Modification of biologically active amides and amines with fluorine-containing heterocycles 1. Novel fluorine-containing heterocyclic derivatives of streptocide

Article abstract of DOI:10.1007/s11172-010-0061-z

An approach to the modification of the known antimicrobial drug, streptocide, with fluorine-containing five-membered heterocycles is proposed. The reaction of the generated in situ methyl 2-[4-(N-acetylamino)phenylsulfonyl] imino-3,3,3-trifluoropropionate

Full text of DOI:10.1007/s11172-010-0061-z

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 192—196, January, 2010
192
Modification of biologically active amides
and amines with fluorineꢀcontaining heterocycles
1. Novel fluorineꢀcontaining heterocyclic derivatives of streptocide
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva, and I. V. Martynov
Institute of Physiologically Active Substances, Russian Academy of Sciences,
1 Severnyi proezd, Chernogolovka, 142432 Moscow Region, Russian Federation,
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
An approach to the modification of the known antimicrobial drug, streptocide, with
fluorineꢀcontaining fiveꢀmembered heterocycles is proposed. The reaction of the generated
in situ methyl 2ꢀ[4ꢀ(Nꢀacetylamino)phenylsulfonyl]iminoꢀ3,3,3ꢀtrifluoropropionate with
1,3ꢀC,Nꢀ or 1,3ꢀN,Nꢀbinucleophiles and subsequent hydrolysis of the resulting products furꢀ
nished different novel fluorineꢀcontaining heterocyclic derivatives of streptocide, including
fused heterocycles.
Key words: 4ꢀ(Nꢀacetylamino)benzenesulfonamide, methyl trifluoropyruvate, 6ꢀamiꢀ
nouracils, 6ꢀaminothiouracils, Nꢀsubstituted 3ꢀaminocyclohexenones, Nꢀsubstituted ureas, fluoꢀ
rineꢀcontaining dihydroꢀ1Hꢀpyrroles, hexahydroꢀ1Hꢀindoles, hexahydroꢀ1Hꢀpyrrolo[2,3ꢀd]ꢀ
pyrimidines, 2,5ꢀdioxoimidazolidines, cyclocondensation.
Functionalization of biologically active substances
stantially in the pharmacological parameters (absorption,
(BAS) with fluorineꢀcontaining heterocycles is one
of the fruitful trends in organic chemistry. In general, the
introduction of fluorineꢀcontaining substituents into BAS
does not influence their biological activities and, at the
same time, impart the molecule with unique physicoꢀ
chemical properties, which in turn enhance the pharmaꢀ
cological parameters, and in some cases change them in
a controlled fashion.1—5 The progress in this field is assoꢀ
ciated mainly with the development of the affordable and
effective methods for the introduction of the fluorineꢀconꢀ
taining, including heterocyclic, substituents in the BAS
structure, which could be carried out using highly electroꢀ
philic fluorineꢀcontaining synthons. The study of the beꢀ
havior of Nꢀsubstituted imines of methyl trifluoropyruꢀ
vate and hexafluoroacetone in cyclocondensations with
1,3ꢀC,Nꢀ, 1,3ꢀC,Oꢀ or 1,3ꢀN,Nꢀbinucleophiles and estiꢀ
mation of the synthetic potential of these reactions for the
synthesis of various trifluoromethylꢀcontaining fiveꢀ and
sixꢀmembered heterocycles,6—13 allowed us to develop an
original approach to the modification of biologically acꢀ
tive amides using fluorineꢀcontaining heterocycles. In the
present paper, a strategy for the modification of streptocide
with fluorineꢀcontaining fiveꢀmembered heterocycles is
presented.
accumulation in the blood and organs in bacteriostatic
concentrations, overcoming the blood brain barrier, excreꢀ
tion time, etc.), which is largely due to the nature of the
substituents at the nitrogen atom of the sulfamide group.14
The variation of the substituents at this atom has
been, and apparently will be, the main approach to the
streptocide modification. From this viewpoint, we proꢀ
posed a synthetic approach for the introduction of a vaꢀ
riety of fluorineꢀcontaining fiveꢀmembered heterocycꢀ
les at the nitrogen atom of the sulfamide group that inꢀ
volved threeꢀcomponent reaction of 4ꢀ(Nꢀacetylamino)ꢀ
benzenesulfonamide with methyl trifluoropyruvate and
1,3ꢀbinucleophiles. This strategy may be regarded as an
example of a general approach to the modification of bioꢀ
logically active amides with fluorineꢀcontaining heteꢀ
rocycles.
The synthesis of the fluorineꢀcontaining heterocyclic
streptocide derivatives involved two steps: 1) in situ genꢀ
eration of 4ꢀ(Nꢀacetylamino)benzenesulfonylimine of
methyl pyruvate by sequential addition of pyridine, meꢀ
thyl trifluoropyruvate (1) and thionyl chloride to a soluꢀ
tion of 4ꢀ(Nꢀacetylamino)benzenesulfonamide (2) in DMF,
the formation of imine 3 being confirmed by 19F NMR
spectroscopy (in the 19F NMR spectra of the reaction
mixtures, the signal for the trifluoromethyl group at δ 4.9
was observed in the range characteristic of the known meꢀ
thyl trifluoropyruvate imines15), 2) cyclocondensation of
3 with 1,3ꢀC,Nꢀ or N,Nꢀbinucleophiles (Scheme 1). Meꢀ
Despite the advent of penicillin and other antibiotics,
sulfonylamides have not lost their significance and are
successfully used in therapy of infectious diseases. The
currently used sulfonylamide pharmaceuticals differ subꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 188—192, January, 2010.
1066ꢀ5285/10/5901ꢀ0192 © 2010 Springer Science+Business Media, Inc.

Fluorineꢀcontaining streptocides
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
193
Scheme 1
6, 12, 18: R = Ph (a), 4ꢀFC6H4CH2 (b);
7, 13, 19: R = Me (a), 4ꢀMeOC6H4 (b);
9, 15, 21: R = 3ꢀClC6H4 (a), 3,4ꢀ(MeO)2C6H3CH2CH2 (b)

194
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Sokolov et al.
thyl 3ꢀpropylaminobytꢀ2ꢀenoate (4), 4ꢀ(4ꢀfluoroanilino)ꢀ
pentꢀ3ꢀenꢀ2ꢀone (5), Nꢀsubstituted 3ꢀaminocyclohexeꢀ
nones 6a,b, 6ꢀaminouracils 7a,b and 8, Nꢀsubstituted ureas
9a,b were involved in the cyclocondensation with imine 3.
The reactions of 3 with 1,3ꢀbinucleophiles 4—9 were carꢀ
ried out in DMF at 90—100 °С for 2 h in the presence of
catalytic amounts of Et3N. All the reactions resulted
in fluorineꢀcontaining heterocycles bearing 4ꢀ(Nꢀaceꢀ
tylamino)phenylsulfonyl residue: the corresponding
4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ1Нꢀpyrroles 10 and 11,
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀindoles 12a,b, 2,4,6ꢀtrioxoꢀ5ꢀ
trifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]ꢀ
pyrimidines 13a,b, 4,6ꢀdioxoꢀ2ꢀthioxoꢀ5ꢀtrifuoromethylꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidine 14,
and 2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidazolidines 15a,b. The
Nꢀacetylated heterocyclic streptocide derivatives 10, 11,
12a,b, 13a,b, 14, and 15a,b underwent hydrolysis upon
reflux in 10% hydrochloric acid for 1 h to give the correꢀ
sponding trifluoromethyl heterocyclic derivatives 16, 17,
18a,b, 19a,b, 20, and 21a,b (Scheme 1, Table 1).
The data on antimicrobial and antifungal activities of
compounds 16, 17, 18a,b, 19b, 20, and 21a,b against
Staphilloccus aureus, Salmonella enteritidis, Bacillus anꢀ
thracis, Candida albicans, and E. coli, which were obtained
by the ´diffusion in agar´ method (Table 2), in several cases
indicated significant selective increase in the activity, esꢀ
pecially for 18а, 19b, and 21b, relative to the parent strucꢀ
ture, streptocide.
Thus, it was found that the threeꢀcomponent reaction
of 4ꢀ(Nꢀacetylanimo)benzenesulfamide with methyl trifluꢀ
oropyruvate and 1,3ꢀC,Nꢀ or 1,3ꢀN,Nꢀbinucleophiles folꢀ
lowed by hydrolysis of the cyclocondensation products
resulted in novel fluorineꢀcontaining heterocyclic derivaꢀ
tives of streptocide. The introduction of the fluorineꢀconꢀ
taining heterocyclic substituent at the nitrogen atom
Table 1. Yields and physicochemical data for compounds 10—21
Comꢀ Yield m.p.
pound (%) /°С
Molecular
formula
Found
Calculated
(%)
N
C
H
Table 2. Antimicrobial and antifungal activities of fluorineꢀconꢀ
taining Nꢀhetarylꢀ4ꢀaminobenzenesulfonamides 16—21
10
71 177— C19H22F3N3O6S
47.69 4.81 8.59
47.80 4.64 8.80
51.64 3.82 8.01
51.46 3.73 8.18
56.32 4.26 7.66
56.07 4.52 7.85
55.33 4.22 7.62
55.02 4.44 7.40
41.42 3.22 14.95
41.65 3.06 15.18
47.56 3.03 12.86
47.74 3.28 12.65
45.49 2.88 12.78
45.24 2.71 12.56
179
11
78 194— C22H19F4N3O5S
Comꢀ
C
Zones of delayed growth/mm
196
pound (%)
12a
12b
13a
13b
14
69 196— C25H24F3N3O5S
S. aureus S. enterꢀ B. anthꢀ Cand. E. Coli
198
itidis
racis
85 241— C26H25F4N3O5S
243
Strepꢀ
tocide
1.0
0.1
0.01
1.0
0.1
0.01
1.0
0.1
0.01
1.0
0.1
0.01
1.0
0.1
0.01
1.0
0.1
0.01
1.0
0.1
51
35
22
0
—
—
0
—
—
0
—
—
11
0
58
29
18
0
—
—
0
—
—
0
—
—
11
0
11
0
0
12
0
—
0
—
—
69
19
0
12
0
0
11
0
0
38
30
20
0
—
—
0
—
—
25
20
19
12
0
81 237— C16H14F3N5O6S
239
77 254— C22H18F3N5O7S
16
13
16
25
13
16
25
19
12
0
17
29
30
19
12
11
17
11
256
76 247— C21H15F4N5O5S2
249
70 119— C18H14ClF3N4O5S 44.32 2.69 11.59
17
15a
15b
16
121
44.05 2.87 11.41
48.12 4.02 10.42
48.33 4.26 10.29
51.22 3.81 9.12
50.96 3.63 8.91
44.06 2.36 13.42
44.27 2.54 13.59
55.77 4.72 8.44
55.98 4.49 8.51
54.66 4.19 7.85
54.85 4.41 8.00
40.33 3.06 16.49
40.10 2.88 16.70
47.14 3.38 13.52
46.97 3.15 13.69
44.06 2.36 13.42
44.27 2.54 13.59
82 144— C22H23F3N4O7S
18a
18b
19b
20
146
86 142— C20H17F4N3O4S
144
17
91 183— C19H13F4N5O4S2
185
0
0
0
18a
18b
19a
19b
20
78 162— C23H22F3N3O4S
12
11
0
16
12
13
15
11
32
16
24
16
0
19
13
12
11
0
17
15
164
85 204— C24H23F4N3O4S
206
88 227— C14H12F3N5O5S
229
0.01
0
0
11
0
0
93 304— C20H16F3N5O6S
21a
21b
1.0
0.1
18
11
18
11
17
12
27
19
17
15
306
78 221— C19H13F4N5O4S2
223
71 178— C16H12ClF3N4O4S 42.59 2.89 12.22
0.01
0
0
0
0
0
21a
21b
1.0
0.1
11
0
12
0
13
0
13
34
11
0
180
42.82 2.70 12.48
47.60 4.42 11.37
47.81 4.21 11.15
85 138— C20H21F3N4O6S
140
0.01
0
0
0
44
0

Fluorineꢀcontaining streptocides
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
195
of the sulfamide group increased the antimicrobial and
antifungal activity of the final compounds relative to the
parent streptocide structure. This suggests that the develꢀ
oped strategy is a promising approach to the modification
of the biologically active amides using fluorineꢀcontaining
heterocycles.
Experimental
The 1H and 19F NMR spectra were recorded on a Bruker
DPX 200 instrument at 200.13 MHz and 188.29 MHz relative to
tetramethylsilane (internal standard) and CF3COOH (external
standard), respectively. Melting points were determined in open
Table 3. 1Н and 19F NMR spectral data of compounds 10—21 in DMSOꢀd6
Comꢀ
pound
1H NMR
(δ, J/Hz)
19F NMR
(δ)
10
0.98 (t, 3 H, Me, J = 7.4); 1.64 (m, 2 H, CH2); 2.11 (s, 3 H, MeCO); 2.52 (s, 3 H, Me);
3.25 (s, 3 H, MeO); 3.54 (t, 2 H, CH2, J = 7.5); 7.63 (АВꢀsystem, 4 H, CAr, J = 11.6);
8.87, 10.11 (both s, 1 H, NH)
5.11 s
11
1.91 (s, 3 H, Me); 2.11 (s, 3 H, MeCO); 2.30 (s, 3 H, Me); 7.27—7.38 (m, 4 H, CHAr);
7.73 (m, 4 H, CHAr); 9.44, 10.17 (both s, 1 H, NH)
5.36 s
4.86 s
12a
1.03, 1.10 (both s, 3 H, Me); 2.04 (s, 2 H, CH2); 2.11 (s, 3 H, MeCO); 2.50 (АВꢀsystem,
2 H, CH2, J = 17.8 ); 7.35 (d, 2 Н, CHAr, J = 7.2); 7.56 (m, 3 H, CHAr); 7.72 (m, 4 H,
CHAr); 9.28, 10.14 (both s, 1 H, NH)
12b
0.95, 1.08 (both s, 3 H, Me); 1.95 (s, 2 H, CH2); 2.11 (s, 3 H, MeCO); 2.50 (АВꢀsystem,
2 H, CH2, J = 17.9); 4.83 (s, 2 H, CH2); 7.10 (m, 2 H, CHAr); 7.35 (m, 2 H, CHAr); 7.64
(m, 4 H, CHAr); 9.14, 10.12 (both s, 1 H, NH)
4.77 s
13a
13b
2.10 (s, 3 H, MeCO); 3.34 (s, 3 H, MeN); 7.62 (АВꢀsystem, 4 H, CHAr, J = 9.1); 9.21
(s, 1 H, NH); 10.17 (s, 1 H, NH); 10.74 (s, 1 H, NH); 12.10 (s, 1 H, NH)
2.12 (s, 3 H, MeCO); 3.89 (s, 3 H, MeO); 7.07 (m, 2 H, CHAr); 7.26 (m, 2 H, CHAr);
7.71 (АВꢀsystem, 4 H, CHAr, J = 8.8); 9.27 (s, 1 H, NH); 10.20 (s, 1 H, NH); 10.84
(s, 1 H, NH); 11.43 (s, 1 H, NH)
4.65 s
4.74 s
14
2.11 (s, 3 H, MeCO); 7.18—7.48 (m, 4 H, CHAr); 7.72 (АВꢀsystem, 4 H, CHAr, J = 14.2);
9.42, 10.19 (both s, 1 H, NH); 11.56 (s, 1 H, NH); 12.37 (s, 1 H, NH)
2.12 (s, 3 H, MeCO); 7.29—7.57 (m, 4 H, CHAr); 7.77 (m, 4 H, CHAr); 9.88 (s, 1 H, NH);
10.08 (s, 1 H, NH); 10.22 (s, 1 H, NH)
4.98 s
0.20 s
15a
15b
2.12 (s, 3 H, MeCO); 2.80 (m, 2 H, CH2); 3.59 (m, 2 H, CH2); 3.78 (s, 3 H, MeO); 3.81 (s,
3 H, MeO); 6.77 (m, 3 H, CHAr); 7.74 (АВꢀsystem, 4 H, CHAr, J = 6.5); 9.50 (s, 1 H,
NH); 10.05 (s, 1 H, NH); 10.20 (s, 1 H, NH)
–0.16 s
16
0.97 (t, 3 H, Me, J = 7.2); 1.62 (m, 2 H, CH2); 2.50 (s, 3 H, Me); 3.32 (s, 3 H, MeO); 3.51
(t, 2 H, CH2, J = 7.2); 5.76 (s, 2 H, NH2); 6.53 (d, 2 H, CHAr, J = 8.6); 7.28 (d, 2 H,
CHAr, J = 8.6); 8.38 (s, 1 H, NH)
4.60 s
17
1.96 (s, 3 H, Me); 2.27 (s, 3 H, Me); 5.82 (s, 2 H, NH2); 6.60 (d, 2 H, CHAr, J = 8.8); 7.30
(m, 4 H, CHAr); 7.43 (d, 2 H, CHAr, J = 8.8); 9.03 (s, 1 H, NH)
5.37 s
4.47 s
18a
0.99, 1.07 (both s, 3 H, Me); 2.04 (s, 2 H, CH2); 2.31 (АВꢀsystem, 2 H, CH2, J = 18.6);
5.65 (s, 2 H, NH2); 6.56 (d, 2 Н, CHAr, J = 9.4); 7.30 (d, 2 H, CHAr, J = 6.3); 7.40 (d,
2 Н, CHAr, J = 9.4); 7.57 (m, 3 H, CHAr); 8.81 (s, 1 H, NH)
18b
0.96, 1.09 (both s, 3 H, Me); 1.99 (s, 2 H, CH2); 2.44 (m, 2 H, CH2); 4.80 (s, 2 H, CH2);
4.73 s
5,71 (s, 2 H, NH2); 7.10 (m, 2 H, CHAr); 6.55 (d, 2 H, CHAr, J = 9.8); 7.10 (t, 2 H, CHAr
J = 8.6); 7.35 (d, 2 H, CHAr, J = 8.4); 8.57 (s, 1 H, NH)
,
19a
19b
3.34 (s, 3 H, MeN); 5.65 (s, 2 H, NH2); 6.54 (d, 2 H, CHAr, J = 8.6); 7.30 (d, 2 H, CHAr
J = 8.6); 8.67 (s, 1 H, NH); 10.81 (s, 1 H, NH); 12.04 (s, 1 H, NH)
,
4.59 s
4.65 s
3.89 (s, 3 H, MeO); 5.74 (s, 2 H, NH2); 6.56 (d, 2 H, CHAr, J = 8.6); 7.04 (m, 2 H, CHAr);
7.22 (m, 2 H, CHAr); 7.41 (d, 2 H, CHAr, J = 8.6); 8.70 (s, 1 H, NH); 10.89 (s, 1 H, NH);
11.29 (s, 1 H, NH)
20
5.81 (s, 2 H, NH2); 6.59; 7.41 (d, 2 H, CHAr, J = 8.9); 7.06—7.77 (m, 6 H, CHAr); 8.78, 11.04
(both s, 1 H, NH); 11.51 (s, 1 H, NH)
4.81 s
0.25 s
21a
21b
5.87 (s, 2 H, NH2); 6.62 (d, 2 H, CHAr, J = 8.8); 7.28—7.41 (m, 2 H, CHAr); 7.43—7.61 (m,
4 H, CHAr); 9.42 (s, 1 H, NH); 10.06 (s, 1 H, NH)
2.79 (m, 2 H, CH2); 3.56 (m, 2 H, CH2); 3.78 (s, 3 H, MeO); 3.81 (s, 3 H, MeO); 5.82 (s,
2 H, NH2); 6.63 (d, 2 H, CHAr, J = 8.6); 6.77 (m, 3 H, CHAr); 7.43 (d, 2 H, CHAr, J = 8.6);
9.13 (s, 1 H, NH); 9.53 (s, 1 H, NH)
–0.25 s

196
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Sokolov et al.
capillaries. The starting methyl 3ꢀpropylaminobutꢀ2ꢀenoate (4),
4ꢀ(4ꢀfluoroanilino)pentꢀ3ꢀenꢀ2ꢀone (5), Nꢀsubstituted 3ꢀamiꢀ
nocyclohexenones 6a,b were synthesized in accordance with the
known procedure,16 aminouracils 7a,b and 8 were obtained by
the known method,17 Nꢀsubstituted ureas 9a,b and methyl
trifluoropyruvate were used as purchased (Aldrich).
and water (20 mL) was added. The reaction mixtures were neuꢀ
tralized with 10% aqueous ammonia, the precipitates that formed
were filtered off and recrystallized from 50% EtOH. The yields,
melting points, elemental analysis data, and the spectral data of
compounds 16, 17, 18a,b, 19a,b, 20, and 21a,b are listed in
Tables 1 and 3.
Methyl 4ꢀ[4ꢀ(NꢀAcetylamino)phenylsulfonylamino]ꢀ2ꢀmeꢀ
thylꢀ5ꢀoxoꢀ1ꢀpropylꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ1Нꢀpyrroleꢀ
3ꢀcarboxylate (10), Nꢀ[4ꢀacetylꢀ1ꢀ(4ꢀfluorophenyl)ꢀ5ꢀmethylꢀ2ꢀ
oxoꢀ3ꢀtrifluoromethylꢀ2,3ꢀdihydroꢀ1Нꢀpyrrolꢀ3ꢀyl]ꢀ4ꢀacetamiꢀ
dobenzenesulfonamide (11), Nꢀ(6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1ꢀphenylꢀ
3ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀindolꢀ3ꢀyl)ꢀ4ꢀacetꢀ
amidobenzenesulfonamide (12а), Nꢀ[1ꢀ(4ꢀfluorobenzyl)ꢀ6,6ꢀdimeꢀ
thylꢀ2,4ꢀdioxoꢀ3ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀ
indolꢀ3ꢀyl]ꢀ4ꢀacetamidobenzenesulfonamide (12b), Nꢀ[(1ꢀmethylꢀ
2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrꢀ
rolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]ꢀ4ꢀacetamidobenzenesulfonamide
(13а), Nꢀ[1ꢀ(4ꢀmethoxyphenyl)ꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]ꢀ4ꢀ
acetamidobenzenesulfonamide (13b), Nꢀ[1ꢀ(4ꢀfluorophenyl)ꢀ4,6ꢀ
dioxoꢀ5ꢀtrifluoromethylꢀ2ꢀthioxoꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀ
pyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]ꢀ4ꢀacetamidobenzenesulfonamide
(14), Nꢀ[1ꢀ(3ꢀchlorophenyl)ꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidꢀ
azolidinꢀ4ꢀyl]ꢀ4ꢀacetamidobenzenesulfonamide (15a), Nꢀ{1ꢀ[2ꢀ
(3,4ꢀdimethoxyphenyl)ethyl]ꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidꢀ
azolidinꢀ4ꢀyl}ꢀ4ꢀacetamidobenzenesulfonamide (15b) (general proꢀ
cedure). To a stirred solution of 4ꢀacetamidobenzenesulfonamide
(2) (2.14 g, 0.01 mol) in DMF (20 mL), pyridine (1.56 g,
0.01 mol) and methyl trifluoropyruvate 1 (1.56 g, 0.01 mol) was
added successively. The reaction mixture was stirred for 30 min,
then SOCl2 (1.19 g, 0.01 mol) was added, after 1 h of stirring
the corresponding C,Nꢀ or N,Nꢀbinucleophile 4—9 (0.01 mol)
and Et3N (0.1 g) were added. The resulting mixture was stirred
at 20 °C for 1 h and at 90—100 °C for 2 h, cooled to room
temperature, and poured into water (50 mL). The precipitates
that formed were filtered off and recrystallized from 50% EtOH.
The yields, melting points, elemental analysis data, and the specꢀ
tral data of compounds 10, 11, 12a,b, 13a,b, 14, and 15a,b are
listed in Tables 1 and 3.
Methyl 4ꢀ(4ꢀaminophenylsulfonylamino)ꢀ2ꢀmethylꢀ5ꢀoxoꢀ1ꢀ
propylꢀ4ꢀtrifluorometylꢀ4,5ꢀdihydroꢀ1Нꢀpyrroleꢀ3ꢀcarboxylate
(16), Nꢀ[4ꢀacetylꢀ1ꢀ(4ꢀfluorophenyl)ꢀ5ꢀmethylꢀ2ꢀoxoꢀ3ꢀtriꢀ
fluoromethylꢀ2,3ꢀdihydroꢀ1Нꢀpyrrolꢀ3ꢀyl]ꢀ4ꢀaminobenzenesulfonꢀ
amide (17), 4ꢀaminoꢀNꢀ(6,6ꢀdimethylꢀ2,4ꢀdioxoꢀ1ꢀphenylꢀ3ꢀ
trifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀindolꢀ3ꢀyl)benzeneꢀ
sulfonamide (18a), 4ꢀaminoꢀNꢀ[1ꢀ(4ꢀfluorobenzyl)ꢀ6,6ꢀdimethylꢀ
2,4ꢀdioxoꢀ3ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀindolꢀ
3ꢀyl]benzenesulfonamide (18b), 4ꢀaminoꢀNꢀ(1ꢀmethylꢀ2,4,6ꢀ
trioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrroloꢀ
[2,3ꢀd]pyrimidinꢀ5ꢀyl)benzenesulfonamide (19a), 4ꢀaminoꢀNꢀ[1ꢀ
(4ꢀmethoxyphenyl)ꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]benzenesulfonamide
(19b), 4ꢀaminoꢀNꢀ[1ꢀ(4ꢀfluorophenyl)ꢀ4,6ꢀdioxoꢀ5ꢀtrifluoroꢀ
methylꢀ2ꢀthioxoꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyꢀ
rimidinꢀ5ꢀyl]benzenesulfonamide (20), 4ꢀaminoꢀNꢀ[1ꢀ(3ꢀchloꢀ
rophenyl)ꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidazolidinꢀ4ꢀyl]benzꢀ
enesulfonamide (21a), 4ꢀaminoꢀNꢀ{1ꢀ[2ꢀ(3,4ꢀdimethoxypheꢀ
nyl)ethyl]ꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidazolidinꢀ4ꢀyl}benzꢀ
enesulfonamide (21b) (general procedure). NꢀAcetylated strepꢀ
tocide derivatives 10, 11, 12a,b, 13a,b, 14, and 15a,b (0.005 mol)
were refluxed in 10% HCl for 1 h, cooled to room temperature
This work was financially supported by Russian Acadꢀ
emy of Sciences (program «Medicinal and Biomedicinal
Chemistry» of the Devision of Chemistry and Materials
Science) and the Russian Foundation for Basic Research
(Project 08ꢀ04ꢀ12074).
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Received December 18, 2008;
in revised form April 9, 2009