3 Amlodipine (Novasc)

Cl
MeO2C CO2Et
SO3
O
Me N NH3
H
1, amlodipine besylate (Norvasc)

USAN: Amlodipine Besylate

Brand Name: Norvasc (Pfizer)
Molecular Weight: 567.06 (Parent 408.88)
FDA Approval: 1990
Drug Class: 1,4-Dihydropyridine Calcium Channel Blocker
Indications: Treatment of Hypertension and Angina Pectoris
Mechanism of Action: Calcium Channel Blocker (Inhibition of the
Trans-membrane Influx of Calcium Ions into
Vascular Smooth Muscle and Cardiac Muscle
with Peripheral Arterial Vasodilatation)

■■ 1  H I S T O R Y

Hypertension (high blood pressure) is estimated to afflict 1 billion individuals

worldwide and is a major risk factor for stroke, coronary artery disease, heart
failure, and end-stage renal disease.1 The first class of drugs to treat hypertension
was the mercurial diuretics, discovered by Alfred Vogl in 1919 in Vienna.2 Diuret-
ics, by removing fluid from the body, reduce the pressure on the heart. Mercurial
diuretics revolutionized the treatment of congestive heart failure resulting from
severe edema and were the primary treatment until the late 1950s, when thiazide
diuretics emerged. In 1957, Merck chemist Frederick C. Novello prepared chloro-
thiazide (2, Diuril), a potent diuretic that does not cause elevation of bicarbonate
excretion, an undesired side effect associated with mercurial diuretics.3 Shortly
after chlorothiazide’s (2) success, George deStevens at Ciba reduced a double bond
on chlorothiazide (2) to a single bond to give hydrochlorothiazide (3, HydroDiu-
ril) which was 10-fold more potent than the prototype 2.4 Hydrochlorothiazide
was introduced to medical practice in 1959 and within a short time became the
drug of choice for the treatment of mild hypertension.
One of the liabilities of these drugs is thiazide diuretic-induced hyperglycemia.

37
38  ■  Cardiovascular Drugs

O O O O O O O O
S S S S
H2N NH H2N NH

Cl N Cl N
H
2, chlorothiazide (Diuril) 3, hydrochlorothiazide (HydroDiuril)

As early as 1948, Raymond P. Ahlquist at the Medical College of Georgia specu-

lated that there were two types of adrenergic receptors (adrenoceptors in short),
which he termed α-adrenoceptor and β-adrenoceptor, that are 7-transmembraned
protein as GPCR.5 In 1957, Irwin H. Slater and C. E. Powell at Eli Lilly prepared
dichloroisoprenaline (DCI, 4), the dichloro analog of isoprenaline; it was later
found to be the first selective β-adrenoreceptor blocking reagent, also known as a
β-blocker. However, DCI was not further pursued as a drug candidate because it
had a marked undesirable stimulant effect on the heart, an intrinsic sympathomi-
metic action (ISA).6 Beginning in 1958, James Black at Imperial Chemical Indus-
tries (ICI) led a team to look for β-blockers that were devoid of the stimulant effect
on the heart. In 1962, the first selective β-adrenoreceptor inhibitor pronethalol (5)
was discovered but was withdrawn from further development when it was found
to cause thymic tumors in mice. ICI eventually in 1964 produced a drug propran-
olol (6, Inderal), which possessed a better efficacy and safety profile.7 Propranolol
(6) is now widely used in the management of angina, hypertension, arrhythmia,
and migraine headaches. Two additional β-blockers, atenolol (Tenormin) and
practolol (Dalzic), were later discovered and marketed by ICI. Dozens of “me-too”
selective beta-blockers have since been discovered and marketed.

Me
OH OH
H H O N Me
Cl N Me N Me H
OH
Me Me
Cl
4, dichloroisoprenaline (DCI) 5, pronethalol 6, propranolol (Inderal)

Angiotensin converting enzyme (ACE) inhibitors are widely used to treat hy-
pertension, congestive heart failure, and heart attacks. The MOA of ACE inhibi-
tors is through inhibiting ACE in the renin–angiotensin system (RAS), which is
the master regulator of blood pressure and cardiovascular function. RAS provided
numerous targets for pharmacologic intervention (Fig. 3.1).11 Although renin cat-
alyzes the first and rate-limiting step (see 12 below) in the activation of the RAS, it
was the inhibition of the downstream ACE that first established the clinical rele-
vance of this pathway in the treatment of hypertension.
David Cushman and Miguel A. Ondetti at the Squibb Institute isolated teprot-
ide, a nonapeptide, from the poisonous venom extract of the Brazilian pit viper
 Amlodipine (Novasc)  ■  39

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu—Val-Ile...
Angiotensinogen renin

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe—His-Leu
Angiotensin I ACE

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe +
Angiotensin II
AT1 receptor

vasoconstriction, aldosterone release, sodium resorption

Fig. 3.1.  The Renin–Angiotensin System (RAS) as the Master Regulator of Blood Pressure11

Bothrops jararaca. Using teprotide, a potent ACE inhibitor in vitro, as a starting

point, Cushman and Ondetti curtailed the molecule, replaced its carboxylate
group with a thiol (–SH), and achieved a 2,000-fold increase in potency in ACE
inhibition. The resulting drug became the first oral ACE inhibitor, captopril (7,
Capoten).8 Merck scientists led by Arthur A. Patchett discovered the second oral
ACE inhibitor, enalapril (8, Vasotec), which has been on the market since 1981.9
Another popular ACE inhibitor is Parke-Davis’s quinapril hydrochloride (9, Ac-
cupril), launched in 1991.10

EtO O
Me
EtO O O
Me N O
H
O O N
HO2C N OH
H O
N SH N
Me OH
7, captopril (Capoten) 8, enalapril (Vasotec) 9, quinapril (Accupril)

Also as shown in Fig. 3.1, angiotensin II is a potent vasoconstrictor; blocking its

action would result in vasodilation. DuPont-Merck Pharmaceuticals discovered
the first inhibitor of the angiotensin II receptor, losartan (10, Cozaar), which after
its launch in 1995 quickly became one of the most important drugs for the treat-
ment of high blood pressure.12 Other angiotensin II receptor antagonists (also
known as angiotensin receptor blockers, or ARBs) include Novartis’s valsartan
(11, Diovan),12 Sanofi-Aventis’s irbesartan (Avapro), AstraZeneca’s candesartan
(Atacand), and Boehringer-Ingelheim’s telmisartan (Micardis). They all proved to
be superior to ACE inhibitors because they did not cause the irritating cough that
occurs in a small percentage of patients taking ACE inhibitors.
40  ■  Cardiovascular Drugs

Cl
N CO2H N NH
OH Me N N
N N
N N
N NK Me
O
Me

Me
10, losartan (Cozarr) 11, valsartan (Diovan)

Since renin is extremely specific for angiotensinogen and is the first and rate-
limiting enzyme of the RAS, renin inhibition was recognized for decades as an
attractive approach for the treatment of hypertension and hypertension-related
target organ damage. Novartis’s aliskiren (12, Tekturna) is the first and the only
renin inhibitor on the market for treatment of hypertension, and has been since
2007.11

MeO
OH i-Pr Me Me
H
H2N N NH2

O O O

MeO i-Pr 12, aliskiren (Tekturna)

OMe

S
Me O
Me CN Me Me
N
MeO N OMe O

MeO OMe Me N
13, verapamil Me 14, diltiazem

The concept of calcium channel blockers (CCBs), also known as calcium chan-
nel antagonists or calcium entry blockers, was developed several years after some
CCBs including phenylalkylamines such as verapamil (13), perhexiline, and pre-
nylamine; and benzodiazepines such as diltiazem (14) were discovered. Albrecht
Fleckenstein at University of Freiburg in Germany and Winifred G. Nayler helped
to elucidate the mechanism of action (MOA) of those structurally diversified
drugs as CCBs.13
In 1969, Bayer Company investigated the pharmacology of Bay-a-1040 (15, ni-
fedipine) and Bay-a-7168 (niludipine). Both compounds were strong coronary
vasodilators and exerted significant negative inotropic effects on the myocardium.
With Fleckenstein’s help, Bayer elucidated their MOA as CCBs. Nifedipine (15,
 Amlodipine (Novasc)  ■  41

Adalat) heralded the beginning of one of the most important classes of calcium
antagonists: 1,4-dihydropyridines.13

NO2 Cl
MeO2C CO2Me MeO2C CO2Et
SO3
Me N Me O
Me N NH3
H H
15, nifedipine (Adalat), t1/2 ~ 1 h 1, amlodipine besylate (Norvasc), t1/2 ~ 34 h

Bayer’s nifedipine (15, Adalat), known as a first-generation CCB, is a short-acting

CCB with a short plasma half-life (in the range of 0.5 to 2 h). Therefore, Adalat has
to be taken 3 or 4 times a day to elicit 24-h blood pressure control. Efforts to im-
prove bioavailability resulted in the second-generation CCBs, including isradipine
(t1/2 ~2 h), nicardipine (t1/2, ~5 h), and felodipine (t1/2, ~10 h). Pfizer’s amlodipine
(1, Norvasc), launched in 1990, belongs to the third-generation of CCBs. It has a
high bioavailability (64%) and a longer half-life (~45 h) in plasma, so it can be
taken once daily.14 All of these features made amlodipine (1, Norvasc) the most
prescribed antihypertensive agent in the world in 2003 with an annual sale of $4.3
billion. The worldwide sales of calcium channel blockers totaled $6 billion that
year.

■■ 2  P H A R M A C O L O G Y

2.1  Mechanism of Action

Inside a normal cell, the concentration of free Ca2+ ions is low (10–7 M) in compar-
ison to that of the extracellular fluid (1–2 mM). The concentration may be regu-
lated by opening or closing of the calcium channels. Calcium channels are opened
temporarily by exogenous impulses, whereby the calcium ion concentration rises
briefly and Ca2+ ions are bound to calcium-binding proteins (calmodulin). The
activated calmodulin elicits actual reactions in the cell and the increased calcium
concentration is reduced rapidly to the initial value by uptake of Ca2+ ions into in-
tracellular reserves.
The calcium channel, located on the cell membrane, is an ion channel that is
selectively permeable to calcium ions (Fig. 3.2). Since the results of calcium ions
entering the cell membrane include contraction of smooth muscle cells, blocking
the entrance of calcium ions into the cell would result in vasodilation, thus lower-
ing the blood pressure. When a CCB enters the opening of a calcium channel, the
drug figuratively gets stuck, like a fat man caught halfway through a porthole, thus
preventing calcium ions from getting through the channel.
Amlodipine (1, Norvasc) and other CCBs inhibit the influx of Ca2+ ions into
cells without affecting inward Na+ or outward K+ currents to a significant degree.
42  ■  Cardiovascular Drugs

Ca2+

SS

Fig. 3.2.  The Calcium Channel

The sizes of Ca2+, Na+, and K+ are quite different so selectivity might be relatively
easier to achieve if the drug is not too small.
Amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing
total peripheral resistance and hence reducing blood pressure; in angina, it in-
creases blood flow to the heart muscle. In vitro, amlodipine (1) inhibits Ca2+-in-
duced contractions of depolarized rat aorta with an IC50 of 1.9 nM, which is twice
as potent as nifedipine (15, IC50 of 4.1 nM).16
Calcium channel blockers selectively slow or block the movement of the cal-
cium ion into muscle cells via L-type voltage-gated calcium channels. The selec-
tivity of their pharmacological effects appears to arise in particular because of the
abundance of L channels in cardiac and smooth muscle. Dihydropyridines such as
amlodipine (1) may also inhibit cyclic nucleotide phosphodiesterases (PDE). The
dual capacity of the dihydropyridines to decrease cytosolic Ca2+ and to increase
extracellular Ca2+ may contribute to their greater effects on vascular relaxation.

2.2  Structure–Activity Relationship

The structure–activity relationship (SAR) of the 1,4-dihydropyridines as CCBs has

been extensively investigated.17 As shown in Fig. 3.3, the NH group is critical to its
activity, which is present on all 1,4-dihydropyridine CCBs. The R group at the C-2
position is alkyl (mostly methyl) in the majority of first- and second-generation
1,4-dihydropyridine CCBs. Amlodipine (1) carries a basic amine (pKa, 8.6) group
at the C-2 position, which is likely to contribute to its long half-life (~45 h) as well
as its high bioavailability (64%). The ester function at the C-3 position seems to be
able to accommodate a large variety of esters, α,β-unsaturated esters, and long-
chain esters with bulky groups. As far as the C-4 aryl substitution is concerned, the
o-group apparently prefers to be electron-withdrawing, as exemplified by the –Cl
on amlodipine (1) and the –NO2 on nifedipine (15). In addition, a fused bicyclic
aryl group is also tolerated as exemplified by isradipine (not shown) with its
benzo[c][1,2,5]oxadiazole group. Finally, the ester function at C-5 seems to be op-
timal in comparison to ketones, nitrile, and proton.
 Amlodipine (Novasc)  ■  43

p substituents o > m >> p

m electron-withdrawing >
electron-releasing
o
ester function optimum R1O2C CO2R2 bulk tolerance
−CO2R > COMe > CN > H selectivity?
Me N R
H
R = small alkyl, amine, aminoalkyl
critical

Fig. 3.3.  The Structure–Activity Relationship (SAR) of the 1,4-Dihydropyridines

Like most of the newer CCBs, amlodipine (1) also has two different ester sub-
stituents and thus is sold as a mixture of isomers. Initial work on the analysis of the
2 possible isomers suggested that the R isomer (+)-1 was more potent than the
corresponding S isomer (–)-1; this suggested that amlodipine (1) differs in this
respect from other dihydropyridine CCBs in which the S isomer is usually the
more active. A more recent preparation of the (–)-(1S)-camphanic derivatives of
amlodipine (1) and the subsequent X-ray of its derivatives clearly showed that it is
the S derivative that is more active.18

Cl
MeO2C CO2Et

O
Me N NH2
H
Cl
(+)-1, (+)-(R)-amlodipine
MeO2C CO2Et

O
Me N NH2
H Cl
MeO2C CO2Et
(±)-1, (±)-amlodipine
O
Me N NH2
H
(−)-1, (−)-(S)-amlodipine

2.3  Bioavailability, Metabolism, and Toxicology

One unique feature of amlodipine (1) is that its 1,4-dihydropyridine ring carries a
basic amine (pKa, 8.6) group at the C-2 position. This renders the molecule >90%
ionized at physiologic pH, and this feature is believed to be primarily responsible
for the marked difference in physicochemical and pharmacokinetic properties dis-
played by amlodipine (1) as compared to other 1,4-dihydropyridines.
Initial evaluation of amlodipine (1) pharmacokinetics in dogs, mice, and rats
indicated absolute bioavailability of 88%, 100%, and 100%, respectively.19 Their
corresponding calculated half-lives are 30 h, 11 h, and 3 h, respectively.
44  ■  Cardiovascular Drugs

Single-dose pharmacokinetics in healthy male subjects after 10-mg intravenous

injection indicated clearance of 7 mL/min/kg, volume of distribution by the area
method of 21 L/kg, and calculated elimination half-life of 34 h. Absolute bioavail-
ability of amlodipine (1) was determined by comparison of a single 10-mg oral
dose (the highest dosage approved by the FDA) to the intravenous dose and was
estimated to be 64%.20
Amlodipine (1) shows a preference for binding vascular smooth muscle cells
over cardiac muscle cells, thus acting as a peripheral arterial vasodilator. Like most
other CCB dihydropyridines, amlodipine (1) is highly protein-bound (98%) and
heavily metabolized. In contrast to felodipine, amlodipine (1) is not influenced by
grapefruit juice and appears to show fewer DDI.21
The major metabolic pathway for amlodipine (1) is oxidation by CYP450 to the
corresponding pyridine 16, which is not active. All 1,4-dihydropyridines undergo
similar metabolism to produce inactive pyridyl metabolites.22

Cl
Cl
MeO2C CO2Et
CYP450 MeO2C CO2Et
O
Me N NH2 O
H Me N NH2
(±)-amlodipine [(±)-1] 16, inactive

Besides being effective on left ventricular hypertrophy, CCBs in general appear

to be beneficial in slowing the progression of carotid hypertrophy and atheroscle-
rosis. They are widely used in the treatment of high blood pressure, angina and
rapid heartbeat (tachycardia) including arterial fibrillation.
The long duration of action makes amlodipine ideal for long-term treatment of
hypertension. Moreover, it is safe and gradually reduces blood pressure. This is a
good attribute, because reducing blood pressure too quickly can cause fainting
spells, which happens with some of the 1,4-dihydropyridine calcium antagonists.
The adverse effects reported with amlodipine (1) are peripheral edema in 8.3%
of users; fatigue in 4.5% of users; dizziness, palpitations, muscle-, stomach-, or
headache, dyspepsia, and nausea in 1% of users.23 Amlodipine (1) is contraindi-
cated in breast feeding women and in patients with cardiogenic shock, unstable
angina, and aortic stenosis, because amlodipine (1) causes vasodilatation which
can result in reduced cardiac output in patients with severe aortic stenosis.

■■ 3  S Y N T H E S I S

3.1  Discovery Route

The discovery synthesis of amlodipine (1) is outlined in Scheme 1, whose key step
is a Hantzsch condensation of three-components.17,18, 23
 Amlodipine (Novasc)  ■  45

O
CO2H O Me
HO NaH, THF, ClCH2CO2Na
N3 O Me
N3 O
TBA-I, reflux, 24 h, 47%
17 O

O O MeO2C
CDI, HOCH2CH2CN CN Cl
O
pyr., CH2Cl2, rt Me NH2 CHO
O
overnight, 48% N3 18 19 20

Cl
EtOH, reflux MeO2C CO2CH2CH2CN 1 M NaOH, diglyme
2 h, 41% O rt, 2 h, 74%
Me N N3
H
21

1. NaOEt, diglyme
Cl EtOH, reflux, 1 h
MeO2C CO2H 2. H2, 5% Pd/CaCO3, EtOH amlodipine
besylate (1)
O 3. PhSO2Cl, Et3N, CH2Cl2
Me N N3 rt, overnight, 75%
H 22

Scheme 1. Discovery Synthesis of Amlodipine Besylate (1)17

An SN2 displacement of sodium chloroacetate with sodium azidoethoxide was

accomplished with the aid of tetrabutylammonium iodide (TBA-I) as a phase-
transfer catalyst (PTC) to afford (2-azidoethoxy)acetic acid (17). Esterification of
acid 17 with 3-hydroxypropionitrile was helped with Meldrun’s acid to give ester
18. The crucial Hantzsch condensation of ester 18 with (E)-methyl 3-aminobut-
2-enoate 19 and o-chlorobenzaldehyde (20) delivered 1,4-dihydropyridine 21.
After hydrolysis of ester 21 with 1 N NaOH to give acid 22, treatment of 22 with
NaOEt afforded the ethyl ester, which was hydrogenized to the corresponding
amine using catalytic palladium on calcium carbonate or zinc and acetic acid.
A number of salts of amlodipine (1) have been prepared, but the final commercial
compound was obtained by treating the intermediate amine with benzenesulfonic
chloride to prepare the corresponding besylate salt (1).24

3.2  Process Route

One of Pfizer’s process preparations of amlodipine (1) is outlined in Scheme 2.23–26

In this case, methyl-2-(2-chlorobenzylidene)acetoacetate (25) was prepared via
46  ■  Cardiovascular Drugs

CO2Et CO2Et
CO2Et
HOCH2CH2N3 O NH4OAc, EtOH H2N

O O O
NaH, THF, rt reflux, 1 h
Cl 16 h, 73% 23 N3 24 N3

Cl
Cl EtOH, reflux
+ MeO2C MeO2C CO2Et
5.5 h, 75%
O
2 steps Me N N3
Me O H
25 26

Cl
1. H2, 5% Pd/CaCO3, EtOH MeO2C CO2Et
SO3
2. PhSO2Cl, Et3N, CH2Cl2 O
Me N NH3
rt, overnight, 75% H
1, amlodipine besylate (Norvasc)

Scheme 2. Pfizer Process Synthesis of Amlodipine Besylate (1)23

Knoevenagel condensation of methyl acetoacetate and 2-chlorobenzaldehyde.

Meanwhile, ethyl-4-(2-azidoethoxy)acetoacetate (23) was prepared via an SN2
reaction from the sodium salt of 2-azidoethanol and ethyl-4-­chloroacetoacetate.
Intermediate azide 23 was then treated with ammonium acetate to give en-
amine 24. The Hantzsch condensation of 24 with Knoevenagel adduct 25 then
furnished the dihydropyridine 26. After recrystallization, the azide functionality
of 26 was reduced to the corresponding amine by using hydrogen and catalytic
palladium on calcium carbonate or zinc and acetic acid to give the intermediate
amine, which was treated with benzenesulfonic acid to prepare the corresponding
besylate salt 1.23
To overcome the real or the perceived safety issues associated with azide inter-
mediates, an alternative process route not involving azide was explored.25

CO2Et

MeO2C i-PrOH
O
O
Cl O reflux, 21 h
Me NH2 N
CHO
27 28
O
 Amlodipine (Novasc)  ■  47

Cl
MeO2C CO2Et MeNH2 in MeOH PhSO2Cl
O 1
O or NH2NH2•H2O
Me N N
H or KOH followed by HCl
29
O

Scheme 3. Pfizer Process Synthesis of Amlodipine Besylate (1)25

■■ 4  C O N C L U D I N G R E M A R K S

The last 50 years saw tremendous advances in the number of treatments available
for managing hypertension, angina, and related coronary artery diseases: diuretics,
beta-blockers, ACE inhibitors, ARBs, renin inhibitor, and CCBs. Among CCBs,
amlodipine (1, Norvasc) and other long-acting 1,4-dihydropyridines have the ad-
ditional advantage of only requiring a once-daily dosing regimen.
Unfortunately, despite the availability of a wide range of antihypertensive med-
ications, about 45.5% of treated patients in the US fail to achieve a blood pressure
control target of <140/90 mmHg. Since the detrimental ramifications of hyperten-
sion include damage to the arteries, heart, kidneys, and brain, there is still a large
unmet medical need in the field of antihypertensives. One recent trend is the com-
bination pill. For instance, Pfizer combined amlodipine (1, Norvasc) with atorvas-
tatin (Lipitor, see Chapter 1) and sold it as one pill under the trade name Caduet.

■■ 5  R E F E R E N C E S

1. (a) Mancia, G.; Grassi, G. J. Hypertens. Suppl. 1998, 16, S1–S7. (b) Prichard, B. N.
Drugs 1988, 35(Suppl 6), 40–52.
2. Vogl, A. Am. Heart. J. 1950, 39, 881–883.
3. Beyer, K. H. Persp. Biol. Med. 1977, 20, 410–420.
4. deStevens, G. J. Med. Chem. 1991, 34, 2665–2670.
5. Ahlquist, Raymond P. Ann. Rev. Pharmacol. 1968, 8, 259–272.
6. Powell, C. E.; Slater, I. H.; LeCompte, L., Jr.; Waddell, J. E. J. Pharmacol. Exp. Ther.
1958, 122, 480–488.
7. Crowther, A. F. Drug Des. Deliv. 1990, 6, 149–156.
8. Smith, C. G.; Vane, J. R. FASEB J. 2003, 17, 788–789.
9. Patchett, A. A. J. Med. Chem. 2002, 45, 5609–5616.
10. Klutchko, S.; Blankley, C. J.; Fleming, R. W. et al. J. Med. Chem. 1986, 29, 1953–1961.
11. Cee, V. in Modern Drug Synthesis, Li, J. J.; Johnson, D. S., Eds, Wiley: Hoboken, NJ
2010, pp. 141–158.
12. Yet, L. Advances in the development of methods for the synthesis of antihypertensive
drugs (angiotensin At1 antagonists) in The Art of Drug Synthesis, Johnson, D. S.; Li, J. J., Eds,
Wiley: Hoboken, NJ, 2007, pp. 129–141.
48  ■  Cardiovascular Drugs

13. (a) Fleckenstein-Grün, G. High Blood Pressure, 1994, 3, 284–290. (b) Goldmann,
S. Pharmazie 2005, 34, 366–373.
14. Epstein, B. J.; Vogel, K.; Palmer, B. F. Drugs 2007, 67, 1309–1327.
15. Hanlon, M. R.; Berrow, N. S.; Dolphin, A. C.; Wallace, B. A. FEBS Lett. 1999, 445,
366–370. Burges, R. A.; Dodd, M. G.; Gardiner, D. G. Am. J. Cardiol. 1989, 64, 10I–20I.
16. Triggle, D. J. Ion Channels, in A Textbook of Drug Design and Development,
Krogsgaard-Larsen, P.; Bundgaard, H., Eds, Harwood Academic Publishers: Chur, Switzerland,
1991, pp. 357–386.
17. Arrowsmith, J. E.; Campbell, S. F.; Cross, P. E.; Stubbs, J. K.; Burges, R. A.; Gardiner,
D. G.; Blackburn, K. J. J. Med. Chem. 1986, 29, 1696–1702.
18. Abernethy, D. R. Am. Heart J. 1989, 118, 1100–1103.
19. Murdoch, D.; Heel, R. C. Drugs 1991, 41, 478–505.
20. Josefsson, M.; Zackrisson, A. L.; Ahlner, J. Eur. J. Clin. Pharmacol. 1996, 51, 189–193.
21. Beresford, A. P.; McGibney, D.; Humphrey, M. J.; Macrae, P. V.; Stopher, D. A.
Xenobiotica 1988, 18, 245–254.
22. Osterloh, I. H. J. Cardiovas. Pharmacol. 1991, 17(Suppl 1), S65–S68.
23. Davison, E.; Wells, J. I. (to Pfizer, Inc.). Pharmaceutically Acceptable Salts. US
4,879,303 (1989).
24. Campbell, S. F.; Cross, P. E.; Stubbs, J. K. (to Pfizer, Inc.). Dihydropyridine Anti-
Ischemic and Antihypertensive Agents and Pharmaceutical Compositions Containing Them
EP 89167 (1983).
25. Campbell, S. F.; Cross, P. E.; Stubbs, J. K. (to Pfizer, Inc.). 2-(Secondary Amino­
alkoxymethyl)-Dihydropyridine Derivatives as Anti-Ischaemic and Antihypertensive Agents.
US 4,572,909 (1986).