Note: Descriptions are shown in the official language in which they were submitted.
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ANALGESICS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of priority to US provisional application
serial no.
60/315,530 filed on August 29, 2001, which is hereby incorporated by reference
in its entirety.
FIELD OF INVENTION
The invention relates to d-methadone metabolites and their analogs, as well as
to methods
of their use to induce analgesia and/or to inhibit abuse of abusive substances
such as opioids,
cocaine, nicotine, etc.
DESCRIPTION OF THE RELATED ART
The study of pain and pain alleviation has made it clear that the development
of pain
alleviation is not a singular path. Many, varied sources of pain and its
alleviation are known and
suspected. For this reason, scientists continually search for more, different,
and better ways of
treating pain and of reducing side effects associated therewith.
Nicotinic acetylcholine receptors are distributed throughout the central and
peripheral
nervous systems where they mediate the actions of endogenous acetylcholine, as
well as nicotine
and other nicotinic agonists. They are often associated with cell bodies and
axons of major
neurotransmitter systems, and nicotinic agonists are thought to act through
these receptors to
promote the release of a number of neurotransmitters such as dopamine,
norepinephrine, y-
aminobutyric acid, acetylcholine, and glutamate (for review, see Wonnacott,
1997), as well as
certain pituitary hormones (Andersson et al., 1983; Sharp et al., 1987; Flores
et al., 1989;
Hulihian-Giblin et al., 1990). The release of this wide array of
neurotransmitters and hormones
probably contributes to the diverse, and sometimes opposite, effects of
nicotine. For example, the
release of norepinephrine is usually associated with arousal, while the
stimulation of y-
aminobutyric acid systems is associated with sedation.
Nicotine was first examined for its potential as an analgesic drug almost 70
years ago
(Davis et al., 1932), but its dose-response relationship for analgesia yielded
a poor therapeutic
index, which did not favor its development. More recently, following the
discovery of the
analgesic properties of epibatidine, a potent nicotinic agonist isolated from
the skin of an
Ecuadorian frog by Daly and colleagues (Spande et al., 1992), there has been
renewed interest in
the analgesic potential of drugs that act at nicotinic receptors (Bannon et
al., 1998; Flores and
Hargreaves, 1998; Flores, 2000).
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It is likely that more than one neurotransmitter system plays an important
role in
analgesia. For example, methadone, a synthetic p-opioid agonist, has analgesic
properties
similar to those of morphine (Kristensen et al., 1995), and it is also useful
in the treatment of
opiate addiction. Most of the morphine-like analgesic properties of (t)-
methadone are as
ascribed to the (-)-enantiomer, since the (+)-enantiomer has much weaker
opiate properties
(Scott et al., 1948; Smits and Myers. 1974; Horng et al., 1976). However, (+)-
methadone does
show analgesic potency in some experimental models (Shimoyama et al., 1997;
Davis and
Inturrisi, 1999), and it also appears to attenuate development of morphine
tolerance (Davis and
Inturrisi, 1999).
In addition to its agonist action at opiate receptors, methadone competes for
[3H]MK801
binding sites within the NMDA receptor channel and blocks NMDA receptor-
mediated responses
(Ebert et al., 1995); furthermore, the two enantiomers of methadone are nearly
equipotent at
[3H]MK801 binding sites (Gorman et al., 1997). Several drugs such as MK801,
phencyclidine,
dextromethorphan, and dextrorphan, that block NMDA receptors, also block
neuronal nicotinic
receptors (Ramoa et al., 1990; Amador and Dani, 1991; Hernandez et al., 2000).
Both nicotinic
receptors and NMDA receptors have been implicated in pain pathways and
possible mechanisms
underlying the perception of pain. Therefore, the inventors examined the
effects of methadone, its
metabolites, and structural analogs (Fig. 1 ) on neuronal nicotinic receptors.
In addition to being involved in pain alleviation, recently, it has been
discovered that
certain nicotinic receptors may play a role in limiting abusive behavior.
Substances which may be subject to abuse include opioids, methamphetamines,
hallucinogens, psychotropics, cocaine, and others. Some abusive substances are
subtle and
pervasive. Perhaps one of the most pervasive is nicotine, found in tobacco
products. The term
"abusive substances," as used herein, refers to any substance that can lead to
abuse by creating
dependence or otherwise inducing drug-seeking behavior.
During their research into d-methadone and its metabolites, EMDP and EDDP, the
inventors discovered that the EMDP and EDDP and novel analogs thereof induce
analgesia and
may be useful in independently or simultaneously deterring abuse of one or
more abusive
substances listed above.
SUMMARY OF THE INVENTION
A method for inducing analgesia and/or inhibiting abuse of abusive substances
includes
administration of EMDP, EDDP, and novel analogs thereof. The compounds of the
present
invention may be incorporated into a suitable pharmaceutical composition for
administration to
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patients. The invention includes novel compounds, a method for inducing
analgesia and/or
inhibiting abuse of an abusive substance, and pharmaceutical compositions for
use in the method.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts the chemical structures of methadone, EMDP, EDDP, analogs, and
mecamylamine.
Fig. 2 is a graph depicting the effects of methadone versus nicotine on 86Rb+
efflux from
KXa3~4R2 cells.
Fig. 3 is a graph depicting the inhibition of nicotine-stimulated g6Rb+efflux:
from
KXa3[I4R2 cells by methadone and its two enantiomers.
Fig. 4 is a graph depicting the competition by methadone for [3H]EB binding
sites in
membrane homogenates from KXa3[i4R2 cells.
Fig. 5 is a graph depicting the noncompetitive inhibition of nicotine-
stimulated 86Rb+
efflux from KXa3(34R2 cells by methadone.
Fig. 6 is a graph depicting the comparison of the inhibition of nicotine-
stimulated 86Rb+
efflux from KXa3(34R2 cells by methadone, (+)-EDDP, LAAM, and mecamylamine.
Fig. 7 is a graph depicting the noncompetitive inhibition of nicotine-
stimulated $6Rb+
efflux from KXa3(34R2 cells by (+)-EDDP and LRAM.
Fig. 8 is a schematic of a synthesis reaction scheme for making various
compounds in
accordance with the invention.
Fig. 9 is another schematic of a synthesis reaction scheme for making various
compounds
in accordance with the invention.
Fig. 10 is a graph showing the analgesic effect of EDDP.
Fig. 11 depicts sample current inhibition by EDDP.
Fig. 12 depicts a concentration response curve.
Fig. 13 is a graph comparing the Glutamate stimulated Catecholamine release
with
treatment with MK-801, d-methadone, and R(+)EDDP in the hippocampus.
Fig. 14 is a graph comparing the Glutamate stimulated Catecholamine release
with
treatment with MK-801, d-methadone, and R(+)EDDP in the striatum.
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DETAILED DESCRIPTION
DEFINITIONS
Throughout this specification, reference simply to "the metabolites" or "d-
methadone
metabolites," means EDDP and EMDP, as defined below, and the pharmaceutically
acceptable
salts thereof, unless otherwise indicated.
The term "(+)-methadone" means S-(+)-methadone hydrochloride;
the term "(-)-methadone" means R-(-)-methadone hydrochloride;
the term "LAAM" means (-)-a-acetylmethadol hydrochloride;
the term "(+)-EDDP" means R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium
perchlorate;
the term "(-)-EDDP" means S-(-)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium
perchlorate;
the term "(+)-EMDP" means R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline
hydrochloride;
the term (-)-EMDP" means S-(-)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline
hydrochloride;
the term "EMDP" means (+)-EMDP, (-)-EMDP, or mixtures thereof;
the term "EDDP" means (+)-EDDP, (-)-EDDP, or mixtures thereof.
Despite the structural similarity to d-methadone, EMDP and EDDP, and analogs
thereof,
have different properties from d-methadone. Figs. 13 and 14 demonstrate this
by comparing the
effect of MK-801, d-methadone and (+)-EDDP on glutamate stimulated
catecholamine release in
rat brain slices from the hippocampus and striatum. The hippocampus and
striatum are both
important and well-studied anatomical areas of the brain. The hippocampus is
associated with
learning and memory functions while the striatus is linked to motor function.
Slices were loaded
with [3H]norepinephrine or (3H]dopamine and then exposed to 1 mM glutamate for
2 min in the
absence or presence of MK-801, d-methadone or (+)-EDDP. The baseline release
was measured
in the absence of glutamate. These results indicate, that (+)-EDDP is
physiologically different
from d-methadone, an opioid blocker, and MK-801, an NMDA blocker. This
difference is
apparent from the dose shift to the right, as seen in both Figs. 13 and 14.
Just IOpM of d-
methadone or MK-801 achieves partial block of catecholamine release while no
effect is seen
from (+)-EDDP until 100pM.
The inventors believe, without being limited to this theory, that the success
of the
compounds of the present invention in inducing analgesia and/or inhibiting
abuse is in their
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ability to block the nicotinic receptors. It should be noted, however, that
binding or blocking of
other sites may also contribute to the effect.
The action of d-methadone and the compounds of the present invention at a3(34
neuronal
nicotinic receptors stably expressed in human embryonic kidney 293 cells was
measured. These
compounds are potent nicotinic receptor blockers. One of the compounds
disclosed herein is
among the most potent nicotinic receptor Mockers that have been reported.
Effects of Methadone and Related Drugs on nAChRs
Experimental Procedures
Materials and Drugs. Tissue culture medium, antibiotics, and serum were
obtained
from Invitrogen (Carlsbad, CA). [3H](~)-epibatidine and [B~Rb]rubidium
chloride ($~Rb+) were
obtained from PerkinElmer Life Science Products (Boston, MA). All other
chemicals were
purchased from Sigma Chemical Co. (St. Louis, MO) unless otherwise stated. (~)-
Methadone
hydrochloride (methadone), S-(+)-methadone hydrochloride [(+)-methadone], and
R-(-)-
methadone hydrochloride [(-)-methadone] were obtained from Sigma/RBI (Natick,
MA). The
1 S following compounds were obtained from Research Triangle Institute
(Research Triangle Park,
NC) through the National Institute on Drug Abuse: (-)-a-acetylmethadol
hydrochloride (LAAM,
a methadone analog); R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium
perchlorate ((+)-
EDDP, a methadone metabolite]; S-(-)-2-ethyl-1,5-dimethyl-3,3-
diphenylpyrrolinium perchlorate
[(-)-EDDP, a methadone metabolite]; R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-
pyrroline
hydrochloride [(+)-EMDP, a methadone metabolite]; S-(-)-2-ethyl-5-methyl-3,3-
diphenyl-1-
pyrroline hydrochloride [(-)-EMDP, a methadone metabolite]; (+)-a-propoxyphene
hydrochloride (a methadone analog); and (+)-a-N norpropoxyphene maleate (a
propoxyphene
metabolite). The structures of methadone, EMDP, EDDP, and several analogs used
here are
shown in Fig. 1, along with mecamylamine, a well-known nicotinic channel
blocker.
Cell Culture. The cell line KXa3[34R2 was established previously by stably
cotransfecting human embryonic kidney 293 cells with the rat a3 and (34 nAChR
subunits genes
(Xiao et al., 1998). Cells were maintained in minimum essential medium
supplemented with
10% fetal bovine serum, 100 units/ml penicillin G, 100 mg/ml streptomycin, and
0.7 mg/ml of
geneticin (G418) at 37°C with 5% COZ in a humidified incubator.
86Rb+ Efflux Assay. Function of nAChRs expressed in the transfected cells was
measured using a 86Rb+ efflux assay as described previously (Xiao et al.,
1998). In brief, cells in
the selection growth medium were plated into 24-well plates coated with poly(D-
lysine). The
plated cells were grown at 37°C for 18 to 24 h to reach 70 to 95%
confluence. The cells were
then incubated in growth medium (0.5 ml/well) containing 86Rb+ (2 ~Ci/ml) for
4 h at 37°C. The
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loading mixture was then aspirated and the cells were washed three times with
buffer (15 mM
HEPES, 140 mM NaCI, 2 mM KC1, 1 mM MgS04, 1.8 mM CaCI, 11 mM glucose, pH 7.4;
1
ml/well) for 30 s, S min, and 30 s, respectively. One milliliter of buffer,
with or without
compounds to be tested, was then added to each well. After incubation for 2
min, the assay
buffer was collected for measurements of 86Rb+ released from the cells. Cells
were then lysed by
adding 1 ml of 100 mM NaOH to each well, and the lysate was collected for
determination of the
amount of g6Rb+ that was in the cells at the end of the efflux assay.
Radioactivity of assay
samples and lysates was measured by liquid scintillation counting. Total
loading (cpm) was
calculated as the sum of the assay sample and the lysate of each well. The
amount of 86Rb+
efflux was expressed as a percentage of 86Rb+ loaded. Stimulated 86Rb+ efflux
was defined as the
difference between efflux in the presence and absence of nicotine.
Experiments with antagonists were done in two different ways. For obtaining an
ICso
value, inhibition curves were constructed in which different concentrations of
an antagonist were
included in the assay to inhibit efflux stimulated by 100 mM nicotine. For
determination of the
mechanism of antagonist blockade, concentration-response curves for receptor
activation by
nicotine were constructed in the presence or absence of an antagonist. The
maximal nicotine
stimulated 86Rb+ efflux (Emax) was defined as the difference between maximal
efflux in the
presence of nicotine and basal efflux. ECSO, Emax~ and ICSO, values were
determined by nonlinear
least-squares regression analyses (GraphPad, San Diego, CA).
Ligand Binding Studies. The ability of compounds to compete for the agonist
recognition site of nAChRs was determined in ligand binding studies as
described previously
(Houghtling et at., 1995; Xiao et a1.,1998). Briefly, membrane preparations
were incubated with
[3H]EB for 4 h at 24°C. Bound and free ligands were separated by vacuum
filtration through
Whatman GF/C filters treated with 0.5% polyethylenimine. The radioactivity
retained on the
filters was measured by liquid scintillation counting. Total binding and
nonspecific binding were
determined in the absence and presence of (-)-nicotine (300 pM) respectively.
Specific binding
was defined as the difference between total binding and nonspecific binding.
Binding curves
were generated by incubating a series of concentrations of each compound with
a single
concentration of [3H]EB. The ICSO and K; values of binding inhibition curves
were determined
by nonlinear least squares regression analyses.
Results
Effects of Methadone on 86Rb+ Efflux from KXa3~i4R2 Cells. Fig. 2. Effects of
methadone versus nicotine on g6Rb+ efflux from KXa3(34R2 cells. g6Rb+ efflux
as measured as
described under Experimental Procedures. Cells were loaded with 86Rb+and then
exposed for 2
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min to buffer alone (to measure basal release), or buffer containing methadone
at the
concentration, shown. 100 p.M nicotine or 100 pM nicotine plus 200 pM
methadone. The 86Rb+
efflux was response was expressed as a percentage of $6Rb+loaded. Data shown
in Fig. 2 are the
mean t standard error of four independent determinations. As shown in Fig. 2,
at concentrations
up to 1 mM, methadone did not increase 86Rb+ efflux from KXa3[i4R2 cells. In
parallel assays,
however, 100 N.M nicotine stimulated $6Rb+ efflux approximately 10-fold over
basal levels, and
this stimulation was completely blocked by 200 pM methadone. Thus
demonstrating the
blocking of a3[i4 by methadone.
Potency of Methadone and Its Enantiomers in Inhibiting Nicotine-Stimulated
86Rb+
Efflux from KXa3[34R2 Cells. The potencies of racemic methadone and its
enantiomers as
antagonists of the nAChRs were examined by measuring $6Rb+efflux stimulated by
100 pM
nicotine in the presence of increasing concentrations of the compounds. Cells
were loaded with
and then exposed for 2 min to buffer alone (basal release) or buffer
containing 100 p.M nicotine
in the absence or presence of racemic methadone or one of the methadone
enantiomers at the
concentrations shown. g6Rb+efflux was expressed as a percentage of
g6Rb+loaded, and control
values were defined as g6Rb+ efflux stimulated by 100 pM nicotine in the
absence of methadone.
Inhibition curves shown in Fig. 3 are from a single experiment measured in
quadruplicate. See
Table 1 for mean and standard error of the ICSO values. As illustrated in Fig.
3, racemic
methadone potently inhibited nicotine-stimulated g6Rb+efflux in a
concentration-dependent
manner with an ICSO of approximately 2 pM. Moreover, (+)-methadone and (-)-
methadone
inhibited the, function of these receptors with similar potencies (Fig. 3;
Table 1).
TABLE 1 lists the inhibitory properties of enantiomers of methadone and
compounds of the present invention on nicotine-stimulated 86Rb+~efflux from
ICXa3(34R2 cells.
ICSO values were calculated front inhibition curves in which 86Rb+ efflux was
stimulated by 100
pM nicotine, as described under Experimental Procedures. Mecamylamine, a
standard nAChR
antagonist, was included for comparison. Data shown are the mean t standard
error of three to
six independent measurements.
Low Affinities of Methadone for nAChR Agonist Binding Sites. The ability of
methadone to compete for a3[34 receptor agonist recognition sites labeled by
[3H]EB in
membranes from KXa3(34R2 cells was examined. Binding assays were carried out
as described
under Experimental Procedures using 323 pM [3H]EB. The K; value for nicotine
was 559 nM.
The K; values for methadone and mecamylamine cannot be estimated because there
was less
than 50% inhibition even at the highest concentration used (1 mM). As shown in
Fig. 4
methadone does not compete effectively for [3H]EB binding sites. Mecamylamine
is shown for
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comparison. Thus, even at the highest concentration used (1mM), methadone
inhibited less than
SO% of [3H]EB binding to a3(34 receptors. This was comparable to the weak
binding potency of
mecamylamine. In parallel assays carried out as positive controls, nicotine
competed effectively
for the agonist binding sites of a3~i4 receptors, yielding a dissociation
constant (K;) of 560 nM,
which is similar to that previously reported in these cells (Xiao et al.,
1998). Methadone's very
low affinity for the agonist recognition sites of a3(34 receptors contrasts
with its high potency in
blocking receptor function (ICso of about 2p,M) and suggests a noncompetitive
mechanism of
receptor antagonism.
TABLE 1
Drug ICso
(+)-Mehtadone p.M
(-)-Methadone 1.9 t 0.2
(+)-Methadone 2.5 t 0.2
(-)-Methadone 2.0 t 0.3
(+)-EDDP 0.4 0.2
(-)-EDDPa 0.4 t 0.1
(+)-EMDP 5.8 1.0
(-)-EMDP 6.3 t 0.7
Propoxyphene 2.7 0.4
Norpropoxyphene 1.8 t 0.1
LAAM 2.5 f 0.4
Mecamylamine 1.1 t 0.2
Dextromethorphan 8.9 t 1.1
Dextrorphan 29.6 5.7
Mecamylamine 1.0 t 0.04
MK-801 26.6 t
9.6
aThe ICso value for (-)-EDDP significantly lower than that for mecamylamine (p
< 0.02).
Noncompetitive Block of nAChR Function by Methadone. To definitively identify
the type of receptor blockade by methadone, we examined its effect on
concentration-response
curves for receptor activation by nicotine. 86Rb+ efflux was measured as
described under
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Experimental Procedures. Cells were loaded with '86Rb+ and then exposed to
buffer containing
increasing concentrations of nicotine for 2 min in the absence (control) or
presence of 1 p,M
methadone. The86Rb+ efflux was calculated as a percentage of g6Rb+ loaded, and
the EmaX was
defined as the maximum response in the absence of methadone. The curves shown
are from a
single experiment measured in quadruplicate. The ECSO Values in the absence
and presence of
methadone were 28.8 t 1.2 and 21.3 t 2.1 pM, respectively (mean t standard
error from four
independent experiments). The Emax, value (mean t standard error) in the
presence of 1 p,M
methadone was 63 ~ 2% of control values. Both the ECmaX (p <0.05) and Emu
values (p <0.01)
in the presence of methadone are, significantly different from control values
As shown in Fig.
5, in the presence of 1 pM methadone, the maximum 86Rb+efflux stimulated by
nicotine (Em~)
was markedly reduced, but the ECSO for nicotine was altered only slightly, if
at all. This result
indicates that methadone does, in fact, block a3[34 nAChR function primarily
by a
noncompetitive mechanism.
Inhibitory Effects of Methadone Metabolites and Structural Analogs on 86Rb+
Efflux from KXa,3(34R2 Cells. We tested seven compounds related to methadone,
including its
metabolites and structural analogs, for their agonist and antagonist effects
on $6Rb+ efflux from
KXa3(34R2 cells At concentrations up to 100 pM, none of these compounds
increased g6Rb+
efflux (data not shown).
Effects of Methadone and Related Drugs on nAChRs
However, all of the compounds tested here were relatively potent blockers of
nicotine-
stimulated 86Rb+ efflux (See Table 1). Thus, the long-acting methadone analog
LAAM as well
as propoxyphene and norpropoxyphene were about as potent as methadone in
blocking this a3~i4
receptor-mediated response. The methadone metabolite EDDP was even more
potent; in fact,
EDDP appears to be one of the most potent nAChR antagonists that has been
reported, being
about 5 times more potent than methadone and about twice as potent as
mecamylamine (Fig. 6;
Table 1). Furthermore, like methadone, the two enantiomers of the metabolites
were equipotent
in blocking a3/34 nAChR (Table 1), although in these studies the difference in
ICSO values
between (-)-EDDP and mecamylamine was statistically significant (p < 0.02),
while that for (+)-
EDDP was not (0.05 < p < 0.1 ).
Fig. 6 Shows the comparison of the inhibition of nicotine-stimulated g6Rb+
efflux from
KXa3(34R2 cells by methadone, (+)-EDDP, LAAM, and mecamylamine. g6Rb+ efflux
was
measured as described under Experimental Procedures. Cells were loaded with
g6Rb+ and then
exposed for 2 min to buffer alone (basal release) or buffer containing 100 pM
nicotine in the
absence or presence of racemic methadone, (+)-EDDP, LAAM, or mecamylamine at
the
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concentrations shown. 86Rb+ efflux was expressed as percentage of 86Rb+ loaded
and control
values were defined as g6Rb+ efflux stimulated by 100 pM nicotine in the
absence of methadone.
Noncompetitive Block of nAChR Function by Methadone Metabolites and
Structural Analogs. None of the compounds examined here competed effectively
for [3H]EB
binding sites), suggesting that, like methadone, they block receptor function
via a
noncompetitive mechanism. To examine this more directly, the effects of (+)-
EDDP and LAAM
on concentration-response curves for receptor activation by nicotine were
examined. 86Rb+
efflux was measured as described under Experimental Procedure. Cells were
loaded with g6Rb+
and then exposed to buffer containing increasing concentrations of nicotine
for 2 min in the
absence (control) or presence of 0.5 N.M EDDP of 3 pM LAAM. The g6Rb+ efflux
was calculated
as a percentage of $6Rb+ loaded, and the ECSO was defined as the maximum
response in the
absence of antagonists. The curves shown are from a single experiment measured
in
quadruplicate. The ECSO values for nicotine-stimulated g6Rb+ efflux in the
control cells, in the
presence of 0.5 N.M (+)EDDP, and in the presence of 3p M LAAM were,
respectively, 28.2 t
1.5, 25.5 ~ 1.5, and 18.8 t 1.4 pM*. The Emax, values in the presence of 0.5
pM (+)-EDDP and
3N.M LAAM were, respectively 60 ~ 3** and 44 ~ 5%** of control. Values are
mean ~ standard
error from three independent experiments. The values that were significantly
different from
values of control are indicated by *p <0.05 and **p< 0.01, respectively. As
shown in Fig. 7,
both of these compounds acted as noncompetitive blockers of a3 (34 nicotinic
receptors.
Discussion
We investigated the effects of the enantiomers of methadone and its
metabolites
as well as three structural analogs of methadone on the function of rat a3~4
nAChRs stably
expressed in KXa3(34R2 cells. All of these compounds inhibited nicotine-
stimulated 86Rb efflux
in a concentration-dependent manner and with relatively high potencies,
comparable with that of
mecamylamine. In particular, EDDP, the major oxidative metabolite of
methadone, with an ICso
of about 0.4 p,M, is one of the most potent nicotinic antagonists that has
been reported.
A noncompetitive mechanism of nAChR blockade by methadone, EDDP, and
LAMM is clearly indicated by the marked decrease in the maximum receptor-
mediated response
without a substantial change in the ECSO value for nicotine-stimulated B~Rb+
efflux in the
presence of these compounds. A noncompetitive mechanism is also consistent
with the
observation that neither methadone, its metabolites, nor its structural
analogs compared
effectively for [3H]EB binding sites, which represent the agonist recognition
site of the receptor.
Taken together, these data indicate that all of these compounds most likely
block within the
a3~34 nAChR channel. There also appeared to be a slight but statistically
significant decrease in
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the ECSO value for nicotine-stimulated $6Rb+ efflux in the presence of
methadone and LAAM,
implying that these drugs might actually increase the potency of nicotine at
the receptor.
Although it is very probable that the small difference in nicotine's ECso
values represents a
statistical artifact, we cannot rule out an allosteric effect.
The (+)-and (-)-enantiomers of methadone and its metabolites are equipotent in
blocking
nAChR. This is in contrast to methadone's agonist actions at opiate receptors,
which are ascribed
almost entirely to its (-)-enantiomer. Therefore, the high potency of the (+)-
enantiomers of
methadone and its metabolites should allow blockade of nicotinic receptors
without necessarily
stimulating opiate receptors. This could then permit these (+)-enantiomers to
be used in
conditions where blockade of neuronal nicotinic receptors might be beneficial.
For example,
receptor blockade by mecamylamine is reported to aid in smoking cessation
(Rose et al., 1994,
1998), and the most potent of the methadone metabolites is approximately twice
as potent as
mecamylamine. In addition, nicotinic receptors are thought to play a
potentially important role
in some analgesia pathways (Flores, 2000). Although analgesia has most often
been associated
with nicotinic agonists, these actions are incompletely understood, and it is
possible that
nicotinic antagonists can also contribute to analgesia (Hamann and Martin,
1992). If this were
the case for methadone and its metabolites, their analgesic effect through
nicotinic mechanisms
would perhaps be additive to analgesia mechanisms mediated by opiate
receptors. This would be
particularly useful where tolerance to opiates and/or ceiling effects are
issues. In fact, both
dextromethorphan, which blocks NMDA and nicotinic receptors, and (+)-methadone
are reported
to attenuate the development of tolerance to morphine analgesia (Elliott et
al., 1994; Davis and
Inturrisi, 1999).
The plasma concentration of methadone following a single dose is approximately
0.25
~,M (Inturrisi and Verebely, 1972) and the steady-state concentration in
patients taking
methadone chronically can exceed 1 wM (de Vos et al., 1995; Alburges et al.,
1996; Dyer et al.,
1999). At these concentrations, methadone could be expected to produce
significant blockade of
a3~i4 nicotinic receptors. The steady-state plasma concentration of the more
potent EDDP is
usually much lower, but the peak concentration following administration of
methadone can
approach 0.2 ~,M (de Vos et al., 1995).
It should also be noted that (+)-methadone blocks NMDA receptor channels with
potencies similar to, although slightly lower than, those found here at
nicotinic receptors
(Gorman et al., 1997; Stringer et al., 2000). Methadone's block of NMDA
receptors also has
been linked to its analgesic actions (Shimoyama et al., 1997; Davis and
Inturrisi, 1999), and
particularly to its potential usefulness for treating chronic and/or
neuropathic pain (Elliott et al.,
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1995; Hewitt, 2000; Stringer et al., 2000). In addition, methadone's possible
attenuation of
morphine tolerance may involve NMDA receptors (Gorman et al., 1997; Davis and
Inturrisi,
1999). In this regard, however, the block of nicotinic receptors by EDDP and
(+)-methadone
might also contribute directly to analgesic actions and even to the
attenuation of morphine
tolerance. Thus, it is possible that methadone and its metabolites can affect
three different
neurotransmission systems that have been associated with analgesia pathways
and tolerance to
opiates.
Accordingly, the compounds of the present invention block a3~34 nicotinic
cholinergic
receptors by a noncompetitive mechanism consistent with channel blockade. Both
the (+)- and (-
)-enantiomers of methadone and its metabolites are active; therefore, the high
potency of the (+)-
enantiomers of these compounds, particularly EDDP, in blocking nicotinic
receptors should
allow them to be used as probes of nicotinic receptors without affecting
opiate receptors.
The Compounds
In describing the compounds, the following definitions are used, each of which
includes
all possible geometric, racemic, diasteriomeric, and enantiomeric forms
thereof.:
The term alkyl includes branched and straight chain, saturated and
unsaturated,
substituted and unsubstituted alkyl groups. Examples of alkyls include methyl,
ethyl, propyl,
isopropyl, butyl, tert-butyl, etc.
The term alkenyl refers to an ethylenically unsaturated hyrdocarbon group,
straight or
branched, which may be substituted or unsubstituted.
The term alkynyl refers to a straight or branched hydrocarbon group having 1
or 2
acetylenic bonds, which may be substituted or unsubstituted.
The term aryl refers to phenyl, which may be substituted with 1-5
substituents.
The term azaaromatic refers to an aromatic ring containing 1-3 nitrogen atoms,
which
may be substituted with 1-5 substituents.
The general structure of these compounds is set forth as Formulae I and II
below, and
include all possible geometric, racemic, diasteriomeric, and enantiomeric
forms thereof:
R
R.. Ra
Formula I Formula II
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where:
R' is H, (C,-C6)alkyl, (C3-C6)cycloalkyl-(C,-C6)alkyl, (C3-C6)cycloalkyl-(C~-
C6)alkenyl,
and aryl or azaaromatic having 1-5 substituents independently selected from
the group consisting
S of hydrogen, (C,-C6)alkyl, (C3-C6)cycloalkyl, (Cz-C6)alkenyl, aryl, and
aryl(C~-C6)alkyl, N
methylamino, N,N-dimethylamino, carboxylate, (C1-C3)alkylcarboxylate,
carboxaldehyde,
acetoxy, propionyloxy, isopropionyloxy, cyano, aminomethyl, N-
methylaminomethyl, N,N
dimethylaminomethyl, carboxamide, N-methylcarboxamide, N,N-
dimethylcarboxamide, acetyl,
propionyl, formyl, benzoyl, sulfate, methylsulfate, hydroxyl, methoxy, ethoxy,
propoxy,
isopropoxy, thiol, methylthio, ethylthio, propiothiol, fluoro, chloro, bromo,
iodo, trifluoromethyl,
propargyl, nitro, carbamoyl, ureido, azido, isocyanate, thioisocyanate,
hydroxylamino, and
mtroso;
Rz is hydrogen, (C1-C6)alkyl, (Cz-C6)alkene, or (Cz-C6)alkynyl, and in Formula
I, Rz may
also be selected from O= or HN=;
R3 is selected from hydrogen, (C,-C6)alkyl, (C3-C6)cycloalkyl, (Cz-C6)
alkenyl, aryl, and
aryl(C 1-C6)alkyl;
Preferably, R3 is methyl or ethyl;
R4 is C~-C6 alkyl, and (C3-C6)cycloalkyl; and
RS is aryl or azaaromatic having 1-5 substituents independently selected from
the group
consisting of hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (Cz-C6)alkenyl, aryl,
and aryl(C,
C6)alkyl, N-methylamino, N,N-dimethylamino, carboxylate, (CI-
C3)alkylcarboxylate,
carboxaldehyde, acetoxy, propionyloxy, isopropionyloxy, cyano, aminomethyl, N
methylaminomethyl, N,N-dimethylaminomethyl, carboxamide, N-methylcarboxamide,
N,N
dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate,
methylsulfate, hydroxyl,
methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio,
propiothiol, fluoro, chloro,
bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azido,
isocyanate,
thioisocyanate, hydroxylamino, and nitroso and may form a bond to R' to result
in a conjugated
ring system.
The compounds may be in the form of pharmaceutically acceptable salts,
including but
not limited to inorganic acid addition salts such as hydrochloride,
hydrobromide, sulfate,
phosphate and nitrate; organic acid addition salts such as acetate,
galactarate, propionate,
succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate,
methanesulfonate,
salicylate, p-toluenesulfonate, benzenesulfonate, and ascorbate; salts with
acidic amino acids
such as aspartate and glutamate; the salts may in some cases by hydrates or
solvates with
13
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alcohols and other solvents. Salt forms can be prepared by mixing the
appropriate amine with
the acid in a conventional solvent, with or without alcohols or water.
More specifically, the following compounds are contemplated:
Structure X RI R R R R Formula/
Series
C phenyl CHZCH3 H CH3 phenyl I/1
\ \
H ~ ~o
pr
r
1 trans
/ / C phenyl CHZCH3 H CH3 phenyl I/1
\ \
~N
H
2 cis
/ / C phenyl CHZCH3 CH3 CH3 phenyl I/1
\ \
H
C/N ..o
3
rp
3 trans
/ / C phenyl CH2CH3 CH3 CH3 phenyl I/1
\ \
N
H3C/
4 trans
/ / C phenyl =O H CH3 phenyl I/1
\ \
0
.....,v
H ~ N
.
iii
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Structure X R R R R~ R Formula/
Series
/ / C phenyl =O H CH3 phenyl I/1
\ \
0
~N
H
6
/ / C phenyl =O CH3 CH3 phenyl I/1
\ . \
0
N
C~ ......o
H
3
pi
7
/ ~ C phenyl =O CH3 CH3 phenyl I/I
\ \
0
N
H3C/
/ / C phenyl =NH H CH3 phenyl I/1
\ \
HN
H ~ N '.~''o~i
9
/ / C phenyl =NH H CH3 phenyl Ul
\ \
HN
/ N
H
l~
/ / C phenyl =NCH3 H CH3 phenyl I/1
\ \
HN
N
C/ .'~~'
H
3
~i
1l
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Structure X R R R R R Formula/
Series
/ / C phenyl =NCH3 H CH3 phenyl I/1
\ \
HN
N
H3C/
12
/ / C phenyl - H CH3 phenyl II/1
CCH3CHz
\ \
N+
H/
13
/ / C phenyl - CH3 CH3 phenyl II/1
CCH3CHz
N+
H3C~
14
/ / C phenyl - H CH3 phenyl II/1
CH(CH3)z
/H+
H
15
/ / C phenyl - CH3 CH3 phenyl II/1
CH(CH3)z
/H+
H C
3
16
/ / C phenyl - H CH3 phenyl II/1
CH(CH3)z
/ H
H
iii
17
16
CA 02458015 2004-02-18
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Structure X R' R R' R R Formula/
Series
/ / C phenyl - CH3 CH3 phenyl II/1
CH(CH3)2
\ . \
/H+ .''
H3C
~~'rr
18
/ C H -CHZCH3 H CH3 phenyl II/2
H
H / ..,,,
ipr
19 TRANS
/ C H -CHZCH3 H CH3 phenyl II/2
H
N+
H/
20 CIS
/ C H -CHZCH3 CH3 CH3 phenyl II/2
H
C/ ...,,~
H
3
i0
21 TRANS
/ C H -CHZCH3 CH3 CH3 phenyl II/2
H
N+
H3C/
22 CIS
N H -CHZCH3 H CH3 3- II/2
pyridinyl
~
N
H
H / ..,,,~
~i
r
23TRANS
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Structure X R R R3 R R Formula/
Series
/ N H -CHZCH3 H CH3 3- II/2
pyridinyl
N \ H
N+
H/
24 CIS
/ N H -CHZCH3 CH3 CH3 3- II/2
pyridinyl
~
N
H
~~+~
H
c/ ..,~~~
3
~i
25 TRANS
N H -CHZCH3 CH3 CH3 3- II/2
pyridinyl
N \ H
N+
H3C~
26 CIS
c~ / N H -CHZCH3 H CH3 4-chloro-II/2
3-
N ~ H pyridinyl
H / ...oqi
27TRANS
c~ / N H -CHzCH3 H CH3 4-chloro-II/2
3-
~
H pyridinyl
N ~
N+
H/
28 CIS
cn / N H -CHZCH3 CH3 CH3 4-chloro-II/2
3-
N ~ H pyridinyl
C/
H
3
oG
29 TRANS
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Structure X R R R R R Formula/
Series
/ N H -CHZCH3 CH3 CH3 4-chloro-II/2
3-
I
N ~ pyridinyl
H
N+
H3C/
30 CIS
/ / N phenyl -CHZCH3 H CH3 pyridinylII/1
N\ I \
H / o
''~
31
/ / N pyridinyl-CHZCH3 H CH3 pyridinylII/1
N~ I \
H / ...,o
pi
32
/ / N phenyl -CH2CH3 CH3 CH3 pyridinylII/1
N\ I \
C/ ..,,,~0
H
s
4
33
/ / ~ N pyridinyl-CHZCH3 CH3 CH3 pyridinylII/1
N \
C/ ..,,,0
H
3
'4
34
c' / / N phenyl -CHZCH3 H CH3 4-chloro-II/1
3-
N ~ \ pyridinyl
H/
i0
35
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WO 03/018004 PCT/US02/27936
Structure X R R R R R Formula/
Series
c' / / N pyridinyl-CHZCH3 H CH3 4-chloro-II/1
3-
~ ~
\ pyridinyl
H /
~'ii
36
c~ c' N 4-chloro--CHZCH3 H CH3 4-chloro-II/1
/ /
3_ 3_
ridin ridin
\ I 1
pY Y pY Y
H / ...,o
~~i
37
c~ / / N phenyl -CHZCH3 CH3 CH3 4-chloro-II/1
3-
\ pyridinyl
C/ ...,,0
H
s
i
38
c' / / N pyridinyl-CHZCH3 CH3 CH3 4-chloro-II/1
3-
~~
\ pyridinyl
H
c/ ..~
3
~~i
39
/ c~ N 4-chloro--CHZCH3 CH3 CH3 4-chloro-II/1
/
3_ 3_
ridin pyridinyl
\ 1
pY Y
C/ ...,,0
H
3
~4
40
* =N indicates that there is a double bond in the five membered ring between
R' and the
carbon carrying R2.
Compounds where RS bonds to R' such as those set forth below may also be used,
and
can be made through simple alterations to the synthesis of the above
compounds.
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WO 03/018004 PCT/US02/27936
R6 R
Rs Rs ..
where
X and Y are independently selected from the group consisting of C and N;
R3 is as set forth above;
R6 is independently selected from the group consisting of hydrogen, (C,-
C6)alkyl, (C3-
C~)cycloalkyl, (CZ-C6)alkenyl, aryl, and aryl(C,-C6)alkyl, N-methylamino, N,N-
dimethylamino,
carboxylate, (C~-C3)alkylcarboxylate, carboxaldehyde, acetoxy, propionyloxy,
isopropionyloxy,
cyano, aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, carboxamide,
N-
methylcarboxamide, N,N-dimethylcarboxamide, acetyl, propionyl, formyl,
benzoyl, sulfate,
methylsulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol,
methylthio, ethylthio,
propiothiol, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro,
carbamoyl, ureido,
azido, isocyanate, thioisocyanate, hydroxylamino.
Exemplary Syntheses
Figs. 8 and 9 show some exemplary synthesis reactions that may be used to
produce these
compounds. The compounds disclosed in the syntheses include all possible
geometric, racemic,
diasteriomeric, and enantiomeric forms unless otherwise noted. Structures
listed in parentheses
correspond to those listed in the above table. Those skilled in the art will
recognize that these
compounds may be formed by other sythesis reactions, and that simple
modifications to these
syntheses will produce similar products, all of which are considered within
the scope of this
invention.
Series 1
Fig. 8 shows the basic synthesis reaction, which produces Compound (f)
(Structures 9
and 10). First, bromobenzene (a), or bromoheterocycle where X is a heteroatom
at any position,
is mixed with CH3CN and KNHz in liquid ammonia to yield (b). Which is then
mixed with a
second bromobenzene or heterocycle, where Y is a heteroatom selected
independently of X at
any location, with Br2 at 105-110°C to yield the diphenyl cyanide (c).
This product is then
reacted in a basic solution, with t-butylenemethoxylate to yield compound (d).
Compound (d) is
21
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WO 03/018004 PCT/US02/27936
reacted with SOCIz and ammonia to produce compound (f), the amidino analogs.
Those' skilled
in the art will recognize that, in light of this synthesis, compounds 11 and
12, and other
variations, may be made simply by similar methods.
Synthesis of compounds (g), and (~)
The compound (f) is further reacted with 1.2N HCl with NaNOz for about 1 hour
to yield
a compound (g), (Structures 5 and 6). Reaction of this mixture with LAH/THF
yields compound
(j), which also may be used in the methods disclosed herein.
Synthesis of compounds (h) and (k)
Beginning where the reaction left off with compound (g), above, further
reaction with
CH3I substitutes a methyl group to the nitrogen of the five membered ring to
yield compound (h)
(Structures 7 and 8). Compound (k) is achieved by reacting this mixture with
LAH/THF.
Synthesis of compounds (i), (l), (m), (n), (o), and (p)
Picking up the reaction at the formation of compound (h), further reaction
with EtLi to
open the double bonded oxygen yields compound (i) (Structures 33 and 34).
Compound (i) is
then the basis for three other chains of reaction.
Compound (1) is formed by reacting compound (i) with MCPBA and CHC13 for 12
hours
at 0°C. Compound (m) (Structures 1 and 2) is then formed by reacting
this with NaBH4.
Compound (n) (Structures 3 and 4) are produced by reacting compound (i) with
NaBH4.
Compound (i) is reacted with HCHO and CH30H to produce compound (o) (Structure
14), which is then reacted.with Hz and Pd-C to yield Compound (p) (Structures
16, 18).
Series 2
The synthesis reaction for series two is identical to that for series one
except that the
second step of mixing a second bromobenzene (bz), or bromoheterocycle, is
omitted. Similar
mono-phenyl compounds are thus produced. Fig. 9 sets out the synthesis
reaction for series two.
Parrallel compounds to those of Series 1 are indicated with references
characters with the
subscript 2.
Analgesia and Abuse Deterrence
To confirm their suspicions that the compounds of the present invention, do in
fact have
an analgesic effect, the inventors experimented with mice. Fig. 10 shows the
results of an
experiment conducted on naive, adult, Swiss-Webster mice. Each enantiomer of
EDDP, in 40~g
doses, was administered intracerebrally to the mice. The animals were
monitored for baseline
sensitivity using the warm-water tail-withdrawal nociception assay and the
latency to tail
withdrawal was monitored as a measurement of analgesia. The results
demonstrate that tail
withdrawal latency increased with the administration of either enantiomer of
EDDP. Thus, it is
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clear that the d-methadone metabolite EDDP has significant analgesic effect.
Likewise, the
metabolite EMDP and the structural analogs of both EDDP and EMDP are expected
to do the
same. Figs 11 and 12 illustrate the effect of EDDP concentration on the
inhibition of nicotine
activated currents, which is one explanation for the analgesic effect.
As discussed in detail above, the inventors believe the d-methadone
metabolites and their
analogs block the nicotinic a3(34 receptor. Recently, it has been reported
that dextromethorphan
and dextrorphan, a3(34 blockers, actually deter abuse of abusive substances.
Glick et al. report a
decrease in self administration of each of morphine, methamphetamine, and
nicotine in rats
when exposed to 5-30 mg/kg of these specific a3(34 Mockers. Glick SD,
Maisonneuve IM,
Dickinson HA, Kitchen BA; Comparative effects of dextromethorphan and
dextrorphan on
morphine, methamphetamine, and nicotine self administration in rats; Eur J
Pharmacol. 2001 Jun
22;422(1-3):87-90. Because of their discovery that the d-methadone metabolites
and their
structural analogs are a3~i4 blockers, the current inventors contemplate that
the d-methadone
metabolites and their analogs also have such deterrent affects.
The inventors do not wish to be bound by this theory, but believe that the d-
methadone
metabolites or structural analogs interfere with the reward component of the
abusive substance.
The reward component is often thought of as the euphoric effect, as inducing
drug seeking
behavior. The administration of the d-methadone metabolites or structural
analogs interferes
with these effects, and deters abuse as a result. Such administration will aid
in smoking
cessation and deter abuse of more hard core substance.
Accordingly, administration of the d-methadone metabolites or their structural
analogs
can actually deter abuse of abusive substances from the opioids to nicotine.
Administration
The compounds of the present invention may be administered to patients in
effective
amounts or effective doses to alleviate pain and/or deter abuse of an abusive
substance. In
another embodiment, the compounds are administered in combination with abusive
substances,
particularly opioids or other analgesics, in a single pharmaceutical
composition. In this scenario,
the compounds of the present invention contribute to the analgesic effect
while also deterring the
abuse of the companion compound. Thus, patients benefit from the added
analgesic effect of the
compound, while gaining the added benefit of reduced potential for abuse. In
another
embodiment, the compounds of the present invention are administered
independently of an
abusive substance to induce analgesia. In yet another embodiment, the
independent
administration of the compounds serves to deter abuse of a separately
administered abusive
substance.
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By "effective amount," "therapeutic amount," or "effective dose" is meant that
the
amount sufficient to elicit the desired pharmacological or therapeutic effect,
thus resulting in
effective prevention or treatment of the condition or disorder. Thus, when
treating a CNS
disorder, an effective amount of compound is that amount sufficient to pass
across the blood-
s brain barrier of the subject to interact with relevant receptor sites in the
brain of the subject.
Prevention of the condition or disorder is manifested by delaying the onset of
the symptoms of
the condition or disorder. Treatment of the condition or disorder is
manifested by a decrease in
the symptoms associated with the condition or disorder, or an amelioration of
the recurrence of
the symptoms of the condition of disorder.
The effective dose can vary, depending upon factors such as the condition of
the patient,
the severity of the symptoms of the disorder, age, weight, metabolic status,
concurrent
medications, and the manner in which the pharmaceutical composition is
administered.
Typically, the effective dose of compounds generally requires administering
the compound in an
amount of about 0.1 to 500 mg/kg of the subject's weight. In an embodiment of
the present
invention, a dose of about 0.1 to about 300 mg/kg is administered per day
indefinitely or until
symptoms associated with the condition or disorder cease. Preferably, about
1.0 to 50 mg/kg
body weight is administered per day. The required dose is less when
administered parenterally.
Those skilled in the art will recognize that the compounds of the present
invention may
be incorporated with suitable pharmaceutical agents to form a pharmaceutical
composition for
appropriate administration. Such compositions may limit the active ingredient
to a compound of
the present invention, or may optionally include other active ingredients or
multiple compounds
of the present invention.
Pharmaceutical Compositions
The compounds of the present invention are useful in pharmaceutical
compositions for
systemic administration to mammals including humans as a single agent, or as a
primary or
adjunct agent with any other medication, chemical, drug or non-drug therapy,
or combination
thereof. In addition to the compounds, a pharmaceutical composition according
to the invention
may include one or more pharmaceutical agents including earners, excipients,
actives, fillers,
etc.
Administration of the compounds or pharmaceutically acceptable salts or
complexes
thereof can be employed acutely, or as a single dose, or administered
intermittently, or on a
regular schedule of unspecified duration, or by continuous infusion of
unspecified duration, by
an acceptable route of administration including, but not limited to, the oral,
buccal, intranasal,
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WO 03/018004 PCT/US02/27936
pulmonary, transdermal, rectal, vaginal, intradermal, intrathecal,
intravenous, intramuscular,
and/or subcutaneous routes.
The pharmaceutical preparations can be employed in unit dosage forms, such as
tablets,
capsules, pills, powders, granules, suppositories, sterile and parenteral
solutions, or suspensions,
sterile and non-parenteral solutions or suspensions, oral solutions or
suspensions, oil in water or
water in oil emulsions and the like, containing suitable quantities of an
active ingredient.
Topical application can be in the form of ointments, creams, lotions, jellies,
sprays, douches, and
the like. For oral administration either solid or fluid unit dosage forms can
be prepared with the
compounds of the invention.
Either fluid or solid unit dosage forms can be readily prepared for oral
administration.
For example, the compounds can be mixed with conventional ingredients such as
dicalciumphosphate, magnesium aluminum silicate, magnesium stearate, calcium
sulfate, starch,
talc, lactose, acacia, methylcellulose and functionally similar materials as
pharmaceutical
excipients or Garners. A sustained release formulation may optionally be used.
Capsules may be
formulated by mixing the compound with a pharmaceutical diluent which is inert
and inserting
this mixture into a hard gelatin capsule having the appropriate size. If soft
capsules are desired, a
slurry (or other dispersion) of the compound, with an acceptable vegetable,
light petroleum or
other inert oil can be encapsulated by machine into a gelatin capsule.
Suspensions, syrups, and elixirs may be used for oral administration of fluid
unit dosage
forms. A fluid preparation including oil may be used for oil soluble forms. A
vegetable oil, such
as corn oil, peanut oil, or safflower oil, for example, together with
flavoring agents, sweeteners,
and any preservatives produces an acceptable fluid preparation. A surfactant
may be added to
water to form syrup for fluid dosages. Hydro-alcoholic pharmaceutical
preparations may be used
that have an acceptable sweetener, such as sugar, saccharine, or a biological
sweetener and a
flavoring agent in the form of an elixir.
Pharmaceutical compositions for parental and suppository administration can
also be
obtained using techniques standard in the art. Another preferred use of these
compounds is in a
transdermal parenteral pharmaceutical preparation in a mammal such as a human.
The above and other compounds can be present in the reservoir alone, or in
combination
form with pharmaceutical carriers. The pharmaceutical Garners acceptable for
the purpose of
this invention are the art known carriers that do not adversely affect the
drug, the host, or the
material comprising the drug delivery device. Suitable pharmaceutical carriers
include sterile
water, saline, dextrose, dextrose in water or saline, condensation products of
castor oil and
ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole
of castor oil,
CA 02458015 2004-02-18
WO 03/018004 PCT/US02/27936
liquid acid, lower alkanols, oils (such as corn oil, peanut oil, sesame oil
and the like), with
emulsifiers such as mono- or di- glyceride of a fatty acid or a phosphatide
(e.g., lecithin and the
like), glycols, polyalkyne glycols, aqueous media in the presence of a
suspending agent (for
example, sodium carboxymethylcellulose), sodium alginate,
poly(vinylpyrolidone), and the like
(alone or with suitable dispensing agents such as lecithin), or
polyoxyethylene stearate and the
like. The Garner may also contain adjuvants such as preserving, stabilizing,
wetting, emulsifying
agents and the like together with the penetration enhancer of this invention.
Although the invention has been described in connection with specific forms
thereof,
those skilled in the art will appreciate that a wide variety of equivalents
may be substituted for
the specified elements described herein without departing from the scope and
spirit of this
invention as described in the claims below.
26
