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StructureActivity Investigations of 5-Substituted 3-Methylisoxazole[5 4-d]1 2 3-triazin-4-one Derivatives.

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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
Aneta Jezierskaa,
Marcin Ma̧czyńskib,
Aleksander Kolla,
Stanisław Ryngb
3-Methylisoxazole[5,4-d]1,2,3-triazin-4-one Derivatives 81
Structure/Activity Investigations of 5-Substituted
3-Methylisoxazole[5,4-d]1,2,3-triazin-4-one
Derivatives
a
University of Wrocław,
Faculty of Chemistry,
14 F. Joliot-Curie,
50-383 Wrocław, Poland
b
Wroclaw Medical University,
Faculty of Pharmacy,
Department of Organic
Chemistry, 9 Grodzka,
50-137 Wroc{al}aw, Poland
The series of 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives was obtained by diazotization of 5-amino-3-methylisoxazol-4-carboxylic
acid hydrazide. The immunological activity of these compounds was investigated experimentally in several in vitro and in vivo assays in mice and human
models. In the next step, quantum-chemical investigations were performed using
density functional theory with the B3LYP hybrid exchange-correlation energy
functional and 6-31G(d,p) basis set. The Polarizable Continuum (SCRF/PCM)
solvent model was also taken into account in order to show solvent influence
on electron density and electrostatic potential around the exemplary molecules.
Correlations between molecular structure and biological properties were found
using a stepwise selection of scales for the multiple linear regression (MLR).
Keywords: 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one; Immunological activity; DFT; SCRF/PCM; Molecular properties
Received: January 6, 2003; Accepted: March 19, 2003 [FP757]
DOI 10.1002/ardp.200300757
Introduction
The isoxazole derivatives are interesting objects for
synthesis in the search for various sorts of biological
activity and in quantum-chemical investigations. A few
of them have found practical application as drugs in
therapy [1] or have been investigated as potential
drugs in clinical trials [2]. They are, for instance, inhibitors of Xa Factor [3], multidrug resistance protein
(MRP1) [4], and estrogen synthase [5]. They also act
as muscarinic agonists [6]. Their anticonvulsant [7],
anti-inflammatory [8], antifungal [9], and immunological [10⫺13] activity is well known in professional literature. They have also found their place in combinatorial synthesis as antithrombotic agents [14]. Our research group is also searching for new isoxazole derivatives exhibiting immunological activity. A series of
these derivatives was synthesized in our laboratory
and their structures are presented in Table 1. A detailed description of the synthesis is presented below.
Their immunological activity was investigated experimentally in several in vitro and in vivo assays in mice
and human models. The immunological tests applied
were the humoral (plaque-forming cells ⫺ PFC) and
cellular (delayed type hypersensitivity ⫺ DTH) immune
responses in vivo to sheep red blood cells (SRBC) in
mice and two in vitro assays measuring mitogenCorrespondence: Stanisław Ryng, Faculty of Pharmacy,
Department of Organic Chemistry, Wroclaw Medical University, 9 Grodzka, 50-137 Wrocław, Poland. Phone: +48 71 78403-48, Fax: +48 71 784-03-41, e-mail: saryng@bf.uni.wroc.pl
induced lymphocyte proliferation in mice and antibody
production in humans. Generally, our compounds exhibit inhibitory properties. A detailed description of the
number of plaque-forming cells (PFC) and delayed
type hypersensitivity (DTH) reaction assays has already been published with experimental data [15]. The
assay results of CBA mice splenocytes and polyclonal
antibody production by human peripheral blood
mononuclear cells are available on request. The second part of this paper contains a theoretical study of
these molecules. Density functional theory (DFT) [16,
17] with the B3LYP hybrid exchange correlation energy functional and 6-31G(d,p) basis set [18-20] were
used for geometry optimization. Single-point calculations with the solvent reaction field (SCRF/PCM)
model [21⫺23] and water (ε = 78.39) as the solvent
were performed to show solvent influence on electron
density and electrostatic potential [24]. Maps of these
properties and their analysis are presented in the “Results and discussion”-section. The second part of the
theoretical analysis contains the QSAR models obtained for the investigated compounds. A stepwise
selection of scales for the multiple linear regression
(MLR) was used to determine correlations between
biological activity and molecular structure. Some interesting structure/activity relationships were found and
are described in detail in the study. In accordance with
the equations obtained, new compounds were predicted and their biological activities were calculated,
as well.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
82 Jezierska et al.
Table 1. The structures of 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives and their
spectroscopic data.
The core part of the molecules
CH550 IR (nujol) cm⫺1: 1657 C=O,
1554 C=N; 1H NMR (DMSO-d6)
ppm: 2.40 (s, 3H, CH3); 7.60 (m,
5H, phenyl); 8.0 (s, 1 H, CH)
CH551 IR (nujol) cm⫺1: 1660 C=O,
1538 C=N; 1H NMR (DMSO-d6)
ppm 2.42 (s, 3 H, CH3); 7.40 (q,
4 H, aromatic); 7.50 (s, 1 H, CH)
CH552 IR (nujol) cm⫺1: 1656 C=O,
1532 C=N; 1H NMR (DMSO-d6)
ppm: 2.46 (s, 3 H, CH3); 7.67 (m,
4 H, aromatic); 7.85 (s, 1 H, CH)
CH553 IR (nujol) cm⫺1: 1667 C=O,
1532 C=N; 1H NMR (DMSO-d6)
ppm: 2.40 (s, 3 H, CH3); 7.60 (s,
4 H, aromatic); 7.80 (s, 1 H, CH);
10.9 (s, 1 H, OH)
CH554 IR (nujol) cm⫺1: 1658 C=O,
1532 C=N; 1H NMR (DMSO-d6)
ppm: 2.20 (s, 3 H, CH3); 2.39 (s,
3 H, CH3); 7.50 (m, 4 H, aromatic);
7.70 (s, 1 H, CH)
CH555 IR (nujol) cm⫺1: 1668 C=O,
1542 C=N; 1H NMR (DMSO-d6)
ppm: 2.30 (s, 3 H, CH3); 7.65 (m,
4 H, aromatic); 7.71 (s, 1 H, CH)
CH556 IR (nujol) cm⫺1: 1657 C=O,
1538 C=N; 1H NMR (DMSO-d6)
ppm: 2.28 (s, 3 H, CH3); 7.50 (q,
4 H, aromatic); 7.71 (s, 1 H, CH)
CH557 IR (nujol) cm⫺1: 1635 C=O,
1530 C=N; 1H NMR (DMSO-d6)
ppm: 2.15 (s, 3 H, CH3); 2.37 (s,
3 H, CH3); 7.43 (s, 5 H, aromatic)
CH558 IR (nujol) cm⫺1: 1635 C=O,
1542 C=N; 1H NMR (DMSO-d6)
ppm: 1.57 (m, 8 H, cyclohexyl);
2.35 (s, 3 H, CH3); 3.28(s, 2 H,
cyclohexyl); 4.30 (s, 1 H, NH)
CH559 IR (nujol) cm⫺1: 1635 C=O,
1542 C=N; 1H NMR (DMSO-d6)
ppm: 2.20 (s, 3 H, CH3); 2.50 (s,
3 H, CH3)
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
Chemistry
The method of the synthesis of the 5-substituted 3methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives
has already been presented in our previous publication [15]. These compounds were proposed by
Ryng, who has been working on isoxazole moiety for
several years [25⫺27]. The synthesis of 5-amino-3methyl-4-isoxazolecarboxylic acid hydrazide was accomplished according to a procedure described previously [26]. In the reaction of 5-amino-3-methyl-4isoxazolecarboxylic acid hydrazide with the carbonyl
compounds, a first intermediate was obtained and,
subsequently, the second heterocyclic ring was
formed as a result of the diazotization of the amino
group and, finally, cyclization to the expected 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives.
Theoretical study
Computational methodology
Quantum-chemical calculations were carried out for
the investigated compounds. The scheme of the calculations is as follows. Density functional theory (DFT)
[16, 17] and the three-parameter hybrid functional
(B3LYP) with the standard 6-31G(d,p) basis set were
used for full geometry optimization in gas-phase
[18⫺20]. Additionally, single-point calculations with the
polarizable continuum (SCRF/PCM) model [21⫺23]
and water (e = 78.39) as the solvent were performed
in order to describe the environmental influence on the
properties of the molecules. Electron densities and
electrostatic potentials around the compounds were
also generated using the DFT method. The calculations were carried out with the Gaussian98 series of
programs [30]. The second part of the theoretical
study contains the QSAR study. The determination of
the molecular descriptors and the statistical analysis
were performed using the Molecular Descriptors
QSAR/QSPR program [31]. This package enables the
calculation of various types of physicochemical parameters. Constitutional, topological, topographical, and
geometrical descriptors (70 independent variables)
were calculated and used in our study [32, 33]. In order to find correlations between molecular structure
and immunological activity, a stepwise selection of
scales for the MLR was used. Correlations with experimental biological activity were, however, described by
only a few of the calculated descriptors. The names of
the descriptors were coded as capital letters in alphabetical order. This coding was also used in the equations and is presented below:
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
B
C
D
E
F
G
H
I
J
K
L
M
N
=
=
=
=
=
=
=
=
=
=
=
=
=
logarithmic value of biological activity
relative number of H atoms
number of rings
structural information content (order 1)
information content (order 0)
moment of inertia A
complementary information content (order 1)
molecular surface area
number of single bonds
relative number of single bonds
number of H atoms
Kier & Hall index (order 2)
number of double bonds
3-Methylisoxazole[5,4-d]1,2,3-triazin-4-one Derivatives 83
Separate equations were proposed for each immunological assay and dose. This was necessary because
experiment indicates that dosage and type of immunological assay have a very strong influence on activity.
The equations found are presented in the “Results and
discussion”-section. The correlation coefficient (R2),
Fisher criterion (F) and standard error (s2) give information about the quality of the results.
Results and discussion
The synthesis of the series of 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives are pre-
Figure 1. Differential map of the electron density around CH550 generated using the DFT B3LYP/6-31G(d,p)
method. Dark grey regions (⫺0.002 a.u.) represent an increase in the electron density upon solvent influence
and light grey (0.003 a.u.) a decrease in the electron density upon solvent treatment.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
84 Jezierska et al.
sented. They are very promising as potential drugs because of their immunological properties, confirmed experimentally. DFT calculations were performed to optimize the geometry and describe the most sensitive
places in ligand/receptor interactions. Water as a solvent was taken into account in order to reproduce an
environment similar to a biological one. Changes in
electron density upon solvent influence were studied
and are presented in Figure 1 as differential maps for
the exemplary compounds with different substituents
of the core part. The dark grey regions represent an
increase, and light grey a decrease in electron density
upon solvent treatment. The electron density is increased around atoms with lone electron pairs. We la-
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
bel these areas as potential proton acceptors for receptor interactions. The SCRF/PCM maps of electrostatic potential are presented in Figure 2. The dark
grey regions represent an increase of negative, and
light grey of positive electrostatic potential upon
SCRF/PCM treatment. A very strong solvent influence
is visible in the isoxazole ring and between the carbonyl oxygen and bridging nitrogen atoms. These
atoms are suggested as being very important in the
interaction with the electrophilic part of the receptor
because of their lone electron pairs. This is consistent
with our expectations, based on the well-known pharmacophore properties of the isoxazole derivatives,
which play a key role in ligand/receptor interactions.
Figure 2. SCRF/PCM maps of electrostatic potential around the molecules: dark grey isosurface at -0.04 a.u.,
light grey at +0.5 a.u.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
3-Methylisoxazole[5,4-d]1,2,3-triazin-4-one Derivatives 85
Table 2. Comparison between experimental and predicted immunological activity for DTH reaction (foot
pad test) in CBA/Iiw mice sensitized with SRBC and
treated (i.p.) with the preparation 2 h before administration of an inductive dose of the antigen.
Compound
CH550
CH551
CH552
CH553
CH554
CH555
CH556
CH557
CH558
CH559
Dose
Experimental Predicted
(µg/mouse) activity (Units) activity
[15]
100
100
100
100
100
100
100
100
100
100
0.98
0.97
0.86
0.83
0.77
0.82
0.95
0.85
0.86
0.72
0.98
0.98
0.84
0.84
0.77
0.86
0.91
0.84
0.87
0.72
Table 4. CBA splenocyte assay.
Compound
Dose
(µg/mL)
Experimental
activity (X)
Predicted
activity
CH550
CH551
CH552
CH553
CH554
CH555
CH556
CH557
CH558
CH559
5
5
5
5
5
5
5
5
5
5
⫺0.24
⫺0.006
⫺0.25
⫺0.21
⫺0.26
⫺0.23
⫺0.17 (NS)
⫺0.29
⫺0.25
⫺0.25
⫺0.23
⫺0.03
⫺0.25
⫺0.19
⫺0.25
⫺0.21
⫺
⫺0.33
⫺0.24
⫺0.26
An experimental value of CH556 was not statistically
significant (NS). An experimental procedure description is available on request. The experimental and predicted data are presented as logarithmic values.
An experimental procedure description is available on
request. The experimental and predicted data are presented as logarithmic values.
Table 3. Comparison between experimental and predicted immunological activity for the number of the
plaque-forming cells (PFC) in the spleens of CBA/Iiw
mice immunized with SRBC and treated (i.p.) with
the preparation.
Compound
Dose
µg/mouse
Experimental
activity
(PFC/106) [15]
Predicted
activity
CH550
CH551
CH552
CH553
CH554
CH555
CH556
CH557
CH558
CH559
10
10
10
10
10
10
10
10
10
10
3.29 (NS)
3.21
3.28 (NS)
3.23
3.26
3.21
3.20
3.14
2.96
3.16
⫺
3.20
⫺
3.24
3.25
3.20
3.21
3.14
2.96
3.16
Table 5. Polyclonal antibody production by human
peripheral blood mononuclear cells.
Compound
Dose
(µg/mL)
Experimental
activity
(PFC/106)
Predicted
activity
CH550
CH551
CH552
CH553
CH554
CH555
CH556
CH557
CH558
CH559
5
5
5
5
5
5
5
5
5
5
3.45
3.54 (NS)
3.39 (NS)
3.21
3.05
3.61 (NS)
3.45
3.03
3.39
2.81
3.45
⫺
⫺
3.19
3.05
⫺
3.45
3.04
3.39
2.81
The experimental values of CH551, CH552 and
CH555 were not statistically significant (NS). An experimental procedure description is available on request. The experimental and predicted data are presented as logarithmic values.
The experimental values of CH550 and CH552 were
not statistically significant (NS). An experimental procedure description is available on request. The experimental and predicted data are presented as logarithmic values.
Summarizing, the DFT study of electron densities and
electrostatic potentials of the exemplary compounds
indicated the most important sites in drug/receptor interactions for the series of compounds studied.
In the next step, correlations between immunological
activity and molecular structure were found for each
assay and dose separately. This was necessary be-
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
86 Jezierska et al.
cause biological activity was measured in several in
vitro and in vivo assays for different doses. Several
types of physicochemical properties were calculated
for all the studied compounds. The results of the
QSAR investigations are presented in Tables 2, 3, 4,
and 5. The best equations, obtained after statistical
analysis describing the relationship between molecular properties and biological activity, are presented below.
For the assay describing DTH reaction (foot pad test)
in CBA/Iiw mice sensitized with SRBC and treated i.p.
with the preparation 2 h before administration of an
inductive dose of the antigen and a dose of 100
µ/mouse, the equation found was:
B = 0.891(0.204)⫺2.300(0.474)*C+0.470(0.066)
*D-0.081(0.017)*E+0.012(0.005)*F
+9.563(2.678)*G
R2 = 0.94 F = 12.436 s2 = 0.001
The number of plaque-forming cells (PFC) in the
spleens of CBA/Iiw mice immunized with SRBC and
treated i.p. with the preparation was the next immunological assay. For a dose of 10 µg/mouse the equation
found was:
B = 2.280(0.142)⫺0.012(0.001)*H+0.003(0.0003)
*I+2.295(0.342)*C⫺0.121(0.045)*D
R2 = 0.99 F = 82.408 s2 = 0.0002
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
Table 6. The structures of predicted compounds.
Compound
CH660
CH661
CH662
CH663
CH664
The equation for CBA splenocytes assay and a dose
of 5 µg/ml was:
B = ⫺1.053(0.171)⫺0.053(0.009)*L+14.492(2.602)*G
+0.278(0.043)*M⫺0.026(0.006)*N
R2 = 0.93 F = 13.055 s2 = 0.001
The last biological assay was polyclonal antibody production by human peripheral blood mononuclear cells
with a dose of 5 µg/ml.
CH665
CH666
B = ⫺5.688(0.396)+0.274(0.011)*J+0.056(0.002)
*I⫺0.38<PS>8(0.013)*F+20.165(0.850)*K
R2 = 0.99 F = 309.556 s2 = 0.0003
The correlations were described by constitutional,
topological, and geometrical descriptors. Topographical (mixed descriptors) variables did not correlate with
immunological activity. Constitutional descriptors describe only the composition of the molecule [32]. They
were very useful during our investigations and six of
them found application in our QSAR equations. The
topological indices are closely related to structure and
describe the two-dimensional (2D) projection of the
molecule [34]. Our compounds are similar to each
other (see Table 1). They contain the same core part
(two connected rings), but with different substituents.
A few of them are substituted by a phenyl ring, but one
CH667
CH668
CH669
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
The structures of predicted
compounds
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
3-Methylisoxazole[5,4-d]1,2,3-triazin-4-one Derivatives 87
Table 7. Predicted immunological activity of proposed compounds according to the obtained models.
Compound
CH660
CH661
CH662
CH663
CH664
CH665
CH666
CH667
CH668
CH669
Predicted biological activity
Biological assays
DTH biological assay;
dose 100 µg/mouse
(Unit)
PFC/106 biological
assay; dose
10 µg/mouse (PFC/106)
CBA splenocytes; dose
5 µg/ml (X)
Polyclonal antibody
production; dose
5 µg/ml (PFC/106)
0.47
0.70
0.90
0.70
0.84
0.80
0.41
0.61
0.78
0.75
3.12
3.22
3.11
3.20
3.17
3.16
3.22
3.22
3.14
3.15
⫺0.61
⫺0.30
⫺0.29
⫺0.28
⫺0.26
⫺0.05
⫺0.31
⫺0.31
⫺0.03
⫺0.15
1.15
2.47
1.19
2.18
1.62
2.21
2.80
1.70
7.21
1.25
The predicted data is presented as logarithmic values.
Table 8. Physical data of the 5-substituted 3-methylisoxazole[5,4-d]1,2,3-triazin-4-one derivatives.
Compound
Melting point
(°C)
Yield
(%)
Formula
Molecular weight
g/mol
CH550
CH551
CH552
CH553
CH554
CH555
CH556
CH557
CH558
CH559
142⫺143
121⫺123
140⫺141
132⫺133
143⫺144
104⫺105
106⫺108
144⫺145
143⫺144
135⫺136
22.9
58.4
14.6
65.2
14.6
58.8
44.1
29
21.6
5.6
C12H9N5O2
C12H8N5O2Cl
C12H8N5O2Cl
C12H9N5O3
C13H11N5O3
C12H8N6O4
C12H8N6O4
C13H11N5O2
C11H13N5O2
C 7H7N5O2
255
289.5
289.5
271
285
300
300
269
247
193
of the phenyl protons has been changed into atoms
or groups. The general topology of the compounds is
similar, but different substituents have an influence on
biological activity. The geometrical descriptors are also
related to immunological activity. Moment of inertia
and molecular surface area are connected to the 3Dcoordinates of the atoms in the molecule. Constitutional descriptors (C, D) described correlations in
both in vivo assays. Moment of inertia A also seems
to be important both in in vitro and in vivo activity. The
descriptor characterizes the mass distribution and the
susceptibility of the molecule to different rotational
transitions [32]. Our molecules are quite rigid (two connected rings), but substituents can rotate. It is quite
difficult to estimate the global minimum for flexible
compounds because of the several degrees of freedom. After the geometry optimization, harmonic frequencies were also calculated in order to confirm that
the found geometry corresponded to the minimum on
the potential energy surface (PES). Subsequently, the
predictions of new compounds and their immunological properties were performed according to the obtained QSAR equations. Ten proposed structures are
presented in Table 6 and their predicted immunological activities are presented in Table 7. The predicted
compounds will be synthesized in the near future and
their biological activity will be investigated for only a
few of them in order to confirm the quality of the pre-
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
88 Jezierska et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 81−89
[6] S. M. Lenz, E. Meier, H. Pedersen, K. Frederiksen, K. P.
BgesH, P. Krogsgaard-Larsen, Eur. J. Med. Chem.
1995, 30, 263⫺270.
diction. Generally, the new isoxazole derivatives seem
to be very promising as drugs in immunological therapy.
[7] N. D. Eddington, D. S. Cox, R. R. Roberts, R. J. Butcher,
I. O. Edafiogho, J. P. Stables, N. Cooke, A. M. Goodwin,
C. A. Smith, K. R. Scott, Eur. J. Med. Chem. 2002, 37,
635⫺648.
Acknowledgments
The project was financially supported by the Community of the University of Medicine (grant GR-433).
The WROCŁAW SUPERCOMPUTER CENTER
(WCSS) and the Academic Computer Center
CYFRONET-KRAKÓW (Grant KBN/SGI/UWrocl/078/
2001) are gratefully acknowledged for providing computer time and facilities.
Experimental
Melting points were determined on a Buchi apparatus (Laboratoriums-Technik AG, Flawil, Switzerland) and are uncorrected. TLC (thin layer chromatography) was carried out on
Kieselgel G-Merck glass silica gel plates (E. Merck, Darmstadt, Germany) using the developing system CHCl3 ⫺
CH3OH = 9:1, detected with J2 fog. IR spectra were recorded
with a Specord M-80 spectrophotometer (Carl Zeiss, Jena,
Germany) in Nujol mull supported on a KBr disk and H1NMR
spectra were obtained in DMSO-d6 using a Tesla 80 MHz
spectrometer (using TMS as the internal standard). The spectroscopic data are presented in Table 1. Elemental analyses
(C, H, N) were performed within ± 0.3 % of the theoretical
values (Carlo Erba NA, 1500 ⫺ equipement). The physical
constants are summarized and presented in Table 8. To 3.2
mmol of 5-amino-3-methylisoxazole-4-carboxylic acid hydrazide [28, 29] dissolved in 10 ml of isopropanol, 4.8 mmol of
aldehyde or ketone was added. The solution was stirred and
heated for 2 h. At the end of reaction (controlled in a TLC),
the solution was cooled. The solid which separated out was
filtered and recrystallized from methanol. To 5 mmol of the
obtained product, 5 ml of conc. HCl was added, the solution
was cooled to 5 °C, and 13.7 mmol of NaNO2 dissolved in 10
ml of water was added drop wise to the reaction mixture. The
solution was stirred and cooled for 0.5 h. After reaction, the
crude products were collected and recrystallized from ethanol.
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