4-hydroxy-2-quinolones. 197*. The search for novel diuretics amongst halo-substituted 6-hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo-[3,2,1-ij] quinoline-5-carboxylic acid anilides

Article abstract of DOI:10.1007/s10593-011-0842-9

A targeted synthesis of a series of halo-substituted 6-hydroxy-2-methyl-4- oxo-1,2-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid anilides have been carried out. Peculiarites of the ¹H NMR spectra and the results of investigating the

Full text of DOI:10.1007/s10593-011-0842-9

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
4-HYDROXY-2-QUINOLONES. 197*. THE SEARCH FOR NOVEL
DIURETICS AMONGST HALO-SUBSTITUTED 6-HYDROXY-
2-METHYL-4-OXO-1,2-DIHYDRO-4H-PYRROLO-
[3,2,1-ij]QUINOLINE-5-CARBOXYLIC ACID ANILIDES
I. V. Ukrainets1*, N. Yu. Golik1, A. L. Shemchuk1,
O. I. Naboka1, Yu. V. Voronina1, and A. V. Turov2
A targeted synthesis of a series of halo-substituted 6-hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo-
[3,2,1-ij]quinoline-5-carboxylic acid anilides have been carried out. Peculiarites of the 1H NMR spectra
and the results of investigating the diuretic activity of these compounds are discussed.
Keywords: anilides, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, methylindoline, amidation, diuretic
activity.
Hypertensive disease is not by chance considered to be one of the main problems in current medicine.
This is not simply a disease, but it intrinsically decreases the quality of human life. Unfortunately, it is also a
factor triggering a cascade of many pathological changes in various organs and tissues and leads to a whole
series of other illnesses and pathological conditions, which contribute to widespread complications and a sharp
increase in mortality. In the last decade, diuretics have secured a place in the treatment of arterial hypertension
and chronic heart failure. Although being not strictly antihypertensive medicines, they lead to the elimination of
a large amount of liquid from the organism thus lowering arterial pressure to a physiological norm [2, 3].
Indapamide is a particularly widely used medicine amongst this pharmacological group [4–9]. Our interest in
this medicine is due not only to its biological properties. Its known structure [10] is a 2-methylindoline
derivative. Quite recently, compounds with a high diuretic activity and clear antihypertensive and anti-
edematous properties have been found amongst 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-
2-carboxamides [11] structurally based on an unsubstituted indoline. From this there arose the idea of including
methylated analogs of the above mentioned pyrroloquinolines into our search for novel diuretic compounds.
_______
* For Communication 196, see [1].
*2To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, 53 Pushkinska St., Kharkiv 61002, Ukraine.
2Taras Shevchenko National University, 64 Volodimirska St., Kyiv 01033, Ukraine; e-mail:
nmrlab@univ.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1009–1017, July, 2011. Original
article submitted June 22, 2010.
826
0009-3122/11/4707-0826©2011 Springer Science+Business Media, Inc.

In order to achieve this particular goal, 2-methylindoline (1) was condensed with triethylmethane
tricarboxylate (2) by our previously reported method [12]. The ethyl 6-hydroxy-2-methyl-4-oxo-1,2-dihydro-
4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (3) obtained in this way reacts with primary amines to give the
corresponding anilides 4a–r. In order to avoid breakdown of ester 3, the amidation was carried out at
temperature not higher than 140ºC. At a higher temperature, the final product is contaminated with an admixture
of the side 6-hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (5).
R
O
O
OH
N
O
O
OH
OH
CH(COOEt)3
H2N
OEt
R
N
2
H
+
NH
N
O
N
Me
Me
Me
Me
1
3
4a–r
5
4 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 = 2,4-Cl2, j R = 2,5-Cl2,
k R = 5-Cl-2-OMe, l R = 2-Br, m R = 3-Br, n R = 4-Br, o R = 2-Br-4-Me, p R = 2-CF3, q R = 3-CF3, r R = 4-CF3
All of the anilides 4a–r obtained (Table 1) are colorless or white with a yellowish tinge, crystalline
substances. At room temperature, they are moderately soluble in DMF and DMSO, slightly soluble in alcohol,
and practically insoluble in water. The structure of the compounds synthesized was confirmed by their 1H NMR
spectra (Table 2).
Overall, the interpretation of the proton signals does not cause a problem. A question arises only in the
more specific task, in particular of assigning the protons of the methylene group in the pyrroline ring. All of the
compounds studied contain a "rigid" methylpyrroline fragment, the protons and methyl group of which have
1
fixed orientations giving rise to this problem in the detailed structural analysis. Thus, in the H NMR spectrum
of the starting ester 3, the pyrroline ring protons appear as a doublet at 1.42 ppm for the CH3 group, a multiplet
for a methine proton at 4.83 ppm, and two double doublets for the methylene group protons centred at 3.57 and
2.90 ppm. The first two of these signals are clear, but a specific assignment of the methylene group protons
signals is impossible without additional study. Theoretically, to solve the stereochemical problems the well
known Karplus equation or its graphical representation [13], which relates the value of the dihedral angle
between interacting protons to their 3J spin-spin coupling value, can be used.
At first, a steric model of the compound studied should be constructed by one of the available methods.
We used the HyperChem computer modelling program. In the case of ester 3 the calculations indicated that one
proton of the methylene group in the pyrrole plane ring is found in a trans orientation to the methine proton and
has a torsional angle of 117º and the second proton in the cis position is at the angle of 6.3ºC. From the
graphically presented Karplus formula it follows that a vicinal spin-spin coupling of 2.6 Hz corresponds to the
1
angle of 117º and the coupling of 8.5 Hz corresponds to the angle 6.3º. As mentioned above, the H NMR
spectrum of ester 3 shows an ABX spin system corresponding to the methine proton multiplet and the two
double doublets for the methylene group protons. They arise from the combination of geminal and vicinal spin-
spin coupling. Standard geminal spin-spin couplings 2J are about 17 Hz, while the vicinal are somewhat smaller.
Thanks to this it is possible to show that in the double doublet at 3.56 ppm the vicinal coupling is 9.4, while in
the double doublet at 2.89 ppm it is 3.6 Hz. The experimental values determined are quite close to those
calculated and this allows us to confirm unambiguously that the proton signal for the methylene group having a
cis partner in spin-spin coupling is observed in the lower field.
827

TABLE 1. Characteristics of 6-Hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-
pyrrolo[3,2,1-ij]quinoline-5-carboxylic Acid Anilides 4a–r
Found, %
Diuretic
activity,
%*
Com-
pound
Empirical
formula
Mp, °С
(DMF–ethanol)
Yield,
%
Calculated, %
C
H
N
4a
4b
4c
4d
4e
4f
C19H16N2O3
71.12
71.24
4.95
5.03
8.83
8.74
127–129
179–181
156–158
143–145
190–192
197–199
166–168
171–173
208–210
203–205
195–197
174–176
188–190
171–173
185–187
150–152
155–157
196–198
91
83
88
90
92
80
85
89
77
80
78
76
88
94
75
77
90
87
-28
+42
+21
+105
+24
+5
C19H15FN2O3
C19H15FN2O3
C19H15FN2O3
C19H14F2N2O3
C19H15ClN2O3
C19H15ClN2O3
C19H15ClN2O3
C19H14Cl2N2O3
C19H14Cl2N2O3
C20H17ClN2O4
C19H15BrN2O3
C19H15BrN2O3
C19H15BrN2O3
C20H17BrN2O3
C20H15F3N2O3
C20H15F3N2O3
C20H15F3N2O3
Hydrochlorothiazide
67.34
67.45
4.54
4.47
8.39
8.28
67.52
67.45
4.55
4.47
8.36
8.28
67.34
67.45
4.53
4.47
8.38
8.28
63.95
64.04
4.08
3.96
7.97
7.86
64.40
64.32
4.35
4.26
7.86
7.90
4g
4h
4i
64.43
64.32
4.37
4.26
7.81
7.90
+5
64.25
64.32
4.31
4.26
7.96
7.90
+5
58.52
58.63
3.54
3.63
7.11
7.20
+14
+9
4j
58.50
58.63
3.55
3.63
7.13
7.20
4k
4l
62.54
62.42
4.58
4.45
7.19
7.28
--26
+17
+83
+4
57.07
57.16
3.66
3.79
6.91
7.02
4m
4n
4o
4p
4q
4r
57.24
57.16
3.90
3.79
7.12
7.02
57.25
57.16
3.86
3.79
7.07
7.02
58.03
58.13
4.22
4.15
6.67
6.78
-21
+13
+4
61.78
61.86
3.80
3.89
7.14
7.21
61.95
61.86
3.98
3.89
7.33
7.21
61.94
61.86
3.96
3.89
7.30
7.21
-37
+59
_______
* A "+" indicates the increase and a "-" indicates the inhibition of diuresis
compared with the control taken as 100%.
The diuretic properties of the compounds synthesized were studied on white, nonpedigree rats of both
sexes of weight 180–200 g by the standard method [14]. The test samples were introduced using gastric intubation
as a fine aqueous suspension stabilized by Tween-80. The primary screening was carried out at the dose of
10 mg/kg corresponding to the ED50 of one of the most active 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-
quinoline-5-carboxylic acid amides [11]. Diuresis indicators were recorded in 4 h and compared with the control
and with the known diuretic hydrochlorothiazide [15] used at its effective dose of 40 mg/kg.
828

829

830

It has been found that the starting ethyl ester 3 has a weak diuretic effect increasing the diuresis by an
average of 20%. Loss of the ethoxycarbonyl group markedly changed the biological effect and the 6-hydroxy-
2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (5) even lowered the loss of urine by 37% when
compared with the control data, i.e. behaved as a rather strong antidiuretic agent. An even greater variation is
shown when changing to the halo-substituted 6-hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]-
quinoline-5-carboxylic acid anilides 4a–r. The indicators found for these experiments (Table 1) were so
haphazard that no general structure–activity relationship was apparent. At the same time in a smaller series the
relationship of the diuretic effect on the nature and position of the halogen in the anilide fragment is seen quite
clearly. Hence amongst the fluoroanilides, only the para isomer 4d showed strong diuretic properties –
substantially greater than hydrochlorothiazide. However, an additional fluorine atom in a meta position (anilide
4e) caused almost full deactivation of the molecule. For the bromo-substituted analogs, only the meta isomer 4m
attracted attention, while compounds with one or two chlorine atoms, similarly to the trifluoromethyl analogs,
proved virtually inactive towards diuresis in the experimental animals.
Overall, the comparison of the halo-substituted anilides 4a–r and the closely structurally related 1-hyd-
roxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxamides with similar substituents in the anilide
fragments [11] has demonstrated that the methylation of the pyrroline ring can increase the diuretic effect. As an
obvious method for increasing these pharmacological properties this needs further study.
EXPERIMENTAL
1H NMR spectra for the compounds synthesized were recorded on a Varian Mercury-VX-200
(200 MHz) instrument using DMSO-d6 as solvent and TMS as internal standard.
The commercial 2-methylindoline (1) and triethylmethane tricarboxylate (2) were obtained from the
Aldrich company.
Ethyl 6-hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (3) was
obtained by the reaction of 2-methylindoline (1) with a 30% excess of triethylmethane tricarboxylate (2) using
1
the method in [12]. Yield 78%; mp 77–79ºC (diethyl ether). H NMR spectrum, , ppm (J, Hz): 12.99 (1H, s,
OH); 7.68 (1H, d, J = 8.3, H-7); 7.49 (1H, d, J = 7.2, H-9); 7.16 (1H, t, J = 7.5, H-8); 4.83 (1H, s, NCH); 4.30
(2H, q, J = 6.9, OCH2CH3); 3.57 (1H, dd, J = 17.1, J = 9.4, NCHCH2-cis); 2.90 (1H, dd, J = 17.1, J = 3.6,
NCHCH2-trans); 1.42 (3H, d, J = 6.4, NCHCH3); 1.28 (3H, t, J = 6.9, OCH2CH3). Found, %: C 66.02; H 5.61;
N 5.17. C15H15NO4. Calculated, %: C 65.93; H 5.53; N 5.13.
6-Hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic Acid Anilides
4a–r (General Method). A mixture of ethyl ester 3 (2.73 g, 0.01 mol), the corresponding aniline (0.01 mol),
and DMF (1 ml) was stirred and allow to stand at 140ºC for 10–15 min. The reaction mixture was then cooled to
about 100ºC, ethanol (10–15 ml) was carefully added, and thoroughly triturated. The precipitated anilide 4a–r
was filtered off, washed with cold alcohol, dried, and recrystallized from the mixture of DMF and alcohol.
6-Hydroxy-2-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (5) was prepared as the main
product from the reaction of the ethyl ester 3 with ortho-bromoaniline when the general reaction is carried out at
160ºC. Yield 69%; mp 293–295ºC (ethanol). 1H NMR spectrum, , ppm (J, Hz): 11.24 (1H, s, OH); 7.49 (1H, d,
J = 8.0, H-7); 7.36 (1H, d, J = 7.1, H-9); 7.08 (1H, t, J = 7.6, H-8); 5.73 (1H, s, H-3); 4.79 (1H, m, NCH); 3.56
(1H, dd, J = 17.0, J = 9.4, NCHCH2-cis); 2.88 (1H, dd, J = 17.0, J = 3.6, NCHCH2-trans); 1.39 (3H, d, J = 6.3,
CH3). Found, %: C 71.75; H 5.64; N 6.87. C12H11NO2. Calculated, %: C 71.63; H 5.51; N 6.96.
831

REFERENCES
1.
2.
3.
I. V. Ukrainets, E. V. Mospanova, A. V. Turov, and V. A. Parshikov, Khim. Geterotsikl. Soedin., 885
(2011).
J. M. Pascual, E. Rodilla, J. A. Costa, F. Perez-Lahiguera, C. Gonzalez, E. Lurbe, and J. Redón, Blood
Pressure, 18, 247 (2009).
E. Rodilla, J. A. Costa, F. Pérez-Lahiguera, C. González, and J. M. Pascual, Med. Clin. (Barcelona),
131, 406 (2008).
4.
5.
L. Ghiadoni, Expert Opin. Pharmacother., 11, 1647 (2010).
T. Ninomiya, S. Zoungas, B. Neal, M. Woodward, A. Patel, V. Perkovic, A. Cass, M. Cooper,
D. Grobbee, P. Hamet, S. Harrap, L. Liu, G. Mancia, C.-E. Mogensen, N. Poulter, A. Rodgers,
B. Williams, S. MacMahon, and J. Chalmers, J. Hypertens., 28, 1141 (2010).
H. Yamada, Y. Mishiro, K. Kusunose, and M. Sata, J. Cardiovasc. Pharmacol. Ther., 15, 145 (2010).
Y. Hasegawa, K. Shimada, and T. Yamaguchi, Blood Pressure, Suppl., 19, 10 (2010).
S. A. Brandão, M. C. Izar, S. M. Fischer, A. O. Santos, C. M. Monteiro, R. M. Póvoa, T. Helfenstein,
A. C. Carvalho, A. M. Monteiro, E. Ramos, M. Gidlund, A. M. Figueiredo Neto, and F. A. Fonseca,
Am. J. Hypertens., 23, 208 (2010).
6.
7.
8.
9.
H. Arima, C. Anderson, T. Omae, L. Liu, C. Tzourio, M. Woodward, S. Macmahon, B. Neal,
A. Rodgers, and J. Chalmers, J. Hypertens., 28, 395 (2010).
10.
A. Kleemann and J. Engel, Pharmaceutical Substances. Synthesis, Patents, Applications, Multimedia
Viewer, Version 2.00, Georg Thime Verlag, Stuttgart (2001).
11.
12.
E. V. Mospanova, Diss. Cand. Pharmaceut. Sci., Kharkiv (2008).
I. V. Ukrainets, N. Yu. Golik, K. V. Andreeva, and O. V. Gorokhova, Khim. Geterotsikl. Soedin., 1806
(2010). [Chem. Heterocycl. Comp., 46, 1459 (2010)].
13.
14.
M. Karplus, J. Chem. Phys., 30, 11 (1959).
L. N. Sernov and V. V. Gatsura, Elements of Experimental Pharmacology [in Russian], Moscow, 2000,
p. 103.
15.
M. D. Mashkovskii, Drugs, RIA, Novaya Volna, Umerenkov Publishing House, Moscow, 2009, p. 499.
832