4-hydroxy-2-quinolones. 201*. Synthesis, structure, and diuretic activity of hydroxy- and alkoxy- anilides of 6-hydroxy-2-methyl-4-oxo- 2,4-dihydro- 1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid

Article abstract of DOI:10.1007/s10593-011-0882-1

Hydroxy- and alkoxyanilides of 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H- pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids have been synthesized as potential diuretic agents. Features of their purification, their steric structure, and biological activity are d

Full text of DOI:10.1007/s10593-011-0882-1

Chemistry of Heterocyclic Compounds, Vol. 47, No. 9, December, 2011 (Russian Original Vol. 47, No. 9, September, 2011)
4-HYDROXY-2-QUINOLONES. 201*. SYNTHESIS, STRUCTURE,
AND DIURETIC ACTIVITY OF HYDROXY- AND ALKOXY-
ANILIDES OF 6-HYDROXY-2-METHYL-4-OXO-2,4-DIHYDRO-
1H-PYRROLO[3,2,1-ij]QUINOLINE-5-CARBOXYLIC ACID
I. V. Ukrainets1**, N. Yu. Golik1, A. L. Shemchuk1, and V. N. Kravchenko1
Hydroxy- and alkoxyanilides of 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-
5-carboxylic acids have been synthesized as potential diuretic agents. Features of their purification,
their steric structure, and biological activity are discussed.
Keywords: anilides, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, amidation, diuretic activity, X-ray
structural analysis.
A comparative analysis of the effect of halo-substituted anilides of 6-hydroxy-4-oxo-2,4-dihydro-
1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids on the urinary function of the kidney has shown that
methylation of the pyrroline ring at position 2 leads to an increased diuretic effect. As a method for improving
the pharmacological properties of this class of compounds, it deserves more detailed attention [2]. The most
promising substance or structural leader in the group of unmethylated derivatives was found to be the 6-hydroxy-
4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 4-methoxyanilide [3]. Hence it was quite
logical that the next step in our study should be examination of the corresponding alkoxy- and hydroxyanilides of
6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 1a-j.
O
O
O
O
OH
N
OH
H2N
R
OEt
N
H
R
N
Me
Me
1a–j
2
1a R = 2-ОH; b R = 3-ОН; c R = 4-ОН; d R = 2-ОМе; e R = 3-ОМе; f R = 4-ОМе;
g R = 2-Me-4-OMe; h R = 4-OEt; i R = 4-OPr; j R = 4-OC6H13
_______
* For Communication 200, see [1].
**To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
National University of Pharmacy, 53 Pushkinska St., Kharkiv 61002, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1364-1371, September, 2011.
Original article submitted October 17, 2010.
1122
0009-3122/11/4709-1122©2011 Springer Science+Business Media, Inc.

TABLE 1. Characteristics of Anilides 1a-j
Found, %
mp, °С
(DMF–
EtOH)
——————
Calculated, %
Com-
pound
Empirical
formula
Diuretic
activity, %*
Yield, %
C
H
N
C19H16N2O4
C19H16N2O4
C19H16N2O4
C20H18N2O4
C20H18N2O4
C20H18N2O4
C21H20N2O4
C21H20N2O4
C22H22N2O4
C25H28N2O4
67.96
67.85
4.92
4.79
8.24
8.33
278–280
213–215
202–204
169–171
167–169
163–165
172–174
181–183
135–137
84–86
76
84
87
71
89
92
73
94
90
82
- 12
- 28
- 19
- 58
+ 3
1a
1b
1c
1d
1e
1f
67.93
67.85
4.88
4.79
8.40
8.33
67.81
67.85
4.84
4.79
8.29
8.33
68.43
68.56
5.07
5.18
7.91
8.00
68.65
68.56
5.14
5.18
7.96
8.00
68.47
68.56
5.23
5.18
8.07
8.00
+ 68
- 7
69.10
69.22
5.42
5.53
7.58
7.69
1g
1h
1i
69.26
69.22
5.50
5.53
7.74
7.69
+ 6
69.92
69.83
5.95
5.86
7.51
7.40
+ 29
+ 26
+ 59
71.49
71.41
6.80
6.71
6.57
6.66
1j
Hydrochloro-
thiazide
_______
* "+" indicates increase and "-" inhibition of diuresis when compared
with the control taken as 100%.
The objects of this study were prepared by the reaction of ethyl ester 2 with the corresponding anilines
at about 140ºC in the presence of a small amount of DMF. The syntheses occurred smoothly and generally in
good yields (see Table 1). Problems, however, sometimes emerged at the time of purification. Thus, upon the
addition to solutions of the substances synthesized in hot DMF (needed because of the poor solubility of anilides
1a-j in most other organic solvents) of activated carbon, we often observed the appearance of a deep-blue
coloration which was virtually impossible to remove subsequently. Neither the DMF itself nor other starting
reagents dissolved in it showed similar properties.
It is unlikely that the reason for this phenomenon is the tendency for 4-hydroxyquinolones (including
tricyclic) of anilide type 1 to form stable and frequently colored complexes with the cations of many heavy
metals [4]. In this case a similar effect might be observed when working with the majority of quinoline
carboxamides (if not all of the family) and this is not consistent with the facts. Moreover, purification by
recrystallization from another solvent and then solution of such a compound in DMF no longer gave colored
products upon addition of the carbon. Hence the source of the problem lies not in the quinoline carboxamides
themselves but in admixtures formed in the process of side reactions which then, in the presence of activated
carbon, form extremely intense dyes with DMF, which can give strongly colored solutions, even in low
concentrations. We have already observed a similar effect in our work with other 2-quinolone derivatives [5, 6].
In order to overcome this drawback, one should initially test a small sample of quinoline carboxamide in
boiling DMF with the addition of carbon. The appearance of a color will testify the necessity to change DMF for
another more suitable solvent (e.g. alcohol, ethyl acetate, or dioxane). As a last resort, DMF can be used for
recrystallization but without activated carbon.
The synthesized anilides 1a-j were identified using 1H NMR spectroscopy (Table 2).
1123

1124

For further information regarding the structure of studied compounds class we examined the 4-ethoxy-
substituted anilide 1h using X-ray structural analysis (see Figure 1 and Tables 3, 4).
Fig. 1. The structure of the 4-ethoxyanilide 1h molecule with atomic numbering.
In this way we obtained absolute confirmation for the previous conclusion, made on the basis of
computer modelling, that the tricyclic pyrroloquinoline system in such compounds is planar [2]. The atoms O(1),
O(2) and the carbamide group lie in virtually the same plane as the tricycle (accuracy 0.02 Å) and this is due to the
presence of two, strong intramolecular hydrogen bonds O(2)–H(2O)···O(3) (H···O 1.49 Å, O–H···O 155º) and
N(2)–H(2N)···O(1) (H···O 1.84 Å, N–H···O 145º). Formation of the hydrogen bonds also leads to marked
lengthening of the O(1)–C(9) bond to 1.243(2) and O(3)–C(12) to 1.261(2) Å compared to their average value [7]
TABLE 3. Bond Lengths (l) in the 4-Ethoxyanilide 1h Structure
Bond
l, Å
Bond
l, Å
N(1)–C(9)
1.367(2)
1.489(2)
1.416(2)
1.326(2)
1.370(2)
1.382(2)
1.365(2)
1.396(2)
1.398(2)
1.380(2)
1.466(2)
1.555(2)
1.387(2)
1.374(2)
1.376(2)
N(1)–C(1)
1.370(2)
1.334(2)
1.243(2)
1.261(2)
1.425(2)
1.383(2)
1.502(2)
1.367(2)
1.438(2)
1.460(2)
1.476(3)
1.370(2)
1.388(2)
1.382(2)
1.534(1)
N(1)–C(10)
N(2)–C(13)
O(2)–C(7)
O(4)–C(16)
C(1)–C(2)
N(2)–C(12)
O(1)–C(9)
O(3)–C(12)
O(4)–C(19)
C(1)–C(6)
C(2)–C(3)
C(2)–C(11)
C(4)–C(5)
C(3)–C(4)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
C(8)–C(9)
C(8)–C(12)
C(10)–C(11)
C(13)–C(18)
C(15)–C(16)
C(17)–C(18)
C(10)–C(21)
C(13)–C(14)
C(14)–C(15)
C(16)–C(17)
C(19)–C(20)
1125

TABLE 4. Valence Angles () in the 4-Ethoxyanilide 1h Structure
Valence Angle
, deg.
Valence Angle
, deg.
C(9)–N(1)–C(1)
122.6(1)
110.6(1)
116.7(1)
123.8(2)
118.4(2)
108.0(2)
121.0(2)
116.9(2)
127.5(2)
116.6(2)
121.3(2)
121.0(2)
123.9(2)
114.5(2)
102.9(1)
121.4(2)
119.3(2)
123.6(2)
121.0(2)
124.4(2)
119.4(2)
120.8(2)
C(9)–N(1)–C(10)
C(12)–N(2)–C(13)
N(1)–C(1)–C(2)
C(2)–C(1)–C(6)
C(3)–C(2)–C(11)
C(2)–C(3)–C(4)
C(4)–C(5)–C(6)
C(1)–C(6)–C(7)
O(2)–C(7)–C(8)
C(8)–C(7)–C(6)
C(7)–C(8)–C(12)
O(1)–C(9)–N(1)
N(1)–C(9)–C(8)
C(21)–C(10)–C(11)
C(2)–C(11)–C(10)
O(3)–C(12)–C(8)
C(14)–C(13)–C(18)
C(18)–C(13)–N(2)
C(16)–C(15)–C(14)
O(4)–C(16)–C(17)
C(18)–C(17)–C(16)
O(4)–C(19)–C(20)
126.4(2)
126.9(2)
112.7(2)
123.5(2)
133.7(2)
119.9(2)
120.5(2)
115.6(2)
122.4(2)
120.9(2)
117.7(2)
120.3(2)
115.8(2)
112.9(2)
105.5(1)
119.3(2)
118.5(2)
117.9(2)
120.0(2)
116.2(2)
120.2(2)
108.0(1)
C(1)–N(1)–C(10)
C(16)–O(4)–C(19)
N(1)–C(1)–C(6)
C(3)–C(2)–C(1)
C(1)–C(2)–C(11)
C(5)–C(4)–C(3)
C(1)–C(6)–C(5)
C(5)–C(6)–C(7)
O(2)–C(7)–C(6)
C(7)–C(8)–C(9)
C(9)–C(8)–C(12)
O(1)–C(9)–C(8)
C(21)–C(10)–N(1)
N(1)–C(10)–C(11)
O(3)–C(12)–N(2)
N(2)–C(12)–C(8)
C(14)–C(13)–N(2)
C(13)–C(14)–C(15)
O(4)–C(16)–C(15)
C(15)–C(16)–C(17)
C(17)–C(18)–C(13)
of 1.210 Å and to shortening of the O(2)–C(7) bond to 1.326(2) Å (average value 1.362 Å). The C(7)–C(8) bond
is lengthened to 1.380(2) Å (average value 1.326 Å) and this is characteristic for quinolone compounds series.
The methyl group on atom C(10) is found in an equatorial position (torsional angle C(1)–N(1)–C(10)–C(21)
127.9(2)º). The para-ethoxyphenyl substituent is found in an ap-type conformation relative to the C(8)–C(12)
bond and slightly twisted relative to the carbamide fragment plane (torsional angles C(13)–N(2)–C(12)–C(8)
174.7(2)º and C(12)–N(2)–C(13)–C(14) 30.5(3)º) despite the formation of the intramolecular hydrogen bond
C(14)–H(14)···O(3) (H···O 2.35 Å, C–H···O 113º). The ethoxy group is coplanar with the aromatic ring
(torsional angle C(19)–O(4)–C(16)–C(15) -3.9(2)º) despite the strong repulsion between the aromatic ring atoms
and the ethyl group atoms (shortened intramolecular contacts H(15)···C(19) 2.51 Å (sum of van der Waal radii
[8] 2.87 Å), H(15)···H(19b) 2.32 Å (2.34 Å), H(15)···H(19a) 2.27 Å (2.34 Å), H(19a)···C(15) 2.70 Å (2.87 Å),
and H(19b)···C(15) 2.78 Å (2.87 Å)). The C(19)–C(20) bond is antiperiplanar to the C(16)–O(4) bond (torsional
angle C(16)–O(4)–C(19)–C(20) 174.9(2)º)
The 4-ethoxyanilide 1h molecules form stacks in the crystal along the crystallographic (1 0 0) direction.
Within the stacks the molecules are positioned "head to tail" with a separation of 3.5 Å and it allows us to suggest the
existence of a - type interaction in the stacks. There are also C–H··· type intermolecular interactions in the crystal:
C(10)–H(10)···C(15)' [(x, y-1, z) H··· 2.74 Å, C–H··· 148º] and C(20)–H(20b)···C(18') [(1.5-x, 0.5+y, 0.5-z) H···
2.81 Å, C–H··· 149º].
The diuretic activity of anilides 1a-j was studied on white rats using a standard method [2, 9] by oral
introduction and in comparison with hydrochlorothiazide [10]. Comparison of the experimental data obtained
1126

(Table 1) with the results of the previous investigations [3] shows that, in the case of the hydroxy- and
alkoxyanilides, the transition from pyrroloquinoline derivatives to their 5-methyl-substituted analogs is
accompanied by some decrease in diuretic activity but that the overall nature of the structure–biological
relationship remains the same.
EXPERIMENTAL
1H NMR spectra of anilides 1a-j were measured on a Varian Mercury VX-200 instrument (200 MHz)
with DMSO-d6 solvent and TMS as internal standard. The synthesis of ethyl 6-hydroxy-2-methyl-4-oxo-
2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (2) and its amidation by hydroxy- and alkoxyanilines
was carried out by the method in the study [2].
X-ray Structural Investigation. Crystals of the 4-ethoxyanilide 1h are monoclinic (DMF), at 20ºC:
a = 7.5136(7), b = 9.8478(7), c = 23.673(2) Å,  = 96.160(7)º, V = 1741.5(2) Å3, Mr = 364.39, Z = 4, space
group P21/n, dcalc = 1.390 g/cm3, (MoK) = 0.097 mm-1, F(000) = 768. Unit cell parameters and intensities for
13731 reflections (3062 independent, Rint = 0.047) were measured on an Xcalibur-3 diffractometer (MoK
radiation, CCD detector, graphite monochromator, -scanning, 2max = 50º).
The structure was interpreted by a direct method using the SHELXTL program package [11]. In the
structure refinement a limit was placed on the ethyl group bond length of 1.54(1) Å. The positions of the
hydrogen atoms were revealed from electron density difference synthesis and refined using the "rider" model
with Uiso = nUeq for a non-hydrogen atom bonded to the given hydrogen (n = 1.5 for a methyl group and n = 1.2
for other hydrogen atoms). Hydrogen atoms involved in formation of hydrogen bonds were refined in the
isotropic approximation. The structure was interpreted by F2 full-matrix least-squares analysis in the anisotropic
approximation for non-hydrogen atoms to wR2 = 0.073 for 3023 reflections (R1 = 0.035 for 1585 reflections with
F > 4 (F), S = 0.760). The full crystallographic information for the 4-ethoxyanilide 1h has been placed in the
Cambridge Crystallographic Data Center as deposit CCDC 801477. Interatomic distances and valence angles are
given in Tables 3 and 4, respectively.
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