Synthesis of new cyclic imides derivatives with potential hypolipidemic activity

Article abstract of DOI:10.1007/s00044-010-9492-1

Certain new nitrogen-substituted derivatives of cyclic imides phthalimide (a), 1,8-naphthalimide (b), and diphenimide (c), were synthesized aiming to obtain potent hypolipidemic agents. Thus, 2-(N-imido) propanoic acids, 2-(N-phthalimido)-2-methylpropionic acid, and their ethyl esters were synthesized (Target derivative A). Also their corresponding N-substituted-2-(N- imido) propionamides and 2-(N-phthalimido)-2-methylpropionamides were prepared (Target derivative B). In addition, N-phthalimidomethyleneoxy acetate was prepared. Some of the newly prepared compounds were subjected to 3D studies and were found to be superimposed on Clofibrate, which is the first generation of fibrate drugs. The preliminary evaluation of hypolipidemic activity of the newly prepared compounds against triton WR-1339-induced hyperlipidemia in rat showed that several derivatives have demonstrated significant lowering of serum total cholesterol and triglyceride levels at dose of 150 mg/kg/i.p. comparing with Fenofibrate which is one of the second generations of fibrate drugs. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9492-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:75–84
DOI 10.1007/s00044-010-9492-1
ORIGINAL RESEARCH
Synthesis of new cyclic imides derivatives with potential
hypolipidemic activity
•
Mohamed A. El-Zahabi Laila M. Gad
•
•
Faida H. Bamanie Zohair Al-Marzooki
Received: 16 November 2009 / Accepted: 28 October 2010 / Published online: 25 November 2010
ꢀ Springer Science+Business Media, LLC 2010
Abstract Certain new nitrogen-substituted derivatives of
cyclic imides phthalimide (a), 1,8-naphthalimide (b), and
diphenimide (c), were synthesized aiming to obtain potent
hypolipidemic agents. Thus, 2-(N-imido) propanoic acids,
2-(N-phthalimido)-2-methylpropionic acid, and their ethyl
esters were synthesized (Target derivative A). Also their
corresponding N-substituted-2-(N-imido) propionamides
and 2-(N-phthalimido)-2-methylpropionamides were pre-
pared (Target derivative B). In addition, N-phthalimidom-
ethyleneoxy acetate was prepared. Some of the newly
prepared compounds were subjected to 3D studies and
were found to be superimposed on Clofibrate, which is the
first generation of fibrate drugs. The preliminary evaluation
of hypolipidemic activity of the newly prepared com-
pounds against triton WR-1339-induced hyperlipidemia in
rat showed that several derivatives have demonstrated
significant lowering of serum total cholesterol and tri-
glyceride levels at dose of 150 mg/kg/i.p. comparing with
Fenofibrate which is one of the second generations of
fibrate drugs.
Introduction
Hypolipidemic agents or antihyperlipidemic agents are a
diverse group of pharmaceuticals that are used in the
treatment of hyperlipidemias; some may lower ‘‘bad
cholesterol’’ (LDL) more so than others, while others may
prudentially increase (HDL) ‘‘the good cholesterol’’.
Other studies showed that elevating the high-density
lipoprotein (HDL) and lowering the triglyceride levels
(TGs) in the serum were accepted measures in treating
hyperlipidemias and atherosclerosis (Steinberg et al.,
1989); (Ginsberg, 1990); (Levine et al., 1995); (Larsen
and Spilman, 1993).
LDL and VLDL carry cholesterol towards tissues, and
elevated levels of these lipoproteins are associated with
atheroma formation. HDL, in contrast, carries cholesterol
back to the liver and is associated with protection against
cardiovascular disease (Miller, 2000).
The efficacy of the hypolipidemic drugs revealed to their
effects: (a) decreased cholesterol levels and increased
clearance of LDL from the blood stream that is by inhi-
bition of the synthesis of cholesterol, e.g., Statins (Boden,
2000) which are particularly well suited for lowering LDL
in people at risk for cardiovascular diseases because of
hypercholesterolemia. Or (b) increased HDL and lowered
triglyceride level (TGs) , e.g., the first and second gener-
ation of Fibrates (Staels et al., 1998); (Spieker et al., 2000).
Niacin and Nicotinamide which are well suited for patient
with hypertriglyceridemia (Parsons, 2003). Or (c) inhibit
the dietary cholesterol absorption or sequestering the cho-
lesterol-containing bile acids released into the gut and
preventing their reabsorption from the gut thus decreasing
cholesterol levels in blood plasma. , e.g., Ezetimibe and
Bile acid sequestrants (Rossi, 2006). Clinically, the choice
of any agent will depend on the patient’s cholesterol
Keywords Synthesis of cyclic imides ꢀ
Hypolipidemic activity ꢀ Antihyperlipidemic activity
M. A. El-Zahabi ꢀ L. M. Gad (&)
Department of Pharmaceutical Chemistry, King Abdulaziz
University, 80260, 21589 Jeddah, KSA
e-mail: lgad@kau.edu.sa; gad_laila@yahoo.com
F. H. Bamanie ꢀ Z. Al-Marzooki
Department of Clinical Biochemistry, King Abdulaziz
University, Jeddah, KSA
123

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Med Chem Res (2012) 21:75–84
profile, cardiovascular risk and the liver and kidney func-
tions of the patient. (Farnier, 1998); (Gavish et al., 2000).
Many agents having cyclic imide’s functions were
generally potent hypolipidemic agents lowering serum
cholesterol levels on an average of 35% and serum tri-
glyceride levels on an average of 29% after 16 days dosing
at 20 mg/kg/day intrapretonially (i.p.) in mice. (Chapman
et al., 1984); (Voorstad et al., 1985); (Murthy et al., 1985);
(Hall et al., 1986). They possess hypolipidemic activity
superior in many cases to Clofibrate (I). Design and syn-
thesis of structurally related N-substituted cyclic imides;
imido-propionic acid and imido-2-methylpropionic acid
derivatives was the main objective of the present investi-
gation. Therefore, the design of newly prepared compounds
proposed the replacement of the phenoxy ring of the Clo-
fibrate with phthalimido (a), 1,8-naphthalimido (b),
diphenimido (c) rings, aiming to obtain potent hypolipi-
demic agents of high therapeutic index and minimal side
effects in comparison with the widely used and commer-
cially available Clofibrate drug (Barakat et al., 2000).
Overlaying Clofibrate (I) as a prototypic compound with
some proposed imide’s derivatives at the position of the
ether’s oxygen atom of Clofibrate (I) and the imide’s
nitrogen atom assists our planning. The research design
was made by the aid of molecular modeling programs of
computer Accelry’s softwares.
the ether’s oxygen atom of Clofibrate (I) and the imide’s
nitrogen atom. The software strives to find the best fit in
such way that the equivalent centers; the ether oxygen
with the cyclic imido nitrogen and the different aromatic
rings together. It was found that they are matched up
Fig. 1 Overlay of Ethyl 2-(N-phthalimido)propionate (IIIa) (yellow),
and Ethyl-2-(N- diphenimido)propionate (IIIc) (red), with Clofibrate
(I) (blue); attached at the imido nitrogen of both phthalimido and
diphenimido derivatives against the ether oxygen of Clofibrate
Research design
Fig. 2 Overlay of Ethyl 2-(N-1,8-naphthalimido)propionate (IIIb)
(magenta), with Clofibrate (I) (blue); attached at the carbonyl carbon
of both
The overlay of certain analogs namely, 2-(N-phthalimi-
do)-, 2-(N-1,8-naphthalimido)-, 2-(N-diphenimido)-propi-
onates, and 2-(N-phthalimido)-2-methylpropionates with
the already known ethyl ester of 2,2-dimethylphenoxy-
acetic acid; Clofibrate (I), as a prototypical compound
were made with the aid of computer Accelry’s softwares
at the Computer laboratory, Faculty of Pharmacy, KAU.
These overlays are illustrated in Figs. 1, 2 and 3:
Molecular modeling programs were used to compare
the 3D structures of the different cyclic imide’s analog,
and then overlaying Clofibrate (I) as a prototypic com-
pound with some imide’s derivatives at the position of
Fig. 3 Overlay of Ethyl 2-(N-phthalimido)-2-methylpropionate
(VIa) (yellow), with Clofibrate (I) (blue) prototypic compound,
attached at the carbonyl carbon of both
CH3
H2C
CH3
R3
O
O
O
CH2
N
O
O
H
CH3
CH3
N
N
Cl
O
O
R1
O
R2
R2
R1
O
O
Target Derivatives (A)
Clofibrate (I)
Target Derivatives (B)
123

Med Chem Res (2012) 21:75–84
77
activity by enhancing the lipophilicity of these
compounds.
resulting in the overlay shown in the previous Figs. 1, 2
and 3.The following points were considered:
(1) The interatomic distance between ester oxygen and
the aromatic ring within the imido compound analogs
should be nearly the same as that in the prototypic
compound Clofibrate(I).
Materials and methods
For the preparation of the desired derivatives, Schemes 1,
2, and 3 were adopted.
(2) Synthesis of bulky esters or amides of the imido-
propionic acids may enhance the hypolipidemic
O
CH3
b
N
O
CH3
O
O
O
O
CH3
OH
(IIIa-c)
H2N
COOH
N
O
O
a
O
O
O
Ia = phthalic anhydride
Ib = 1,8-naphthalic anhydride
Ic = diphenic anhydride
CH3
(IIa-c)
N
R
c
N
(Ia-c)
O
O
H
R= Et , n-Pr, iso-Pr, Ph, Bn, (CH2)2-Ph
NHR= Pyrrolidinyl
(IVa-c)
Scheme 1 Preparation of N-imidopropionates (Target derivatives A, IIIa–c) and N-imidopropionamides (Target derivatives B, IVa–c)
O
O
O
b
N
CH3
H3C
H3C
H2N
O
COOH
CH3
(VIa)
O
O
CH
3 OH
O
N
a
O
CH3
O
O
R
(Ia)
(Va)
O
HN
O
N
c
CH3
H3C
O
R: Et , Ph, Bn
(VIIa1-3
)
Scheme 2 Preparation of N-phthalimidomethyopropionate (Target derivatives A, VIa) and N-Phthalimidomethylpropionamides (Target
derivatives B, VIIa1–3
)
123

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Med Chem Res (2012) 21:75–84
O
O
O
O
O
a
b
N
O
NH
N
OH
O
O
O
(a)
(VIIIa)
(IXa)
Scheme 3 Preparation of Ethyl N-phthalimidomethyleneoxyacetate (IXa)
Chemistry
ppm: the spectra were carried out at Faculty of Science,
King Abdul-Aziz University. Elemental analyses were
performed in Perkin Elmer 2400, series II micro-analyzer
at Micro-analytical laboratory, Faculty of Science, King
Abdul-Aziz University. Melting points were determined
with Barnstead electro thermal melting point apparatus and
are uncorrected. Chemicals are an Aldrich and Fluka
products and are used without further purification. Thin
layer chromatography was performed using CHCl3/CH3OH
(9.5:0.5) or ethyl acetate/cyclohexane (7:3) or (5:5) as
eluent.
2-(N-imido)propanoic acids (IIa–c) were prepared—as
described in the text—via two steps reaction of the corre-
sponding cyclic anhydride (Ia–c) with L-alanine at first
step followed by cyclodehydration using acetic anhydride
and a catalytic amount of anhydrous sodium acetate at the
second step. Esterification of (IIa–c) with absolute ethanol
in the presence of ethylchloroformate and triethyl amine
TEA in methylene chloride via a mixed anhydride proce-
dure afforded 2-(N-imido)propionate (IIIa–c), while ami-
dation of (IIa–c) using appropriate aliphatic amines and
aromatic amines in the presence of ethylchloroformate and
TEA and a catalytic amount of dimethylaminopyridine
DMAP in methylene chloride yielded series of N-substi-
tuted-2-(N-imido)propionamides (IVa 1–7, IVb1–3 and
IVc) Scheme 1.
2-[N-(1,8-naphthalimido)]propionic acid (iib), Scheme 1:
General method (Ossman et al., 1991); (El-Helby et al.,
2003); (El-Zahabi et al., 1998): 1,8-Naphthalic anhydride
(Ib) (19. 8 g, 0.1 mol) and (8.9 g, 0.1 mol) of L-alanine
were refluxed in (300 ) DME for 5 h. The solvent was
evaporated under vacuum, and the residue washed with
ethanol, air-dried. Acetic anhydride (100 ml) and sodium
acetate (2.0 g) were added and heated under reflux for
additional 2 h. The reaction mixture was cooled, poured in
to ice cold water (500 ml), and the precipitated product
was filtered, washed with water, air dried, and crystallized
from DMF (Table 1).
Furthermore, aminolysis of phthalic anhydride (Ia) with
2-methyl-L-alanine followed by cyclodehydration with
acetic anhydride yield 2-(N-phthalimido)-2-methylprop-
ionic acid (Va), which was then esterfied to produce
ethyl 2-(N-phthalimido)-2-methylpropionate (VIa), and
also, allowed to react with appropriate primary amines to
afford the N-substituted-2-(N-phthalimido)-2-methylpropi-
onamides (VIIa1–3) (Scheme 2)1.
In addition, N-Hydroxymethylphthalimide (VIIIa) was
prepared as described in the text and was allowed to react
with ethylchlorofomate producing the alkyl ether ester of
phthalimide;N-(phthalimido)-2-methyleneoxyacetate (IXa)
(Scheme 3).2
Ethyl-2-[N-(1,8-naphthalimido)]propionate (IIIb),
Scheme 1:
General method A solution of 2-[N-(1,8-naphthalimi-
do)]propionic acid (IIb) (2,84 g, 0.01 mol) in CH2Cl2
(50 ml), was placed in a flask equipped with two dropping
funnels and stirred in ice bath. A solution of triethylamine
TEA (1.5 ml, 0.01 mol) in CH2Cl2 (5 ml) was placed in
one of the dropping funnel, and was added dropwise to the
solution of imidopropionic acid while stirring over a period
of half an hour in the ice bath, then, ethyl chloroformate
(0.12 ml, 0.01 mol) in CH2Cl2 (5 ml) was placed in the
other dropping funnel, and was added dropwise to the
reaction mixture while stirring at room temperature for 1 h.
Ethyl alcohol (5 ml) was added dropwise to the reaction
mixture while stirring at room temperature for additional
1 h. The prepared ester was extracted with CHCl3 (30 ml),
Experimental
Proton nuclear magnetic resonance spectra (1H NMR) were
recorded on Bruker Advance DP9400 spectrometer using
Me4Si as internal reference and DMSO-d6 or CDCl3 were
used as solvent, the chemical shifts were measured in d
1
Reagent and Condition for Schemes 1 and 2: (a) i. DMF/Reflux
for 4 h, ii. Ac2O/reflux for 2 h. (b) i. NEt3/DMAP/CH2Cl2 (-5 to
-10ꢁC), ii. ClCOOEt, iii. Et-OH. (c) i. NEt3/DMAP/CH2Cl2 (-5 to
-10ꢁC), ii. ClCOOEt, iii. R-NH2
2
Reagent and Condition for Scheme 3: (a) HCHO/H2O Reflux for
OC2H5
Cl
2–6 h. (b)
/DMF/Na2CO3
O
123

Med Chem Res (2012) 21:75–84
79
washed with citric acid (2 ml 10% solution), followed by
washing with brine (10 ml), dried over MgSO4. The extract
was evaporated under reduced pressure and the obtained
solid ester was crystallized from CHCl3/n-hexane
(Table 2).
preparation of N-substituted amides are ethyl amine, n-
propyl amine, isopropyl amine, aniline, benzyl amine, and
phenethyl amine, and pyrrolidine (Table 3).
2-(N-Phthalimido)-2-methylpropionic acid (Va), Scheme 2
N-Substituted-2-[N-(1,8-naphthalimido)]propionamides
(IVb 1-3), Scheme 1
A mixture of phthalic anhydride (Ia) (7.4 g, 0.05 mol), and
2-methyl-L-alanine (5.15 g, 0.05 mol), and DMF (80 ml)
was stirred under reflux for 4 h. The DMF was then
removed under vacuum, and the residue was dissolved in
acetic anhydride (60 ml). The reaction mixture was stirred
under reflux for 2 h., then cooled, poured in to ice cold
water (200 ml) and the precipitated product was filtered,
washed with water, air dried and crystallized from ethanol,
C12H14NO3 (M.Wt. 233.22), mp 155–157ꢁC in 35% yield.
General method The previous procedure used for the
preparation of ester derivatives was adopted for the for-
mation of N-substituted-2-[N-(1.8-naphthalimido)]propi-
onamides, and instead of addition of ethyl alcohol, an
equivent amount of the appropriate amine (0.012 mol) was
added, and the reaction mixture was stirred, and refluxed
gently for 2 h. The appropriate amines that are used for the
Table 1 Physicochemical
properties of 2-(N-
imido)propanoic acids (IIa–c):
Serial Amide moiety
no.
Mol.
formula
(mol. wt)
Cryst.solvent M.p 8C 1H NMR DMSO-d6
yield %
O
IIa
IIb
Phthalimido
C
11H9NO4 CHCl3/
(219.19)
163–165 (IIa) d: 1.58–1.59 (d, 3H, CH3),
4.80–4.85 (q, 1H, CH), 7.91 (s, 4H,
Ar–H).
C2H5OH
(70)
CH3
N
1,8- C
Naphthalimido (269.25)
15H11NO4 DMF (63)
226–228 (IIb) d: 1.58–1.59 (d, 3H, CH3),
5.62–5.65 (q, 1H, CH), 7.92–7.96 (t,
2H, Ar–H), 8.51–8.53 (d, 2H, Ar–H),
8.56–8.58 (d, 2H, Ar–H).
OH
O
O
IIc
Diphenimido
C17H13NO4 2-propanol
(295.29) (43)
191–193
Table 2 Physicochemical properties of ethyl 2-(N-imido)propionates (IIIa–c):
O
CH3
N
OC2H5
O
O
Serial no.
IIIa
Amide moiety
Phthalimido
Mol. formula (mol. wt)
Cryst. solvent yield %
CHCl3/C2H5OH (78)
M.p 8C
Microanalysis
Calc.
Fd.
C13H13NO4 (247.25)
61–62
C
H
N
C
H
N
C
H
N
63.15
5.30
5.67
68.68
5.09
4.71
70.58
5.30
4.33
62.43
6.24
6.28
68.47
5.74
5.43
70.59
5.16
4.17
IIIb
IIIc
1,8-Naphthalimido
Diphenimido
C
C
17H15NO4 (279.31)
19H17NO4 (323.34)
Ethyl acetate (73)
CH2Cl2 (65)
109–111
90–92
123

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Med Chem Res (2012) 21:75–84
Table 3 Physicochemical properties of N-substituted-2-(N-imido)propionamides (IVa–c):
O
CH3
R
N
N
O
O
H
Serial no.
IVa-1
Substituent
–CH2–CH3
Mol. formula (mol. wt)
Cryst. solvent yield %
C2H5OH (78)
M.p 8C
Microanalysis
Calc.
Fd.
C13H14N2O3 (246.26)
C14H16N2O3 (260.29)
C14H16N2O3 (260.29)
143–145
C
H
N
C
H
N
C
H
N
63.40
5.73
63.43
6.22
11.38
64.60
6.20
11.52
64.45
6.70
IVa-2
IVa-3
–CH2CH2CH3
C2H5OH (71)
C2H5OH (68)
136–138
167–168
10.76
64.60
6.20
10.72
65.01
6.71
CH3
CH3
10.76
10.84
IVa-4
IVa-5
IVa-6
IVa-7
C17H14N2O3 (294.30)
C18H16N2O3 (308.33)
C19H18N2O3 (322.13)
C15H16N2O3 (272. 3)
C2H5OH (73)
C2H5OH (83)
C2H5OH (75)
C2H5OH (66)
163 –164
142–144
178–180
148–149
C
H
N
69.38
4.79
9.52
68.83
4.10
9.47
C
H
N
70.12
5.23
9.09
69.37
5.96
9.14
H2C
C
H
N
70.79
5.63
8.69
70.65
5.21
8.73
(H2C)2
NHR=
C
H
N
66.16
5.92
65.52
5.95
N
10.29
10.32
IVb-1
IVb-2
–CH2–CH3
C17H16N2O3 (296.32)
C21H18N2O3 (344.36)
CH2Cl2 (82)
212–214
222–223
C
H
N
C
H
N
68.91
5.44
9.45
73.24
4.68
8.13
68.47
5.74
9.12
72.65
5.25
8.57
CH2Cl2 (84) (76)
IVb-3
IVc
C22H18N2O3 (358.39)
C24H20N2O3 (384.43)
CH2Cl2 (87)
249–251
145–147
C
H
N
73.73
5.06
7.82
73.13
5.67
8.18
H2C
H2C
C2H5OH (35)
C
H
N
74.98
5.24
7.29
73.51
5.24
7.12
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Med Chem Res (2012) 21:75–84
81
1H NMR of (Va), DMSO-d6, d: 1.72 (s, 6H, 2CH3),
7.83 (s, 4H, Ar–H), 12.7–13.0 (brs, 1H, COOH).
CH2), 4.66–4.71 (q, 1H, CH), 7.84–7.89 (m, 4H, Ar–
H), 8.01–8.03 (broad, 1H, NH).
•
•
(IVa-3) d: 0.99–1.01 (d, 3H, CH3), 1.03–1.04 (d, 3H,
CH3), 1.51–1.53 (d, 3H, CH3), 3.86–3.91 (septet, 1H,
CH (CH3)2), 4.63–4.69 (q, 1H, CH), 7.81–7.89 (m, 4H,
Ar–H).
N-(2-Hydroxymethyl)phthalimide (VIIIa), Scheme 3
Phthalimide (a) (10.2 g) (5.2 ml) formalin, and (35 ml)
water refluxed until clear, filtered while hot, and the filtrate
cooled yielded 11.2 g. of N-(2-Hydroxymethyl)-phthali-
mide (VIIIa) C9H7NO3 (M.Wt. 177.16) mp 138–41ꢁC
(recorded mp 140–145ꢁC) (Winstead et al., 1955).
(IVa-4) d: 1.60–1.62 (d, 3H, CH3), 4.91–4.96 (q, 1H,
CH), 7.04–7.07(t, 1H, Ar–H), 7.27–7.31 (t, 2H, Ar–H),
7.53–7.55 (d, 2H, Ar–H), 7.86–7.93 (m, 4H, Ar–H),
9.89 (s, 1H, NH).
•
•
(IVa-5) d: 1.59–1.61 (d, 3H, CH3), 4.29–4.31 (d, 2H,
CH2), 4.79–4.84 (q, 1H, CH), 7.20–7.33 (m, 5H, Ar–
H), 7.84–7.91 (m, 4H, Ar–H), 8.61–8.64 (t, 1H, NH).
(IVa-6) d: 1.53–1.54 (d, 3H, CH3), 2.63–2.72 (m, 2H,
CH2), 3.22–3.27 (q, 2H, CH2), 4.67–4.72 (q, 1H, CH),
7.17–7.29 (m, 5H, Ar–H), 7.85–7.91 (m, 4H, Ar–H),
8.17–8.18 (t, 1H, NH).
Ethyl N-(phthalimido)-2-methyleneoxyacetate (IXa),
Scheme 3
Equimolar quantities (0.01 mol) of ethyl cloroacetate was
mixed with anhydrous Na2CO3 (1.06 g, 0.01 mol) in DMF
(50 ml).
N-(2-Hydroxymethyl)-phthalimide
(VIIIa)
•
•
(IVa-7) d: 1.54–1.55 (d, 3H, CH3), 1.64–1.76 (m, 2H,
CH2), 1.77–1.84 (m, 2H, CH2), 3.14–3.92 (q, 1H, CH),
3.24–3.34 (m, 2H, CH2), 3.38–3.42 (m, 1H, CH),
4.94–4.98 (q, 1H, CH), 7.86 (s, 4H, Ar–H).
(IVb-1) d: 1.02–1.06 (t, 3H, CH3), 1.60–1.61 (d, 3H,
CH3), 3.1–3.2 (q, 2H, CH2), 5.50–5.60 (q, 1H, CH),
7.95–8.0 (t, 2H, Arom.-H), 8.0–8.15 (broad t-like, 1H,
NH), 8.53–8.55 (d, 2H, Ar–H), 8.56–8.58 (d, 2H, Ar–
H).
(0.01 mol) was added, and the mixture was heated under
reflux on a boiling water bath for 1 h., then cooled, and
poured in to ice-cold water (200 ml) and stirred well for
30 min. The solid obtained was filtered, washed with
water, dried, and crystallized from ethanol, yielded Ethyl
N-(phthalimido)-2-methyleneoxyacetate (IXa) in 74%
yield, C13H13NO5 (M.Wt. 263.25) mp 107–109ꢁC.
1HNMR of (IXa) DMSO-d6, d: 1.18–1.22 (t, 3H, CH3),
4.13–4.18 (q, 2H, CH2–CH3), 4.45 (s, 2H, CH2–COO),
6.06 (s, 2H, N–CH2-O), 7.82–7.95 (m, 4H, Ar–H).
Calculated analysis C 59.31; H 4.98; N 5.32%
•
•
•
(IVb-2) d: 1.81–1.85 (d, 3H, CH3), 5.88–5.93 (q, 1H,
CH), 7.07–7.10 (t, 1H, Ar–H), 7.28–7.31 (t-like, 2H,
Ar–H), 7.51–7.53 (d, 2H, Ar–H), 7.57 (broad, 1H, NH),
7.75–7.79 (d, 2H, Ar–H), 8.24–8.26 (d, 2H, Ar–H),
8.61–8.63 (d, 2H, Ar–H).
Found analysis C 58.83; H 5.46; N 5.43%
1H NMR of (IIIa–c), DMSO-d6
(IVb-3) d: 1.75–1.77 (d, 3H, CH3), 4.50–4.61 (dd,
2H, CH2), 5.78–5.83 (q, 1H, CH), 6.06 (broad, 1H,
NH), 7.32–7.35 (brs, 5H, Ar–H), 7.76–7.79 (t, 2H,
Ar–H), 8.23–8.25 (d, 2H, Ar–H), 8.61–8.63 (d, 2H,
Ar–H).
•
•
(IIIa) d: 1.13–1.17 (t, 3H, CH2–CH3), 1.56–1.58 (d,
3H, N–CH-CH3), 3.9–4.1 (q, 2H, CH2-CH3), 4.9–5.1 (q,
1H, CH–CH3), 7.92 (brs, 4H, Ar–H).
(IIIb) d: 1.16–1.19 (t, 3H, CH2–CH3), 1.61 -1.63 (d,
3H, N–CH-CH3), 4.15–4.19 (q, 2H, CH2-CH3),
5.71–5.73 (q, 1H, CH), 7.94–7.98 (t, 2H, Ar–H),
8.53–8.55 (d, 2H, Ar–H), 8.58–8.59 (d, 2H, Ar–H).
(IIIc) CDCl3, d: 1.23–1.15 (t, 3H, CH2–CH3),
1.66–1.62 (d, 3H, CH–CH3), 4.25–4.10 (q, 2H,
–CH2–CH3), 5.59–5.53 (q, 1H, –CH–CH3), 7.89–7.48
(m, 8H, Ar–H).
(IVc) d: 1.61–1.63 (d, 3H, CH3), 4.30–4.33 (t, 2H,
CH2), 5.44–5.45 (q, 1H, CH), 7.23–7.25 (t, 1H, Ar–H),
7.29–7.35 (m, 4H, Ar–H), 7.57–7.60 (t, 2H, Ar–H),
7.69–7.71 (d, 2H, Ar–H), 7.73–7.76 (t, 2H, Ar–H),
7.80–7.81 (d, 2H, Ar–H), 8.38–8.40 (t, broad, 1H, NH)
(Table 4).
•
1H NMR of (VIIa-2, 3), DMSO-d6
1H NMR of (IVa 1–7, IVb 1–3 and IVc), DMSO-d6
•
•
(VIIa-2) d: 1.76 (s, 6H, 2 CH3), 7.02–7.05 (t, 1H, Ar–
H), 7.26–7.29 (t, 2H, Ar–H), 7.52–7.53 (d, 2H, Ar–H),
7.85 (s, 4H, Ar–H), 9.71 (brs, 1H, NH).
•
(IVa-1) d: 1.05–1.08 (t, 3H, CH2–CH3), 1.61–1.63 (d,
3H, N–CH-CH3), 3.16–3.20 (pented, 2H, CH2–CH3),
4.74–4.82 (q, 1H, N–CH–CH3), 7.95 (brs, 4H, Ar–H),
8.15–8.25 (broad, 1H, NH).
(VIIa-3) d: 1.73 (s, 6H, 2 CH3), 4.258–4.269 (d, 2H,
CH2), 7.20–7.24 (q, 3H, Ar–H), 7.26–7.31 (t-like 2H,
Ar–H), 7.83 (s, 4H, Ar–H), 8.49–8.51 (t-like, broad,
1H, NH).
•
(IVa-2) d: 0.77–0.81 (t, 3H, CH3), 1.33–1.42 (septet,
2H, CH2), 1.52–1.54 (d, 3H, CH3), 2.95–3.06 (m, 2H,
123

82
Med Chem Res (2012) 21:75–84
Table 4 Physicochemical properties of Ethyl ester of 2-(N-phthalimido)-2-methylpropionic acid (VIa) and its N-substituted-2-(N-phthalimido)-
2-methylpropionamides (VIIa1–3):
O
Z
O
N
CH3
H3C
O
Serial no.
VIa
Z
Mol. formula (mol. wt)
C14H15NO4 (261.27)
Cryst. solvent yield %
C2H5OH (72)
M.p 8C
Microanalysis
Calc.
Fd.
OC2H5
83–85
C
H
N
C
H
N
C
H
N
64.36
5.79
63.89
5.39
4.96
64.72
5.44
9.84
69.98
4.34
9.06
5.36
VII1
VII2
NH–C2H5
C14H16N2O3 (260.29)
C18H16N2O3 (308.33)
C2H5OH (55)
C2H5OH (50)
114–116
199–201
64.60
6.20
10.76
70.12
5.23
HN
9.09
VII3
C19H18N2O3 (322.36)
C2H5OH (65)
142–144
C
H
N
70.79
5.63
8.69
69.75
6.13
8.49
H2C
HN
•
Unexpected phthalamic acid derivative (Xa)
was obtained while performing the amidation of
2-(N-phthalimido)propionic acid (IIa) with excess
ethylamine (Scheme1), and its structure was con-
firmed by both spectral and elemental analyses,
C15H21N3O3 (M.Wt. 291.35), mp 157–157ꢁC.
Hypolipidemic activity
The pharmacological screening for the antihyperlipidemic
activity of selected imido derivatives as performed against
Triton WR-1339-induced hyperlipidemia in rats following
the procedure reported by Kuroda et al. (1977) with some
modifications and using Fenofibrate drug as reference
standard.
1HNMR spectrum of N1-Ethyl,N2-(N-ethyl-2-methylace-
tamido)phthalic dicarboxamide (Xa), DMSO-d6, d:
1.062–1.263 (m- 6H, 2 CH3), 1.28–1.29 (d, 3H, CH3),
3.09–3.15 (q, 1H, CH of CH2), 3.21–3.27 (q, 1H, CH of
CH2), 4.25–4.29 (pentet, 1H, CH), 7.41–7.57 (m, 4H,
Arom-H), 8.02–8.04 (t, 1H, NH), 8.53–8.55 (d, 2H, 2NH).
Calculated analysis C 61.84; H 7.27; N 14.42%
O
O
O
O
Found analysis C 68.83; H 6.59; N 14.26%.
Fenofibrate
Cl
O
Thus, antihyperlipidemic activity of 17 compounds
including Target derivative (a): N-imidopropionate (IIIa,b),
N-phthalimidomethyl-propionate (VIa), and N-(Ethox-
ycarbonyl-methoxymethyl)phthalimides (IXa); and Target
derivative (b): N-imidopropionimide (IVa 1–7, IVb 1–3
and IVc) and N-phthalimidomethyl-prpionimide (VIIa)
and compound N1-Ethyl,N2-(N-ethyl-2-methylacetamido)
phthalic dicarboxamide (Xa) were performed.
CH3
CONH-CH2CH3
NH
NH-CH2CH3
O
(Xa)
123

Med Chem Res (2012) 21:75–84
83
the potent antihyperlipidemic activity and they signif-
icantly increased the serum levels of HDL 246–29.3%,
protective therapeutic effects against CHD. The tested
compounds showed a little effect on the LDL serum
levels, since the induced reduction ranged from 37 to
4.5%.
Materials and apparatus
Fenofibrate (Sigma) was used as a reference antihyperlip-
idemic drug available in the market. Triton WR-1339
(Tyloxapol, Sigma) was used to induce the suitable
hyperlipidemia within 24 h by intraperitoneal injection
(i.p.) at a dose of 300 mg/kg rat body weight. Male albino
Wister rats (5–6 week-old, 150–190 g body weight) were
used as experimental animals. Carboxymethylcellulose
sodium (CMC–Na, Sigma, 1% in normal saline) was used
as a suspending agent. The tested compounds and the ref-
erence drug were suspended in carboxymethylcellulose
sodium solution (1% in normal saline). Fenofibrate and
tested compounds suspension were given orally to rats by
Gavage at a dose of 150 mg/kg 2 h before the injection of
triton. Triton was dissolved in normal saline to give 10%
solution.
This potent antihyperlipidemic activity of 1,8-naphthalim-
ido, diphenimido derivatives seems to be due to the good
efficacy of their binding to the fatty acid receptor sites,
which are responsible for regulating the modulation of
lipoproteins. These receptors may require larger imide’s
nucleus or cyclic imide’s derivatives containing relatively
bulky N-substituent for modulation of the receptor activity.
Phthalimide without such bulky imido nitrogen substitution
may bind to the receptor less efficaciously.
•
While none of the tested N-phthalimidopropinimide
derivatives were as potent as the parent compound
phthalimide (a) in hypolipidemic activity, but, in
contrary, the pharmacological screening showed that
all derivatives, (IVa 1–3 and 5–7) except (IVa-4),
induced unexpected hyperlipidemia by elevating both
TC and TG serum levels; they also induced significant
elevation in the LDL serum levels ranging from 87.6 to
35.5%. The worse effect of these compounds is that
they are capable of inducing serious reduction in the
HDL serum levels. However, we still unable to explain
such experimental evidence which needs more exten-
sive research. Compound N-phenyl-N-(phthalimido)
propionimide (IVa-4) induced slight lowering effect
but not significant reduction (<24% reduction in both
TC and TG). The authors are still unable to explain
such experimental evidence which needs more exten-
sive research.
Procedure: (Kuroda et al., 1977)
Male albino Wister rats were arranged in 20 group (100
animals/20 = 5 in each group). Animals in the first group
were injected with saline and kept as a normal control
group. Hyperlipidemia in rats was induced in the other
groups (19 groups) by i.p. injection of triton. The second
group was used as hyperlipidemic (HL) control rats. Ani-
mals in the third group were orally dosed with 150 mg/kg
Fenofibrate and kept as a reference group. At the same
time, the remaining groups (17 groups) were orally given
the tested compounds at a dose level of 150 mg/kg body
weight. 2 h later, rats in groups from the second group to
the 20 group (19 group) were injected by triton in the given
dose, and once they injected by triton they were deprived
from food but were allowed free on excess of drinking
water ad libitum over the next 24 h. After 24 h, blood
samples were withdrawn from the rat’s orbital sinus and
serum was separated. Total cholesterol (TC), and Total
triacyl glycerol (triglyceride, TG), HDL, and LDL levels
were determined using automated analyzer RXL-MAX1.
•
The open structure of phthalimidopropionimide (Xa) to
give the dicarboxamide derivative induces significant
lowering effects -48.6%, and -46.5% in TC and TG
respectively, which is better than the cyclic structure
(IV-a) and reference standard Fenofibrate.
Discussion of pharmacological screening
Results
•
Fenofibrate, as reference standard, induced slightly but
non-significant decrease in serum levels of TC (23%),
and TG (20%). However, it slightly increase the HDL
(11.7%) and but this unexpected increase of effect in
LDL (13%) may be due to that Fenofibrate was used in
a single dose only that was not sufficient to provide the
expected effect.
The comparative study of the antihyperlipidemic activities
(SAR) of the N-substituted-phthalimide and other
N-substituted-imides based on the obtained results of the
pharmacological screening were limited to three areas:
(i) Changes in the structure of phthalimides: involving
the imide’s ring system by the replacement of the
phenyl group of phthalimide with the aromatic
system of naphthalimide (comp. IIIb, IVb1–3), or
diphenimide (comp. IVc), led to a potent significant
•
The biaryl imides (IVb, IVc), the substituted amide
derivatives of 1,8-naphthalimidopropionamdes (IVb 1–
3) and benzyl-N-diphenimidopropionamide (IVc) show
123

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lipid parameters (TC, TG or LDL).
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(ii) N-Substitution of phthalimide with 2,2-dimethyl
acetic acid moiety: (ethyl N-phthalimidomethylpro-
pionate comp. (VIa) have regained the activity for the
phthalimido ring and showed appreciable decrease of
TC, TG, and LDL with parallel increase in HDL.
Meanwhile, its corresponding phthalimido amides
(VIIa) have demonstrated good lowering of TC and
TG and have shown the maximum decrease of LDL
(among all tested compounds) with good increase in
HDL. This could be explained in terms of increasing
steric bulk, and lipophilicity on the phthalimido
nitrogen-afforded compounds proved to have signif-
icant hypolipidemic activity.
(iii) N-Substitution of imide’s nitrogen of phthalimide
with four atom side chain— one of them is oxygen
(alkyl ether ester) proven to have significant antihy-
perlipidemic effect such as comp.(IXa), has shown a
similar decrease of TC and TG similar to that of
(VIa) with over 15-fold increase of HDL.
Acknowledgments A part of this was supported by funds from
Institute of Research and Consultation, King Abdul-Aziz University,
Ministry of Higher Education, Jeddah, Kingdom of Saudi Arabia.
Therefore, the authors would like to express our special thanks and
profound appreciation to all members in the institute. Deepest thank
to Dr. Salah A. Ghareib, Professor of Pharmacology and toxicology,
Pharmacology and Toxicology Department, Faculty of Pharmacy,
King AbdulaAziz University, Jeddah, Kingdom of Saudi Arabia, for
carrying out the pharmacological screening of the antihyperlipidemic
activity of the prepared compounds.
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tolerability of fluvastatin and bezafibrate in patients with
hyperlipidemia and persistently high triglyceride levels. J Car-
diovasc Pharmacol 35:361–365
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