N7O6S2 39.86 2.41 18.12
39.64 2.59 17.94
77 237—239 C21H20F3N7O8S2 40.56 3.02 15.65
40.71 3.25 15.83
69 259—261 C17H12F3N7O5S3 37.05 2.33 18.13
37.29 2.21 17.91
81 261—263 C18H14F3N7O5S3 38.72 2.69 17.58
38.50 2.51 17.46
9c
79 257—259 C15H13F3N6O5S2 37.85 2.58 17.39
37.66 2.74 17.57
86 227—229 C13H14F3N7O5S2 33.08 2.89 20.62
33.26 3.01 20.89
85 233—235 C19H18F3N7O7S2 39.33 3.29 16.72
39.52 3.14 16.98
82 243—245 C15H10F3N7O4S3 36.44 2.16 19.18
36.64 1.99 19.40
84 228—230 C7H7F3N6O4S2 23.19 1.81 23.18
23.34 1.96 23.33
79 219—221 C11H13F3N6O4S2 31.99 2.95 20.11
31.88 3.16 20.28
86 240—242 C13Н11F3N6O4S2 35.59 2.36 19.42
35.78 2.54 19.26
10a
10b
11
75 265—267 C18H14F3N7O5S3 38.76 2.33 17.28
38.50 2.51 17.46
12a
12b
12c
73 248—250 C9H9F3N6O5S2
29.11 2.06 20.63
28.87 2.25 20.89
76 241—243 C13H15F3N6O5S2 34.38 3.11 18.62
34.21 3.31 18.41

2126
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Sokolov and Aksinenko
Table 2. 1Н и 19F NMR spectroscopy data for compounds 5, 7, 9—12 in DMSOꢀd6
Comꢀ
pound
1H, , J/Hz
19F, 
5b
5c
2.12 (s, 3 H, MeC(O)); 2.25 (s, 3 H, Me); 7.24—7.62 (m, 4 H, CHAr);
10.51 (s, 1 H, NH); 10.98 (s, 1 H, NH); 11.75 (s, 1 H, NH); 13.04 (s, 1 H, NH)
2.24 (s, 3 H, MeC(O)); 2.81 (t, 2 H, CH2, J = 6.7); 3.73 (s, 3 H, MeO);
3.77 (s, 3 H, MeO); 4.02 (t, 2 H, CH2, J = 6.7); 6.66—6.80 (m, 2 H, CHAr);
6.85 (s, 1 H, CHAr); 10.57 (s,1 H, NH); 10.83 (s, 1 H, NH); 12.32 (s, 1 H, NH);
13.02 (s, 1 H, NH)
2.22 (s, 3 H, MeC(O)); 7.21—7.61 (m, 5 H, CHAr); 10.92 (s, 1 H, NH);
11.73 (s, 1 H, NH); 12.52 (s,1 H, NH); 13.15 (s, 1 H, NH)
2.23 (s, 3 H, MeC(O)); 2.42 (s, 3 H, Me); 7.00—7.19 (m, 1 H, CHAr);
7.33 (t, 1 H, CHAr, J = 7.3); 7.38—7.51 (m, 2 H, CHAr); 10.71 (s, 1 H, NH);
11.64 (s, 1 H, NH); 12.38 (s, 1 H, NH); 13.09 (s, 1 H, NH)
2.26 (s, 3 H, MeC(O)); 2.44 (s, 3 H, Me); 7.09—7.44 (m, 4 H, CHAr);
10.63 (s, 1 H, NH); 11.61 (s, 1 H, NH); 12.28 (s, 1 H, NH); 13.10 (s, 1 H, NH)
2.29 (s, 3 H, MeC(O)); 3.22 (s, 3 H, Me); 9.11 (s, 1 H, NH); 11.01 (s, 1 H, NH);
13.16 (s, 1 H, NH)
1.57 (m, 2 H, CH2); 1.84 (m, 6 H, CH2); 2.24 (s, 3 H, MeC(O));
4.30 (quint, 1 H, CH, J = 7.3); 9.73 (s, 1 H, NH); 11.23 (s, 1 H, NH);
13.08 (s, 1 H, NH)
2.29 (s, 3 H, MeC(O)); 4.57 (s, 2 H, CH2); 7.27—7.48 (m, 5 H, CHAr);
9.33 (s, 1 H, NH); 11.12 (s, 1 H, NH); 13.25 (s, 1 H, NH)
0.95 (t, 3 H, Me, J = 7.6); 1.16—1.39 (m, 2 H, CH2); 1.53—1.69 (m, 2 H, CH2);
3.75—3.92 (m, 2 H, CH2); 7.82 (s, 2 H, NH2); 10.05 (s, 1 H, NH);
10.62 (s, 1 H, NH); 11.92 (s, 1 H, NH)
2.84 (t, 2 H, CH2, J = 6.7); 3.71 (s, 3 H, MeO); 3.80 (s, 3 H, MeO);
4.09 (t, 2 H, CH2, J = 6.7); 6.61—6.76 (m, 2 H, CHAr); 6.81 (s, 1 H, CHAr);
7.76 (s, 2 H, NH2); 10.15 (s, 1 H, NH); 10.78 (s, 1 H, NH); 11.85 (s, 1 H, NH)
7.30—7.66 (m, 5 H, CHAr); 7.91 (s, 2 H, NH2); 10.33 (s, 1 H, NH);
10.62 (s, 1 H, NH); 12.03 (s, 1 H, NH)
3.34 (s, 3 H, Me); 7.72 (s, 2 H, NH2); 9.42 (s, 1 H, NH); 10.88 (s, 1 H, NH)
1.42 (m, 2 H, CH2); 1.73 (m, 6 H, CH2); 4.08 (quint, 1 H, CH, J = 7.2);
7.67 (s, 2 H, NH2); 9.33 (s, 1 H, NH); 10.88 (s, 1 H, NH)
4.48 (s, 2 H, CH2); 7.31—7.52 (m, 5 H, CHAr); 7.58 (s, 2 H, NH2);
9.51 (s, 1 H, NH); 11.05 (s, 1 H, NH)
5.41 (s)
4.78 (s)
4.54 (s)
7a
7b
5.14 (s)
5.07 (s)
0.21 (s)
7c
9a
9b
0.12 (s)
0.35 (s)
9c
10a
5.04 (с)
5.11 (s)
10b
11
4.98 (s)
0.35 (s)
12a
12b
0.22 (s)
0.52 (s)
12c
CF3COOH (external standard). Melting point determination was
performed in a sealed capillary. Starting compounds 6ꢀaminoꢀ
uracils 4а—с and 6ꢀaminothiouracils 6а—с were obtained acꢀ
cording to the published earlier method13, Nꢀ(5ꢀsulfamoylꢀ1,3,4ꢀ
thiazolꢀ2ꢀyl)acetamide (1), methyl ester of trifluoropyruvic acid
(2) and Nꢀsubstituted ureas 8a—c were purchased from Aldrich
and used without further purification.
Nꢀ{5ꢀ[(1ꢀButylꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀyl)sulfamoyl]ꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl}acetamide (5a) (general procedure). To the stirred
solution of 2.22 g (0.01 mol) of Nꢀ(5ꢀaminosulfamoylꢀ1,3,4ꢀ
thiazolꢀ2ꢀyl)acetamide (1) in 20 mL of DMF, 1.56 g (0.02 mol)
of pyridine and 1.56 g (0.01 mol) of MTFP (2) were added
consistently. The reaction mixture was stirred for 30 min, then
1.19 g (0.01 mol) of SOCl2 was added, the mixture was stirred for
1 h, then 1.83 g (0.01 mol) of aminouracyl 4а was added, the
mixture was stirred for 1 h at 20 C, then 0.1 g of Et3N was added
and the mixture was kept at 90—100 C for 2 h. Then the reaction
mixture was cooled and poured into 50 mL of 10% aqueous solꢀ
ution of NaCl. The residue was filtered and recrystallized from
50% EtOH. The yield of 5а was 4.1 g (80%). M.p. 207—209 С.
Found (%)): C, 35.44; H, 3.31; N, 19.36. C15H16F3N7O6S2.
investigated using the agar diffusion test. Data shown in
Table 3 demonstrated high activity of compounds 12а—с
against B. Anthracis and Candida, in comparison with
streptocide12.
Herewith, three component reaction of Nꢀ(5ꢀsulfaꢀ
moylꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)acetamide, MTFP, and 1,3ꢀbiꢀ
nucleophiles results in novel fluorineꢀcontaining heteroꢀ
cyclic derivatives of acetazolamide and presents the proꢀ
spective approach to modification of this medical prodꢀ
uct. The following hydrolysis of heterocyclic derivatives of
acetazolamide results in formation of fluorineꢀcontaining
heterocyclic derivatives of 5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀ
sulfonic acid, which are potential bactericidal sulfonamide
compounds.
Experimental
1
H and 19F NMR spectra were registered on the NMR
spectrometer Bruker DPX 200 (200.13 and 188.29 МHz correꢀ
spondingly) in CDCl3 using Me4Si (internal standard) and

Fluorinated derivatives of acetazolamide
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2127
Table 3. Bactericidal and fungicidal activity of fluorineꢀcontaining heterocyclic derivatives of 5ꢀaminoꢀ1,3,4ꢀtiadiaꢀ
zolꢀ2ꢀsulfonic acid 10—12
Compound
Concenꢀ
Size of the inhibitory area/mm
tration (%)
S. aureus
S. enteritidis
B. anthracis
Candida
E. Coli
Streptocide
10a
1.00
0.10
0.01
1.00
0.10
0.01
1.00
0.10
0.01
1.00
0.10
0.01
1.00
0.10
0.01
1.00
0.10
0.01
1.00
0.10
0.01
51
35
22
11
0
0
0
0
0
58
29
18
0
0
0
0
0
0
0
11
0
0
15
11
0
0
0
0
15
13
0
71
23
11
12
11
0
11
0
0
13
12
0
11
11
0
38
30
20
0
0
0
0
0
0
0
10b
11
0
0
0
11
0
0
0
0
0
0
12a
15
13
11
15
0
0
16
0
16
12
0
11
0
19
12
0
32
29
30
27
25
11
23
22
19
11
0
12b
0
0
12c
13
16
11
24
16
0
11
11
0
0
Calculated (%): C, 35.23; H, 3.15; N, 19.17. 1H NMR (DMSOꢀd6),
: 0.98 (t, 3 H, Me, J = 7.7); 1.31—1.48 (m, 2 H, CH2);
1.51—1.67 (m, 2 H, CH2); 2.26 (s, 3 H, MeC(O)); 3.75—3.92
(m, 2 H, CH2); 10.51 (s, 1 H, NH); 10.74 (s, 1 H, NH); 12.26
(s, 1 H, NH); 13.00 (s, 1 H, NH). 1H NMR (DMSOꢀd6), : 4.70 s.
Nꢀ[5ꢀ{[2,4,6ꢀTrioxoꢀ1ꢀ(оꢀtolyl)ꢀ5ꢀtrifluoromethylꢀ2,3,4,
5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀyl]sulfamoyl}ꢀ
1,3,4ꢀthiadiazolꢀ2ꢀyl]acetamide (5b), Nꢀ[5ꢀ({1ꢀ[2ꢀ(3,4ꢀdimethꢀ
oxyphenyl)ethyl]ꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀyl}sulfamoyl)ꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl]acetamide (5c), Nꢀ{5ꢀ[(4,6ꢀdioxoꢀ2ꢀthioxoꢀ5ꢀ
trifluoromethylꢀ1ꢀphenylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrroloꢀ
[2,3ꢀd]pyrimidinꢀ5ꢀyl)sulfamoyl]ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl}acetꢀ
amide (7a), Nꢀ{5ꢀ[(4,6ꢀdioxoꢀ2ꢀthioxoꢀ1ꢀmetaꢀtolylꢀ5ꢀtrifluoroꢀ
methylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀ
yl)sulfamoyl]ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl}acetamide (7b), Nꢀ{5ꢀ[(4,6ꢀ
dioxoꢀ2ꢀthioxoꢀ1ꢀparaꢀtolylꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀyl)sulfamoyl]ꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl}acetamide (7c), Nꢀ(5ꢀ{[2,5ꢀdioxoꢀ1ꢀmethylꢀ4ꢀ
(trifluoromethyl)imidazolidineꢀ4ꢀyl]sulfamoyl}ꢀ1,3,4ꢀthiadiazolꢀ
2ꢀyl)acetamide (9a), Nꢀ(5ꢀ{1ꢀcyclopentylꢀ[2,5ꢀdioxoꢀ4ꢀ(triꢀ
fluoromethyl)imidazolidineꢀ4ꢀyl]sulfamoyl}ꢀ1,3,4ꢀthiadiazolꢀ2ꢀ
yl)acetamide (9b), Nꢀ(5ꢀ{[1ꢀbenzylꢀ2,5ꢀdioxoꢀ4ꢀ(trifluoromethꢀ
yl)imidazolidineꢀ4ꢀyl]sulfamoyl}ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)acetamide
(9c) were obtained similarly to the compound 5а. Yields,
melting points, elemental analysis data and NMR spectroꢀ
scopy data for compounds 5b,c, 7a—c, and 9a—c are given in
Tables 1 and 2.
ethyl]ꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ
1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ5ꢀyl}amide of 5ꢀaminoꢀ1,3,4ꢀthiaꢀ
diazolꢀ2ꢀsulfonic acid (10b), (4,6ꢀdioxoꢀ2ꢀthioxoꢀ5ꢀtrifluoroꢀ
methylꢀ1ꢀphenylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrꢀ
imidineꢀ5ꢀyl)amide of 5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀsulfonic acid (11),
[2,5ꢀdioxoꢀ1ꢀmethylꢀ4ꢀ(trifluoromethyl)imidazolidineꢀ4ꢀyl]amide
of 5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀsulfonic acid (12a), [1ꢀcyclopentylꢀ
2,5ꢀdioxoꢀ4ꢀ(trifluoromethyl)imidazolidineꢀ4ꢀyl]amide of 5ꢀamiꢀ
noꢀ1,3,4ꢀthiadiazolꢀ2ꢀsulfonic acid (12b), [1ꢀbenzylꢀ2,5ꢀdioxoꢀ
4ꢀ(trifluoromethyl)imidazolidineꢀ4ꢀyl]amide of 5ꢀaminoꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀsulfonic acid (12c) (general procedure). Acetylated
heterocyclic derivative of acetazolamide (0.05 mol) 5a,c, 7a or
9a—c was refluxed for 1 h in 10 mL 10% HCl. The cooled soluꢀ
tion was diluted with 20 mL of water, and the solution was neuꢀ
trolized with 10% aqueous ammonia, the residue was filtered
and recrystallized from 50% EtOH. Yields, melting points, eleꢀ
mental analysis data and NMR spectroscopy data for compounds
10a,b, 11, and 12a—c are given in Tables 1 and 2.
The work financiallly supported by the Russian Acadꢀ
emy of Sciences (program DCMS RAS "Medicinal chemꢀ
istry: molecular design of physiologically active comꢀ
pounds and medicinal products").
References
1. V. B. Sokolov, A. Yu. Aksinenko, Russ. Chem. Bull. (Int. Ed.),
2012, 61, 1965 [Izv. Akad. Nauk, Ser. Khim., 2012, 1949].
2. I. Sibon, I. Ghorayer, P. Henry, Neurology, 2003,
61, 1157.aaa
(1ꢀButylꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexaꢀ
hydroꢀ1Нꢀpyrrolo[2,3ꢀd]pirimidineꢀ5ꢀyl)amide of 5ꢀaminoꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀsulfonic acid (10a), {1ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ

2128
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Sokolov and Aksinenko
3. C. W. Zwillich, M. R. Natalino, F. D. Sutton, J. V. Weil,
J. Lab. Clin. Med., 1978, 92, 262.
4. M. A. Mashkovskyi, Lekarstvennihe Sredstva, Medicina,
Moscow, 1994, 1, p. 582.
5. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreꢀ
va, I. V. Martynov, Russ. Chem. Bull. (Int. Ed.), 2005, 54,
472 [Izv. Akad. Nauk, Ser. Khim., 2005, 462].
9. V. B. Sokolov, A. Yu. Aksinenko, Russ. Chem. Bull. (Int. Ed.),
2007, 56, 2252 [Izv. Akad. Nauk, Ser. Khim., 2007, 2176].
10. V. B. Sokolov, A. Yu. Aksinenko, Russ. Chem. Bull. (Int. Ed.),
2010, 59, 197 [Izv. Akad. Nauk, Ser. Khim., 2010, 193].
11. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreꢀ
va, I. V. Martynov, Russ. Chem. Bull. (Int. Ed.), 2010, 59,
288 [Izv. Akad. Nauk, Ser. Khim., 2010, 281].
6. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Gorꢀ
eva, A. N. Pushin, I. V. Martynov, Russ. Chem. Bull.
(Int. Ed.), 2005, 54, 1667 [Izv. Akad. Nauk, Ser. Khim.,
2005, 1619].
7. A. Yu. Aksinenko, T. V. Goreva, T. A. Epishina, A. N.
Pushin, V. B. Sokolov, Russ. Chem. Bull. (Int. Ed.), 2006, 55,
1052 [Izv. Akad. Nauk, Ser. Khim., 2006, 1014].
8. V. B. Sokolov, A. Yu. Aksinenko, I. V. Martynov, Russ. Chem.
Bull. (Int. Ed.), 2007, 56, 2247 [Izv. Akad. Nauk, Ser. Khim.,
2007, 2171].
12. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreꢀ
va, I. V. Martynov, Russ. Chem. Bull. (Int. Ed.), 2010, 59,
192 [Izv. Akad. Nauk, Ser. Khim., 2010, 188].
13. W. Hatzenlaub, W. Pfleiderer, Liebigs Ann. Chem.,
1979, 1847.
Received March 28, 2012;
in revised form November 15, 2012