Two 1,4-dihydro-pyridine derivatives with potential calcium-channel antagonist activity

Article abstract of DOI:10.1107/S0108270111003362

The title compounds, benzyl 4-(3-chloro-2-fluoro-phenyl)-2-methyl-5-oxo-4, 5,6,7-tetra-hydro-1H-cyclo-penta-[b]pyridine-3-carboxyl-ate, C ₂₃H₁₉ClFNO₃, (I), and 3-pyridyl-methyl 4-[2-fluoro-3-(trifluoro-methyl)phenyl]-2,6,6

Full text of DOI:10.1107/S0108270111003362

organic compounds
blocking the influx of Ca2+ through calcium channels and are
used as anti-anginal and antihypertensive drugs (Triggle &
Swamy, 1980; Janis & Triggle, 1984). 1,4-Dihydropyridine (1,4-
DHP) derivatives are the most studied group and nifedipine is
the prototype of calcium-channel antagonists (Triggle, 1990,
Acta Crystallographica Section C
Crystal Structure
Communications
ISSN 0108-2701
¨
¨
2003; S¸afak & S¸ims¸ek, 2006; Bulbul et al., 2009). Modifications
to the nifedipine structure, such as replacing the ester moiety
with various acyl analogues or fusing one of the carbonyl
groups into the ring system, produces some active molecules
Two 1,4-dihydropyridine derivatives
with potential calcium-channel
antagonist activity
¨
¨
(S¸ims¸ek et al., 2006; Gunduz et al., 2009). Following on from
these structure–activity relationship studies and our experi-
ence in this area, we synthesized benzyl 4-(3-chloro-2-fluoro-
phenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]-
pyridine-3-carboxylate, (I), and 3-pyridylmethyl 4-[2-fluoro-3-
(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-3-carboxylate, (II). Compound (I) shows
calcium-channel blocker activity in isolated rat ileum and rat
thoracic artery. Compound (II) also demonstrates calcium-
channel blocker activity. The maximum relaxant responses
(Emax) and pD2 values of (II) were determined on isolated
strips of rabbit gastric fundus smooth muscle (S¸afak, 2010).
Anthony Linden,a* Cihat S¸afak,b Rahime S¸im¸sekb and
Miyase G. Gunduzb
¨
¨
aInstitute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190,
¨
CH-8057 Zurich, Switzerland, and bDepartment of Pharmaceutical Chemistry,
¨
Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
Correspondence e-mail: alinden@oci.uzh.ch
Received 25 January 2011
Accepted 25 January 2011
Online 27 January 2011
The title compounds, benzyl 4-(3-chloro-2-fluorophenyl)-
2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-
3-carboxylate, C23H19ClFNO3, (I), and 3-pyridylmethyl
4-[2-fluoro-3-(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C26H24F4N2O3,
(II), belong to a class of 1,4-dihydropyridines whose members
sometimes display calcium modulatory properties. The 1,4-
dihydropyridine ring in each structure has a shallower than
usual shallow-boat conformation and is nearly planar in (I). In
each structure, the halogen-substituted benzene ring is
oriented such that the halogen substituents are in a
synperiplanar orientation with respect to the 1,4-dihydro-
pyridine ring plane. The oxocyclopentene ring in (I) is planar,
while the oxocyclohexene ring in (II) has a half-chair
conformation, which is less commonly observed than the
envelope conformation usually found in related compounds.
In (I), the frequently observed intermolecular N—Hꢀ ꢀ ꢀO
hydrogen bond between the amine group and the carbonyl O
atom of the oxocyclopentene ring of a neighbouring molecule
links the molecules into extended chains; there are no other
significant intermolecular interactions. By contrast, the amine
group in (II) forms an N—Hꢀ ꢀ ꢀN hydrogen bond with the
pyridine ring N atom of a neighbouring molecule. Additional
C—Hꢀ ꢀ ꢀO interactions complete a two-dimensional hydro-
gen-bonded network. The halogen-substituted benzene ring
has a weak intramolecular ꢀ–ꢀ interaction with the pyridine
ring. A stronger ꢀ–ꢀ interaction occurs between the 1,4-di-
hydropyridine rings of centrosymmetrically related molecules.
Views of the asymmetric units of the structures of (I) and
(II) are shown in Figs. 1 and 2, respectively. Most of the bond
lengths and angles in (I) and (II) have normal values. There
are small angular distortions about atom C2 and the ester C
atom [C9 in (I) and C10 in (II)] (Tables 1 and 3), which result
from steric interactions between the methyl substituent at C2
and atom O1 of the ester substituent at C3 [O1ꢀ ꢀ ꢀC8 in (I) and
˚
O1ꢀ ꢀ ꢀC9 in (II) are both 2.847 (2) A]. The presence of
ꢀ-electron conjugation keeps the ester group at C3 almost
coplanar with the endocyclic double bond [C2 C3—
C9 O1 = ꢁ11.3 (3)ꢂ for (I) and C2 C3—C10 O1 =
ꢁ5.6 (3)ꢂ for (II)] and prevents the ester group from rotating
into a sterically more amenable orientation. These properties
are consistent with those of related compounds (Linden et al.,
2005, 2006).
The 1,4-DHP rings in (I) and (II) have very shallow boat
conformations. In (I), the ring is almost completely planar,
˚
with atoms N1 and C4 lying just 0.0342 (18) and 0.0612 (19) A,
respectively, from the plane defined by atoms C2/C3/C4a/C7a.
The corresponding displacements in (II) are 0.0296 (14) and
˚
0.1004 (16) A, respectively [atom C8a is in the position
Comment
represented by C7a in (I)]. The conformations of 4-aryl-1,4-
DHP rings have been discussed previously (Goldmann &
Stoltefuss, 1991; Linden et al., 1998, 2002, 2005; S¸ims¸ek et al.,
2000) and it is usual for the ring to have a shallow-boat
conformation, although considerable variation in the shal-
Cardiovascular diseases include disorders of the heart and
blood vessels, hypertension, peripheral artery disease, rheu-
matic heart disease, congenital heart disease and heart failure.
Calcium-channel antagonists inhibit muscle contraction by
o80 # 2011 International Union of Crystallography
doi:10.1107/S0108270111003362
Acta Cryst. (2011). C67, o80–o84

organic compounds
Figure 2
A view of the molecule of (II), showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 1
A view of the molecule of (I), showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
lowness of the boat is evident. The displacement of atom C4
from the base of the boat in 1,4-DHP rings is frequently found
˚
to be around 0.30 A (S¸ims¸ek et al., 2000). The deviations
shown by atom N1 are generally smaller and spread fairly
raises the halophenyl ring up higher and thereby points the
C22—H22 bond more deeply into the centre of the 1,4-DHP
ring.
The oxocyclopentene ring in (I) is almost planar, with a
maximum deviation from the mean plane defined by the five
˚
evenly over the range 0.00–0.19 A (S¸ims¸ek et al., 2000; Linden
˚
ring atoms of 0.0292 (19) A for atom C7a. The angle between
et al., 2002). The deviations shown by atoms N1 in (I) and (II)
fall well within this range, while those of C4 show that the C4
end of the boat is much flatter than normal. A completely
planar 1,4-DHP ring was found in the structure of N,N-diethyl-
2,6,6-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydro-
quinoline-3-carboxamide (Linden et al., 2002).
the plane defined by the base of the 1,4-DHP ring boat (atoms
C2/C3/C4a/C7a) and that of the oxocyclopentene ring is
5.05 (12)ꢂ, which indicates that the fused rings are essentially
coplanar. The oxocyclohexene ring in (II) adopts a nearly
ideal half-chair conformation twisted on the C6—C7 bond,
˚
Another measure of the planarity of 1,4-DHP rings is the
sum of the magnitudes of the six intraring torsion angles, P,
around the ring (Fossheim et al., 1988). For (I) and (II), the
values of P are 20.0 (7) and 25.2 (7)ꢂ, respectively, which
demonstrates that the boat conformations are indeed quite
shallow. A mean value of 77 (2)ꢂ was found previously for 1,4-
DHP rings (Linden et al., 2002), although the P values
generally vary over a wide range from 4 to 130ꢂ. For nifedipine
itself, P is 72ꢂ (Miyamae et al., 1986).
The planes of the 3-chloro-2-fluorophenyl ring in (I) and the
2-fluoro-3-(trifluoromethyl)phenyl ring in (II) lie in the usual
synperiplanar orientation, which places the benzene-ring
substituents above the C4—H bond rather than over the 1,4-
DHP ring, which, because of the substituent in the 2-position
of the phenyl ring, would be sterically unfavourable. The
N1ꢀ ꢀ ꢀC4—C17—C22 torsion angles are 10.9 (2) and 5.8 (2)ꢂ
for (I) and (II), respectively. The corresponding torsion angles
in related structures are clustered around 0ꢂ and rarely exceed
ꢃ30ꢂ (Linden et al., 2002). The observed orientation of the
halophenyl ring brings the C22—H22 bond over the centre of
the 1,4-DHP ring, and the distance from atom H22 to the
with atoms C6 and C7 lying 0.289 (2) and 0.382 (2) A,
respectively, from the plane defined by the remaining four ring
atoms, viz. C4a/C5/C8/C8a. The ring-puckering parameters
˚
(Cremer & Pople, 1975) for this ring are Q = 0.4370 (19) A, ꢁ =
130.1 (2)ꢂ and ’2 = 335.1 (3)ꢂ for the atom sequence C4a–C5–
C6–C7–C8–C8a. The ideal values for a half-chair conforma-
tion in a six-membered ring are ꢁ = 50ꢂ (or 180 ꢁ 50 = 130ꢂ)
and ’2 = (n ꢄ 60) + 30ꢂ, where n is an integer. Atom C7 of the
ring flips down on the opposite side of the oxocyclohexene
ring plane to the 2-fluoro-3-(trifluoromethyl)phenyl ring
substituent of the adjacent 1,4-DHP ring. A half-chair con-
formation was also observed in the structure of methyl
4-(2,4-chlorophenyl)-2-methyl-7-phenyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate monohydrate (Linden et
al., 2006). More frequently, the oxocyclohexene ring in similar
structures involving the 5-oxoquinoline or 1,8-dioxoacridine
fragment adopts an envelope conformation, with atom C7
always being the out-of-plane atom, and the side of the
oxocyclohexene ring to which C7 deviates is, in the majority,
but not all, of these structures, opposite to that in (I) (Linden
et al., 2002, 2005).
˚
˚
centroid of the 1,4-DHP ring is just 2.81 A in (I) and 2.67 A in
(II). The shorter distance for the latter is a consequence of the
slightly deeper boat conformation of the 1,4-DHP ring, which
The angle between the plane of the 3-chloro-2-fluorophenyl
ring and that of the phenyl ring of the ester substituent in (I) is
32.65 (10)ꢂ, which precludes any chance of there being a ꢀ–ꢀ
ꢅ
Acta Cryst. (2011). C67, o80–o84
Linden et al.
C23H19ClFNO3 and C26H24F4N2O3 o81

organic compounds
Figure 4
A view, down the b axis, of the crystal packing in (II), showing the chains
of molecules formed by the N—Hꢀ ꢀ ꢀN hydrogen bonds (thin lines). The
sheets formed by the additional C—Hꢀ ꢀ ꢀO interactions lie parallel to the
(100) plane. Most H atoms have been omitted for clarity.
the [001] direction and can be described by a graph-set motif
of C(10). Atom O5 of the oxocyclohexene ring now acts as an
acceptor of a weak C—Hꢀ ꢀ ꢀO interaction from atom C15—H
of a neighbouring molecule. This interaction links the mol-
ecules into extended chains which run parallel to the [010]
direction and can be described by a graph-set motif of C(12).
A further C—Hꢀ ꢀ ꢀO interaction between C7—H and ester
atom O1 of another neighbouring molecule forms a centro-
symmeteric R22(18) ring. The combination of all the hydrogen-
bonding interactions in (II) leads to sheets of molecules which
lie parallel to the (100) plane.
Figure 3
Aview, down the a axis, of the crystal packing in (I), showing the chains of
molecules formed by the N—Hꢀ ꢀ ꢀO hydrogen bonds (thin lines). Most H
atoms have been omitted for clarity.
interaction between these rings. There are also no other ꢀ–ꢀ
interactions evident in the structure. In contrast, a weak
intramolecular ꢀ–ꢀ interaction may be present between the
2-fluoro-3-(trifluoromethyl)phenyl ring and the pyridine ring
in (II). The angle between the planes of these rings is 2.94 (8)ꢂ.
The distance between the ring centroids is quite long at
Experimental
Compounds (I) and (II) were prepared according to the method
described by S¸ims¸ek et al. (2008) by refluxing the appropriate
dicarbonyl compound, 2,3-disubstituted benzaldehyde, acetoacetate
derivative and ammonium acetate in methanol for 8 h. After cooling,
compound (I) was poured into ice–water. The obtained precipitate
was crystallized from ethyl acetate to give diffraction quality crystals
(yield 35%, m.p. 445 K). Analysis calculated for C23H19ClFNO3:
C 67.07, H 4.65, N 3.40%; found: C 66.67, H 4.67, N 3.40%.
Compound (II) was obtained in a crystalline state suitable for crys-
tallographic analysis after cooling the reaction mixture (yield 79%,
m.p. 462 K). Analysis calculated for C26H24F4N2O3: C 63.93, H 4.95,
N 5.73%; found: C 63.76, H 4.86, N 5.86%. The structures of the
˚
4.0014 (10) A, although the perpendicular distance from the
pyridine ring centroid to the plane of the other ring is
ꢂ
˚
3.8258 (7) A. The angle between these two vectors is 17.0 ,
which indicates a significant degree of offset of the two
parallel rings. A stronger ꢀ–ꢀ interaction in (II) appears to
exist between the 1,4-DHP rings of adjacent molecules related
by a centre of inversion. The distance between the ring
centroids of the molecules at (x, y, z) and (ꢁx + 2, ꢁy, ꢁz + 2)
˚
is 3.7634 (9) A, while the perpendicular distance from the
˚
centroid of one ring to the plane of the other is 3.6037 (6) A.
The angle between these two vectors is 16.8ꢂ and the slippage
˚
of the centroids is 1.09 A.
1
compounds were elucidated by IR, H NMR, 13C NMR and mass
spectroscopy; the spectroscopic details are available in the archived
CIF.
In compound (I), an intermolecular N—Hꢀ ꢀ ꢀO hydrogen
bond between the amine group and the carbonyl O atom of
the oxocyclopentene ring of a neighbouring molecule (Table 2
and Fig. 3) links the molecules into extended chains which run
parallel to the [010] direction and can be described by a graph-
set motif of C(6) (Bernstein et al., 1995). The same C(6) motif
has been observed in the crystal structures of several other
closely related 1,4-DHP compounds (Linden et al., 1998, 2002,
2004, 2005, 2006; S¸ims¸ek et al., 2000). There are no significant
inter- or intramolecular C—Hꢀ ꢀ ꢀX (X = O, N or halogen)
interactions in the structure.
Compound (I)
Crystal data
3
˚
C23H19ClFNO3
Mr = 411.86
V = 1988.58 (7) A
Z = 4
Monoclinic, P21=c
Mo Kꢃ radiation
ꢄ = 0.23 mmꢁ1
T = 160 K
˚
˚
a = 10.7944 (2) A
b = 13.5205 (3) A
˚
c = 14.0573 (3) A
0.30 ꢄ 0.28 ꢄ 0.15 mm
ꢂ = 104.2378 (13)ꢂ
Data collection
A more unusual hydrogen bond is present in the structure
of (II). This time, the amine group forms an intermolecular
N—Hꢀ ꢀ ꢀN hydrogen bond with the pyridine ring N atom of a
neighbouring molecule (Table 4 and Fig. 4). This interaction
links the molecules into extended chains which run parallel to
Nonius KappaCCD area-detector
diffractometer
Absorption correction: multi-scan
(Blessing, 1995)
Tmin = 0.914, Tmax = 0.974
49390 measured reflections
4536 independent reflections
3193 reflections with I > 2ꢅ(I)
Rint = 0.076
ꢅ
o82 Linden et al. C23H19ClFNO3 and C26H24F4N2O3
Acta Cryst. (2011). C67, o80–o84

organic compounds
Table 1
Selected geometric parameters (A, ) for (I).
Table 3
Selected geometric parameters (A, ) for (II).
ꢂ
ꢂ
˚
˚
O1—C9
O2—C9
N1—C7a
N1—C2
C2—C3
1.214 (2)
1.350 (2)
1.353 (2)
1.395 (2)
1.353 (2)
C3—C9
C3—C4
C4—C4a
C4a—C7a
1.480 (3)
1.533 (2)
1.503 (3)
1.354 (2)
O1—C10
O2—C10
N1—C8a
N1—C2
C2—C3
1.209 (2)
1.360 (2)
1.373 (2)
1.385 (2)
1.353 (2)
C3—C10
C3—C4
C4—C4a
C4a—C8a
1.466 (2)
1.527 (2)
1.517 (2)
1.353 (2)
C2—N1—C7a
N1—C2—C3
N1—C2—C8
C3—C2—C8
C2—C3—C4
C2—C3—C9
120.52 (16)
120.74 (17)
111.90 (16)
127.37 (17)
123.47 (17)
120.55 (16)
C3—C4—C4a
C4—C4a—C7a
N1—C7a—C4a
O1—C9—O2
O1—C9—C3
O2—C9—C3
109.00 (14)
123.67 (16)
122.29 (17)
122.37 (17)
127.26 (17)
110.36 (15)
C2—N1—C8a
N1—C2—C3
N1—C2—C9
C3—C2—C9
C2—C3—C4
C2—C3—C10
122.48 (14)
120.37 (15)
112.87 (14)
126.76 (15)
122.23 (14)
121.32 (15)
C3—C4—C4a
C4—C4a—C8a
N1—C8a—C4a
O1—C10—O2
O2—C10—C3
O1—C10—C3
111.13 (12)
122.22 (15)
120.97 (15)
121.85 (15)
110.26 (14)
127.89 (15)
Table 2
Hydrogen-bond geometry (A, ) for (I).
Table 4
Hydrogen-bond geometry (A, ) for (II).
ꢂ
ꢂ
˚
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
N1—H1ꢀ ꢀ ꢀO5i
Symmetry code: (i) ꢁx þ 1; y þ ; ꢁz þ .
0.88 (2)
1.92 (2)
2.772 (2)
163 (2)
N1—H1ꢀ ꢀ ꢀN2i
0.90 (2)
0.99
0.95
2.11 (2)
2.54
2.58
3.0073 (19)
3.427 (3)
3.172 (2)
169.5 (19)
149
120
C7—H72ꢀ ꢀ ꢀO1ii
C15—H15ꢀ ꢀ ꢀO5iii
1
2
3
2
1
2
1
2
Symmetry codes: (i) x; ꢁy þ ; z þ ; (ii) ꢁx þ 2; ꢁy; ꢁz þ 2; (iii) x; y þ 1; z.
Refinement
R[F2 > 2ꢅ(F2)] = 0.048
wR(F2) = 0.130
S = 1.03
4536 reflections
268 parameters
H atoms treated by a mixture of
independent and constrained
refinement
For both compounds, data collection: COLLECT (Nonius, 2000);
cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data
reduction: DENZO-SMN and SCALEPACK (Otwinowski & Minor,
1997); program(s) used to solve structure: SIR92 (Altomare et al.,
1994); program(s) used to refine structure: SHELXL97 (Sheldrick,
2008); molecular graphics: ORTEPII (Johnson, 1976); software used
to prepare material for publication: SHELXL97 and PLATON
(Spek, 2009).
ꢁ3
˚
Áꢆmax = 0.31 e A
ꢁ3
˚
Áꢆmin = ꢁ0.22 e A
Compound (II)
Crystal data
3
˚
V = 2298.89 (7) A
Z = 4
C26H24F4N2O3
Mr = 488.48
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SK3400). Services for accessing these data are
described at the back of the journal.
Monoclinic, P21=c
Mo Kꢃ radiation
ꢄ = 0.11 mmꢁ1
T = 160 K
0.25 ꢄ 0.25 ꢄ 0.25 mm
˚
a = 11.3696 (2) A
˚
b = 9.2177 (2) A
˚
c = 21.9577 (3) A
ꢂ = 92.5683 (11)ꢂ
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˚
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ꢅ
Acta Cryst. (2011). C67, o80–o84
Linden et al.
C23H19ClFNO3 and C26H24F4N2O3 o83

organic compounds
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