4-Hydro-2-quinolones. 192. *relationship of xy structure and analgesic activity of 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acids and their derivatives

Article abstract of DOI:10.1007/s10593-011-0674-7

Some 4-N-R-2-Oxo-1,2-dihydroquinoline-3-carboxylic acids and their derivatives were synthesized as close structural analogs of the highly-active analgesic 4-benzylamino-2-oxo-1,2-dihydroquinoline-carboxylic acid. Pharmacological testing showed that manife

Full text of DOI:10.1007/s10593-011-0674-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
4-HYDROXY-2-QUINOLONES. 192.* RELATIONSHIP OF
STRUCTURE AND ANALGESIC ACTIVITY OF 4-AMINO-
2-OXO-1,2-DIHYDROQUINOLINE-3-CARBOXYLIC ACIDS
AND THEIR DERIVATIVES
I. V. Ukrainets1**, E. V. Mospanova2, A. A. Davidenko3, and S. V. Shishkina4
Some 4-N-R-2-Oxo-1,2-dihydroquinoline-3-carboxylic acids and their derivatives were synthesized as
close structural analogs of the highly-active analgesic 4-benzylamino-2-oxo-1,2-dihydroquinoline-
carboxylic acid. Pharmacological testing showed that manifestation of an analgesic effect depends on
the presence of a carboxylic group and benzyl fragment in these molecules.
Keywords: 4-N-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, analgesic activity, X-ray diffraction
crystallographic structural analysis.
A study of the pharmacological properties of 4-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids has
shown that such compounds may be effective analgesics [2]. The 4-amino derivatives have attracted special
attention not only in light of their strong pain-relief activity but also due to their extremely weak acidic
properties. Many non-narcotic analgesics are such strong acids that even their salts can cause ulcers and, thus,
have many contra-indications for use [3]. There is no basis for such a side effect in case of 4-amino derivatives,
at least, in such pronounced form. For comparison, the pKa value of the carboxylic group for
4-benzylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (1) is more than 14, while the corresponding
value for one of the most powerful non-narcotic analgesics, Ketorolac is only 3.49 ± 0.02 [4]. If we also
consider its pronounced biological activity, 4-benzylaminoquinoline 1 holds clear interest as an intermediate
leader structure in the search for improved analgesics. We have synthesized a series of close analogs of this
compound and carried out pharmacological testing to clarify the structural fragments most affecting the
analgesic properties.
_______
* Communication 191, see [1].
** To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, Kharkiv 61002, Ukraine.
2Institute of Chemical Technology, Vladimir Dal' Eastern Ukrainian National University, Rubizhne 93003,
Ukraine; e-mail: mospanov@rune.lg.ua.
3N. I. Pirogov Vinnitsa National Medical University, Vinnitsa 21018, Ukraine; e-mail: almusel@mail.ru.
4Institute for Single Crystals, National Academy of Sciences of Ukraine, Kharkiv 61001, Ukraine; e-mail:
sveta@xray.kharkov.com.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1690-1701, November, 2010.
Original article submitted October 28, 2009.
0009-3122/11/4611-1371©2011 Springer Science+Business Media, Inc.
1371

The first representative of the modified derivatives was 4-(benzylamino)quinolin-2-one (2), which is
readily obtained by the decarboxylation of initial structure 1 or by the reaction of 4-chloro-2-oxo-1,2-di-
hydroquinoline-3-carboxylic acid (3a) with benzylamine in high-boiling solvents [5]. The removal of the
carboxylic group from the molecule leads to a significant drop in analgesic activity, namely, the capacity to raise
the pain sensitivity threshold is reduced by a factor of 3 in comparison with starting acid 1 (see Table 1).
Esterification of the carboxylic group (ethyl ester 4a), N(1)-ethylation of the quinolone system (acid 5), and
esterification with concurrent N(1)-alkylation (N(1)-propyl-substituted ester 4b) all lead to similar results. This
finding is a convincing evidence for the extremely important role of the carboxylic group in producing the
biological effect. The introduction of N(1)-alkyl substituents, judging from the examples studied, is undesirable
although, on the whole, their effect is not as straightforward and, in principle, may be the subject for further
research.
Bn
Bn
Bn
NH
NH
NH
COOEt
O
COOH
O
– CO2
O
N
N
H
N
H
R
4a,b
1
2
BnNH2
R
Bn
NH
NH
N
Cl
N
COOH
COOH
O
COOR1
O
BnNH2
RNH2
O
N
H
Et
R
6a–p
5
3a–d
3 a R = R1 = H, b R = H, R1 = Et, c R = Pr, R1 = Et, d R = Et, R1 = H;
4 a R = H, b R = Pr; 6 a R = Ph, b R = Ph(СH2)2, c R = Ph(CH2)3, d R = (±)-MeCH(Ph),
e R = S(+)-MeCH(Ph), f R = R(–)-MeCH(Ph), g R = 4-FC6H4CH2, h R = 2-ClC6H4CH2,
i R = 4-ClC6H4CH2, j R = 4-MeC6H4CH2, k R = 2-MeOC6H4CH2, l R = 4-MeOC6H4CH2,
m R = 3,4-(MeO)2C6H3CH2, n R = piperonyl, o R = S(+)-MeCHC6H4OMe-4,
p R = R(–)-MeCHC6H4OMe-4
Hence, all our subsequent efforts in the chemical modification of 4-benzylamino-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid (1) were directed toward introducing changes exclusively in the benzyl part of the
molecule. The synthesis of the 4-N-R-substituted quinoline-3-carboxylic acids 6a-t was carried out by a single
scheme through the reaction of the corresponding primary amines with 4-chloro-2-oxo-1,2-dihydroquinoline-
2-carboxylic acid (3a) in ethanol at reflux, i.e., under conditions excluding the possibility of decarboxylation.
1
The structure of the compounds obtained was confirmed by H NMR spectroscopy. The presence of all
the proton-containing functional groups was reliably determined (Table 2). Only the question concerning the
three-dimensional structure of acids 6e,f and 6o,p synthesized using optically active 1-arylethylamines remained
open.
1372

TABLE 1. Characteristics of Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound*
Empirical
formula
mp, °С
(ethanol)
Yield,
%
A. a.*2
C
H
N
2
C16H14N2O
C19H18N2O3
C22H24N2O3
C19H18N2O3
C16H12N2O3
C18H16N2O3
C19H18N2O3
C18H16N2O3
C18H16N2O3
C18H16N2O3
C17H13FN2O3
C17H13ClN2O3
C17H13ClN2O3
C18H16N2O3
C18H16N2O4
C18H16N2O4
C19H18N2O5
C18H14N2O5
C19H18N2O4
C19H18N2O4
—
76.64
76.78
70.65
70.79
72.62
72.51
70.68
70.79
68.68
68.57
70.23
70.12
70.90
70.79
70.03
70.12
70.05
70.12
69.98
70.12
65.47
65.38
62.20
62.11
62.22
62.11
70.25
70.12
66.54
66.66
66.53
66.66
64.31
64.40
63.79
63.90
67.34
67.45
67.31
67.45
—
—
—
5.53
5.64
5.74
5.63
6.58
6.64
5.56
5.63
4.40
4.32
5.31
5.23
5.75
5.63
5.17
5.23
5.15
5.23
5.14
5.23
4.33
4.20
4.12
3.99
4.07
3.99
5.34
5.23
4.84
4.97
4.85
4.97
5.20
5.12
4.06
4.17
5.27
5.36
5.22
5.36
—
—
—
11.13
11.19
8.78
8.69
7.52
7.69
8.57
8.69
10.08
9.99
8.97
9.09
8.83
8.69
9.16
9.09
8.95
9.09
9.13
9.09
9.09
8.97
8.66
8.52
8.43
8.52
8.97
9.09
8.55
8.64
8.57
8.64
8.02
7.91
8.19
8.28
8.17
8.28
8.14
8.28
—
—
—
250-252
92
90
72
93
95
90
84
75
78
74
93
91
96
89
93
95
88
92
76
74
—
—
—
24.8
18.0
28.8
7.6
4a
4b
5
140-142
121-122
104-106 (dec.)
243-245 (dec.)
209-211 (dec.)
194-196 (dec.)
225-227 (dec.)
230-232 (dec.)
230-232 (dec.)
227-229 (dec.)
238-240 (dec.)
240-242 (dec.)
229-231 (dec.)
222-224 (dec.)
218-220 (dec.)
215-217 (dec.)
207-209 (dec.)
166-168 (dec.)
166-168 (dec.)
—
6a
6b
6c
6d
6e
6f
26.0
35.2
7.5
40.1
2.2
2.0
6g
6h
6i
35.0
42.7
18.1
20.5
5.8
6j
6k
6l
11.9
28.3
32.2
46.1
31.6
75.4 [2]
34.1
46.4
6m
6n
6o
6p
1
Diclofenac
Keterolac
—
—
_______
* []20 (c = 3, DMF): +190.7° (6e); -190.7° (6f); +157.4° (6o); -157.4° (6p).
D
*2 Analgesic activity (increase of the pain threshold), %.
We attempted to obtain an unequivocal answer to this question by X-ray analysis and initially studied
4-(1-phenylethylamino)quinoline-3-carboxylic acid 6f obtained from R-1-phenylethylamine (see Fig. 1 and
Tables 3 and 4). The bicyclic quinolone system, atom N(2), carbonyl group, and carboxylic group in this
compound lie in the same plane within ±0.02 Å due to the formation of two strong intramolecular hydrogen
bonds N(2)–H(2N)···O(2) (H···O, 1.81 Å; N–H···O, 146°) and O(3)–H(3O)···O(1) (H···O, 1.43 Å; O–H···O,
148°). The formation of these hydrogen bonds accounts for the significant redistribution of electron density in
the quinolone fragment indicated by lengthening of the O(1)–C(9) (1.273(1) Å) and O(2)-C(10) bonds
(1.234(2) Å) in comparison with the mean value (1.210 Å [6]), lengthening of the C(7)-C(8) bond (1.410(2) Å,
1373

mean value 1.326 Å), and contraction of the O(3)-C(10) (1.316(1) Å, mean value 1.362 Å) and C(8)-C(9) bonds
(1.420(2) Å, mean value 1.455 Å). The substituent on the amino group is (1.273(1) Å) and O(2)–C(10) bonds
(1.234(2) Å) in comparison with the mean value (1.210 Å [6]), lengthening in syn-periplanar conformation
TABLE 2. 1H NMR Spectra of 4-N-R-2-Oxo-1,2-dihydroquinolines 4-6
Com-
pound
Chemical shifts, , ppm (J, Hz)
4a
4b
11.13 (1Н, s, NH); 8.13 (1Н, d, J = 8.2, H-5);
7.54-7.10 (9H, m, H-6,7,8 + NHCH2C6H5); 4.46 (2Н, d, J = 6.1, NCH2);
3.91 (2Н, q, J = 7.0, СООCH2); 0.97 (3Н, t, J = 7.0, СН3)
8.22 (1Н, d, J = 8.3, H-5); 7.64 (1Н, t, J = 7.7, H-7);
7.40-7.05 (8H, m, H-6,8 + NHCH2C6H5); 4.47 (2Н, d, J = 6.2, NHCH2);
4.07 (2Н, t, J = 7.2, NCH2СН2Me); 3.93 (2Н, q, J = 7.1, СООCH2);
1.55 (2Н, m, NCH2СН2Me); 1.11 (3Н, t, J = 7.1, ОCH2СН3);
0.96 (3Н, t, J = 6.9, NCH2СН2СН3)
5
16.57 (1Н, s, COOH); 11.26 (1Н, t, J = 4.8, NH); 8.29 (1Н, d, J = 8.1, H-5);
7.85-7.28 (8H, m, H-6,7,8 + CH2C6H5); 5.05 (2Н, d, J = 5.3, NHCH2C6H5);
4.29 (2Н, q, J = 7.1, NCH2Me); 1.23 (3Н, t, J = 7.2, NCH2СН3)
6а
16.71 (1Н, s, COOH); 12.42 (1Н, s, NHPh); 12.21 (1H, s, NH); 7.58 (1Н, t, J = 7.8, H-7);
7.45-7.20 (7H, m, H-5,6,8 + Н-2',3',5',6'); 6.93 (1Н, t, J = 7.7, H-4')
6b
16.58 (1Н, s, COOH); 11.92 (1Н, s, NH); 11.15 (1Н, t, J = 4.2, NHCH2);
8.23 (1Н, d, J = 8.4, H-5); 7.66 (1Н, t, J = 7.6, H-7); 7.40-7.15 (7H, m, H-6,8 + CH2C6 H5);
4.12 (2Н, q, J = 4.8, NCH2CH2Ph); 2.99 (2Н, t, J = 6.9, NCH2CH2Ph)
6c
16.67 (1Н, s, COOH); 11.86 (1Н, s, NH); 11.22 (1Н, t, J = 4.2, NHCH2);
8.14 (1Н, d, J = 8.4, H-5); 7.65 (1Н, t, J = 7.6, H-7); 7.38 (1Н, d, J = 8.4, H-8);
7.30-7.12 (6H, m, H-6 + CH2C6H5); 3.85 (2Н, q, J = 5.1, NCH2);
2.72 (2Н, t, J = 7.6, NCH2CH2CH2Ph); 1.99 (2Н, q, J = 7.2, NCH2CH2CH2Ph)
6df
6g
16.78 (1Н, s, COOH); 12.01 (1Н, s, NH); 11.63 (1Н, d, J = 7.5, NHCH);
7.97 (1Н, d, J = 8.5, H-5); 7.58 (1Н, t, J = 7.8, H-7); 7.43-7.19 (6H, m, H-8 + CHC6H5);
7.07 (1Н, t, J = 7.7, H-6); 5.54 (1Н, q, J = 6.8, NНCH); 1.59 (3Н, d, J = 6.8, CH3)
16.65 (1Н, s, COOH); 12.06 (1Н, s, NH); 11.35 (1Н, t, J = 4.9, NHCH2);
8.24 (1Н, d, J = 8.6, H-5); 7.67 (1Н, t, J = 7.8, H-7); 7.55-7.17 (6H, m, H-6,8 + CH2Ar);
5.06 (2Н, d, J = 5.2, NНCH2)
6h
6i
16.59 (1Н, s, COOH); 12.01 (1Н, s, NH); 11.20 (1Н, t, J = 4.9, NHCH2);
8.14 (1Н, d, J = 8.6, H-5); 7.68 (1Н, t, J = 7.6, H-7); 7.62-7.19 (6H, m, H-6,8 +CH2Ar);
5.12 (2Н, d, J = 5.3, NНCH2)
16.66 (1Н, s, COOH); 11.77 (1Н, s, NH); 11.35 (1Н, t, J = 5.0, NHCH2);
8.20 (1Н, d, J = 8.6, H-5); 7.67 (1Н, t, J = 7.8, H-7); 7.49-7.36 (5H, m, H-8 + CH2Ar);
7.23 (1Н, t, J = 7.7, H-6); 5.09 (2Н, d, J = 5.5, NНCH2)
6j
16.64 (1Н, s, COOH); 11.93 (1Н, s, NH); 11.34 (1Н, t, J = 4.8, NHCH2);
8.26 (1Н, d, J = 8.6, H-5); 7.66 (1Н, t, J = 7.7, H-7); 7.39 (1Н, d, J = 8.1, H-8);
7.31 (2Н, d, J = 8.1, H-2',6'); 7.20 (3H, m, H-6 + H-3',5'); 5.04 (2Н, d, J = 5.1, NНCH2);
2.29 (3Н, s, СН3)
6k
6l
16.57 (1Н, s, COOH); 11.91 (1Н, s, NH); 11.21 (1Н, t, J = 5.1, NHCH2);
8.21 (1Н, d, J = 8.4, H-5); 7.67 (1Н, t, J = 7.9, H-7); 7.44-6.89 (6Н, m, H-6,8,3',4',5',6');
4.98 (2Н, d, J = 5.4, NНCH2); 3.79 (3Н, s, ОСН3)
16.63 (1Н, s, COOH); 11.98 (1Н, s, NH); 11.30 (1Н, t, J = 4.6, NHCH2);
8.28 (1Н, d, J = 8.6, H-5); 7.67 (1Н, t, J = 7.8, H-7); 7.42-7.31 (3Н, m, H-8,2',6');
7.24 (1Н, t, J = 7.8, H-6); 6.95 (2Н, d, J = 8.6, H-3',5'); 5.00 (2Н, d, J = 5.1, NНCH2);
3.74 (3Н, s, ОСН3)
6m
6n
16.64 (1Н, s, COOH); 11.92 (1Н, s, NH); 11.33 (1Н, t, J = 4.7, NHCH2);
8.27 (1Н, d, J = 8.3, H-5); 7.67 (1Н, t, J = 7.7, H-7); 7.40 (1Н, d, J = 8.3, H-8);
7.25 (1Н, t, J = 7.7, H-6); 7.05 (1Н, s, H-2'); 6.96 (2Н, s, H-5',6');
5.01 (2Н, d, J = 5.0, NНCH2); 3.74 (3Н, s, ОСН3); 3.72 (3Н, s, ОСН3)
16.65 (1Н, s, COOH); 12.04 (1Н, s, NH); 11.28 (1Н, t, J = 4.5, NHCH2);
8.25 (1Н, d, J = 8.2, H-5); 7.68 (1Н, t, J = 7.8, H-7); 7.39 (1Н, d, J = 8.2, H-8);
7.25 (1Н, t, J = 7.6, H-6); 7.00 (1Н, s, H-2'); 6.92 (2Н, s, H-5',6'); 6.02 (2H, s, OCH2O);
4.98 (2Н, d, J = 4.6, NНCH2)
6o,p
16.75 (1Н, s, COOH); 11.95 (1Н, s, NH); 11.57 (1Н, d, J = 7.6, NHCH);
8.01 (1Н, d, J = 8.2, H-5); 7.59 (1Н, t, J = 7.6, H-7);
7.38-7.27 (3H, m, H-8 + H-3',5'); 7.10 (1Н, t, J = 7.8, H-6);
6.91 (2H, d, J = 8.7, H-2',6'); 5.49 (1Н, q, J = 7.0, NНCH); 3.70 (3Н, s, ОСН3);
1.57 (3Н, d, J = 7.0, СНCH3)
1374

relative to the C(6)–C(7) bond (the C(11)–N(2)–C(7)–C(6) torsion angle is -19.7(2)°) and rotated such that the
methyl group has –ac-orientation relative to the C(7)–N(2) bond (the C(7)–N(2)–C(11)–C(12) torsion angle is
-143.0(2)°), while the phenyl substituent is almost perpendicular to the C(7)–N(2) bond and somewhat twisted
relative to the N(2)–C(11) bond (the C(7)–N(2)–C(11)–C(13) torsion angle is 94.6(2)° and the N(2)–C(11)–
C(13)–C(14) torsion angle is 10.7(2)°). This position of the amino group substituent leads to strong repulsion
between it and the aromatic ring of the quinolone fragment (short contacts H(5)···C(11), 2.46 Å (sum of the van
der Waals radii [7] 2.87 Å), H(5)···H(11), 2.07 Å (2.34 Å), H(5)···C(13), 2.42 Å (2.87 Å), H(11)···C(5), 2.65 Å
(2.87 Å)). We may assume that the steric strain is partially compensated by some out-of-plane deformation of
the aromatic fragment of the quinolone fragment (the torsion angle C(2)–C(1)–C(6)–C(5) is 4.1(2)°), distortion
of the C(5)–C(6)–C(7)–N(2) (-6.1(2)°) and C(6)–C(7)–C(8)–C(9) torsion angles (4.0(2)°), as well as slight
pyramidalization of the amino group nitrogen atom (the sum of the valence angles centered at atom N(2) is
358.7°). In previous work [8], we have shown that the benzene ring is conformationally flexible and may be
deformed by external forces such as steric strain. We cannot exclude that this accounts for the degeneration of
1
the H NMR signals for H-5' and H-6' protons in the 3,4-dimethoxy-benzyl (6m) and piperonyl (6o) derivatives
into one singlet with intensity 2H instead of two theoretical doublets (Table 2).
Fig. 1. Molecular structure of acid 6f with numbering of the atoms.
A series of shortened contacts was found for this sample: H(2)···H(1N), 2.23 Å (sum of van der Waals
radii 2.34 Å); H(12a)···H(2N), 2.24 Å (2.34 Å); H(12b)···C(18), 2.78 Å (2.87 Å); H(14)···N(2), 2.51 Å (2.67 Å).
The crystal of acid 6f features stacks along the crystallographic direction (1 0 0), in which the distance
between the quinolone aromatic ring and the -system of the carbonyl and carboxylic groups of adjacent
1375

TABLE 3. Bond Lengths (l) in the Structure of Acid 6f
Bond
O(1)–C(9)
l, Å
Bond
O(2)–C(10)
l, Å
1.273(1)
1.316(1)
1.380(2)
1.457(2)
1.401(2)
1.381(2)
1.402(2)
1.410(2)
1.472(2)
1.531(2)
1.373(2)
1.350(2)
1.383(2)
1.234(2)
1.343(2)
1.338(2)
1.396(2)
1.355(2)
1.378(2)
1.462(2)
1.420(2)
1.511(2)
1.360(2)
1.410(2)
1.349(2)
O(3)–C(10)
N(1)–C(1)
N(1)–C(9)
N(2)–C(7)
C(1)–C(6)
C(2)–C(3)
C(4)–C(5)
C(6)–C(7)
C(8)–C(9)
C(11)–C(13)
C(13)–C(14)
C(14)–C(15)
C(16)–C(17)
N(2)–C(11)
C(1)–C(2)
C(3)–C(4)
C(5)–C(6)
C(7)–C(8)
C(8)–C(10)
C(11)–C(12)
C(13)–C(18)
C(15)–C(16)
C(17)–C(18)
TABLE 4. Valence Angles () in the Structure of Acid 6f
Valence angle
C(9)–N(1)–C(1)
, deg
Valence angle
C(7)–N(2)–C(11)
, deg
123.8(1)
120.2(1)
121.4(1)
120.7(2)
122.0(2)
118.2(1)
118.2(1)
118.4(1)
122.5(1)
117.4(1)
118.7(1)
123.7(1)
114.4(1)
110.7(1)
123.2(1)
120.8(2)
119.8(2)
121.7(2)
133.3(1)
118.4(1)
119.8(2)
119.6(2)
116.5(1)
125.3(1)
123.5(1)
120.6(1)
116.9(1)
123.9(1)
119.6(1)
116.8(1)
106.2(1)
117.5(1)
119.4(1)
120.0(2)
120.1(2)
N(1)–C(1)–C(6)
C(6)–C(1)–C(2)
C(2)–C(3)–C(4)
C(4)–C(5)–C(6)
C(1)–C(6)–C(7)
N(2)–C(7)–C(8)
C(8)–C(7)–C(6)
C(7)–C(8)–C(10)
O(1)–C(9)–N(1)
N(1)–C(9)–C(8)
O(2)–C(10)–C(8)
N(2)–C(11)–C(13)
C(13)–C(11)–C(12)
C(14)–C(13)–C(11)
C(13)–C(14)–C(15)
C(17)–C(16)–C(15)
C(13)–C(18)–C(17)
N(1)–C(1)–C(2)
C(3)–C(2)–C(1)
C(5)–C(4)–C(3)
C(1)–C(6)–C(5)
C(5)–C(6)–C(7)
N(2)–C(7)–C(6)
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)
N(2)–C(11)–C(12)
C(14)–C(13)–C(18)
C(18)–C(13)–C(11)
C(16)–C(15)–C(14)
C(16)–C(17)–C(18)
molecules is 3.37 Å, indicating a stacking interaction between these moieties. The molecules of adjacent stacks
are connected by hydrogen bonds N(1)–H(1N)···O(2)' [(-x, 0.5 + y, 1-z), H···O, 2.15 Å, N–H···O, 148°] and
C(16)–H(16)···C(9)' [x, y, 1+z), H···, 2.84 Å, C–H···, 152°].
Absolutely identical crystallographic parameters were found for the optical antipode of acid 6f, i.e.,
4-(1-phenylethylamino)quinoline-3-carboxylic acid 6e obtained from S-1-phenylethylamine. Nevertheless, in
none of these examples, the chiral center configuration unfortunately failed to be determine reliably. We can
only confirm that each of the crystals studied indeed contains only one of the enantiomers since both compounds
give crystals with the noncentrosymmetric P21 space group. The true configuration of a chiral center is
determined using the Flack parameter. The absolute configuration is considered true if the Flack parameter is
equal to zero but requires inversion if this parameter is equal to 1 [9, 10]. However, since crystals of acids 6f and
6e lack heavy atoms, there is no anomalous X-ray scattering permitting the correct calculation of the Flack
parameter. The value of this parameter for these compounds is -0.4(6), which is a meaningless value.
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We have encountered a similar situation in an attempt to use X-ray diffraction structural analysis to
determine the absolute configuration of 1-phenylethylamides of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acids [11]. In this work [12], we were able to obtain convincing proof that neither racemization nor
inversion of configuration occurs upon the amidation of the ethyl esters of the corresponding quinoline-
3-carboxylic acids with optically pure 1-phenylethylamines. In other words, we have additional experimental
proof that the long-known considerable optical stability of 1-arylethylamines in reactions are not affecting the
asymmetric sites [13]. On the basis of these results and taking into account the identical melting points,
1
completely identical H NMR spectra, and furthermore, the same specific rotations differing only in sign (this
finding in itself serves as rather reliable proof for the optical purity of the compounds studied [13]), we may
conclude that acids 6e,f, similar to the enantiomer pair 6o,p, retain the configuration of the starting
1-arylethylamines.
Our chemical modification of the benzyl fragment of acid 1 may be divided into three directions. The
first two directions affect separately the methylene unit or phenyl ring, respectively. The third direction affects
both these groups concurrently. The pharmacological testing showed that removal of the methylene bridge
connecting the secondary amino group and aromatic ring (4-N-phenyl derivative 6a) has the same effect on the
analgesic properties as decarboxylation discussed above, i.e., leads to a drop in activity by a factor of about 3
(Table 1). The replacement of the methylene group by ethylene and, especially, propylene chain also should be
considered unsuccessful. While the analgesic effect in going to 2-phenylethyl derivative 6b drops by a factor of
2, which nevertheless remains on the level of Diclofenac, there is almost no analgesic effect found for the
3-phenylpropyl derivative 6c.
Methylation of the methylene unit in acid 1 led to somewhat unusual results. One asymmetric carbon
atom appears as the result of this transformation. Thus, the final product may be seen as racemic mixture 6d, or
one of the enantiomers with S- or R-configuration of the chiral center (6e or 6f, respectively). Depending on the
three-dimensional structure of the biological target and another of other factors, enantiomers can display
identical pharmacological properties or differ sharply, sometimes giving completely opposite effects. Hence, the
retention of activity on the former level usually observed in practice and the significant drop or even complete
loss in the latter would appear to be logical consequences. In this regard, the rather high analgesic activity of
racemic 2-oxo-1-phenylethyl-1,2-dihydroquinoline-3-carboxylic acid 6d despite the lack of biological activity
of pure enantiomers 6e and 6f would appear somewhat unexpected. The water-insoluble tested compounds were
introduced into the experimental animals as aqueous suspensions. Thus, it is not excluded that the observed
effect results from differences in the crystal forms. Grounds for this proposal exist. For example, in contrast to
optical antipodes 6e and 6f, racemic acid 6d cannot crystallize in a noncentrosymmetric space group. However,
the final conclusion in this matter can be drawn only after special additional experiments. Presently, we can only
note that there have been so many examples of a significant effect of the crystal structure of drugs on their
pharmacological action that polymorphism of pharmaceutical compounds has grown from a curious
phenomenon into an extremely important subject for investigation relative to its scientific aspects and industrial
applications [14].
The second direction in the chemical modification of the leading structure is represented by
4-benzylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 6g-n with substituents in the aromatic ring of the
benzyl fragment. Unfortunately, in all cases, without regard to the substituents introduced and their position in
the ring, a drop in analgesic activity is consistently observed (Table 1). 2-Chlorobenzyl derivative 6h, which is
only slightly inferior in its specific activity relative to ketorolac, is perhaps the only compound of this group
deserving further attention.
Finally, the third group with modifications of the 4-N-benzyl substituent of acid 1 featuring changes
both in the methylene unit and aromatic ring is represented by only two compounds, optically active
4-[1-ethyl(4-methoxyphenyl)amino]-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 6o and 6p.
Here, we clearly
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discern the effect of the spatial configuration of the asymmetric carbon atom on the strength of the analgesic
effect: S-enantiomer 6o is much more active than its R-antipode 6p. It is also interesting to note that the
separately-introduced methyl group into the methylene unit (acid 6e) or 4-methoxyl group into the aromatic ring
(acid 6l) lead to complete loss of analgesic properties. However, the effect of the same substituents when
introduced concurrently is not as clear-cut. In particular, the activity of acid 6o is on the level of Ketorolac,
which is one of the most powerful non-narcotic analgesics.
Therefore, our results indicate that the carboxylic group in the structure of 4-benzylamino-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids undoubtedly plays the key role in binding to receptors. The benzyl
group is another important structural fragment providing a tighter interaction with the biological target. On the
other hand, the role of the 1-N-alkyl substituents is not as unequivocal and requires careful investigation. The
importance of the benzene part of the quinolone system and the secondary amino group at C-4 still remains
completely unclear.
EXPERIMENTAL
1
The H NMR spectra were taken on a Varian Mercury-VX-200 spectrometer at 200 MHz in DMSO-d6
as the solvent with TMS as the internal standard. The specific rotations of acids 6e, 6f, 6o, and 6p were
determined on a Polamat A polarimeter. These compounds were synthesized using commercial samples of
S(-)- and R(+)-1-phenyl- and 1-(4-methoxyphenyl)ethylamines with optical purity of at least 99.5 and 99.0%,
respectively, supplied by Fluka. The analgesic activity of the resultant 4-N-R-2-oxo-1,2-dihydroquinolines was
studied on the standard model of irritation of rectal mucous membrane by an electrical shock [15] described in
detail in our previous work [2].
4-Benzylamino-1H-quinolin-2-one (2). A solution of 4-benzylamino-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid (1) (2.94 g, 0.01 mol) in DMF (10 ml) was heated at reflux for 30 min. The reaction mixture
was cooled and diluted with cold water. The formed precipitate of quinolone 2 was filtered off, washed with
water, and dried. A mixed probe with a sample of 4-benzylaminoquinolin-2-one obtained by the reaction of
4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid with benzylamine in DMF [5] does not give a melting
point depression. The 1H NMR spectra of the two samples were identical.
4-N-R-2-Oxo-1,2-dihydroquinoline-3-carboxylic Acids and their Ethyl Esters 4-6 (General
Method). Corresponding amine (0.011 mol) and triethylamine (1.4 ml, 0.01 mol) were added to a solution of
corresponding 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid or its ethyl ester 3a-d (0.01 mol) in
20 ml ethanol, heated at reflux for 2-3 h, and then cooled. The resultant 4-N-R-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid 5 or 6a-p was filtered off, washed with water and then ethanol, and dried. In the
separation of ethyl esters 4a,b, the reaction mixture was diluted with cold water. The precipitate was filtered off,
washed with water, and dried.
X-ray Diffraction Structural Analysis. Monoclinic crystals of acid 6f obtained by recrystallization
from ethanol were studied at 20°C. The unit cell parameters are a = 5.2967(5), b = 12.564(1), c = 11.272(1) Å,
 = 92.806(8)°, V = 749.2(1) Å3, Mr = 308.33, Z = 2, space group P21, dcalc = 1.367 g/cm3, (MoK) = 0.094
mm-1, F(000) = 324. The unit cell parameters and intensities of 8525 reflections (4057 independent reflections,
Rint = 0.026) were measured on an Xcalibur-3 diffractometer using MoK radiation, CCD detector, graphite
monochromator, -scanning, 2max = 60°.
The structure was solved by the direct method using the SHELXTL program package [16]. The hydrogen
atoms were revealed from the electron density difference map and refined isotropically. The structure was
refined anisotropically by the full-matrix method of least squares relative to F2 for the non-hydrogen atoms
1378

to wR2 = 0.042 for 4001 reflections (R1 = 0.028 for 2013 reflections with F > 4(F), S = 0.716). The complete
crystallographic data set has been deposited in the Cambridge Crystallographic Data Center (CCDC 756717).
The interatomic distances and valence angles are given in Tables 3 and 4, respectively.
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