Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives

Article abstract of DOI:10.1021/jm700938n

A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed m

Full text of DOI:10.1021/jm700938n

J. Med. Chem. 2007, 50, 5833-5839
5833
Synthesis and Evaluation of Antiparasitic Activities of New
4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Derivatives
Sabine Kuettel, Alfonso Zambon,†,‡,# Marcel Kaiser, Reto Brun, Leonardo Scapozza, and Remo Perozzo*
†
£
£
†
,†
Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, UniVersity of GeneVa, UniVersity of Lausanne, Quai Ernest-Ansermet
3
0, CH-1211 GeneVa 4, Switzerland, Dipartimento di Scienze Ambientali, UniVersita’ di Venezia “Ca’Foscari”, Venezia, Italy, and
Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
ReceiVed July 31, 2007
A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic
routes, were in vitro assayed against three Trypanosoma strains, Leishmania donoVani, and Plasmodium
falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T.
b. rhodesiense, with 10 and 17 exhibiting highest potency (IC50 of 1.0 and 1.1 µM, respectively). Interestingly,
the â-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values
of 1.0-3.4 µM. Among different compounds with moderate activity against T. cruzi, compound 17 showed
the lowest IC50 value of 9.5 µM; thus, the series seemed to act selectively toward the different Trypanosoma
parasites. Eight compounds were moderately active against L. donoVani, with 2, 3, and 12 being the most
promising ones (IC50 values of 2.3-5.2 µM), whereas compound 14 was the only derivative with good
activity against P. falciparum (IC50 of 3.7 µM).
Introduction
and it affects annually about 2 million people, with ap-
proximately 350 million individuals at risk worldwide.3
Malaria is one of the world’s most important infectious dis-
eases in terms of both mortality and morbidity. There are about
Trypanosomiasis, leishmaniasis, and malaria belong to the
major parasitic diseases distributed throughout the world. Human
African Trypanosomiasis (HAT, sleeping sickness) is a vector-
borne parasitic disease transmitted by a protozoan parasite of
the genus Trypanosoma via the bites of infected tsetse flies.
Two different forms of HAT are known. The chronic form (90%
of reported cases) is caused by Trypanosoma brucei gambiense
a
0
.5 billion clinical attacks every year, including 2-3 million
severe attacks, with more than 1 million deaths annually. The
disease is caused by four different species of the malaria parasite
of which Plasmodium falciparum (P. falciparum) is the most
virulent and potentially deadly. The parasites are transmitted
via the bites of infected mosquitoes of the genus Anopheles.4
Generally, the presently used drugs on the market possess
severe side effects and do not provide complete eradication of
the disease. In addition, drug resistance develops rapidly and
has become a major problem in the treatment of neglected
diseases. Therefore, new efficacious chemotherapeutic agents
(T. b. gambiense) infection, whereas Trypanosoma brucei
rhodesiense (T. b. rhodesiense) is responsible for the acute form
of the disease. Both forms are fatal if untreated. About 0.5
million people on the African continent are affected, causing
50 000 deaths per year. Another parasite occurring in South and
Central America, Trypanosoma cruzi (T. cruzi), enters the
human body through broken skin via the feces of the blood-
feeding triatominae bugs, leading to South American Trypano-
5
and novel targets are urgently needed. There has been a revival
of drug research and development regarding neglected parasitic
diseases compared to the last 15 years, and a number of drug
development projects are currently ongoing. Approved drugs
are being improved (e.g., arthemisinin, trimethoprim, amino-
somiasis or Chagas’ disease, which affects 8 to 11 million people
and is responsible for 13 000 deaths annually.1
Leishmaniases is also a vector-borne disease caused by blood-
and tissue-dwelling protozoan parasites of the genus Leishmania
that are transmitted by phlebotomine sandflies. The infection
in man results in a broad range of clinical manifestations
involving the skin, mucous membranes and visceral organs.
Leishmania donoVani (L. donoVani) is the causative agent of
visceral leishmaniasis, the most severe form of the disease,
5
quinolines), but also, new potential drug targets have emerged
and have been validated (e.g., fatty acid biosynthesis, hemo-
globin degradation, protein prenylation, purine metabolism,
5-7
erogsterol biosynthesis), and novel chemical classes are being
pursued for treatment of protozoan parasitic diseases (e.g.,
diamindines,syntheticperoxides,proteaseinhibitors,triclosan).5
However, only few enter preclinical/clinical phases; thus,
discovering lead compounds with antiparasitic activity remains
a crucial step to sustain the progress achieved to date.
In the course of our search for new antiprotozoal lead com-
pounds, we investigated the antitrypanosomal and antiplasmodial
activity of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]mor-
pholine derivatives and their synthetic precursors. This report
presents the synthesis of the compounds and their activity against
the parasites.
,8-10
2
which is almost always fatal if left untreated. Leishmaniasis is
endemic in areas of the tropics, subtropics, and southern Europe,
*
To whom correspondence should be addressed. Address: Groupe de
Biochimie Pharmaceutique, Laboratoire de Chimie Th e´ rapeutique, Section
des Sciences Pharmaceutiques, Universit e´ de Gen e` ve, Quai Ernest-Ansermet
3
2
0, CH-1211 Gen e` ve 4, Switzerland. Phone: +41-22-3793371. Fax: +41-
2-3793360. E-mail: remo.perozzo@pharm.unige.ch.
†
University of Geneva.
Universita’ di Venezia “Ca’Foscari”.
Swiss Tropical Institute.
‡
£
#
Current address: Cancer Research Institute, 15 Cotswold Road, Sutton,
Surrey SM2 5NG, United Kingdom.
a
Abbreviations. HAT, Human African Trypanosomiasis; WHO, World
Results and Discussion
Health Organization; TDR, Program for Research and Training in Tropical
Diseases; TLC, thin layer chromatography; EtOH, ethanol; MeOH, metha-
nol; Et2O, diethylether; THF, tetrahydrofuran; Boc, tert-butoxycarbonyl.
Chemistry. Two different synthetic routes were used to
synthesize 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine
1
0.1021/jm700938n CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/20/2007

5
834 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Kuettel et al.
Scheme 1. Synthesis Strategy using â-diketones
Scheme 2. Synthesis Strategy using 2,2-Bis(methylthio)vinyl Ketones
derivatives. The first approach, depicted in Scheme 1, proceeds
via a condensation reaction between the corresponding substi-
tuted acetophenones and the substituted ethyl carboxylate to
pholine-4-yl-1H-pyrazol-3-yl)-phenoxy]phenylamine (15), 4-[5-
morpholine-4-yl-3-(4-phenoxyphenyl)-pyrazol-1-yl]phenyl-
amine (16), and 1-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]pip-
erazine (17) are shown in Figure 1.
11
form the â-diketones 1-3 . Compounds 4-6 were prepared
through cyclization using hydrazine hydrate in EtOH.1 Scheme
2
Antiprotozoal Activity. The activity of compounds 1-17
toward T. b. rhodesiense, T. b. cruzi, L. donoVani, and P.
falciparum as well as their cytotoxicity is presented in Table 1.
As a general observation, all compounds exhibit very low
cellular toxicity (at least more than 1800-fold lower) compared
to podophyllotoxin used as the standard. The antiparasitic
potential of all compounds was analyzed by applying the WHO/
TDR screening activity criteria specified for each parasite.17
Among the newly prepared derivatives, compounds 5, 6, 10,
11, 12, 13, and 17 exhibit moderate to very good activity against
T. b. rhodesiense (blood trypomastigotes). Compounds 10 and
17 are the most potent ones, with IC50 values around 1 µM.
However, compound 17 shows a threefold increased toxicity
on L6 cells compared to that of 10. Interestingly, compounds
5, 6, 10, 11, 12, 13, and 17 act in a stage-specific manner, thus
inhibiting preferably blood trypomastigotes of T. b. rhodesiense
and not the procyclic (insect stage) form. In contrast, the
â-diketone precursors 1-3 exhibit good antitrypanosomal
activity (IC50 values of 1.0-3.4 µM) toward the procyclic form
of T. b. rhodesiense, giving evidence for stage-specific targets
within the parasite cell. In line with the WHO/TDR activity
criteria for T. cruzi, several compounds (1-8, 10, 12, 13, and
16) are moderately active against T. cruzi. Compound 17 is the
most promising hit, with an IC50 value of 9.5 µM, which means
only a fourfold reduced potency when compared to that of the
2
illustrates the second approach, in which substituted acetophe-
nones were reacted with carbon disulfide and methyl iodide in
the presence of sodium hydride to give 4-phenoxyphenyl-2,2-
bis(methylthio)vinyl ketones 7-9.13 The formation of the five-
member ring systems was accomplished through a one-pot, two-
step protocol featuring a prior displacement of one of the
methylthio groups of the 4-phenoxyphenyl-2,2-bis(methylthio)-
vinyl ketones 7-9 by the respective amines (i.e., morpholine
and Boc-protected piperazine) in refluxing EtOH followed by
in situ cyclization of the resulting N,S-acetals with hydrazine
hydrate, hydroxylamine, or 4-nitrophenylhydrazine.1
The 4-phenoxyphenyl-2,2-bis(methylthio)vinyl ketones 7-9
were refluxed with morpholine or Boc-protected piperazine and
cyclized by the addition of hydrazine hydrate in portions to give
the desired products 10-12. Similarly, compound 13 was
obtained using morpholine and hydroxylamine as the reactants,
whereas the reaction with morpholine and 4-nitrophenylhydra-
zine gave compound 14. The final conversion of the nitro groups
of 11 and 14 to amino groups and the deprotection of the pro-
tected piperazine of 12 were carried out under standard
conditions using catalytic hydrogenation or reaction with sodium
dithionite for the reduction steps and trifluoroacetic acid as the
deprotection agent, respectively.1 The structures of 4-[5-(4-
phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (10), 4-[4-(5-mor-
4,15
5,16

4
-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5835
reduction of the activity. Interestingly, compound 12, carrying
an additional voluminous Boc substitution on the piperazine ring,
exhibits similar activity as that of compounds 5, 6, and 17 with
respect to T. b. rhodesiense. The comparison of compounds 4
and 5 allows the dissection of the role of the phenoxy ring in
the compounds. Indeed, replacing it by an ethylene group (as
found in compound 4) reduces efficacy ninefold, indicating the
phenoxy ring in the compounds to be important for biological
activity. Further substitution with a nitro group (11) reduces
potency 4-fold or 18-fold with an amino group at the same
position (15) when compared to that of compound 10.
Conclusion
We report the synthesis of new 4-[5-(4-phenoxyphenyl)-2H-
pyrazol-3-yl]morpholine derivatives as well as their synthesis
precursors and present their antiprotozoal activity and their
general cytotoxicity. Compound 10, 4-[5-(4-phenoxyphenyl)-
2
H-pyrazol-3-yl]morpholine, and compound 17, 1-[5-(4-phe-
noxyphenyl)-2H-pyrazol-3-yl]piperazine, are the most potent
antitrypanosomals of the series and exhibit the same selectivity
toward T. b. rhodesiense while exhibiting low cytotoxicity. The
inhibition results on blood stage and insect stage forms of the
parasite indicate stage-specific action, which may be due to
stage-specific expression of the so-far unknown intracellular
target(s) of these compounds. Further investigation on stage-
specific target expression profiles will be needed to enlighten
the observed specificity. To this end, work is in progress to
identify the corresponding target(s) within the unicellular
parasite using a chemical proteomics approach and to elucidate
the mechanism of action on a molecular level.
Figure 1. Structures of the most potent antitrypanosomal 4-[5-(4-
phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (10) and its amino-
substituted derivatives 4-[4-(5-morpholine-4-yl-1H-pyrazol-3-yl)-
phenoxy]phenylamine (15), 4-[5-morpholine-4-yl-3-(4-phenoxyphenyl)-
pyrazol-1-yl]phenylamine (16), and 1-[5-(4-phenoxyphenyl)-2H-pyrazol-
3
-yl]piperazine (17).
benznidazole standard (IC50 of 2.13 µM); thus, 17 could
therefore be an interesting structure for further development.
Eight compounds (1-3, 5, 9, 10, 12, and 14) show moderate
growth inhibition toward L. donoVani, with 2, 3, and 12
exhibiting the most promising activity (IC50 values of 2.3-5.2
µM). Compound 14 is the only derivative with good activity
against P. falciparum K1. Several other compounds (12, 13,
Experimental Section
Chemistry. The chemicals were purchased from Sigma-Aldrich
or Fluka (Switzerland) unless otherwise noted. All final products
1
13
were characterized by H NMR, C NMR, MS, IR analysis, and
melting points. Melting points were found with a digital melting
point apparatus B u¨ chi B-540; IR spectra were obtained with an
infrared spectrometer system Paragon 500 FT (Perkin-Elmer) in
1
6, and 17) are only moderately active against the malaria
parasite. Due to the good antiplasmodial activity and the very
low cytotoxicity (IC50 > 203 µM), compound 14 represents a
promising starting point for further structural optimization.
-
1
KBr discs, and frequencies are reported in cm ; thin-layer
chromatography (TLC) was carried out with TLC plates (Fluka,
silica gel 60 F254 0.2 mm, 20 × 20 cm, aluminum cards); the
substances were detected in UV light at 254 nm; and MS was
performed with an API 150EX MS System, TurboIonspray, MDS
SCIEX (AB Applied Biosystems). The material for column
chromatography was silica gel 60 (Fluka) (230-400 mesh), pore
diameter 60 Å; NMR spectra were recorded on Varian Gemini 300.
The chemical shifts are reported in parts per million relative to
tetramethylsilane (TMS) as the internal standard.
Structure Activity Relationship. Overall, the lowest IC50
values and highest potencies of the series were achieved toward
T. b. rhodesiense among all different parasites; thus, the new
4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives
seem to act with considerable selectivity toward T. b. rhod-
esiense. Therefore, the discussion will focus on antitrypanosmal
activity. An important element for activity is conferred by the
pyrazol moiety. It is not only crucial for antiparasitic activity
but also for blood stage selectivity. Indeed, the â-diketone
derivatives 1-3 only act toward the insect stage of the parasite,
whereas ring closure to the pyrazol (compounds 5 and 6) leads
to compounds active against blood stage parasites. A pyrazol
ring is found to be very important for activity toward the
clinically more relevant blood stage. Whereas the lack of the
pyrazol group leads to inactive compounds, the substitution by
an isoxazole derivative (13) leads to a sixfold reduced activity
compared to the most potent compound 10. In addition,
substitution with nitrophenyl (14) or aminophenyl (16) also
results in strongly reduced activity. The importance of the
morpholine moiety of the best compound (10) becomes evident
when looking at derivatives exploring this position. While the
piperazine derivative (17) maintains full activity, the introduction
of a tetrahydropyran (5) or a bridging methylene group between
the pyrazol and the morpholine ring (6) leads to a fourfold
1
-(4-Ethyl-phenyl)-3-(tetrahydropyran-4-yl)propane-1,3-di-
one (1). To a mixture of methyl tetrahydro-2H-pyran-4-carboxylate
2.88 g, 20 mmol) and ethylacetophenone (1.48 g, 10 mmol) in
toluene (40 mL), a dispersion of 60% NaH in mineral oil (0.8 g,
0 mmol) was added in small portions. When the effervescence
(
2
ceased, the mixture was refluxed for 6.5 h with vigorous stirring.
The mixture was allowed to cool to room temperature and then
poured into H
pH was acidic, giving rise to an orange oil that was extracted with
Et SO
2
O (70 mL). Hydrochloric acid was added until the
2
O (2 × 50 mL). The combined extracts were dried on Na
2
4
and afforded a reddish oil after solvent evaporation. The residue
was purified by column chromatography (silica gel, dichlo-
romethane) to yield 1 as a light-yellow crystalline solid (0.49 g,
+
1
°
8.8%). MS: calcd mass for M , 261.33; found, 261.5. Mp 57.7
-1
C. IR (KBr, cm ): 2968, 1609, 1117. NMR δ
H
(300 MHz,
CDCl
2
3
): 1.26 (3H, t, J ) 7.8 Hz), 1.83 (4H, m), 2.57 (1H, m),
.71 (2H, q, J ) 7.5 Hz), 3.47 (2H, m), 4.06 (2H, dt, J ) 3.3, 3.6
Hz), 6.17 (1H, s), 7.28 (2H, d, J ) 9.0 Hz), 7.81 (2H, d, J ) 9.0
Hz), 16.29 (1H, s, br); δ (300 MHz, CDCl ): 15.20 (CH ), 28.87
C
3
3

5
836 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Kuettel et al.
Table 1. Antiparasitic Activity of Compounds 1-17 Expressed as IC50 (µM)a
b
T. b. rhodesiense
blood procyclic
T. b. cruzi
L. donoVani
P. falciparum K1 L6-cells
L-6 cells
stage
amastigotes
amastigotes
erythrocyte
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
20.9
25.8
18.9
28.6
3.2
3.4
1.8
1.0
7.8
54.9
54.6
20.6
113.9
59.0
45.3
54.6
24.4
>83
52.0
>81
12.8
46.5
>67
>89
22.0
9.5
9.8
4.6
5.2
15.1
6.4
15.6
20.2
9.7
5.7
8.0
22.3
2.3
12.7
4.8
20.3
10.5
25.8
>19
>15
>15
>19
>15
>14
>18
>15
>13
>15
>13
8.1
201.5
231.0
112.3
164.6
89.6
149.7
40.5
34.5
155.8
61.6
>245
30.0
43.0
54.9
>334
16.6
>249
40.7
93.4
17.6
75.2
>203
>267
61.7
4.7
4.1
223.8
51.4
45.9
1.0
4.4
2.9
0
1
2
3
4
5
6
7
5.9
10.5
3.7
>14
6.5
171.9
>203
>267
61.6
28.8
17.7
10.3
1.1
6.6
18.0
melarsoprol
benznidazole
miltefosine
0.01
0.13
2.13
0.26
chloroquine
podophyllotoxin
0.23
0.01
a
Values represent the average of four determinations (two determinations of two independent experiments); errors for individual measurements differed
b
by less than 50%. Resistant to chloroquine and pyrimethamine.
(
(
CH
2CH), 128.14 (2CH), 132.49, 149.37, 184.71, 196.96.
-(4-Phenoxyphenyl)-3-(tetrahydropyran-4-yl)propane-1,3-di-
one (2). To a mixture of methyl tetrahydro-2H-pyran-4-carboxylate
1.44 g, 10 mmol) and 4-phenoxyacetophenone (2.12 g, 10 mmol)
2
), 29.18 (2CH
2
), 44.00 (CH), 67.38 (2CH
2
), 93.88 (CH), 127.15
2 2 2 2
(2CH ), 66.28 (2CH ), 68.35 (CH , br), 91.38 (CH , br), 117.33
(2CH), 118.98 (2CH), 123.66 (CH), 128.33 (2CH), 130.10 (2CH),
138.87, 156.39, 157.41, 179.97, 187.24.
1
3-(4-Ethyl-phenyl)-5-(tetrahydropyran-4-yl)-1H-pyrazol (4).
Hydrazine hydrate (0.08 g, 1.54 mmol) was added to an EtOH (10
mL) solution of 1 (0.2 g, 0.77 mmol), and the reaction mixture
was refluxed for 4-5 h. The organic phase was evaporated, and
the resulting oil was purified by column chromatography (silica
gel, ethyl acetate) to give a white solid of 4 (93.0 mg, 47.1%).
(
in THF (40 mL) was added a dispersion of 60% NaH in mineral
oil (0.8 g, 20 mmol) in small portions. When the effervescence
ceased, the mixture was refluxed for 3.5 h with vigorous stirring.
The mixture was allowed to cool to room temperature and then
poured into H
pH was acidic, yielding a deep-orange oil that was extracted with
Et
+
2
O (70 mL). Hydrochloric acid was added until the
MS: calcd mass for M , 257.35; found 257.5. Mp 106.5 °C. IR
-
1
(KBr, cm ): 3209, 2964, 1580, 1456, 1079. NMR δ
H
(300 MHz,
2
O (5 × 30 mL). The dried combined extracts were evaporated,
CDCl ): 1.26 (3H, t, J ) 7.8 Hz), 1.88 (4H, m), 2,67 (2H, q, J )
7.5 Hz), 2.95 (1H, m), 3.50 (2H, m), 4.06 (2H, m), 4.50 (1H, NH,
3
and the resulting yellowish solid was recrystallized from hexane
to yield 2 as a white/yellow crystalline solid (0.63 g, 19.3%). MS:
br, variable), 6.37 (1H, s), 7.24 (2H, d, J ) 8.2 Hz), 7.58 (2H, d,
+
calcd mass for M , 325.37; found, 325.3. Mp 87.7 °C. IR (KBr,
J ) 8.2 Hz); δ
C
(300 MHz, CDCl
3
): 15.43 (CH
3 2
), 28.64 (CH ),
-
1
cm ): 2949, 1722, 1586, 1489, 1241, 1121. NMR δ
H
(300 MHz,
32.40 (2CH
2
), 33.47 (CH), 67.64 (2CH
2
), 99.76 (CH), 125.84
CDCl ): 1.83 (4H, m), 2.58 (1H, m), 3.46 (2H, m), 4.01 (2H, m),
3
(2CH), 128.19, 128.41 (2CH), 144.88, 148.24, 153.06.
6
7
)
.13 (1H, s), 7.01 (2H, d, J ) 9.0 Hz), 7.08 (2H, d, J ) 9.0 Hz),
.19 (1H, t, J ) 7.2 Hz), 7.38 (2H, d, J ) 9.0 Hz), 7.87 (2H, d, J
3-(4-Phenoxyphenyl)-5-(tetrahydropyran-4-yl)-1H-pyrazol (5).
Hydrazine hydrate (0.12 g, 2.47 mmol) was added to an EtOH (20
mL) solution of 2 (0.4 g, 1.23 mmol), and the reaction mixture
was refluxed for 19 h. The organic phase was evaporated, and the
resulting oil was purified by column chromatography (silica gel,
ethyl acetate) to give a white solid of 5 (31.2 mg, 7.9%). MS: calcd
9.0 Hz); acidic H could not be detected because of solvent
exchange effects; δ
C
(300 MHz, CDCl
3
): 28.37 (CH
2
), 29.22 (CH
2
),
),
39.69 (CHa), 43.83 (CHb), 66.96 (CH
1
2
), 67.38 (CH ), 93.61 (CH
2
2
17.63 (2CH), 120.02 (2CH), 124.49 (CH), 129.14 (2CH), 130.02
+
-1
(
2CH), 155.61, 161.50, 179.64, 184.52, 196.21.
-Morpholine-4-yl-1-(4-phenoxyphenyl)butane-1,3-dione (3).
To a mixture of ethyl morpholine acetate (3.46 g, 20 mmol) and
-phenoxyacetophenone (2.12 g, 10 mmol) in toluene (40 mL), a
mass for M , 321.39; found, 321.5. Mp 134.5 °C. IR (KBr, cm ):
3236, 2939, 1590, 1490, 1242, 1110. NMR δ (300 MHz,
CDCl ): 1.86 (4H, m), 2.96 (1H, m), 3.52 (2H, m), 4.07 (2H, m),
4
H
3
4
4.3 (1H, NH, br, variable), 6.35 (1H, s), 7.02 (2H, d, J ) 9.0 Hz),
dispersion of 60% NaH in mineral oil (0.8 g, 20 mmol) was added
in small portions. When the effervescence ceased, the mixture was
refluxed for 2 h with vigorous stirring. The mixture was allowed
7.05 (2H, d, J ) 7.5 Hz), 7.14 (1H, t, J ) 7.5 Hz), 7.35 (2H, d, J
) 7.5 Hz), 7.65 (2H, d, J ) 9.0 Hz); δ
C
(300 MHz, CDCl
), 99.75 (CH), 118.82 (2CH),
3
): 32.33
(2CH ), 33.26 (CH), 67.57 (2CH
2
2
to cool to room temperature and then poured into H
2
O (70 mL).
119.28 (2CH), 123.72 (CH), 127.45 (2CH), 129.86 (2CH), 148.49,
152.31, 156.89, 157.32.
Hydrochloric acid was added until the pH was acidic. The organic
phase contained byproducts and was discarded. The pH of the water
phase was set to 6, and the product was extracted with ethyl acetate.
Solvent evaporation afforded a clear oil that was further purified
with basic wash steps, and white crystals of 3 were formed (1.92
4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-ylmethyl]morpholine (6).
Hydrazine hydrate (0.15 g, 2.95 mmol) was added to an EtOH (20
mL) solution of 3 (0.5 g, 1.47 mmol), and the reaction mixture
was refluxed for 16 h. Acetic acid was added until a pH 5 was
reached; then, the reaction solution was extracted with ethyl acetate
(20 mL), and the organic phase was washed with a saturated
+
g, 56.6%). MS: calcd mass for M , 340.39; found, 340.5. Mp 164.2
-
1
°
C. IR (KBr, cm ): 2957, 2855, 2811, 1602, 1488, 1239, 1116.
NMR δ (300 MHz, DMSO): 2.41(4H, s, br), 2.79 (2H, s, br),
.58 (4H, s, br), 5.88 (1H, s, br), 6.93 (2H, d, J ) 8.4 Hz), 7.03
2H, d, J ) 7.5 Hz), 7.15 (1H, t, J ) 7.5 Hz), 7.40 (2H, t, J ) 7.8
Hz), 7.76 (2H, d, J ) 8.4 Hz); acidic H could not be detected
because of solvent exchange effects; δ (300 MHz, DMSO): 53.84
H
NaHCO
3
solution (3×) and brine. The resulting crude product (320
3
(
mg) from the evaporated organic phase was purified by column
chromatography (silica gel, ethyl acetate/MeOH 9:1) to give a beige
solid of 6 (37.8 mg, 7.7%). MS: calcd mass for M , 336.41; found,
+
-
1
C
336.5. Mp 133.6 °C. IR (KBr, cm ): 3094, 2921, 2862, 2829,

4
-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5837
1
588, 1490, 1236, 1114. NMR δ
s, br), 3.64 (2H, s), 3.75 (4H, m), 6.47 (1H, s), 7.04 (2H, d, J )
.7 Hz), 7.04 (2H, d, J ) 8.7 Hz), 7.12 (1H, t, J ) 5.1 Hz), 7.34
2H, t, J ) 8.1 Hz), 7.69 (2H, d, J ) 8.4 Hz); the NH signal could
not be detected because of solvent exchange effects; δ (300 MHz,
CDCl ): 53.36 (2CH ), 54.27 (CH ), 66.52 (2CH ), 102.62 (CH),
19.02 (4CH), 123.46 (CH), 127.01 (2CH), 129.79 (2CH), 157.30.
,3-Bis(methylsulfanyl)-1-(4-nitrophenyl)propenone (7). N,N-
H
(300 MHz, CDCl
3
): 2.55 (4H,
J ) 7.2 Hz), 7.35 (2H, t, J ) 7.5 Hz), 7.49 (2H, d, J ) 8.4 Hz);
the NH signal could not be detected because of solvent exchange
8
(
C 3 2 2
effects; δ (300 MHz, CDCl ): 47.50 (2CH ), 66.25 (2CH ), 89.31
(CH), 118.38 (2CH), 119.68 (2CH), 122.52, 124.15 (CH), 127.33
(2CH), 129.96 (2CH), 156.05, 159.21, 167.63, 169.24.
C
3
2
2
2
4-{5-[4-(4-Nitrophenoxy)phenyl]-2H-pyrazol-3-yl}mor-
pholine (11). To a solution of 9 (1 g; 2.8 mmol) in EtOH (30 mL)
was added morpholine (0.6 mL; 7 mmol), and the reaction mixture
was refluxed for 12 h. It was then brought to room temperature,
and hydrazine hydrate (0.27 g; 5.5 mmol) in EtOH (5 mL) was
added dropwise over a period of 10 min. Then, the reaction mixture
was refluxed for another 12 h (monitored by NMR). The solvent
was removed under reduced pressure, and the residue (1.43 g) was
purified by column chromatography (silica gel, ethyl acetate/
petroleum ether 9:1) to give yellow crystals of 11 (0.64 g, 63%).
1
3
Dimethylacetamide (1 mL; 10.8 mmol) was added to a stirred (30
min) solution of 4-nitroacetophenone (826 mg; 5 mmol), 60% NaH
in mineral oil (0.45 g; 11 mmol), CS (0.5 mL; 8.3 mmol), and
2
MeI (1 mL; 16.6 mmol) in toluene (30 mL) at 25-30 °C. Stirring
was continued overnight before the mixture was poured into ice
water. The whole mixture was extracted with ethyl acetate, and
the organic phase was washed with H O, dried over MgSO , and
2 4
concentrated. The solid residue was washed with ethyl acetate to
give an insoluble, yellow precipitate of 7 (0.12 g, 8.8%). MS: calcd
+
MS: calcd mass for M , 367.38; found, 367.3. Mp 72.5 °C. IR
-
1
(KBr, cm ): 3110, 2960, 2854, 1590, 1515, 1343, 1247, 1111.
NMR δ (300 MHz, CDCl ): 3.25 (4H, t, J ) 4.8 Hz), 3.86 (4H,
+
-1
mass for M , 270.3; found, 270.1. Mp 171.9 °C. IR (KBr, cm ):
621, 1595, 1517, 1347. NMR δ (300 MHz, CDCl ): 2.57 (3H,
s), 2.60 (3H, s), 6.72 (1H, s), 8.04 (2H, d, J ) 9.0 Hz), 8.29 (2H,
(300 MHz, CDCl ): 15.18 (CH ), 17.48 (CH ),
08.46 (CH), 123.74 (2CH), 128.60 (2CH), 144.51, 149.43, 170.42,
83.24.
,3-Bis(methylsulfanyl)-1-(4-phenoxy)phenyl]propenone (8).
H
3
1
H
3
t, J ) 4.9 Hz), 5.97 (1H, s), 7.06 (2H, d, J ) 7.0 Hz), 7.14 (2H,
d, J ) 6.7 Hz), 7.61 (2H, d, J ) 6.7 Hz), 8.23 (2H, d, J ) 7.0 Hz);
the NH signal could not be detected because of solvent exchange
d, J ) 9.0 Hz); δ
C
3
3
3
1
1
C 3 2 2
effects; δ (300 MHz, CDCl ): 48.50 (2CH ), 66.39 (2CH ), 88.67
(CH), 117.34 (2CH), 120.76 (2CH), 125.98 (2CH), 127.32 (2CH),
127.56, 142.86, 144.71, 154.77, 159.33, 162.77.
3
N,N-Dimethylacetamide (4.87 mL; 52.7 mmol) was added to a
stirred (30 min) solution of 4-phenoxyacetophenone (5.16 g; 24.3
mmol), 60% NaH in mineral oil (2.14 g; 53.5 mmol), CS (2.43
2
mL; 40.3 mmol), and MeI (5.1 mL; 81.7 mmol) in toluene (50
mL) at 25-30 °C. Stirring was continued overnight; then, the
mixture was poured into ice water. The whole mixture was extracted
4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]piperazine-1-car-
boxylic Acid Tert-Butyl Ester (12). To a solution of 8 (1 g; 3.2
mmol) in EtOH (16 mL) was added tert-butylpiperazine-1-car-
boxylate (1-Boc-piperazine) (0.62 g; 3.32 mmol), and the reaction
mixture was refluxed for 19 h. It was then brought to room
temperature, and hydrazine hydrate (0.32 g; 6.3 mmol) in EtOH (5
mL) was added dropwise. Then, the reaction mixture was refluxed
for another 23 h (monitored by TLC). The solvent was removed
under reduced pressure, and the oily residue was purified by column
chromatography (silica gel, ethyl acetate/petroleum ether 6:4, and
1% triethylamine) to give a yellow solid of 12 (0.26 g, 19.3%).
with ethyl acetate, and the organic phase was washed with H
dried over MgSO , and concentrated. The residue was recrystallized
from EtOH to give orange needles of 8 (3.72 g, 48.4%). MS: calcd
2
O,
4
+
13
mass for M , 317.4; found, 317.3. Mp 114.2 °C (lit. 105-107 °C).
-
1
13
IR (KBr, cm ): 1617, 1584, 1230 (lit. 1612, 1580). NMR δ
H
+
(
300 MHz, CDCl
2H, d, J ) 8.7 Hz), 7.07 (2H, d, J ) 7.5 Hz), 7.18 (1H, t, J ) 7.5
(300
), 109.27 (CH), 117.47
2CH), 119.92 (2CH), 124.27 (CH), 129.83 (2CH), 129.94 (2CH),
3
): 2.53 (3H, s), 2.56 (3H, s), 6.74 (1H, s), 7.00
MS: calcd mass for M , 421.52; found, 421.3. Mp 178 °C. IR
-
1
(
(KBr, cm ): 3332, 2976, 2969, 2835, 1668, 1589, 1243, 1172.
NMR δ (300 MHz, CDCl ): 1.48 (9H, s), 3.23 (4H, t, J ) 6.0
Hz), 7.38 (2H, t, J ) 7.5 Hz), 7.91 (2H, d, J ) 8.7 Hz); δ
MHz, CDCl ): 15.05 (CH ), 17.32 (CH
C
H
3
3
3
3
Hz), 3.55 (4H, t, J ) 5.1 Hz), 5.92 (1H, s), 7.01 (2H, d, J ) 8.7
Hz), 7.05 (2H, d, J ) 7.9 Hz), 7.15 (1H, t, J ) 7.3 Hz), 7.37 (2H,
t, J ) 7.9 Hz), 7.50 (2H, d, J ) 8.7 Hz); the NH signal could not
(
133.92, 155.8, 160.79, 165.77, 184.45.
3
,3-Bis(methylsulfanyl)-1-[4-(4-nitrophenoxy)phenyl]prope-
be detected because of solvent exchange effects; δ
C
(300 MHz,
none (9). N,N-Dimethylacetamide (2 mL; 21.7 mmol) was added
to a stirred (30 min) solution of 4-acetyl-4′-nitrodiphenyl ether (2.57
g; 10 mmol), 60% NaH in mineral oil (0.9 g; 22 mmol), CS (1
2
CDCl ): 28.42 (3CH ), 48.13 (2CH ), 80.03 (2CH ), 88.67 (CH),
3
3
2
2
118.74 (2CH), 119.42 (2CH), 123.90 (CH), 124.23, 127.28 (2CH),
129.88 (2CH), 145.76, 154.67, 156.34, 158.19.
mL; 16.6 mmol), and MeI (2.1 mL; 33.2 mmol) in toluene (20
mL) at 25-30 °C. Stirring was continued overnight; then, the
mixture was poured into ice water. The whole mixture was extracted
with ethyl acetate, and the organic phase was washed with brine,
dried over MgSO , and concentrated. The residue was recrystallized
4
from EtOH to give orange needles of 9 (1.9 g, 52%). MS: calcd
4-[3-(4-Phenoxyphenyl)isoxazol-5-yl]morpholine (13). To a
solution of 8 (1 g; 3.2 mmol) in EtOH (16 mL) was added
morpholine (0.7 mL; 8 mmol), and the reaction mixture was
refluxed for 48 h. It was then brought to room temperature, and
hydroxylamine hydrochloride (0.44 g; 6.3 mmol) and potassium
hydroxide (0.37 g; 6.6 mmol) were added. This suspension was
refluxed for another 24 h (monitored by NMR). The solvent was
then removed under reduced pressure, and the residue was taken
+
-1
mass for M , 362.4; found, 362.3. Mp 138.7 °C. IR (KBr, cm ):
620, 1585, 1507, 1337, 1248. NMR δ (300 MHz, CDCl ): 2.54
1
(
H
3
3H, s), 2.58 (3H, s), 6.73 (1H, s), 7.08 (2H, d, J ) 9.0 Hz), 7.12
up in 0.5 M Na
The combined extracts were washed with basic brine, dried
(Na SO ), and evaporated. After a final recrystallization in EtOH,
13 was received as white crystals (0.4 g, 39.3%). MS: calcd mass
2
CO
3
and extracted with dichloromethane (3×).
(
2H, d, J ) 8.7 Hz), 7.98 (2H, d, J ) 8.7 Hz), 8.23 (2H, d, J ) 9.0
Hz); δ
C
(300 MHz, CDCl
3
): 15.04 (CH
3
), 17.33 (CH
3
), 108.81
2
4
(
CH), 117.97 (2CH), 119.64 (2CH), 125.96 (2CH), 130.09 (2CH),
+
-1
136.13, 143.14, 157.74, 162.13, 167.22, 184.02.
for M , 323.37; found, 323.5. Mp 135.1 °C. IR (KBr, cm ): 2867,
1590, 1253, 1111. NMR δ (300 MHz, CDCl
4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (10). To
H
3
): 3.32 (4H, t, J )
a solution of 8 (0.25 g; 0.79 mmol) in EtOH (10 mL) was added
morpholine (0.07 mL; 0.81 mmol), and the reaction mixture was
refluxed for 3 h. It was then brought to room temperature, and
hydrazine hydrate (0.06 g; 1.2 mmol) in EtOH (4 mL) was added
dropwise over a period of 10 min. Then, the reaction mixture was
refluxed for another 16 h. The solvent was removed under reduced
pressure, and the oily residue was purified by column chromatog-
raphy (silica gel, ethyl acetate) to give a white solid of 10 (30.4
4.8 Hz), 3.83 (4H, t, J ) 4.8 Hz), 6.09 (1H, s), 7.03 (2H, d, J )
7.8 Hz), 7.06 (2H, d, J ) 9.0 Hz), 7.17 (1H, t, J ) 7.5 Hz), 7.38
(2H, t, J ) 7.8 Hz), 7.68 (2H, d, J ) 9.0 Hz); δ
C
(300 MHz,
2
), 89.31 (CH), 118.38 (2CH),
CDCl ): 47.50 (2CH ), 66.25 (2CH
3
2
119.68 (2CH), 122.52, 124.15 (CH), 127.33 (2CH), 129.96 (2CH),
156.05, 159.21, 167.63, 169.24.
4-[2-(4-Nitrophenyl)-5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]-
morpholine (14). To a solution of 8 (1 g; 3.2 mmol) in EtOH (16
mL) was added morpholine (0.7 mL; 8 mmol), and the reaction
mixture was refluxed for 60 h. It was then brought to room
temperature, and 4-nitrophenylhydrazine (0.97 g; 6.3 mmol) was
added. Then, the reaction mixture was refluxed for another 48 h
+
mg, 12%). MS: calcd mass for M , 322.38; found, 322.3. Mp 171.6
-
1
°
δ
4
C. IR (KBr, cm ): 3268, 2967, 2826, 1590, 1246, 1107. NMR
(300 MHz, CDCl ): 3.21 (4h, t, J ) 4.6 Hz), 3.82 (4h, t, J )
.9 Hz), 5.90 (1H, s), 7.02 (4H, dd, J ) 8.4, 7.5 Hz), 7.14 (1H, t,
H
3

5
838 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Kuettel et al.
(
monitored by MS and NMR). The solvent was removed under
(2CH), 118.81 (2CH), 123.61 (CH), 126.54 (2CH), 130.12 (2CH),
119.23, 124.03, 128.45, 156.11, 156.50.
reduced pressure, and the residue was purified by column chro-
matography (silica gel, ethyl acetate/petroleum ether 4:6, followed
by ethyl acetate/petroleum ether 5:5). The residue was recrystallized
from ethyl acetate to give 14 (103.8 mg, 7.4%) as orange crystals.
MS: calcd mass for M , 443.48; found, 443.3. Mp 183.4 °C. IR
(
MHz, CDCl
6
1
Hz); δ
(
1
1
Antiprotozoal Activity. The tests were performed at pH 7.4 as
microplate assays using T. b. rhodesiense (STIB900), T. cruzi
(Tulahuen C4), L. donoVani (MHOM-ET-67/L82), and P. falci-
parum K1 (resistant to chloroquine and pyrimethamine), and the
cytotoxicity was assessed with rat skeletal myoblasts (L-6 cells),
as described earlier.18 Compounds were measured in duplicate in
the range of 0.2 to 19.5 µM, and IC50 values were calculated from
the sigmoidal inhibition curves. The assay was repeated in duplicate
for active compounds while using concentrations as low as 3.5 nM.
The following substances were used as reference standards:
melarsoprol (T. b. rhodesiense), benznidazole (T. cruzi), miltefosine
(L. donoVani), chloroquine (P. falciparum), and podophyllotoxin
+
-
1
KBr, cm ): 2970, 1592, 1520, 1329, 1240, 1114. NMR δ
H
(300
): 3.32 (4H, t, J ) 4.7 Hz), 3.86 (4H, t, J ) 4.8 Hz),
3
.01 (1H, s), 6.97 (2H, dt, J ) 9.0, 2.1 Hz), 7.07 (2H, dd, J ) 8.5,
.0 Hz), 7.20 (3H, m), 7.40 (4H, m), 8.13 (2H, dt, J ) 9.6, 2.1
C
(300 MHz, CDCl
3
): 47.80 (2CH
2
), 66.50 (2CH
2
), 97.49
CH), 118.26 (2CH), 119.78 (2CH), 123.18 (2CH), 124.25 (CH),
24.41 (2CH), 124.74, 129.99 (2CH), 130.21 (2CH), 144.29,
44.70, 145.05, 155.89, 158.50, 159.99.
(cytotoxicity assay).
4
-[4-(5-Morpholine-4-yl-1H-pyrazol-3-yl)phenoxy]phenyl-
amine (15). To the solution of 11 (0.3 g; 0.8 mmol) in MeOH or
ethyl acetate was added palladium-on-carbon (<10% of the
product). After the degassing the liquid under vacuum, the solution
Acknowledgment. We thank Dr. E. Rivara-Minten and Dr.
R. Haddoub for support with NMR and the chemistry.
2
was kept under H overnight at room temperature. Adding dichlo-
romethane to the solution stopped the reaction; then, the solution
was washed with activated carbon and filtered over celite. Solvent
evaporation yielded pure 15 as a white powder (0.28 g, 98.7%).
Supporting Information Available: Analytical and spectral
1
13
characterization data ( H, C NMR, MS, HRMS, and HPLC). This
material is available free of charge via the Internet at http://
pubs.acs.org.
+
MS: calcd mass for M , 337.4; found, 337.5. Mp 197.1 °C. IR
-
1
(
KBr, cm ): 3417, 3343, 3198, 2964, 1618, 1506, 1274, 1249,
112. NMR δ (300 MHz, CDCl ): 3.20 (4H, t, J ) 4.8 Hz), 3.65
2H, NH , s), 3.81 (4H, t, J ) 4.8 Hz), 5.88 (1H, s), 6.68 (2H, dt,
J ) 8.8, 2.1 Hz), 6.88 (2H, dt, J ) 8.8, 2.1 Hz), 6.92 (2H, d, J )
.0 Hz), 7.42 (2H, d, J ) 9.0 Hz), 10.35 (1H, NH, s); δ (300
MHz, CDCl ): 48.51 (2CH ), 66.52 (2CH ), 88.62 (CH), 116.26
2CH), 117.37 (2CH), 121.29 (2CH), 123.92, 126.71 (2CH), 143.02,
1
H
3
References
(
2
(
1) Barrett, M. P.; Burchmore, R. J.; Stich, A.; Lazzari, J. O.; Frasch,
A. C.; Cazzulo, J. J.; Krishna, S. The trypanosomiases. Lancet 2003,
9
C
362, 1469-1480.
3
2
2
(2) Campos-Ponce, M.; Ponce, C.; Ponce, E.; Maingon, R. D. Leishmania
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Exp. Parasitol. 2005, 109, 209-219.
(
144.63, 147.96, 159.29, 160.13.
4
-[5-Morpholine-4-yl-3-(4-phenoxyphenyl)pyrazol-1-yl]-
(3) Piscopo, T. V.; Mallia Azzopardi, C. Leishmaniasis. Postgrad. Med.
phenylamine (16). To a solution of 14 (70 mg; 0.158 mmol) in
hot ethanol (11.25 mL) was added gradually a solution of sodium
dithionite (0.28 g; 1.58 mmol) in 1 mL of water. The mixture was
refluxed for 1 h, cooled to room temperature, and filtered to remove
inorganic matter. The filtrate was diluted with 3 volumes of water;
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(
5) Renslo, A. R.; McKerrow, J. H. Drug discovery and development
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Jacobs, W. R., Jr.; Fidock, D. A.; Sacchettini, J. C. Structural
elucidation of the specificity of the antibacterial agent triclosan for
malarial enoyl acyl carrier protein reductase. J. Biol. Chem. 2002,
(
then, the pH was brought to 9 with Na
extracted with ethyl acetate (5×). The combined extracts were dried
over Na SO , and the solvent removed. The crude product was
2 3
CO , and the solution was
2
4
277, 13106-13114.
purified by column chromatography (silica gel, ethyl acetate/MeOH,
(
7) Surolia, N.; Surolia, A. Triclosan offers protection against blood
stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium
falciparum. Nat. Med. 2001, 7, 167-173.
first 9:1, then 7:3) to give 16 as a brown solid (30.3 mg, 46.5%).
+
MS: calcd mass for M , 413.5; found, 413.5. Mp 160.7 °C. IR
-
1
(
KBr, cm ): 3439, 3331, 2964, 1629, 1588, 1292, 1232, 1114.
NMR δ (300 MHz, CDCl ): 3.28 (4H, t, J ) 4.8 Hz), 3.85 (4H,
t, J ) 4.8 Hz), 5.91 (1H, s), 6.60 (2H, dt, J ) 9.0, 2.1 Hz), 6.88
2H, dt, J ) 9.0, 2.1 Hz), 7.02 (2H, d, J ) 7.5 Hz), 7.05 (2H, d,
J ) 8.7 Hz), 7.15 (1H, t, J ) 7.5 Hz), 7.17 (2H, d, J ) 8.7 Hz),
.35 (2H, t, J ) 7.2 Hz); the NH signal could not be detected
because of solvent exchange effects; δ (300 MHz, CDCl ): 48.37
2CH ), 66.67 (2CH ), 93.09 (CH), 115.08 (CH), 118.02 (2CH),
19.41 (2CH), 123.75 (2CH), 125.54, 126.66 (2CH), 129.81 (2CH),
29.94 (2CH), 156.34, 157.30.
-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]piperazine (17). Tri-
(8) Tasdemir, D.; Lack, G.; Brun, R.; Ruedi, P.; Scapozza, L.; Perozzo,
R. Inhibition of Plasmodium falciparum fatty acid biosynthesis:
evaluation of FabG, FabZ, and FabI as drug targets for flavonoids.
J. Med. Chem. 2006, 49, 3345-3353.
H
3
(
(
9) Freundlich, J. S.; Anderson, J. W.; Sarantakis, D.; Shieh, H. M.; Yu,
M.; Valderramos, J. C.; Lucumi, E.; Kuo, M.; Jacobs, W. R., Jr.;
Fidock, D. A.; Schiehser, G. A.; Jacobus, D. P.; Sacchettini, J. C.
Synthesis, biological activity, and X-ray crystal structural analysis
of diaryl ether inhibitors of malarial enoyl acyl carrier protein
reductase. Part 1: 4′-substituted triclosan derivatives. Bioorg. Med.
Chem. Lett. 2005, 15, 5247-5252.
10) Go, M. L. Novel antiplasmodial agents. Med. Res. ReV. 2003, 23,
456-487.
11) Campo, J. A.; Cano, M.; Heras, J. V.; Lagunas, M. C.; Perles, J.;
Pinilla, E.; Torres, M. R. Investigation of structural characteristics
of bis(â-diketonato)copper(II) complexes containing alkoxy or aryl-
oxy side chains: X-ray structures of 1,3-bis(4-butoxyphenyl)propane-
7
2
C
3
(
2
2
1
1
(
1
(
fluoroacetic acid (2 mL) was added slowly under argon to an ice-
cooled solution of 12 (169.7 mg; 0.4 mmol) in dichloromethane (2
mL). The mixture was stirred on ice for 1 h and then poured onto
cold water (10 mL). The pH of the solution was brought to 9 by
adding concentrated ammonia, and then, the product was extracted
into dichloromethane (3 × 20 mL). The combined extracts were
1,3-dione, bis[1,3-bis(4-butoxyphenyl)propane-1,3-dionato-κO,κO′]-
copper(II) and bis[1,3-bis(4-phenoxyphenyl)propane-1,3-dionato-
κO,κO′]copper(II). HelV. Chim. Acta 2001, 84, 2316-2329.
12) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.;
Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.;
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DNA gyrase inhibitors with azole ring. Bioorg. Med. Chem. 2004,
12, 5515-5524.
(
2 4
washed with brine (30 mL), dried over Na SO , and concentrated
in vacuo to yield a white precipitation of 17 (116.7 mg, 90.3%).
+
MS: calcd mass for M , 321.4; found, 321.5. Mp 213.3 °C. IR
-
1
(
KBr, cm ): 3266, 3147, 2952, 1591, 1244. NMR δ
H
(300 MHz,
DMSO): 2.79 (4H, t, br, J ) 5.1 Hz), 3.03 (4H, t, br, J ) 5.1 Hz),
(13) Tomisawa, K.; Kameo, K.; Matsunaga, T.; Saito, S.; Hosoda, K.;
Asami, Y.; Sota, K. Studies on hypolipidemic agents. III. Omega-
6
.07 (1H, s, br), 7.04 (2H, d, J ) 7.8 Hz), 7.04 (2H, d, J ) 7.8
(
4-phenoxybenzoyl)-alkanoic acid derivatives. Chem. Pharm. Bull.
Hz), 7.16 (1H, t, J ) 7.2 Hz), 7.41 (2H, t, J ) 7.8 Hz), 7.69 (2H,
d, J ) 8.7 Hz), 12.19 (1H, NH, s, br); the second NH signal could
(Tokyo) 1986, 34, 701-712.
(
14) Mahata, P. K.; Syam Kumar, U. K.; Sriram, V.; Ila, H.; Junjappa,
H. 1-Bis(methoxy)-4-bis(methylthio)-3-buten-2-one: Useful three
carbon synthon for synthesis of five and six membered heterocycles
not be detected because of solvent exchange effects; δ
DMSO): 45.11 (2CH ), 49.06 (2CH
C
(300 MHz,
2
), 88.23 (CH, br), 118.72
2

4
-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine
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