Synthesis of piperazino and morpholino derivatives of aryloxypropane with potential analgesic and possible antimigraine activities

Article abstract of DOI:10.1007/s00044-010-9316-3

Modeling studies demonstrate that aryl piperazines (I), aryloxyalkylamines (II), phenylalkykamines (III) and indolylalkylamines (VI) may interact at 5-HT receptors in a similar manner. Examination of these structures (I-VI) reveals that all possess an aromatic moiety and terminal amine binding sites (Glennon et al., J Med Chem 32(8):1921-1926, 1989). In the present investigation a new series of aryloxyalkylamines (4, 5, 8, and 9) was designed and synthesized, in which the aromatic moiety is a phenyl group substituted at the 2,3-, 2,4-, 2,5-, or 2,6-positions by halogens and the terminal amine is N-methylpiperazine, or morpholine. In addition, the alkyl side chain is ethyl, or substituted ethyl at the α- or β-carbon by a methyl group. The length of the alkyl chain that separates the terminal amine from the ether oxygen atom of the aryloxy group is of major importance, and two-carbon chain appears optimal. The structures of the new compounds were assessed by microanalyses, IR, and NMR. The analgesic activity of selected compounds was performed on experimental animals and proved to be in the range of 85-100% relative to aspirin. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-010-9316-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:381–387
DOI 10.1007/s00044-010-9316-3
ORIGINAL RESEARCH
Synthesis of piperazino and morpholino derivatives
of aryloxypropane with potential analgesic and possible
antimigraine activities
•
Abdulkhader M. Ismaiel Laila M. Gad
•
•
Salah A. Ghareib Faida H. Bamanie
•
Mohamed A. Moustafa
Received: 31 January 2009 / Accepted: 12 February 2010 / Published online: 12 March 2010
Ó Springer Science+Business Media, LLC 2011
Abstract Modeling studies demonstrate that aryl piper-
azines (I), aryloxyalkylamines (II), phenylalkykamines
(III) and indolylalkylamines (VI) may interact at 5-HT
receptors in a similar manner. Examination of these
structures (I–VI) reveals that all possess an aromatic
moiety and terminal amine binding sites (Glennon et al., J
Med Chem 32(8):1921–1926, 1989). In the present inves-
tigation a new series of aryloxyalkylamines (4, 5, 8, and 9)
was designed and synthesized, in which the aromatic
moiety is a phenyl group substituted at the 2,3-, 2,4-, 2,5-,
or 2,6-positions by halogens and the terminal amine is
N-methylpiperazine, or morpholine. In addition, the alkyl
side chain is ethyl, or substituted ethyl at the a- or b-carbon
by a methyl group. The length of the alkyl chain that
separates the terminal amine from the ether oxygen atom of
the aryloxy group is of major importance, and two-carbon
chain appears optimal. The structures of the new com-
pounds were assessed by microanalyses, IR, and NMR. The
analgesic activity of selected compounds was performed on
experimental animals and proved to be in the range of
85–100% relative to aspirin.
Keywords Aryloxyalkylamines Á Design and synthesis Á
Analgesic activity
Introduction
The role of serotonin, agonists, at serotonin receptors
5-HT1B/1D in the treatment of migraine attack was studied
(Hamon and Bourgoin, 2000; Ferrari et al., 2001; Newman
et al., 2001). These studies showed that 5-HT1D receptors
are the dominant receptors in human cerebral blood ves-
sels, and 5-hydroxytryptamine (5-HT) is implicated in
migraine. Structure affinity relationships for 5-HT1D sero-
tonin receptors have been reported for many indolylalkyl-
amines, or tryptamine derivatives, which bind with high
affinity and little selectivity (Glennon et al., 1989; Glennon
et al., 1991). Some were designed as h5-HT1D agonists for
the treatment of migraine (Bourrain et al., 1999); (Sternfeld
et al., 1999). A new agonist series of aryloxyalkylamines,
with enhanced affinity for human h5-5HT1B serotonin
receptors (Ismaiel et al., 1997; Glennon and Dukat, 2002)
were prepared. Also, new agents displaying high affinity
and reasonable selectivity for h5-5HT1D/h5-5HT1B recep-
tors over a population of 5-HT receptors were synthesized
(Jones and Blackurn, 2002). There are ongoing investiga-
tions to develop new agonists that possess h5-HT1D/h5-
HT1B selectivity, which have analgesic activity, and may
be used to treat migraine (Glennon and Dukat, 2002; Ward
et al., 2005).
A. M. Ismaiel Á L. M. Gad (&) Á M. A. Moustafa
Faculty of Pharmacy, Pharmaceutical Chemistry Department,
King Abdulaziz University, P. O. Box 80260, Jeddah 21589,
Kingdom of Saudi Arabia
e-mail: lgad@kau.edu.sa; gad_laila@yahoo.com
M. A. Moustafa
e-mail: mmoustafa50@hotmail.com
S. A. Ghareib
Faculty of Pharmacy, Pharmacology and Toxicology
Department, King Abdulaziz University, P. O. Box 80260,
Jeddah 21589, Kingdom of Saudi Arabia
F. H. Bamanie
Faculty of Faculty of medicine, Clinical Biochemistry
Department, King Abdulaziz University, P. O. Box 80260,
Jeddah 21589, Kingdom of Saudi Arabia
e-mail: fbamane@yahoo.com
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Med Chem Res (2011) 20:381–387
General procedures for the preparation of the target
compounds (B), Scheme 2
Materials and methods
Chemistry
Reaction of ( )1-chloro-2-propanol with the correspond-
ing morpholine and N-methylpiperazine in NaOH afforded
1-morpholino-2-propanol (6a) and 1-(4-methylpiperazin-1-
yl)-2-propanol (6b), respectively. These were reacted with
thionyl chloride in benzene to give the corresponding 4-(2-
chloropropyl)morpholine and 1-(2-chloropropyl)-4-meth-
ylpiperazine hydrochlorides (7a, b). Reaction of (7a,
b) with the respective phenol (1a–f) in 2 N NaOH, fol-
lowed by treatment of ethereal solution of the free base
with saturated solution of oxalic acid, gave ( )4-[2-(sub-
stitutedphenoxy)propyl]morpholine oxalates (8a, b) and
1-[2-(substitutedphenoxy)propyl]-4-methy-piperazine di-
oxalates (9a–g) (Scheme 2; Table 3).
General procedure for the preparation of the target
compounds (A), Scheme 1
Reaction of substituted phenols (1a–f) with ( )1-chloro-2-
propanol in 2N NaOH for 24 h afforded ( )1-(substituted-
phenoxy)-2-propanol (2a–f). In order to introduce the
terminal amine moiety (2a–f), they were first reacted with
p-toluenesulfonyl chloride in dry pyridine at 0°C for 3 days
to afford ( )1-(substituted-phenoxy)propan-2-yl-p-meth-
ylbenzene-sulfonates (3a–f). Then, the reacting p-methyl-
benzene-sulfonate derivatives (3a–f) were treated with the
corresponding 4-methylpiperazine or morpholine in dioxan
and in the presence of anhydrous K2CO3 for 18 h, followed
by treatment of ethereal extract of the free base with a
saturated solution of oxalic acid, or HCl, to give the target
compounds (A); ( )4-[1-(substituted-phenoxy)prop-2-
yl]morpholine oxalates (4a, b) and hydrochloride (4c),
( )1-[2-(substituted-phenoxy)prop-2-yl]-4-methylpiperazine
dioxalates (5a–f) (Scheme 1; Tables 1, 2).
Experimental section
Proton nuclear magnetic resonance spectra (1H NMR) were
recorded on a Bruker Avance DPX400 spectrometer using
Me4Si as internal standard, and were carried out at the
Faculty of Science, King Abdulaziz University. Elemental
Scheme 1 Preparation of
CH3
oxalate and hydrochloride salts
of 1-aryloxy-2-(4-morpholino)-
or (4-N-methylpiperazino)-
propane(4a–c & 5a–f)
OH
O
X1
X1
X2
OH
ClCH2CH(CH3)OH
TsCl
2N Na OH
X2
(2)
(1)
CH3
OTs
CH3
O
X1
O
X1
N
HN
X
1.
X
X2
(3)
(4 a-c), (5a-f)
COOH
n
X2
(COOH)2/Et2O
2.
COOH
Target compounds A
X = O, N-CH3
Scheme 2 Preparation of 1-[4-
morpholino- & 4-(1-N-
methylpiperazino)]
-2-aryloxypropane derivatives
(8a,b & 9a–g)
OH
CH3
Cl
X
X
X
OH
CH3
. HCl
Cl
CH3
X1
SOCl2
N
N
NH
(7a,b)
(6a,b)
X = O, N-CH3
OH
2N NaOH
X2
O
ß
O
ß
X1
X2
(COOH)2/Et2O
X1
N
N
X
X
CH3
CH3
COOH
X2
(8a,b) and (9a-g)
n
COOH
Target compounds
B
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Med Chem Res (2011) 20:381–387
383
Table 1 Physicochemical properties of ( )4-[1-(substituted-phenoxy)prop-2-yl]morpholines
O
N
1
X
O
2
X
Serial no.
X1, X2
Mol. formula (mol. wt)
C15H19Cl2NOa6 (380.22)
Cryst. solvent
M.p. (°C)
Microanalysis
Calc/Fd.
C
H
N
4a
4b
4c
2,3-Dichloro
2,4-Dichloro
2,4-Dibromo
EtOH/Et2O
EtOH/Et2O
EtOH/Et2O
118–120
102–103
150–152
47.38
47.04
47.38
47.25
37.57
37.25
5.04
4.50
5.04
4.07
4.37
3.78
3.68
3.43
3.68
3.49
3.37
2.72
C
15H19Cl2NOa6 (380.22)
C
13H18Br2ClNOb2 (415.55)
a
Oxalate salt
b
Hydrochloride salt
Table 2 Physicochemical properties of ( )1-[1-(substituted-phenoxy)prop-2-yl]-4-methylpiperazine dioxalates
O
COOH
N
X1
2
N
COOH
X2
Serial no.
X1, X2
Mol. formula (mol. wt)
Cryst. solvent
M.p. (°C)
Microanalysis
Calc/Fd.
C
H
N
5a
5b
5c
5d
5e
5f
2,3-Dichloro
2,4-Dichloro
2,5-Dichloro
2,4-Dibromo
2,6-Dibromo
C18H24Cl2N2O9 (483.3)
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
215–217
210–212
220–222
216–217
218–220
205–207
44.73
44.45
44.73
44.68
43.91
44.12
37.78
37.60
37.78
37.72
56.91
56.91
5.01
4.48
5.01
2.76
5.12
4.12
4.23
3.75
4.23
3.59
5.97
4.31
5.80
5.44
5.80
5.41
5.69
5.31
4.90
4.46
4.90
4.56
5.53
5.33
C
C
C
C
18H24Cl2N2O9 (483.3)
18H24Cl2N2O9. 0.5 H2O (492.3)
18H24Br2N2O9 (572.2)
18H24Br2N2O9 (572.2)
X1 = H
X2 = 3-OC6H5
C24H30N2O10 (506.5)
analyses were performed with a Perkin Elmer 2400, series II
micro analyzer at the Micro-analytical laboratory, Faculty
of Science, Abdulaziz University. Melting points were
determined with a Barnstead electro thermal melting point
apparatus (uncorrected). Column chromatography was per-
formed using silica gel with CHCl3/MeOH (9:1) as an eluent.
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Table 3 Physicochemical properties of ( )4-[2-(2,3- and 2,4-dichlorophenoxy)-propyl]morpholine oxalates
O
N
COOH
Cl
O
COOH
Cl
Serial no.
X1, X2
Mol. formula (mol. Wt)
Cryst. solvent
M.p. (°C)
Microanalysis
Calc/Fd.
C
H
N
8a
8b
2,3-Dichloro
2,4-Dichloro
C15H19Cl2NO6 (380.22)
EtOH/Et2O
EtOH/Et2O
131–133
131–133
47.38
47.27
47.38
47.59
5.04
4.87
5.04
3.54
3.68
3.92
3.68
3.93
C18H29Cl2NO5 (380.22)
1H NMR spectrum of (–)4-[1-(2,4-dibromophen-
oxy)prop-2-yl]morpholine hydrochloride (4c); DMSO-
d6, d 1.25 (d, 3H, CH3), d 3.6–3.7 (m, 4H, CH2–O–CH2), d
3.4 (m, 1H, CH), d 3.7 (m, 4H, 2CH2), d 4.25 (d, 2H,
OCH2), d 7.1 (d, 1H, Ar–6–H), d 7.5 (d,1H, Ar–5–H), d 7.8
(s,1H, Ar–3–H).
Synthesis of the compounds
4-[1-(2,4-Dibromophenoxy) prop-2-yl] morpholine
hydrochloride (4c)
A mixture of 2,4-dibromophenol (1) (5.02 g, 20 mmol) and
1-chloro-2-propanol (2.4 g, 25 mmol) in 2 N NaOH
(20 ml) was heated, at reflux, for 24 h. The reaction mix-
ture was diluted with water (20 ml) and extracted with
CH2Cl2 (3 9 30 ml), washed with NaOH 10% (50 ml) and
with water (3 9 30 ml), dried (MgSO4), and evaporated to
give 4.9 g (80%) of ( )1-(2,4-dibromophenoxy)-2-propa-
nol (2) as an oil. p-Toluenesulfonyl chloride (1.9 g,
0.01 mol) was added portion-wise to (2) (3.1 g, 0.01 mol)
in pyridine (10 ml) at 0°C, the reaction mixture was
refrigerated for 3 days, after which the reaction mixture
was poured into ice-water (60 ml) and extracted with ether
(3 9 25 ml); the ether extract was washed with 5% HCl
(30 ml) and H2O (30 ml). The ether extract was dried
(MgSO4) and the solvent evaporated to give 4 g of ( )1-
(2,4-dibromophenoxy)propan-2-yl-p-methylbenzenesulfonate
(3) as an oil, which was pure enough (TLC) to proceed to
the next step. A mixture of (3) (0.47 g, 0.001 mol) and
morpholine (2 ml) and K2CO3 in dioxan was heated under
reflux for 18 h. The solvent was evaporated in vacuo, and
the residue was extracted with ether (3 9 30 ml). The
combined ethereal solution was washed with water
(3 9 20 ml) and dried (MgSO4), then, the solvent was
evaporated. The product was separated by column chro-
matography using silica gel with CHCl3/MeOH (9:1) as an
eluent. The hydrochloride salt was prepared and crystal-
lized from the appropriate solvent. Compounds (4a, b) and
(5a–f) were prepared following the same procedures.
Microanalyses, crystallization, solvents, % yields, melting
points are shown in Tables 1, 2.
1H NMR spectrum of (–)4-[1-(2,3-dichlorophen-
oxy)prop-2-yl]morpholine oxalate (4a); d 1.2–1.3 (dd,
3H, CH3), d 2.8–3 (tt, 4H, 2CH2), d 3.4 (m, 1H, CH), d
3.6–3.7 (tt, 4H, 2CH2), d 4.2, 4.4 (mm, 2H, OCH2), d
7.2–7.4 (mm, 3H, Ar–H).
1H NMR spectrum of (–)1-(2,4-(dichlorophenoxy)
prop-2-yl]morpholine oxalate (4b); DMSO-d6, d 1.15–1.3
(dd, 3H, CH3), d 2.95–3.15 (m, 4H, 2CH2), d3.4 (m, 1H,
CH), d 3.6–3.7 (m, 4H, CH2–), d 4.2, 4.8 (mm, 2H, OCH2),
d 7.15–7.5 (m, 3H, Ar–H).
1H NMR of spectrum of (–)1-[1-(2,3-dichlorophen-
oxy)prop-2-yl]-4-methylpiperazine dioxalate (5a);
DMSO-d6: d 1.1–1.2 (dd, 3H, CH3), d 2.7(s, 3H, N–CH3), d
2.8 (m, 4H, 2CH2), d 3.2 (m, 4H, 2CH2), d 4.0 (m, 1H,
CH), d 4.1, 4.8 (mm, 2H, OCH2), d 7.1–7.4 (m, 3H, Ar–H).
1H NMR of spectrum of (–)1-[1-(2,4-dichlorophen-
oxy)prop-2-yl]-4-methylpiperazine dioxalate (5b);
DMSO-d6, d 1.1–1.12 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d
2.9 (m, 4H, 2CH2), d 3.1(m, 4H, 2CH2), d 3.9 (m, 1H, CH),
d 4.1–4.7 (br s, 2H, CH2), d 7.10–7.15 (dd, 1H, Ar–H), d
7.49 (m, 1H, Ar–H) and 7.75 (m, 1H, Ar–H).
1H NMR of (–)1-[1-(2,5-dichlorophenoxy)propan-2-
yl]-4-methylpiperazine dioxalates (5c); DMSO-d6, d
1.1–1.12 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d 2.9 (m, 4H,
2CH2), d 3.1(m, 4H, 2CH2), d 3.9 (mm, 1H, CH), d 4.1, 4.7
(mm, 2H, CH2), d 7.0–7.50 (m, 3H, Ar–H).
1H NMR of (–)1-[1-(2,4-dibromophenoxy)propan-2-
yl]-4-methylpiperazine dioxalates (5d); DMSO-d6, d
1.1–1.12 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d 2.9 (m, 4H,
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Med Chem Res (2011) 20:381–387
385
2CH2), d 3.1(m, 4H, 2CH2), d 3.9–4.0 (mm, 1H, CH), d
4.0–4.7 (mm, 2H, CH2), d 6.90–7.15 (dd, 1H, Ar–H), d 7.5
(m, 1H, Ar–H) and 7.75 (m, 1H, Ar–H).
1H NMR of (–)1-[1-(2,6-bromophenoxy)propan-2-
yl]-4-methylpiperazine dioxalates (5e); DMSO-d6, d
1.1–1.12 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d 2.9 (m 4H,
2CH2), d 3.1(m, 4H, 2CH2), d 3.80–3.85 (m, 1H, CH), d
3.9–4.1 (m, 2H, CH2), d 6.9–7.0 (m, 1H, Ar–H), d 7.5–7.6
(m, 2H, Ar–H).
1H NMR of (–)1-[1-(3-phenoxyphenoxy)propan-2-
yl]-4-methylpiperazine dioxalates (5f); DMSO-d6, d
1.1–1.12 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d 2.9 (m 4H,
2CH2), d 3.1(m, 4H, 2CH2), d 3.8–3.9 (mm, 1H, CH), d
4.1, 4.7 (mm, 2H, CH2), d 6.5, 6.8, 7.0, 7.15, 7.3 and 7.4
(m, 9H, Ar–H).
3.05 (m, 4H, 2CH2), d 3.9–4.1(mm, 1H, CH), d 4.6 (s, 2H,
CH2), d 6.9 (d, 2H, Ar–H), d 7.3 (d, 2H, Ar–H).
Compounds (8a, b) and (9b–g) were prepared following
the same procedures. Microanalyses, crystallization, sol-
vents, % yields, melting points are shown in Tables 3
and 4.
1H NMR spectrum of (–)4-[2-(2,3-dichlorophenoxy)
propyl]morpholine oxalate (8a); DMSO-d6, d 1.35–1.40
(d, 3H, CH3), d 2.8–3.0 (brs, H, CH), d 3.0–3.2 (m, 6H,
3CH2–N), d 3.70–3.80 (br, 4H, 2CH2–O), d 7.20–7.35 (m,
3H, Ar–H).
1H NMR spectrum of (–)4-[2-(2,4-dichlorophenoxy)
propyl]morpholine oxalate (8b); DMSO-d6, d 1.30–1.35
(dd, 3H, CH3), d 2.8–3.2 (m, 6H, 3CH2–N), d 3.70–3.85
(m, 4H, 2 CH2–O), d 4.8–4.9 (brs, 1H, CH), d 7.2–7.5 (m,
3H, Ar–H).
1H NMR spectrum of (–)1-(2-(2,3-dichlorophenoxy)
propyl)-4-methylpiperazine dioxalate (9b); DMSO-d6, d
1.15–1.125 (dd, 3H, CH3), d 2.7 (s, 3H, CH3), d 2.85 (m,
4H, 2CH2), d 3.15 (m, 4H, 2CH2), d 4.0–4.15 (mm, 1H,
CH), d 4.25 (m, 2H, CH2), d 7.15 (m, 2H, Ar–H), d 7.3 (m,
1H, Ar–H).
The following procedures are representatives of the
general methods applied for the preparation of:
( )1-[2-(4-Chlorophenoxy) propyl]-4-methylpiperazine
dioxalate (9a)
( )1-Chloro-2-propanol (0.2 mol) was added portion-
wise to the 4-methylpiperazine (0.1 mol) in the presence
of 2 N NaOH (20 ml). The mixture was stirred at 40°C
for 2 h, then, overnight at room temperature. The reaction
mixture was treated with NaOH (4 gm), then extracted
with ether (30, 20 and 10 ml), which was washed with
water (30, 20 and 10 ml), dried and evaporated. The
crude amine product was purified by column chroma-
tography, using silica gel with CHCl3/MeOH (9:1) as an
eluent. The product 1-(4-methylpiprazin-1-yl)propan-2-ol
(6b) was pure enough to proceed to the next step. Thus,
(6b) (1.6 gm; 0.01 mol) was dissolved in benzene (5 ml),
then treated with thionyl chloride (5 ml). The reaction
mixture was heated under reflux for 2 h, and stirred at
room temperature for 18 h. The excess thionyl chloride
was evaporated in vacuo and the residue triturated with
ether (20 ml), filtered and crystallized from benzene to
give 1.9 g, 88.4% of 1-(2-chloropropyl)-4-methylpipera-
zine hydrochloride (7b) pure enough to continue to the
next step. A mixture of 1-(2-chloropropyl)-4-methylpi-
perazine hydrochloride (7b) (0.213 gm; 1 mmol) and p-
chlorophenol (0.129 gm; 1 mmol) in 2 N NaOH (10 ml)
was heated under reflux for 2 h, then cooled and
extracted with ether (20, 10 and 5 ml). The combined
ethereal solution was washed with water (3 9 20 ml),
dried (MgSO4), and the solvent was evaporated. The
product was separated by column chromatography using
silica gel with CHCl3/MeOH (9:1) as an eluent. The
oxalate salt was prepared and crystallized from the
appropriate solvent.
1H NMR spectrum of (–)1-(2-(2,4-dichlorophenoxy)
propyl)-4-methylpiperazine dioxalate (9c); DMSO-d6, d
1.10–1.15 (dd, 3H, CH3), d 2.65 (s, 3H, CH3), d 2.75 (m,
4H, 2CH2), d 3.0 (m, 4H, 2CH2), d 3.9–4.1(mm, 1H, CH),
d 4.6 (m, 2H, CH2), d 6.9 (d, 2H, Ar–H), d 7.3 (d, 2H,
Ar–H).
1H NMR spectrum of (–)1-(2-(2,5-dichlorophenoxy)
propyl)-4-methylpiperazine dioxalate (9d); DMSO-d6, d
1.1–1.5 (dd, 3H, CH3), d 2.65 (s, 3H, CH3), d 2.8 (m 4H,
2CH2), d 3.0 (m, 4H, 2CH2), d 4.05–4.1(mm, 1H, CH), d
4.75 (m, 2H, CH2), d 7.10 (m, 1H, Ar–H), d 7.30 (d, 1H,
Ar–H) and d 7.45 (d, 1H, Ar–H).
1H NMR spectrum of (–)1-(2-(2,6-dibromophenoxy)
propyl)-4-methylpiperazine dioxalate (9f); DMSO-d6, d
1.1–1.15 (dd, 3H, CH3), d 2.65 (s, 3H, CH3), d 2.75 (m 4H,
2CH2), d 3.05 (m, 4H, 2CH2), d 3.9–4.1(mm, 1H, CH), d
4.6 (m, 2H, CH2), d 7.1 (d, 1H, Ar–H), d 7.65 (m, 2H,
Ar–H).
1H NMR spectrum of (–)1-(2-(3-phenoxyphenoxy)
propyl)-4-methylpiperazine dioxalate (9g); DMSO-d6, d
1.1–1.15 (dd, 3H, CH3), d 2.65 (s, 3H, CH3), d 2.75 (m, 4H,
2CH2), d 3.0 (m, 4H, 2CH2), d 3.9–4.1(mm, 1H, CH), d 4.6
(m, 2H, CH2), d 6.55–7.35 (m, 9H, Ar–H).
Pharmacological screening
The analgesic activities of the compounds tested versus
aspirin (acetylsalicylic acid) as the standard analgesic drug
were determined by the writhing technique according to the
method of Hendershot and Forsaith (1959). MFI mice of
1H NMR spectrum of (9a); DMSO-d6, d 1.1–1.12 (dd,
3H, CH3), d 2.65 (s, 3H, CH3), d 2.75 (m, 4H, 2CH2), d
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Med Chem Res (2011) 20:381–387
Table 4 Physicochemical properties of ( )1-(2-(disubstituted-phenoxy)propyl)-4-methylpiperazine dioxalates
O
COOH
N
1
2
X
COOH
N
2
X
Serial no.
X1, X2
Mol. formula (mol. wt)
Cryst. solvent
M.p. (°C)
Microanalysis
Calc/Fd.
C
H
N
9a
9b
9c
9d
9e
9f
X1 = H
X2 = 4-Cl
C18H25ClN2O9 (448.85)
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
Aq.EtOH
228–230
219–221
218–220
218–220
207–209
209–211
211–213
48.17
48.26
44.73
44.55
44.73
45.55
44.73
44.90
35.54
35.17
37.78
37.91
56.91
56.92
5.61
5.07
5.01
3.54
5.01
3.26
5.01
4.64
4.64
3.42
4.23
4.24
5.97
6.13
6.24
5.94
5.80
5.29
5.80
5.56
5.80
5.43
4.61
3.75
4.90
4.58
5.53
5.44
2,3-Dichloro
C18H24Cl2N2O9 (483.3)
C18H24Cl2N2O9 (483.3)
C18H24Cl2N2O9 (483.3)
C18H24Br2N2O9. 2 H2O (608.23)
C18H24Br2N2O9 (572.2)
2,4-Dichloro
2,5-Dichloro
2,4-Dibromo
2,6-Dibromo
9g
X1 = H
X2 = 3-OC6H5
C24H30N2O10 (506.5)
both sexes, 6–7 weeks old, and body weight range of
20–35 g were chosen, and were purchased from the animal
house of King Fahed Medical Research Center, King
Abulaziz University, Jeddah, KAS. Animals were kept
under a 12 h day and night light cycle. They were left on
free excess standard diet and water ad libitum.
(0.25 ml/mouse). Animals were left for 10 min, then were
observed for the presence of writhing. Mice that did not
induce writhing at this dose of (PBQ) were considered
insensitive and were discarded. Aspirin was suspended in
2% carboxymethyl cellulose sodium (CMC). The com-
pounds tested were dissolved in hot bidistilled water. All
compounds were given to mice via IP injection at 0.1 ml/
10 g body weight. After one and a half hours, animals were
Twenty-four hours before the experiment, animals were
injected intrapretonially (IP) with p-benzoquinone (PBQ)
Table 5 The analgesic effect (%) of the tested compounds relative to aspirin in mice
Group
Treatment
Dose (mg/kg)
No. per group
No. of mice writhing
No. of ?ve analgesia
% Response
1
2
3
Bidistilled water
Aspirin
10
100
180
120
60
6
6
6
8
8
6
8
8
6
6
8
8
6
0
0
2
5
0
3
4
1
0
5
7
0
6
6
6
3
6
5
4
5
6
3
1
0
100
100
75
(5a)
37.5
100
62.5
50
4
(5c)
135
90
50
7
8
(9b)
(9f)
90
85
110
75
100
37.5
12.5
40
123

Med Chem Res (2011) 20:381–387
387
re-injected with (PBQ) and were left for 10 min, then
observed for writhing. The assay was carried out by the
method of an ‘‘all or none response’’. The animals exhib-
iting writhing were considered negative for the analgesic
effect and were discarded. The remaining animals in the
same group that showed positive analgesia were calculated
in percent of the total number per group for each com-
pound, and compared with aspirin, thereby the relative
potency of each compound was calculated.
template, may lead to agents for use as analgesic and
migraine therapeutics.
Acknowledgments This work was supported by funds from Insti-
tute of Research and Consultation, King Abdulaziz University, Min-
istry of Higher Education, Jeddah, Kingdom of Saudi Arabia.
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Our finding strongly suggests that further synthetic
modifications, using the parent molecule as a chemical
123