1,5-diphenyl-1h-1,2,4-triazol-3-yl

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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 63 No. 4 pp. 255ñ259, 2006
ISSN 0001-6837
Polish Pharmaceutical Society
SYNTHESIS OF NEW 1-(AMINO)-3-[(1,5-DIPHENYL-1H-1,2,4-TRIAZOL-3-YL)
OXY] PROPAN-2-OL AND 1-[(1,5-DIPHENYL-1H-1,2,4-TRIAZOL-3-YL)
OXY]-3-(4-ARYLPIPERAZIN-1-YL) PROPAN-2-OL DERIVATIVES
WITH AN EXPECTED β-ADRENOLYTIC ACTIVITY
JERZY KOSSAKOWSKIa, MARTA STRUGAa and ANNA E. KOZIO£b
a
The Medical University, Department of Medical Chemistry, 3 Oczki Str., 02-007 Warsaw
b
Faculty of Chemistry, Maria Curie-Sk≥odowska University, 20-031 Lublin, Poland
Abstract: 3-(Oxiran-2-ylmethoxy)-1,5-diphenyl-1H-1,2,4-triazole [I] was obtained in the reaction of 1,5-diphenyl-1H-1,2,4-triazol-3-ol with 2-(chloromethyl) oxirane. Then I was converted into the corresponding aminoalkanol derivatives of 1,5-diphenyl-1H-1,2,4-triazol-3-ol, IIa,b ñVIIa,b. Molecular structure of I was confirmed by an X- ray structure analysis. The receptor affinities for IVa, VIIa were determined.
Keywords: 1,5-diphenyl-1H-1,2,4-triazol-3-ol, substitution reaction, X-ray structure analysis, β-adrenoceptor,
[H3] CGP 12177 binding
Derivatives of 1H-1,2,4-triazole are reported to
show a broad spectrum of biological activities such
as antifungal, antimicrobial, hypoglycemic, antihypertensive, analgesic, antiparasitic, hypocholesteremic, antiviral, anti-inflammatory, antitumor and anti-HIV properties (1-18). Compounds from this
group are also used as herbicides (19, 20) and fungicides (21, 22). These observations prompted us to
synthesize some new 1,2,4-triazol-3-one derivatives
with potential biological activity.
This paper presents the preparation of a number of new derivatives of 1,5-diphenyl-1H-1,2,4triazol-3-ol with an expected β-adrenolytic activity.
1,5-Diphenyl-1H-1,2,4-triazol-3-ol derivatives
can exist in two tautomeric forms:
ves with soothing effect on the central nervous system (24, 25). This paper is a continuation of investigations on nucleophilic substitution of pharmacophoric group into the 3H-1,2,4-triazol-3-one system.
The 3-amino-2-hydroxypropyl group is characteristic for compounds possessing analgesic (28, 29),
hypotensive and antiarrhytmic (30, 31) activities.
1,5-Diphenyl-1H-1,2,4-triazol-3-ol was obtained in the reaction of phenyl hydrazine and benzoyl
isocyanate (32). The reaction of 1,5-diphenyl-1H-1,2,4-triazol-3-ol with 2-(chloromethyl) oxirane in
the presence of anhydrous K2CO3 was carried out at
room temperature.
In the IR spectrum of compound I, the characteristic absorption band at 1700-1715 cm-1 for the
C=O group, indicating the 1,5-diphenyl-1H-1,2,4triazol-3-ol form, was not observed. The molecular
structure of this compound was confirmed by an X-ray analysis (Figure 1).
Then compound I was converted with appropriate amines into corresponding aminoalkanol derivatives of 1,5-diphenyl-1H-1,2,4-triazol-3-ol IIa, b
ñVIIa, b (Figure 2). The reactions were performed
by heating the reactants in methanol in the presence
of small quantities of water.
The structure of all new compounds was confirmed by elemental analysis as well as by the 1H
NMR spectra.
Radioligand binding studies were carried out
for compounds (IVa and VIIa) in the Department of
Cytobiology and Histochemistry, Collegium Medicum, Jagiellonian University. The binding data of
the compounds are presented in Table 1. The tested
In earlier papers, studying properties of these
derivatives, some nucleophilic substitution reactions
were carried out to obtain O- or N- derivatives (23 ñ
27).
In the case of 4-phenyl-4,5-dihydro-1H-1,2,4triazol-3-one and 4,5-diphenyl-4,5-dihydro-3H-1,2,4-triazol-3-one in the nucleophilic substitution
reaction a lot of new compounds with potential
pharmacological action were obtained, e.g. N-aminomethyl derivatives and N-aminoalkanol derivati-
255
256
JERZY KOSSAKOWSKI et al.
compound IVa showed a low affinity for β-adrenoceptor (Ki 9.2 ± 0.7 µM), whereas compound VIIa
exibited no receptor affinity (Ki > 100).
EXPERIMENTAL
Chemistry
Melting points were determined in a capillary Koflerís apparatus and are uncorrected. The 1H
NMR spectra were recorded on a Bruker DMX400
spectrometer, operating at 400.13 MHz for 1H or
on a Varian UNITYplus-200 spectrometer, operating at 199.97 MHz for 1H. The chemical shift values, expressed in ppm, were references downfield
to TMS at ambient temperature. The IR spectra
were recorded in KBr on a Perkin Elmer FT
1725X spectrophotometer. All values of microanalyses were within ± 0.4% of the calculated
compositions. Column flash chromatography and
TLC were performed on silica gel 60 (Merck)
using chloroform or chloroform/methanol (19:1,
v/v) mixture as eluent.
Figure 2. Method of preparing the reported compounds.
Figure 1. Perspective drawing of the molecule I. Second position
of the disordered epoxide group is marked by open line. Bond distances within the heterocyclic ring system are: N1ñN2 1.372 (3);
N2ñC3 1.315 (3); C3ñN4 1.341 (4); N4ñC5 1.334 (3); C5ñN1
1.348 (3) and C3ñO3 1.337 (3) Å.
Synthesis of new 1-(amino)-3-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl)oxy]propan-2-ol...
Diffraction data for I were measured at 295 K
on a KM4 diffractometer using variable scan speed
in the ω-2θ scan mode and graphite monochromated
CuKα radiation (λ = 1.54178 Å).
5-(Oxiran-2-ylmethoxy)-2,3-diphenyl-1H-1,2,4triazole [I]
A mixture of 2,3-diphenyl-1H-1,2,4-triazol-5ol (0.015 mol), 2-(chloromethyl) oxirane (40 cm3)
and anhydrous K2CO3 (4.5 g, 0.033 mol) was left at
room temperature for 48 h. The inorganic precipitate was filtered off, the solvent was evaporated. The
oily residue was extracted several times with boiling
heptane. The crude product precipitated on cooling.
Then the mixture was filtered and purified by flash
chromatography (a developing system: chloroform).
m.p. 108 -110OC. 1H NMR (CDCl3) δ (ppm): 7.34 ñ
7.53 (m, 10H, arom.); 4.69 (d, 2H, CH2); 4.5 (d, 2H,
CH2); 2.70 ñ 2,91 (m, 1H, CH). IR (cm-1) KBr: 3063
(CH arom.); 2944, 1411, 777 (CH alif.); 1378, 1178,
864 (C-O-C); 1599 (C=N). For C17H15N3O2 (293.32)
calculated: 69.64% C, 5.11% H, 14.33% N; found:
70.0% C, 5.1% H, 14.5% N.
C17H15N3O2, FW = 293.32, monoclinic, space
group P21/n, a = 9.521 (2) Å, b = 8.408 (2) Å, c
=18.790 (3) Å, α = 90O, β =102.26 (3)O, γ = 90O, V =
1499.8 (5) Å3, Z = 4, F (000) = 616, dcalc = 1.326 g
cm-3, µ(CuKa) = 0.725 mm-1.
In the θ range 4.82 ñ75.16O, 3043 reflections
were collected. The structure was solved by direct
methods using SHELXS-93 program (34). Refinement was performed by the full-matrix least-squares method on F2 using 2978 unique reflections (Rint = 0.027) and SHELXL-97 program
(35). The Fourier maps indicated disorder of the
epoxide fragment over two positions. The refinement of the site occupancy factors of three atoms
(O2, C2 and C12) converged at 0.5. The non-hydrogen atoms were refined with anisotropic displacement parameters. The H-atom positions were
calculated from the geometry and were given isotropic factors of 1.2 Ueq of the bonded C-atoms;
the CñH bond Ñridingî model was used in the refinement. For 227 parameters refined, final discrepancy factors are R1 = 0.0451, wσ2 = 0.1316
for 1286 reflections with I > 2s (I), and R1 =
0.1228, wσ2 = 0.1702 for all data, S = 1.041. Residual peaks on final difference map were -0.15 to
0.17 e Å3.
Crystallographic data have been deposited with
the Cambridge Crystallographic Data Centre as
CCDC No. 602943. Copies of the data can be obtained on application to The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (Fax: +44-
257
1223-336-033; e-mail: [email protected] or
www: http://www.ccdc.cam.ac.uk).
General procedure of preparing 1-(amino)-5-[(2,3diphenyl-1H-1,2,4-triazol-5-yl) oxy] propan-2-ol
[IIa ñ VIIa] and 1-[(2,3-diphenyl-1H-1,2,4-triazol-5-yl) oxy]-5-(4-arylpiperazin-1-yl) propan-2-ol
[IIb ñ VIIb].
A mixture of the compound I (0.003 mol) and
the corresponding amine (0.015 mol), was refluxed
in a mixture of methanol and water (39:1 v/v)
(40 cm3). The reaction was monitored by TLC.
When the reaction was complete, the mixture was
filtered and the solvent evaporated. The residue was
crystallized from heptane [IIb ñ VIIb] or purified
by flash chromatography (developing system: chloroform/methanol 9:1, v/v) [IIa ñ VIIa].
[IIa] m.p. 139OC. 1H NMR (CDCl3) δ (ppm): 7.29 ñ
7.48 (m, 10H, arom.); 4.35 ñ 4.46 (qq, 2H, CH2-O);
4.09 ñ 4.1 (m, 1H, CH-O); 2.4 ñ 2.63 (m, 2H, CH2-N); 2.32 (s, 6H, CH3). For C19H22N4O2 (338.4) calculated: 67.44% C, 6.55% H, 16.56% N; found:
67.75% C, 6.48% H, 17.02% N.
[IIIa] m.p. 78OC. 1H NMR (CDCl3) δ (ppm): 7.29 ñ
7.48 (m, 10H, arom.); 4.4 (d, 2H, CH2, J=8 Hz);
4.07 (m, 1H, CH-O); 2,56-2.71 (m, 6H, CH2); 1.06
(t, 6H, CH3, J=7.2 Hz). For C21H26N4O (366.45) calculated: 68.83% C, 7.15% H, 15.29% N; found:
68.73% C, 7.2% H, 15.03% N.
[IVa] m.p. 161-2OC. 1H NMR (CDCl3) δ (ppm): 7.3
ñ 7.47 (m, 10H, arom.); 4.41 (d, 2H, CH2-O, J=5.2
Hz); 4.12 ñ 4.13 (m, 1H, CH-O); 2.78 ñ 2.94 (m, 2H,
CH2-N); 1.68 (s, 9H, CH3). For C21H26N4O (366.45)
68.88% C, 7.15% H, 15.28% N.
[Va] m.p. 127-8OC. 1H NMR (CDCl3) δ (ppm): 7.3 ñ
7.47 (m, 10H, arom); 4.36 ñ 4.43 (m, 2H, CH2); 4.07
ñ 4.12 (m, 1H, CH-O); 2.74 ñ 2.9 (m, 2H, CH-N);
1.07 (d, 6H, CH3, J=6.4 Hz). For C20H24N4O (352.4)
67.95% C, 6.91% H, 15.76% N.
[VIa] m.p. 123-4OC. 1H NMR (CDCl3) δ (ppm):
7.37 ñ 7.47 (m, 10H, arom.); 4.96 (s, 1H, OH); 3.99
ñ 4.16 (m, 2H, CH2); 4.49 ñ 4.36 (m, 2H, CH2);
2.28-2.46 (m, 6H, (CH2)2 piper., CH2); 1.23 ñ 1.57
(m, 6H (CH2)3 piper., CH2). For C22H26N4O (378.46)
70.06% C, 6.84% H, 14.71% N.
[VIIa] m.p. 99-100OC. 1H NMR (CDCl3) δ (ppm):
7.29 ñ 7.47 (m, 10H, arom.); 4.35 ñ 4.43 (dq, 2H,
CH2); 4.12 ñ 4.17 (m, 1H, CH-O); 3.6 (s, 1H, OH);
2.46 ñ 2.7 (m, 10H, CH2); 2.29 (s, 3H, CH3). For
C22H27N5O2 (393.51) calculated: 67.15% C, 6.91% H,
17.80% N; found: 67.12% C, 6.62% H, 17.62% N.
258
JERZY KOSSAKOWSKI et al.
[IIb] m.p. 181-2OC. 1H NMR (CDCl3) δ (ppm): 7.29
ñ 7.48 (m, 10H, arom.); 6.86 ñ 6.94 (m, 5H, arom.);
4.45 (s, 2H, CH2); 4.29 (s, 1H, CH-O); 3.28 (s, 4H,
CH2); 2.91 (s, 2H, CH2-N); 2.77 ñ 2.78 (m, 4H,
(CH2)2-N). For C27H29N5O (455.54) calculated:
71.18% C, 6.42% H, 15.38% N; found: 71.02% C,
6.31% H, 15.34% N.
[IIIb] m.p. 130OC. 1H NMR (CDCl3) δ (ppm): 7.26
ñ 7.48 (m, 10H, arom.); 6.86 ñ 6.96 (m, 4H, arom.);
4.38 ñ 4.49 (m, 2H, CH2); 4.18 ñ 4.22 (m, 1H, CH-O); 3.59 (s, 1H, OH); 3.14 (s, 4H, (CH2)2-N); 2.71
ñ 2.74 (m, 2H, CH2-N); 2.61 ñ 2.69 (m, 4H, (CH2)2N). For C27H28FN5O2 (473.54) calculated: 68.48%
C, 5.96% H, 14.79% N; found: 68.56% C, 5.82% H,
14.79% N.
[IVb] m.p. 170-1OC. 1H NMR (CDCl3) δ (ppm):
7.35 ñ 7.48 (m, 10H, arom.); 6.93 ñ 7.04 (m, 4H,
arom.); 4.4 (m, 2H, CH2); 4.19 ñ 4.2 (m, 1H, CH-O);
3.13 (s, 4H, (CH2)2-N); 2.85 ñ 2.86 (m, 2H, CH2-N);
2.62 ñ 2.69 (m, 4H, (CH2)2-N). For C27H28FN5O2
(473.54) calculated: 68.48% C, 5.95% H, 14.79% N;
found: 68.20% C, 5.88% H, 14.54% N.
[Vb] m.p. 127-8OC. 1H NMR (CDCl3) δ (ppm): 7.26
ñ 7.48 (m, 10H, arom.); 6.86 ñ 6.94 (m, 4H, arom.);
4.39 ñ 4.48 (m, 2H, CH2); 4.2 (s, 1H, CH-O); 3.87
(s, 3H, CH3-O); 3.12 (s, 4H, (CH2)2-N); 2.88 (s, 2H,
CH2-N); 2.7 (s, 4H, (CH2)2-N). For C28H31N5O3
(485.57) calculated: 69.25% C, 6.44% H, 14.42% N;
found: 69.28% C, 6.41% H, 14.39% N.
[VIb] m.p. 173-4OC. 1H NMR (CDCl3) δ (ppm):
8.17 (dd, 1H, Hα pyr., J1=0.5 Hz, J2=0.45 Hz); 7.47
(m, 1H, Hγ pyr.); 6.63 (m, 2H, Hβ pyr.); 4.52 ñ 4.36
(m, 2H, CH2); 4.26 ñ 4.15 (m, 1H, CH-O); 3.56 (t,
4H, (CH2)2-N, J=4.5 Hz); 2.83 ñ 2.56 (m, 6H,
(CH2)2-N, CH2). For C26H28N6O2 (456.52) calculated: 68.40% C, 6.17% H, 18.4% N; found: 68.39%
C, 5.97% H, 18.26% N.
[VIIb] m.p. 140OC. 1H NMR (CDCl3) δ (ppm): 7.267.47 (m, 15H, arom.); 4.35 ñ 4.45 (m, 2H, CH2);
4.13 ñ 4.15 (m, 1H, CH-O); 3.51 (s, 2H, CH2); 2.5 ñ
2.69 (m, 10H, (CH2)2-N, CH2). For C28H31N5O
(469.57) calculated: 71.61% C, 6.65% H, 14.92% N;
found: 71.87% C, 6.64% H, 14.76% N.
Radioligand binding assay
The experiment was carried out on the rat cerebral cortex. [3H] CGP-12177 (48 Ci/mmol) was
used. Tissue was homogenized in 20 volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.6), and centrifuged at 1000 × g for 10 min (0-4OC). The supernatant
was centrifuged at 20 000 × g for 20 min. The cell
pellet was resuspended in Tris-HCl buffer and centrifuged again. The final incubation mixture (final
volume 300 µL) consisted of 240 µL membrane su-
Table 1. The β-adrenoceptor affinities of the investigated
compounds.
Compound
IVa
VIIa
Propranolol
IC50 (µM)
20.5 ± 1.5
> 100
6.5 nM
KI (µM)
9.2 ± 0.7
> 100
3 nM
spension, 30 µL of [3H] CGP-12177 (0.2 nM) solution and 30 µL buffer containing from seven to eight
concentrations (10-11 ñ 10-4 M) of the investigated
compounds. For measuring unspecific binding, propranolol ñ 1 µM was applied. The incubation was
terminated by rapid filtration over glass fiber filters
(Whatman GF/C) using a vacuum manifold (Millipore). The filters were then washed 2 times with the
assay buffer and placed in scintillation vials with liquid scintillation cocktail. Radioactivity was measured in a WALLAC 1409 DSA ñ liquid scintillation
counter. All assays were done in duplicates. Radioligand binding data were analyzed using iterative
curve fitting routines (GraphPAD/Prism, Version
3.02 ñ San Diego, CA, USA). Ki values were calculated from the Cheng and Prusoff equation (33):
LO ñ labeled ligand concentration
KD ñ dissociation constant of labeled ligand
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Received: 5.05.2006

1,5-diphenyl-1h-1,2,4-triazol-3-yl

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