4-Hydroxy-2-quinolones 142. 4-Methyl-2-oxo-1,2-dihydroquinoline-3- carboxylic acid anilides as potential diuretics

Article abstract of DOI:10.1007/s10593-008-0029-1

A large series of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides has been prepared as potential diuretic agents. The effect of all of the synthesized compounds on the urinary function of the kidney has been investigated. The appearance of a structure - diuretic activity relationship is discussed.

Full text of DOI:10.1007/s10593-008-0029-1

Chemistry of Heterocyclic Compounds, Vol. 44, No. 2, 2008
4-HYDROXY-2-QUINOLONES
142*. 4-METHYL-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLIC ACID
ANILIDES AS POTENTIAL DIURETICS
I. V. Ukrainets, N. L. Bereznyakova, V. A. Parshikov, and O. I. Naboka
A large series of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides has been prepared as
potential diuretic agents. The effect of all of the synthesized compounds on the urinary function of the
kidney has been investigated. The appearance of a "structure – diuretic activity" relationship is
discussed.
Keywords: anilides, diuretics, 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, amidation.
In recent years along with the well known efficient use of diuretics in the treatment of kidney deficiency
[2], glaucoma [3], epilepsy [4], and insipid diabetes [5, 6] the attention of pharmacologists and doctors has been
increasingly paid to currently uncommon areas of use of the extrarenal effects of diuretic medicines in the
treatment of bronchial obstruction syndrome, mucoviscidose [7], oncological [8, 9], and a series of other
illnesses. There is particular interest in the medicinal uses of diuretics which show both their diuretic properties
together with anti-inflammatory [10, 11], antioxidant [12, 13], antimicrobial [14, 15], cholagogue [16], hepato-
protective [17], hypolipidemic [18], and other useful activity. Even a cursory glance at the literature shows a
marked and steadily increasing tendency to broaden the catalog of indications for diuretic agents in clinical
practice. At the same time, over the last 30 years not a single class of novel diuretic has appeared in the world
pharmaceutical market although the need for such preparations is obvious.
It is interesting that quinoline type compounds have not been considered up to recent times as possible
diuretic agents because such a type of pharmacological activity is considered atypical. None the less, in the
process of carrying out systematic investigations, potential diuretics have been discovered by us amongst
4-hydroxyquinol-2-ones. It was possible to discover an interesting relationship, particularly fully and clearly
identified in the case of amide derivatives of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-
2-carboxylic acids. As a result it was convincingly shown that the level of the diuretic effect of the quinolone
compounds depends significantly on the structure of the amide fragment and increases in the sequence:
alkylamides < cycloalkylamides < 3-arylpropylamides < 2-arylethylamides < benzylamides << anilides [19, 20].
_______
* For Communication 141 see [1]
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 239-245, February, 2008. Original article submitted June 8,
2007.
178
0009-3122/08/4402-0178©2008 Springer Science+Business Media, Inc.

A similar dependence was found in a study of the alkyl- and arylalkylamides of 4-methyl-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids [21]. It follows that a high probability is retained of still higher diuretic
properties on transition to the anilides of these acids. This proposal served as the basis for undertaking the
current investigation.
Although, as shown earlier [21], amidation of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
(1) via the corresponding acid chloride is possible, it is somewhat complicated by the formation of cyanine dye
by-products which can impart a red coloration to the final reaction products even at low concentration. With this
in mind we have attempted to activate the carbonyl carbon atom of the carboxyl group in acid 1 by another
means, viz. the use of the well known organic synthetic reagent N,N'-carbonyldiimidazole (CDI).
Carrying out the experiment showed that the 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
imidazolide (2) is formed quite readily and in virtually quantitative yield. However its reactivity with relation to
N-nucleophiles proved extremely low and quite rigid conditions (prolonged refluxing with anilines in high
boiling solvents) were needed for full transformation to the anilides 3 and 4. An unusual inertness (at least at
room temperature) was noted for the imidazolide 2 towards water and, in principle, it can be used for separation
of this compound in the pure state even though similar treatment would inevitably end in hydrolysis. The
intermediate imidazolides are generally not separable from the reaction mixture. Our case is not an exception and
allsuccessive stages of the conversion of acid 1 to anilides are carried out in a single vessel.
O
Me
O
Me
OH
N
CDI
N
O
N
H
O
N
H
1
2
H2N–Ar
H2N–Ar
O
O
O
Me
Me
N
H
N
H
R
A
N
H
O
N
H
4a–i
3a–z
3 a R = H, b R = 2-F, c R = 3-F, d R = 4-F, e R = 3,4-F2, f R = 2-Cl, g R = 3-Cl, h R = 4-Cl,
i R = 2,3-Cl2, j R = 2,4-Cl2, k R = 2,5-Cl2, l R = 2-Br, m R = 2-Br-4-Me, n R = 3-Br, o R = 4-Br,
p R = 2-Me, q R = 3-Me, r R = 4-Me, s R = 2,3-Me2, t R = 2,4-Me2, u R = 2,5-Me2, v R = 2-OMe,
w R = 2-OMe-5-Cl, x R = 3-OMe, y R = 4-OMe, z R = 4-OEt; 4 a A = 2-CF3, b A = 3-CF3,
c A = 2-C≡N, d A = 2-COOH, e A = 3-COOH, f A = 4-COOH, g A = 4-COOEt,
h A = 2-CONH2, i A = 2-SO2NH2
All of the synthesised 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides 3 and 4 (Table 1)
are colorless or white tinged with yellow, crystalline substances insoluble in water at room temperature, of low
1
solubility in alcohol, and moderately soluble in DMF and DMSO. A characteristic feature of the H NMR
spectra of anilides 3 and 4 (Table 2) is the grouping of the signals for 7-9 aromatic protons in a rather narrow
(1 ppm) region of the spectrum hence specific assignments are frequently complex or quite not possible without
the use of special NMR methods.
179

TABLE 1. Characteristics of 4-Methyl-2-oxo-1,2-dihydroquinoline-
3-carboxylic Acid Anilides 3a-z, 4a-i
Found, %
Calculated, %
Diuretic
activity,*
% to control
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
3
H
4
N
5
1
3a
3b
3c
3d
3e
3f
2
6
7
8
C17H14N2O2
C17H13FN2O2
C17H13FN2O2
C17H13FN2O2
C17H12F2N2O2
C17H13ClN2O2
C17H13ClN2O2
C17H13ClN2O2
C17H12Cl2N2O2
C17H12Cl2N2O2
C17H12Cl2N2O2
C17H13BrN2O2
C18H15BrN2O2
C17H13BrN2O2
C17H13BrN2O2
C18H16N2O2
C18H16N2O2
C18H16N2O2
C19H18N2O2
C19H18N2O2
C19H18N2O2
C18H16N2O3
C18H15ClN2O3
C18H16N2O3
C18H16N2O3
C19H18N2O3
C18H13F3N2O2
C18H13F3N2O2
C18H13N3O2
C18H14N2O4
73.46
73.37
5.13
5.07
4.34
4.42
4.51
4.42
4.48
4.42
3.77
3.85
4.14
4.19
4.16
4.19
4.28
4.19
3.40
3.48
3.55
3.48
3.53
3.48
3.75
3.67
4.11
4.07
3.73
3.67
3.62
3.67
5.63
5.52
5.59
5.52
5.50
5.52
5.84
5.92
5.98
5.92
5.86
5.92
5.31
5.23
4.33
4.41
5.30
5.23
5.27
5.23
5.54
5.63
3.85
3.78
3.70
3.78
4.39
4.32
4.31
4.38
10.15
10.07
280-282
275-277
283-285
291-293
304-306
295-297
276-278
307-309
322-324
335-337
330-332
291-293
283-285
288-290
304-306
248-250
269-271
275-277
299-301
250-252
272-274
228-230
291-293
280-282
264-266
253-255
264-266
277-279
296-298
288-290
82
75
78
80
76
72
74
77
70
73
71
70
72
76
80
73
75
79
72
74
70
70
73
77
85
82
69
78
72
68
+52
+9
68.97
68.91
9.40
9.45
68.99
68.91
9.53
9.45
0
68.85
68.91
9.54
9.45
-9
64.90
64.97
8.85
8.91
-11
+30
-11
-22
+4
65.22
65.29
9.03
8.96
3g
3h
3i
65.35
65.29
9.07
8.96
65.37
65.29
8.99
8.96
58.88
58.81
8.00
8.07
3j
58.75
58.81
8.14
8.07
-4
3k
3l
58.73
58.81
8.12
8.07
-17
-4
57.24
57.16
7.76
7.84
3m
3n
3o
3p
3q
3r
3s
58.21
58.24
7.50
7.55
-9
57.07
57.16
7.92
7.84
-30
+30
+9
57.10
57.16
7.94
7.84
74.05
73.96
9.66
9.58
73.90
73.96
9.63
9.58
0
73.88
73.96
9.53
9.58
+43
+57
+9
74.57
74.49
9.06
9.14
3t
74.55
74.49
9.19
9.14
3u
3v
3w
3x
3y
3z
4a
4b
4c
4d
74.41
74.49
9.22
9.14
+22
+57
0
70.20
70.12
9.16
9.09
62.94
63.07
8.10
8.17
70.17
70.12
9.02
9.09
-35
+57
-13
+9
70.18
70.12
9.13
9.09
70.70
70.79
8.58
8.69
62.32
62.43
8.13
8.09
62.35
62.43
8.02
8.09
+52
-4
71.33
71.28
13.94
13.85
67.16
67.08
8.77
8.69
+9
180

TABLE 1. (continued)
1
2
3
4
5
6
7
8
4e
4f
C18H14N2O4
C18H14N2O4
C20H18N2O4
C18H15N3O3
C17H15N3O4S
Hypothiazide
67.12
67.08
67.05
67.08
68.64
68.56
67.21
67.28
4.42
4.38
4.34
4.38
5.23
5.18
4.65
4.71
8.64
8.69
8.65
8.69
8.06
8.00
13.15
13.08
355-357
372-374
256-258
311-313
307-309
74
77
83
74
72
-22
-2
4g
4h
4i
+2
+30
+30
+57
57.04
57.13
4.30
4.23
11.68
11.76
—
—
—
—
—
_______
* "+" represents an increase and "-" an inhibition of diuresis relative to
control, taken as 100%.
Pharmacological screening for the appearance in the anilides 3 and 4 of the ability to stimulate the
excretory function of the kidney in laboratory animals was carried out by a standard method described by us in
detail before [21] in a parallel comparison with hypothiazide. On the basis of a comparison of the experimental
data (Table 1) with the results of preceding investigations [20, 21] we found that the anilides prove to more
active than the corresponding benzylamides with similar substituents in the aromatic ring. Only in one example
(the 4-chloroanilide 3h) where a methylene unit separating the amide nitrogen atom and the aromatic ring was
removed were diuretic properties lowered. In all of the remaining cases the same change can be considered
desirable.
In the group of anilides 4 which contain powerful electron-acceptor substituents attention was only
merited by one compound (the m-trifluoromethyl derivative 4b) in which the activity was not inferior to the
known diuretic hypothiazide. It was interesting that diuretic properties were generally not present in the anilides
4d-f which contain carboxyl groups as substituent or also in their structural analogs 4c,g with groups able to
undergo conversion to a carboxyl in vivo. The 2-sulfamoyl derivative 4i and its neutral 2-carbamoyl analog 4h
show an identical moderate level of diuretic activity despite the marked difference in their acidic properties. This
gives us grounds to propose that, as regards the mechanism of action of diuretic activity, the quinolone
compounds differ somewhat from the widely used carbonic anhydrase inhibitors.
EXPERIMENTAL
1H NMR spectra for the synthesized compounds were recorded on a Varian Mercury VX-200 (200 MHz)
instrument using DMSO-d6 solvent and TMS internal standard. The mass spectrum of the imidazolide 2 was
taken on a Varian 1200L instrument with full scanning in the range 35-700 m/z, ionization energy 70 eV, and
with direct introduction. Anhydrous DMF for peptide synthesis and N,N'-carbonyldiimidazole were used from
the Fluka company.
4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid Imidazolide (2). N,N'-Carbonyldiimidazole
(1.78 g, 0.011 mol) was added to a solution of the acid 1 (2.03 g, 0.01 mol) in anhydrous DMF (10 ml) and
protected from atmospheric moisture using a CaCl2 tube. It was held for about 2 h at 90ºC until CO2 evolution had
ceased. The reaction mixture was cooled and diluted with cold water. The precipitated imidazolide 2 was filtered
off, washed with cold water, and dried. Yield 2.50 g (99%); mp 295-297ºC (DMF). 1H NMR spectrum, δ, ppm (J,
Hz): 12.19 (1H, s, NH); 8.29 (1H, s, 2'-H imidazole); 7.88 (1H, dd, J = 8.2 and J = 1.0, H-5); 7.72 (1H, t,
181

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Chemical shifts, δ, ppm (J, Hz)
Com-
pound
NH`
(1H, s)
NH-Ar
(1H, s)
4-СН3
Н arom., m
Other functional groups
(3Н, s)
3a
3b
3c
3d
3e
3f
11.96
11.97
12.01
11.96
12.02
12.00
12.01
11.99
12.07
12.03
12.08
12.02
11.99
12.00
11.98
11.91
11.97
11.96
11.91
10.38
10.42
10.61
10.45
10.63
10.43
10.59
10.52
10.64
10.61
10.82
10.33
10.24
10.58
10.52
9.86
7.85-7.04 (9H)
8.11-7.18 (8H)
7.86-6.88 (8H)
7.87-7.12 (8H)
7.94-7.19 (7H)
7.97-7.18 (8H)
7.98-7.12 (8H)
7.84-7.22 (8H)
8.05-7.18 (7H)
8.01-7.22 (7H)
8.18-7.23 (7H)
7.89-7.09 (8H)
7.90-7.19 (7H)
8.08-7.22 (8H)
7.86-7.18 (8H)
7.87-7.08 (8H)
7.82-6.86 (8H)
7.83-7.11 (8H)
7.86-7.03 (7H)
2.42
2.45
2.41
2.41
2.43
2.56
2.41
2.41
2.57
2.55
2.58
2.56
2.57
2.42
2.41
2.43
2.40
2.39
2.44
—
—
—
—
—
—
3g
3h
3i
—
—
—
3j
—
3k
3l
—
—
3m
3n
3o
3p
3q
3r
3s
2.30 (3H, s, 4'-СН3)
—
—
2.28 (3H, s, 2'-СН3)
2.29 (3H, s, 3'-СН3)
2.26 (3H, s, 4'-СН3)
10.30
10.27
9.88
2.26 (3H, s,СН3);
2.17 (3H, s, СН3)
3t
11.84
11.93
9.79
9.82
7.84-6.99 (7H)
7.87-6.89 (7H)
2.45
2.44
2.25 (3H, s, СН3);
2.22 (3H, s, СН3)
3u
2.27 (3H, s, СН3);
2.21 (3H, s, СН3)
3v
3w
3x
3y
3z
11.96
12.01
11.97
11.94
11.95
9.99
8.21-6.93 (8H)
8.39-7.00 (7H)
7.85-6.63 (8H)
7.84-6.87 (8H)
7.82-6.86 (8H)
2.52
2.52
2.42
2.41
2.41
3.79 (3H, s, 2'-OСН3)
3.84 (3H, s, 2'-OСН3)
3.75 (3H, s, 3'-OСН3)
3.71 (3H, s, 4'-OСН3)
10.35
10.40
10.22
10.22
3.97 (2Н, q, J = 7.0, OСН2);
1.29 (3Н, t, J = 7.0, OСН2СН3)
4a
4b
4c
4d
4e
4f
12.00
12.04
12.02
12.05
12.01
12.02
12.00
10.43
10.76
10.84
11.57
10.59
10.72
10.76
7.90-7.20 (8H)
8.22-7.18 (8H)
7.89-7.22 (8H)
8.66-7.20 (8H)
8.39-7.22 (8Н)
7.98-7.21 (8Н)
7.99-7.21 (8Н)
2.51
2.43
2.55
2.45
2.41
2.40
2.42
—
—
—
12.80 (1H, br. s, 2'-СООН)
13.00 (1H, br. s, 3'-СООН)
12.83 (1H, br. s, 4'-СООН)
4g
4.28 (2Н, q, J = 7.1, OСН2);
1.30 (3Н, t, J = 7.1, OСН2СН3)
4h
4i
11.99
12.25
11.90
9.79
8.63-7.13 (8Н)
2.45
2.56
8.28 (1Н, s, СONH);
7.67 (1Н, s, СONH);
7.98-7.26 (10H,
See Н arom.
Н arom. + SO2NH2)
J = 1.5, H-5' imidazole); 7.63 (1H, td, J = 7.7 and J = 1.2, H-7); 7.38 (1H, dd, J = 8.3 and J = 0.7, H-8); 7.29
(1H, td, J = 7.4 and J = 1.2, H-6); 7.10 (1H, dd, J = 1.8 and J = 1.0, H-4' imidazole); 2.38 (3H, s, CH3). Mass
spectrum, m/z (Irel, %): 253 [M]+ (11), 186 [M–imidazole]+ (100), 157 [M–imidazole–CHO]+ (3), 142 [M–
imidazole–CHO–CH3]+ (1), 130 (31), 103 (10), 77 (15). Found, %: C 66.47; H 4.49; N 16.65. C14H11N3O2.
Calculated, %: C 66.40; H 4.38; N 16.59.
4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid Anilides (3, 4) (General Method). At the end
of the reaction of acid 1 (2.03 g, 0.01 mol) in anhydrous DMF (10 ml) with N,N'-carbonyldiimidazole (1.78 g,
0.011 mol) (see preceding example) the corresponding aniline (0.01 mol) was added to the reaction mixture and
182

refluxed for 6-8 h. It was cooled, diluted with cold water, and acidified with diluted (1:1) HCl to pH 4-5. The
precipitated anilide 3 or 4 was filtered off, washed with water, dried, and crystallized from DMF.
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