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Synthesis and Calcium Channel Modulating Effects of Alkyl 14-Dihydro-26-dimethyl-4-pyridinyl or 2-trifluoromethylphenyl-5-1H-tetrazol-5-yl-3-pyridinecarboxylates.

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Iqbal and Knaus
Synthesis and Calcium Channel Modulating Effects of Alkyl
or 2-trifluoromethylpheny1)5 41H-tetrazol-5-yl)-3-pyridinecarboxylates
Nadeem Iqbal and Edward E. Knaus"
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
Key Words: Hantzsch 1,4-dihydropyridines, tetrazoles, calcium channels, smooth muscle relaxation, inotropic effects
hypertensive rats[*].In an earlier study, we described a novel
group of (k)-isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4A group of racemic alkyl 1,4-dihydro-2.6-dimethyl-4-(pyridinyl (pyridinyl)-5-pyridinecarboxylateisomers (5-7). The rac-2or 2-tritluoromethylphenyl)-5-( IH-tetrazol-5-yl)-3-pyridinecar- pyridinyl isomer 5 acted as a dual cardioselective calcium
boxylates 11-14 were prepared using the Hantzsch reaction that
channel agonisthmooth muscle selective calcium channel
involved the condensation of 2-, 3- or 4-pyridinecarboxaldehyde,
antagonist. In contrast, the rue-3-pyridinyl6 and rac-4-pyridor 2-trifluoromethyIbenzaldehyde, 8a-d with isopropyl or methyl
inyl 7 isomers exhibited agonist activity on both heart and
3-aminocrotonate (9a-b) and 5-(2-oxopropyl)- 1H-tetrazole (10a)
smooth muscle. The (-)-2-pyridinyl enantiomer (-)-5exhibitor 5-(2-oxopropyl)- 1-methyl- I H-tetrazole (lob). In vitro calcium
ed in vitro cardiac agonist and smooth muscle antagonist
channel (CC) antagonist and agonist activities were determined
A dual cardioselective agonisthmooth muscle
using guinea pig ileum longitudinal smooth muscle (GPILSM) and
selective antagonist third generation modulator such as (-)guinea pig left atrium (GPLA) assays, respectively. In the series of
2-pyridinyl 5 would have an ideal therapeutic profile for
compounds 11-14, only compounds 14a and 14b exhibited some
treating CHF patients. It was therefore of interest to continue
weak CC antagonist activity
M range) relative to the referthese important structure-activity correlations by replacing
ence drug nifedipine (IC50= 1.43x lo-* M). Compounds llb-14b
the nitro group of Bay K 8644 (2) and the pyridinyl analogs
having a I -methyl- 1H-tetrazol-5-yl substituent were inactive CC
agonists on GPLA. In contrast, compounds 12a-14a having a
5-7 by a 1H-tetrazol-5-yl moiety. This latter modification
IH-tetrazol-5-yl substituent exhibited CC agonist activity on
would be expected to alter the nature of the drug-receptor
GPLA. but the C-4 2-pyridinyl analog l l a exhibited a mild negainteraction and perhaps tissue selectivity. We now report the
tive inotropic effect. The approximately equipotent CC agonist
synthesis and in vitro calcium channel modulating effects of
activity (GPLA) exhibited by the C-4 pyridinyl 13a and 4-(2-trian alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl or 2-trifluofluoromethylphenyl) 14a compounds compared favorably with
romethylpheny1)-5-(1H-tetrazol-5-yl)-3-pyridinecarboxylthat of the reference drug (+)-Bay K 8644 (EC5o = 7.7 x lo-' M)
class of compounds.
indicating that the I H-tetrazol-S-yl moiety is a suitable replace-
ment for the nitro group present in Bay K 8644 with respect to
cardiac CC agonist activity. These latter compounds 13a and 14a
should serve as useful probes to study the structure-function relationships of calcium channels.
The design of tissue-selective 1,4-dihydropyridine (DHP)
calcium channel modulators, that act at the L-type voltage
dependent calcium channel, has provided a significant challenge to medicinal chemists[']. DHP calcium channel antagonists that have enhanced vascular selectivity such as
felodipine (l),which exhibit a minimal inotropic effect, are
useful for the treatment of hypertension and vasospasm[21.In
contrast, the calcium channel agonist Bay K 8644 (2) exhibits
a positive inotro ic effect by stimulating calcium entry into
cardiac muscleL3p However, Bay K 8644 also induces vasocontriction which recludes its clinical use in congestive
heart failure (CHF)p41.
The 1,4-DHP compound 3, containing a 1-methyl- 1H-tetrazol-5-yl moiety, designed to act as a latent carboxylate appendage or carboxylate i s o ~ t e r e [ ~was
~ l , prepared but no
pharmacological data were reported[71. A related class of
compounds (4) possessing a 2-methyl-2H-tetrazol-5-yl substituent has been described that reduces blood pressure in
Arch. Pharni. (Weinheim) 328, 750-754
5, R = 2-pyridinyl
6, R = 3-pyridinyl
7 , R = 4-wridinyl
Figure 1. Structures of felodipine (l),Bay K 8644 (2). tetrazol-5-yl compounds 3 4 and pyridinyl isomers 5-7.
The alkyl 1,4-dihydr0-2,6-dimethyl-4-(pyridinylor 2-trifluoromethylpheny1)-5-(1H-tetrazol-5-yl)-3-pyridinecarboxylates (11-14) were prepared by a modified Hantzsch
reaction. Thus, condensation of the respective aldehyde (8ad) with the respective alkyl3-aminocrotonate (9a-b) and the
respective 5-(2-oxopropyl)-lH-tetrazole(10a-b) afforded
(1995) 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1995
0365-6233/95/1111-0750$5.00 + .25/0
75 1
ioa, ~3 = H
lob, R2 = Me
Reagents and conditions: (a) EtOH, reflux, 14 h,
the title compounds in 22-66% yields as illustrated in
Scheme 1.
Results and Discussion
The development of calcium channel agents which are
acceptable for the treatment of CHF will be dependent upon
the separation and/or elimination of their vasoconstrictor
effect from their positive inotropic (calcium agonist)
cardiostimulant property.[lol Differences in the molecular
electrostatic potentials, with respect to the C-3 and C-5 DHP
regions, between activator and antagonist structures has been
observed which may allow the receptor to distinguish between activator and antagonist ligands. Thus, calcium channel agonists have a strong negative potential in the region
adjacent to their C-3 nitro substituent, while antagonists
displayed a positive potential in this region when a C-3 ester
group is present"']. Recently, a new model was proposed,
where the direction of the 4-phenyl group at the receptor acts
as a molecular switch in determining state-dependent affinity
for the calcium channel. It was proposed that enantiomers
having a pseudoaxially up-oriented C-4 aryl group (normal
boat) exhibit a calcium antagonist effect, and that enantiomers having a pseudoaxially down-oriented C-4 aryl moiety
(capsized boat) will have calcium agonist activity.['21Furthermore, the effect of substituents in the C-4 henyl ring of
IP-DHP agonists and antagonists is different!13] These observations prompted us to investigate analogs of Bay K 8644
(2) and the pyridinyl analogs 5-7 in which the 3-nitro substituent is replaced by a 1H-tetrazol-5-yl moiety. It was anticipated that the position of the pyridinyl nitrogen and the
1H-tetrazol-5-yl moiety, due to their potential to act as additional electron donors for hydrogen bonding to the calcium
channel receptor, may offer an approach to modulate calcium
channel binding and/or tissue specificity.
The in vitro calcium channel-modulatingactivities of compounds 11-14 were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left
atrium (GPLA). The calcium channel antagonist activities of
11-14, determined as the concentration re uired to produce
50% inhibition of GPILSM contractility,[li are presented in
Arch P h a m (Weinheim)328,750-754 (1995)
l l a , R1 = 2-py, R2 = rPr, R3 = H
l l b , R1 = 2-py, R2 = /Pr, R3 = Me
128, R1 = 3-py, R2 = P r , R3 = H
12b, R1 = 3-py, R2 = rPr, R3 = Me
l a , R1 = 4-py, R2 = iPr, R3 = H
13b, R1 = 4-py, R2 = rPr, R3 = Me
14a, R1 = 2-CF3-CsH4-, R2 = Me, R3 = H
14b, R1 = 2-CFs-C6H4-, R2 = Me,R3 = Me
Table 1. Compounds 11-14 exhibited weak calcium channel
antagonist activity
to 10" M range) relative to the
reference drug nifedipine (IC50 = 1.43 x
M). The differences in antagonist activity for active compounds were about
one log unit. The correlations described therefore represent
activity profiles, since the potency differences often have a
low level of significance.A comparison of compounds lla13a having a 5-( 1H-tetrazol-5-yl) substituent showed the
relative potency order was 2-py (lla) > 4-py (13a)>> 3-py
(12a, inactive). A similar comparison for llb-13b having a
5-( 1-rnethyl-lH-tetrazol-5-y1) moiety displayed an activity
order 3-py (12b) > 4-py (13b) >> 2-py (llb, inactive).There
was no correlation for compounds having 1 -methyl-1H-tetra201-5-yl substituents(11b13b) relative to the corresponding
1H-tetrazol-5-yl analogs lla-13a [2-py (lla) >> 2-py (llb,
inactive); 3-py (12b) >> 3-py (12a, inactive) and 4-py (13b)
= 4-py (13a). The equipotent 4-(2-trifluoromethylphenyl)
analogs (14a, 14b) were more active antagonists than compounds 11-13 having C-4 pyridinyl subsitituents. This latter
observation was unexpected since a prior study showed that
a C-4 pyridinyl subsituent is bioisosteric with a C-4 nitrophenyl substituent on a 1,CDHP ring with respect to
calcium channel antagonist activity, where ortho-, meta-, and
para-nitrophen 1are bioisosteric with 2-, 3-, and 4-pyridinyl,
respectively.['d The results of this study indicate that the
moiety is not a useful isostere of
the alkyl ester substituent present in classical 1,4-DHP calcium channel antagonists.
Calcium channel agonist activities were determined as the
molar concentration eliciting 50% (EC50) of the maximum
contractile response produced by the test drug on guinea pig
left atrium (GPLA), as determined graphically from the doseresponse curve. In this assay, the reference drug (*)-Ba K
8644 showed an agonist EC50 value of 7.70 k 5.90 x 10- M
( n = 3).19] Compounds having a 1-methyl-lH-tetrazol-5-yl
substituent (llb-14b) did not exhibit a calcium channel
agonist effect on GPLA. In contrast, compounds 12a-14a
having a lH-tetrazol-5-yl substituent exhibited agonist activity (12a, 3-py, 10% increase in contractile force relative to its
basal contractile force in the absence of 12a at 4.46 x
13a, 4-py, Ec50 = 3.14 k 10.50 x
M, n = 3; 14a,
Iqbal and Knaus
Table 1. Physical and calcium channel antagonist activities of alkyl I ,4-dihydro-2,6-dimethyl-4-(pyridinyl
or 2-trifluoromethylphenyl)-5-( IH-tetrazol-5-yl)3-pyridinecarboxylates (11-14).
Calcium channel
antagonist act: 1 ~ s o [ ~ 1
C I sHzzN60r
CI x H ~ ~ N 6 0 2
5.60 k 0.07 x 10" ( 3 )
5.96 x 1 0 - ~(3)"'
5.96 x LO" (3)Ie1
2.21 S_ 0.34 x 104 (3)
1.87 ? 0.03 x 10" ( 3 )
1.43 f 0.38 x lo-' (8)
c 17H?oN602
CI ~ H I ~ F ~ N s O ?
C I X HxF3N502
ia'Microanalytical analyses were within f 0.4% of theoretical values, unless otherwise indicated.
lblThe molar concentration of antagonist test compound causing a 50% decrease in the slow component or tonic contractile response (IC50 f SEM) in
guinea pig ileal longitudinal smooth muscle by the muscarinic agonist carbachol (1.6 x
M)was determined graphically from the dose-response
curves. The number of experiments is shown in brackets.
['IN: calcd, 23.71; found, 22.71
Id] 1/4 molecule water of recrystallization.
leiA test drug concentration of 5.96 x lo-' M caused a 29% antagonist effect.
['IN: calcd, 23.71; found, 23.13
lg'A test drug concentration of 5.96 x
M caused a 24% antagonist effect.
4-(2-cF3-C&-, EC50 = 1.80 93.1 x lov7 M, n = 3). The
2-pyridinyl analog l l a exhibited a mild negative inotropic
effect causing a 9%decrease in GPLA contractile force at a
concentration of 1.64 x
M. The approximately equipotent agonist activity exhibited by the 4-pyridinyl 13a and
4-(2-trifluoromethylphenyl) 14a compounds compares favorably with that of (+)-Bay K 8644 indicating that the
1H-tetrazol-5-ylmoiety is a suitable replacement for the nitro
group in Bay K 8644 with respect to cardiac calcium channel
agonist activity. The relatively large difference in drug concentration (> two log units) for 13a re uired for its agonist
effect on GPLA (EC50 = 3.14 x 10- M), relative to its
antagonist effect on GPILSM (Ic50 = > 5.96 x
M), is
suggestive of cardioselectivity at low drug concentrations.
These results indicate that introduction of a C-5 IH-tetrazol5-yl substituent, but not a 1-methyl-lH-tetrazol-5-yl
substituent, in place of the C-5 nitro group present in 7 or Bay K
8644 (2) in combination with a C-4 pyridinyl (13a) or 2-trifluoromethylphenyl(14a) substituent confers cardiac agonist
activity. The differences between the IH-tetrazol-5-yl and
I-methyl-lH-tetrazol-5-yl moieties with respect to agonist
activity could be due to a number of possibilities which
include differenences in the drug-receptor interaction and
preferential affinity for/or access to the resting (R), open (0)
or inactivated (I) states of the calcium channel receptor.[161
A molecular mechanics calculation (Alchemy I1 minimizer
program from Tripos Associates, IBM PC version) indicated
that isopropyl 1,4-dihydro-2,6-dimethyl-4-(4-pyridinyl)-5( 1H-tetrazol-5-yl)-3-pyridinecarboxylate(13a) exists in a
boat conformation with an energy minimum (Emin) of 8.7 kcal
mol-' (see Figure 2). The C(2)-C(3)-C(4)-C(7) and C(6)C(5)-C(4)-C(7) torsion angles were -76.3' and 76.0', respectively which indicates that the C-4 4-pyridinyl substituent is
pseudomid (perpendicular) to the plane of the boat-shaped
1,4-DHP ring. The N( 1)-C(4) interatomic distance, which
Figure 2. Energy-minimized structure for isopropyl 1,4-dihydro-2,6-dimethyl-4-(4-pyridiny1)-5-(
Arch. Phamr. (Weinhrinr)328, 7SO-754 (1995)
which was purified by silicagel column chromatography using Et0Ac:EtOH
(955, v/v) as eluent for compounds 11-13 and EtOAc as eluent for compounds 14. The recrystallization solvent, mp and Ti yield of products 11-14
are summarized in Table I . Representative spectral data ('H NMR, IR) for
compounds l l a , 12b, 13a, and 14b are provided since the spectral data are
qualitatively similar.
Isopropyl 1,4-Dihydro-2,6-dimethyl-4-(2-pyridinyl)-5-(
IH-tetrazol-5-y1)3-pyridinecarboxylate 1l a
IR (KBr): v = 3262 cm-' (NH), 1671 (C=O), 1507, 1470 (C=N), 1376
(N=N).- 'H NMR (DMSO-&): 6 0.96 and 1. I6 (two d, JCH.M~
= 6 Hz, 3H,
CHMez), 2.18 and 2.31 (twos, 3H each, C-2 and C-6 Me), 4.81 (sept, JCH,M~
= 6 Hz, 1 H, CHMeMe'), 5.13 (s, IH, H-4), 7.1 1 (dd, 55.6 = 5,543 = 8 Hz, 1
H, pyridinyl H-5),7.20 (d, 53.4 = 8 Hz, 1 H, pyridinyl H-3). 7.64 (ddd, 53.4 =
8, 54.5 = 8, 54.6 = 2 Hz, lH, pyridinyl H-4). 8.40 (dd, Js.6 = 5, 54.6 = 2 Hz, 1
Figure 3. Boat-shape, structure for isopropyl 1,4-dihydro-2,6-dimethyl-4- H, pyridinyl H-6), 8.79 (s, IH, dihydropyridyl NH).
(4-pyridinyl)-5-( 1 H-tetrazol-5-yl)-3-pyridinecarboxylate(13a)
Isopropyl 1,4-Dihydro-2,6-dimethyl-4-(3-pyridin~~~)-S-(l-mefhyl.
I H-tetraiol-5-yl)-3-pyridinecarboxylate
gives a measure of the flatness of the boat-shaped 1,4-DHP
IR (KBr): v = 3360 cm-' (NH), 1695 (C=O), 1517, 1432 (C=N), 1390
ring, was 2.64 A for compound 13a (see Figure 3). The 1,4= 6 Hz, 3H
DHP ring in 13a is similarly distorted to that of the calcium (N=N).- 'H NMR (DMSO-Q): 6 0.88 and 1.12 (two d, JCH.M~
channel antagonist nifedipine [3,5-dimethyl 1,4-dihydro- each, CHMez), 1.67 and 2.33 (two s, 3 H each, C-2 and C-6 Me's), 3.61 (s,
= 6 Hz, 1 H, CHMe2). 7.26
2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate] 3 H, NMe), 4.59 (s, 1 H, H-4), 4.75 (sept, JCH,M~
(dd, 54,s = 8, 55.6 = 5 Hz, I H, pyridinyl H-5), 7.47 (ddd, 54.5 = 8.54.6 = 2,
which has a N( 1)-C(4) interatomic distance of 2.66 A.['] A 52.4 = 2 Hz, 1 H, pyridinyl H-4), 8.19 (d, J2.4 = 2 Hz, 1 H, pyridinyl H-2),
comparison of the N(1)-C(8) (3.45 A) and N(l)-C(9) (3.83 8.34 (dd, J5.6 = 5, 54.6 = 2 Hz, 1 H, pyridinyl H-6). 8.90 (s, 1 H, NH).
A) interatomic distances indicates that the C-8 carbon of the
C-4 4-pyridinyl substituent is orientated more closely to the IsopropyI1,4-Dihydro-2,6-dimethyl-4-(4-pyridinyl)-5-(
I H-tetra:ol-5-yl)area above the 1,4-DHP ring. In addition, the respective 3-pyridinecarboxylate (13a)
C(2)-C(3)-C( 10)-O(11) and (C6)-C(5)-C(12)-N(13) torsion
IR (KBr): v = 3451 cm-' (NH), 1671 (C=O), 1520 and 1425 (C=N), 1376
angles of -179" and 178" indicates that the C=O (C02-iPr) (N=N).- 'H NMR (DMSO-d6): 6 1.05 and I .24 (two d, JCH.M~
= 6 Hz, 3H
and C=N (1H-tetrazol-5-yl) moieties are in the same plane as each, CHMez), 2.26 and 2.3 1 (two S, 3 H each, C-2 and C-6 Me 's), 4.84 (sept,
the respective C(2)-C(3) and C(5)-C(6)olefinic bonds to JCH.Me = 6 Hz, 1 H. CHMe2), 5.05 (S, IH, H-4). 7.18 (d, J2.3 = J5.6 = 5 Hz, 2
H, pyridinyl H-3 and H-5), 8.37 (d, 52.3 = Js.6 = 5 Hz, 2 H, pyridinyl H-2 and
which they are attached.
In summary, compounds 13a and 14a provide potential H-6). 8.91 ( s , 1 H, dihydropyridyl NH).
probes to study the structure-function relationship of calcium
channels, and drug discovery targeted to the treatment of Methyl 1,4-Dih~~dro-2,6-dimethyl-4-(2-tr~uoromethylphen~l)-5-(I-methylIH-tetrazol-5-yl)-3-pyridinecarbox~~late
congestive heart failure.
We are grateful to the Medical Research Council of Canada (Grant No.
MT-8892) for financial support of this research. The authors would also like
to acknowledge the technical assistance of C.-A. McEwen.
IR (KBr): v = 3262 cm-' (NH), 1690 (C=O), 1515 and 1440 (C=N), 1385
(N=N).- 'H NMR (DMSO-&): 6 I S O and 2.37 (twos, 3H each, C-2 and C-6
Me's), 3.35 (s, 3 H, NMe), 3.40 (s, 3 H, OMe), 4.83 (s, 1 H, H-4), 7.38 (dd,
53.4=7.5,54,5=7.5Hz, 1 H,phenyIH-4),7.48(d,J5.6=7.5Hz, I H,phenyl
H-6), 7.67-7.74 (m, 2 H, phenyl H-3 and H-5). 8.97 (s, 1 H, NH).
h Vitro Calcium Channel Antagonist and Agonist Assays
Melting points were determined using a Thomas-Hoover capilliary apparatus and are uncorrected. 'H NMR spectra were recorded on a Bruker
AM-300 spectrometer. The assignment of exchangeable protons (NH) was
confirmed by the addition of [D2]H20. Infrared spectra were acquired using
a Nicolet 5DX-FT spectrometer. Silica gel column chromatography was
carried out using Merck 7734 (60-200 mesh) silica gel. Microanalyses were
within 0.4% of theoretical values for all elements listed, unless otherwise
stated. Methyl (9a) and isopropyl 3-aminocrotonate (9b) were purchased
from the Aldrich Chemical Co. 5-(2-Oxoprop I) 1H tetrazole (lOa)"" and
l-methyl-5-(2-oxopropyl)-lH-tetrazole (lob)$] were prepared according to
the reported procedures.
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, I .6 x lo-' M) Ca2+dependent
contraction (tonic response) of guinea pig ileum longitudinal smooth muscle
(GPILSM) using the procedure reported previo~sly."~'The ICso value
(+ SEM, n = 3) was determined graphically from the dose-response curve.
Calcium channel agonist activity (positive inotropic effect) was calculated
as the percentage increase in contractile force of isolated guinea pig left
atrium (GPLA) relative to its basal contractile force in the absence of test
General Method for the Preparation of Alkyl 1,4-Dihydro-2,6-dimethyl-4[I]
(pyridinyl or 2-trijluoromethylphenyl)-5-(IH-tetrazol-5-yl)-3-pyridinecarboxylates 11-14
A mixture of the respective aldehyde Sa, 8b, Sc, or 8d (1 mmol), the
respective alkyl 3-aminocrotonate 9a or 9b ( I rnmol) and the respective
1H-tetrazol-5-yl compound 1Oa or 10b (1 mmol) in ethanol (20 ml) was
refluxed for 14h. Removal of the solvent in vacuo afforded an oil-like residue
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M. Schrarnm, G. Thomas, R. Towart, G. Franckowiak, Nature 1983,
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Received: July 21, 1995 [FF943]
Arch. P h m . (Weinheim)328, 75&754 (1995)
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channel, alkyl, dihydro, effect, synthesis, tetrazoles, trifluoromethylphenol, pyridinecarboxylates, pyridinyl, calcium, modulation, dimethyl
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