4-Hydroxy-2-quinolones. 47. Synthesis and diuretic activity of (2H-1,2,4,benzothiadiazine-1,1-dioxide-3-yl)methylamides of 1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acids

Article abstract of DOI:10.1023/A:1017527802266

With the aim of investigating the relationship between chemical structure and biological activity we have synthesized and studied the effect of (2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)methylamides of 1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acids on kidney urinary output.

Full text of DOI:10.1023/A:1017527802266

Chemistry of Heterocyclic Compounds, Vol. 37, No. 2, 2001
4-HYDROXY-2-QUINOLONES.
47*. SYNTHESIS AND DIURETIC
ACTIVITY OF (2H-1,2,4-BENZOTHIADIAZINE-
1,1-DIOXIDE-3-YL)METHYLAMIDES OF
1R-4-HYDROXY-2-OXOQUINOLINE-
3-CARBOXYLIC ACIDS
S. G. Taran, I. V. Ukrainets, N. V. Likhanova, O. V. Gorokhova, and P. A. Bezugly
With the aim of investigating the relationship between chemical structure and biological activity we
have synthesized and studied the effect of (2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)methylamides of
1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acids on kidney urinary output.
Keywords: benzothiadiazine, diuretics, carbostyril, 4-hydroxy-2-quinolone.
Following the introduction into medicinal usage of chlorothiazide (the first representative of
the benzothiadiazine diuretics) and with its structural analog hypothiazide in mind, we have carried out a
search for novel and more active compounds through a broad investigation of changes to the parent structures.
In this way we have revealed the influence of the specific substitutents both in the benzene and in the
heterocyclic ring on the strength of the urinary effect. In particular, the highest diuretic activity was found for
benzothiadiazines which have alkyl or aralkyl substituents at position 3 [2]. Bearing this in mind, and with the
aim of establishing a structure–activity relationship, we have synthesized (2H-1,2,4-benzothiadiazine-1,1-
dioxide-3-yl)methylamides of 1-R-4-hydroxy-2-oxoquinoline-3-carboxylic acids (1) as analogs of
1-R-3-(2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)-4-hydroxy-2-oxoquinolines [3] and studied their effect on
kidney urinary output.
(2H-1,2,4-Benzothiadiazine-1,1-dioxide-3-yl)methylamine (2) was prepared by acylation of
o-aminobenzenesulfonamide (3) by phthaloylaminoacetyl chloride (4) and subsequent cyclization of
anilide 5 using an aqueous solution of potassium carbonate to give benzothiadiazine (6). Hydrazinolysis [4]
of the latter in the final step gives amine 2. Under thermolysis conditions (170-190°C) amine 2 readily
reacts with ethyl esters of 1-R-2-oxo-4-hydroxyquinoline-3-carboxylic acids 7 to give the target amides 1
(Tables 1, 2).
_______
* For Communication 46 see [1].
____________________________________________________________________________________________
National Pharmaceutical Academy of the Ukraine, Kharkov 310002 e-mail: igor@uiv.kharkov.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 262-265, February, 2001. Original article
submitted February 10, 1999.
0009-3122/01/3702-0237$25.00©2001 Plenum Publishing Corporation
237

O
O
SO2NH2
O
SO2NH2
NH2
O
+
N
N
Cl
N
H
3
O
O
O
5
4
O
O
S
O
O
NH
1. K2CO3, H2O
2. HCl
NH
H2NNH2 . H2O
S
N
N
NH2
N
6
O
2
O
O
OH
O
OH
N
N
H
OEt
2, 170–190 oC
HN
O
S
N
R
O
N
R
O
1
7
1, 7 a R = Me; b R = Et; c R = CH2CH=CH2; d R = Pr; e R = Bu; f R = i-Bu;
g R = C5H11; h R = C6H13; i R = C7H15
The effect of the synthesized compounds on diuresis in white rats was studied by the method proposed
earlier [3]. 1-N-Methyl derivative 1a was found to show antidiuretic activity (21% inhibition of diuresis when
compared with control data).
Lengthening of the hydrocarbon chain in the N-alkyl substituent is accompanied by strengthening of the
urinary effect, gradually approaching a maximum at (2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)methylamide
of 1-hexyl-4-hydroxy-2-oxoquinoline-3-carboxylic acid (1h) whose activity approaches that of hypothiazide. As
a whole, the comparative analysis of diuretic properties of amides 1a-i and their structural analogs –
1-R-3-(2H-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)-4-hydroxy-2-oxoquinolines [3] – allows us to conclude that
the introduction of methylaminocarbonyl bridge between the quinoline and benzothiadiazine rings in
compounds 1 leads to a decrease in the diuretic activity.
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
Empirical
mp, °C
Yield,
%
Calculated, %
pound formula
(DMF–EtOH)
C
H
N
S
C19H16N4O5S
55.41
55.33
3.84
3.91
13.66
13.58
7.68
7.77
279-281
254-256
242-244
257-259
228-230
234-236
229-231
225-227
189-191
84
80
78
83
75
78
71
76
75
1a
1b
1c
1d
1e
1f
C20H18N4O5S
C21H18N4O5S
C21H20N4O5S
C22H22N4O5S
C22H22N4O5S
C23H24N4O5S
C24H26N4O5S
C25H28N4O5S
56.25
4.33
13.21
7.45
56.33
4.25
13.14
7.52
57.44
57.53
4.20
4.14
12.71
12.78
7.37
7.31
57.32
4.51
12.70
7.25
57.26
4.58
12.72
7.28
58.07
58.14
4.96
4.88
12.25
12.33
7.13
7.05
58.19
4.93
12.40
7.00
58.14
4.88
12.33
7.05
58.90
58.96
5.23
5.16
11.99
11.96
6.76
6.84
1g
1h
1i
59.85
5.49
11.52
6.58
59.74
5.43
11.61
6.64
60.55
60.47
5.60
5.68
11.33
11.28
6.54
6.46
238

TABLE 2. 1H NMR Spectral Characteristics of (2H-1,2,4-Benzothiadiazine-
1,1-dioxide-3-yl)methylamides of 1-R-4-Hydroxy-2-oxoquinoline-3-carboxylic
Acids, ppm
Com-
OH
SO2NH
CONH
Harom
NCH2
R
pound (1Н, s)
(1Н, t)
(1Н, t)
(8Н, m)
(2Н, d)
16.70
16.68
12.28
12.22
10.75
10.75
8.11-7.27
8.26-7.29
4.59
4.57
3.63 (3H, s, Me)
1a
1b
4.33 (2H, quartet, CH2);
1.25 (3H, t, Me)
16.61
12.16
10.70
8.19-7.26
4.57
5.95 (1H, m, CH=);
5.17 (2H, d, NCH2);
4.95 (2H, d, CH2=)
4.24 (2H, t, NCH2);
1.65 (2H, m, CH2Me);
0.97 (3H, t, Me)
1c
16.69
16.72
12.21
12.26
10.75
10.75
8.18-7.28
8.19-7.27
4.54
4.55
1d
1e
4.28 (2H, t, NCH2);
1.51 (4H, m, (CH2)2Me);
0.94 (3H, t, Me)
16.70
16.74
12.26
12.21
10.76
10.74
8.18-7.29
8.16-7.28
4.56
4.56
4.18 (2H, d, NCH2);
2.14 (1H, m, СНMе2);
0.92 (6H, d, Me2)
1f
4.26 (2H, t, NCH2);
1g
1.74 (2Н, quintet, NCH2CH2);
1.39 (4H, m, (CH2)2Me);
0.88 (3H, t, Me)
16.73
16.71
12.21
12.26
10.74
10.76
8.14-7.25
8.17-7.28
4.55
4.55
4.25 (2H, t, NCH2);
1h
1i
1.76 (2Н, quintet, NCH2CH2);
1.32 (6H, m, (CH2)3Me);
0.85 (3H, t, Me)
4.24 (2H, t, NCH2);
1.75 (2Н, quintet, NCH2CH2);
1.29 (8H, m, (CH2)4Me);
0.85 (3H, t, Me)
EXPERIMENTAL
1H NMR spectra for the synthesized compounds were recorded on a Bruker WP-100 SY instrument
using DMSO-d6 solvent and TMS as internal standard. The mass spectrum of amine 2 was recorded on a
Finnigan MAT Incos 50 quadrupole spectrometer over the m/z range of 33-700 and electron impact ionization of
70 eV with direct introduction and heating rate of ~5°C / sec.
General Method for Preparing of (2H-1,2,4-Benzothiadiazine-1,1-dioxide-3-yl)methylamides of
1-R-4-Hydroxy-2-oxoquinoline-3-carboxylic Acids (1a-i). Mixture of (2H-1,2,4-benzothiadiazine-1,1-
dioxide-3-yl)methylamine 2 (2.11 g, 0.01 mol) and the corresponding ester 7 (0.01 mol) was held for 5-10 min
on a metal bath at 170-190°C. The residue was dissolved in refluxing DMF (20 ml), filtered, ethanol (50 ml)
added, and the residue was left for several hours at room temperature. The precipitated amide 1 was filtered,
washed with alcohol, and dried.
(2H-1,2,4-Benzothiadiazine-1,1-dioxide-3-yl)methylamine (2). Triethylamine (14 ml, 0.1 mol) was
added to solution of o-aminobenzenesulfonamide (17.22 g, 0.1 mol) in acetone (100 ml). Phthaloylaminoacetyl
chloride (22.36 g, 0.1 mol) was added under cooling and stirring. After 5 h the reaction mixture was diluted with
water and acidified with HCl to pH 4. The precipitated anilide 5 was filtered, transferred to a flask, solution of
K2CO3 (15 g) in water (100 ml) added, the product was stirred until the precipitate dissolved, and then acidified
with HCl to pH 4. The precipitated benzothiadiazine 6 was filtered off, washed with water, and dried to give
24.0 g (81%). Benzothiadiazine 6 was suspended in water (50 ml), hydrazine hydrate (8.5 ml) was added, and
239

the mixture was refluxed for 3 h. After cooling it was acidified with HCl to pH 3 and filtered. The filtrate was
neutralized with an aqueous solution of NaOH and left for 10-12 h at 8-10°C. The precipitate was filtered off,
washed with cold water, and dried. Yield of amine 2 10.12 g (48% calculated on the starting
o-aminobenzenesulfonamide). Mp 258-260°C (ethanol). Mass spectrum, m/z (Irel, %): 211 (100) [M]+, 183 (31),
155 (17), 146 (60), 131 (27), 118 (86), 91 (90), 64 (78), 52 (31). Found, %: C 45.57; H 4.18; N 19.92; S 15.13.
C8H9N3O2S. Calculated, %: C 45.49; H 4.29; N 19.89; S 15.18.
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Moscow (1988), Issue 2, p. 55.
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4.
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