Note: Descriptions are shown in the official language in which they were submitted.
W094/07476 PCT/US93/09463
MET~ODS AND COMPOSITIONS FOR TREATING
HYPERTENSION, ANGINA AND OTHER DISORDERS
USING OPTICALLY PURE S(-) NITRENDIPINE
This application is a continuation-in-part of
U.S. application Serial No. 07/492,647, filed March
13, 1990.
1. TECHNICAL FIELD
This invention relates to novel compositions of
matter containing optically pure S(-) nitrendipine.
These compositions possess potent activity in treating
both systolic and diastolic hypertension while
avoiding adverse effects including but not limited to
insulin resistance, edema of the extremities,
headache, dizziness, flushing and weakness which are
associated with administration of the racemic mixture
of nitrendipine. Additionally, these novel
compositions of matter containing optically pure S(-)
nitrendipine are useful in treating angina and such
2 other conditions as may be related to the activity of
S(-) nitrendipine as a calcium channel antagonist
including but not limited to cerebral ischemia,
cerebral disorders, arrhythmias, cardiac hypertrophy,
coronary vasospasm, myocardial infarction, renal
2 impairment and acute renal failure -- while avoiding
the adverse effects associated with administration of
the racemic mixture of nitrendipine. Also disclosed
are methods for treating the above-described
conditions in a human while avoiding the adverse
effects that are associated with the racemic mixture
of nitrendipine, by administering the optically pure
S(-) isomer of nitrendipine to said human.
W094/07476 PCT/US93/09463
2~4~5~5 - 2 - -
2. BACKGROUND OF THE INVENTION
2.1. Steric Relationship and Druq Action
Many organic compounds exist in optically active r
forms, i.e., they have the ability to rotate the plane
5 of plane-polarized light. In describing an optically
active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the
molecule about its chiral center(s). The prefixes d
and 1 or (+) and (-) are employed to designate the
10 sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is
levorotatory. A compound prefixed with (+) or d is
dextrorotatory. For a given chemical structure, these
compounds, called stereoisomers, are identical except
15 that they are mirror images of one another. A
specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often
called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the
20 field of pharmaceuticals, where 12 of the 20 most
prescribed drugs exhibit chirality. A case in point
is provided by the L-form of the ~-adrenergic blocking
agent, propranolol, which is known to be lOo times
more potent than the D-enantiomer.
Furthermore, optical purity is important since
certain isomers may actually be deleterious rather
than simply inert. For example, it has been suggested
that the D-enantiomer of thalidomide was a safe and
effective sedative when prescribed for the control of
morning sickness during pregnancy, while the
corresponding L-enantiomer has been thought to be a
potent teratogen.
The active compound of the present invention is
the S(-) isomer of the compound nitrendipine, which is
described in United States Patent No. 3,799,934.
~W094/07476 ~ 54~ PcT/us93/o9463
-- 3
Chemically, this compound is the S(-) isomer of 1,4-
dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-
- dicarboxylic acid ethyl methyl ester or ethyl 1,4-
dihydro-5-(acetoxycarbonyl)-2,6-dimethyl-4-(3-
nitrophenyl)-3-pyrindinecarboxylate. This isomer W7
hereinafter be referred to as S(-) nitrendipine. The
terms "S(-) nitrendipine" and "S(-) isomer of
nitrendipine" as used herein includes substantially
optically pure S(-) nitrendipine as well as optically
pure S(-) nitrendipine. Further, these terms as used
herein refers to any biologically acceptable form
thereof, such as a salt or ester of this compound.
2.2. Pharmacoloqic Action
Nitrendipine is a drug belonging to the general
class of compounds known as dihydropyridine calcium
channel blockers. This class of drugs has the
property of inhibiting the transmembrane influx of
calcium ions into cardiac and smooth muscle cells.
The contractile processes of cardiac and vascular
smooth muscle cells are dependent upon the movement of
extracellular calcium ions into these cells through
specific ion channels. Nitrendipine relaxes coronary
vascular smooth muscle, and exerts anti-hypertensive
activity at drug levels which cause little or no
weakening of cardiac contractility.
Nitrendipine is presently administered and is
available commercially only as the 1:1 racemic
mixture. That is, it is available as a mixture of
optical isomers, called enantiomers. As stated above,
enantiomers are structurally identical compounds which
differ only in that one isomer is a mirror image of
the other and the mirror images cannot be
superimposed. This phenomenon is known as chirality.
~6~ 4 - PCT/US93/09463
Dihydropyridine calcium channel blockers are also
known as calcium antagonists. The concept of a
specific mechanism of pharmacologic action related to
the antagonism of calcium movement in the process of
excitation-contraction was suggested by Fleckenstein
et. al. See Calcium Antagonism in Heart and Smooth
Muscle:Experimental Facts and Therapeutic Prospects,
New York, Wiley, 1983. (See also Swamy, V. and D.
Triggle, Modern Pharmacology, 2nd. Ed., Craig and
Stitzel, Eds., Little, Brown and Co., Boston, 1986,
Chapt. 26, 373-380; and Triggle, D.J., and R.A. Janis,
Ann. Rev. Pharm. and Tox. 27: 347-369, 1987). Many of
the currently available calcium antagonists appear to
antagonize the entry of calcium through voltage
dependent channels in the plasma membrane of cells.
The pharmacologic class of calcium antagonists
consists of chemically diverse compounds. Given the
structural heterogeneity of the class it is likely
that the pharmacological action involves more than one
site or mechanism of action.
Nitrendipine is one of a series of
dihydropyridine calcium antagonists. Its ability to
block calcium channels in smooth muscle produces
peripheral vasodilation resulting in decreases in both
systolic and diastolic blood pressure in hypertensive
animals and humans.
With regard to the enantiomers of nitrendipine,
these are disclosed in Mikus et al. Eur. ~. Clin.
Pharmac. 36 (Suppl.):A179 (1989). This abstract
reports that S(-) nitrendipine alone is responsible
for the pharmacological effects observed in six
healthy humans. The abstract further alleges that
racemic nitrendipine exhibits stereoselective first
pass metabolism with a possible interaction of the
enantiomers when it is administered as a racemate.
W O 94/07476 2 1 4 ~ ~4 5 PC~r/US93/09463
_ 5
However, O'Neill et al. Proc. West Pharmacol. Soc. 33:
235-241 (l990) states that t3H]-nitrendipine is a
racemic mixture of two enantiomers with only minimal
difference, <5 fold, in their affinity for
dihydropyridine (DHP) receptors. Moreover, Soons et
al. Clin. Pharmacol . Ther. 47(2): 158 (1990) report a
marked difference in the AUC of the enantiomers of
nitrendipine, which they report is most likely due to
stereoselective first-pass metabolism. Furthermore,
Eltze et al. Chirality 2: 233-240 (1990) report that
the enantiomers of nitrendipine effectively inhibit
vasoconstriction due to the TxA2-mimetic U-46619 in
guinea pig Langendorff hearts, displace (+) [3H]
isradipine from calcium channel-binding sites in
guinea pig skeletal muscle T-tubule membranes, and
decrease blood pressure in SHR with a similar rank
order of potency.
The racemic mixture of nitrendipine is presently
used primarily as an antihypertensive agent, and it is
generally taken orally as a once-daily therapy.
Pharmacologic management of hypertension is generally
directed to the normalization of altered hemodynamic
parameters, and many drugs and drug classes, either as
monotherapy or in combination treatment, can reduce
and control elevated blood pressure.
Furthermore, the racemic mixture of nitrendipine
is useful in treating other disorders such as angina
pectoris. Angina pectoris is a clinical syndrome
reflecting myocardial ischemia. A condition where
cardiac work or myocardial oxygen demand exceeds the
ability of the coronary arterial vascular system to
supply oxygen results in myocardial ischemia, which
may cause either a painful angina attack or an angina
attack that is not accompanied by pain (silent
ischemia). Under extreme circumstances, the lack of
W094/07476 PCT/US93/09463
2~ 45 - 6 - -
oxygen may cause a myocardial infarction or cardiac
arrhythmias. The treatment of angina is directed to
the underlying disease, usually atherosclerosis, or to
drugs which either reduce myocardial oxygen demand or
improve oxygen supply. Calcium antagonists such as
nitrendipine have been particularly useful in treating
vasospastic angina, the angina of effort, and the
unstable angina, due to the effect of the calcium
channel antagonist on cardiac and vascular smooth
muscle.
Nitrendipine may be useful in the treatment of
cerebral ischemia. Cerebral ischemia, often the
result of atherosclerotic disease or hypertension,
results from insufficient cerebral circulation. Under
normal circumstances, an extensive collateral
circulation ensures adequate blood flow. However,
cerebral ischemia may result from either an intra- or
extracranial interruption of arterial blood flow
caused by atherosclerosis or arterial
vasoconstriction. If interruption is transient, the
cause is usually arterial vasoconstriction and a
calcium antagonist may be of therapeutic value. If
the ischemia lasts for a more extended period, it is
usually caused by carotid or cerebral atherosclerosis
that may be accompanied by a vasospecific condition
that can be treated with a vasodilating calcium
antagonist.
Because of its activity as a calcium channel
antagonist, nitrendipine may also be useful in
treating cardiac arrhythmias. Cardiac arrhythmias
represent a broad, complex group of electrophysiologic
disorders that effects the mechanical properties of
the heart and vasculature, altering normal cardiac
rhythm, function and output. Normal cardiac rhythm
originates as a calcium dependent action potential
W094t07476 2 1 ~ ~ ~4 S PCT/US93/09463
- 7 -
within the sinoatrial node, propagates through the
atria and passes as a calcium dependent potential
~ through the atrioventricular node and along the
purkinje fibers into the ventricles of the heart.
Adequate automaticity and conduction are necessary
elements of normal functional heart beat. Calcium
antagonists may be of value in conditions where
calcium-related changes in membrane potential and
conduction alter normal rhythm and in cases of
ischemia-induced cardiac arrhythmias.
Nitrendipine may be useful to treat cardiac
hypertrophy. Cardiac hypertrophy can result from
excessive workload either due to an obstruction to
outflow, termed systolic overload, or to excessive
volumes presented to the heart in diastole, termed
diastolic overload. Systolic overload results in
concentric ventricular hypertrophy, in which there is
an increased thickness in the walls of the heart not
associated with increased volume. Diastolic overload
causes dilation and hypertrophy with an increased
blood volume. An inadequate cardiac output results
from the heart's failure in systolic or diastolic
overload. Calcium channel antagonists dilate
peripheral capacitance blood vessels and thereby
reduce the amount of blood returning to the heart and
the risk for diastolic overload. Calcium antagonists
also dilate peripheral resistance blood vessels,
thereby reducing blood pressure (cardiac afterload)
and the risk for systolic overload.
Myocardial infarction may be precipitated by
coronary artery vasospasm or acute coronary
thrombosis. Calcium channel antagonists may find
utility in the management of myocardial infarction
patients due to "direct" anti-ischemic effects or due
W094/07476 PCT/US93/0946~
~4~5
to their effects on coronary artery vasospasm, blood
pressure or other cardiac or vascular functions.
Nitrendipine may be used to treat congestive
heart ~ailure. Congestive heart failure can be caused
by hypertension, cardiomyopathy, coronary artery
disease or valvular heart disease. Congestive failure
results in poor cardiac output and elevated left-
ventricular diastolic pressure, leading to dyspnea,
fatigue, peripheral edema, and coughing. The ability
of some calcium antagonists to lower arterial blood
pressure by dilating peripheral arteries without
having a significant inotropic effect may increase
their use in treating congestive heart failure.
Nitrendipine may be of use in treating migraine.
Classic migraine typically begins with visual auras
followed by severe headaches, often accompanied by
nausea and vomiting. Common migraine has similar
symptoms without the preceding visual aura. The
causes of migraine have been studied intensely, and
are still a matter of debate. The most generally
accepted cause is an initial cerebral
vasoconstriction, followed by a cerebral
vasodilatation. Calcium channel antagonists have been
used for migraine prophylaxis since they can inhibit
the initial vasoconstriction.
Nitrendipine may also be useful for treating
Raynaud's phenomenon, which is characterized by
vascular spasm of the extremities. These vasospasms
can be caused by cold or stress. A pallor or cyanosis
is usually present due to severe constriction of the
digital arteries. The phenomenon is often seen as a
secondary disorder with arterial diseases or
connective tissue diseases such as sclèroderma,
arthritis or lupus erythematosus. Calcium channel
~ 094/07476 ~I4~5 PCT/US93/09463
antagonists have been shown to be effective in
treating Raynaud's phenomenon.
Nitrendipine may be useful in the treatment of
asthma and bronchospasm. Symptoms of asthma -
coughing, wheezing, and dyspnea - are caused by
constriction of tracheobronchial smooth muscle.
Asthma attacks can be triggered by antigenic stimuli
(pollen, dust) or non-antigenic stimuli (exercise,
pollution, infection). The response to these stimuli
lead to secretions of chemical mediators that cause
smooth muscle contraction. Calcium channel
antagonists can cause relaxation of the bronchial
smooth muscles and thereby relieve or prevent asthma
attacks.
In addition, the racemic mixture of nitrendipine
may be useful to treat renal impairment and acute
renal failure. Renal impairment and acute renal
failure are clinical conditions of diverse etiology,
which are associated with an increasing azotemia or
urea nitrogen in the blood, and often an oliguria or a
diminished volume of urine in relation to fluid
intake. The pathophysiology may originate prerenally,
manifest as inadequate renal perfusion, due to
extracellular fluid volume depletion or cardiac
failure. The most common cause of intrinsic renal
failure is prolonged renal ischemia. Postrenal
azotemia may be associated with obstruction or renal
glomerular and tubular dysfunction. Laboratory
findings in patients with renal failure often disclose
progressive azotemia, acidosis, hyperkalemia, and
hyponatremia. Factors aggravating kidney impairment
or failure must be specifically treated, including
heart failure, obstruction and the like. Moderate or
severe hypertension has a deleterious effect on renal
function, and management of the hypertension with a
W094/07476~ ~6~ ~ PCT/US93/0946~
-- 10 --
variety of drugs including calcium channel antagonists
may be useful therapy.
In addition, the racemic mixture of nitrendipine
could be useful in the treatment of cognitive
disorders. Cognitive disorders include but are not
limited to dementia and age-associated memory
impairment.
Calcium antagonists such as nitrendipine may also
be used for the treatment of ocular (retinal)
ischemia, that often is the result of local
vasoconstriction.
Many calcium channel antagonists cause
significant adverse effects. These adverse effects
include but are not limited to tachycardia,
orthostatic hypotensiGn, fluid retention and insulin
resistance. The administration of the racemic mixture
of nitrendipine to a human has been found to cause
still other adverse effects. These adverse effects
include but are not limited to peripheral edemas,
headache, flushing, hot flashes, fatigue, weakness,
vertigo, muscle cramps, dizziness and gastro-
intestinal symptoms.
Thus, it would be particularly desirable to find
a compound with the advantages of the racemic mixture
of nitrendipine which would not have the
aforementioned disadvantages.
3. SUMMARY OF THE INVENTION
It has now been discovered that the
optically pure S(-) isomer of nitrendipine is an
effective antihypertensive agent for both systolic and
diastolic hypertension, particularly in mild to
moderate disease and angina, which avoids the adverse
effects including but not limited to insulin
resistance, edema of the extremities, headache,
W 0 94/07476 2 1 ~ 6 ~ ~ ~ PC~r/US93/09463
flushing, weakness and dizziness which are associated
with the administration of the racemic mixture of
nitrendipine. It has also been discovered that these
novel compositions of matter containing optically pure
S(-) nitrendipine are useful in treating other
conditions as may be related to the activity of S(-)
nitrendipine as a calcium channel antagonist,
including but not limited to cerebral ischemia,
cerebral disorders, arrhythmias, cardiac hypertrophy,
coronary vasospasm, myocardial infarction, renal
impairment and acute renal failure while avoiding the
above-described adverse effects associated with the
administration of the racemic mixture of nitrendipine.
The present invention also includes methods for
treating the above-described conditions in a human
while avoiding the adverse effects that are associated
with the racemic mixture of nitrendipine by
administering the S(-) isomer of nitrendipine to said
human.
The present invention relates to a method of
treating hypertension in an individual, comprising
administering to the individual a therapeutically
effective amount of the optically pure S(-) enantiomer
of nitrendipine which has anti-hypertensive activity.
The optically pure S(-) enantiomer is substantially
free of the R(+) enantiomer which lacks or has a lower
level of such activity. The present method is useful
in treating hypertension while reducing or avoiding
undesirable adverse effects, such as insulin
resistance, headache, flushing, dizziness, weakness,
and peripheral edema which are often associated with
administration of a racemic mixture of nitrendipine.
In these applications, it is important to have an
anti-hypertensive composition which minimize these
side effects. A composition containing the optically
W094/07476 PCT/US93/0946~
~ 5~ - 12 - -
pure S(-) isomer of nitrendipine having anti-
hypertensive activity is particularly useful for this
application because the S(-) isomer exhibits both of
these desired characteristics.
The present method provides a safe, highly
effective method for treating severe hypertension
while reducing undesirable adverse effects associated
with anti-hypertensive drugs, including the racemic
mixture of nitrendipine.
4. DETAILED DESCRIPTION O~ THE INVENTION
The present invention relies on the calcium
channel blocking activity of the optically pure S(-)
enantiomer of nitrendipine to provide enhanced calcium
channel antagonist activity, for example, for
treatment or prevention of hypertension, while
simultaneously avoiding many of the undesirable
adverse effects associated with anti-hypertensive
drugs including the racemic mixture of nitrendipine.
Such effects include but are not limited to insulin
resistance, headache, flushing, dizziness, weakness
and peripheral edema. In the present method, the
optically pure S(-) isomer of nitrendipine which
exhibits anti-hypertensive activity is administered
alone, or in combination with other drugs in
adjunctive treatment to an individual suffering from
hypertension.
The present invention encompasses a method of
treating hypertension in a human, while avoiding the
concomitant liability of adverse effects associated
with the racemic mixture of nitrendipine, which
comprises administering to a human in need of such
antihypertensive therapy, an amount of S(-)
nitrendipine or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer,
O 94/07476 ~ ~ 4 6 ~ 4 ~ PC~r/US93/09463
- 13 -
said amount being sufficient to alleviate
hypertension, but insufficient to cause said adverse
- effects associated with administration of racemic
nitrendipine.
The present invention also encompasses an
pharmaceutical composition for the treatment of
hypertension in a human in need of antihypertensive
therapy, which comprises an amount of S(-)
nitrendipine or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer,
said amount being sufficient to alleviate said
hypertension but insufficient to cause adverse effects
of racemic nitrendipine. The antihypertensive
composition may optionally contain a pharmaceutically
acceptable carrier.
The present invention further encompasses a
method of treating angina in a human, while avoiding
the concomitant liability of adverse effects
associated with the administration of racemic
nitrendipine, which comprises administering to a human
in need of anti-angina therapy, an amount of S(-)
nitrendipine, or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer,
said amount being sufficient to alleviate angina but
insufficient to cause said adverse effects associated
with administration of racemic nitrendipine.
In addition, the present invention encompasses an
pharmaceutical composition for the treatment of a
human having angina, which comprises an amount of S(-)
nitrendipine or a pharmaceutically acceptable salt
thereof, substantially free of its R(+) stereoisomer,
said amount being sufficient to alleviate angina but
insufficient to cause adverse effects associated with
the administration of racemic nitrendipine. ~The
2~
W O 94/07476 PC~r/US93/09463
- 14 -
antianginal composition may optionally contain a
pharmaceutically acceptable carrier.
A further aspect of the present invention
includes a method of treating a condition caused by
excessive calcium influx in cells in a human, while
avoiding the concomitant liability of adverse effects
associated with the administration of racemic
nitrendipine, which comprises administering to a human
in need of a reduction in excessive calcium influx, an
amount of S(-) nitrendipine, or a pharmaceutically
acceptable salt thereof, substantially free of its
R(~) stereoisomer, said amount being sufficient to
alleviate or prevent excessive calcium influx in cells
but insufficient to cause said adverse effects
associated with the administration of racemic
nitrendipine. Conditions caused by excessive calcium
influx in cells in a human include, but are not
limited to, cerebral ischemia, cerebral disorders such
as cognitive disorders including but not limited to
Alzheimer's dementia and memory impairment, retinal
ischemia, arrhythmias, cardiac hypertrophy, congestive
heart failure, coronary vasospasm, migraine,
bronchospasm and asthma, Raynaud's phenomenon,
myocardial infarction, renal impairment and acute
renal failure.
Furthermore, the present invention includes a
pharmaceutical composition for treating a condition
caused by excessive calcium influx in cells in a
human, which comprises an amount of S(-) nitrendipine,
or a pharmaceutically acceptable salt thereof,
substantially free of its R(+) stereoisomer, said
amount being sufficient to alleviate said condition
but insufficient to cause adverse effects associated
with the administration of racemic nitrendipine. This
~1~6~
W O 94/07476 PC~r/US93/09463
- 15 -
pharmaceutical composition may optionally contain a
pharmaceutically acceptable carrier.
The commercially available racemic mixture of
nitrendipine (e.q.., a 1:1 racemic mixture of the two
S enantiomers) demonstrates antihypertensive and
antianginal activity; however, this racemic mixture,
while offering the expectation of efficacy, causes
adverse effects. Utilizing the optically pure S(-)
isomer of nitrendipine results in clearer dose-related
definitions of efficacy, surprisingly diminished
adverse effects, and accordingly, an improved
therapeutic index. It is, therefore, more desirable
to use the optically pure S(-) isomer of nitrendipine.
The term "adverse effects of racemic
nitrendipine" or "adverse effects associated with the
racemic mixture of nitrendipine as used herein
includes, but is not limited to, cardiovascular
effects (including tachycardia and diminished
contractility of the heart), insulin resistance, edema
of the extremities, headache, dizziness, flushing,
fatigue, weakness, vertigo, and muscle cramps.
The term "substantially free of its R(+)
stereoisomer" as used herein means that the
composition contains a greater proportion or
percentage of the S(-) isomer of nitrendipine in
relation to the R(+) isomer of nitrendipine, said
percentage being based on the total amount of
nitrendipine in the composition. In a preferred
embodiment the term "substantially free of its R(+)
stereoisomer" means that the composition contains at
least 90% by weight of S(-) nitrendipine, and 10% by
weight or less of R(+) nitrendipine. In the most
preferred embodiment the term "substantially free of
the R(+) stereoisomer" means that the composition
contains at least 99% by weight S(-) nitrendipine, and
WO94/074762~ ~S ~ PCT/US93/0946
- 16 -
1% or less of R(+) nitrendipine. In another preferred
embodiment the term ~substantially free of its R(+)
stereoisomer" as used herein means that the
composition contains about 100% by weight of S(-)
nitrendipine. The terms "substantially optically pure
S(-) isomer of nitrendipine" and "optically pure S(-)
isomer of nitrendipine" are also encompassed by the
above-described meanings.
The term "a method of treating hypertension" as
used herein means providing a normalization to
otherwise elevated systolic and/or diastolic blood
pressure, and by so doing providing relief from any
possible symptoms or other hemodynamic effects caused
by the elevated pressure.
The term "a method of treating angina" as used
herein means relief from the symptoms of myocardial
ischemia, which include, but are not limited to,
episodes of precordial pressure, discomfort, or a
severe intense, crushing pain which may radiate, and
which may be accompanied by changes in respiration,
pulse rate, and blood pressure.
The term "a condition caused by excessive calcium
influx in cells in a human" includes but is not
limited to conditions involving calcium influx in
human cell that may be present in smooth muscle,
cardiac, and other tissues including lung and brain.
These conditions include, but are not limited to,
cerebral ischemia, cerebral disorders such as
cognitive disorders including Alzheimer's dementia and
memory impairment, retinal ischemia, arrhythmias,
cardiac hypertrophy, congestive heart failure,
coronary vasospasm, migraine, bronchospasm and asthma,
Raynaud's phenomenon, myocardial infarction, renal
impairment and acute renal failure. The symptoms
associated with these disorders include, but are not
W O 94/07476 PC~r/US93/09463
- 17 - 2~
limited to, the symptoms of precordial discomfort or
pain, headache, fatigue, decreased exercise tolerance,
syncope, shortness of breath, nausea, lightheadedness,
edema, pulmonary congestion, arrhythmia or
~ 5 palpitation, azotemia, and/or oliguria.
Optically pure S(-) nitrendipine can be prepared
in a number of ways. Among these methods, the
resolution of a racemic mixture of nitrendipine or its
precursors and the asymmetric synthesis of
nitrendipine or precursors thereof are particularly
useful. Resolution of a racemic mixture by fractional
crystallization of diastereomeric derivatives or salts
is perhaps the most straightforward method for
obtaining optically pure S(-) nitrendipine.
Optically active resolving agents are employed in
the resolution of these racemic mixtures of the
nitrendipine enantiomers which are obtained following
synthetic procedures known in the art (See, for
example, U.S. Patent No. 3.799,934.~. The resolution
of racemates by fractional crystallization of
diastereomeric salts formed with such resolving agents
is perhaps the most commonly used conventional
technique for producing optically pure compounds.
See, for example, "Stereochemistry of Carbon
Compounds," E.L. Eliel (McGraw-Hill, NY, 1986) and
"S.H. Wilen, p. 268, in "Tables of Resolving Agents
and Optical Resolutions," E.L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, IN, 1972.
Since nitrendipine is a basic compound,
diastereomeric salts suitable for separation by
fractional crystallization are readily formed by the
addition of chiral acid resolving agents in optically
pure form to racemic nitrendipine. Suitable resolving
agents for use here include optically pure tartaric
acid and its derivatives, camphorsulfonic acid,
W094/07476 ~ - 18 - PCT/US93/09463
mandelic acid and derivatives thereof, and other
optically active acids. The desired S(-) nitrendipine
isomer may be recovered either from the crystallized
diastereomer or from the mother liquor, depending on
the solubility properties of the particular acid
resolving agent employed and depending on the
particular acid enantiomer used. The identity of the
S(-) nitrendipine isomer so obtained may be confirmed
by polarimetry and other analytical methods.
A particular preferred means of obtaining S(-)
nitrendipine is based on the fractional
crystallization of diastereomeric mixtures formed by
basic resolving agents and racemic carboxylic-acid-
containing precursors of nitrendipine. See, for
example, T. Shibanuma et al., Chem. Pharm. Bull.
28(9): 2809-2812 (1980) (who resolved the structurally
related dihydropyridine nicardipine) and M. Eltze et
al., Chirality 2: 233-240 (1990) and references cited
therein. In particular, S(-) nitrendipine is obtained
by means of resolution of the corresponding racemic 4-
aryl-1-ethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2,6-
dimethylpyridine-3-carboxylic acids by means of
crystallization of the diastereomeric salts formed
upon addition of basic resolving agents to the racemic
precursor -- followed by subsequent alkylation and
esterification as described in International Patent
Applications WO 88/07524 and Wo 88/07525, Byk Gulden,
1988. Optically pure cinchonine and cinchonidine
salts are basic resolving agents that have proven
useful in the resolution of the dihydropyridines
including nitrendipine.
The chemical synthesis of the racemic mixture of
nitrendipine can be performed by the mèthod described
in U.S. Patent No. 3,799,934 as well as by other means
known to those skilled in the art. See, for example,
WO 94/07476 1 9 Z1 5 6 545 Pcr/usg3/o9463
Arrowsmith, J. E. et al., J. Med. Chem ., 29 : 1696-1702
( 1986) .
~N02
~J
H3C02C~2H
HsC N 3
1) cinrhoni~in~
2) fr~ n~lly cryst~lli7e
~2
C` 3~H
H8 N
HCI
2 0 ~N02
H3 C02C~!~C02H
H3 I H3
1) CDI
2) NaOEV~3tOH
~,N2
H3 C2 ~C~2 Et
H~ N H3
S - (-) - llit~n(~i
SUBSTITUTE SHE-~
W O 94/07476 ~ PC~r/US93/0946
The racemic acid ester is converted to its
cinchonidine salt in methanol solution. Upon dilution
with water and standing at room temperature, a
crystalline precipitate is formed which can be
subsequently recrystallized to constant rotation to
give the diastereomerically pure cinchonidine salt.
Further, the mother liquids from the original
crystallization can be reduced in volume and stirred
at room temperature, e.q. overnight, to afford a fine
precipitate which can also be recrystallized to give
the diastereomerically pure cinchonidine salt. The
cinchonidine salt is partitioned between ethyl acetate
and dilute hydrochloric acid to liberate the
enantiomerically pure acid. The acid is then
esterified using carbonyldiimidazole (CDI) and
ethanolic sodium ethoxide, yielding S~-) nitrendipine.
The magnitude of a prophylactic or therapeutic
dose of S(-) nitrendipine in the acute or chronic
management of disease will vary with the severity of
the condition to be treated and the route of
administration. The dose, and perhaps the dose
frequency, will also vary according to the age, body
weight, and response of the individual patient. In
general, the total daily dose ranges, for the
conditions described herein, is from about lo mg to
about 180 mg. Preferably, a daily dose range should
be between about 20 mg to about 120 mg, while most
preferably, a daily dose range should be between about
30 mg to about 90 mg. In managing the patient, the
therapy should be initiated at a lower dose and
increased depending on the patient's global response.
It is further recommended that children and patients
over 6S years, and those with impaired renal or
hepatic function, initially receive low doses, and
that they be titrated based on global response and
0 94/07476 ~ 1 ~ B ~ 5 PC~r/US93/09463
- 21 -
blood level. It may be necessary to use dosages
outside these ranges in some cases as will be apparent
to those skilled in the art. Further, it is noted
that the clinician or treating physician would know
S how and when to interrupt, adjust, or terminate
therapy in eonjunetion with individual patient
response.
The various terms "an amount sufficient to
alleviate hypertension but insufficient to cause said
adverse effects associated with the administration of
raeemie nitrendipine", "an amount sufficient to
alleviate angina but insufficient to cause said
adverse effeets assoeiated with the administration of
raeemie nitrendipine" "an amount suffieient to
alleviate ocular (retinal) ischemia, but insuffieient
to cause said adverse effeets assoeiated with the
administration of raeemie nitrendipine" and "an amount
suffieient to alleviate said condition but
insuffieient to eause said adverse effects assoeiated
with the administration of racemic nitrendipine"
wherein said eondition ineludes but is not limited to
eerebral isehemia, eerebral disorders, arrhythmias,
eardiac hypertrophy, eoronary vasospasm, myoeardial
infaretion, renal impairment and acute renal failure,
are encompassed by the above described dosage amounts
and dose frequency schedule.
In one embodiment of the present method, the
optieally pure S(-) isomer of nitrendipine is
administered to an individual suffering from
hypertension. For example, S(-) nitrendipine is
administered therapeutically to an individual to
reduce or ameliorate hypertension. In another
embodiment, optically pure S(-) nitrendipine ean be
administered prophylaetically to reduce the
probability of occurrence of hypertension.
W 0 94/07476 ~ 22 - PC~r/US93/0946
Any suitable route of administration may be
employed for providing the patient with an effective
dosage of (-) nitrendipine. For example, oral,
rectal, parenteral, ocular, subcutaneous, intravenous,
intramuscular, transdermal, and the like may be
employed. Dosage forms include tablets, troches,
dispersions, suspensions, solutions, capsules,
patches, and the like.
The pharmaceutical compositions of the present
invention comprise S(-) nitrendipine as active
ingredient, or a pharmaceutically acceptable salt
thereof, and may also contain a pharmaceutically
acceptable carrier, and optionally, other therapeutic
ingredients.
In the methods of the present invention, the
optically pure isomer of nitrendipine can be
administered along with one or more additional drugs.
For example, other anti-hypertensive agents, such as
thiazide-type diuretics and beta blockers, can be
given with or in close temporal proximity to
administration of optically pure nitrendipine. The
two (or more) drugs (optically pure S(-) nitrendipine
and another drug) can be administered in one
composition or as two separate entities. For example,
they can be administered in a single capsule, tablet,
powder, liquid, etc. or as individual compounds. The
components included in a particular composition, in
addition to optically pure S(-) nitrendipine, and
another drug or drugs, are determined primarily by the
manner in which the composition is to be administered.
For example, a composition to be administered orally
in tablet form can include, in addition to the drugs,
a filler (e.q., lactose), a binder (e.q.,
carboxymethyl cellulose, gum arabic, gelatin), an
adjuvant, a flavoring agent, a coloring agent and a
W094/07476 2 1 ~ S PCT/US93/09463
coating material (e.q., wax or a plasticizer). A
composition to be administered in liquid form can
include the combination of drugs and, optionally, an
emulsifying agent, a flavoring agent and/or a coloring
- 5 agent.
The term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically
acceptable non-toxic acids including inorganic acids
and organic acids. Optionally, ester analogues of
S(-) nitrendipine may be used in the present
invention.
Since the compound of the present invention is
basic, salts may be prepared from pharmaceutically
acceptable non-toxic acids including inorganic and
organic acids. Such acids include acetic,
benzene-sulfonic (besylate), benzoic, camphorsulfonic,
citric, ethenesulfonic, fumaric, gluconic, glutamic,
hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric,
tartaric acid, p-toluenesulfonic, and the like.
Particularly preferred are besylate, hydrobromic,
hydrochloric, phosphoric and sulfuric acids. (See
Campbell, S.F. et al., US 4,806,557.)
The compositions include compositions suitable
for oral, ocular, rectal and parenteral (including
subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in
any given case will depend on the nature and severity
of the condition being treated. The most preferred
route of the present invention is the oral route. The
compositions may be conveniently presented in unit
dosage form, and prepared by any of the methods well
known in the art of pharmacy.
W O 94/07476 PC~r/US93/09463~6~ 24 - ~
In the case where an oral composition is
employed, a suitable dosage range for use is from
about 10 mg to about 180 mg total daily dose, given as
a once daily administration in the morning or in
divided doses if required. Preferably, a dose range
of between about 20 mg to about 120 mg is given as a
once daily administration or in divided doses if
required, and most preferably a dose range of from
between about 30 mg to about 90 mg is given as a once
daily administration or in divided doses if required.
Patients may be upward titrated from below to within
this dose range to a satisfactory control of symptoms
or blood pressure as appropriate.
In practical use, S(-) nitrendipine can be
combined as the active ingredient in intimate
admixture with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending
on the form of the preparation desired for
administration, e.q., oral or parenteral (including
intravenous injections or infusions). In preparing
the compositions for oral dosage form any of the usual
pharmaceutical media may be employed. Usual
pharmaceutical media include, for example, water,
glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents, and the like in the
case of oral liquid preparations (such as for example,
suspensions, solutions, and elixirs); aerosols; or
carriers such as starches, sugars, microcrystalline
~0 cellulose, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like, in the
case of oral solid preparations (such as for example,
powders, capsules, and tablets) with the oral solid
preparations being preferred over the oral lïquid
W094/07476 2 ~ PCT/US93/09463
25 -
preparations. The most preferred oral solid
preparation is tablets.
Because of their ease of administration, tablets
and capsules represent the most advantageous oral
- 5 dosage unit form, in which case solid pharmaceutical
carriers are employed. If desired, tablets may be
coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out
above, the compounds of the present invention may also
be administered by controlled release means and/or
delivery devices such as those described in U.S.Patent
Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and
4,008,719, the disclosures of which are hereby
incorporated by reference. Further, the compounds of
the present invention are particularly suitable for
administration by standard means for transdermal
delivery as known to those skilled in the art.
Moreover, these compounds can be administered by means
described in U.S. Patent Nos. 4,992,445 and 5,001,139
which are hereby incorporated by reference.
For the treatment of ocular (retinal) ischemia,
the compounds of the present invention may be
administered orally, as described above, or in the
form of liquid eyedrops, preferably containing from
about 0.2 to about 10 mg active ingredient per drop.
Pharmaceutical compositions of the present
invention suitable for oral administration may be
presented as discrete units such as capsules, cachets,
or tablets, or aerosols sprays, each containing a
predetermined amount of the active ingredient, as a
powder or granules, or as a solution or a suspension
in an aqueous liquid, a non-aqueous liquid, an
oil-in-water emulsion, or a water-in-oil liquid
emulsion. Such compositions may be prepared~by any of
the methods of pharmacy, but all methods include the
W094/07476 - PCT/US93/0946~
~ 5~ - 26 - -
step of bringing into association the active
ingredient with the carrier which constitutes one or
more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately
admixing the active ingredient with liquid carriers or
finely divided solid carriers or both, and then, if
necessary, shaping the product into the desired
presentation.
For example, a tablet may be prepared by
compression or molding, optionally, with one or more
accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the
active ingredient in a free-flowing form such as
powder or granules, optionally mixed with a binder,
lubricant, inert diluent, and/or surface active or
dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid
diluent. Desirably, each tablet contains from about 5
mg to about 20 mg of the active ingredient, and each
cachet or capsule contains from about 5 mg to about 20
mg of the active ingredient, S(-) nitrendipine. Most
preferably, the tablet, cachet or capsule contains
either one of three dosages, 5 mg, 10 mg and 20 mg (as
scored tablets, the preferable dose form) of the
active ingredient.
The invention is further defined by reference to
the following examples describing in detail the
testing and preparation of the compositions of the
present invention. It will be apparent to those
skilled in the art, that many modifications, both to
materials and methods, may be practiced without
departing from the purpose and interest of this
invention.
O 94/07476 - 27 _ 21~ PC~r/US93/09463
5. EXAMPLES
5.1. EXAMPLE 1
Vascular Selectivity Studies
The relative potency of optically pure S(-)
- 5 nitrendipine and racemic nitrendipine as calcium
channel antagonists and negative inotropic agents are
determined by a pharmacological study. Evaluation of
these compounds and others in in vi tro test systems
provide results, from which the vascular selectivity
of a particular compound can be assessed. Calcium
channel antagonist activity of the compounds as a
function of their molar concentration can be evaluated
by measuring their inhibition of the calcium-induced
contraction of strips of rat aorta immersed in a bath
of Krebs-Henseleit buffer containing 45mM K+and no
Ca2+. In the presence of various concentrations of the
antagonists, inhibition would occur in the contraction
of this isolated tissue preparation in response to the
addition of calcium chloride. Antagonists may be
compared by examining the molar concentration of
compounds inhibiting the calcium-induced contraction
by 50%.
As an index of cardiac depression, negative
inotropic activity may be comparably assessed using
isolated heart preparations of adult rats. The
tissues are prepared and perfused in vi tro with Krebs-
Henseleit buffer solution, with the activity of the
calcium channel antagonists evaluated as a function of
their concentration. The compounds are tested for
their ability to alter cardiac contraction. Relative
potency is calculated from the IC2s values of the
compounds, i.e., the concentration required to depress
contraction by 25%.
W094/07476 PCT/US93/09463
28 -
5.2. EXAMPLE 2
Radioliqand Bindinq Studies
Hind limb skeletal muscles from rats or guinea
pigs are minced and homogenized. After filtration and
repeated centrifugation, the pellet is homogenized and
diluted in a Tris buffer to a protein concentration of
1-3 mg/ml. Volumes of this suspension containing 3-lO
~g protein are incubated in the presence of a fixed
concentration of 0.2 to 0.5 nM (+)-t3H]-isradipine or a
similar radioactive ligand and increasing
concentrations of racemic nitrendipine, S(-)
nitrendipine or R(+) nitrendipine. After 1 hour
incubation, the bound and free radioactivity is
measured in a scintillation counter and the affinity
of the test compounds to the receptors is calculated.
5.3. EXAMPLE 3
Effects on Coronary Muscular Resistance
in the Guinea Piq Lanqendorff Heart Preparation
Male guinea pigs weighing between 400 and 450 g
are killed by cervical dislocation. The hearts are
removed and perfused with Krebs-Henseleit solution at
constant pressure (60 cm water) by means of
retrograde cannulation of the aorta in a Langendorff
apparatus. The Krebs-Henseleit solution, consisting
of 118.0 mM NaCl, 4.7 mM KCl, 5.5 mM CaCl2, 1.2 mM
MgSO4, 25.0 mM NaHCO3 and 5.0 mM glucose, is prewarmed
to 37~ C and gassed with a mixture of 95% oxygen/5%
carbon dioxide. A balloon catheter connected to a
pressure transducer is placed in the left ventricle
via the left atrium and is preloaded to a pressure of
40 mm Hg. Coronary perfusate flow is measured
continuously, and changes in heart rate and left
ventricular contractility are also monitored-
continuously.
W O 94/07476 2 1~ ~4 ~ PC~r/US93/09463
- 29 -
Each experiment consists of a 30 minute
equilibrium period during which coronary flow is
stabilized at 9-12 ml/min. Following this period, a
vasoconstrictor is injected 3 times at 40 minute
S intervals into the cannulated aorta. This dose of U-
46619 (9,11-methanoepoxy-PGH2) evokes approximately a
75~ decrease in coronary flow within 30-40 sec, and
the effect is fully reversible after 20-25 min
continuous perfusion. Racemic nitrendipine, S(-)
nitrendipine or R(+) nitrendipine dissolved in
dimethyl sulfoxide or the vehicle are injected in
increasing concentrations prior to further U-46619
injections.
The mean decrease in coronary flow obtained with
three consecutive injections of U-46619 in the absence
of the test substance is taken to be 100~ and the
percent inhibition of this effect in the presence of
increasing concentrations of the test drugs is
calculated. Complete individual dose-response curves
for each test drug are generated in five hearts,
enabling the calculation of the dose for the half-
maximal antivasoconstrictor effect (ID50).
5.4. EXAMPLE 4
Antihypertensive Efficacy in
SPOntaneOUS 1Y HyPertensive Rats
Male spontaneously hypertensive rats (300-350 g)
are anesthetized, and polyethylene catheters are
implanted in the abdominal aorta via a femoral artery,
and in the abdominal vena cava via a femoral vein.
The arterial catheters are connected to pressure
transducers by means of an intraflow device, flushing
the catheters with 3 ml/hr. Mean arterial pressures
are derived electronically from the blood pressure
wave. Mean pretreatment values of mean arterial
pressure are in the range of 160-220 mm Hg. Doses of
W094/07476 PCT/US93/Og463
~ 30 -
racemic nitrendipine, S(-) nitrendipine and R(+)
nitrendipine, or of the solvent vehicle, are injected
into the venous catheter. Responses in mean arterial
pressure to the respective drug or solvent are
registered and the relative potencies of the test
compounds are calculated.
5.5. EXAMPLE 5
Cardiovascular
Calcium Antagonism, Guinea Pig Ileum (in vitro):
Test substance (3 ~g/ml) inhibition of the
contractile response of the K+-depolarized isolated
guinea pig ileal segment, bathed in Ca-free
physiological salt solution at 37- C, to added calcium
(20 ~g/ml of CaCl), indicates calcium antagonist
activity.
Reference Agents (ED~ g/ml):
atropine >2 isoxuprine 4
cinnazrizine 1 mepyramine >5
cyproheptadine 0.025 nifedipine 0.001
25 diltiazem 0.01 papaverine 4
diphenhydramine 1 promethazine 0.25
flunarizine 0.1 propranolol 4
ipratropium bromide >2 verapamil 0.01
5.6. EXAMPLE 6
Studies on Insulin Resistance
Insulin is a hormone that activates various
biochemical processes in the body, the most well known
being facilitation of glucose transport over cell
.
W O 94/07476 PC~r/US93/09463 - 31 _ 21~
membranes and activation of cell growth. The
development of insulin resistance is common both in
diabetics and nondiabetics, but it is only the glucose
transport system that develops resistance to insulin.
5 To compensate for the impaired glucose transport, the
normal body produces more insulin and the diabetic
patient has to inject higher doses of insulin. Since
insulin also is a growth hormone, the increased
insulin concentration induces an accelerated growth of
atherosclerotic lesions and increased risk for
cardiovascular morbidity and mortality.
Several calcium antagonists of the
dihydropyridine class, such as nifedipine, are known
to make the insulin resistance worse, while other
blood-pressure-lowering agents, such as captopril,
have a beneficial effect by decreasing insulin
resistance. The present studies are performed in old,
spontaneously hypertensive rats, which are known to
develop insulin resistance. Racemic nitrendipine, S(-
) nitrendipine, and R(+) nitrendipine are studied fortheir effects on glucose transport, insulin plasma
concentration and arterial blood pressure.
W O 94J07476 PC~r/US93/0946~
4~
5.7. EXAMPLE 7
ORAL FORMULATION
Capsules:
Formula Quantity per capsule in mg.
A B C
Active ingredient 5.0 10.0
20.0
S(-) Nitrendipine
Lactose 79.0 74.0
64.0
Corn Starch 15.0 15.0
15.0
Magnesium Stearate 1.0 1.0
1 . O
Weight 100.0 100.0
100. 0
The active ingredient, S(-) nitrendipine,
lactose, and corn starch are blended until uniform;
then the magnesium stearate is blended into the
resulting powder. The resulting mixture is
encapsulated into suitably sized two-piece hard
gelatin capsules.
W O 94/07476 2 1 ~ 6 ~ ~ ~ PC~r/US93/09463
- 33 -
5.8. EXAMPLE 8
ORAL FOFUMULATION
Tablets:
Formula Quantity per capsule in Gm.
_ B
Active ingredient 5.0 10.0
20.0
S(-) Nitrendipine
Lactose 178.5 173.5
163.5
Corn Starch 15.0 15.0
15.0
Magnesium Stearate 1. 5 1.5
1.5
Compression Weight 200.0 200.0
200.0
The active ingredient, S(-) nitrendipine, is
sieved through a suitable sieve and blended with
lactose, starch, and pregelatinized maize starch.
Suitable volumes of purified water are added and the
powders are granulated. After drying, the granules
are screened and blended with the magnesium stearate.
The granules are then compressed into tablets using 7
mm diameter of punches.
Tablets of other strengths may be prepared by
altering the ratio of active ingredient to lactose or
the compression weight and using punches to suit.
