4580 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 23
Yiu and Knaus
Removal of the solvent in vacuo gave a residue which was
purified by silica gel column chromatography using n-hexane-
EtOAc (1:1, v/v) as eluent to afford 7 as pale yellow crystals
(2.0 g, 48%) after recrystallization from n-hexane-CH2Cl2: mp
hydroxyethyl) compound 7 in brain suggests that hy-
drolysis of felodipine-CDS to 7 is not a major biotrans-
formation (in agreement with the in vitro incubation
study, Figure 1, panel D). It is also possible that the
low brain concentration of 3-(2-hydroxyethyl) 7 (Kp )
236) could be due in part to its egress from brain.
118-132 °C; IR (KBr) 3336 (br, NH, OH), 1688 (CO2) cm-1
;
1H NMR (CDCl3) δ 2.03 (br s, 1H, OH), 2.33 and 2.36 (2 s, 3H
each, C-2, C-6 Me’s), 3.64 (s, 3H, OMe), 3.77 (t, J ) 4.5 Hz,
2H, CH2OH), 4.15-4.18 (m, 2H, CO2CH2), 5.48 (s, 1H, H-4),
5.74 (br s, 1H, NH), 7.11 (dd, J 4,5 ) J 5,6 ) 7.8 Hz, 1H, aryl
H-5), 7.28 (dd, J 5,6 ) 7.8 Hz, J 4,6 ) 1.4 Hz, 1H, aryl H-6), 7.33
Su m m a r y
A new felodipine-CDS (10) has been evaluated as a
potential anticonvulsant agent which provided modest
protection against MES-, but not scMet-, induced sei-
zures in mice. These results reinforce the concept that
calcium is only one of several factors that are involved
in seizure generation.3 Since the 1,4-dihydropyridines
investigated in this study are ineffective in the scMet
screen, a role for calcium other than interaction with
L-type calcium channels may be pertinent for absence
seizures.23-25 The felodipine-CDS (10) enters the brain
readily, and it undergoes facile oxidation to a pyridinium
species that is retained in brain tissues up to 4 days
after drug administration. Further studies will address
a method to increase the hydrolysis rate by replacement
of the pyridinium ester moiety of 9 [-CO2CH2CH2O2C-
(1-methyl-3-pyridiniumyl)] by a more esterase sensitive
[-CO2CH 2CH 2O2C-CH 2O2C-(1-m et h yl-3-pyr idin i-
umyl)], or a less hindered trigonelline [-CO2CH2-
CH2O2C-CH2CH2-(3-amido-1-pyridiniumyl)], moiety.
These latter analogs of 9 should undergo a more facile
hydrolysis to 3-(2-hydroxyethyl) 5-methyl 1,4-dihydro-
2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicar-
boxylate (7) to increase its efficacy as an anticonvulsant
agent.
(dd, J 4,5 ) 7.8 Hz, J 4,6 ) 1.4 Hz, 1H, aryl H-4). Anal. (C18H19
Cl2NO5) C, H, N.
-
3-[2-[(3-P yr id ylca r bon yl)oxy]eth yl] 5-Meth yl 1,4-Di-
h ydr o-2,6-dim eth yl-4-(2,3-dich lor oph en yl)-3,5-pyr idin edi-
ca r boxyla te (8). A solution of 7 (4.53 g, 11.3 mmol), Et3N
(3.7 g, 37 mmol), and nicotinoyl chloride hydrochloride (3.27
g, 18.4 mmol) in dry CH2Cl2 (50 mL) was stirred at 25 °C for
16 h. The reaction mixture was washed with H2O (3 × 25
mL), and the organic fraction was dried (Na2SO4). Removal
of solvent from the organic fraction in vacuo afforded a yellow
foam, which on recrystallization from n-hexane-EtOAc gave
8 as a pale yellow crystalline solid (5.14 g, 90%): mp 146-
148 °C; IR (KBr) 3345 (NH), 1713 (CO2), 736 (pyridine CH)
cm-1; 1H NMR (CDCl3) δ 2.33 and 2.39 (2 s, 3H each, C-2, C-6
Me’s), 3.60 (s, 3H, OMe), 4.27-4.31 and 4.52-4.68 (2 m, 2H
each, O2CCH2CH2OCO), 5.46 (s, 1H, H-4), 5.93 (s, 1H, NH),
7.04-7.10 (m, 2H, aryl H-5, H-6), 7.36 (dd, J 4,5 ) 7.9 Hz, J 4,6
) 1.6 Hz, 1H, aryl H-4), 7.77 (dd, J 4,5 ) 7.9 Hz, J 5,6 ) 5.0 Hz,
1H, pyridyl H-5), 8.61 (dd, J 4,5 ) 7.9 Hz, J 2,4 ) 1.4 Hz, 1H,
pyridyl H-4), 8.86 (d, J 5,6 ) 5.0 Hz, 1H, pyridyl H-6), 8.96 (d,
J 2,4 ) 1.4 Hz, 1H, pyridyl H-2). Anal. (C24H22Cl2N2O6‚1/2H2O)
C, H, N.
3-[2-[[(1-Met h ylp yr id in iu m -3-yl)ca r b on yl]oxy]et h yl]
5-Meth yl 1,4-Dih ydr o-2,6-dim eth yl-4-(2,3-dich lor oph en yl)-
3,5-p yr id in ed ica r boxyla te Iod id e (9). A solution of 8 (0.86
g, 1.7 mmol) and iodomethane (0.53 mL, 8.52 mmol) in dry
acetone (50 mL) was refluxed for 16 h. The pale yellow solid
which precipitated was filtered, washed with dry diethyl ether
(3 × 15 mL), and dried in vacuo to afford 9 (1.0 g, 91%): mp
Exp er im en ta l Section
205-207 °C; IR (KBr) 3443 (NH), 1740, 1698, 1641 (CO2) cm-1
;
1H NMR (DMSO-d6) δ 2.21 and 2.26 (2 s, 3H each, C-2, C-6
Me’s), 3.45 (s, 3H, OMe), 4.24-4.43 (m, 5H, NMe, O2CCH2CH2-
OCO), 4.51-4.55 (br m, 2H, CO2CH2CH2OCO), 5.30 (s, 1H,
H-4), 7.16 (dd, J 4,5 ) J 5,6 ) 7.7 Hz, 1H, aryl H-5), 7.22-7.29
(m, 2H, aryl H-4, H-6), 8.27 (dd, J 4,5 ) 8.2 Hz, J 5,6 ) 6.4 Hz,
1H, pyridinium H-5), 8.73 (d, J 4,5 ) 8.2 Hz, 1H, pyridinium
H-4), 9.01 (s, 1H, pyridinium H-2), 9.20 (d, J 5,6 ) 6.4 Hz, 1H,
pyridinium H-6), 9.46 (s, 1H, NH). Anal. (C25H25Cl2IN2O6)
C, H, N.
Melting points were determined using a Thomas-Hoover
capillary apparatus and are uncorrected. IR spectra were
recorded using a Nicolet 5DX-FT spectrometer. 1H NMR
spectra were recorded on a Bruker AM-300 spectrometer, and
all assignments of exchangeable protons (NH, OH) were
confirmed by addition of D2O. Analytical HPLC studies were
performed using a Water’s HPLC system comprised of a Model
U6K injector, Model 510 pumps, and a Model 486 variable
wavelength UV detector controlled by Millennium 2010 soft-
ware. Silica gel column chromatography was carried out using
Merck ASTM (70-230 mesh) silica gel. Microanalyses were
within (0.4% of theoretical values for all elements listed.
Diketene, 2,3-dichlorobenzaldehyde, methyl 3-aminocrotonate,
and nicotinoyl chloride hydrochloride were purchased from
Aldrich Chemical Co. Felodipine26 and nimodipine27 were
prepared according to the reported procedures.
3-[2-[[(1-Meth yl-1,4-d ih yd r op yr id -3-yl)ca r bon yl]oxy]-
eth yl] 5-Meth yl 1,4-Dih yd r o-2,6-d im eth yl-4-(2,3-d ich lo-
r op h en yl)-3,5-p yr id in ed ica r boxyla te (10). Diethyl ether
(10 mL) was added to a solution of 9 (0.27 g, 0.421 mmol) and
NaHCO3 (0.18 g, 2.1 mmol) in degassed water (10 mL) with
stirring under an argon atmosphere. Sodium dithionite (0.37
g, 2.1 mmol) was then added, and the reaction was allowed to
proceed at 25 °C with stirring for 1 h. The organic phase was
separated, washed with degassed water (3 × 10 mL), and dried
(Na2SO4), and the solvent was removed in vacuo. The yellow
solid obtained was recrystallized from MeOH to yield 10 as
yellow crystals (0.126 g, 57%): mp 160-165 °C; IR (KBr) 3329
2-H yd r oxyet h yl Acet oa cet a t e (6). Freshly distilled
diketene (8.2 g, 97 mmol) was added dropwise with stirring
to a solution of dry ethylene glycol (24 g, 387 mmol) and Et3N
(0.25 mL, 4.6 mmol) at 60 °C with stirring at a rate such that
the reaction temperature did not exceed 80 °C. The reaction
was allowed to proceed at 95 °C for 3 h, and then the reaction
mixture was cooled to 25 °C and placed on the top of a silica
gel column. Elution with n-hexane-EtOAc (1:2, v/v) gave a
bis-O-substituted ethylene glycol acetoacetate (0.65 g, 2.8
mmol) which was discarded. Continued elution afforded 6 as
a yellow oil (11.9 g, 84%) that was used immediately in the
subsequent reaction: IR (film) 3074-3706 (OH), 1760 (CO2),
1
(NH), 1701 (CO2) cm-1; H NMR (DMSO-d6) δ 2.22 and 2.25
(2 s, 3H each, C-2, C6 Me’s), 2.87 (br s, 2H, dihydropyridyl
H-4), 2.91 (s, 3H, NMe), 3.48 (s, 3H, OMe), 4.09-4.17 (br m,
4H, CO2CH2CH2OCO), 4.67-4.72 (m, 1H, dihydropyridyl H-5),
5.31 (s, 1H, H-4), 5.83 (dd, J 4,5 ) 7.9 Hz, J 4,6 ) 1.4 Hz, 1H,
dihydropyridyl H-6), 6.87 (s, 1H, dihydropyridyl H-2), 7.21 (dd,
J 4,5 ) J 5,6 ) 7.7 Hz, aryl H-5), 7.28 (dd, J 5,6 ) 7.7 Hz, J 4,6
)
1720 (CdO) cm-1 1H NMR (CDCl3) δ 2.24 (s, 3H, COCH3),
;
1.7 Hz, 1H, aryl H-6), 7.36 (dd, J 4,5 ) 7.7 Hz, J 4,6 ) 1.7 Hz,
1H, aryl H-4), 8.98 (s, 1H, NH). Anal. (C25H26Cl2N2O6‚1/2H2O)
C, H, N.
2.90 (br s, 1H, OH), 3.49 (s, 2H, COCH2CO), 3.78 (t, J ) 4.6
Hz, 2H, CH2OH), 4.24 (t, J ) 4.6 Hz, 2H, CO2CH2).
3-(2-Hyd r oxyeth yl) 5-Meth yl 1,4-Dih yd r o-2,6-d im eth yl-
4-(2,3-d ich lor op h en yl)-3,5-p yr id in ed ica r boxyla te (7). A
solution of 6 (1.5 g, 10.3 mmol), 2,3-dichlorobenzaldehyde (1.8
g, 10.3 mmol), and methyl 3-aminocrotonate (1.18 g, 10.3
mmol) in EtOH (50 mL) was heated at reflux for 16 h.
In Vitr o Ca lciu m Ch a n n el An ta gon ist Assa y. The
calcium channel antagonist activities were determined as the
molar concentration of the test compound required to produce
50% inhibition of the muscarinic receptor-mediated (carbachol,
1.67 × 10-7 M) Ca2+-dependent contractions (tonic response)