Synthesis of new imidazole derivatives

Article abstract of DOI:10.1002/jhet.5570450453

(Chemical Equation Presented) The derivatives of 1-propyl- and 1-butyl- of 2-methyl-5-nitroimidazole containing phenylpiperazine, m-chloro- and o-methoxyphenylpiperazine attached at the end of alkyl chain were synthesed. For the obtained new compounds, th

Full text of DOI:10.1002/jhet.5570450453

Jul-Aug 2008
1247
Synthesis of New Imidazole Derivatives
Krystyna Nowak and Barbara Szpakiewicz*
Cracow University of Technology, Institute of Organic Chemistry and Technology,
Warszawska 24 st., 31-155 Kraków, Poland, E-mail: kn@indy.chemia.pk.edu.pl
*E-mail: bszpak@indy.chemia.pk.edu.pl
Received November 23, 2007
Z
(CH2)n
N
N
N
(CH2)nX
N
Z
H N
N
O2N
CH3
O2N
CH3
N
N
DMF, K2CO, KI
n = 3,4
X = Cl, Br
Z = H, m-Cl, o-CH3
The derivatives of 1-propyl- and 1-butyl- of 2-methyl-5-nitroimidazole containing phenyl-
piperazine, m-chloro- and o-methoxyphenylpiperazine attached at the end of alkyl chain were
synthesed. For the obtained new compounds, the biological activity was predicted using the
computer program PASS.
J. Heterocyclic Chem., 45, 1247 (2008).
INTRODUCTION
activity [12], we have obtained the phenylpiperazinyl
derivatives 7-12 of 2-methyl-5-nitroimidazole (1), shown
in Scheme.
Nitro derivatives of imidazole exhibit broad pharma-
cological activity [1-5]. Their earliest recognized
biological activity was their antiprotozoal action [6].
Nitroimidazoles can act also as photosensitizes, which
makes them good candidates for antitumor treatment
[7-10]. Moreover, some imidazole derivatives belong to
the non-nucleoside reverse transcription inhibitors
(NNRIs). The following imidazole derivatives, including
some nitro-derivatives, have been evaluated as potential
drugs against HIV-1 virus [11]:
The compounds 7-12 were synthesized in two steps. In
the first step, 1-(3-chloropropyl)-2-methyl-5-nitro-imidazole
(2) and its 1-(4-bromobutyl)- analog (3) were obtained by
alkylation of the N1 nitrogen in 1 with 1-bromo-3-chloro-
propane and 1,4-dibromobutane, respectively. Next, the
compounds 2 and 3 were reacted with the phenylpiperazines
4-6. The reactions were carried out in dimethylformamide
(DMF), in the presence of anhydrous potassium carbonate,
at room temperature, for 30 h.
R5
Scheme
R4
O
R1
N
H
N
(CH2)nX
N
N
O2N
CH3
O2N
CH3
alkilation with
2 n = 3, X = Cl
3 n = 4, X = Br
R2
N
N
Cl (CH2)3Br or
Br(CH2)4Br
1
R3
N
kondensation with
Where: R1 = H, CH3; R2 = H, NO2, R3 = H, F, Cl, CH3, t-Bu;
4 - 6
R4 = R5 = H, Cl
(CH2)nR
N
Structure-activity relationships (SARs) suggest that the
introduction of nitro group and methyl group into the
imidazole ring renders its anti-HIV-1 activity, while the
presence of various substituents in the benzhydrol
fragment modulates effectiveness and cytotoxicity of the
drug. In general, the effect of electron-withdrawing
substituents on the anti-HIV-1 activity is stronger than the
effect of electron-donating ones.
O2N
CH3
N
Cl
R =
N
N
N
N
7 n = 3
8 n = 4
9 n = 3
10 n = 4
H3CO
N
RESULTS AND DISCUSSION
N
Upon continuation of our studies on the synthesis of
azaheterocyclic compounds with potential biological
11 n = 3
12 n = 4

1248
K. Nowak and B. Szpakiewicz
Vol 45
Structure of the phenylpiperazinyl derivatives 7-12 of
1500-1494 cm-1 (asymmetric stretching vibrations) and
1291-1293 cm-1 (the corresponding symmetric ones).
Moreover, in IR spectra of the compounds 11 and 12,
characteristic stretching vibrations of CR-O-CAr bonds
2-methyl-5-nitroimidazole (1) have been confirmed by 1H
nmr, ir and ms spectral methods, and elemental analysis
(Table 1 and 2).
Table 1
Characterization Data of Compounds 7-12
Melting point
(oC)
Yield
(%)
Molecular
Formula
MW
Ms
m/z
Analysis
Calcd./ Found
H
Compound
(M+. %)
C
N
7
8
133 – 135
isopropyl alcohol
60
62
41
41
64
42
C17H23N5O2
C18H25N5O2
329.40
343.43
363.84
377.87
359.43
391.47
329 (30)
343 (47)
-
61.99 7.04
61.72 7.12
21.26
21.21
88 – 90
cyclohexane
62.95 7.34
62.74 7.40
20.39
20.20
9
136 – 137
isopropyl alcohol
C17H22N5O2Cl
C18H24N5O2Cl
C18H25N5O3
56.12 6.09
55.93 6.17
19.25
19.03
10
11
12
89 – 90
isopropyl alcohol
-
57.21 6.40
56.88 6.52
18.53
18.50
101 – 103
cyclohexane
359 (66)
373 (11)
60.15 7.01
59.91 6.98
19.48
19.31
88 – 91
methyl alcohol
C19H27N5O3
x H2O
58.30 7.47
58.29 7.52
17.89
17.86
Mass spectra of the compounds 7, 8, 11 and 12 show
well-defined signals of parent molecular ions, which
decompose by subsequent detachment of the fragments
with molecular weights of 17 (M+ꢀ-OH), 17 and 15 (M+ꢀ-
CH3). No fragment ions characteristic for decomposition
of typical nitro compounds (M+ꢀ-NO or M+ꢀ-NO2) and no
cleavage of HCN from the parent ions are observed in the
mass spectra.
In order to confirm the identity of the compounds 7-12
by infrared spectroscopy, several characteristic absorption
bands have been identified. Stretching vibrations of C-H
bonds in CH3 and CH2 groups occur at 2344-2937 cm-1
(asymmetric vibrations) and 2822-2821 cm-1 (symmetric
vibrations). For all of the compounds studied, asymmetric
scissors-type bending of the CH3 and CH2 groups show up
in the range 1471-1362 cm-1. Two strong bands
characteristic for NO2 group are observed at
appear at 1242-1239 cm-1 and 1027-1025 cm-1,
respectively. Additionally, in the spectrum of 12, a broad
absorption band within the range 3500-3260 cm-1
indicates that this compound formed a hydrate.
1
The H nmr spectra of compounds 7-12 revealed (from
high to low field) signals consistent with alkyl protons of
propyl and butyl chain and of the piperazine ring, the
signals of methyl groups of the imidazole ring (singlet),
additionally in case of 11 and 12 signals of methoxy
groups (singlet), and the signals of the aromatic protons of
phenyl and imidazole ring. The exact number of protons
was given by integration (see Table 2).
Finding a correlation between a compound structure
and its biological activity is very difficult, because of
complexity of biological systems. However, application
of special computer techniques makes some predictions
possible. Using PASS program [13], developed in the
Table 2
1H nmr spectra of compounds 7-12
ꢁ (ppm) in CDCl3
Comp.
7
2.03 (quintet, 2H, CH2CH2CH2), 2.37 (t, 2H, CH2N-piperazine), 2.47 (s, 3H, CH3), 4.09 (t, 2H, CH2N- imidazole), 2.60 and
3.22 (t, 4H and t, 4H, piperazine), 6.78-7.03 (m, 3H, Ph 2,4,6-H), 7.31 (t, 2H, Ph 3,5-H) 7.73 (s, 1H, imidazole)
1.38-2.00 (m, 4H, CH2CH2CH2CH2), 2.37- (2H, CH2N-piperazine signal overlap), 2.45 (s, 3H, CH3), 2.62 and 3.22 (t, 4H and t,
4H, piperazine), 4.00 (t, 2H, CH2N-imidazole), 6.78-7.03 (m, 3H, Ph 2,4,6-H), 7.31 (t, 2H, Ph 3,5-H), 7.71 (s, 1H, imidazole)
2.03 (quintet, 2H, CH2CH2CH2), 2.38 (t, 2H, CH2N-piperazine), 2.47 (s, 3H, CH3), 2.56 and 3.27 (t, 4H and t, 4H, piperazine),
4.05 (t, 2H, CH2N-imidazole), 6.67-6.92 (m, 3H, Ph 2,4,6-H), 7.17 (t, 1H, Ph 5-H), 7.73 (s, 1H, imidazole)
8
9
10
11
12
1.42- 2.08 (m, 4H, CH2CH2CH2CH2), 2.36- (2H, CH2N-piperazine signal overlap), 2.45 (s, 3H, CH3) 2.57 and 3.20 (t, 4H and t,
4H, piperazine), 3.96 (t, 2H, CH2N-imidazole), 6.69-6.90 (m, 3H, 2,4,6-H Ph), 7.17 (t, 1H, 5-H Ph), 7.71 (s, 1H, imidazole)
2.02 (quintet, 2H, CH2CH2CH2), 2.38 (t, 2H, CH2N- piperazine), 2.48 (s, 3H, CH3), 2.65 and 3.16 (t, 4H and t, 4H, piperazine),
3.87 (s, 3H, OCH3), 4.06 (t, 2H, CH2N-imidazole), 6.94 (pseudo s, 4H, Ph), 7.74 (s, 1H, imidazole)
1.47-2.00 (m, 4H, CH2CH2CH2CH2), 2.34 (t, 2H, CH2N-piperazine), 2.45 (s, 3H, CH3), 2.63 and 3.12 (t, 4H and t, 4H,
piperazine), 3.86 (s, 3H, OCH3), 3.96 (t, 2H, CH2N-imidazole), 7.02 (pseudo s, 4H, Ph), 7.71 (s, 1H, imidazole)

Jul-Aug 2008
Synthesis of New Imidazole Derivatives
1249
EXPERIMENTAL
nstitute of Biomedical Chemistry at Russian Academy of
Medical Sciences, we have determined probability of
pharmacological activity (Pa) and probability of the lack
of such activity (Pi) for the compounds 7-12. The
biological activities with highest probability of
appearance in the compounds studied are collected in
Table 3.
Melting points (uncorrected) were determined on a Boetius
1
melting point apparatus. The H nmr spectra were recorded on
Tesla BS-587A (80 MHz) spectrometer in CDCl3 solution, using
TMS as internal standard; the chemical shifts (ꢀ) are expressed
in parts per million (ppm). The infrared spectra were recorded
on Bio-Rad FTS-175C spectrometer (in potassium bromide
Table 3
Probabilities of biological activity (Pa) of the compounds 7-12
Activity Type
Compound
7
8
9
10
11
12
Antiprotozoal
0.880
0.879
0.857
0.826
0.799
0.703
0.687
0.689
0.588
0.619
0.873
0.880
0.857
0.831
0.809
0.703
0.696
0.694
0.651
0.527
0.846
0.868
0.807
0.803
0.703
0.676
0.634
0.648
0.572
0.623
0.839
0.868
0.807
0.808
0.709
0.676
0.657
0.643
0.633
0.549
0.831
0.835
0.755
0.777
0.672
0.665
0.629
0.654
0.721
0.711
0.802
0.836
0.755
0.783
0.678
0.665
0.638
0.662
0.752
0.643
Convulsant
Dopaminne D4 agonist
Antialcoholic
Antiprotozoal (Trichomonas)
Antiprotozoal (Amoeba)
Oxidizing agent
Radiosensitizer
Cardioprotectant
Urologic disorders treatment
pellets). The mass spectra (EI) were recorded with Varian- MAT
112 spectrometer at 70 eV. Elemental analyse was performed on
a Perkin-Elmer 2400 analyzer. Starting materials, solvents and
reagents were purchased from commercial sources (Aldrich and
Merck) and were used without further purification, except of
DMF, which was purified by distillation shortly before use.
Synthesis of Alkylation Reagents, 2 and 3. 1-(3-Chloro-
propyl)-2-methyl-5-nitroimidazole (2) was prepared according
to described procedure [12]. 1-(4-Bromobutyl)-2-methyl-5-nitro-
imidazole (3) was obtained likewise as compound 2 in reaction
with 2-methyl-5-nitroimidazole (1) using of 1,4-dibromobutane
instead of 1-bromo-3-chloropropane. Recrystalization from
water gives compound 3 in shape of colourless crystals with mp
80-82°C, yield 85 %.
General Procedure for Synthesis of compounds 7-12. The
mixture of 6.4 mmoles halogeno derivatives of 2-methyl-5-
nitroimidazole 2 or 3, 6.4 mmoles of phenylpiperazine (4), m-
chloro- (5) and o-methoxyphenylpiperazine (6), 19.1 mmoles
anhydrous potassium carbonate and few crystals (~0.01g)
potassium iodide in 15-20 mL of fresh distillated DMF were placed
into an Erlenmeyer flask. All was stirred with magnetic stirrer at
room temperature for 30 hours. Next, the reaction mixture was
poured into 100-150 mL of water and the precipitate was collected
by filtration, dried and recrystallizated with appropriate solvents.
When an oil was obtained, it was extracted with chloroform, which
was dried over magnesium sulphate, evaporated and residue
recrystallized. In case of compound 11 unreacted o-methoxy-
phenylpiperazine (6) separated on chromatography column, before
crystallization. The compounds 8-12 were obtained in shape of
colourless needles and compound 7 as plates.
The compounds 7-12 exhibit high probability of
appearance of convulsant activity (83-88 %), while the
probability that such activity will not appear is low (about
1.3 %). High (i.e., 80-88 %) is also the probability that
these compounds will show general antiprotozoal action.
Moreover, the probability of antialcoholic activity is
relatively high (78-83 %), while the highest values are
obtained for the derivatives, where the phenyl ring of the
phenylpiperazinyl residue is not substituted. The presence
of ortho-methoxy substituent in the phenyl ring of 11 and
12 enhances their potential cardioprotectant properties in
comparison to the other compounds studied (increase by 7
to18% - penultimate line of Table 3).
Similar trend is observed in the case of urologic
disorder treatment, where the probability is highest for the
compound 11 having trimethylene link between the
imidazole and the piperazine rings. There is also high
probability that the compounds obtained will be effective
Dopamine D4 agonists (80
%
probability) and
radiosensitizers (60 % probability). The aliphatic chain
length within the structure of the compounds 7-12 does
not have significant effect on their pharmacological
properties. On the other hand, the probability that the
predicted biological activities will not appear is very low
for all of the compounds studied.
Concluding, these results shows, that the new 2-methyl-
5-nitroimidazole derivatives 7-12 synthesized by us, can
be considered as candidates for testing them, especially,
as the agents with potential Antiprotozoal`s and
Convulsive effect.
Acknowledgement. Authors wish to thank the Research
Group of Institute of Biomedical Chemistry of Russian
Academy of Medicinal Sciences (www.ibmh.msk.su/PASS) for
the access to the computer program applied for the research
presented in this paper.

1250
K. Nowak and B. Szpakiewicz
Vol 45
2000069414, 2000; Chem. Abstr. 2001, 134, 9358.
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