4-Hydroxy-2-quinolones. 194*. 1-Hydroxy-3-oxo-6,7-dihydro-3H,5H- pyrido[3,2,1-ij]quinoline-2-carboxylic acid alkylamides. Synthesis, structure, and biological properties

Article abstract of DOI:10.1007/s10593-011-0692-5

Modified methods are proposed for the preparation of the ethyl ester and alkylamides of 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2- carboxylic acid. A comparative analysis has been carried out of the steric structure and diuretic activity of the synthesized compounds and the previously studied, and closely structurally related, 1-hydroxy-3-oxo-5,6-dihydro-3H- pyrrolo-[3,2,1-ij]quinoline-2-carboxamides.

Full text of DOI:10.1007/s10593-011-0692-5

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
4-HYDROXY-2-QUINOLONES. 194*. 1-HYDROXY-
3-OXO-6,7-DIHYDRO-3H,5H-PYRIDO[3,2,1-ij]QUINOLINE-
2-CARBOXYLIC ACID ALKYLAMIDES. SYNTHESIS,
STRUCTURE, AND BIOLOGICAL PROPERTIES
I. V. Ukrainets1*, N. Yu. Golik1, K. V. Andreeva1, and O. V. Gorokhova1
Modified methods are proposed for the preparation of the ethyl ester and alkylamides of 1-hydroxy-
3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid. A comparative analysis has been
carried out of the steric structure and diuretic activity of the synthesized compounds and the previously
studied, and closely structurally related, 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo-[3,2,1-ij]quinoline-2-
carboxamides.
Keywords: 4-hydroxy-2-oxoquinoline-3-carboxylic acid alkylamides, amidation, diuretic activity, X-ray
structural analysis.
The accidental discovery of stimulation of diuretic function of the kidney [2] using 4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxamides (which had not previously been considered as a specific feature) has since
then proved to be a trigger for carrying out a broad investigation targeted towards a novel class of diuretic
chemicals. As a result, compounds have been synthesized which (due to the mechanism of the removal of a large
volume of liquid [3]) have proved efficient agents in the fight against serious pathology such as hypertensive
disease and also edema in the brain and lungs [4].
With the aim of discovering novel compounds which would be of interest as the basis for preparing
therapeutically useful diuretic materials, one of the directions of our further work related to the 1-hydroxy-
3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid N-R-amides 1. A justification for
studying such substances is their close structural similarity to 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo-
[3,2,1-ij]quinoline-2-carboxamides [4, 5] which have high diuretic activity. Expansion of the ring annelated to
the quinolone nucleus by just one unit should certainly lead to a conformational rearrangement of of the basic
molecule and this, in turn, can bring about changes in pharmacological properties.
In principle, the synthesis of the starting ethyl 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]-
quinoline-2-carboxylate (2) can be achieved by the reaction of 1,2,3,4-tetrahydroquinoline (3) with triethyl-
methane tricarboxylate (4) using different methods, i.e. holding a mixture of the amine and a twofold excess of
acylating agent at 220ºC [6] or by the stepwise addition of the amine to an equimolar amount of the
_______
* For Communication 193, see [1].
* To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, Kharkiv 61002, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1806-1815, December, 2010.
Original article submitted June 22, 2010.
0009-3122/11/4612-1459©2011 Springer Science+Business Media, Inc.
1459

triester previously heated to 215ºC [7]. In should be noted that both variants only give good results for working
with small amounts of the ester 2 (up to 0.1 mol). With larger loads, problems specific to each of the methods
appear. In the first, besides the wasteful use of the expensive triethylmethane tricarboxylate, it becomes
impossible to heat a bulky reaction mixture to the required 220ºC sufficiently rapidly. Side processes are
activated, the main of which is partial transformation of the initially formed diethyl methanecarboxylate
monoquinolin-1-ylamide not to the target product but to the methanedi- or tri(quinolin-1-yl)carboxamides. With
use of the second method the reaction mixture becomes too viscous at the end of the reaction. For large
quantities the mixing is severely challenged with the result that subsequent portions of the 1,2,3,4-tetra-
hydroquinoline (3) are markedly consumed not by reaction with the residual triethylmethane tricarboxylate (4)
but by amidation of tricyclic ester 2 which became the main component of the mixture.
O
OH
O
OH
CH(COOEt)3
NH-R
OEt
(4)
H2N–R
NH
N
O
O
N
1a–q
2
3
1 a R = Me; b R = Et; c R = All; d R = Pr; e R = i-Pr; f R = Bu; g R = i-Bu; h R = s-Bu;
i R = C5H11; j R = i-C5H11; k R = C6H13; l R = 2-hydroxyethyl; m R = 3-hydroxypropyl;
n R = cyclo-C3H5; o R = cyclo-C5H9; p R = cyclo-C6H11; q R = cyclo-C7H13
Our modified method for carring out this reaction adapted for large loads allows to remove mentioned
drawbacks. In fact, this is the previously discussed second method differing only in the fact that the amine is added
not to the triethylmethane tricarboxylate but to its solution in an inert, high boiling solvent (diphenyl ether or
Dowtherm A). This apparently small change allows us to prepare not only ester 2 but also its numerous analogs in
virtually any amount. The only limitation of the method can be the degree of thermal stability of the secondary
amine used.
Refluxing ester 2 for 20 h with a 40% excess of the corresponding amine in bromobenzene [6] has
previously been used for the preparation of 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-
2-carboxylic acid alkylamides 1. We have meanwhile accumulated practical experience of the synthesis of
4-hydroxy-2-oxoquinoline-3-carboxamides and this infers that such rigorous conditions are clearly excessive. In
fact, carrying out further experiments has shown that ester 2 is readily amidated by alkylamines in just refluxing
ethanol. The reaction is complete after 2-4 h and its success needs only a 10% excess of the alkylamine.
All of the synthesized alkylamides 1a-q (Table 1) are colorless, crystalline materials, soluble in alcohol,
DMF or DMSO, and virtually insoluble in water, diethyl ether, and hexane. Their structure is confirmed from 1H
NMR spectroscopy (Table 2). The different feature from the previously reported analogous 1-hydroxy-3-oxo-
5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acids [8] is the signal for the protons of the methylene
group at position 6 of the pyridoquinolone ring which appears as a quintet of intensity 2H in the region 2.1 ppm. In
addition, to clarify the features of the steric structure of the group of compounds obtained, we have carried out an
X-ray structural analysis of the sec-butylamide 1h (see Figure 1 and Tables 3 and 4).
In this way it was shown that, thanks to the presence of the two intramolecular hydrogen bonds (O(2)–
H(2O)···O(3) 1.72 Å. O–H···O 149º and N(2)–H(2N)···O(1) 1.96 Å. N–H···O 135º), the quinolone fragment in
the polycyclic system and the carbamide group of this compound lie in a single plane to an accuracy of 0.01 Å.
The formation of the hydrogen bonds also leads to a marked redistribution of electron density in this fragment,
as shown by lengthening of the bonds O(1)–C(9) 1.241(2) and C(13)–O(3) 1.268(2) Å when compared with
their mean value [9] of 1.210 Å and also of the C(7)–C(8) bond 1.370(3) (1.326 Å). The O(2)–C(7) bond
1.326(2) is markedly shortened (mean value 1.362 Å).
1460

TABLE 1. Characteristics of the 1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-
pyrido[3,2,1-ij]quinoline-2-carboxylic Acid Alkylamides 1a-q
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
(ethanol)
Yield,
%
Diuretic
activity, %*
C
H
N
C14H14N2O3
C15H16N2O3
C16H16N2O3
C16H18N2O3
C16H18N2O3
C17H20N2O3
C17H20N2O3
C17H20N2O3
C18H22N2O3
C18H22N2O3
C19H24N2O3
C15H16N2O4
C16H18N2O4
C16H16N2O3
C18H20N2O3
C19H22N2O3
C20H24N2O3
Furosemide
65.23
65.11
66.27
66.16
67.47
67.59
67.20
67.12
67.23
67.12
68.09
67.98
68.07
67.98
67.90
67.98
68.65
68.77
68.66
68.77
69.58
69.49
62.39
62.49
63.46
63.57
67.67
67.59
69.32
69.21
70.04
69.92
5.55
5.46
6.04
5.92
5.59
5.67
6.45
6.34
6.46
6.34
6.80
6.71
6.83
6.71
6.78
6.71
6.94
7.05
6.92
7.05
7.45
7.37
5.51
5.59
5.92
6.00
5.76
5.67
6.55
6.45
6.92
6.79
10.93
10.85
10.18
10.29
9.96
9.85
9.91
9.78
9.88
9.78
9.39
9.33
9.42
9.33
9.26
9.33
8.83
8.91
8.97
8.91
8.44
8.53
9.63
9.72
9.19
9.27
9.97
9.85
9.08
8.97
8.47
8.58
147-149
116-118
135-137
141-143
137-139
90-92
97
96
94
93
78
93
95
82
90
92
95
97
96
84
88
88
85
-48
-73
-81
+27
-78
-76
+8
1a
1b
1c
1d
1e
1f
103-105
138-140
75-77
1g
1h
1i
+11
-84
-81
-82
-5
101-103
69-71
1j
1k
1l
130-132
109-111
104-106
156-158
193-195
162-164
-71
-26
+17
+43
+16
+104
1m
1n
1o
1p
1q
70.48
70.57
7.22
7.11
8.15
8.23
_______
* "+" indicates an increase and "-" an inhibition of diuresis with respect to the
control taken as 100%
Fig. 1. Structure of the sec-butylamide 1h molecule with atom numbering.
1461

1462

1463

TABLE 3. Bond Lengths (l) in the sec-Butylamide 1h Structure
Bond
N(1)–C(9)
l, Å
Bond
N(1)–C(1)
l, Å
1.377(2)
1.477(2)
1.471(1)
1.241(2)
1.268(2)
1.409(2)
1.494(3)
1.364(3)
1.434(3)
1.451(3)
1.464(3)
1.540(1)
1.540(1)
1.539(1)
1.388(2)
1.322(3)
1.471(1)
1.326(2)
1.401(3)
1.377(3)
1.376(3)
1.410(3)
1.370(3)
1.472(3)
1.502(3)
1.540(1)
1.539(1)
1.540(1)
N(1)–C(10)
N(2)–C(14B)
O(1)–C(9)
N(2)–C(13)
N(2)–C(14A)
O(2)–C(7)
O(3)–C(13)
C(1)–C(6)
C(1)–C(2)
C(2)–C(3)
C(2)–C(12)
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(13)
C(11)–C(12)
C(14A)–C(15A)
C(14B)–C(16B)
C(16B)–C(17B)
C(10)–C(11)
C(14A)–C(16A)
C(16A)–C(17A)
C(14B)–C(15B)
TABLE 4. Valence Angles () in the sec-Butylamide 1h Structure
Angle
, deg
Angle
, deg
C(9)–N(1)–C(1)
123.6(2)
120.0(2)
128.4(4)
119.3(2)
117.7(2)
121.0(2)
119.7(2)
119.7(2)
121.8(2)
116.5(2)
120.1(2)
121.4(2)
123.4(2)
111.7(2)
111.1(2)
119.8(2)
105.0(5)
101.1(8)
102.9(4)
106.9(6)
C(9)–N(1)–C(10)
C(13)–N(2)–C(14B)
N(1)–C(1)–C(2)
116.4(2)
118.7(3)
120.8(2)
120.0(2)
121.3(2)
123.2(2)
119.8(2)
118.5(2)
122.4(2)
121.1(2)
118.5(2)
119.2(2)
117.4(2)
113.1(2)
121.2(2)
119.0(2)
114.7(7)
112.1(6)
114.4(5)
110.3(7)
C(1)–N(1)–C(10)
C(13)–N(2)–C(14A)
N(1)–C(1)–C(6)
C(2)–C(1)–C(6)
C(3)–C(2)–C(1)
C(3)–C(2)–C(12)
C(4)–C(3)–C(2)
C(1)–C(2)–C(12)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
C(1)–C(6)–C(5)
C(1)–C(6)–C(7)
C(5)–C(6)–C(7)
O(2)–C(7)–C(8)
O(2)–C(7)–C(6)
C(8)–C(7)–C(6)
C(7)–C(8)–C(9)
C(7)–C(8)–C(13)
O(1)–C(9)–N(1)
C(9)–C(8)–C(13)
O(1)–C(9)–C(8)
N(1)–C(9)–C(8)
C(11)–C(10)–N(1)
C(2)–C(12)–C(11)
O(3)–C(13)–C(8)
N(2)–C(14A)–C(16A)
C(16A)–C(14A)–C(15A)
N(2)–C(14B)–C(16B)
C(16B)–C(14B)–C(15B)
C(10)–C(11)–C(12)
O(3)–C(13)–N(2)
N(2)–C(13)–C(8)
N(2)–C(14A)–C(15A)
C(14A)–C(16A)–C(17A)
N(2)–C(14B)–C(15B)
C(14B)–C(16B)–C(17B)
The tetrahydropyridine ring is found in a sofa conformation (folding parameters [10]: S = 0.69,  = 38.8, 
= 10.3º). The deviation of the C(11) atom from the mean square plane of the remaining ring atoms is -0.59 Å. An
attractive interaction H(10a)···O(1) is found between the C(10)H2 methylene group and the C(9)–O(1) carbonyl
group (2.29 Å) (sum of van der Waal radii [11] 2.46 Å) which is not correctly to consider as an intramolecular
hydrogen bond because of the acute C–H···O angle (101º).
The secondary butyl substituent at the N(2) atom is randomized in two positions (marked A and B) with
equal population densities due to the rotation around the C(13)–N(2) and N(2)–C(14) bonds and is found in an
antiperiplanar conformation relative to the C(8)–C(13) bond (torsional angle C(14)–N(2)–C(13)–C(8) 157.7(5)º
in conformer A and -174.6(3)º in B). The methyl group in this substituent in conformer A exists in a
-ac-conformation relative to the C(13)–N(2) bond but in B it is placed virtually perpendicularly to this bond
1464

(torsional angle C(13)–N(2)–C(14)–C(15) -132.5(7)º in A and 81.7(6)º in B). The ethyl group is found in +ac
and ap-conformations relative to the N(2)–C(13) bond in A and B respectively and is twisted relative to the
N(2)–C(14) bond (torsional angles C(13)–N(2)–C(14)–C(16) 117.5(7)º in A and -162.8(5)º in B, N(2)–C(14)–
C(16)–C(17) -54(1)º in A and 65.4(9)º in B). There also arise shortened intramolecular contacts H(17b)···N(2)
2.44 (2.67), H(17f)···N(2) 2.52 (2.67), and H(2Nb)···C(17b) 2.77 Å (2.87 Å).
In the crystal the molecules of the sec-butylamide 1h form dimers, the molecules of which are placed
head to tail with a distance between the planes of the quinolone fragments of 3.6 Å. This allows us to propose
the existence of stacking interactions in the dimers.
A comparative analysis of the X-ray structural data for the sec-butylamide 1h and its direct analog
1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid sec-butylamide [8] shows that
expansion of the ring annelated to the quinoline does bring about an arrangement of the molecule. In particular,
by contrast with the completely planar pyrroloquinolone system, the tetrahydropyridine ring in the
pyridoquinolone 1h takes on a clear sofa type conformation. However, despite these differences in the steric
structure of the two homologs, the remaining parameters remain virtually identical. It is of interest that the
crystal packing of the sec-butylamide 1h and its pyrroloquinolone analog are remarkably similar.
The pharmacological properties of the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo- and 1-hydroxy-3-oxo-
6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acids alkylamides are also very similar, at least as
regards their effect on the diuretic function of the kidney.
Studies were carried out on white, nonpedigree rats of weight 180-200 g by a standard method [12].
Furosemide [13] was used as the standard comparator. The investigated compounds were introduced orally in a
dose of 25 mg/kg (the effective dose for furosemide) and diuresis was measured after 2 h. The structure –
biological activity relationship found showed an almost identical absence of activity and even an antidiuretic
effect in compounds with open alkyl chains in the amide fragments. The diuretic properties increased with a
change to some of the cyclic derivatives (see Table 1).
EXERIMENTAL
1H NMR spectra for the synthesized compounds were recorded on a Bruker WM-360 instrument (360
MHz) for solutions in DMSO-d6 and with TMS as internal standard. Commercial 1,2,3,4-tetrahydroquinoline
and triethylmethane tricarboxylate used in the synthesis of ethyl ester 2 were obtained from the Aldrich
company.
1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid alkylamides 1a-q
were prepared by the methods reported in [8].
Ethyl 1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (2). A mixture
of triethylmethane tricarboxylate (4) (46.4 g, 0.2 mol) and diphenyl ether (100 ml) was heated to 215ºC and
1,2,3,4-tetrahydroquinoline (3) (25 ml, 0.2 mol) was added dropwise with stirring at such a rate that the reaction
mixture temperature stayed within the limits of 215 ± 5ºC. The ethanol formed in the process was distilled off.
After addition of all of the 1,2,3,4-tetrahydroquinoline the mixture was held for 20 min at 220ºC to complete the
reaction. The product was cooled and diluted with a solution of Na2CO3 (30 g) in water (500 ml), vigorously
stirred, and transferred to a separating funnel. After phase separation the aqueous layer was poured off and the
extraction was repeated twice more (5 g Na2CO3 in 200 ml water). The solutions of the sodium salt of ester 2
obtained were combined, purified through carbon, and filtered, The filtrate was acidified with dilute (1:1) HCl to
pH 4.5-5.0. The precipitated ester 2 was filtered, washed with cold water, and dried. Yield 51.9 g (95%); mp
102-104ºC (hexane). A mixed sample with a sample of ester 2 [7] did not give a depression of melting point and
their 1H NMR spectra were found to be identical.
1465

X-ray Structural Analysis. Crystals of the sec-butylamide 1h are triclinic (ethanol). At 20ºC:
a = 6.938(5), b = 8.677(5), c = 13.257(5) Å,  = 101.335(5)º,  = 97.258(5)º,  = 97.795(5)º, V = 765.6(8) Å3,
M = 300.35, Z = 2, space group P , d = 1.303 g/cm3, (MoK) = 0.090 mm-1, F(000) = 320. The unit cell
1
r
calc
parameters and intensities of 5947 reflections (2649 independent, Rint = 0.032) were measured on an Xcalibur-3
diffractometer (MoK radiation, CCD detector, graphite monochromator, -scanning to 2max = 50º).
The structure was solved by the direct method using the SHELXTL program package [14]. For
refinement of the structure, limits were placed on the bond lengths in the randomized fragment for N–Csp3 of
1.47(1) and Csp3–Csp3 1.54(1) Å. The positions of the hydrogen atoms were revealed by electron density
difference synthesis and for the randomized part calculated geometrically and refined using the "riding" model
with Uiso = nUeq for a non-hydrogen atom bound to the given hydrogen (n = 1.5 for a methyl and hydroxyl group
and n = 1.2 for remaining hydrogen atoms). The structure was refined using F2 full-matrix least-squares analysis
in the anisotropic approximation for non-hydrogen atoms to wR2 = 0.090 for 2589 reflections (R1 = 0.043 for
1095 reflections with F ˃ 4 (F), S = 0.760). The complete crystallographic information has been placed in the
Cambridge structural data bank (reference CCDC 801475). Interatomic distances and valence angles are given
in Tables 3 and 4 respectively.
REFERENCES
1.
S. V. Shishkina, O. V. Shishkin, I. V. Ukrainets, and E. V. Mospanova, Acta Crystallogr., E66, o3195
(2010).
2.
3.
I. V. Ukrainets, Diss. Cand. Pharm. Sci., Kharkiv (1988).
I. V. Ukrainets, O. K. Yarosh, A. M. Demchenko, N. L. Bereznyakova, and O. I. Naboka, Ukr. Pat.
86883; Byul. No 10 (2009). http://base.ukrpatent.org/searchINV/
O. I. Naboka, Diss. Doct.Med. Sci., Kiev (2009).
E. V. Mospanova, Diss. Cand. Pharm. Sci., Kharkiv (2008).
A. Kutyrev and T. Kappe, J. Heterocyclic. Chem., 34, 969 (1997).
I. V. Ukrainets, A. A. Tkach, and L. A. Grinevich, Khim. Geterotsikl. Soedin., 1189 (2008). [Chem.
Heterocycl. Comp., 44, 956 (2008)].
4.
5.
6.
7.
8.
I. V. Ukrainets, N. L. Bereznyakova, and E. V. Mospanova, Khim. Geterotsikl. Soedin., 1015 (2007).
[Chem. Heterocycl. Comp., 43, 856 (2007)].
9.
10.
11.
12.
H.-B. Burgi and J. D. Dunitz, Structure Correlation, Vol. 2, VCH, Weinheim (1994), p. 741.
N. S. Zefirov, V. A. Palyulin, and E. E. Dashevskaya, J. Phys. Org. Chem., 3, 147 (1990).
Yu. V. Zefirov, Kristallografiya, 42, 936 (1997).
L. N. Sernov and V. V. Gatsura, Elements of Experimental Pharmacology [in Russian], Moscow (2000),
p. 103.
13.
14.
M. D. Mashkovskii, Drugs [in Russian], RIA, Novaya Volna: Umerenkov Publishing House, Moscow
(2009), p. 502.
G. M. Sheldrick, Acta Crystallogr., A64, 112 (2008).
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