Novel 2-oxoquinoline-6-sulfonamides as thiazide-like diuretics

Article abstract of DOI:10.1007/s11172-012-0273-5

A series of novel N-aryl-7-chloro-4-methyl-2-oxo-1,2-dihydroquinoline-6- sulfonamides were obtained. The structure-activity relationship (SAR) approach was used to study their diuretic effect on rats. Diuretic activity was exhibited by all the test compounds, with 7-chloro-4-methyl-2-oxo-1,2-dihydroquinoline-6- sulfonanilide being most active. A SAR analysis revealed that the substituted (especially ortho-substituted in the benzene ring) arylamides diminish diuresis compared to the most active compound. For the most and least active compounds, their effects on the electrolyte excretion (Na⁺, K⁺, and Cl^-) and creatinine level were also studied.

Full text of DOI:10.1007/s11172-012-0273-5

Russian Chemical Bulletin, International Edition, Vol. 61, No. 10, pp. 1969—1974, October, 2012
1969
Novel 2ꢀoxoquinolineꢀ6ꢀsulfonamides as thiazideꢀlike diuretics
V. A. Zubkov, T. A. Tsapko, I. S. Gritsenko, A. L. Zagayko, and L. V. Galuzinskaya
National University of Pharmacy,
53 ul. Pushkinskaya, 61002 Kharkov, Ukraine.
Fax: +38 (0572) 67 3141. Eꢀmail: medchem@ukrfa.kharkov.ua
A series of novel Nꢀarylꢀ7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonamides
were obtained. The structure—activity relationship (SAR) approach was used to study their
diuretic effect on rats. Diuretic activity was exhibited by all the test compounds, with 7ꢀchloroꢀ
4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonanilide being most active. A SAR analysis reꢀ
vealed that the substituted (especially orthoꢀsubstituted in the benzene ring) arylamides diminꢀ
ish diuresis compared to the most active compound. For the most and least active compounds,
their effects on the electrolyte excretion (Na+, K+, and Cl–) and creatinine level were also
studied.
Key words: quinolinꢀ2ꢀones, sulfonamides, thiazideꢀlike diuretics, structure—activity relaꢀ
tionship.
Scheme 1
Currently available diuretic drugs that are widely used
to treat various diseases include loop, thiazide, and potasꢀ
siumꢀsparing diuretics and carbonic anhydrase inhibitors.1
Specifically, diuretics are mostly indispensable for the
treatment of cardiovascular (including hypertension and
strokes), kidney, and liver diseases as well as glaucoma.2—5
In the last few decades, thiazides and thiazideꢀlike diuretꢀ
ics have taken a key role in treating hypertension because
they are drugs of choice for elderly people. This is due to
their antihypertensive effect produced even in low doses,
which minimizes the unwanted metabolic effect.6 Howevꢀ
er, some side effects (notably, hypokalemia, hypomagneꢀ
semia, hyponatremia, hypercalcemia, and hypochloremic
alkalosis3,4,7—9) have been reported for this group of drugs.
Thus, a search for novel efficient thiazideꢀlike diuretics
with as few side effects on the human organism as possible
is still a challenge.
Earlier,10 we have proposed quinolone scaffold I as
a basis for searching for novel thiazideꢀlike diuretics
(Scheme 1), in compliance with the main concepts of
the quantitative structure—activity relationship (QSAR)
theory for thiazide diuretics.11
It becomes evident from comparison of structure I with
thiazide drugs (see Scheme 1) that most of the indispensꢀ
able pharmacophores are already present in basic strucꢀ
ture I. This structural similarity suggests a possible diuretꢀ
ic effect of sulfonamides I, which has been confirmed preꢀ
viously.10 It should be noted that hydrochlorothiazide (II)
and thiazideꢀlike diuretics contain an unsubstituted sulꢀ
fonamide group. However, the closest analog to hydroꢀ
chlorothiazide II among the test compounds, namely,
7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulꢀ
R = H, Alk, Ar, Het
A is the sulfonamide group, B denotes absolutely indispensable
groups, C is a halogenꢀcontaining group, D is a heterocyclic or
aromatic amino group, E is a substituent, F denotes promoting
groups, G denotes lipophilic groups, H denotes inhibiting groups,
and I is an electronꢀwithdrawing group.
fonamide (I, R = H), unexpectedly showed moderate acꢀ
tivity (62%), while 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdiꢀ
hydroquinolineꢀ6ꢀsulfonanilide (I, R = Ph) was most acꢀ
tive. The goal of the present work was to obtain a series of
novel Nꢀarylꢀ7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinoꢀ
lineꢀ6ꢀsulfonamides and examine their diuretic effect.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1953—1958, October, 2012.
1066ꢀ5285/12/6110ꢀ1969 © 2012 Springer Science+Business Media, Inc.

1970
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
Zubkov et al.
Scheme 2
Results and Discussion
The synthesis of the target compounds 1a—n is sketchꢀ
ed in Scheme 2. 7ꢀChloroꢀ4ꢀmethylꢀ1,2ꢀdihydroquinoꢀ
linꢀ2ꢀone (2) used as a starting material was prepared acꢀ
cording to a known procedure.12 Sulfochlorination of
quinolone 2 with a fivefold excess of chlorosulfonic acid
gave 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀ
sulfonyl chloride (3) in high yield.10 Further reactions of
sulfonyl chloride 3 with various arylamines in the presꢀ
ence of a hydrogen chloride scavenger produced a number
of the corresponding arylamides 1a—n. The compounds
obtained were identified from elemental analysis data and
1H NMR and mass spectra (Table 1).
The diuretic effect of compounds 1a—n on rats was
estimated by Berkhin´s method. The test compounds and
hydrochlorothiazide13 (II) as a reference diuretic were adꢀ
ministered orally. To select a proper dose, we tested comꢀ
pound 1a in doses of 1.0, 5.0, 10.0, and 50.0 mg kg–1
(Table 2). The maximum diuresis was observed for a dose
of 5 mg kg–1. That is why the whole series of Nꢀarylꢀ7ꢀ
chloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonꢀ
amides (1a—n) was tested for a dose of 5 mg kg–1. The
results obtained are given in Table 3.
i. Conc. H2SO4; ii. HSO3Cl, SOCl2; iii. NHRR, EtOH.
1
a
b
c
d
e
f
R
H
H
H
H
H
H
H
R´
Ph
1
h
i
j
k
l
R
H
H
H
H
Et
H
H
R´
2ꢀCOOH—C6H4
3ꢀCOOH—C6H4
4ꢀCOOH—C6H4
3ꢀClC6H4
2ꢀMeC6H4
3ꢀMeC6H4
4ꢀMeC6H4
2ꢀMeOC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
Ph
2ꢀEtC6H4
m
n
g
2,4ꢀMe2C6H3
Table 1. Physicochemical characteristics of compounds 1a—n
Comꢀ Yield
pound (%)
T/C
Found
Calculated
Molecular
formula
MS (EI),
m/z (Irel (%))
1H NMR
(DMSOꢀd6, , J/Hz)
(%)
C
H
N
1a
71
283—285 55.06 3.72 8.09 С16Н13ClN2O3S 350 [M + 2]+ (13), 348 [M]+ (42), 2.39 (s, 3 H, С(4)Me);
55.10 3.76 8.03
249 [M – Cl – SO2]+ (45), 210
[M + 2 – Ph – SO2]+ (23), 208
[M – Ph – SO2]+ (57), 194
[M + 2 – PhSO2NH]+ (8), 192
[M – PhSO2NH]+ (31), 166
6.49 (s, 1 H, H(3)); 6.98
(t, 1 H, Ar, J = 6.0);
7.05—7.26 (m, 4 H, Ar);
7.38, 8.22 (both s, each 1 H,
H(8), H(5)); 10.52, 11.86
[M + 2 – PhSO2NH – CO]+ (13), (both br.s, each 1 H,
164 [M – PhSO2NH – CO]+ (36), SO2NH, N(1)H)
157 [M – PhSO2NH – Cl]+ (28),
92 [PhNH]+ (100), 65 [C5H4]+ (58)
1b
1c
68
64
276—277 56.23 4.15 7.74 C17H15ClN2O3S 364 [M + 2]+ (5), 362 [M]+ (12),
2.16, 2.29 (both s, each 3 H,
56.28 4.17 7.72
107 [MeC6H4NH + 1]+ (20), 106 С(2´)Me, С(4)Me); 6.47
[MeC6H4NH]+ (100),
77 [Ph]+ (27)
(s, 1 H, H(3)); 6.83—7.23
(m, 4 H, Ar); 7.47, 8.02
(both s, each 1 H, H(8),
H(5)); 9.74, 11.93 (both br.s,
each 1 H, SO2NH, N(1)H)
252—254 56.30 4.20 7.79 C17H15ClN2O3S 364 [M + 2]+ (1), 362 [M]+ (6),
2.15, 2.40 (both s, each 3 H,
С(3´)Me, С(4)Me); 6.50 (s, 1 H,
H(3)); 6.77 (d,1 H, Ar, J = 7.0);
6.86—6.98 (m, 2 H, Ar); 7.06
(t, 1 H, Ar, J = 8.1); 7.37,
8.22 (both s, each 1 H, H(8),
H(5)); 10.53, 11.94 (both s,
each 1 H, SO2NH, N(1)H)
56.28 4.17 7.72
263 [M – SO2 – Cl]+ (60), 107
[CH3C6H4NH + 1]+ (48), 106
[CH3C6H4NH]+ (100), 77
[Ph]+ (57)
(to be continued)

2ꢀOxoquinolinesulfonamides as novel diuretics
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
1971
Table 1 (continued)
Comꢀ Yield
pound (%)
T/C
Found
Calculated
Molecular
formula
MS (EI),
m/z (Irel (%))
1H NMR
(DMSOꢀd6, , J/Hz)
(%)
C
H
N
1d
1e
1f
69
62
66
294—296 56.32 4.22 7.80 C17H15ClN2O3S 364 [M + 2]+ (7), 362 [M]+ (23),
2.12, 2.39 (both s, each 3 H,
С(4´)Me, С(4)Me); 6.49
(s, 1 H, H(3)); 6.87—7.07
(m, 4 H, Ar); 7.37, 8.19 (both s,
each 1 H, H(8), H(5));
56.28 4.17 7.72
106 [MeC6H4NH]+ (100), 77
[Ph]+ (27)
10.43, 11.93 (both br.s,
each 1 H, SO2NH, N(1)H)
285—286 53.97 3.95 7.45 C17H15ClN2O4S 380 [M + 2]+ (16), 378 [M]+ (46), 2.30, 3.50 (both s, each 3 H,
53.90 3.99 7.39 С(4)Me, OMe); 6.47 (s, 1 H,
122 [MeOC6H4NH]+ (83), 94
[PhOH]+ (100), 92 [PhNH]+ (47), H(3)); 6.75—6.96 (m, 2 H, Ar);
65 [C5H4]+ (42)
7.01—7.31 (m, 2 H, Ar); 7.43,
8.01 (both s, each 1 H, H(8),
H(5)); 9.50, 11.94 (both s,
each 1 H, SO2NH, N(1)H)
234—235 53.93 3.97 7.44 C17H15ClN2O4S 380 [M + 2]+ (5), 378 [M]+ (16),
2.40, 3.61 (both s, each 3 H,
С(4)Me, OMe); 6.42—6.60
(m, 2 H, H(3), Ar); 6.61—6.78
(m, 2 H, Ar); 7.09 (t, 1 H,
Ar, J = 8.0); 7.38, 8.24 (both s,
each 1 H, H(8), H(5)); 10.62,
11.95 (both s, each 1 H,
53.90 3.99 7.39
299 (25), 279 [M – SO2 – Cl]+
(100), 278 (53), 166 [M + 2 –
– MeOC6H4SO2NH – CO]+ (6),
164 [M – MeOC6H4SO2NH –
– CO]+ (25), 123 (63), 122
[CH3OC6H4NH]+ (58), 95 (70)
SO2NH, N(1)H)
1g
1h
1i
69
63
62
274—276 53.94 3.93 7.49 C17H15ClN2O4S 380 [M + 2]+ (9), 378 [M]+ (20),
53.90 3.99 7.39
122 [CH3OC6H4NH]+ (100)
2.36, 3.61 (both s, each 3 H,
С(4)Me, OMe); 6.48 (s, 1 H,
H(3)); 6.77 (d, 2 H, Ar, J = 9.2);
7.03 (d, 2 H, Ar, J = 9.2); 7.39,
8.12 (both s, each 1 H, H(8),
H(5)); 10.22, 11.93 (both s,
each 1 H, SO2NH, N(1)H)
293—295 52.00 3.38 7.18 C17H13ClN2O5S 394 [M + 2]+ (7), 392 [M]+ (23),
2.48 (s, 3 H, С(4)Me); 6.51 (s,
1 H, H(3)); 6.91—7.14 (m, 1 H,
Ar); 7.38 (s, 1 H, H(8));
7.41—7.50 (m, 2 H, Ar); 7.91
(d, 1 H, Ar, J = 7.7); 8.36 (s, 1 H,
H(5)); 11.70, 11.97 (both br.s,
each 1 H,SO2NH, N(1)H)
51.98 3.34 7.13
210 [M + 2 – C6H4COOH –
– SO2]+ (9), 208 [M –
– C6H4COOH – SO2]+ (37),
120 [C6H4COO] (81), 119
[NHC6H4COOH – H2O] (100),
92 [PhNH]+ (26)
300—302 51.94 3.31 7.20 C17H13ClN2O5S 394 [M + 2]+ (12), 392 [M]+ (36), 2.42 (s, 3 H, С(4)Me);
51.98 3.34 7.13
293 [M – SO2 – Cl]+ (38), 292
[M – SO2 – Cl – H]+ (30), 258
[M + 2 –C6H4COOH]+ (9), 256
[M –C6H4COOH]+ (27), 210
[M + 2 – C6H4COOH – SO2]+
(29), 208 [M – C6H4COOH –
– SO2]+ (100), 194 [M + 2 –
– COOH—C6H4SO2NH]+ (15),
192 [M – COOH—C6H4SO2NH]+
(41), 166 [M + 2 – COOH—
—C6H4—SO2NH – CO]+ (13),
164 [M – COOH—C6H4SO2NH –
– CO]+ (34), 157 [M – COOH—
—C6H4SO2NH – Cl]+ (27),
137 [NHC6H4COOH] (28), 119
[NHC6H4COOH – H2O] (82),
65 [C5H4]+ (26)
6.50 (s, 1 H, H(3));
7.29—7.36 (m, 2 H, Ar);
7.38 (s, 1 H, H(8));
7.48—7.55 (m, 1 H, Ar);
7.73 (s, 1 H, Ar); 8.28
(s, 1 H, H(5)); 10.90
(s, 1 H,SO2NH); 11.95
(br.s, 1 H, NH)
(to be continued)

1972
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
Zubkov et al.
Table 1 (continued)
Comꢀ Yield
pound (%)
T/C
Found
Calculated
Molecular
formula
MS (EI),
m/z (Irel (%))
1H NMR
(DMSOꢀd6, , J/Hz)
(%)
C
H
N
1j
69
292—293 51.91 3.30 7.18 C17H13ClN2O5S 394 [M + 2]+ (12), 392 [M]+ (34), 2.46 (s, 3 H, С(4)Me);
51.98 3.34 7.13
293 [M – SO2 – Cl]+ (30), 292
[M – SO2 – Cl – H]+ (25), 210
[M + 2 – C6H4COOH – SO2]+
(23), 208 [M – C6H4COOH –
– SO2]+ (68), 194 [M + 2 –
6.51 (s, 1 H, H(3)); 7.18
(d, 2 H, Ar, J = 8.6); 7.37
(s, 1 H, H(8)); 7.77
(d, 2 H, Ar, J = 8.6); 8.32,
11.14 (both s, each 1 H,
– COOH—C6H4SO2NH]+ (10), H(5), SO2NH); 11.96
192 [M – COOH—C6H4SO2NH]+ (br.s, 1 H, N(1)H)
(31), 166 [M + 2 – COOH—
—C6H4SO2NH – CO]+ (11), 164
[M – COOH—C6H4SO2NH – CO]+
(26), 137 [NHC6H4COOH] (40),
119 [NHC6H4COOH – H2O] (62),
43 [NHCO]+ (100)
1k
70
273—275 50.19 3.20 7.40 С16Н12Cl2N2O3S 386 [M + 4]+ (2), 384 [M + 2]+
50.14 3.16 7.31
(10), 382 [M]+ (14), 285 [M + 2 – 6.52 (s, 1 H, H(3));
– SO2 – Cl]+ (22), 283 [M –
6.99—7.15 (m, 3 Н, Ar);
– SO2 – Cl]+ (100), 258 [M + 2 – 7.23 (t, 1 H, Ar, J = 8.0);
– NHC6H4Cl]+ (9), 256 [M –
7.40, 8.26 (both s, each 1 H,
2.43 (s, 3 H, С(4)Me);
– NHC6H4Cl]+ (25), 210 [M + 2 – H(8), H(5)); 10.92, 11.98
– C6H4Cl – SO2]+ (25), 208 [M – (both s, each 1 H, SO2NH,
– C6H4Cl – SO2]+ (76), 194 [M + N(1)H)
+ 2 – Cl—C6H4SO2NH]+ (15),
192 [M – ClC6H4SO2NH]+ (66),
166 [M – ClC6H4SO2NH – CO]+
(11), 164 [M + 2 –ClC6H4SO2NH –
– CO]+(30), 157 [M –
– ClC6H4SO2NH – Cl]+ (54)
1l
64
68
244—245 57.40 4.59 7.50 С18Н17ClN2O3S 378 [M + 2]+ (2), 376 [M]+ (3),
1.00 (t, 3 H, СН3СН2, J = 7.0);
2.28 (s, 3 H, С(4)Me); 3.76
(q, 2 H, СН3СН2, J = 7.0);
6.49 (s, 1 H, H(3)); 7.14—7.39
(m, 5 H, Ar); 7.46, 7.92
57.37 4.55 7.43
277 [M – SO2 – Cl]+ (100), 120
[EtNHPh]+ (99), 77 [Ph]+ (36)
(both s, each 1 H, H(8), H(5);
12.00 (s, 1 H, N(1)H)
1m
239—240 57.43 4.60 7.57 С18Н17ClN2O3S 378 [M + 2]+ (1), 376 [M]+ (3),
57.37 4.55 7.43
120 [EtC6H3NH]+ (100)
1.02 (t, 3 H, СН3СН2,
J = 7.6); 2.30 (s, 3 H,
С(4)Me); 2.61, 6.49 (q, 2 H,
СН3СН2, J = 7.6);
(s, 1 H, H(3)); 6.85 (d, 1 H,
Ar, J = 7.2); 7.03 (td, 1 H, Ar,
J = 7.2, J = 2.0); 7.09—7.25
(m, 2 H, Ar); 7.48, 8.01
(both s, each 1 H, H(8), H(5));
9.81, 12.00 (both s, each
1 H, SO2NH, N(1)H)
1n
71
290—291 57.34 4.53 7.39 C18H17ClN2O3S 378 [M + 2]+ (2), 376 [M]+ (5),
57.37 4.55 7.43
120 [(Me)2C6H3NH]+ (100)
2.11, 2.15, 2.29 (all s,
each 3 H, С(4´)Me, С(2´)Me,
С(4)Me); 6.49 (s, 1 H, H(3));
6.74—6.89 (m, 2 H, Ar);
6.95 (s, 1 H, Ar); 7.46, 7.99
(both s, each 1 H, H(8),
H(5)); 9.70, 11.99 (both s,
each 1 H, SO2NH, N(1)H)

2ꢀOxoquinolinesulfonamides as novel diuretics
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
1973
Table 2. Dependence of the diuretic activity of compound 1a and hydrochlorothiazide II on their doses*
Compound
Dose
/mg kg–1
Urine volume
/mL (4 h)
Diuretic activity
(%)
1a
1.0
5.0
10.0
50.0
5.83 1.72
6.08 1.68
5.58 1.24
4.50 1.30
208
221
195.2
131.1
Hydrochlorothiazide II
1.5
5.0
5.30 0.98
5.83 1.47
189.6
208
Control
—
1.83 0.53
—
* Here and in Tables 3 and 4, P < 0.05.
Table 3. Diuretic activity of sulfonamides 1a—n
Comꢀ
pound
Urine volume
/mL (4 h)
Diuretic
activity (%)
Comꢀ
pound
Urine volume
/mL (4 h)
Diuretic
activity (%)
1a
1b
1c
1d
1e
1f
6.01 0.29
3.50 0.36
3.83 0.60
3.96 0.41
3.38 0.50
4.30 0.28
4.11 0.51
3.76 0.43
145.3
42.9
56.3
61.6
38.0
75.5
67.8
53.5
1i
1j
1k
1l
1m
1n
3.70 0.52
4.82 0.55
4.00 0.44
4.16 0.49
3.66 0.48
3.46 0.54
5.77 0.38
2.45 0.17
51.0
96.7
63.3
69.8
49.4
41.2
135.0
—
1g
1h
Hydrochlorothiazide II
Control
Table 4. Effects of compounds 1a,b,e,j on the electrolyte excretion and creatinine levels
Comꢀ
pound
Fluid studied
Electrolyte excretion
/mmol L–1
Na+/K+
/mmol L–1
Creatinine level
/mL min–1
Creatinine
clearance
К+
Na+
Cl–
1a
1b
1e
1j
Blood serum
Urine
Blood serum
Urine
Blood serum
Urine
Blood serum
Urine
008.99 1.30
155.10 9.16
245.70 26.75
505.71 54.30
17.25
1.53
18.38
1.24
15.30
1.25
19.65
1.19
19.79
1.42
16.92
1.18
0.073 0.005
1.125 0.085
0.085 0.007
1.205 0.035
0.079 0.004
1.112 0.217
0.089 0.003
1.212 0.189
0.090 0.003
1.158 0.156
0.088 0.013
1.280 0.093
0.383 0.056
0.383 0.056
0.206 0.035
0.206 0.035
0.170 0.030
0.170 0.030
0.280 0.048
0.280 0.048
0.362 0.032
0.362 0.032
0.145 0.015
0.145 0.015
110.70 11.22 170.00 6.40
009.25 1.56
157.50 15.52 195.40 7.85
011.12 2.10 169.80 17.22 254.85 15.60
168.00 12.15 209.20 9.35
008.26 1.02 162.30 8.16
139.33 17.01 165.90 15.80 530.32 47.35
008.40 0.95 166.20 15.78 244.50 31.50
138.35 10.69 195.90 7.90 548.21 36.95
170.00 12.60 274.35 22.18
609.20 61.55
587.25 44.25
248.75 18.95
Hydrochloroꢀ Blood serum
thiazide II
Control
Urine
Blood serum
Urine
010.11 1.25
155.8 10.76
171.10 21.70 268.59 15.60
184.60 10.35 521.83 34.95
According to the experimental data, the presence of
any substituent in the benzene ring of the sulfonamide
fragment of structure I reduces diuresis. For instance, the
diuretic effect of 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
quinolineꢀ6ꢀsulfonanilide 1a is comparable with that of
hydrochlorothiazide II (145.3 and 135.0%, respectively).
A high activity (96.7%) was also exhibited by compound 1j.
Most of the test compounds produce moderate diuretic
effects: the urine volumes excreted by rats exceed those in
the control group by 50—75%. The presence of the orthoꢀ
substituted benzene ring (1b,e,h,m,n) reduces diuresis most
substantially. It should also be noted that the diuretic efꢀ
fect is virtually insensitive to the electronic nature of the
radical (Me, Et, OMe, or COOH).
To analyze a possible mechanism of diuretic action,
we measured the contents of electrolytes and creatinine in

1974
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
Zubkov et al.
lized from ethanol—DMF. The yield of compound 1h was 2.47 g
(63%), colorless crystals, m.p. 293—295 C.
urine and serum for the most (1a,j) and least active comꢀ
pounds (1b,e) (Table 4). According to the results obtained,
all of them produce a similar effect on the excretion of
Na+, K+ and Cl– by rats as hydrochlorothiazide II does.
In all the cases, diuresis is mainly due to the excretion
of Na+; the Na+/K+ ratio for novel compounds is more
favorable than that for hydrochlorothiazide II. Comꢀ
pound 1a is superior to all the other compounds (includꢀ
ing II) in Na+ excretion and potassiumꢀsparing effect.
The best creatinine clearance was also observed for sulꢀ
fonamide 1a.
An acute toxicity test with mice (per os)14 for 7ꢀchloroꢀ
4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonanilide
(1a) as the most active compound showed that its LD50 is
>10 000 mg kg–1. This value makes it more attractive than
hydrochlorothiazide II (cf. LD50 = 3000 mg kg–1 (per os)15).
To sum up, our biological tests revealed that novel
Nꢀarylꢀ7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ
6ꢀsulfonamides 1a—n are similar in diuretic activity to
hydrochlorothiazide II. The best results among the comꢀ
pounds studied were achieved with 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀ
oxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonanilide (1a), which is
of interest as a potential antihypertensive drug. Analysis of
the structure—activity relationship showed that the sulꢀ
fonamides containing a substituted benzene ring diminish
diuresis compared to unsubstituted analog 1a.
NꢀAryl sulfonamides 1i,j were obtained as described for comꢀ
pound 1h, with appropriate aromatic amino acids instead of
oꢀaminobenzoic acid. The products were recrystallized from
ethanol—DMF. Their yields are specified in Table 1.
Diuretic activity was studied according to Berkhin´s method
with outbred white male rats (150 30 g in weight). The dose of
the test compounds was 5 mg kg–1 (for compound 1a, doses of
1.0, 5.0, 10.0, and 50.0 mg kg–1 were used). Each dose was tested
in six animals, with hydrochlorothiazide II as a reference diuretic.
The compounds were intragastrically administered in one porꢀ
tion as aqueous suspensions stabilized by Tween 80 with water
burden (3 mL per 100 g of body weight). The results obtained
were compared with those of a control group (the animals of this
group were given saline and Tween 80 in the same amounts).
The concentrations of K+ and Na+ ions in urine and blood
serum were measured on a PAZhꢀ3 flame automated photoꢀ
meter. The concentration of chloride ions was determined by
titration.13
Urinary and serum creatinine concentrations were deterꢀ
mined using the Jaffe method.13 The creatinine clearance was
calculated by a known formula.
References
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Experimental
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Melting points were determined on a Kofler hot stage.
1H NMR spectra were recorded on a Varian Mercury VXꢀ200
instrument (200 MHz) in DMSOꢀd6 with Me4Si as the internal
standard. Mass spectra (EI, 70 eV) were recorded on a Varian
1200L instrument.
7ꢀChloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonꢀ
anilide (1a). A mixture of 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydꢀ
roquinolineꢀ6ꢀsulfonyl chloride (3) (2.92 g, 10 mmol), aniline
(11 mmol), triethylamine (11 mmol) and ethanol (50 mL) was
refluxed for 1 h. The reaction mixture was cooled, diluted with
water, and acidified with HCl to pH 3—4. The precipitate that
formed was filtered off, washed with water, and recrystallized
from ethanol. The yield of compound 1a was 2.48 g (71%), colorꢀ
less crystals, m.p. 283—285 C.
NꢀAryl sulfonamides 1b—g,k—n were obtained as described
for compound 1a, with appropriate arylamines instead of aniline.
The products were recrystallized from ethanol. Their yields are
specified in Table 1.
2ꢀ(7ꢀChloroꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfꢀ
onylamino)benzoic acid (1h). A mixture of 7ꢀchloroꢀ4ꢀmethylꢀ2ꢀ
oxoꢀ1,2ꢀdihydroquinolineꢀ6ꢀsulfonyl chloride (3) (2.92 g, 10 mmol)
and oꢀaminobenzoic acid (2.74 g, 20 mmol) in ethanol (50 mL)
was refluxed for 1 h. The reaction mixture was cooled, diluted
with water, and acidified with HCl to pH 3—4. The precipitate
that formed was filtered off, washed with water, and recrystalꢀ
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Received June 21, 2012