New 1,4-dihydropyridine derivatives with hetero and saturated B rings

Article abstract of DOI:10.1023/A:1020209608962

The single crystal structures of 4-(5-(1,3-benzodioxole)-2,6-dimethyl-1,4-dihydropyridine-3, 5-bis(methoxycarbonyl) (I), 4-(3-pyridyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis (methoxycarbonyl) (II), 4-(3(1-methyl-1H-indole))-2,6-dimethyl-1,4-dihydropyrid

Full text of DOI:10.1023/A:1020209608962

Journal of Chemical Crystallography, Vol. 32, No. 9, September 2002 (�
2002)
C
New 1,4-dihydropyridine derivatives
with hetero and saturated B rings
(1)
(1) �
Gregori A. Caignan and Elizabeth M. Holt
Received August 12, 2001
The single crystal structures of 4-(5-(1,3-benzodioxole)-2,6-dimethyl-1,4-dihydropyridine-
,5-bis(methoxycarbonyl) (I), 4-(3-pyridyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis
methoxycarbonyl) (II), 4-(3(1-methyl-1H-indole))-2,6-dimethyl-1,4-dihydropyridine-3,
3
(
5
3
-bis(methoxycarbonyl) (III), and 4-cyclopentadienyl-2,6-dimethyl-1,4-dihydropyridine-
,5-bis(methoxycarbonyl) (IV) suggest that these members of a calcium beta blocking
family may dock with their receptor sites from the A ring end of the molecule.
KEY WORDS: Heterocycle; hydrogen bonds; 1,4-dihydropyridine; calcium beta blocker; structure; hetero
1
,4-dihydropyridine derivatives.
Introduction
,4-Dihydropyridine derivatives (DHPs)
Thus, it is appropriate to seek other av-
enues of understanding of the characteristics
of the DHP docking site and of drug interac-
tion with it, i.e. of molecular recognition of the
docking site. The crystallization process repre-
sents a form of molecular recognition in that
the crystallizing molecule seeks interactions with
other molecules on the surface of the grow-
ing crystal that are stronger than interactions
with the solvent and that impose an orientation
on the approach of the incoming molecule. Thus
the molecule is driven energetically to align in
a specific way with the molecules of the crys-
talline solid and to shed interactions with the
solvent. These interactions must involve hydro-
gen bonding, dipole–dipole interactions, and Van
der Waals interactions, in the order of decreasing
strength.
1
form a class of compounds widely prescribed for
1
their antihypertensive activity. They are thought
to block calcium passage through the walls of
smooth muscle by interaction with a receptor
2
site in voltage-gated manner. The attention paid
to molecular modeling of the docking of rigid
DHP derivatives with a particular rigid receptor
site in the � subunit of cardiac smooth muscle
1
seemed to have led to a consistent view of the
correlation of molecular conformation parameters
3
with molecular activity. However the lack of
consistency seen on application of second gen-
eration molecular modeling programs that permit
4
flexibility of drug and docking site has led to the
suspicion that the receptor site(s) may be other
than that used widely for modeling experiments.
Patterns of molecular recognition as seen in
the resulting crystal structure may mimic recogni-
tion of binding site patterns. For a DHP molecule,
these patterns involve variations in conformation
of the A ring (Fig. 1), relative orientation of ring A
(1)
Chemistry Department, Oklahoma State University, Stillwater,
Oklahoma 74078.
*
To whom correspondence should be addressed. E-mail: betsy@
biochem.okstate.edu.
315
1
074-1542/02/0900-0315/0 �C 2002 Plenum Publishing Corporation

3
16
Caignan and Holt
of the carbonyl groups. 4-(2,4-Dichlorophenyl)-
2,6-dimethyl-1, 4-dihydropyridine-3, 5-bis(meth-
oxycarbonyl) is seen with the ester group attached
at C5 in ap conformation and uninvolved in hy-
drogen bonding; however there is a hydrogen
bond involving the C3-substituted carbonyl group
that is in sp conformation.13
Normally the hydrogen-bonding donor is the
N---H group of the A ring, and the carbonyl oxy-
gen atom serves as acceptor. Hetero atoms of the
B ring such as S and O have not been seen to
participate in hydrogen bonding.1
4,11
However, in
one instance, a bifurcated hydrogen bond has been
observed to form between the H1 of N1 and the
oxygen atoms of two adjacent methoxy groups
substituted on ring B.12
Fig. 1. General view of a 1,4-dihydropyridine framework,
with numbering scheme and terminology of carbonyl con-
formation indicated.
Previous work has shown that the orientation
of an ortho substituent on the B ring in prow-
forward or prow-backward conformation is easily
reversed. Diethyl 4-(2,5-dimethoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
crystallized from nitrobenzene or urea is seen as
the prow backwards rotamer.12 Cystallized from
to ring B, carbonyl orientation at C3 and C5, and
hydrogen bonding involving the hydrogen atom
of N1.
Previous work in this laboratory has shown
that the presence of the hydrogen on N1 of the
A ring is important for DHP potency.5 Indeed,
the aromatization of the A ring, which occurs on
oxidation of 2-nitro-DHP, results in serious loss
,6
15
ethanol, the prow forward rotamer is observed.
Furthermore, in DHP molecules with 2- and
3-thiophene groups serving as the B ring, both
prow forward and prow backward orientations are
seen.14 The 2-chloro derivative has been found
to crystallize, with both rotamers present in the
same unit cell.16
Of interest is the effect of bulky B rings
on crystal packing as an indication of possible
interactive behavior with a receptor site. We have
determined the single crystal x-ray structures
7
of pharmacological activity.
Coplanarity of the carbonyl of the ester group
with the conjugated double bond of the A ring is
to be expected because of the stabilization gained
by efficient charge delocalization. The esterifi-
cation alkyl group should be small in volume
for better DHP activity. Groups larger than iso-
propyl lead to a significant drop in the binding
strength.8
–10
of
4-(5-(1,2-benzodioxole)-2,6-dimethyl-1,4-
Our previous work has shown that the
carbonyl groups attached to C3 and C5 are
preferentially in ap (antiperiplanar) conformation
when hydrogen bonded, but sp (synperiplanar)
dihydropyridine-3,5-bis(methoxycarbonyl) (I),
4-(3-pyridyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-bis(methoxycarbonyl) (II), and 4-(3(1-
methyl-1H-indole))-2, 6-dimethyl-1,4-dihydro-
pyridine-3,5-bis(methoxycarbonyl) (III). For
comparison purposes, we have determined
the single crystal structure of a 4-cyclohexyl
DHP derivative, 4-cyclohexyl-2,6-dimethyl-1,4-
dihydropyridine-3,5-bis(methoxycarbonyl) (IV)
in which the B ring is totally devoid of polar
groups.
1
1,12
otherwise.
to this generalization. 4-(2,3-Dichlorophenyl)-2,
-dimethyl-1, 4-dihydropyridine-3, 5-bis(metho-
There are, however, exceptions
6
xycarbonyl), 4-(2,3,5-trichlorophenyl)-2,6-dime-
thyl-1,4-dihydropyridine-3,5-bis(methoxycarbo-
nyl) display sp, sp orientation of carbonyl groups,
yet they display hydrogen bonding to one

1
,4-dihydropyridine derivatives with hetero and saturated B rings
317
Experimental
over MgSO , yielding crystals suitable for
4
x-ray.
4
-(5-(1, 3-Benzodioxole))-2,6-dimethyl-1, 4-
4-(3-(1-Methyl-1H-indole))-2,6-dimethyl-1,
dihydropyridine-3,5-bis(methoxycarbonyl) (I):
4-dihydropyridine-3,
5-bis(methoxycarbonyl)
1
1
2
,3-Benzodioxole-5-carboxaldehyde (2.175 g,
(III):
1-Methyl-1H-indole-3-carboxaldehyde
�
3
� 3
4.5 � 10 mol), methyl acetoacetate (3.364 g,
(2.245 g, 14.12 � 10
mol), methyl ace-
�
3
� 3
9 � 10 mol), and concentrated ammonium
toacetate (3.276 g, 28.24 � 10
mol), and
�
3
hydroxide (1.015 g, 29 � 10 mol) were mixed
in methanol and allowed to reflux for 5 h.
The resulting yellow solution was concentrated
by rotary evaporation and dried over MgSO4.
Crystals suitable for x-ray diffraction formed
from the solution.
concentrated ammonium hydroxide (0.985 g,
�
3
28.24 � 10 mol) were mixed in methanol and
allowed to reflux for 5 h. Crystals suitable for
x-ray diffraction formed from the yellow solution
after concentration under reduced pressure.
4-Cyclohexano-2, 6-dimethyl-1, 4-dihydro-
pyridine-3,5-bis(methoxycarbonyl) (IV): Cyclo-
4
-(3-Pyridyl)-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-bis(methoxycarbonyl) (II): 3-Formylpy-
hexanocarboxaldehyde (1.58 g, 14.12 �
�
3
� 3
ridine (1.772 g, 16.56 � 10
mol), methyl
acetoacetate (3.835 g, 33.12 � 10 mol), and
10
mol), methyl acetoacetate (3.276 g,
�
3
� 3
28.24 � 10 mol), and concentrated ammonium
�
3
concentrated ammonium hydroxide (1.160 g,
hydroxide (0.985 g, 28.24 � 10
mol) were
�
3
3
3.12 � 10 mol) were refluxed in methanol
mixed in methanol and allowed to reflux for 5 h,
yielding a yellow solution that crystallized on
standing.
for 5 h. The resulting yellow solution was
concentrated under reduced pressure and dried
Table 1. Crystallographic Data for Compounds I, II, III, and IV
Compound
I
II
III
IV
Molecular formula
CCDC deposit no.
Mass
C18H19NO6
CCDC-1003/6117
345.3
C16H18N2O4
CCDC-1003/6118
302.3
C20H22N2O4
CCDC-1003/6119
354.4
C17H25NO4
CCDC-1003/6120
307.4
˚
a, A
7.498(6)
8.525(5)
8.209(5)
9.451(3)
˚
b, A
9.698(6)
22.070(13)
8.996(9)
90.0
111.24(1)
90.0
10.524(4)
10.856(5)
90.0
95.56(1)
90.0
13.081(4)
13.923(6)
90.0
100.62(3)
90.0
˚
c, A
12.374(7)
100.90(2)
97.49(3)
�
�
�
, deg
, deg
, deg
99.73(3)
Z M
d, mg/m3
2
4
2
4
1.336
1.273
1.261
1.207
Crystal system
Space group
Diffractometer
Crystal size
Triclinic
P1bar
Monoclinic
P21/c
Monoclinic
P21
Monoclinic
P21/c
Siemens P4
0.2 � 0.2 � 0.2
2.5–30.0
� 1 < h < 10; � 14 <
k < 1; � 15 < l < 15
3431
Siemens P4
0.2 � 0.3 � 0.1
1.8–30.0
� 8 < h < 1; � 10 <
k < 10; � 13 < l < 13
3183
Siemens P4
0.05 � 0.1 � 0.1
2.56–30.0
� 1 < h < 11; � 1 <
k < 31; � 12 < l < 12
5656
Siemens P4
0.2 � 0.2 � 0.2
1.8–30.0
� 1 < h < 10; � 1 <
k < 13; � 13 < l < 13
2879
�
range, deg
Reciprocal lattice
segment
Reflections measured
Number of symmetry
independent reflections
Fo/parameter
2525
4574
2394
2595
2525/228
6.50
8.5
4574/200
5.87
8.74
2394/236
5.17
7.57
2595/199
6.27
7.39
R [I > 2�(I)]
Rw

3
18
Caignan and Holt
X-ray crystallographic study
For IV, the average plane of the cyclohex-
ane ring subtends an angle of 81.9 with the base
�
The collection of diffraction data using suit-
able crystals was accomplished using a Siemens
P4 automated single crystal x-ray diffractometer
equipped with monochromatized Mo K� radia-
of the dihydropyridine ring (atoms C2, C3, C5,
and C6). The fused and hetero B rings are seen in
orientations closer to orthogonality with the basal
�
�
�
plane of the boat: 93.3 (I), 88.5 (II), and 88.5
1
7
˚
tion (0.71073 A) and a �–2� scan. Cell constants
were determined using the least-squares fit of the
four diffractometer angles for an appropriate num-
ber of reflections (Table 1). The intensities of three
standard reflections were monitored after every 97
reflections. Crystaldecompositionwasfoundtobe
insignificant. The structures were solved and re-
fined using the programs SHELXS and SHELXL
(III), suggesting that B ring bulk or the presence of
hetero atoms in the B ring leads to more rigorous
orthogonality.
The conformations of carbonyl groups sub-
stituted at C5 and C3 may be quantified by the
0
0
0
0
C6---C5---C5 ---O5 and C2---C3---C3 ---O3 tor-
sion angles, respectively. Values close to 0 in-
dicate sp conformation, whereas those close to
1
8
�
of the SHELX package. Refinement of an ex-
tinction coefficient showed it to be insignificant.
180 denote ap conformation. Delocalization of
charge over the conjugated C---C---C---O sys-
0
The hydrogen atoms of methyl groups C2 and
tem normally insures that these angles remain
close to their theoretical values. The absolute
0
0
00
00
0
0
C6 of I; C2 , C3 , C5 , and C6 of II; and C2 ,
0
0
00
0
C3 , C5 , and C6 of III showed a rotational dis-
order. The two sets of hydrogen positions associ-
ated with each methyl group, which were apparent
from a difference Fourier synthesis, were refined
with 50% occupancy factors in the final cycles of
refinement.
Table 2. Atomic Coordinates and Equivalent Isotropic Displacment
˚
Coefficients (A) for Compound I
Atom
x
y
z
Ueqa
N(1)
C(2)
C(2 )
0.7867(5)
0.6539(6)
0.7325(7)
0.4759(6)
0.3252(6)
0.2241(7)
0.1698(4)
0.3703(5)
0.4167(6)
0.5804(6)
0.5417(7)
0.3069(9)
0.6517(5)
0.3591(5)
0.7551(6)
0.9301(7)
0.3324(6)
0.1401(6)
0.2921(4) 0.4190(3) 0.055(1)
0.2438(5) 0.4810(4) 0.050(1)
0.1880(6) 0.5782(4) 0.062(1)
0.2521(4) 0.4465(3) 0.045(1)
0.2203(5) 0.5104(4) 0.048(1)
0.1214(6) 0.6595(5) 0.074(2)
0.2428(4) 0.4857(3) 0.063(1)
0.1613(4) 0.5978(3) 0.069(1)
0.2917(5) 0.3350(3) 0.047(1)
0.3830(5) 0.3015(4) 0.048(1)
0.4749(5) 0.2224(4) 0.055(1)
0.5693(6) 0.1274(5) 0.078(2)
0.5397(4) 0.1762(3) 0.084(1)
0.4776(4) 0.2013(3) 0.066(1)
0.3742(5) 0.3400(4) 0.051(1)
0.4466(5) 0.3078(5) 0.068(2)
0.1548(4) 0.2449(3) 0.045(1)
0.1039(4) 0.2254(4) 0.050(1)
Results and discussion
0
C(3)
Projection drawings of the four structures are
given in Fig. 2 on the basis of positional parame-
ters of Tables 2, 4, 6, and 8. Tables 3, 5, 7, and 9
display selected bond angles and distances based
on the final positional parameters.
0
C(3 )
0
0
C(3 )
0
O(3 )
0
0
O(3 )
C(4)
C(5)
0
C(5 )
In molecule IV, with a six-membered B ring
in chair conformation containing no hetero atoms,
the sum of the torsion angles of ring A (boat
0
0
C(5 )
0
O(5 )
00
O(5 )
�
conformation) is 114.5 . The two structures with
C(6)
0
C(6 )
bulky fused rings substituted at C4, i.e. I and III,
are seen with flatter boat conformations of the
C(7)
C(8)
C(9)
O(10)
C(11)
O(12)
C(13)
C(14)
C(15)
�
A ring (torsion angle sum = 0 for a totally flat
0.0703(7) � 0.0204(5) 0.1464(4) 0.055(1)
� 0.1129(5) � 0.0871(4) 0.1096(3) 0.075(1)
� 0.1098(9) � 0.2210(6) 0.0371(5) 0.081(2)
0.0746(6) � 0.2170(4) 0.0128(3) 0.078(1)
0.1813(8) � 0.0977(5) 0.0883(4) 0.058(1)
0.3697(7) � 0.0499(5) 0.1048(4) 0.062(1)
�
ring and 240 for a boat of idealized conforma-
�
tion). Their torsion angle sums are 94.8 (I) and
�
1
08.1 (III). Structure II, in which the aromatic
B ring has an unshared pair localized on the ni-
trogen atom in the meta position, is the most dis-
torted from idealized boat geometry: torsion angle
0.4433(7)
0.0775(5) 0.1837(4) 0.054(1)
a
Equivalent isotropic U defined as one third of the trace of the or-
thogonalized Ui j tensor.
�
sum = 78.6 .

1
,4-dihydropyridine derivatives with hetero and saturated B rings
319
Fig. 2. Projection views with ellipsoids shown at the 50% probability level of (a) 4-(5-(1,2-benzodioxole)2,6-dimethyl-1, 4-
dihydropyridine-3, 5-bis(methoxycarbonyl) (I); (b) 4-(3-pyridyl)2,6-dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl)
(II); (c) 4-(3(1-methyl-1H-indole))-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-bis(methoxycarbonyl) (III); (d) 4-cyclohexyl-2,6-
dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl) (IV).
magnitudes of the values seen for the torsion an-
The respective conformations are thus sp,ap
(I); ap,sp (II); and sp,sp (III); and sp,ap (IV).
Molecules I and IV follow the expected pattern of
the carbonyl atom not involved in hydrogen bond-
ing being seen in sp conformation (torsion angle
ꢀ
ꢀ
ꢀ
ꢀ
gles C6---C5---C5 ---O5 and C2---C3---C3 ---O3
◦
◦
◦
◦
◦
are 6.8 and 181.7 for I, 160.5 and 0.8 for II,
5
◦
◦
◦
.9 and 16.2 for III, and 26.2 and 169.9 for IV,
respectively; this confirms the influence of elec-
tron delocalization upon carbonyl conformation.
◦
near 0 ) whereas the carbonyl that is hydrogen

3
20
Caignan and Holt
Table 4. Atomic Coordinates and Equivalent Isotropic Displacment
bonded is seen in ap conformation (torsion an-
˚
�
0
Coefficients (A) for Compound II
gle near 180 ). For I, H1A ���O3 (1 + x, y, z)
0
�
Ueqa
2
.138 A with a N1 H1a O3 angle of 168 . For
---
˚
---
Atom
x
y
z
0
1
1
IV, N1---H1a ���O3 (x, � y, � + z) 2.116 A
˚
2
2
�
N(1)
C(2)
C(2 )
0.4075(2)
0.5473(2)
0.6274(3)
0.5972(2)
0.7528(2)
0.9201(3)
0.8512(2)
0.7756(2)
0.4884(2)
0.3641(2)
0.2897(2)
0.0603(4)
0.3518(2)
0.1393(2)
0.3277(2)
0.2091(3)
0.3917(2)
0.2731(2)
0.1822(2)
0.2150(3)
0.3312(2)
0.4165(2)
0.6256(1)
0.6528(1)
0.7007(1)
0.6358(1)
0.6603(1)
0.6563(1)
0.6970(1)
0.6361(1)
0.5935(1)
0.5574(1)
0.5044(1)
0.4345(1)
0.4803(1)
0.4864(1)
0.5749(1)
0.5443(1)
0.6292(1)
0.6732(1)
0.7039(1)
0.6904(1)
0.6498(1)
0.6198(1)
1.0689(2)
1.0521(2)
1.1782(3)
0.9294(2)
0.9137(2)
0.7489(4)
0.9999(2)
0.7839(2)
0.7966(2)
0.8509(2)
0.7479(3)
0.6544(4)
0.6613(2)
0.7518(2)
0.9809(2)
1.0499(3)
0.6437(2)
0.6435(2)
0.5025(2)
0.3653(2)
0.3618(2)
0.4995(2)
0.041(1)
0.042(1)
0.061(1)
0.039(1)
0.045(1)
0.070(1)
0.072(1)
0.061(1)
0.036(1)
0.037(1)
0.045(1)
0.087(1)
0.076(1)
0.071(1)
0.041(1)
0.058(1)
0.035(1)
0.042(1)
0.050(1)
0.050(1)
0.053(1)
0.046(1)
with an angle 171.7 . This pattern is seen for
the majority of published DHP structures and
can be said to be indicative of hydrogen bonding
0
C(3)
0
C(3 )
---
causing ap orientation of the C---O group. With-
out hydrogen-bonding involvement, the group is
mostly sp.
00
C(3 )
0
O(3 )
0
0
O(3 )
C(4)
C(5)
Structures II and III do not follow the pat-
tern. For II, hydrogen bonding involves the N---H
0
C(5 )
0
0
C(5 )
of the A ring as a donor and the pyridine nitro-
gen atom of the B ring of an adjacent molecule
as the acceptor [H1a---N9 (x, y, 1 + z) 2.131 A
0
O(5 )
00
O(5 )
˚
C(6)
0
�
C(6 )
with a N1---H1a ���N11 angle of 157.5 ]. Yet one
C(7)
C(8)
C(9)
C(10)
N(11)
C(12)
˚
Table 3. Bond Lengths (A) and Angles (deg) for Compound I
0
N(1)--- C(2)
N(1)--- C(6)
C(2)--- C(2 )
1.405(6) C(3 )--- C(3)--- C(4)
114.8(4)
123.7(4)
a
0
0
1.394(6) C(3)--- C(3 )--- O(3 )
Equivalent isotropic U defined as one third of the trace of the or-
0
0
00
1.502(6) C(3)--- C(3 )--- O(3 ) 114.5(4)
thogonalized U tensor.
ij
0 0 00
C(2)--- C(3)
1.368(6) O(3 )--- C(3 )--- O(3 ) 121.8(4)
0
0 00 00
1.484(6) C(3 )--- O(3 )--- C(3 ) 116.5(4)
C(3)--- C(3 )
˚
Table 5. Bond Lengths (A) and Angles (deg) for Compound II
C(3)--- C(4)
C(3 )--- O(3 )
1.532(6) C(3)--- C(4)--- C(5)
1.231(5) C(3)--- C(4)--- C(7)
1.347(5) C(5)--- C(4)--- C(7)
1.457(6) C(4)--- C(5)--- C(5 )
1.538(6) C(4)--- C(5)--- C(6)
110.2(4)
110.0(3)
112.1(3)
118.2(4)
120.7(4)
121.1(4)
127.0(5)
0
0
N(1)--- C(2)
N(1)--- C(6)
C(2)--- C(2 )
1.390(2) C(2)--- C(3)--- C(4)
121.1(2)
117.1(2)
127.8(2)
110.5(2)
121.7(2)
0
00
C(3 )--- O(3 )
0
1.397(2) C(3 )--- C(3)--- C(4)
00
00
0
C(3 )--- O(3 )
C(4)--- C(5)
C(4)--- C(7)
0
0
0
1.520(3) C(3)--- C(3 )--- O(3 )
0 00
1.371(3) C(3)--- C(3 )--- O(3 )
C(2)--- C(3)
0
1.542(6) C(5 )--- C(5)--- C(6)
0
0
0
0
00
00
C(3)--- C(3 )
1.484(4) O(3 )--- C(3 )--- O(3 )
---
0
0
0
C(5)--- C(5 )
1.476(6) C(5)--- C(5 )--- O(5 )
00 ---
C(3) C(4)
---
1.535(3) C(3 ) O(3 ) C(3 ) 117.6(2)
0
00
C(5)--- C(6)
1.357(6) C(5)--- C(5 )--- O(5 ) 111.8(4)
0
0
C(3 ) O(3 )
---
1.221(2) C(3) C(4) C(5)
1.360(3) C(3)--- C(4)--- C(7)
1.448(2) C(5)--- C(4)--- C(7)
---
---
111.0(1)
111.1(1)
110.0(1)
125.3(2)
121.3(2)
113.3(2)
124.1(2)
114.1(2)
121.8(2)
0
0
00
0
0
00
00
0 00
C(5 )--- O(5 )
1.219(6) O(5 )--- C(5 )--- O(5 ) 121.2(5)
C(3 )--- O(3 )
0
0
00
00
00
C(5 )--- O(5 )
1.366(6) C(5 )--- O(5 )--- C(5 ) 116.2(4)
C(3 )--- O(3 )
C(4)--- C(5)
C(4)--- C(7)
00
00
0
C(5 )--- O(5 )
1.453(5) N(1)--- C(6)--- C(5)
119.4(4)
113.2(4)
127.4(4)
119.2(4)
121.3(4)
119.5(4)
117.6(4)
128.0(5)
122.5(5)
1.540(2) C(5 )--- C(5)--- C(6)
0
0
C(6)--- C(6 )
1.518(6) N(1)--- C(6)--- C(6 )
1.541(3) C(6)--- C(5)--- C(4)
0
C(5) C(5 )
---
0
1.485(3) C(5 ) C(5) C(4)
---
0
---
C(7)--- C(8)
C(7)--- C(15)
C(8)--- C(9)
C(9)--- O(10)
C(9)--- C(13)
O(10)--- C(11)
C(11)--- O(12)
O(12)--- C(13)
C(13)--- C(14)
C(14)--- C(15)
1.416(6) C(5)--- C(6)--- C(6 )
0 0
1.369(3) C(5)--- C(5 )--- O(5 )
1.409(6) C(4)--- C(7)--- C(8)
1.375(6) C(4)--- C(7)--- C(15)
1.392(6) C(8)--- C(7)--- C(15)
1.391(7) C(7)--- C(8)--- C(9)
1.438(7) C(8)--- C(9)--- O(10)
1.448(7) C(8)--- C(9)--- C(13)
1.391(6) O(10)--- C(9)--- C(13) 109.5(4)
1.386(7) C(9)--- O(10)--- C(11) 105.5(4)
1.399(6) O(10)--- C(11)--- O(12) 108.2(4)
C(5)
-
-- C(6)
0
0
0 00
1.211(2) C(5)--- C(5 )--- O(5 )
C(5 )--- O(5 )
C(5 )--- O(5 )
C(5 )--- O(5 )
C(6)--- C(6 )
0
00
0 0 00
1.355(2) O(5 )--- C(5 )--- O(5 )
0
0
00
0 00 00
1.452(3) C(5 )--- O(5 )--- C(5 ) 116.8(2)
0
1.522(2) N(1)--- C(6)--- C(5)
119.7(2)
112.5(2)
127.8(2)
116.9(2)
120.5(2)
122.6(2)
119.9(2)
118.5(2)
0
0
C(7)--- C(8)
C(7)--- C(12)
C(8)--- C(9)
C(9)--- C(10)
C(10)--- N(11)
N(11)--- C(12)
1.401(2) N(1)--- C(6)--- C(6 )
1.404(3) C(5)--- C(6)--- C(6 )
1.399(3) C(8)--- C(7)--- C(12)
1.392(3) C(8)--- C(7)--- C(4)
1.345(3) C(12)--- C(7)--- C(4)
1.360(3) C(7)--- C(8)--- C(9)
C(2)--- N(1)--- C(6) 123.4(5)
N(1)--- C(2)--- C(2 ) 113.1(4)
C(11)--- O(12)--- C(13) 104.9(4)
C(9)--- C(13)--- O(12) 110.3(5)
C(9)--- C(13)--- C(14) 121.2(4)
O(12)--- C(13)--- C(14) 128.4(5)
C(13)--- C(14)--- C(15) 117.2(5)
C(7)--- C(15)--- C(14) 122.0(5)
0
C(2)--- N(1)--- C(6) 123.0(2) C(8)--- C(9)--- C(10)
N(1)--- C(2)--- C(2 ) 112.9(2) C(9)--- C(10)--- N(11) 123.3(2)
N(1)--- C(2)--- C(3) 117.9(4)
0
0
C(2 )--- C(2)--- C(3) 129.0(4)
N(1) C(2) C(3) 119.9(2) C(10) N(11) C(12) 117.3(2)
---
---
---
---
---
---
0
C(2)--- C(3)--- C(3 ) 123.8(4)
0
---
C(2 ) C(2) C(3) 127.2(2) C(7) C(12) N(11) 124.0(2)
---
C(2)--- C(3)--- C(4) 121.4(4)
C(2)--- C(3)--- C(3 ) 121.7(2)
0

1
,4-dihydropyridine derivatives with hetero and saturated B rings
321
Table 6. Atomic Coordinates and Equivalent Isotropic Displacment
˚
Table 7. Bond Lengths (A) and Angles (deg) for Compound III
˚
Coefficients (A) for Compound III
0
0
00
N(1)--- C(2)
N(1) C(6)
C(2)--- C(2 )
1.395(5) C(3)--- C(3 )--- O(3 )
0 ---
---
126.3(3)
111.3(3)
Atom
x
y
z
Ueqa
---
1.394(4) C(3) C(3 ) O(3 )
0
0 0 00
1.512(5) O(3 )--- C(3 )--- O(3 ) 122.4(3)
0 00 00
N(1)
C(2)
0.3044(3) 0.6629
0.3599(4) 0.5468(4)
0.5121(5) 0.4995(5)
0.2715(4) 0.4868(4)
0.3216(4) 0.3607(4)
0.2355(6) 0.1835(5)
0.4566(3) 0.3108(4)
0.1994(3) 0.3054(4)
0.1224(4) 0.5538(4)
0.0467(4) 0.6481(4)
� 0.1288(4) 0.6801(5)
� 0.3712(5) 0.6531(6)
� 0.2072(3) 0.7481(5)
� 0.1994(3) 0.6223(4)
0.1440(4) 0.7051(4)
0.0978(5) 0.8141(5)
0.1743(4) 0.6221(5)
0.2471(4) 0.7401(5)
0.2880(4) 0.7667(4)
0.4939(2) 0.039(1)
0.4521(3) 0.036(1)
0.5278(4) 0.056(1)
0.3568(3) 0.033(1)
0.3121(3) 0.035(1)
0.1847(5) 0.070(1)
0.3339(2) 0.051(1)
0.2394(2) 0.047(1)
0.2875(3) 0.031(1)
0.3738(3) 0.035(1)
0.3510(3) 0.042(1)
0.2138(4) 0.068(1)
0.4132(3) 0.071(1)
0.2472(2) 0.052(1)
0.4667(3) 0.038(1)
0.5487(4) 0.049(1)
0.1722(3) 0.034(1)
0.1673(3) 0.040(1)
0.0493(3) 0.045(1)
C(2)--- C(3)
1.361(5) C(3 )--- O(3 )--- C(3 ) 116.7(3)
0
C(3)--- C(3 )
1.485(5) C(5)--- C(4)--- C(7)
1.543(5) C(5)--- C(4)--- C(3)
1.228(4) C(7)--- C(4)--- C(3)
110.7(3)
110.3(3)
109.9(3)
119.4(3)
119.5(3)
121.1(3)
127.2(3)
111.6(3)
0
C(2 )
C(3)--- C(4)
0 0
C(3 )--- O(3 )
C(3)
0
0
00
0
C(3 )
C(3 )--- O(3 )
1.347(4) C(4)--- C(5)--- C(5 )
0
0
00
00
C(3 )
C(3 )--- O(3 )
C(4)--- C(5)
C(4)--- C(7)
1.456(5) C(4)--- C(5)--- C(6)
0
0
1.538(4) C(5 )--- C(5)--- C(6)
O(3 )
0
0
0 0
1.539(4) C(5)--- C(5 )--- O(5 )
O(3 )
C(4)
C(5)
0
0 00
1.476(5) C(5)--- C(5 )--- O(5 )
C(5)--- C(5 )
0 0 00
1.363(5) O(5 )--- C(5 )--- O(5 ) 121.3(3)
C(5)--- C(6)
0
0
0
00
0 00 00
C(5 )
C(5 )--- O(5 )
1.211(4) C(5 )--- O(5 )--- C(5 ) 115.5(3)
0
0
0
C(5 )
C(5 )--- O(5 )
1.360(5) N(1)--- C(6)--- C(5)
1.458(5) N(1)--- C(6)--- C(6 )
1.523(5) C(5)--- C(6)--- C(6 )
119.4(3)
113.6(3)
127.0(3)
127.3(3)
127.1(3)
105.5(3)
111.2(3)
108.0(3)
126.3(3)
0
00
00
0
0
O(5 )
C(5 )--- O(5 )
0
0
0
O(5 )
C(6)
C(6)--- C(6 )
C(7)--- C(8)
C(7)--- C(15)
C(8)--- N(9)
1.381(5) C(4)--- C(7)--- C(8)
1.453(5) C(4)--- C(7)--- C(15)
1.385(5) C(8)--- C(7)--- C(15)
1.384(5) C(7)--- C(8)--- N(9)
1.463(5) C(8)--- N(9)--- C(10)
1.412(5) C(8)--- N(9)--- C(16)
1.421(5) C(10)--- N(9)--- C(16) 125.6(3)
1.385(7) N(9)--- C(10)--- C(11) 129.5(4)
1.397(7) N(9)--- C(10)--- C(15) 108.2(3)
1.401(6) C(11)--- C(10)--- C(15) 122.4(4)
1.410(5) C(10)--- C(11)--- C(12) 116.9(4)
0
C(6 )
C(7)
C(8)
N(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
N(9)--- C(10)
N(9)--- C(16)
C(10)--- C(11)
C(10)--- C(15)
C(11)--- C(12)
C(12)--- C(13)
C(13)--- C(14)
C(14)--- C(15)
0.2403(4) 0.6646(5) � 0.0260(3) 0.041(1)
0.2565(5) 0.6461(6) � 0.1530(3) 0.061(1)
0.1954(6) 0.5337(6) � 0.2052(4) 0.066(1)
0.1197(6) 0.4426(6) � 0.1365(4) 0.063(1)
0.1051(5) 0.4598(5) � 0.0101(3) 0.047(1)
0.1688(4) 0.5719(4)
0.3626(6) 0.8840(5)
0.0472(3) 0.037(1)
0.0091(5) 0.067(1)
C(2)--- N(1)--- C(6) 122.8(3) C(11)--- C(12)--- C(13) 122.0(4)
N(1)--- C(2)--- C(2 ) 113.0(3) C(12)--- C(13)--- C(14) 121.2(4)
0
a
N(1)
-
-- C(2)--- C(3) 119.1(3) C(13)--- C(14)--- C(15) 118.5(4)
Equivalent isotropic U defined as one third of the trace of the or-
0
C(2 )
-
-- C(2)--- C(3) 127.8(3) C(7)--- C(15)--- C(10) 107.2(3)
thogonalized U tensor.
ij
0
C(2)--- C(3)--- C(3 ) 121.3(3) C(7)--- C(15)--- C(14) 133.9(3)
C(2)--- C(3)--- C(4) 119.9(3) C(10)--- C(15)--- C(14) 118.9(3)
C(3 )--- C(3)--- C(4) 118.7(3)
0
carbonyl group, uninvolved in hydrogen bonding,
is seen in ap conformation.
In structure III, the carbonyl oxygen
0
0
atom O3 is involved in a hydrogen bond
1
20
H1a---O3 2.114 A, 1 � x, + y, 1 � z, with a
˚
ride] do not involve the carbonyl oxygen groups
[
2
0
�
N1---H1a---O3 angle of 172.7 ], and yet the car-
bonyl group is seen in sp orientation. This is rare
in reported DHP structures. The observation of
sp,sp conformation has been mostly attributable
to the presence of an additional hydrogen bonding
site in the molecule and thus the lack of involve-
ment of either of the carbonyl oxygen atoms. For
in hydrogen bonding because of the presence of
a better receptor (Cl ).
�
Structure II may be compared to a structural
observation of 4-(3-pyridyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-bis(ethoxycarbonyl)21
in
which both carbonyl groups are seen in sp con-
formation. Hydrogen atoms were not located in
this structure and thus the influence of hydrogen
bonding on carbonyl conformation cannot be
assessed.
There are also two reported observations of
4-(2-pyridyl) DHP derivatives that differ in esteri-
fication groups. Both crystallize withthe 2-pyridyl
example,
4-(3-nitrophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3-methyl-5-(1-phenylmethyl)-3-
piperidinyl ester) hydrochloride and YM-09730
hydrochloride [(3S)-1-benzyl-3-pyrrolidinyl
methyl(4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate hydrochlo-
1
9

3
22
Caignan and Holt
Table 8. Atomic Coordinates and Equivalent Isotropic Displacment
˚
Table 9. Bond Lengths (A) and Angles (deg) for Compound IV
˚
Coefficients (A) for Compound IV
N1--- C6
1.382(5)
1.387(5)
1.361(5)
1.518(5)
1.462(5)
1.522(5)
1.223(4)
1.343(4)
1.446(5)
1.517(5)
1.554(5)
1.357(5)
1.471(5)
1.211(5)
1.348(5)
1.441(5)
1.496(6)
1.525(5)
1.532(5)
1.528(6)
1.527(6)
1.516(6)
1.522(6)
122.5(3)
118.8(3)
128.5(4)
112.7(3)
125.7(3)
C2--- C3--- C4
C3 C3 C4
119.8(3)
114.5(3)
120.4(4)
123.9(3)
115.7(3)
116.2(3)
109.5(3)
112.9(3)
112.0(3)
120.4(4)
120.1(3)
119.5(3)
121.8(4)
126.7(4)
111.5(4)
116.3(4)
118.9(4)
127.0(4)
114.1(3)
109.4(3)
114.5(3)
111.6(3)
112.2(3)
111.6(4)
110.1(4)
110.8(4)
111.7(3)
Atom
x
y
z
Ueqa
---
0 --- ---
N1 C2
C2--- C3
0
0
00
O3 --- C3 --- O3
0
0
0 0
N1
C2
0.0965(3)
0.1954(4)
0.3450(4)
0.1511(4)
0.2447(4)
0.4751(5)
0.2040(3)
0.3827(3)
� 0.0084(4)
� 0.0821(4)
� 0.2064(4)
� 0.3216(5)
� 0.3029(4)
� 0.2044(3)
� 0.0332(4)
� 0.1029(5)
� 0.0805(4)
� 0.0768(5)
0.2684(2) 0.5845(2) 0.0433(8)
0.2239(3) 0.6587(3) 0.0379(9)
0.2170(3) 0.6341(3) 0.0510(11)
0.1948(3) 0.7423(3) 0.0362(9)
0.1604(3) 0.8320(3) 0.0391(9)
0.1056(5) 0.9125(3) 0.0730(15)
0.1478(2) 0.9096(2) 0.0523(8)
0.1433(2) 0.8253(2) 0.0575(9)
0.1967(3) 0.7472(3) 0.0374(9)
0.2813(3) 0.6821(3) 0.0397(9)
0.3343(3) 0.7090(3) 0.0489(11)
0.3787(5) 0.8407(4) 0.087(2)
0.3766(3) 0.6540(3) 0.0829(11)
0.3292(2) 0.8060(2) 0.0602(9)
0.3079(3) 0.5998(3) 0.0417(10)
0.3801(4) 0.5219(3) 0.0599(12)
0.0906(3) 0.7233(3) 0.0408(10)
0.0516(3) 0.6206(3) 0.0531(12)
C2--- C2
C3--- C3
C3--- C4
O3 --- C3 --- C3
00
0
00
O3 --- C3 --- C3
0
0
00
C2
C3
C3
C3
C3 --- O3 --- C3
C5--- C4--- C3
C5--- C4--- C7
C3--- C4--- C7
0
0
00
00
C3 --- O3
0
C3 --- O3
0
0
0
00
C3 --- O3
C4--- C5
C4--- C7
C5--- C6
0
0
0
O3
O3
C4
C5
C6--- C5--- C5
0
C6--- C5--- C4
0
C5 --- C5--- C4
0
0
0
00
C5--- C5
O5 --- C5 --- O5
0
0
0
00
0
00
00
0 0
C5
C5
O5
O5
C6
C5 --- O5
C5 --- O5
O5 --- C5 --- C5
00
00 0
O5 --- C5 --- C5
0
0
0
00
00
C5 --- O5
C5 --- O5 --- C5
C5--- C6--- N1
0
0
C6--- C6
0
C7--- C8
C7--- C12
C8--- C9
C9--- C10
C10--- C11
C11--- C12
C6--- N1--- C2
C3--- C2--- N1
C3--- C2--- C2
C5--- C6--- C6
0
0
C6
C7
C8
C9
N1--- C6--- C6
C8--- C7--- C12
C8--- C7--- C4
C12--- C7--- C4
C7--- C8--- C9
C8--- C9--- C10
C11--- C10--- C9
C10--- C11--- C12
C11--- C12--- C7
� 0.1480(5) � 0.0531(3) 0.6013(4) 0.0631(13)
� 0.3020(5) � 0.0525(4) 0.6206(3) 0.0654(13)
� 0.3035(5) � 0.0159(4) 0.7237(4) 0.0678(14)
C10
C11
C12
� 0.2361(4)
0.0898(3) 0.7404(3) 0.0522(11)
0
0
a
--- C2--- C2
-
Equivalent isotropic U defined as one third of the trace of the or-
N1
C2
0
-- C3--- C3
thogonalized U tensor.
ij
group turned back over the DHP ring and with the
taining hetero atoms at C4 tend to flatten the boat
conformation of the A ring. Furthermore, these
factors lead to greater mutual orthogonality of the
A and B rings and also to greater coplanarity of the
carbonyl groups with their adjacent double bonds.
The general expectation of hydrogen bonding in-
volving a carbonyl group oxygen in ap conforma-
tionappearstobeconfirmed, butitbecomesappar-
ent that bulky groups at the ortho position as in III,
or ortho substituents such as chloride , with large
numbers of unshared pairs of electons can lead to
hydrogen bonding to carbonyl oxygen atoms in
sp conformation. The implications for docking ge-
ometry are these: the lack of observation of hydro-
gen bonding activity of any type involving halide
orO, orSatomsoftheBringsuggeststhatthisring
is largely uninvolved in receptor site recognition
except perhaps as a space filling moiety. The con-
sistent observation of N1---H as a hydrogen bond-
2
-pyridyl nitrogen atom serving as an acceptor
for a hydrogen donated by N1 of a neighboring
2
2
molecule. Thus the pyridyl ring is capable of
rotation.
The structure of ethyl-methyl-2,6-dimethyl-
4
5
-(2, 3-methylenedioxyphenyl)-1, 4-dihydro-3,
-pyridinecarboxylate differs from I in the at-
2
3
tachment of the fused oxo ring at the ortho and
meta position of the B ring and not at the meta and
para position as in I. In this structure the carbonyl
groupsubstitutedatC6isturnedapandisinvolved
in hydrogen bonding. The carbonyl group at C3 is
seen in sp conformation as usual.
15
Conclusion
Comparison of the structural details of I, II,
andIIIwiththoseofIVshowsthatthesubstitution
of bulky fused ring systems or ring systems con-
ing donor and of carbonyl group oxygen atoms as

1
,4-dihydropyridine derivatives with hetero and saturated B rings
323
hydrogen bonding acceptors, plus the observation
that both carbonyl atoms and B rings are capable
of rotation to sp and “folded back” conformations,
respectively, suggests that the DHP molecule may
interact with its receptor site from the N1 end of
the A ring and not via the B ring being driven head
6. Rowan, K.R.; Holt, E.M. Acta Cryst. 1996, C52, 1565–1570.
. Rowan, K.R. PhD Dissertation, Oklahoma State University,
996.
8. Rowan, K.R.; Holt, E.M. Acta Cryst. 1996, C52, 2207–2212.
. Rowan, K.R.; Holt, E.M. Acta Cryst. 1997, C53, 257–261.
0. Rowan, K.R.; Holt, E.M. Acta Cryst. 1997, C53, 106–108.
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