4-Hydroxy-2-quinolones 140. Synthesis and diuretic activity of arylalkylamides of 4-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid

Article abstract of DOI:10.1007/s10593-008-0009-5

The interaction of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid with thionyl chloride in oxygen-containing solvents leads to the formation of a significant amount of colored side products, consequently it was proposed the reaction be carried out

Full text of DOI:10.1007/s10593-008-0009-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 1, 2008
4-HYDROXY-2-QUINOLONES
140*. SYNTHESIS AND DIURETIC
ACTIVITY OF ARYLALKYLAMIDES
OF 4-METHYL-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLIC ACID
I. V. Ukrainets, N. L. Bereznyakova, V. A. Parshikov, and V. N. Kravchenko
The interaction of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid with thionyl chloride in
oxygen-containing solvents leads to the formation of a significant amount of colored side products,
consequently it was proposed the reaction be carried out in carbon tetrachloride. The synthesis of a
series of amides was effected by the amidation of the obtained acid chloride with appropriate primary
arylalkylamines. Results are presented of a study of the effect of the synthesized compounds on the urine-
excreting function of the kidney.
Keywords: amides, 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, diuretic action, X-ray
structural analysis.
Diuretics are widely used in the treatment of illnesses accompanied by retention of fluid in the organism.
Until recently indications to their use have been in the main limited only to edematous syndromes of heart,
kidney, liver, or endocrine origin. However after revealing their antihypertensive action many diuretics acquired
a new importance in medical practice and became basic agents for various forms and stages of hypertension,
glaucoma, and other illnesses [2, 3].
Almost half the world market for diuretics today is provided by three biologically active substances,
furosemide, hypothiazide, and spironolactone. A large number of different prepared medicinal forms and
combined preparations has been designed based on these. Altogether the contemporary arsenal of drug
substances capable of strengthening the eliminatory function of the kidney and authorized for medical use
amounts to about 60 names [4]. Regrettably, not one of them is devoid of side effects, the most important of
which, depending on the mechanism of action, may be hyper- or hypokalemia, hyperglycemia, exacerbation of
sugar diabetes, deterioration of hearing, nausea, dermatitis, etc [2, 3]. Proceeding from this, the search for new
potential diuretic agents with improved properties remains an urgent problem of pharmaceutical science.
Previously we have repeatedly noted the marked diuretic properties displayed by derivatives of
4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids [5-8]. There is interest in the replacement of the 4-OH
group in such compounds by methyl. A preliminary prognosis of biological properties carried out with the PASS
_______
* For Communication 139 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 78-87, January, 2008. Original article submitted March 22,
2007.
64
0009-3122/08/4401-0064©2008 Springer Science+Business Media, Inc.

program [9] served as the basis for this modification, according to which the probability of the display of diuretic
activity by amidated derivatives of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (1) proved to be far
higher than the 4-hydroxy analogs (on average 40% and 0 respectively).
Acid 1 and its esters, as is known, are inert towards primary aliphatic amines. Consequently for
successful amidation, the preliminary activation of the 3-COOH group is necessary, for example, by way of
conversion to the acid chloride 2 [10]. Acid 1 reacts with thionyl chloride in carbon tetrachloride without
significant complications. Only the unusual pink coloration of the resulting acid chloride was noted. In oxygen-
containing solvents, tetrahydrofuran, dioxane, and, especially, nitrobenzene, the reaction mixture acquired an
intense dark-red coloration directly after mixing. The compound, isolated literally after several minutes from the
start of the reaction, had a uniform bright-red color over the whole mass of crystals. To eliminate this with the
aid of complexones (ethylenediaminetetraacetic acid, its disodium or ditriethylamine salt), usually effective in
similar cases [11], was unsuccessful. Consequently the formation of complexes with metals may be excluded
from the probable reasons for the display of color.
Me
O
Me
O
Cl
H2N–R
OH
SOCl2, CCl4
O
N
H
O
N
H
2
1
Me
O
O
R
N
H
N
H
3a–u
3 a R = PhCH2, b R = 2-FC6H4CH2, c R = 4-FC6H4CH2, d R = 2-ClC6H4CH2,
e R = 4-ClC6H4CH2, f R = 4-MeC6H4CH2, g R = 2-MeOC6H4CH2, h R = 4-MeOC6H4CH2,
i R = 3,4-(MeO)2C6H3CH2, j R = piperonyl, k R = furfuryl, l R = picolyl-2,
m R = picolyl-3, n R = picolyl-4, o R = PhCHMe, p R = PhCH2CH2,
q R = 3-ClC6H4CH2CH2, r R = 4-ClC6H4CH2CH2, s R = 4-MeOC6H4CH2CH2,
t R = 3,4-(MeO)2C6H3CH2CH2, u R = Ph(CH2)3
A special experiment was carried out. The acid (colorless substance) was dissolved in nitrobenzene and
thionyl chloride was added. Straight away an intense dark-red coloration was displayed. The precipitated red
solid was immediately filtered off (literally, a few minutes after adding the thionyl chloride), recrystallized from
anhydrous acetone and investigated by X-ray structural analysis. It is interesting that according to the results of
the X-ray structural analysis the compound being investigated was identified as the initial acid 1 (see Fig. 1 and
Tables 1, 2). It is evident that after such a short time the acid simply did not have time to be converted into the
acid chloride.
Evidently the content of the red substance formed in the crystal was so low that its presence did not
interfere with such a type of investigation and was not essentially reflected in its results. Of the special features
of the spatial structure of acid 1 it should be noted that its bicyclic fragment and the O(1) atom lie in one plane
with a precision of 0.02 Å. The bond lengths in the pyridine ring are close to the bond lengths in 2-oxo-
1,2-dihydroquinolines studied previously in [12-14], and in 4-methyl-substituted derivatives [15]. The formation
of a very strong intramolecular hydrogen bond O(3)–H(30)···O(1) (H···O 1.63 Å, O–H···O 152°) leads to significant
65

Fig. 1. Structure of the acid 1 molecule with numbering of atoms.
lengthening of the O(1)–C(9) bond to 1.257(5) Å in comparison with its mean value [16] 1.210 Å and stabilizes
the practically coplanar bicyclic orientation of the carboxyl group (torsion angle C(9)–C(8)–C(10)–O(3) 9.8(6)°).
Significant steric repulsion between the methyl group and the atoms of the aromatic ring [shortened
intramolecular contacts H(5)···C(11) 2.64 Å (sum of van der Waals radii 2.87 Å [17], H(5)···H(11c) 2.05 (2.34) and
H(11c)···C(5) 2.58 Å (2.87 Å)] leads to deviation of the methyl and carboxyl group from the plane of the quinolone
nucleus (torsion angle C(11)–C(7)–C(8)–C(10) is 8.6(6) °). A shortened intramolecular contact H(11b)···O(2) of 2.31 Å
(2.46 Å) was detected between the methyl group and the O(2) oxygen atom.
TABLE 1. Bond Lengths (l) in the Structure of Acid 1
Bond
l, Å
Bond
l, Å
N(1)–C(9)
O(1)–C(9)
O(3)–C(10)
C(1)–C(6)
C(3)–C(4)
C(5)–C(6)
C(7)–C(8)
C(8)–C(9)
1.346(5)
1.257(5)
1.321(5)
1.420(5)
1.403(6)
1.420(5)
1.380(6)
1.464(6)
N(1)–C(1)
O(2)–C(10)
C(1)–C(2)
C(2)–C(3)
C(4)–C(5)
C(6)–C(7)
C(7)–C(11)
C(8)–C(10)
1.377(5)
1.224(5)
1.394(5)
1.379(5)
1.371(6)
1.442(5)
1.527(6)
1.505(6)
TABLE 2. Valence Angles (ω) in the Structure of Acid 1
Angle
C(9)–N(1)–C(1)
ω, deg
Angle
N(1)–C(1)–C(2)
ω, deg
124.8(3)
118.7(3)
119.8(4)
120.7(4)
117.1(3)
119.2(3)
122.0(4)
120.7(3)
117.4(3)
122.5(3)
120.5(4)
116.4(4)
119.9(4)
121.3(3)
120.1(4)
120.9(4)
123.7(4)
119.0(4)
118.9(3)
121.9(4)
120.3(4)
117.2(3)
123.0(4)
N(1)–C(1)–C(6)
C(3)–C(2)–C(1)
C(5)–C(4)–C(3)
C(5)–C(6)–C(1)
C(1)–C(6)–C(7)
C(8)–C(7)–C(11)
C(7)–C(8)–C(9)
C(9)–C(8)–C(10)
O(1)–C(9)–C(8)
O(2)–C(10)–O(3)
O(3)–C(10)–C(8)
C(2)–C(1)–C(6)
C(2)–C(3)–C(4)
C(4)–C(5)–C(6)
C(5)–C(6)–C(7)
C(8)–C(7)–C(6)
C(6)–C(7)–C(11)
C(7)–C(8)–C(10)
O(1)–C(9)–N(1)
N(1)–C(9)–C(8)
O(2)–C(10)–C(8)
66

TABLE 3. Characteristics of Arylalkylamides of 4-Methyl-2-oxo-
1,2-dihydroquinoline-3-carboxylic Acid 3a-u
Found, %
Calculated, %
H
Diuretic
activity*,
% control
——————
Com-
pound
Empirical
formula
Yield,
%
mp, °C
C
N
3a
3b
3c
3d
3e
3f
C18H16N2O2
C18H15FN2O2
C18H15FN2O2
C18H15ClN2O2
C18H15ClN2O2
C19H18N2O2
C19H18N2O3
C19H18N2O3
C20H20N2O4
C19H16N2O4
C16H14N2O3
C17H15N3O2
C17H15N3O2
C17H15N3O2
C19H18N2O2
C19H18N2O2
C19H17ClN2O2
C19H17ClN2O2
C20H20N2O3
C21H22N2O4
C20H20N2O2
Hypthiazide
73.84
73.96
5.50
5.52
9.44
9.58
239-241
(ethanol)
90
86
89
85
94
91
90
92
88
89
93
83
86
81
85
88
90
92
86
85
84
—
+8.4
-28.1
-39.2
-44.6
+45.9
+58.0
+62.1
- 44.9
-8.4
69.78
69.67
4.96
4.87
9.11
9.03
266-268
(DMF)
69.70
69.67
4.91
4.87
9.07
9.03
261-263
(DMF)
66.05
66.16
4.54
4.63
8.50
8.57
243-245
(DMF)
66.22
66.16
4.71
4.63
8.48
8.57
256-258
(DMF)
74.58
74.49
5.99
5.92
9.24
9.14
222-224
(ethanol)
3g
3h
3i
70.68
70.79
5.55
5.63
8.60
8.69
213-215
(ethanol)
70.86
70.79
5.70
5.63
8.74
8.69
204-206
(ethanol)
68.28
68.17
5.81
5.72
7.86
7.95
209-211
(ethanol)
3j
67.74
67.85
4.70
4.79
8.25
8.33
234-236
(DMF)
-17.5
-50.9
+6.4
3k
3l
68.19
68.08
4.93
5.00
10.04
9.92
200-202
(DMF)
69.53
69.61
5.04
5.15
14.22
14.33
228-230
(ethanol)
243-245
(ethanol)
3m
3n
3o
3p
3q
3r
3s
3t
69.55
69.61
5.07
5.15
14.39
14.33
-18.1
-74.0
+39.3
-1.1
69.70
69.61
5.26
5.15
14.21
14.33
247-249
(ethanol)
74.58
74.49
5.86
5.92
9.06
9.14
206-208
(ethanol)
74.44
74.49
5.87
5.92
9.10
9.14
211-213
(ethanol)
66.88
66.96
4.95
5.03
8.31
8.22
202-204
(ethanol)
-6.0
66.90
66.96
5.09
5.03
8.17
8.22
240-242
(ethanol)
- 42.5
+26.9
-75.5
-50.9
+62.0
71.33
71.41
5.92
5.99
8.25
8.33
199-201
(ethanol)
68.76
68.84
6.13
6.05
7.74
7.65
164-166
(ethanol)
3u
74.87
74.98
6.21
6.29
8.65
8.74
191-193
(ethanol)
—
—
—
—
_______
"+" indicates strengthening, "-" indicates suppression of diuresis compared
to control taken as 100%.
In the crystal acid 1 molecules from stacks along the (0 0 1) crystallographic direction, which are linked
with an intermolecular hydrogen bond N(1)–H(1H)···O(2), (0.5+x,1.5-y, z-1) H···O 1.83 Å, N-H···O 175°. Within the
stacks the distance between the molecules is 3.82 Å, which enables an important stacking interaction to be
assumed.
67

68

69

Pure 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (1), as is known [10], is colorless. On
treatment of 4-hydroxy or 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids with thionyl chloride the
formation of intensivity colored substances was also not observed [18].
It therefore follows that the appearance of the red coloration in the case of 4-methyl-substituted analogs
is caused by the presence of the methyl group in the molecule, which preferably takes part in intermolecular
reactions leading to the formation of compounds of the cyanine dye type [19]. The experiments carried out by us
showed that, after conversion of acid 1 into acid chloride 2 in carbon tetrachloride, the content of coloring
substances proved to be insignificant and is usually readily removed with activated carbon at the stage of
purifying the final N-R-amides 3. The reasons by which oxygen-containing solvents significantly increase the
rate of formation of undesirable coloring materials remain unclear, nonetheless the inexpediency of their use in
the synthesis of acid chloride 2 is evident.
All the synthesized arylalkylamides of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 3a-u
(Table 3) were colorless crystalline substances, practically insoluble in water, moderately soluble in hot alcohol,
and very soluble in DMF and DMSO. Their structures were confirmed by 1H NMR spectroscopy (Table 4).
The ability of amides 3a-u to stimulate or, on the other hand, to depress the urine-excretory function of
the kidney was studied by the method of Taylor and Topliss [20] in white mongrel rats in comparison with
hypothiazide.
When analyzing the results of pharmacological testing given in Table 3, we may draw the conclusion
that notwithstanding expectations the majority of the investigated arylalkylamides of 4-methyl-2-oxo-1,2-
dihydroquinoline-3-carboxylic acid 3 display an expressed, but sometimes a very high (amides 3n,t) antidiuretic
effect. The initial acid 1 has practically no effect on diuresis. Its indicator was only +7.9% in comparison with
control, consequently the structure of the amide fragment shows a significant influence on the biological
properties of its derivatives 3. However, to make any general conclusion for all the group of amides 3 clearly
characterizing the interconnection between their chemical structure and the ability to influence the urine-
secretory function of the kidney is impossible. Nonetheless, in the finer homologous series definite regularities
can be traced successfully. For example, in the series of phenylalkylamides 3a→3p→3u the ability to suppress
diuresis clearly grows with the distancing of the phenyl nucleus from the amide nitrogen atom. An analogous
picture is also observed in the case of p-chloro (3e→3r) and 3,4-dimethoxy (3i→3t) derivatives. At the same
time the p-methoxyphenyl-substituted amides 3h and 3s in the indicated modification demonstrate a completely
contrasting tendency towards a significant strengthening of diuretic properties. Only two compounds of the
whole group tested merit special attention. These are the 4-methyl- and 2-methoxybenzylamides 3f and 3g,
displaying diuretic action at the level of hypothiazide, which suggests the need for a more detailed
pharmacological study of them.
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Varian Mercury VX-200
instrument (200 MHz), solvent was DMSO-d6, and internal standard TMS.
Arylalkylamides of 4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid 3a-u (General
Method). Thionyl chloride (1.44 ml, 0.02 mol) was added to a solution of acid 1 (2.03 g, 0.01 mol) in dry CCl4
(50 ml) and the mixture boiled until evolution of HCl and SO2 had stopped (~2 h). The solvent and the excess of
SOCl2 were then distilled (finally, in vacuum). The residue (acid chloride 2) was dissolved in dry acetone (20
ml) and the obtained solution was added dropwise with stirring and cooling to a mixture of the appropriate
arylalkylamine (0.01 mol) and triethylamine (1.4 ml, 0.01 mol) in dry acetone (20 ml). After 3-4 h the reaction
mixture was diluted with cold water and acidified with dilute (1:1) HCl to pH 4. The precipitated solid amide 3a-
u was filtered off, washed with cold water, and dried.
70

X-ray Structural Investigation. Crystals of acid 1 were rhombic (acetone), at -173oC: a = 12.233(2),
b = 18.849(3), c = 3.816(1) Å, V = 879.9(3) Å3, Mr = 203.19, Z = 4, space group Pna21, dcalc = 1.534 g/cm3,
µ(MoKα) = 0.113 mm-1, F(000) = 424. The parameters of the unit cell and the intensities of 6454 reflections
(1543 independent, Rint = 0.105) were measured on a Xcalibur-3 diffractometer (MoKα radiation, CCD detector,
graphite monochromator, ω-scanning, 2θmax = 50°).
The structure was solved by the direct method with the SHELXTL set of programs [21]. The positions of
hydrogen atoms were made apparent from an electron density difference synthesis and were refined according to
the rider model with Uiso = nUeq of the non-hydrogen atom linked with the given hydrogen (n = 1.5 for a methyl
group and n = 1.2 for the remaining hydrogen atoms). Refinement for the H(30) and H(1N) atoms was carried out
isotropically. The structure was refined on F2 by the full matrix least squares method in an anisotropic approach
for the non-hydrogen atoms to wR2 = 0.145 at 1496 reflections (R1 = 0.065 at 1280 reflections with F >4σ(F), S
= 1.041). Full crystallographic information has been deposited in the Cambridge structural database, deposit No.
CCDC 650596. Interatomic distances and valence angles are given in Tables 1 and 2.
Determination of Diuretic Activity. Each test animal (white mongrel rats of weight 180-200 g) was
given an aqueous charge of estimated 25 mg/kg through a stomach probe. The control group of animals received
only the aqueous charge. The investigated compounds were introduced perorally at a dose of 40 mg/kg (the
effective dose of hypothiazide) as a fine aqueous suspension, stabilized with Tween 80. After this the test
animals were placed in volume cells. The amount of urine excreted by animals after 4 h served as a measure of
the intensity of urine elimination. The results of the determination of diuretic activity are summarized in Table 3.
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