Synthesis of novel isoxazolines via 1,3-dipolar cycloaddition and evaluation of anti-stress activity

Article abstract of DOI:10.1007/s00044-010-9299-0

We have synthesized a series of novel isoxazolines via 1,3-dipolar cycloaddition of in situ generated nitrile oxide from 2,4-dimethoxy benzaldoxime and naphthaldehyde oxime with 4-allyl-2-methoxyphenol derivatives. The synthesized compounds were evaluated for anti-stress activity in acute stress (AS) induced peripheral changes. Adult male Sprague-Dawley rats, subjected to AS, cause a significant increase in gastric ulceration, adrenal gland weight, plasma glucose, corticosterone levels, and creatine kinase activity. Compounds 3d, 3g, 5b, 5c, 5d, and 5g displayed most promising anti-stress effect by reverting these peripheral stress parameters at a dose of 40 mg/kg p.o.

Full text of DOI:10.1007/s00044-010-9299-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:139–145
DOI 10.1007/s00044-010-9299-0
ORIGINAL RESEARCH
Synthesis of novel isoxazolines via 1,3-dipolar cycloaddition
and evaluation of anti-stress activity
•
Rakesh Maurya Ausaf Ahmad Prasoon Gupta
•
•
•
Kailash Chand Manmeet Kumar Jayendra
•
•
•
Preeti Rawat Naila Rasheed Gautam Palit
•
Received: 13 April 2009 / Accepted: 12 January 2010 / Published online: 29 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract We have synthesized a series of novel isoxaz-
olines via 1,3-dipolar cycloaddition of in situ generated
nitrile oxide from 2,4-dimethoxy benzaldoxime and naph-
thaldehyde oxime with 4-allyl-2-methoxyphenol deriva-
tives. The synthesized compounds were evaluated for anti-
stress activity in acute stress (AS) induced peripheral
changes. Adult male Sprague–Dawley rats, subjected to
AS, cause a significant increase in gastric ulceration,
adrenal gland weight, plasma glucose, corticosterone lev-
els, and creatine kinase activity. Compounds 3d, 3g, 5b, 5c,
5d, and 5g displayed most promising anti-stress effect by
reverting these peripheral stress parameters at a dose of
40 mg/kg p.o.
disease (Roy et al., 2001), gastric ulcers (Yadin and Tho-
mas, 1996), immunosuppression (Purett, 2001), metabolic
disorders like diabetes (Fitzpatrick et al., 1992), repro-
ductive dysfunction (Dabson and Smith, 2000), mental
depression and memory loss (Gareri et al., 2000). Thus, the
treatment of stress pathologies is of great concern because
of their increasing incidence (McEwen and Wingfield,
2003). Due to the limitations of tolerance, sedation and
physical dependence on prolonged use of modern anti-
stress drugs; the identification of new effective and safe
anti-stress agents is desperately needed.
Previous studies showed that several isoxazoline moie-
ties possessed a wide spectrum of activities like PTP1B
inhibitory activity (Ahmad et al., 2006), antimicrobial
(Gaonkar et al., 2007), anti-influenza virus (Kai et al.,
2001), antifungal (Basappa et al., 2003), glycoprotein IIb/
IIIa receptor antagonists (Sielecki et al., 2001), anti-HIV
(Ichiba et al., 1993), spermicidal and anti-HIV (Srivastava
et al., 1999), analgesic and anti-inflammatory (Habeeb
et al., 2001), and b-adrenergic receptor antagonist prop-
erties (Conti et al., 1998). However, their role during
stressful condition is unknown. We report herein the syn-
thesis of series of new 3,5-disubstituted isoxazolines and
their evaluation for anti-stress activity under acute stress
(AS) condition in relation to the peripheral (ulcer severity
and adrenal hypertrophy) and biochemical changes [glu-
cose, creatine kinase (CK), and corticosterone].
Keywords Isoxazoline ꢀ 1,3-Dipolar cycloaddition ꢀ
Acute stress ꢀ Corticosterone ꢀ Ulcer
Introduction
Hyperactivity of hypothalamic–pituitary–adrenal axis
(HPA) during stressful conditions has been implicated in
etiopathogenesis of various disorders of central and
peripheral systems like hypertension, coronary heart
CDRI communication no. 7613.
R. Maurya (&) ꢀ P. Gupta ꢀ K. Chand ꢀ M. Kumar ꢀ Jayendra ꢀ
P. Rawat
Division of Medicinal and Process Chemistry, Central Drug
Research Institute, CSIR, Lucknow 226 001, India
e-mail: mauryarakesh@rediffmail.com
Results and discussion
Chemistry
A. Ahmad ꢀ N. Rasheed ꢀ G. Palit
The starting materials, aldoximes 1 (Maurya et al., 2008)
and 4 (Yamada et al., 2006), were prepared from the
Division of Pharmacology, Central Drug Research Institute,
CSIR, Lucknow 226 001, India
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Med Chem Res (2011) 20:139–145
Scheme 1 Synthesis of
isoxazoline compounds by
altering the substituent in
4-allyl-2-methoxy-phenol
H3CO
OCH3
OCH3
H3CO
OCH3
N
OR
chloramine T
OCH3
OR
O
N
OH
EtOH
3
2
1
OCH3
OR
OCH3
OR
OH
chloramine T
N
O
N
EtOH
2
5
4
a: R=H, b: R=COCH3, c: R=CH3, d: R=CH2CH3, e: R=CH2C6H5,
f: R= , g: R=
H2CH2CN
H2CH2CN
2,4-dimethoxy benzaldehyde and 1-naphthaldehyde. The
olefin 2b was prepared by acetylating 2 with acetic anhy-
dride and pyridine. The olefins 2c–g were prepared in
almost quantitative yield by treatment of 2 with methyl
iodide, ethyl iodide, benzyl bromide, N-(2-chloroethyl)
pyrrolidine hydrochloride, and N-(2-chloroethyl) piperi-
dine hydrochloride in presence of K2CO3 in dry acetone,
respectively. The cycloaddition reaction of oximes 1, 4
with olefins 2 in presence of chloramines-T (Hassner and
Rai, 1989) afforded new isoxazolines 3a–d, 5a–d in
77–88% yields (Scheme 1). The structure of cycloadducts
was determined by elemental analysis and their spectral
data.
as compared to AS group. Also exposure to AS (F(16,
85) = 9.38, P \ 0.001) significantly increased the adrenal
gland weight when compared to NS group. These results
are in accordance to a number of studies, suggesting that
stress caused an increased adrenocorticoid secretion,
plasma corticosterone levels, and enlarged pituitary and
adrenal size (Dhabhar et al., 1997). Pretreatment of 3b
(P \ 0.001), 3d (P \ 0.01), 3e (P \ 0.05), 3g (P \ 0.01),
5b (P \ 0.01), 5c (P \ 0.01), 5d (P \ 0.05), 5g (P \
0.001), and PQ (P \ 0.001) significantly normalized the
increased adrenal gland weight, whereas administration of
3a, 3c, 3f, 5a, 5e, and 5f produced no significant changes as
compared to AS group (Table 1).
AS exposure resulted in a significant increase in the
plasma glucose level (F(16, 85) = 14.09, P \ 0.001), CK
activity (F(16, 85) = 10.98, P \ 0.001), and corticosterone
levels (F(16, 85) = 12.95, P \ 0.001) when compared to
NS group. This could be attributed to the release of gluco-
corticoids as a result of HPA axis stimulation, to compensate
the initial demand of energy (Mason, 1968). Stress hormones
not only stimulate and insure supply of glucose, but also
increase CK activity during stress (Adelbert, 2000). Pre-
treatment of 3b (P \ 0.05), 3d (P \ 0.001), 3e (P \ 0.05),
3g (P \ 0.001), 5b (P \ 0.001), 5c (P \ 0.001), 5d
(P \ 0.001), 5g (P \ 0.001), and PQ (P \ 0.001) signifi-
cantly normalized the increased plasma corticosterone levels
when compared to AS group, whereas 3a (P \ 0.05), 3b
(P \ 0.001), 3d (P \ 0.001), 3e (P \ 0.001), 3g
(P \ 0.001), 5a (P \ 0.001), 5b (P \ 0.001), 5c (P \ 0.05),
5d (P \ 0.001), 5g (P \ 0.001), and PQ (P \ 0.001) were
found effective in normalizing AS-induced hyperglycemia
(Table 1). Also, pretreatment of 3b (P \ 0.01), 3d
(P \ 0.01), 3e (P \ 0.001), 3g (P \ 0.01), 5b (P \ 0.001),
5c (P \ 0.001), 5d (P \ 0.001), 5g (P \ 0.001), and PQ
(P \ 0.001) significantly normalized the decreased CK
activity when compared to AS group.
Biological activity
We select immobilization stressor in our AS model because
of the fact that it produces both physical as well as ines-
capable psychological stress (Marty et al., 1997). All the
synthesized isoxazolines (3a–g, 5a–g) were screened for
anti-stress activity in AS model at a dose of 40 mg/kg p.o.
body weight (Table 1) (Gupta et al., 2007). We used PQ at
a dose of 100 mg/kg p.o. body weight as a standard drug
(Rai et al., 2003). AS (F(16, 85) = 6.397, P \ 0.001)
resulted in significant increase in the scores of ulcer index
when compared to non-stress control (NS) group. So the
stimulation of Para ventricular nucleus of hypothalamus
increased intestinal motility, acid secretion, and group of
other factors during stressful conditions (Glavin et al.,
1991; Mayer, 2000). Pretreatment of 3b (P \ 0.05), 3d
(P \ 0.01), 3e (P \ 0.05), 3g (P \ 0.05), 5b (P \ 0.05),
5c (P \ 0.01), 5d (P \ 0.05), 5g (P \ 0.05), and PQ
(P \ 0.01) significantly decreased mean ulcer score when
compared to AS group, whereas administration of 3a, 3c,
3f, 5a, 5e, 5f produced no significant changes in ulcer index
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Med Chem Res (2011) 20:139–145
141
Table 1 Effect of 3a–g, 5a–g, and PQ on AS-induced perturbations in adrenal hypertrophy, ulcer severity, plasma glucose, CK, and corti-
costerone levels
Groups (dose mg/kg body
weight p.o.)
Adrenal gland weight (mg/100 g Mean ulcer
body weight)
Glucose (mg/dl) CK (IU/dl)
Corticosterone
(ng/ml)
score
Non-stress control
AS ? vehicle
3a (40)
6.87 0.81
10.20 0.69@
9.31 0.45
0.0 0.0
81.50 3.374
323.5 15.72
244.5 15.43
21.67 3.07@ 134.7 4.68@ 1115.0 29.43@ 465.7 15.77@
13.33 2.11
8.33 3.07*
18.33 1.667
112.0 8.22*
107.2 4.42*** 766.71 47.73** 364.2 20.18*
122.0 2.95 1092.0 64.26 446.0 27.18
1004.0 57.30
432.2 18.70
3b (40)
7.01 0.54***
9.63 0.45
3c (40)
3d (40)
7.82 0.47**
8.01 0.42*
9.82 0.42
6.66 2.11** 93.00 5.62*** 729.7 77.58** 275.5 31.65***
3e (40)
8.33 3.07*
16.67 2.11
10.00 2.58*
11.67 3.07
10.00 2.59*
80.50 6.63*** 664.3 77.36*** 354.8 17.78*
127.0 3.12 934.7 75.78 429.8 23.94
101.7 5.16*** 733.8 83.05** 320.0 15.49***
86.24 3.71*** 998.5 33.84 417.2 21.09
74.67 5.68*** 673.0 60.36*** 311.8 18.60***
590.0 82.55*** 293.5 25.02***
72.83 6.29*** 625.7 79.46*** 292.3 34.60***
3f (40)
3g (40)
7.60 0.28**
9.86 0.35
5a (40)
5b (40)
7.77 0.38**
7.54 0.23**
7.89 0.32*
9.60 0.40
5c (40)
6.66 3.33** 109.51 11.01*
5d (40)
10.00 2.58*
25.00 2.23
16.67 2.10
10.00 2.58*
5e (40)
116.3 7.87
125.0 4.83
994.5 50.50
1074.0 73.93
444.7 11.91
421.0 20.96
5f (40)
10.58 0.58
7.23 0.40***
7.32 0.25***
5g (40)
78.17 2.88*** 603.7 78.54*** 282.5 14.01***
PQ (100)
5.00 2.23** 68.33 4.19*** 649.3 101.3*** 247.3 15.27***
Results are represented as means SEM with n = 6 in each group
@
P \ 0.001 when compared to the NS group and * P \ 0.05, ** P \ 0.01, *** P \ 0.001 when compared to AS group. The stress group was
compared with the NS control group and the drug-treated groups were compared with an AS group
Conclusion
results were recorded using a beam of argon (208 eV) on a
Jeol SX 102/DA-6000 mass spectrometer. 1H NMR spectra
In summary, we have synthesized a series of novel isox-
azolines and evaluate their anti-stress potential in AS
model. AS resulted in significant elevation in gastric
ulceration adrenal hypertrophy, hyperglycemia, plasma CK
activity, and corticosterone levels, which was significantly
countered by pretreatment of isoxazolines 3d, 3g, 5b, 5c,
5d, and 5g. Thus, the protective effects of these compounds
during AS condition might be due to the normalization of
increased HPA axis response during an immediate threat
condition such as acute immobilization stress. Hence, these
compounds might have important therapeutic implications
in stress-induced neuropathological conditions, and bio-
logical activity profiles of these compounds are worthy for
further investigation to develop anti-stress drugs.
were recorded at AVANCE DPX 200 spectrometer and 13
C
NMR spectra at 50 MHz on the same spectrometer, and are
quoted relative to C4H12Si as internal reference. Elemental
analyses were obtained in a Carlo-Erba-1108 CHN ele-
mental analyzer. Thin-layer chromatography was run on
precoated 60F254 (Merck, Darmstadt, Germany) plated.
Detection of spots was done either by I2 vapor and spraying
with 1% ceric sulfate in 1 M H2SO4 or spraying with 10%
methanolic sulfuric acid followed by heating at 110°C.
Synthesis of olefins 2c–g
General procedure
The mixture of 2 (1 equiv) with methyl iodide, ethyl iodide,
benzyl bromide, N-(2-chloroethyl) pyrrolidine hydrochlo-
ride, and N-(2-chloroethyl) piperidine hydrochloride (1.2
equiv) and K2CO3 (1.2 equiv) in dry acetone was refluxed
with stirring for 3 h, respectively. After that acetone was
evaporated, water was added and the mixture was extracted
with ethyl acetate, washed with water and brine, and dried
over anhydrous sodium sulfate. The products were purified
by column chromatography over silica gel.
Experimental
General
Mps are uncorrected and were determined on Complab
apparatus. IR spectra were recorded on Perkin–Elmer RX-1
spectrometer using either KBr pallets or neat. The FAB MS
123

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Med Chem Res (2011) 20:139–145
4-Allyl-1,2-dimethoxy-benzene (2c)
Synthesis of isoxazolines 3a–g and 5a–g
Yield 95.0, viscous oil, 1H NMR (CDCl3, 200 MHz) d 6.80
(1H, dd, J = 8.6, 1.6 Hz, H-5), 6.72 (1H, d, J = 8.6 Hz,
H-6), 6.70 (1H, d, J = 1.6 Hz, H-3), 5.94 (1H, m, H-8),
5.10 (1H, d, J = 18.2, 7.6 Hz, H-9a), 5.07 (1H, dd,
J = 18.2 Hz, H-9b), 3.85 (6H, s, 29 OCH3), 3.32 (2H, d,
J = 6.8 Hz, H-7); FAB MS m/z 179 [M?1]?.
General procedure
A mixture of oxime (1.1 equiv), chloramines-Sꢀ3H2O (1.1
equiv) and olefin (1.0 equiv) in ethanol (50 ml) were
refluxed for 3 h. The progress of reaction was monitored by
TLC. After completion of the reaction, the solvent was
removed using rotavapor. The residue was dissolved in
ether, washed with 1 N NaOH solution (39 15 ml), water
(25 ml), and saturated solution of NaCl, dried over anhy-
drous sodium sulfate. The solvent was evaporated and the
cycloadduct was purified by column chromatography over
silica gel.
4-Allyl-1-ethoxy-2-methoxy-benzene (2d)
Yield 89%, viscous oil, 1H NMR (CDCl3, 200 MHz) d 6.82
(1H, dd, J = 8.6 Hz, H-6), 6.69 (2H, d, J = 8.6 Hz, H-
3,5), 5.94 (1H, m, H-8), 5.11-5.02 (2H, m, H-9a,9b), 4.86
(2H, q, J = 7.0 Hz, OCH2CH3), 3.84 (3H, s, OCH3), 3.32
(2H, d, J = 6.6 Hz, H-7), 1.44 (3H, t, J = 7.0 Hz,
OCH2CH3); FAB MS m/z 193 [M?1]?.
4-[3-(2,4-Dimethoxy-phenyl)-4,5-dihydro-isoxazol-5-
ylmethyl]-2-methoxy-phenol (3a)
Yield 78.9%, brown sticky solid; IR (CHCl3) mmax: 3285,
1
2947, 1607, 1528, 1353, 1159 cm-1; H NMR (CDCl3,
4-Allyl-1-benzyloxy-2-methoxy-benzene (2e)
200 MHz) d 7.58 (1H, d, J = 8.4 Hz, H-60), 6.85 (1H, d,
J = 8.0 Hz, H-6), 6.81 (1H, d, J = 1.8 Hz, H-3), 6.72 (1H,
dd, J = 8.0, 1.8 Hz, H-5), 6.57 (1H, d, J = 2.4 Hz, H-30),
6.50 (1H, dd, J = 8.6, 2.2 Hz, H-50), 5.60 (1H, brs, OH),
4.86 (1H, m, H-8), 3.84 (9H, brs, 39 OCH3), 3.41 (1H, dd,
J = 18.1, 10.2 Hz, H-9a), 3.13 (1H, dd, J = 18.1, 7.6 Hz,
H-9b), 3.01 (1H, dd, J = 13.8, 9.7 Hz, H-7a), 2.94 (1H, dd,
J = 13.8, 6.6 Hz, H-7b); FABMS (?ve): m/z 344 [M?1]?.
Elemental anal. calc. for C19H21NO5: C, 66.46; H, 6.16; N,
4.08; found C, 66.50; H, 6.12; N, 4.13%.
1
Yield 84.0%, viscous oil, H NMR (CDCl3, 200 MHz) d
7.44–7.23 (5H, m, Ar), 6.81 (1H, d, J = 8.0 Hz, H-6), 6.72
(1H, d, J = 1.8 Hz, H-3), 6.65 (1H, dd, J = 8.0, 1.8 Hz,
H-5), 5.96 (1H, m, H-8), 5.11 (2H, s, –CH2–Ar), 5.10–4.99
(2H, m, H-9a,9b), 3.86 (3H, s, OCH3), 3.31 (2H, d,
J = 6.6 Hz, H-7); FAB MS m/z 255 [M?1]?.
1-[2-(4-Allyl-2-methoxy-phenoxy)-ethyl]-pyrrolidine (2f)
Yield 88.5%, brown viscous oil, 1H NMR (CDCl3,
200 MHz) d 6.83 (1H, d, J = 8.6 Hz, H-6), 6.69 (2H, brd,
J = 8.6 Hz, H-3,5), 5.93 (1H, m, H-8), 5.11 (2H, m, H-
9a,9b), 4.12 (2H, t, J = 6.2 Hz, OCH2), 3.84 (3H, s,
OCH3), 3.32 (2H, d, J = 6.6 Hz, H-7), 2.93 (2H, t,
J = 6.2 Hz, OCH2CH2N), 2.60 (4H, m, N(CH2)2–), 1.78
(4H, m, 29 CH2); FAB MS m/z (?ve) 262 [M?1]?. Ele-
mental anal. calc. for C16H23NO2: C, 73.53; H, 8.87; N,
5.36%; found C, 73.59; H, 8.39; N, 5.43.
4-[3-(2,4-dimethoxy-phenyl)-4,5-dihydro-isoxazol-5-
ylmethyl]-2-methoxy-phenyl acetate (3b)
Yield 81.9%, white solid, mp 117–118°C. IR (KBr) mmax
:
1
2930, 1762, 1683, 1511, 1101 cm-1; H NMR (CDCl3,
200 MHz) d 7.61 (1H, d, J = 8.4 Hz, H-60), 6.96 (1H, d,
J = 8.0 Hz, H-6), 6.91 (1H, d, J = 1.4 Hz, H-3), 6.81 (1H,
dd, J = 8.0, 1.8 Hz, H-5), 6.52 (1H, d, J = 2.2 Hz, H-30),
6.47 (1H, dd, J = 8.2, 1.8 Hz, H-50), 4.87 (1H, m, H-8),
3.83 (9H, brs, 39 OCH3), 3.49 (1H, dd, J = 17.2, 11.0 Hz,
H-9a), 3.15 (1H, dd, J = 17.2, 7.6 Hz, H-9b), 3.08 (1H, dd,
J = 13.8, 9.2 Hz, H-7a), 2.83 (1H, dd, J = 14.2, 6.6 Hz,
H-7b), 2.29 (3H, s, OCOCH3); FAB MS (?ve): m/z 385
[M?1]?. Elemental anal. calc. for C21H23NO6: C, 65.44;
H, 6.02; N, 3.63; found C, 65.48; H, 6.07; N, 3.58%.
1-[2-(4-Allyl-2-methoxy-phenoxy)-ethyl]-piperidine (2g)
Yield 90.7%, brown viscous oil, 1H NMR (CDCl3,
200 MHz) d 6.82 (1H, d, J = 8.6 Hz, H-6), 6.70 (2H, brd,
J = 8.5 Hz, H-3,5), 5.96 (1H, m, H-8), 5.10 (2H, m, H-
9a,9b), 4.11 (2H, t, J = 6.4 Hz, OCH2), 3.82 (3H, s,
OCH3), 3.32 (2H, d, J = 6.8 Hz, H-7), 2.79 (2H, t,
J = 6.4 Hz, OCH2CH2N), 2.52 (4H, m, N(CH2)2–), 1.62
(6H, m, 39 CH2); FAB MS m/z 276 [M?1]?. Elemental
anal. calc. for C17H25NO2: C, 74.14; H, 9.15; N, 5.09%;
found C, 74.17; H, 9.19; N, 5.14%.
5-(3,4-Dimethoxy-benzyl)-3-(2,4-dimethoxy-phenyl)-4,5-
dihydro-isoxazole (3c)
Yield 82.0%, white needle-shaped crystals, mp 98–99°C.
IR (KBr) mmax: 2938, 1597, 1515, 1351, 1157 cm-1; H
1
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Med Chem Res (2011) 20:139–145
143
NMR (CDCl3, 200 MHz) d 7.80 (1H, d, J = 8.2 Hz, H-60),
7.59 (1H, d, J = 8.4 Hz, H-6), 7.29 (2H, d, J = 8.8 Hz, H-
3,5), 6.80 (1H, d, J = 2.2 Hz, H-30), 6.49 (1H, dd, J = 8.4,
2.4 Hz, H-50), 4.87 (1H, m, H-8), 3.87 (12H, brs, 49
OCH3), 3.41 (1H, dd, J = 17.2, 10.0 Hz, H-9a), 3.12 (1H,
dd, J = 17.2, 7.6 Hz, H-9b), 3.04 (1H, dd, J = 13.4,
6.2 Hz, H-7a), 2.80 (1H, dd, J = 13.8, 6.6 Hz, H-7b); FAB
MS (?ve): m/z 357 [M?], 358 [M?1]?. Elemental anal:
calc. for C20H23NO5: C, 67.21; H, 6.49; N, 3.92; found C,
67.25; H, 6.54; N, 3.98%.
3.95 (2H, t, J = 6.2 Hz, OCH2), 3.85 (3H, brs, OCH3),
3.84 (3H, brs, OCH3), 3.82 (3H, brs, OCH3), 3.39 (1H, dd,
J = 17.1, 10.4 Hz, H-9a), 3.14 (1H, dd, J = 17.1, 10.0 Hz,
H-9b), 3.09 (1H, dd, J = 14.1, 6.8 Hz, H-7a), 2.87 (1H, dd,
J = 14.1, 6.2 Hz, H-7b), 2.85 (2H, t, J = 6.2 Hz, –CH2–
N), 2.60 (4H, m, –N(CH2)2–), 1.79 (4H, m, –CH2CH2–);
FAB MS (?ve): m/z 441 [M?1]?. Elemental anal. calc. for
C25H32N2O5: C, 68.16; H, 7.32; N, 6.36; found C, 68.07;
H, 7.40; N, 6.40%.
1-(2-{4-[3-(2,4-Dimethoxy-phenyl)-4,5-dihydro-isoxazol-
5-ylmethyl]-2-methoxy-phenoxy}-ethyl)-piperidine (3g)
3-(2,4-Dimethoxy-phenyl)-5-(4-ethoxy-3-methoxy-benzyl)-
4,5-dihydro-isoxazole (3d)
Yield 80.9%, brown viscous oil. IR (neat) mmax: 3019,
1
Yield 75.6%, white solid, mp 92–93°C. IR (KBr) mmax
:
1609, 1350, 1216 cm-1; H NMR (CDCl3, 200 MHz) d
3021, 2361, 1769, 1628, 1216 cm-1; H NMR (CDCl3,
200 MHz) d 7.76 (1H, d, J = 8.2 Hz, H-60), 7.58 (1H, d,
J = 8.4 Hz, H-6), 7.34 (1H, s, H-3), 6.79 (2H, dd, J = 8.2,
1.5 Hz, H-30,5), 6.47 (1H, dd, J = 8.4, 2.4 Hz, H-50), 4.86
(1H, m, H-8), 4.06 (2H, q, J = 7.0 Hz, OCH2CH3), 3.82
(9H, brs, 39 OCH3), 3.33 (1H, dd, J = 18.1, 10.0 Hz, H-
9a), 3.12 (1H, dd, J = 18.1, 7.4 Hz, H-9b), 3.01 (1H, dd,
J = 13.1, 6.6 Hz, H-7a), 2.98 (1H, dd, J = 13.1, 6.6 Hz,
H-7b), 1.43 (3H, t, J = 7.0 Hz, OCH2CH3); FAB MS
(?ve): m/z 372 [M?]. Elemental anal: calc. for
C21H25NO5: C, 67.91; H, 6.78; N, 3.77; found C, 67.84; H,
6.71; N, 3.72%.
7.60(1H, d, J = 8.4 Hz, H-60), 6.83 (1H, d, J = 7.6 Hz,
H-6), 6.81 (2H, m, H-3,5), 6.49 (1H, dd, J = 8.0, 1.8 Hz,
H-50), 4.86 (1H, m, H-8), 6.52 (1H, d, J = 1.8 Hz, H-30),
4.13 (2H, t, J = 6.2 Hz, OCH2), 3.85 (3H, brs, OCH3),
3.84 (3H, brs, OCH3), 3.82 (3H, brs, OCH3), 3.39 (1H, dd,
J = 17.2, 10.0 Hz, H-9a), 3.14 (1H, dd, J = 17.2, 10.0 Hz,
H-9b), 3.09 (1H, dd, J = 14.2, 6.2 Hz, H-7a), 2.87 (1H, dd,
J = 14.2, 6.8 Hz, H-7b), 2.84 (2H, t, J = 6.0 Hz, –CH2–
N), 2.58 (4H, m, –N(CH2)2–), 1.66 (6H, m, –CH2CH2CH2–);
FAB MS (?ve): m/z 455 [M?1]?. Elemental anal. calc. for
C26H34N2O5: C, 68.70; H, 7.54; N, 6.16; found C, 68.73; H,
7.48; N, 6.10%.
1
5-(4-Benzyloxy-3-methoxy-benzyl)-3-(2,4-dimethoxy-
phenyl)-4,5-dihydro-isoxazole (3e)
2-Methoxy-4-(3-naphthalen-1-yl-4,5-dihydro-isoxazol-5-
ylmethyl)-phenol (5a)
1
Yield 81.0%, white crystals, mp 83–84°C. IR (KBr) mmax
:
Yield 88.0%, sticky solid. H NMR (CDCl3, 200 MHz) d
3021, 1616, 1216 cm-1; H NMR (CDCl3, 200 MHz) d
7.60(1H, d, J = 8.4 Hz, H-60), 7.45–7.23 (5H, m, H-200 to
600), 6.84 (1H, d, J = 1.8 Hz, H-3), 6.81 (1H, d,
J = 8.2 Hz, H-6), 6.70 (1H, d, J = 8.2, 1.8 Hz, H-5), 6.51
(1H, d, J = 2.4 Hz, H-30), 6.46 (1H, dd, J = 7.0, 2.4 Hz,
H-50), 5.13 (2H, s, CH2Ar), 4.87 (1H, m, H-8), 3.88 (9H,
brs, 39 OCH3), 3.40 (1H, dd, J = 17.2, 10.0 Hz, H-9a),
3.13 (1H, dd, J = 17.2, 7.6 Hz, H-9b), 3.03 (1H, dd,
J = 13.8, 6.8 Hz, H-7a), 2.81 1H, dd, J = 13.8, 6.6 Hz, H-
7b); FAB MS (?ve): m/z 434 [M?1]?. Elemental anal.
calc. for C26H27NO5: C, 72.04; H, 6.28; N, 3.23; found C,
72.12; H, 6.31; N, 3.16%.
8.80 (1H, d, J = 7.3 Hz, H-80), 7.80 (2H, m, H-20,40), 7.58
(4H, m, H-30,50,60,70), 6.80 (3H, m, H-3,5,6), 5.00 (1H, m,
H-8), 3.89 (3H, brs, OCH3), 3.56 (1H, dd, J = 16.1,
10.3 Hz, H-9a), 3.27 (1H, dd, J = 16.1, 7.7 Hz, H-9b),
3.08 (1H, dd, J = 14.5, 7.8 Hz, H-7a), 2.97 (1H, dd,
J = 14.5, 6.4 Hz, H-7b); FAB MS (?ve): m/z 333 [M]?,
334 [M?1]?. Elemental anal. calc. for C21H19NO3: C,
75.66; H, 5.74; N, 4.20; found C, 75.58; H, 5.70; N, 4.13%.
1
2-Methoxy-4-(3-naphthalen-1-yl-4,5-dihydro-isoxazol-5-
ylmethyl)-phenyl acetate (5b)
Yield 85.0%, brown sticky solid. IR (KBr) mmax: 3021,
3-(2,4-Dimethoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-
yl-ethoxy)-benzyl]-4,5-dihydro-isoxazole (3f)
2361, 1601, 1514, 1216 cm-1 1H NMR (CDCl3,
;
200 MHz) d 8.88 (1H, d, J = 7.6 Hz, H-80), 7.78 (2H, m,
H-20,40), 7.58 (4H, m, H-30,50,60,70), 6.98 (1H, d,
J = 8.1 Hz, H-6), 6.95 (1H, d, J = 1.2 Hz, H-3), 6.81 (1H,
dd, J = 8.1, 1.2 Hz, H-5), 5.02 (1H, m, H-8), 3.87 (3H, brs,
OCH3), 3.54 (1H, dd, J = 16.6, 10.2 Hz, H-9a), 3.26 (1H,
dd, J = 16.6, 7.8 Hz, H-9b), 3.17 (1H, dd, J = 13.2,
6.2 Hz, H-7a), 2.95 (1H, dd, J = 13.2, 5.2 Hz, H-7b), 2.45
Yield 73.9%, brown viscous oil. IR (neat) mmax: 3020,
1
1613, 1513, 1216 cm-1; H NMR (CDCl3, 200 MHz) d
7.39(1H, d, J = 8.4 Hz, H-60), 6.62 (1H, d, J = 7.4 Hz, H-
6), 6.56 (2H, m, H-3,5), 6.30 (1H, d, J = 2.2 Hz, H-30),
6.27 (1H, dd, J = 8.3, 1.7 Hz, H-50), 4.72 (1H, m, H-8),
123

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Med Chem Res (2011) 20:139–145
(3H, s, COCH3); FAB MS (?ve): m/z 376 [M?1]?. Ele-
mental anal. calc. for C23H21NO4: C, 73.58; H, 5.64; N,
3.73; found C, 73.66; H, 6.01; N, 3.65%.
5-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-3-
naphthalen-1-yl-4,5-dihydro-isoxazole (5f)
1
Yield 78.6%, brown solid. H NMR (CDCl3, 200 MHz) d
8.87 (1H, dd, J = 9.1, 1.7 Hz, H-80), 7.91 (2H, m, H-20,40),
7.59-7.40 (4H, m, H-30,50,60,70), 6.98 (1H, d, J = 1.8 Hz,
H-3), 6.80 (1H, dd, J = 8.0, 1.8 Hz, H-5), 6.70 (1H, d,
J = 8.0 Hz, H-6), 5.04 (1H, m, H-8), 4.16 (2H, t,
J = 5.8 Hz, –OCH2), 3.88 (3H, brs, OCH3), 3.65 (1H, dd,
J = 15.1, 9.5 Hz, H-9a), 3.32 (1H, dd, J = 15.1, 6.5 Hz,
H-9b), 3.02 (1H, dd, J = 14.0, 6.5 Hz, H-7a), 2.81 (1H, dd,
J = 14.0, 6.2 Hz, H-7b), 2.82 (2H,t, J = 6.0 Hz –NCH2),
2.64 (4H, m, H–N(CH2)2–), 1.72 (4H, m, –CH2CH2–);
FABMS m/z 431 [M?1]?. Elemental anal. calc. for
C27H30N2O3: C, 75.32; H, 7.02; N, 6.51; found C, 75.41;
H, 7.11; N, 6.42%.
5-(3,4-Dimethoxy-benzyl)-3-(naphthalen-1-yl)-4,5-
dihydroisoxazole (5c)
Yield 87.1%, white needle-shaped crystals, mp 103–104°C.
1
IR (KBr) mmax: 2938, 1592, 1235, 1030 cm-1; H NMR
(CDCl3, 200 MHz) d 8.84 (1H, dd, J = 7.4, 2.0 Hz, H-80),
7.88 (2H, m, H-20,40), 7.56 (4H, m, H-30,50,60,70), 6.84 (3H,
m, H-3,5,6), 5.01 (1H, m, H-8), 3.88 (3H, brs, OCH3), 3.85
(3H, brs, OCH3), 3.53 (1H, dd, J = 16.6, 10.2 Hz, H-9a),
3.24 (1H, dd, J = 16.6, 7.6 Hz, H-9b), 3.12 (1H, dd,
J = 14.2, 8.0 Hz, H-7a), 2.94 (1H, dd, J = 14.2, 6.4 Hz,
H-7b); FAB MS (?ve): m/z 348 [M?1]?. Elemental anal.
calc. for C22H21NO3: C, 76.06; H, 6.09; N, 4.03; found C,
76.00; H, 6.01; N, 4.11%.
1-{2-[2-Methoxy-4-(3-naphthalen-1-yl-4,5-dihydro-
isoxazol-5-ylmethyl)-phenoxy]-ethyl}-piperidine (5g)
Yield 88.6%, brown sticky solid. 1H NMR (CDCl3,
200 MHz) d 8.85 (1H, dd, J = 9.2, 1.8 Hz, H-80), 7.94
(2H, m, H-20,40), 7.60-7.43 (4H, m, H-30,50,60,70), 6.96 (1H,
d, J = 2.1 Hz, H-3), 6.82 (1H, dd, J = 8.2, 2.1 Hz, H-5),
6.69 (1H, d, J = 8.2 Hz, H-6), 5.03 (1H, m, H-8), 4.18
(2H, t, J = 5.8 Hz, –OCH2), 3.85 (3H, brs, OCH3), 3.61
(1H, dd, J = 15.6, 9.8 Hz, H-9a), 3.30 (1H, dd, J = 15.6,
6.8 Hz, H-9b), 3.25–3.06 (2H, m, H-7ab), 3.00 (2H,brs, –
NCH2), 2.70 (4H, m, H–N(CH2)2–), 1.71–1.65 (6H, m, H–
CH2CH2CH2–); FAB MS m/z 444 [M]?, 445 [M?1]?.
Elemental anal. calc. for C28H32N2O3: C, 75.65; H, 7.26;
N, 6.30; found C, 75.57; H, 7.1; N, 6.37%.
5-(4-Ethoxy-3-methoxy-benzyl)-3-naphthalen-1-yl-4,5-
dihydro-isoxazole (5d)
Yield 77.4%, brown sticky solid. IR (KBr) mmax: 3377,
1
1596, 1514, 1261 cm-1; H NMR (CDCl3, 200 MHz) d
8.86 (1H, dd, J = 7.6, 1.8 Hz, H-80), 7.87 (2H, m, H-20,40),
7.61 (4H, m, H-30,50,60,70), 6.85 (3H, m, H-3,5,6), 4.99 (1H,
m, H-8), 4.06 (2H, q, J = 7.0 Hz, OCH2CH3)), 3.87 (3H,
brs, OCH3), 3.52 (1H, dd, J = 16.6, 10.2 Hz, H-9a), 3.23
(1H, dd, J = 16.6, 7.8 Hz, H-9b), 3.14 (1H, dd, J = 15.8,
7.8 Hz, H-7a), 2.93 (1H, dd, J = 15.8, 6.6 Hz, H-7b); ESI
MS m/z 361 [M?1]?. Elemental anal. calc. for
C23H23NO3: C, 76.43; H, 6.41; N, 3.88; found C, 76.35; H,
6.49; N, 3.79%.
Acknowledgments The authors are grateful to SAIF for spectral
data and Indian Council of Medicinal Research, New Delhi, for the
award of senior research fellowship to P. Gupta. Kailash and Ausaf
Ahmad are thankful to UGC for financial support.
5-(4-Benzyloxy-3-methoxy-benzyl)-3-naphthalen-1-yl-4,5-
dihydro-isoxazole (5e)
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