Synthesis of pyrazole-based hybrid molecules: Search for potent multidrug resistance modulators

Article abstract of DOI:10.1016/j.bmc.2006.02.046

The hybrid molecules have been designed on the basis of the structural features of pyrazole-based drugs and MDR modulator propafenone. A simple synthetic strategy and solvent-based regioselectivity have been used for the synthesis of newly designed molecu

Full text of DOI:10.1016/j.bmc.2006.02.046

Bioorganic & Medicinal Chemistry 14 (2006) 5061–5071
Synthesis of pyrazole-based hybrid molecules: Search for
potent multidrug resistance modulators
Palwinder Singh,a,* Kamaldeep Paula and Wolfgang Holzerb
aDepartment of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
bInstitute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Wien, Austria
Received 31 January 2006; revised 23 February 2006; accepted 28 February 2006
Available online 22 March 2006
Abstract—The hybrid molecules have been designed on the basis of the structural features of pyrazole-based drugs and MDR mod-
ulator propafenone. A simple synthetic strategy and solvent-based regioselectivity have been used for the synthesis of newly designed
molecules and they are evaluated for their interactions with P-glycoprotein (P-gp). Some of the molecules show considerable
interactions with P-gp and compounds 15, 28 and 40 could be the potential candidates for their use as MDR modulators.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In continuation with our efforts23 to develop such com-
pounds, which could be used in combination with drugs
for suppressing the activity of P-gp, we explored here the
potential of pyrazole derivatives for their interactions
with P-gp. Since the drugs as well as the modulators
[commonly called multidrug resistance (MDR) modula-
tors] interact with P-gp, it was envisaged that if some of
the structural features of pyrazole-based drug24 (A,
Fig. 1) and a known MDR modulator (propafenone,25
B, Fig. 1) are combined in one molecule (C and D,
Pyrazole derivatives have a broad spectrum of biological
activities being used as antiinflammatory,1 antipyretic,2,3
gastric secretion stimulatory,4 antidepressant,5 against
rheumatoid arthritis,6,7 antibacterial,8 anticonvulsant9
and antifilarial agents10 along with their use as herbi-
cides,11,12 fungicides,13 pesticides,14 insecticides14 and
dyestuffs,15–17 in sunscreen materials18 and as analytical
reagents.19 Variously substituted pyrazoles like 4-acyl-5-
hydroxy-3-methyl-1H-pyrazole (or its tautomers) are
used as the chelating and extracting reagents for many
metal ions20 and are used as starting materials for the
syntheses of biologically active compounds as well as
for the construction of condensed heterocyclic systems.
N
O
O
Ph
N
N
NH(CH2)2CH3
O
A common problem faced by most of the pyrazole-
based drugs is the P-glycoprotein21 (a transporter pro-
tein) mediated efflux from the cells leading to the
decrease in their bio-availability and creating a major
obstacle in the successful practice of chemotherapy for
the treatment of various diseases.22 This necessitates
the use of drugs in combination with another suitable
compound (the modulator), which could block P-gp
and help in increasing the bio-availability of the drugs.
OH
B
A
Anticancer Drugs
Propafenone (modulator)
O
O
R
R
R1
R1
OH
N
O
N
N
NR2R3
O
N
NR2R3
OH
C
D
Keywords: Drugs; Modulators; Hybrid molecules; Synthesis; P-glyco-
protein; Interactions.
Hybrids of A and B
*
Corresponding author. Tel.: +91 183 2258802 09x3495; fax: +91 183
2258819; e-mail: palwinder_singh_2000@yahoo.com
Figure 1.
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.02.046

5062
P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
Fig. 1), the resulting hybrid molecules will interact more
effectively with P-gp. These hybrid molecules when used
along with a pyrazole-based drug will block P-gp and
help to decrease the P-gp mediated efflux of the drug.
equivalents of piperidine to give yellowish oils 12
(30%), 13 (30%) and 14 (28%), respectively (Scheme 2).
Similarly, the reactions of 7–10 with morpholine gave
respective compounds 15 (33%), 16 (30%), 17 (32%)
and 18 (32%) (Scheme 2).
Earlier some analogues of these molecules (C and D,
Fig. 1) were evaluated for their MDR modulating prop-
erties.26 The newly designed compounds (C and D,
Fig. 1) were synthesized and their in vitro interactions
with P-gp have been evaluated. The structure–activity
relationship studies clearly highlight the role of different
fragments of the molecules for interacting with P-gp.
Pyrazole 2 on reaction with 1 equivalent of epichlorohy-
drin gave a white solid (40%), mp 215 ꢁC (decomp.),
which from its spectral data has been assigned the struc-
ture 20 (Scheme 2) and seems to be formed by the imme-
diate reaction of second molecule of pyrazole 2 on the
initially formed intermediate 19. We could not detect
the presence of 19 in this reaction (no appearance of
transient spot in TLC or by recording the NMR of the
reaction mixture at different intervals of time). However,
pyrazole 3 did not react with 1 equivalent of epichloro-
hydrin even on prolonged heating and only starting pyr-
azole was recovered.
2. Results
2.1. Chemistry
Treatment of phenylhydrazine with diethyl ethoxymeth-
ylene malonate in ether followed by the acylation27 with
benzoyl chloride/3-phenylpropionyl chloride in 1,4-diox-
ane using Ca(OH)2 as base gave compounds 1 and 2.
Similar reactions of phenylhydrazine with ethyl acetoac-
etate and ethyl benzoylacetate provided compounds 3–6
(Scheme 1).
The sodium salt of pyrazole 1 on refluxing with epichlo-
rohydrin (solvent) gave a white crystalline solid (65%),
mp 175 ꢁC, that from its spectral data has been assigned
structure 21 (Scheme 3). Similarly, pyrazolones 3, 4, 5
and 6 on treatment with NaH followed by refluxing in
epichlorohydrin gave white solids 22 (65%), 23 (84%),
24 (60%) and 25 (70%), respectively (Scheme 3). In all
these reactions, a small amount (<5%)of O-substituted
product (7, 8, 9 and 10) was also formed.
Treatment of pyrazole 1 with NaH in methanol for
5 min followed by the removal of methanol, addition
of 1 equivalent of epichlorohydrin in dry DMF and
refluxing the reaction mixture gave a yellow oily product
(25%) which from its spectral data has been assigned
structure 7 (Scheme 2) and 30% of starting pyrazole
was recovered. Pyrazoles 4, 5, and 6 also reacted with
1 equivalent of epichlorohydrin under the same reaction
conditions to give yellow oily products 8 (30%), 9 (20%),
and 10 (25%), respectively (Scheme 2).
Compound 21 on stirring with 1.25 equivalent of piper-
idine in dry methanol at 50 ꢁC, after usual work up and
recrystallization (ethanol) gave a white crystalline solid
26 (70%), mp 163 ꢁC, [EI mass m/z 406, (M++1)] whose
1
structure has been confirmed on the basis of H NMR,
decoupling, NOE and 13C normal/DEPT-135 NMR
spectra.
Compound 7 on stirring with 1.25 equivalent of piperi-
dine in dry methanol at 50 ꢁC, after usual work up
and chromatography gave a yellowish oil 11 (30%),
[EI mass m/z 406, (M++1)]. Under the same reaction
conditions, compounds 8, 9 and 10 reacted with 1.25
Compounds 22, 23, 24 and 25 also reacted with 1.25
equivalent of piperidine in dry methanol to give white sol-
id compounds 27 (65%), 28 (64%), 29 (69%) and 30 (71%),
respectively (Scheme 3). Under the same reaction condi-
tions compounds 21–25 reacted with morpholine to give
compounds 31 (70%), 32 (76%), 33 (71%), 34 (70%) and
35 (75%) and their reactions with pyrrolidine gave com-
pounds 36 (72%), 37 (77%), 38 (73%), 39 (67%) and 40
(69%) (Scheme 3). However, pyrazolone 2 on reaction
with excess epichlorohydrin provided compound 20.
R
C2H5O
R
H
N
N
OH
N
C2H5OOC
COOC2H5
NH2
OC2H5
i, ii
Therefore, the reaction of sodium salt of pyrazole with 1
equivalent of epichlorohydrin in DMF gave O-substitut-
ed products 7–10 which on reaction with appropriate
cyclic nitrogen base gave compounds 11–18, while the
reaction of sodium salt of pyrazole with excess epichlo-
rohydrin provided N-substituted products 21–25 which
on further reaction with piperidine, morpholine and
pyrrolidine provided compounds 26–40.
O
R = H
R
iii
i, iii
O
O
O
R
R
R'
R'
3
4
2
HN
1
N
1, R = H, R' = Ph,
2, R = H, R' = CH2CH2Ph
3, R = Ph, R' = Ph
N
O
OH
5
N
The formation of N- and O-alkylated products has been
explained on the basis of the polarity of the reaction sol-
vent. The initially formed Na+ salt of pyrazole (41) gets
polarized in presence of polar solvent (DMF) making
Oꢀ free (42) to react at epoxy ring (route 1, Scheme 4)
forming O-alkylated products 7–10 while in the presence
4, R = Ph, R' = CH2CH2Ph
5, R = CH3, R' = Ph
6, R = CH3, R' = CH2CH2Ph
1-6
Scheme 1. Reagents and condition: (i) Ether, stirring; (ii) KOH, HCl;
(iii) R0COCl, Ca(OH)2, 1,4-dioxane.

P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
5063
O
O
R
R
3
R'
4
O
NaH, DMF
R'
H
H
O
8
+
Cl
1 equivalent
N
N
1
9
OH
7
O
N
Ph
2
5
N
6
Ph
7-10
HN
1, 4-6
NaH, DMF
R = H, R' = CH2CH2Ph
(pyrazole 2)
o
X,
,
MeOH 50 C
O
O
R
H
N
3
R'
4
11 12
Ph
O
2
1
N
8
N
13
X
O
9
N
5
7
O
N
OH
Ph
15
14
Ph
19
11-18
7: R = H, R' = Ph
2
8: R = Ph, R' = CH2CH2Ph
9: R = CH3, R' = Ph
10: R = CH3, R' = CH2CH2Ph
11: R = H, R' = Ph, X = CH2
12: R = Ph, R' = CH2CH2Ph, X = CH2
13: R = CH3, R' = Ph, X = CH2
14: R = CH3, R' = CH2CH2Ph, X = CH2
15: R = H, R' = Ph, X = O
16: R = Ph, R' = CH2CH2Ph, X = O
17: R = CH3, R' = Ph, X = O
NOE
O
O
H
H
H
5
Ph
Ph
4
3
7
6
2
N
N
N
O
O
H
1
N
OH
Ph
Ph
20
18: R = CH3, R' = CH2CH2Ph, X = O
Scheme 2.
O
E
O
O
R
N
R
5
R'
R'
4
3
i) NaH
21: R = H, R' = Ph
1
H
O
N
2
N
HN
O
22: R = Ph, R' = Ph
O
7
6
O
8
N
ii) Cl
23: R = Ph, R' = CH2CH2Ph
24: R = CH3, R' = Ph
25: R = CH3, R' = CH2CH2Ph
H
Ph
Ph
excess
20-24
1, 3-6
, MeOH, 50 oC
HN
O
X
R
1
10
5
4
R'
11
OH
7
8
N
N
2
N
X
O
3
6
31: R = H, R' = Ph, X == OCH2
32 R = Ph, R' = Ph, X = OCH2
12/13 14
Ph
25-39
33: R = Ph, R' = CH2CH2Ph, X = OCH2
34: R = CH3, R' = Ph, X = OCH2
35: R = CH3, R' = CH2CH2Ph, X = OCH2
36: R = H, R' = Ph, X = CH2
37: R = Ph, R' = Ph, X = CH2
38: R = Ph, R' = CH2CH2Ph, X = CH2
39: R = CH3, R' = Ph, X = CH2
26: R = H, R' = Ph, X = CH2CH2
27: R = Ph, R' = Ph, X = CH2CH2
28: R = Ph, R' = CH2CH2Ph, X = CH2CH2
29: R = CH3, R' = Ph, X = CH2CH2
30: R = CH3, R' = CH2CH2Ph, X = CH2CH2
40: R = CH3, R' = CH2CH2Ph, X = CH2
Scheme 3.
of epichlorohydrin, a relatively non-polar solvent, Na+
salt of pyrazole (41), is not polarized and the reaction
takes place from nitrogen (route 2, Scheme 4) which
leads to the formation of N-alkylated products 21–25.
To substantiate the role of solvent in these reactions,
41 (R = CH3, R0 = Ph) was treated with excess epichlo-
rohydrin in DMF where it provided a mixture of 9
(20%) and 24 (35%), while no reaction takes place when
41 (R = CH3, R0 = Ph) was made to react with one
equivalent of epichlorohydrin in benzene or toluene at
refluxing temperatures. Therefore, the solvent-depen-
dent regioselectivity forms the basis for the O-alkyla-
tions and N-alkylations of pyrazoles. The formation of
20 from pyrazole 2, on using DMF or epichlorohydrin
as solvents, seems to be due to the easy transfer of the
dipole of 41 (R = H, R0 = CH2CH2Ph) (Scheme 4)
towards N-2 under both types of reaction conditions.
2.2. Biology
In vitro interactions of the compounds with P-gp were
studied using ‘Drug-P-glycoprotein’ assay kit, which

5064
P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
R'
R'
R
R'
O
R
R
+ Na+. S
route 1
O
DMF
O-
O
N
NaH/MeOH
Na+
N
O-
N
N
H
N
O
N
route 2
Cl
O
42
O
O
41
R'
Cl
Without Solvent
R'
R
O
R
O
O
N
O
N
N
O
N
21-25
7-10
Scheme 4.
contains the P-gp vesicles, prepared from highly resis-
tant MDR cells, the DC-3F/ADX line and permits to
assess the interactions of the compounds with P-gp in
terms of increase in the basal activity or decrease in
the stimulated (verapamil, progesterone induced) activi-
ty of P-gp. Here we have studied the modulation of bas-
al ATPase activity of P-gp, which was measured by
spectrophotometric method by continuous monitoring
of ADP formation in the vesicle suspension medium.
The basal ATPase activity of P-gp is its MgATP hydro-
lysis activity determined in the absence of any added
drug. The interactions of the added compound (test
compound) with P-gp result in the inhibition of ATPase
activity of P-gp, which slows down the conversion of
phosphoenolpyruvate to pyruvate and further to lactate
and hence less conversion of NADH to NAD+. There-
fore, the wells (of the 96-well plate) containing test com-
pounds showing better interactions with P-gp have
higher concentration of NADH in comparison to other
wells in which compounds show less interactions with P-
gp or wells without test compounds (basal activity of P-
gp). As a result, the absorption of NADH at 340 nm, in
the wells where compound-P-gp interactions are better,
gets increased which is manifested as increase in the bas-
al activity of P-gp. As per the manufacturer’s specifica-
tions, a 30% increase (modulation) in the basal activity
of P-gp, on the addition of a compound implies that
the compound is interacting with P-gp.
Table 1. Percentage increase of basal activity of P-gp by pyrazole
derivatives at various concentrations
Compound
% increase of basal activity of P-gpa
50 lM
5 lM
0.5 lM
0.05 lM
15
16
5
16
18
6
31
8
nd
ꢀ0.06
0.00
10
17
18
8
18
10
16
ꢀ0.12
33
35
5
13
27
28
ꢀ0.05
35
10
6
15
30
29
30
ꢀ0.56
16
14
2
15
nd
nd
9
31
32
ꢀ0.10
21
16
ꢀ0.06
4
16
nd
14
30
ꢀ0.50
14
nd
33
34
ꢀ0.23
3
29
13
ꢀ0.05
8
ꢀ0.10
ꢀ0.07
15
35
37
nd
nd
38
40
20
7
ꢀ0.10
19
nd
nd
9
37
Propafenone
Verapamil
Vinblastine
Progesterone
31% (10ꢀ5 M)
33% (6 · 10ꢀ5 M)
31% (10ꢀ5 M)
34% (1.2 · 10ꢀ4 M)
nd, not done.
a A 30% increase in basal activity of P-gp signifies the interaction of the
compound with P-gp.
compounds 16–18 which have CH3 and Ph groups at
C-3. From the N-alkylated pyrazoles 27–40, compounds
27 and 28 with piperidine moiety at the end of C-3 chain
and Ph group at C-5 exhibit significant interactions with
P-gp. However, compound 28 with 3-phenylpropionyl
group at C-4 is better interacting with P-gp than 27 with
benzoyl group at C-4. The replacement of piperidine
moiety in compound 28 with morpholine in compound
33 and with pyrrolidine in compound 38 decreases the
interactions with P-gp. The significant modulation of
P-gp basal activity has been observed when Ph group
of compound 38 was replaced with CH3 group in
compound 40. Therefore, a change of substituent at
one position requires a change at another position for
3. Discussion
The results of the interactions of various compounds
with P-gp at different concentrations are given in
Table 1. The anticancer drugs like progesterone, vinblas-
tine and MDR modulators propafenone and verapamil
are also included for comparison.
It has been found that the compounds 15, 27, 28, 33 and
40 exhibit significant interaction with P-gp. Amongst the
O-alkylated pyrazoles 15–18, compound 15 with H at
C-3 shows better interaction with P-gp than the

P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
5065
showing significant interactions with P-gp and a further
tuning of the molecules could improve their interactions
with P-gp.
and CH carbons and ꢀve signals correspond to CH2 car-
bons in the DEPT-135 NMR spectrum. UV spectra were
recorded on a UV-1601 PC-Shimadzu UV–Visible Spec-
trophotometer by using CH3CN as a solvent. Infrared
spectra were recorded on an FTIR Shimadzu 8400 spec-
trometer on a thin dispersed film (chloroform) or on the
solid surface using KBr as medium. The EI mass spectra
were recorded on ‘‘Electrospray Ionization Interface in
the +ve mode’’ and the FAB mass was recorded on a
JEOL SX 102/DA-6000 Mass Spectrometer/Data System
using argon/xenon (6 kV, 10 mA) as the FAB gas. Col-
umn chromatography separations were performed on
Merck Kiesel gel 60–120 meshes. Yields given below are
not optimized and refer to analytically pure material.
The drug–P-glycoprotein interaction assay kit was pur-
chased from Cayman Chemical.
The whole set of compounds could be divided into two
categories: one with compounds 15, 28 and 40 showing
best interactions with P-gp at 0.5 lM concentration
and no dose responses are observed which reflects the
saturation of P-gp and necessitates the evaluation of
these compounds at further low concentrations and
the second category of compounds showing interactions
at 50 lM (27 and 33) concentration or no interactions
(all other compounds) with P-gp and hence no dose
dependency.
Since the structural features of a molecule affect its bio-
logical activities, the properties of the hybrid molecules
(C and D, Fig. 1), obtained by the mixing of two mole-
cules (A and B, Fig. 1), both of which interact with P-gp,
are clearly expressed in the form of better interactions
with P-gp than the parent MDR modulator, propafen-
one (B, Fig. 1) and some of the anticancer drugs (pro-
gesterone and vinblastine) studied here. Due to the
interactions of the anticancer drugs and MDR modula-
tors with the same protein (P-gp), the idea of synthesiz-
ing and evaluating the hybrid molecules will provide a
new platform for the development of better MDR mod-
ulators. However, for a hybrid molecule to be more ac-
tive than the parent molecules, a suitable combination of
substituents placed at the appropriate positions of hy-
brid molecules is very important. The interactions of 3
of the 16 compounds studied here, viz. 15, 28 and 40,
with P-gp are better than those exhibited by anticancer
drugs (progesterone and vinblastine) and MDR modula-
tors propafenone and verapamil, these three compounds
could be further explored for their in vivo MDR modu-
lating properties.
5.1. General procedure of compounds 1–6
With stirring, to a mixture of pyrazolone27 (10 mmol)
and Ca(OH)2 (20 mmol) in dry 1,4-dioxane was added
the appropriate acid chloride (10 mmol) and the reac-
tion mixture was refluxed at 100 ꢁC for 3 h. After cool-
ing to room temperature, 2 N HCl was added and
stirring was continued for 1 h. Then water was added
and the mixture was further stirred for 10 min. The pre-
cipitates were filtered off, washed several times with
water and dried to get a solid product.
5.1.1. 4-Benzoyl-1-phenyl-1,2-dihydropyrazol-5-one (1).
1
Mp 115 ꢁC (ethanol); yield 71%; H NMR (300 MHz)
d 7.39–7.74 (m, 10H, 2· Ph), 7.82 (s, 1H, H-3); 13C nor-
mal/DEPT-135 NMR (75 MHz) d 106 (C-4), 123.3 (+ve,
ArCH), 127.7 (+ve, ArCH), 128.0 (+ve, ArCH), 128.3
(+ve, ArCH), 129.3 (+ve, ArCH), 132.0 (+ve, ArCH),
137.7 (N-ArC), 139.0 (ArC), 143.0 (+ve, C-3), 154.7
(C-5), 190.0 (C@O); UV (CH3CN) kmax (nm): 280, 230.
5.1.2. 1-Phenyl-4-(3-phenylpropionyl)-1,2-dihydropyra-
zol-5-one (2). Mp 128 ꢁC (ethanol); yield 71%; 1H
NMR (300 MHz) d 3.08 (s, 4H, CH2CH2), 7.23–7.84
(m, 10H, 2· Ph), 7.74 (1H, s, H-3); 13C normal/DEPT-
135 NMR (75 MHz) d 30.3 (ꢀve, CH2), 40.4 (ꢀve,
CH2), 104.5 (C-4), 120.9 (+ve, ArCH), 126.4 (+ve,
ArCH), 127.0 (+ve, ArCH), 128.3 (+ve, ArCH), 128.6
(+ve, ArCH), 129.1 (+ve, ArCH), 137.3 (N-ArC),
138.3 (+ve, C-3), 140.4 (ArC), 158.2 (C-5), 197.0
(C@O); UV (CH3CN) kmax (nm): 262, 234.
4. Conclusions
The hybrid molecules (C and D, Fig. 1) carrying the
structural features of the pyrazole-based drugs as well
as the MDR modulators (propafenone) were synthe-
sized by following the simple synthetic strategies and
exploiting the solvent-based tautomerism of pyrazoles.
The compounds 15, 28 and 40 showing significant inter-
actions with P-gp at sub-micromolar concentrations
could be the potential MDR modulators and provide
a new facet for the synthesis of hybrid molecules as
MDR modulators.
5.1.3. 4-Benzoyl-1,3-diphenyl-1,2-dihydropyrazol-5-one
(3). Mp 122 ꢁC (ethanol); yield 68%; 1H NMR
(300 MHz) d 7.18–8.00 (m, 15H, 3· Ph); 13C normal/
DEPT-135 NMR (75 MHz) d 109.7 (C-4), 123.3 (+ve,
ArCH), 127.1 (+ve, ArCH), 127.9 (+ve, ArCH), 128.1
(+ve, ArCH), 128.3 (+ve, ArCH), 128.6 (+ve, ArCH),
129.4 (+ve, ArCH), 130.5 (+ve, ArCH), 132.2 (+ve,
ArCH), 134.3 (ArC), 137.9 (N-ArC), 145.6 (ArC),
151.8 (C-3), 162.2 (C-5), 189.6 (C@O); UV (CH3CN)
kmax (nm): 244.
5. Experimental
Melting points were determined in open capillaries and
1
are uncorrected. The H and 13C NMR spectra were
recorded on Bruker 300 MHz and JEOL JNM
300 MHz NMR spectrometers using CDCl3 solution
containing tetramethylsilane as an internal standard.
The chemical shifts are reported in d values relative to
TMS and coupling constants (J) are expressed in Hz. In
13C NMR spectral data, +ve signals correspond to CH3
5.1.4.
1,3-Diphenyl-4-(3-phenylpropionyl)-1,2-dihydro-
1
pyrazol-5- one (4). Mp 130 ꢁC (ethanol); yield 65%; H
NMR (300 MHz) d 2.76 (t, J = 5.0 Hz, 2H, CH2), 2.88

5066
P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
(t, J = 5.0 Hz, 2H, CH2), 6.94–7.93 (m, 15H, 3· Ph); 13
C
128.2 (+ve, ArCH), 128.3 (+ve, ArCH), 128.8 (+ve,
ArCH), 129.1 (+ve, ArCH), 132.4 (+ve, ArCH), 133.4
(ArC), 137.2 (N-ArC), 140.9 (ArC), 151.9 (C-3), 153.7
(C-5), 195.7 (C@O).
normal/DEPT-135 NMR (75 MHz) d 30.9 (ꢀve, CH2),
40.2 (ꢀve, CH2), 103.6 (C-4), 121.0 (+ve, ArCH),
126.2 (+ve, ArCH), 126.8 (+ve, ArCH), 128.2 (+ve,
ArCH), 128.4 (+ve, ArCH), 128.6 (+ve, ArCH), 129.1
(+ve, ArCH), 129.3 (+ve, ArCH), 133.1 (ArC), 137.3
(N-ArC), 140.2 (ArC), 151.1 (C-3), 160.5 (C-5), 197.4
(C@O); UV (CH3CN) kmax (nm): 257.
5.2.3. (3-Methyl-5-oxiranylmethoxy-1-phenyl-1H-pyra-
zol-4-yl)-phenylmethanone (9). Column chromatogra-
phy (eluent: hexane–ethyl acetate, 8:2) afforded a
1
yellowish oil; yield 20%; H NMR (300 MHz) d 2.27
5.1.5. 3-Methyl-1-phenyl-4-(3-phenylpropionyl)-1,2-dihy-
dro-pyrazol-5-one (6). Mp 118 ꢁC (ethanol); yield 65%;
1H NMR (300 MHz) d 2.41 (s, 3H, CH3), 3.04 (s, 4H,
CH2CH2), 7.19–7.85 (m, 10H, 2· Ph); 13C normal/
DEPT-135 NMR (75 MHz) d 15.7 (+ve, CH3), 30.1
(ꢀve, CH2), 40.7 (ꢀve, CH2), 106.0 (C-4), 120.4 (+ve,
ArCH), 126.3 (+ve, ArCH), 128.2 (+ve, ArCH), 128.6
(+ve, ArCH), 128.9 (+ve, ArCH), 130.2 (+ve, ArCH),
137.3 (N-ArC), 140.5 (ArC), 147.0 (C-3), 160.4 (C-5),
196.0 (C=O); UV (CH3CN) kmax (nm): 264, 235.
(s, 3H, CH3), 2.29 (dd, 2J = 4.9 Hz, 3J = 2.6 Hz, 1H,
H-9), 2.59 (dd, 2J = 6.6 Hz, 3J = 4.9 Hz, 1H, H-9),
2
3
2.84 (m, 1H, H-8), 3.71 (dd, J = 8.0 Hz, J = 3.2 Hz,
1H, H-7), 4.02 (dd, 2J = 8.0 Hz, 3J = 6.1 Hz, 1H, H-
7), 7.34-7.84 (m, 10H, 2· Ph); 13C normal/DEPT-135
NMR (75 MHz) d 15.4 (+ve, CH3), 30.1 (ꢀve, C-9),
44.5 (ꢀve, C-7), 49.5 (+ve, C-8), 107.5 (C-4), 123.6
(+ve, ArCH), 127.9 (+ve, ArCH), 128.9 (+ve, ArCH),
129.8 (+ve, ArCH), 132.9 (+ve, ArCH), 137.8 (N-
ArC), 139.5 (ArC), 150.7 (C-3), 154.1 (C-5), 190.8
(C@O).
5.2. General procedure for the preparation of (5-oxira-
nylmethoxy-1-phenyl-4-acyl-1H-pyrazol) derivatives 7–10
5.2.4. 1-(3-Methyl-5-oxiranylmethoxy-1-phenyl-1H-pyra-
zol-4-yl)-3-phenylpropan-1-one (10). Column chromatog-
raphy (eluent: hexane–ethyl acetate, 8:2) afforded a
Twenty-four milligram (1 mmol) of NaH after washing
with dry hexane was dissolved in dry methanol (5 ml).
Appropriate pyrazoles 1–6 (1 mmol) were added to the
above solution and stirred for 5 min. Methanol was re-
moved under vacuum and the residue was dissolved in
10 ml of dry DMF. To this solution, 0.064 ml (1 mmol)
of epichlorohydrin was added and the reaction mixture
was stirred at 105 ꢁC for 18 h. After filtration, DMF
was removed under vacuum. The remaining gummy
material was purified by column chromatography on sil-
ica gel using ethyl acetate and hexane (2:8) as eluent.
1
yellowish oil; yield 25%; H NMR (300 MHz) d 2.69
(s, 3H, CH3), 2.88 (dd, 2J = 7.6 Hz, 3J = 4.6 Hz, 1H,
H-9), 2.92 (t, J = 8.0 Hz, 2H, CH2), 3.00 (dd,
3
2J = 7.6 Hz, J = 4.0 Hz, 1H, H-9), 3.11 (t, J = 8.0 Hz,
2H, CH2), 3.17 (m, 1H, H-8), 3.70 (dd, J = 12.3 Hz,
2
3J = 7.2 Hz, 1H, H-7), 4.09 (dd, 2J = 12.3 Hz,
3J = 7.0 Hz, 1H, H-7), 7.13–7.49 (m, 10H, 2· Ph).
5.3. General procedure for the reaction of epoxy com-
pounds 7–10 with piperidine and morpholine
5.2.1.
(5-Oxiranylmethoxy-1-phenyl-1H-pyrazol-4-yl)-
One millimole of appropriate epoxy compounds 7–10
and 0.06 ml (1.25 mmol) piperidine/morpholine were
taken in dry methanol and stirred at 50 ꢁC. After the
completion of the reaction (TLC), methanol was
removed under vacuum to get a gummy residue. Com-
pounds 11–18 were purified by column chromatogra-
phy by silica gel using hexane–ethyl acetate (7:3) as
eluent.
phenylmethanone (7). Column chromatography (eluent:
hexane–ethyl acetate, 8:2) afforded a yellowish oil; yield
25%; 1H NMR (300 MHz) d 2.56 (dd, 2J = 5.2 Hz,
3J = 3.0 Hz, 1H, H-9), 2.77 (dd, 2J = 4.8 Hz,
3J = 2.8 Hz, 1H, H-9), 3.24 (m, 1H, H-8), 4.24 (dd,
2J = 12.2 Hz, 3J = 5.8 Hz, 1H, H-7), 4.74 (dd,
2J = 13.8 Hz, 3J = 6.0 Hz, 1H, H-7), 7.39–7.87 (m,
10H, 2· Ph), 7.79 (s, 1H, H-3); 13C normal/DEPT-135
NMR (75 MHz) d 44.1 (ꢀve, C-9), 49.8 (+ve, C-8),
76.1 (ꢀve, C-7), 107.8 (C-4), 123.5 (+ve, ArCH), 127.9
(+ve, ArCH), 128.5 (+ve, ArCH), 129.1 (+ve, ArCH),
132.4 (+ve, ArCH), 137.5 (N-ArC), 139.1 (ArC), 142.9
(+ve, C-3), 154.8 (C-5), 188.7 (C@O); UV(CH3CN) kmax
(nm): 272, 239.
5.3.1. [5-(2-Hydroxy-3-piperidin-1-yl-propoxy)-1-phenyl-
1H-pyrazol-4-yl]-phenylmethanone (11). Column chro-
matography (eluent: hexane–ethyl acetate, 7:3) afforded
1
a yellowish oil; yield 30%; H NMR (300 MHz) d 1.42
(m, 2H, H-13), 1.54 (m, 4H, H-12, H-14), 2.34 (m, 4H,
H-11/H-15, H-9), 2.52 (m, 2H, H-11/H-15), 3.10 (br s,
1H, OH, exchangeable with D2O), 3.98 (m, 1H, H-8),
2
3
5.2.2. 1-(5-Oxiranylmethoxy-1,3-diphenyl-1H-pyrazol-4-
yl)-3-phenylpropan-1-one (8). Column chromatography
(eluent: hexane–ethyl acetate, 8:2) afforded a yellowish
oil; yield 30%; 1H NMR (300 MHz) d 2.50 (dd,
4.24 (dd, J = 10.4 Hz, J = 5 Hz, 1H, H-7), 4.32 (dd,
2J = 10.4 Hz, 3J = 3.4 Hz, 1H, H-7), 7.37–7.87 (m,
10H, 2· Ph), 7.78 (s, 1H, H-3); 13C normal/DEPT-135
NMR (75 MHz) d 23.9 (ꢀve, C-13), 25.7 (ꢀve, C-
12,C-14), 54.6 (ꢀve, C-11,C-15), 60.2 (ꢀve, C-9), 65.5
(+ve, C-8), 77.1 (ꢀve, C-7), 107.7 (C-4), 123.4 (+ve,
ArCH), 127.9 (+ve, ArCH), 128.2 (+ve, ArCH), 128.5
(+ve, ArCH), 128.7 (+ve, ArCH), 132.4 (+ve, ArCH),
137.4 (N-ArC), 138.9 (ArC), 142.8 (+ve, C-3), 155.4
(C-5), 188.9 (C@O); EI MS m/z 406 (M++1). Anal.
Calcd for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.35; H, 6.87; N, 10.01.
3
2J = 4.8 Hz, J = 2.7 Hz, 1H, H-9), 2.74 (t, J = 4.5 Hz,
1H, H-9), 2.87 (m, 4H, 2· CH2), 3.16 (m, 1H, H-8),
2
3
3.92 (dd, J = 11.1 Hz, J = 6.6 Hz, 1H, H-7), 4.36 (dd,
2J = 11.1 Hz, 3J = 3.0 Hz, 1H, H-7), 7.01–7.75 (m,
15H, 3· Ph); 13C normal/DEPT-135 NMR (75 MHz) d
30.2 (ꢀve, CH2), 43.5 (ꢀve, CH2), 44.2 (ꢀve, C-9),
49.6 (+ve, C-8), 76.8 (ꢀve, C-7), 109.0 (C-4), 123.4
(+ve, ArCH), 125.8 (+ve, ArCH), 127.9 (+ve, ArCH),

P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
5067
5.3.2. 1-[5-(2-Hydroxy-3-piperidin-1-yl-propoxy)-1,3-di-
phenyl-1H-pyrazol-4-yl]-3-phenyl-propan-1-one (12).
C27H33N3O3: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.35; H, 7.87; N, 9.20.
Column chromatography (eluent: hexane–ethyl acetate,
7:3) afforded a yellowish oil; yield 30%; 1H NMR
(300 MHz) d 1.26 (m, 2H, H-13), 1.60 (m, 4H, H-12,
5.3.5. [5-(2-Hydroxy-3-morpholin-4-yl-propoxy)-1-phen-
yl-1H-pyrazol-4-yl]-phenylmethanone (15). Column chro-
matography (eluent: hexane–ethyl acetate, 7:3) afforded
2
H-14), 2.05 (m, 2H, H-11/H-15), 2.10 (dd, J = 8.8 Hz,
3J = 3.0 Hz, 2H, H-9), 2.20 (m, 2H, H-11/H-15), 2.75
(t, J = 8.0 Hz, 2H, CH2), 2.95 (t, J = 8.0 Hz, 2H,
CH2), 3.42 (m, 1H, H-8), 3.49 (dd, 2J = 8.4 Hz,
3J = 4.4 Hz, 1H, H-7), 3.56 (dd, 2J = 8.4 Hz,
3J = 6.2 Hz, 1H, H-7), 6.73–8.03 (m, 15H, 3· Ph); 13C
normal/DEPT-135 NMR (75 MHz) d 20.2 (ꢀve, C-13),
29.8 (ꢀve, CH2), 29.9 (ꢀve, C-12, C-14), 43.5 (ꢀve,
CH2), 49.0 (ꢀve, C-11, C-15), 60.3 (ꢀve, C-9), 65.7
(+ve, C-8), 78.3 (ꢀve, C-7), 107.9 (C-4), 123.3 (+ve,
ArCH), 125.8 (+ve, ArCH), 128.1 (+ve, ArCH), 128.2
(+ve, ArCH), 128.3 (+ve, ArCH), 128.4 (+ve, ArCH),
128.6 (+ve, ArCH), 129.3 (+ve, ArCH), 133.2 (ArC),
137.4 (N-ArC), 140.7 (ArC), 152.1 (C-3), 154.4 (C-5),
196.8 (C@O); UV kmax (nm): 291, 253; EI MS m/z 510
(M++1). Anal. Calcd for C32H35N3O3: C, 75.41; H,
6.92; N, 8.25. Found: C, 75.30; H, 6.85; N, 8.01.
a yellowish oil: yield 33%; H NMR (300 MHz) d 2.46
(m, 6H, H-11, H-15, H-9), 3.68 (t, J = 4.8 Hz, 4H, H-
1
2
12, H-14), 3.97 (m, 1H, H-8), 4.24 (dd, J = 10.5 Hz,
3J = 5.4 Hz, 1H, H-7), 4.37 (dd, 2J = 10.5 Hz,
3J = 3.3 Hz, 1H, H-7), 7.27–7.85 (m, 10H, 2· Ph), 7.79
(s, 1H, H-3); 13C normal/DEPT-135 NMR (75 MHz) d
53.6 (ꢀve, C-11, C-15), 60.0 (ꢀve, C-9), 65.6 (+ve,
C-8), 66.7 (ꢀve, C-12, C-14), 77.5 (ꢀve, C-7), 106.8
(C-4), 123.1 (+ve, ArCH), 127.5 (+ve, ArCH), 128.3
(+ve, ArCH), 129.0 (+ve, ArCH), 129.1 (+ve, ArCH),
132.5 (+ve, ArCH), 137.3 (N-ArC), 139.0 (ArC), 150.2
(+ve, C-3), 154.1 (C-5), 190.4 (C@O); FAB MS m/z
408 (M++1). Anal. Calcd for C23H25N3O4: C, 67.80;
H, 6.18; N, 10.31. Found: C, 67.72; H, 6.25; N, 10.12.
5.3.6. 1-[5-(2-Hydroxy-3-morpholin-4-yl-propoxy)-1,3-di-
(16).
phenyl-1H-pyrazol-4-yl]-3-phenyl-propan-1-one
5.3.3. [5-(2-Hydroxy-3-piperidin-1-yl-propoxy)-3-methyl-
1-phenyl-1H-pyrazol-4-yl]-phenylmethanone (13). Col-
umn chromatography (eluent: hexane–ethyl acetate,
7:3) afforded a yellowish oil; yield 30%; 1H NMR
(300 MHz) d 1.40 (m, 2H, H-13), 1.50 (m, 4H, H-12,
H-14), 2.06 (dd, 2J = 7.4 Hz, 3J = 4.8 Hz, 2H, H-9),
2.18 (m, 2H, H-11/H-15), 2.28 (s, 3H, CH3), 2.39 (m,
2H, H-11/H-15), 3.61 (m, 1H, H-8), 3.75 (dd,
Column chromatography (eluent: hexane–ethyl acetate,
7:3) afforded a yellowish oil; yield 30%; 1H NMR
(300 MHz) d 2.38 (m, 4H, H-11/H-15, H-9), 2.49 (m,
2H, H-11/H-15), 2.86 (m, 4H, 2· CH2, two triplets
merged), 3.66 (t, J = 4.5 Hz, 4H, H-12, H-14), 3.90 (m,
2
3
1H, H-8), 4.02 (dd, J = 9.9 Hz, J = 5.4 Hz, 1H, H-7),
2
3
4.12 (dd, J = 9.9 Hz, J = 3.3 Hz, 1H, H-7), 6.97–7.74
(m, 15H, 3· Ph); 13C normal/DEPT-135 NMR
(75 MHz) d 30.2 (ꢀve, CH2), 43.6 (ꢀve, CH2), 53.6
(ꢀve, C-11, C-15), 60.1 (ꢀve, C-9), 65.6 (+ve, C-8),
66.7 (ꢀve, C-12, C-14), 78.0 (ꢀve, C-7), 108.9 (C-4),
123.5 (+ve, ArCH), 125.8 (+ve, ArCH), 128.0 (+ve,
ArCH), 128.2 (+ve, ArCH), 128.3 (+ve, ArCH), 128.4
(+ve, ArCH), 128.8 (+ve, ArCH), 129.1 (+ve, ArCH),
133.4 (ArC), 137.3 (N-ArC), 140.8 (ArC), 152.0 (C-3),
154.2 (C-5), 196.1 (C@O); FAB MS m/z 512 (M++1).
Anal. Calcd for C31H33N3O4: C, 72.78; H, 6.50; N,
8.21. Found: C, 72.70; H, 6.55; N, 8.05.
3
2J = 8.8 Hz, J = 6.0 Hz, 2H, H-7), 7.32–7.97 (m, 10H,
2· Ph); 13C normal/DEPT-135 NMR (75 MHz) d 14.9
(+ve, CH3), 23.9 (ꢀve, C-13), 25.7 (ꢀve, C-12, C-14),
54.5 (ꢀve, C-11, C-15), 60.1 (ꢀve, C-9), 65.0 (+ve, C-
8), 78.0 (ꢀve, C-7) 107.0 (C-4), 123.3 (+ve, ArCH),
127.5 (+ve, ArCH), 128.4 (+ve, ArCH), 129.0 (+ve,
ArCH), 129.2 (+ve, ArCH), 132.5 (+ve, ArCH), 137.7
(N-ArC), 139.3 (ArC), 150.4 (C-3), 154.3 (C-5), 190.5
(C@O); UV kmax (nm): 291, 246; EI MS m/z 420
(M++1). Anal. Calcd for C25H29N3O3: C, 71.57; H,
6.97; N, 10.02. Found: C, 71.55; H, 6.82; N, 10.09.
5.3.7. [5-(2-Hydroxy-3-morpholin-4-yl-propoxy)-3-meth-
yl-1-phenyl-1H-pyrazol-4-yl]-phenylmethanone (17). Col-
umn chromatography (eluent: hexane–ethyl acetate,
7:3) afforded a yellowish oil; yield 32%; 1H NMR
(300 MHz) d 2.03 (m, 4H, H-11/H-15, H-9), 2.39 (m,
2H, H-11/H-15), 2.84 (s, 3H, CH3), 3.38 (t, J = 6.9 Hz,
2H, H-7), 3.64 (t, J = 4.8 Hz, 4H, H-12, H-14), 3.77
(m, 1H, H-8), 7.27–7.85 (m, 10H, 2· Ph); 13C normal/
DEPT-135 NMR (75 MHz) d 14.8 (+ve, CH3), 53.3 (-
ꢀve, C-11, C-15), 59.8 (ꢀve, C-9), 65.0 (+ve, C-8),
66.4 (ꢀve, C-12, C-14), 77.7 (ꢀve, C-7), 106.8 (C-4),
123.1 (+ve, ArCH), 127.5 (+ve, ArCH), 128.3 (+ve,
ArCH), 129.0 (+ve, ArCH), 129.1 (+ve, ArCH), 132.5
(+ve, ArCH), 137.3 (N-ArC), 139.0 (ArC), 150.2 (C-3),
154.1 (C-5), 190.4 (C@O); FAB MS m/z 422 (M++1).
Anal. Calcd for C24H27N3O4: C, 68.39; H, 6.46; N,
9.97. Found: C, 68.35; H, 6.67; N, 9.90.
5.3.4. 1-[5-(2-Hydroxy-3-piperidin-1-yl-propoxy)-3-meth-
yl-1-phenyl-1H-pyrazol-4-yl]-3-phenyl-propan-1-one (14).
Column chromatography (eluent: hexane–ethyl acetate,
7:3) afforded a yellowish oil; yield 28%; 1H NMR
(300 MHz) d 1.30 (m, 2H, H-13), 1.42 (m, 4H, H-12,
2
H-14), 1.70 (dd, J = 5.8 Hz, 3J = 4.0, 2H, H-9), 2.15
(m, 2H, H-11/H-15), 2.45 (m, 2H, H-11/H-15), 2.73
(s, 3H, CH3), 2.98 (t, J = 8.0 Hz, 2H, CH2), 3.09 (t,
J = 8.0 Hz, 2H, CH2), 3.38 (m, 1H, H-8), 3.81 (dd,
2J = 7.2 Hz, 3J = 5.8 Hz, 2H, H-7), 7.24–7.80 (m,
10H, 2· Ph); 13C normal/DEPT-135 NMR (75 MHz)
d 13.1 (+ve, CH3), 19.1 (ꢀve, C-13), 29.8 (ꢀve, C-12,
C-14), 30.1 (ꢀve, CH2), 43.1 (ꢀve, CH2), 48.2 (ꢀve,
C-11, C-15), 59.0 (ꢀve, C-7), 61.0 (ꢀve, C-9), 70.3
(+ve, C-8), 105.0 (C-4), 125.6 (+ve, ArCH), 128.0
(+ve, ArCH), 128.5 (+ve, ArCH), 129.0 (+ve, ArCH),
129.5 (+ve, ArCH), 130.0 (+ve, ArCH), 132.1 (+ve,
ArCH), 134.0 (N-ArC), 141.8 (ArC), 158.0 (C-3),
165.0 (C-5), 196.0 (C@O); UV kmax (nm): 291, 246;
EI MS m/z 448 (M++1). Anal. Calcd for
5.3.8.
1-[5-(2-Hydroxy-3-morpholin-4-yl-propoxy)-3-
methyl-1-phenyl-1H-pyrazol-4-yl]-3-phenyl-propan-1-one
(18). Column chromatography (eluent: hexane–ethyl

5068
P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
acetate, 7:3) afforded a yellowish oil; yield 32%; 1H
NMR (300 MHz) d 2.12 (m, 4H, H-11/H-15, H-9),
2.42 (m, 2H, H-11/H-15), 2.74 (s, 3H, CH3), 2.97 (t,
J = 7.8 Hz, 2H, CH2), 3.24 (t, J = 7.8 Hz, 2H, CH2),
3.56 (t, J = 4.2 Hz, 4H, H-12, H-14), 3.74 (m, 1H, H-
8), 3.78 (m, 2H, H-7 merged with H-8), 7.11–7.51 (m,
10H, 2· Ph); 13C normal/DEPT-135 NMR (75 MHz) d
16.0 (+ve, CH3), 29.8 (ꢀve, CH2), 43.2 (ꢀve, CH2),
53.4 (ꢀve, C-11, C-15), 60.0 (ꢀve, C-9), 65.2 (+ve, C-
8), 66.7 (ꢀve, C-12, C-14), 77.4 (ꢀve, C-7), 108.6 (C-
4), 123.4 (+ve, ArCH), 125.9 (+ve, ArCH), 127.9 (+ve,
ArCH), 128.3 (+ve, ArCH), 129.2 (+ve, ArCH), 137.3
(N-ArC), 141.4 (ArC), 150.1 (C-3), 154.5 (C-5), 194.3
(C@O); FAB MS m/z 450 (M++1). Anal. Calcd for
C26H31N3O4: C, 69.47; H, 6.95; N, 9.35. Found: C,
69.30; H, 6.86; N, 9.22.
3J = 2.5 Hz, 1H, H-8), 2.51 (dd, 2J = 4.8 Hz,
3J = 4.5 Hz, 1H, H-8), 2.86 (m, 1H, H-7), 3.49 (dd,
2J = 15.8 Hz, 3J = 6.6 Hz, 1H, H-6), 3.88 (dd,
2J = 15.8 Hz, 3J = 3.4 Hz, 1H, H-6), 7.28–7.80 (m,
15H, 3· Ph); 13C normal/DEPT-135 NMR
(75 MHz) d 44.3 (ꢀve, C-8), 47.9 (+ve, C-7), 51.1
(ꢀve, C-6), 110.1 (C-4), 125.0 (+ve, ArCH), 127.4
(+ve, ArCH), 127.6 (+ve, ArCH), 128.1 (+ve, ArCH),
128.7 (+ve, ArCH), 129.2 (+ve, ArCH), 129.5 (+ve,
ArCH), 130.6 (+ve, ArCH), 132.7 (+ve, ArCH),
134.0 (ArC), 134.4 (N-ArC), 137.6 (ArC), 159.7
(C-5), 162.2 (C-3), 188.5 (C@O); UV kmax (nm):
249, 319.
5.4.3. 1-Oxiranylmethyl-2,5-diphenyl-4-(3-phenylpropio-
nyl)-1,2-dihydro-pyrazol-3-one (23). Mp 170 ꢁC (etha-
nol); yield 84%; 1H NMR (300 MHz) d 2.89 (dd,
3
5.3.9. Compound 20. Mp 215 ꢁC [decomp.] (ethanol);
2J = 4.8 Hz, J = 2.4 Hz, 1H, H-8), 2.93 (t, J = 6.0 Hz,
1
yield 40%; H NMR (CDCl3/DMSO-d6) (300 MHz) d
2H, CH2), 3.03 (t, J = 6.0 Hz, 2H, CH2), 3.11 (dd,
3
2.83 (t, J = 5.2 Hz, 4H, CH2), 3.03 (t, J = 5.2 Hz, 4H,
CH2), 3.38 (m, 1H, H-7) 3.55 (dd, 2J = 10.0 Hz,
3J = 2.4 Hz, 2H, H-6), 3.65 (dd, 2J = 10.0 Hz,
3J = 5.8 Hz, 2H, H-6), 7.13–7.49 (m, 20H, 4· Ph), 8.45
(s, 2H, H-5); 13C normal/DEPT-135 NMR (75 MHz) d
29.3 (ꢀve, CH2), 41.6 (ꢀve, CH2), 52.6 (ꢀve, C-6),
64.2 (+ve, C-7), 106.7 (C-4), 125.7 (+ve, ArCH), 126.4
(+ve, ArCH), 128.1 (+ve, ArCH), 128.2 (+ve, ArCH),
128.3 (+ve, ArCH), 129.3 (+ve, ArCH), 133.1 (N-
ArC), 141.6 (ArC), 145.4 (+ve, C-5), 162.9 (C-3), 192.4
(C@O); UV kmax (nm): 303, 240; IR (cmꢀ1): 1630
(C@O), 3310 (OH).
2J = 4.8 Hz, J = 4.4 Hz, 1H, H-8), 3.35 (m, 1H, H-7),
2
3
3.67 (dd, J = 15.6 Hz, J = 6.4 Hz, 1H, H-6), 3.70 (dd,
2J = 15.6 Hz, 3J = 3.8 Hz, 1H, H-6), 7.12–7.57 (m,
15H, 3· Ph); 13C normal/DEPT-135 NMR (75 MHz) d
29.7 (ꢀve, CH2), 43.2 (ꢀve, CH2), 50.5 (ꢀve, C-8),
58.8 (+ve, C-7), 66.9 (ꢀve, C-6), 107.4 (C-4), 125.4
(+ve, ArCH), 125.6 (+ve, ArCH), 128.1 (+ve, ArCH),
128.2 (+ve, ArCH), 128.4 (+ve, ArCH), 128.6 (+ve,
ArCH), 129.5 (+ve, ArCH), 130.0 (+ve, ArCH), 130.4
(ArC), 134.0 (N-ArC), 141.6 (ArC), 160.2 (C-5), 164.1
(C-3), 194.2 (C@O).
5.4.4.
1,2-dihydro-pyrazol-3-one (24). Mp 138 ꢁC (ethanol);
yield 60%; 1H NMR (300 MHz)
2.43 (dd,
4-Benzoyl-5-methyl-1-oxiranylmethyl-2-phenyl-
5.4. Synthesis of (4-acyl-1-oxiranylmethyl-2-phenyl-1H-
pyrazole) derivatives 21–25
d
2J = 4.5 Hz, 3J = 2.5 Hz, 1H, H-8), 2.65 (s, 3H,
CH3), 2.74 (dd, 2J = 4.5 Hz, 3J = 4.0 Hz, 1H, H-8),
3.01 (m, 1H, H-7), 3.78 (dd, 2J = 15.9 Hz,
3J = 6.1 Hz, 1H, H-6), 4.04 (dd, 2J = 15.9 Hz,
3J = 3.2 Hz, 1H, H-6), 7.30–7.95 (m, 10H, 2· Ph);
13C normal/DEPT-135 NMR (75 MHz) d 12.5 (+ve,
CH3), 45.2 (ꢀve, C-8), 48.2 (ꢀve, C-6), 48.9 (+ve,
C-7), 108.2 (C-4), 126.2 (+ve, ArCH), 127.7 (+ve,
ArCH), 128.3 (+ve, ArCH), 129.4 (+ve, ArCH),
129.5 (+ve, ArCH), 132.2 (+ve, ArCH), 134.3 (N-
ArC), 138.4 (ArC), 159.1 (C-5), 163.8 (C-3), 190.4
(C@O); UV kmax (nm): 239, 315.
Twenty-four milligram (1 mmol) of NaH was dissolved
in 5 ml of dry methanol followed by the addition of
1 mmol of appropriate pyrazoles 1–6. After stirring for
5 min, methanol was removed under vacuum and to
the residue 0.83 ml (13 mmol) of epichlorohydrin was
added and the reaction mixture was refluxed at 110 ꢁC
for 20 h. After the completion of the reaction (TLC), ex-
cess epichlorohydrin was removed under vacuum and
the washings with ether–ethanol mixture gave a solid
product, which was recrystallized from ethanol.
5.4.1. 4-Benzoyl-1-oxiranylmethyl-2-phenyl-1,2-dihydro-
1
pyrazol-3-one (21). Mp 175 ꢁC (ethanol); yield 65%; H
5.4.5. 5-Methyl-1-oxiranylmethyl-2-phenyl-4-(3-phenyl-
propionyl)-1,2-dihydro-pyrazol-3-one (25). Mp 175 ꢁC
(ethanol); yield 70%; 1H NMR (300 MHz) d 2.73 (s,
3H, CH3), 2.85 (t, J = 6.0 Hz, 2H, CH2), 2.90 (dd,
2J = 7.0 Hz, 3J = 5.6 Hz, 1H, H-8), 2.96 (dd,
2
3
NMR (300 MHz) d 2.43 (dd, J = 4.5 Hz, J = 2.5 Hz,
2
3
1H, H-8), 2.79 (dd, J = 4.5 Hz, J = 4.0 Hz, 1 H, H-
8), 3.07 (m, 1H, H-7), 3.64 (dd, 2J = 15.1 Hz,
3J = 6.5 Hz, 1H, H-6), 4.08 (dd, 2J = 15.1 Hz,
3J = 3.1 Hz, 1H, H-6), 7.32–7.99 (m, 10H, 2· Ph), 8.25
(s, 1H, H-5); 13C normal/DEPT-135 NMR (75 MHz) d
45.4 (ꢀve, C-8), 48.8 (+ve, C-7), 52.1 (ꢀve, C-6), 109.9
(C-4), 126.4 (+ve, ArCH), 128.0 (+ve, ArCH), 128.8
(+ve, ArCH), 129.4 (+ve, ArCH), 129.7 (+ve, ArCH),
133.3 (N-ArC), 137.8 (ArC), 146.9 (+ve, C-5), 162.6
(C-3), 188.1 (C@O); UV kmax (nm): 238, 312.
3
2J = 7.0 Hz, J = 6.0 Hz, 1H, H-8), 3.07 (t, J = 6.0 Hz,
2
2H, CH2), 3.30 (m, 1H, H-7), 3.79 (dd, J = 13.6 Hz,
3J = 4.6 Hz, 1H, H-6), 3.94 (dd, 2J = 13.6 Hz,
3J = 5.6 Hz, 1H, H-6), 7.13–7.45 (m, 10H, 2· Ph); 13C
normal/DEPT-135 NMR (75 MHz) d 13.1 (+ve, CH3),
29.7 (ꢀve, CH2), 43.3 (ꢀve, CH2), 45.5 (ꢀve, C-8),
48.6 (ꢀve, C-6), 67.9 (+ve, C-7), 105.5 (C-4), 125.7
(+ve, ArCH), 126.7 (+ve, ArCH), 128.1 (+ve, ArCH),
128.3 (+ve, ArCH), 129.1 (+ve, ArCH), 129.6 (+ve,
ArCH), 133.3 (N-ArC), 141.6 (ArC), 158.3 (C-5),
164.6 (C-3), 195.6 (C@O).
5.4.2.
4-Benzoyl-1-oxiranylmethyl-2,5-diphenyl-1,2-di-
hydro-pyrazol-3-one (22). Mp 178 ꢁC (ethanol); yield
65%; 1H NMR (300 MHz) d 2.25 (dd, 2J = 4.8 Hz,

P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
5069
5.5. General procedure for the reaction of epoxy com-
pounds 21–25 with piperidine/morpholine/pyrrolidine
C-13), 29.9 (ꢀve, CH2), 43.0 (ꢀve, CH2), 44.4 (ꢀve,
C-10, C-14), 52.0 (ꢀve, C-6), 54.0 (ꢀve, C-8), 63.5
(+ve, C-7), 109.2 (C-4), 125.6 (+ve, ArCH), 128.1
(+ve, ArCH), 128.3 (+ve, ArCH), 128.5 (+ve, ArCH),
129.5 (+ve, ArCH), 130.0 (+ve, ArCH), 135.5 (+ve,
ArCH), 133.9 (ArC), 134.5 (N-ArC), 142.0 (ArC),
160.1 (C-5), 164.5 (C-3), 195.4 (C@O); UV kmax (nm):
306, 240; IR (cmꢀ1): 1610 (CO), 3300 (OH); EI MS m/
z 510 (M++1). Anal. Calcd for C32H35N3O3: C, 75.41;
H, 6.92; N, 8.25. Found: C, 75.60; H, 6.92; N, 7.95.
One millimole of appropriate epoxy compounds 21–25
and 0.06 ml (1.25 mmol) piperidine/morpholine/pyrroli-
dine were taken in dry methanol and stirred at 50 ꢁC.
After the completion of the reaction (TLC), methanol
was removed under vacuum to get a gummy residue.
Compounds 26–40 were obtained as white solids after
washing the residue with ether–ethanol and then recrys-
tallized from ethanol.
5.5.4. 4-Benzoyl-1-(2-hydroxy-3-piperidin-1-yl-propyl)-5-
methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (29). Mp
165 ꢁC (ethanol); yield 69%; 1H NMR (300 MHz) d
1.38 (m, 2H, H-12), 1.47 (m, 4H, H-11, H-13), 2.06
5.5.1. 4-Benzoyl-1-(2-hydroxy-3-piperidin-1-yl-propyl)-2-
phenyl-1,2-dihydro-pyrazol-3-one (26). Mp 163 ꢁC (etha-
1
nol); yield 70%; H NMR (300 MHz) d 1.38 (m, 2H, H-
12), 1.47 (m, 4H, H-11, H-13), 2.22–2.36 (m, 4H, H-10/
H-14, H-8), 2.45 (m, 2H, H-10/H-14), 3.64 (dd,
2
3
(dd, J = 10.8 Hz, J = 6.8 Hz, 2H, H-8), 2.15 (m, 2H,
H-10/H-14), 2.39 (m, 2H, H-10/H-14), 2.67 (s, 3H,
CH3), 3.86 (m, 1H, H-7), 3.80 (dd, 2J = 14.4 Hz,
3J = 8.0 Hz, 2H, H-6), 7.27-7.69 (m, 10H, 2· Ph); 13C
3
2J = 9.8 Hz, J = 5.6 Hz, 1H, H-6), 3.91 (m, 1H, H-7),
2
3
3.93 (dd, J = 9.8 Hz, J = 6.6 Hz, 1H, H-6), 7.35–7.44
(m, 10H, 2· Ph), 8.31 (s, 1H, H-5); 13C normal/DEPT-
135 NMR (75 MHz) d 23.6 (ꢀve, C-12), 25.4 (ꢀve, C-
11, C-13), 54.4 (ꢀve, C-6), 54.5 (ꢀve, C-10, C-14),
61.0 (ꢀve, C-8), 64.1 (+ve, C-7), 107.6 (C-4), 126.9
(+ve, ArCH), 128.0 (+ve, ArCH), 128.8 (+ve, ArCH),
129.2 (+ve, ArCH), 129.6 (+ve, ArCH), 132.0 (+ve,
ArCH), 133.3 (N-ArC), 138.4 (ArC), 147.1 (+ve, C-5),
163.1 (C-3), 188.3 (C@O); UV kmax (nm): 312, 237; IR
(cmꢀ1): 1630 (C@O), 3310 (OH); EI MS m/z 406
(M++1). Anal. Calcd for C24H27N3O3: C, 71.09; H,
6.71; N, 10.36. Found: C, 71.14; H, 7.01; N, 10.04.
normal/DEPT-135 NMR (75 MHz)
d 13.1 (+ve,
CH3), 23.9 (ꢀve, C-12), 25.8 (ꢀve, C-11, C-13), 50.4
(ꢀve, C-6), 54.5 (ꢀve, C-10, C-14), 61.6 (ꢀve, C-8),
64.8 (+ve, C-7), 106.8 (C-4), 126.2 (+ve, ArCH),
127.7 (+ve, ArCH), 128.1 (+ve, ArCH), 129.4 (+ve,
ArCH), 131.9 (+ve, ArCH), 134.5 (N-ArC), 138.8
(ArC), 159.7 (C-5), 164.1 (C-3), 190.6 (C@O); UV kmax
(nm): 317, 236; IR (cmꢀ1): 1635 (CO), 3340 (OH); EI
MS m/z 420 (M++1). Anal. Calcd for C25H29N3O3:
C, 71.57; H, 6.97; N, 10.02. Found: C, 71.37; H,
7.26; N, 9.81.
5.5.2. 4-Benzoyl-1-(2-hydroxy-3-piperidin-1-yl-propyl)-
2,5-diphenyl-1,2-dihydro-pyrazol-3-one (27). Mp 135 ꢁC
5.5.5. 1-(2-Hydroxy-3-piperidin-1-yl-propyl)-5-methyl-2-
phenyl-4-(3-phenylpropionyl)-1,2-dihydro-pyrazol-3-one
(30). Mp 162 ꢁC (ethanol); yield 71%; 1H NMR
(300 MHz) d 1.44 (m, 2H, H-12), 1.56 (m, 4H, H-11,
H-13), 2.07 (dd, 2J = 8.0 Hz, 3J = 5.6 Hz, 2H, H-8),
2.19 (m, 2H, H-10/H-14), 2.29 (m, 2H, H-10/H-14),
2.50 (t, J = 7.6 Hz, 2H, CH2), 2.75 (s, 3H, CH3), 2.97
(t, J = 7.6 Hz, 2H, CH2), 3.31 (dd, 2J = 8.8 Hz,
3J = 4.0 Hz, 1H, H-6), 3.70 (m, 1H, H-7), 3.79 (dd,
2J = 8.8 Hz, 3J = 6.0 Hz, 1H, H-6), 7.15–7.50 (m,
10H, 2· Ph); 13C normal/DEPT-135 NMR (75 MHz)
d 13.3 (+ve, CH3), 23.5 (ꢀve, C-12), 25.3 (ꢀve, C-11,
C-13), 30.0 (ꢀve, CH2), 43.1 (ꢀve, CH2), 49.8 (ꢀve,
C-10, C-14), 54.5 (ꢀve, C-6), 61.5 (ꢀve, C-8), 64.5
(+ve, C-7), 107.0 (C-4), 125.5 (+ve, ArCH), 125.9
(+ve, ArCH), 128.1 (+ve, ArCH), 128.5 (+ve, ArCH),
129.4 (+ve, ArCH), 134.5 (N-ArC), 141.8 (ArC),
160.5 (C-5), 164.3 (C-3), 195.9 (C@O); UV kmax (nm):
301, 242; IR (cmꢀ1): 1650 (CO), 3280 (OH); EI MS
m/z 448 (M++1). Anal. Calcd for C27H33N3O3: C,
72.46; H, 7.43; N, 9.39. Found: C, 72.59; H, 7.38; N,
9.67.
1
(ethanol); yield 65%; H NMR: d 1.37 (m, 2H, H-12),
1.51 (m, 4H, H-11, H-13), 2.14 (dd, 2J = 11.8 Hz,
3J = 6.3 Hz, 2H, H-8), 2.33 (m, 2H, H-10/H-14), 2.49
(m, 2H, H-10/H-14), 3.70 (dd, 2J = 10.2 Hz,
3J = 6.0 Hz, 1H, H-6), 3.80 (dd, 2J = 10.2 Hz,
3J = 5.6 Hz, 1H, H-6), 3.92 (m, 1H, H-7), 7.17–7.78
(m, 15H, 3xPh); 13C normal/DEPT-135 NMR
(75 MHz) d 23.2 (ꢀve, C-12), 24.9 (ꢀve, C-11, C-13),
52.7 (ꢀve, C-6), 54.0 (ꢀve, C-10, C-14), 61.0 (ꢀve, C-
8), 63.6 (+ve, C-7), 109.7 (C-4), 125.0 (+ve, ArCH),
127.7 (+ve, ArCH), 128.5 (+ve, ArCH), 129.3 (+ve,
ArCH), 129.5 (+ve, ArCH), 130.0 (+ve, ArCH), 130.3
(+ve, ArCH), 132.0 (ArC), 134.0 (N-ArC), 137.9
(ArC), 161.0 (C-5), 163.0 (C-3), 189.3 (C@O); UV kmax
(nm): 310, 232; IR (cmꢀ1): 1585 (C@O), 3200 (OH);
EI MS m/z 482 (M++1). Anal. Calcd for C30H31N3O3:
C, 74.82; H, 6.49; N, 8.73. Found: C, 74.99; H, 6.36;
N, 8.53.
5.5.3. 1-(2-Hydroxy-3-piperidin-1-yl-propyl)-2,5-diphen-
yl-4-(3-phenylpropionyl)-1,2-dihydro-pyrazol-3-one (28).
1
Mp 158 ꢁC (ethanol); yield 64%; H NMR (300 MHz)
5.5.6. 4-Benzoyl-1-(2-hydroxy-3-morpholin-4-yl-propyl)-
2-phenyl-1,2-dihydro-pyrazol-3-one (31). Mp 162 ꢁC (eth-
anol); yield 70%; 1H NMR (300 MHz) d 2.21 (m, 4H, H-
d 1.30 (m, 2H, H-12), 1.62 (m, 4H, H-11, H-13), 2.07
2
3
(dd, J = 11.3 Hz, J = 7.0 Hz, 2H, H-8), 2.17 (m, 2H,
H-10/H-14), 2.34 (m, 2H, H-10/H-14), 2.94 (t,
J = 8.0 Hz, 2H, CH2), 3.08 (t, J = 8.0 Hz, 2H, CH2),
2
3
10/H-14, H-8), 2.44 (dd, J = 6.6 Hz, J = 4.2 Hz, 2H,
H-10/H-14), 3.57 (t, J = 4.5 Hz, 4H, H-11, H-13), 3.67
(m, 1H, H-7, merged with H-11, H-13), 3.93 (dd,
2J = 14.7 Hz, 3J = 2.4 Hz, 2H, H-6), 7.34–7.94 (m,
10H, 2· Ph), 8.31 (s, 1H, H-5); 13C normal/DEPT-135
NMR (75 MHz) d 53.4 (ꢀve, C-6), 54.6 (ꢀve, C-10,
2
3
3.36 (m, 1H, H-7), 3.56 (dd, J = 10.0 Hz, J = 6.0 Hz,
2
3
1H, H-6), 3.60 (dd, J = 10.0 Hz, J = 6.6 Hz, 1H, H-
6), 7.14-7.51 (m, 15H, 3· Ph); 13C normal/DEPT-135
NMR (75 MHz) d 22.4 (ꢀve, C-12), 24.7 (ꢀve, C-11,

5070
P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
C-14), 61.1 (ꢀve, C-8), 64.0 (+ve, C-7), 66.7 (ꢀve, C-11,
C-13), 107.4 (C-4), 127.1 (+ve, ArCH), 128.0 (+ve,
ArCH), 128.8 (+ve, ArCH), 129.1 (+ve, ArCH), 129.5
(+ve, ArCH), 132.0 (+ve, ArCH), 133.2 (N-ArC),
138.3 (ArC), 146.9 (+ve, C-5), 163.0 (C-3), 189.5
(C@O); FAB MS m/z 408 (M++1). Anal. Calcd for
C23H25N3O4: C, 67.80; H, 6.18; N, 10.31. Found: C,
67.70; H, 6.15; N, 10.05.
5.5.10. 1-(2-Hydroxy-3-morpholin-4-yl-propyl)-5-methyl-
2-phenyl-4-(3-phenylpropionyl)-1,2-dihydro-pyrazol-3-
one (35). Mp 160 ꢁC (ethanol); yield 75%; 1H NMR
(300 MHz) d 2.24 (m, 4H, H-10/H-14, H-8), 2.42 (m,
2H, H-10/H-14), 2.50 (s, 3H, CH3), 3.04 (t, J = 7.5 Hz,
2H, CH2), 3.18 (t, J = 7.5 Hz, 2H, CH2), 3.62 (t,
J = 4.5 Hz, 4H, H-11, H-13), 3.84 (m, 1H, H-7), 3.88
(m, 2H, H-6, merged with H-7), 7.18–7.64 (m, 10H, 2·
Ph); 13C normal/DEPT-135 NMR (75 MHz) d 13.3
(+ve, CH3), 29.8 (ꢀve, CH2), 43.0 (ꢀve, CH2), 49.7
(ꢀve, C-6), 53.4 (ꢀve, C-10, C-14), 61.3 (ꢀve, C-8),
64.6 (+ve, C-7), 66.7 (ꢀve, C-11, C-13), 106.0 (C-4),
125.5 (+ve, ArCH), 126.1 (+ve, ArCH), 128.1 (+ve,
ArCH), 128.5 (+ve, ArCH), 129.5 (+ve, ArCH), 134.1
(N-ArC), 141.7 (ArC), 158.7 (C-5), 164.9 (C-3), 196.3
(C@O); FAB MS m/z 450 (M++1). Anal. Calcd for
C26H31N3O4: C, 69.47; H, 6.95; N, 9.35. Found: C,
69.70; H, 6.90; N, 9.05.
5.5.7. 4-Benzoyl-1-(2-hydroxy-3-morpholin-4-yl-propyl)-
2,5-diphenyl-1,2-dihydro-pyrazol-3-one (32). Mp 170 ꢁC;
1
yield 76%; H NMR (300 MHz) d 2.00 (m, 4H, H-10/
H-14, H-8), 2.27 (dd, J = 11.4 Hz, J = 3.9 Hz, 2H, H-
10/H-14), 3.47 (t, J = 4.8 Hz, 4H, H-11, H-13), 3.77
2
3
2
3
(m, 1H, H-7), 3.82 (dd, J = 12.6 Hz, J = 5.7 Hz, 2H,
H-6), 7.15-7.80 (m, 15H, 3· Ph); 13C normal/DEPT-
135 NMR (75 MHz) d 53.0 (ꢀve, C-6), 53.4 (ꢀve, C-
10, C-14), 61.4 (ꢀve, C-8), 64.3 (+ve, C-7), 66.6 (ꢀve,
C-11, C-13), 109.7 (C-4), 125.1 (+ve, ArCH), 125.4
(+ve, ArCH), 127.7 (+ve, ArCH), 127.8 (+ve, ArCH),
128.6 (+ve, ArCH), 129.4 (+ve, ArCH), 129.5 (+ve,
ArCH), 129.9 (+ve, ArCH), 130.4 (ArC), 132.3 (+ve,
ArCH), 134.3 (N-ArC), 137.9 (ArC), 160.8 (C-5),
163.3 (C-3), 189.7 (C@O); FAB MS m/z 484 (M++1).
Anal. Calcd for C29H29N3O4: C, 72.03; H, 6.04; N,
8.69. Found: C, 72.31; H, 6.30; N, 8.60.
5.5.11. 4-Benzoyl-1-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-
2-phenyl-1,2-dihydro-pyrazol-3-one (36). Mp 160 ꢁC (eth-
anol); yield 72%; 1H NMR (300 MHz) d 1.88 (t,
J = 6.4 Hz, 4H, H-11, H-12), 2.07 (dd, 2J = 12.0 Hz,
3J = 3.8 Hz, 2H, H-8), 2.32 (dd, 2J = 8.9 Hz,
3J = 4.2 Hz, 2H, H-10/H-13), 3.02 (dd, 2J = 8.9 Hz,
3J = 5.4 Hz, 2H, H-10/H-13), 3.58 (m, 1H, H-7), 4.14
(m, 2H, H-6, merged with H-7), 7.44–7.81 (m, 10H, 2·
Ph), 8.46 (s, 1H, H-5); 13C normal/DEPT-135 NMR
(75 MHz) d 23.4 (ꢀve, C-11, C-12), 52.9 (ꢀve, C-6),
54.0 (ꢀve, C-10, C-13), 58.5 (ꢀve, C-8), 65.8 (+ve,
C-7), 108.6 (C-4), 125.3 (+ve, ArCH), 127.3 (+ve,
ArCH), 127.8 (+ve, ArCH), 128.5 (+ve, ArCH), 129.4
(+ve, ArCH), 132.0 (+ve, ArCH), 132.3 (N-ArC),
137.9 (ArC), 149.9 (+ve, C-5), 163.1 (C-3), 190.5
(C@O); FAB MS m/z 392 (M++1). Anal. Calcd for
C23H25N3O3: C, 70.57; H, 6.44; N, 10.73. Found: C,
70.51; H, 6.34; N, 10.60.
5.5.8. 1-(2-Hydroxy-3-morpholin-4-yl-propyl)-2,5-diphen-
yl-4-(3-phenylpropionyl)-1,2-dihydro-pyrazol-3-one (33).
1
Mp 165 ꢁC (ethanol); yield 71%; H NMR (300 MHz)
2
d 1.94 (d, J = 6.3 Hz, 2H, H-8), 2.07 (dd, J = 9.9 Hz,
3J = 4.2 Hz, 2H, H-10/H-14), 2.33 (dd, 2J = 11.1 Hz,
3J = 4.8 Hz, 2H, H-10/H-14), 2.93 (t, J = 7.8 Hz, 2H,
CH2), 3.34 (t, J = 7.8 Hz, 2H, CH2), 3.50 (t, J = 4.8,
4H, H-11/H-13), 3.65 (m, 2H, H-6), 3.72 (m, 1H, H-7,
merged with H-6), 7.11–7.55 (m, 15H, 3· Ph); 13C nor-
mal/DEPT-135 NMR (75 MHz) d 29.6 (ꢀve, CH2),
43.1 (ꢀve, CH2), 51.8 (ꢀve, C-6), 53.3 (ꢀve, C-10, C-
14), 61.2 (ꢀve, C-8), 64.4 (+ve, C-7), 66.5 (ꢀve, C-11,
C-13), 107.6 (C-4), 125.4 (+ve, ArCH), 125.6 (+ve,
ArCH), 128.1 (+ve, ArCH), 128.3 (+ve, ArCH), 128.4
(+ve, ArCH), 129.5 (+ve, ArCH), 129.9 (ArC), 130.3
(+ve, ArCH), 134.1 (N-ArC), 141.6 (ArC), 160.0 (C-5),
164.0 (C-3), 194.4 (C@O); FAB MS m/z 512 (M++1).
Anal. Calcd for C31H33N3O4: C, 72.78; H, 6.50; N,
8.21. Found: C, 72.70; H, 6.51; N, 8.31.
5.5.12. 4-Benzoyl-1-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-
2,5-diphenyl-1,2-dihydro-pyrazol-3-one (37). Mp 165 ꢁC
(ethanol); yield 77%; 1H NMR (300 MHz) d 1.67 (t,
J = 5.2 Hz, 4H, H-11, H-12), 2.07 (dd, 2J = 12.0 Hz,
3J = 3.9 Hz, 2H, H-8), 2.30 (dd, 2J = 8.4 Hz,
3J = 3.0 Hz, 2H, H-10/H-13), 2.50 (dd, 2J = 8.4 Hz,
3J = 5.4 Hz, 2H, H-10/H-13), 3.67 (m, 1H, H-7), 3.73
(m, 2H, H-6, merged with H-7), 7.06–8.04 (m, 15H, 3·
Ph); 13C normal/DEPT-135 NMR (75 MHz) d 23.2
(ꢀve, C-11, C-12), 52.6 (ꢀve, C-6), 53.9 (ꢀve, C-10, C-
13), 58.8 (ꢀve, C-8), 65.6 (+ve, C-7), 109.6 (C-4), 125.0
(+ve, ArCH), 125.3 (+ve, ArCH), 127.3 (+ve, ArCH),
127.8 (+ve, ArCH), 128.5 (+ve, ArCH), 129.4 (+ve,
ArCH), 129.5 (+ve, ArCH), 129.8 (+ve, ArCH), 130.3
(ArC), 132.0 (+ve, ArCH), 132.3 (N-ArC), 137.9 (ArC),
160.9 (C-5), 163.3 (C-3), 189.5 (C@O); FAB MS m/z
468 (M++1). Anal. Calcd for C29H29N3O3: C, 74.50; H,
6.25; N, 8.99. Found: C, 74.70; H, 6.45; N, 9.05.
5.5.9. 4-Benzoyl-1-(2-hydroxy-3-morpholin-4-yl-propyl)-
5-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (34). Mp
175 ꢁC (ethanol); yield 70%; 1H NMR (300 MHz) d
2.12 (m, 4H, H-10/H-14, H-8), 2.40 (m, 2H, H-10/H-
14), 2.67 (s, 3H, CH3), 3.56 (t, J = 4.5 Hz, 4H, H-11,
H-13), 3.80 (m, 1H, H-7), 3.80 (m, 2H, H-6, merged with
H-7), 7.26–7.88 (m, 10H, 2· Ph); 13C normal/DEPT-135
NMR (75 MHz) d 13.1 (+ve, CH3), 50.3 (ꢀve, C-6), 53.4
(ꢀve, C-10, C-14), 61.5 (ꢀve, C-8), 64.7 (+ve, C-7), 66.7
(ꢀve, C-11, C-13), 106.4 (C-4), 126.4 (+ve, ArCH),
127.7 (+ve, ArCH), 128.3 (+ve, ArCH), 129.3 (+ve,
ArCH), 129.4 (+ve, ArCH), 132.0 (+ve, ArCH), 134.0
(N-ArC), 138.5 (ArC), 159.1 (C-5), 163.8 (C-3), 190.5
(C@O); FAB MS m/z 422 (M++1). Anal. Calcd for
C24H27N3O4: C, 68.39; H, 6.46; N, 9.97. Found: C,
68.45; H, 6.52; N, 9.80.
5.5.13. 1-(2-Hydroxy-3-pyrrolidin-1-yl-propyl)-2,5-di-
phenyl-4-(3-phenylpropionyl)-1,2-dihydro-pyrazol-3-one
(38). Mp 180 ꢁC; yield 73%; 1H NMR (300 MHz) d 1.62
(t, J = 6.6 Hz, 4H, H-11, H-12), 1.95 (dd, J = 12.0 Hz,
2
3J = 4.2 Hz, 1H, H-8), 2.15 (m, 3H, H-10/H-13, and
1H of H-8), 2.37 (dd, 2J = 6.6 Hz, 3J = 2.1 Hz, 2H,

P. Singh et al. / Bioorg. Med. Chem. 14 (2006) 5061–5071
5071
H-10/H-13), 2.93 (t, J = 7.8 Hz, 2H, CH2), 3.35 (t,
References and notes
J = 7.5 Hz, 2H, CH2), 3.60 (m, 1H, H-7), 3.65 (m, 2H,
H-6, merged with H-7), 7.11–7.54 (m, 15H, 3· Ph);
13C normal/DEPT-135 NMR (75 MHz) d 23.2 (ꢀve,
CH2), 29.6 (ꢀve, C-11, C-12), 43.1 (ꢀve, CH2), 51.9
(ꢀve, C-6), 53.7 (ꢀve, C-10, C-13), 58.8 (ꢀve, C-8),
65.8 (+ve, C-7), 107.5 (C-4), 125.4 (+ve, ArCH), 125.5
(+ve, ArCH), 128.1 (+ve, ArCH), 128.3 (+ve, ArCH),
128.4 (+ve, ArCH), 129.4 (+ve, ArCH), 129.8 (ArC),
130.3 (+ve, ArCH), 134.1 (N-ArC), 141.7 (ArC), 159.9
(C-5), 164.1 (C-3), 194.5 (C@O); FAB MS m/z 496
(M+ + 1). Anal. Calcd for C31H33N3O3: C, 75.13; H,
6.71; N, 8.48. Found: C, 75.30; H, 6.60; N, 8.35.
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5.5.14. 4-Benzoyl-1-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-
5-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (39). Mp
154 ꢁC (ethanol); yield 67%; 1H NMR (300 MHz) d
1.81 (t, J = 6.3 Hz, 4H, H-11, H-12), 2.45 (dd,
3
2J = 11.7 Hz, J = 1.8 Hz, 1H, H-8), 2.60 (s, 3H, CH3),
2.74 (m, 3H, H-10/H-13, 1H of H-8), 2.87 (dd,
3
2J = 9.6 Hz, J = 2.4 Hz, 2H, H-10/H-13), 3.80 (m, 1H,
H-7), 3.95 (m, 2H, H-6, merged with H-7), 7.28–7.83
(m, 10H, 2· Ph); 13C normal/DEPT-135 NMR
(75 MHz) d 13.3 (+ve, CH3), 23.1 (ꢀve, C-11, C-12),
49.9 (ꢀve, C-6), 54.4 (ꢀve, C-10, C-13), 58.5 (ꢀve, C-
8), 65.5 (+ve, C-7), 106.7 (C-4), 126.2 (+ve, ArCH),
127.8 (+ve, ArCH), 128.4 (+ve, ArCH), 129.3 (+ve,
ArCH), 129.6 (+ve, ArCH), 132.1 (+ve, ArCH), 134.1
(N-ArC), 138.7 (ArC), 159.6 (C-5), 164.2 (C-3), 190.5
(C@O); FAB MS m/z 406 (M++1). Anal. Calcd for
C24H27N3O3: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.20; H, 6.85; N, 10.52.
14. Londershausen, M. Pestic. Sci. 1996, 48, 269.
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IL Farmaco 2002, 57, 385.
5.5.15. 1-(2-Hydroxy-3-pyrrolidin-1-yl-propyl)-5-methyl-
2-phenyl-4-(3-phenyl-propionyl)-1,2-dihydro-pyrazol-3-
one (40). Mp 148 ꢁC (ethanol); yield 69%; 1H NMR
(300 MHz) d 1.70 (t, J = 6.6 Hz, 4H, H-11, H-12), 2.07
(dd, 2J = 12.0 Hz, 3J = 3.9 Hz, 1H, H-8), 2.11 (dd,
2J = 8.7 Hz, 3J = 2.1 Hz, 2H, H-10/H-13), 2.45 (dd,
2J = 12.0 Hz, 3J = 5.4 Hz, 1H, H-8), 2.52 (dd,
3
2J = 8.7 Hz, J = 2.4 Hz, 2H, H-10/H-13), 2.74 (s, 3H,
CH3), 2.97 (t, J = 7.8 Hz, 2H, CH2), 3.33 (t, J = 7.8 Hz,
2H, CH2), 3.72 (m, 1H, H-7), 3.80 (m, 2H, H-6, merged
with H-7), 7.13–7.51 (m, 10H, 2· Ph); 13C normal/
DEPT-135 NMR (75 MHz) d 13.3 (+ve, CH3), 23.4
(ꢀve, C-11, C-12), 29.9 (ꢀve, CH2), 43.0 (ꢀve, CH2),
49.8 (ꢀve, C-6), 53.8 (ꢀve, C-10, C-13), 59.0 (ꢀve, C-8),
66.4 (+ve, C-7), 105.8 (C-4), 125.5 (+ve, ArCH), 126.3
(+ve, ArCH), 128.3 (+ve, ArCH), 128.5 (+ve, ArCH),
129.5 (+ve, ArCH), 134.1 (N-ArC), 141.7 (ArC), 158.5
(C-5), 165.0 (C-3), 196.2 (C@O); FAB MS m/z 434
(M+ + 1). Anal. Calcd for C26H31N3O3: C, 72.03; H,
7.21; N, 9.69. Found: C, 72.22; H, 6.95; N, 9.55.
23. Singh, P.; Paul, K.; Holzer, W. Org. Biomol. Chem. 2005,
3, 3958.
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Acknowledgments
26. Chiba, P.; Holzer, W.; Landau, M.; Bechmann, G.;
Lorenz, K.; Plagens, B.; Hitzler, M.; Richter, E.; Ecker,
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references therein.
CSIR and DST, New Delhi, is gratefully acknowledged
for financial assistance. Authors are also thankful to the
Austrian Academic Exchange Service (OAD) for finan-
cial support for a part of this research work.