4-Hydroxy-2-quinolones. 90.* Synthesis and antitubercular activity of 4-methyl-2-thiazolylamides of halo-substituted 4-hydroxy-2-oxo-1,2-dihydro-3- quinolinecarboxylic acids

Article abstract of DOI:10.1007/s10593-006-0048-8

Several variants were studied for the synthesis of esters of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids, whose reaction with 2-amino-4-methylthiazole gives the corresponding hetarylamides. Results are given for a study of the antitubercular activity of these products. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0048-8

Chemistry of Heterocyclic Compounds, Vol. 42, No. 1, 2006
4-HYDROXY-2-QUINOLONES. 90.* SYNTHESIS
AND ANTITUBERCULAR ACTIVITY OF 4-METHYL-
2-THIAZOLYLAMIDES OF HALO-SUBSTITUTED
4-HYDROXY-2-OXO-1,2-DIHYDRO-
3-QUINOLINECARBOXYLIC ACIDS
I. V. Ukrainets, L. V. Sidorenko, L. A. Petrushova, and O. V. Gorokhova
Several variants were studied for the synthesis of esters of halogen derivatives of 4-hydroxy-2-oxo-1,2-
dihydro-3-quinolinecarboxylic acids, whose reaction with 2-amino-4-methylthiazole gives the
corresponding hetarylamides. Results are given for a study of the antitubercular activity of these
products.
Keywords: amides, 2-amino-4-methylthiazole, 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic
acids, antitubercular activity.
Since the first fluoroquinolone antibiotics appeared on the market, extensive studies have been carried
out worldwide on the synthesis and biological properties of their numerous structural analogs. This work has led
to the steady introduction of new safer and more efficient drugs from this group [2]. It has been repeatedly noted
that the halogen atom in the benzene part of the quinolone molecule, especially at C(6), always facilitates the
antimicrobial activity [3]. The 6-fluoro derivatives were long thought to be the most active molecules in this
class but it was later convincingly shown that the presence of a fluorine atom at C(6) is not necessary to obtain
highly active compounds. The analogous effect may be obtained for other halogens [4] and even without halogen
[5].
Hence, we have modified the previously described methyl derivatives of 2-thiazolylamides of
4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, which display strong in vitro antitubercular activity
[6], by introducing halogen atoms into the quinoline fragment.
The synthesis of 4-methyl-2-thiazolylamides of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-
quinolinecarboxylic acids 1a-f is possible using several approaches. The major differences between these
approaches lies in the method of obtaining the starting esters of the corresponding 3-quinolinecarboxylic acids 2,
which may then be readily converted into the desired hetarylamides. The traditional method entails the
esterification of anthranilic acids 3, acylation of the resultant alkyl anthranilates 4 using ethoxymalonyl chloride,
and cyclization of the ethyl esters of 2-carbalkoxymalonanilic acids 5 to give quinolones 2 under conditions for
the Dieckmann reaction (method A). This method is highly reproducible and gives
_______
* Communication 89, see ref. [1].
__________________________________________________________________________________________
National Pharmaceutical University, 61002 Kharkov, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 71-76, January, 2006. Original article submitted
September 15, 2004.
64
0009-3122/06/4201-0064©2006 Springer Science+Business Media, Inc.

3-ethoxycarbonyl-4-hydroxy-2-oxo-1,2-dihydroquinolines 2 with satisfactory yields. However, the laborious
esterification of anthranilic acids, which rarely gives high yields, along with the high cost of the halogen
derivatives, significantly lowers the usefulness of this method on the whole.
O
O
OMe
NH2
A: MeOH, H+
OH
R
R
NH2
3
4
ClOCCH2COOEt
Б: ClOCCH2COOEt
O
O
OH
OMe
R
R
NHCOCH2COOEt
NHCOCH2COOEt
6
5
Ac2O
EtONa, EtOH
O
N
OH
O
O
O
O
OEt
R
R
EtOH, Et3N
OEt
N
H
7
Me
2a–f
N
Me
H2N
S
OH
O
N
Br2
S
N
H
R
N
H
1a–f
O
OH
O
O
O
KOH, H2O
OEt
OMe
N
H
NHCOCH2COOEt
9
8
1, 2 a R = 6-F, b R = 6,7-F2, c R = 6-Cl, d R = 7-Cl, e R = 6-Br, f R = 6-I
In order to avoid this disadvantage, we employed another synthetic scheme, in which the anthranilic
acids are directly acylated by ethoxymalonyl chloride. The resultant ethyl esters of 2-carboxymalonanilic acids 6
are condensed with 2-ethoxycarbonylmethyl-3,1-benzoxazin-4-ones 7 by the action of acetic anhydride. In turn,
benzoxazinones 7 are recyclized by treatment with triethylamine in absolute methanol to give esters of
3-quinolinecarboxylic acids 2 (method B). The entire chain of these chemical transformations can be carried out
in high yield without separation of the intermediates, which recommends this approach as a preparative method.
Still another variant is possible for the synthesis of esters 2. This method involves halogenation of
previously prepared unsubstituted ethyl ester of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (8). A
significant advantage of this method lies in the possibility of heterocyclization of diester 9 using aqueous alkali
hydroxide [7], while analogs 5, which are substituted in the benzene ring, undergo hydrolysis under these
65

TABLE. 1. Characteristics of Ethyl Esters of Halogen Derivatives of
4-Hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic Acids 2a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С*
(dec.)
Yield, %
(method
C
H
N
2a
2b
2c
C12H10FNO4
C12H9F2NO4
C12H10ClNO4
57.44
57.37
53.69
53.54
53.80
53.85
4.17
4.01
3.35
3.37
3.71
3.77
5.42
5.58
5.28
5.20
5.31
5.23
~200
~200
~200
80 (B)
78 (B)
57 (A),
83 (B)
2d
2e
2f
C12H10ClNO4
C12H10BrNO4
C12H10INO4
53.93
53.85
46.11
46.18
40.27
40.14
3.76
3.77
3.30
3.23
2.66
2.81
5.16
5.23
4.61
4.49
3.78
3.90
~200
~200
~200
80 (B)
85 (B)
82 (B)
_______
* All esters 2 are converted without melting at about 200°C into compounds
with mp >320°C, which are probably halogen analogs of
6,7,8-trioxodiquinolino[3,4-b;3',4'-e]-4H-pyrans [12].
conditions. Nevertheless, this advantage is lost in the final step since the halogenation of esters 8 at C(6) of the
quinoline system is possible only in thoroughly dried solvents and has been studied so far only for the
bromination [1]. Thus, this method was not examined as an alternative to methods A and B.
Upon fusion with an equimolar amount of 4-methyl-2-thiazolylamine, ethyl esters 2 give the desired
hetarylamides of halogen derivatives of 4-hydroxy-2-oxo-dihydro-3-quinolinecarboxylic acids 1a-f in high
yields. Carboxylic acids 1a-f are colorless crystalline compounds virtually insoluble in water (Table 2). The
structures of all these products were supported by their 1H NMR spectra (Table 3).
TABLE 2. Characteristics of 4-Methyl-2-thiazolylamides of 4-Hydroxy-2-
oxo-1,2-dihydro-3-quinolinecarboxylic Acids 1a-f
MIC*,
%, at
c 6.25
Found, %
Calculated, %
H
Growth delay
M. tuberculosis
at с 6.25 µg/ml, %
——————
Com-
pound
Empirical
formula
mp, °С Yield,
(dec.)
%
C
N
µg/ml
1a
1b
1c
1d
1e
1f
C14H10FN3O3S
C14H9F2N3O3S
52.50 3.24 13.25
52.66 3.16 13.16
49.77 2.80 12.40
49.85 2.69 12.46
296
253
285
294
306
313
91
90
92
95
94
87
100
100
99
0.39
0.39
0.39
0.78
0.39
0.78
C14H10ClN3O3S 50.19 3.08 12.62
50.08 3.00 12.51
C14H10ClN3O3S 50.22 3.13 12.45
50.08 3.00 12.51
C14H10BrN3O3S 44.17 2.59 11.16
44.23 2.65 11.05
C14H10IN3O3S
100
99
39.44 2.28
39.36 2.36
9.75
9.84
100
_______
* MIC – minimal inhibition concentration.
66

67

The antitubercular properties of amides 1a-f were studied at the National Allergy and Infectious
Diseases Institute of the United States according to a program of the Tuberculosis Antimicrobial Acquisition &
Coordinating Facility (TAACF) using a radiometric method [8-11]. These results given in Table 2 indicate that
4-methyl-2-thiazolylamides of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids
1a-f are capable of effecting 99-100% inhibition of the growth of Mycobacterium tuberculosis H37Rv ATCC
27294 at c 6.25 µg/ml independent of the nature of the halogen atom in the quinoline system, while their actual
MIC is lower than the value for the unsubstituted analog [6] by a factor of 2-4.
EXPERIMENTAL
1
The H NMR spectra of the products were recorded on a Varian Mercury-VX-200 spectrometer at
200 MHz in DMSO-d6 using TMS as the internal standard.
4-Methyl-2-thiazolylamides of Halogen Derivatives of 4-Hydroxy-2-oxo-1,2-dihydro-3-
quinolinecarboxylic Acids 1a-f (General Method). A mixture of (0.01 mol) ethyl ester of the corresponding
4-hydroxy-2-oxo-1,2-dihydroquinolinecarboxylic acid 2 , 2-amino-4-methylthiazole (1.14 g, 0.01 mol) and
DMF (1-2 ml) was stirred and maintained for 3 min in a metal bath at 160-180°C. The mixture was cooled and
ethanol (30 ml) was added. The mixture was thoroughly stirred and filtered to give amide 1, which was washed
on a filter with ethanol, dried, and crystallized from DMF.
Ethyl Ester of 6-Chloro-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (2c). A. A sample
of concentrated sulfuric acid (17 ml) was added carefully to a solution of 5-chloroanthranilic acid 3 (17.15 g, 0.1
mol) in methanol (100 ml). The reaction mixture was maintained for 15 h on a steam bath. Excess methanol was
removed and the residue was cooled. Then, cold water (200 ml) was added, followed by sodium carbonate to
bring the pH of the aqueous layer to 8. The precipitate of methyl 5-chloroanthranilate 4 was extracted with three
50-ml portions of CH2Cl2. The organic extracts were combined and the solvent was removed to give 12.8 g
(69%) technical-grade methyl anthranilate 4, which was acylated without further purification as follows. The
sample was dissolved in CH2Cl2 and triethylamine (10.6 ml, 0.076 mol) was added. Then, ethoxymalonyl
chloride (11.44 g, 0.076 mol) was added with stirring to the cooled solution and left at room temperature for
4-5 h. The reaction mixture was diluted with water. The organic layer was separated and dried over anhydrous
calcium chloride. The solvent was removed, initially at normal pressure and, finally, at reduced pressure. A
solution of sodium ethylate obtained by adding metallic sodium (2.3 g, 0.1 mol) to absolute ethanol (150 ml) was
added to the residual 2-carbomethoxyanilide 5 and heated at reflux for 30 min on a steam bath. Heating was
discontinued and the mixture was left for 7-8 h at room temperature. The reaction mixture was diluted with water
and made acidic by adding a solution composed of one part concentrated hydrochloric acid and one part water to
pH 4.5-5.0. The residue was filtered off, washed with water, and dried to give 15.25 g 2c (57% relative to 5-
chloroanthranilic acid 3).
B. A sample of 5-chloroanthranilic acid 5 (17.15 g, 0.1 mol) was acylated using ethoxymalonyl chloride
using the method described in the preceding experiment. After removal of the solvent, the residue of
2-carboxyanilide 6 was heated at reflux for 3 h in acetic anhydride (150 ml). The excess condensing agent was
distilled off and absolute ethanol (100 ml) was added to the resultant 4-benzoxazinone 7, followed by
triethylamine (20 ml). The reaction mixture was heated at reflux for 10 h, cooled, and treated analogously to
method A to give 22.21 g (83%) 2c.
The melting point of a mixed probe of samples of 2c obtained by the different methods was undepressed.
The 1H NMR spectra of these products were identical.
68

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