Note: Descriptions are shown in the official language in which they were submitted.
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THERAPEUTIC FORMULATIONS FOR THE TREATMENT OF
BETA-AMYLOID RELATED DISEASES
Related Auplications
This application claims priority to U.S. provisional application no.
60/436,379,
filed December 24, 2002, identified by Attorney Docket No. NBI-154-1, entitled
Combination Therapy for the Treatment ofAlzheimer's Disease, U.S. provisional
application 60/482,214, filed June 23 2003, identified by Attorney Docket No.
NBI-154-
2, U.S. utility patent application no. 10/746,138, filed December 24, 2003,
identified by
Attorney Docket No. NBI-154, and International patent application no.
PCT/CA2003/00201 1, identified by NBI-154PC entitled Therapeutic Formulations
for
the Treatment of Beta-Amyloid Related Diseases.
This application is related to U.S. provisional patent application no.
60/480,984,
filed June 23, 2003, identified by Attorney Docket No. NBI-152-1, U.S.
provisional
patent application no. 60/512,116, filed October 17, 2003, identified by
Attorney Docket
1.5 No. NBI-152-2, both entitled, and U.S. application 10/871,549, filed June
18, 2004,
identified by Attorney Docket No. NBI-152, entitled Pharmaceutical
Formulations of
Amyloid-Inhibiting Compounds. This application is related to U.S. provisional
patent
application no. 60/482,058, filed June 23, 2003, identified by Attorney Docket
No. NBI-
156-1, U.S. provisional patent application no. 60/512,135, filed October 17,
2003,
identified by Attorney Docket No. NBI-156-2, both entitled Synthetic Process
for
Preparing Compounds for Treating Amyloidosis, and U.S. application 10/871,543,
filed
June 18, 2004, identified by Attorney Docket No. NBI- 156, entitled Improved
Pharmaceutical Drug Candidates and Methodfor Preparation Thereof. This
application is also related to US provisional patent application no.
60/480,918, filed June
23, 2003, identified by Attorney Docket No. NBI-149-1, U.S. provisional
application
60/512,017, filed October 17, 2003, identified by Attorney Docket No. NBI- 149-
2, and
US patent application no. 10/871,613, filed June 18, 2004, identified by
Attorney Docket
No. NBI- 149 entitled Methods for Treating Protein Aggregation Disorders. This
application,is also related to U.S. provisional patent application no.
60/480,906, filed
June 23, 2003, identified by Attorney Docket No. NBI-162-1, U.S. provisional
patent
1
CA 02582385 2006-12-18
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application no. 60/512,047, filed October 17, 2003, identified by Attorney
Docket No.
NBI-162-2, U.S. application 10/871,514, filed June 18, 2004, identified by
Attorney
Docket No. NBI-162A and U.S. application 10/871,365, filed June 18, 2004,
identified
by Attorney Docket No. NCI-162B, all entitled Methods and Compositions for
Treating
Amyloid-Related Diseases; and U.S. provisional patent application no.
60/480,928, also
filed 23 June 2003, identified by Attorney Docket No. NBI-163-1, U.S.
provisional
patent application no. 60/512,018, filed October 17, 2003, identified by
Attorney Docket
No. NBI-163-2 and U.S. application 10/871,512, filed June 18, 2004, identified
by
Attorney Docket No. NBI-163, all entitled Methods and Compositions for the
Treatment
of Amyloid- and Epileptogenesis-Associated Diseases; This application is also
related to
Methodfor Treating Amyloidosis, U.S. patent application no. 08/463,548, now
U.S. Pat.
No. 5,972,328, identified by Attorney Docket No. NCI-003CP4.
The entire contents of each of the foregoing patent applications and patents
are
expressly incorporated by reference in their entirety including, without
limitation, the
specification, claims, and abstract, as well as any figures, tables, or
drawings thereof.
Background
Alzheimer's disease is a devastating disease of the brain that results in
progressive memory loss leading to dementia, physical disability, and death
over a
relatively long period of time. With the aging populations in developed
countries, the
number of Alzheimer's patients is reaching epidemic proportions.
'People suffering from Alzheimer's disease develop a progressive dementia in
adulthood, accompanied by three main structural changes in the brain: diffuse
loss of
neurons in multiple parts of the brain; accumulation of intracellular protein
deposits
termed neurofibrillary tangles; and accumulation of extracellular protein
deposits termed
amyloid or senile plaques, surrounded by misshapen nerve terminals (dystrophic
neurites). A main constituent of these amyloid plaques is the amyloid-(3
peptide (A(3), a
39-43 amino-acid protein that is produced through cleavage of the (3--amyloid
precursor
protein (APP). Extensive research has been conducted on the relevance of A(3
deposits
in Alzheimer's disease, see, e.g., Selkoe, Trends in Cell Biology 8, 447-453
(1998). A(3
naturally arises from the metabolic processing of the amyloid precursor
protein ("APP")
in the endoplasmic reticulum ("ER"), the Golgi apparatus, or the endosomal-
lysosomal
pathway, and most is normally secreted as a 40 ("A(31-40") or 42 ("A(31-42")
amino
acid peptide (Selkoe, Annu. Rev. Cell Biol. 10, 373-403 (1994)). A role for
A(3 as a
primary cause for Alzheimer's disease is supported by the presence of
extracellular
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amyloid (3 peptide ("Ap") deposits in senile plaques of Alzheimer's disease
("Alzheimer's disease"), the increased production of A(3 in cells harboring
mutant
Alzheimer's disease associated genes, e.g., amyloid precursor protein,
presenilin I and
presenilin II; and the toxicity of extracellular soluble (oligomeric) or
fibrillar A(3 to cells
in culture. See, e.g., Gervais, Eur. Biopharm. Review, 40-42 (Autumn 2001);
May,
DDT 6, 459-62 (2001). Although symptomatic treatments exist for Alzheimer's
disease,
this disease cannot be prevented or cured at this time.
Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral
angiopathy, and neurofibrillary tangles. Plaque and blood vessel amyloid is
believed to
be formed by the deposition of insoluble A(3 amyloid protein, which may be
described as
diffuse or fibrillary. Both soluble oligomeric Ap and fibrillar A(3 are also
believed to be
neurotoxic and inflammatory. Amyloid fibrils, once deposited, can become toxic
to the
surrounding cells. For example, the A(3 fibrils organized as senile plaques
have been
shown to be associated with dead neuronal cells and microgliosis in patients
with
Alzheimer's disease. When tested in vitro, A(3 peptide was shown to be capable
of
triggering an activation process of microglia (brain macrophages), which would
explain
the presence of microgliosis and brain inflammation found in the brain of
patients with
Alzheimer's disease. Once these amyloids have formed, there is no known,
widely
accepted therapy or treatment that significantly dissolves amyloid deposits or
prevents
the formation of deposits in situ . Presently available pharmaceutical
technology for
treatment of R-amyloid diseases is almost entirely symptomatic, providing only
temporary or partial clinical benefit. Although some pharmaceutical agents
have been
described that offer partial symptomatic relief, no comprehensive
pharmacological
therapy is currently available for the treatment of Alzheimer's disease.
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Summary of The Invention
The present invention provides a method of concomitant therapeutic treatment
of
a subject. The method generally includes administering to a subject in need
thereof an
effective amount of a pharmaceutical composition for treating or preventing an
amyloid-
(3 disease such that activities of daily living otherwise impaired by said
amyloid-(3
disease are improved or stabilized. In one embodiment, the pharmaceutical
composition
includes a first agent and a second agent in a pharmaceutically acceptable
carrier,
wherein said first agent prevents or treats amyloid-(3 related disease, and
said second
agent is a therapeutic drug or nutritive supplement.
In another embodiment, the present invention provides a method of preventing
or
treating Alzheimer's disease that includes concomitantly administering to a
subject in
need thereof an effective amount of a first agent that is efficacious in
preventing or
treating Alzheimer's disease in said subject and a second agent, wherein said
first agent
comprises 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt
thereof.
In another embodiment, the present invention provides a method of preventing
or
treating Mild Cognitive Impairment that includes concomitantly administering
to a
subject in need thereof an effective amount of a first agent that is
efficacious in
preventing or treating Mild Cognitive Impairment in said subject and a second
agent,
wherein said first agent comprises 3-amino-l-propanesulfonic acid or a
pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method of
preventing or treating comprising concomitantly administering to a subject in
need
thereof an effective amount of a first agent that is efficacious in preventing
or treating
Mild Cognitive Impairment in said subject and a second agent, wherein said
first agent
2 5 comprises 3-amino-l-propanesulfonic acid or a pharmaceutically acceptable
salt thereof.
In yet another embodiment, the present invention provides a method of
preventing or treating Mild Cognitive Impairment that includes concomitantly
administering to a subject in need thereof an effective amount of a first
agent that is
efficacious in preventing or treating Mild Cognitive Impairment in said
subject and a
second agent, wherein said first agent is 3-amino-1-propanesulfonic acid.
In yet another embodiment, the present invention provides a method of
preventing or treating comprising concomitantly administering to a subject in
need
thereof an effective amount of a first agent that is efficacious in preventing
or treating
Mild Cognitive Impairment in said subject and a second agent, wherein said
first agent is
3-amino-l-propanesulfonic acid. The second agent can be a cholinesterase
inhibitor, a
statin, or memantine.
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Brief Description of the Drawinps
Figures 1-13 and 5-68 depict formulae and compounds of the invention; and
Figure 14 is a graph illustrating that a test drug given concomitantly with
AChE
inhibitors is able to maintain and even improve the cognitive function of
patients.
Detailed Description of the Invention
"Amyloidosis" or "amyloid. disease" refers to a pathological condition
characterized by the presence of amyloid fibers. Amyloid is a generic term
referring to a
group of diverse but specific protein deposits (intracellular or
extracellular) which are
seen in a number of different diseases. Though diverse in their occurrence,
all amyloid
deposits have common morphologic properties, stain with specific dyes (e.g.,
Congo
red), and have a characteristic red-green birefringent appearance in polarized
light after
staining. They also share common ultrastructural features and common X-ray
diffraction and infrared spectra. The term "amyloid-(3 diseases" includes
those diseases,
conditions, pathologies, and other abnormalities of the structure or function
of the brain,
including components thereof, in which the causative agent is amyloid. The
area of the
brain affected in an amyloid-O disease may be the stroma including the
vasculature or
the parenchyma including functional or anatomical regions, or neurons
themselves. A
subject need not have received a definitive diagnosis of a specifically
recognized
amyloid-(3 disease.
Local deposition of amyloid is common in the brain, particularly in elderly
individuals. The most frequent type of amyloid in the brain is composed
primarily of
A(3 peptide fibrils, resulting in dementia associated with sporadic (non-
hereditary)
Alzheimer's disease. In fact, the incidence of sporadic Alzheimer's disease
greatly
exceeds forms shown to be hereditary. Nevertheless, fibril peptides forming
plaques are
very similar in both types.
APP is expressed and constitutively catabolized in most cells. The dominant
catabolic pathway appears to be cleavage of APP within the A(3 sequence by an
enzyme
provisionally termed a-secretase, leading to release of a soluble ectodomain
fragment
known as APPsa. In contrast to this non-amyloidogenic pathway, APP can also be
cleaved by enzymes known as P- and y-secretase at the N- and C-termini of the
A(3,
respectively, followed by release of A(3 into the extracellular space. To
date, BACE has
been identified as R-secretase (Vasser, et al., Science 286:735-741, 1999) and
presenilins
have been implicated in y-secretase activity (De Strooper, et al., Nature 391,
387-90
(1998)).
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The 39-43 amino acid A(3 peptide is produced by sequential proteolytic
cleavage
of the amyloid precursor protein (APP) by the 0 and y secretase enzymes.
Although
A(340 is the predominant form produced, 5-7% of total A(3 exists as A(342
(Cappai
et al., lnt. J. Biochem. Cell Biol. 31. 885-89 (1999)). The length of the A(3
peptide
appears to dramatically alter its biochemical/biophysical properties.
Specifically, the
additional two amino acids at the C-terminus of A(342 are very hydrophobic,
presumably
increasing the propensity of A(342 to aggregate. For example, Jarrett, et al.
demonstrated
that A(342 aggregates very rapidly in vitro compared to A(340, suggesting that
the longer
form of A(3 may be the important pathological proteins that are involved in
the initial
seeding of the neuritic plaques in Alzheimer's disease (Jarrett, et al.,
Biochemistry 32,
4693-97 (1993); Jarrett, et al., Ann. N.Y. Acad. Sci. 695, 144-48 (1993)).
This hypothesis has been further substantiated by the recent analysis of the
contributions of specific forms of A(3 in cases of genetic familial forms of
Alzheimer's
disease ("FAD"). For example, the "London" mutant form of APP (APPV717I)
linked
to FAD selectively increases the production of A(3 42/43 forms versus Ap 40
(Suzuki,
et al., Science 264, 1336-40 (1994)) while the "Swedish" mutant form of APP
(APPK670N/M671L) increases levels of both AP40 and A(342/43 (Citron, et al.,
Nature 360, 672-674 (1992); Cai, et al., Science 259, 514-16, (1993)). Also,
it has been
observed that FAD-linked mutations in the Presenilin-1 ("PS 1") or Presenilin-
2 ("PS2")
genes will lead to a selective increase in A042/43 production but not A040
(Borchelt,
et al., Neuron 17, 1005-13 (1996)). This finding was corroborated in
transgenic mouse
models expressing PS mutants that demonstrate a selective increase in brain
A(342
(Borchelt, op cit.; Duff, et al., Neurodegeneration 5(4), 293-98 (1996)). Thus
the leading
hypothesis regarding the etiology of Alzheimer's disease is that an increase
in AP42
production or release is a causative event in the disease pathology.
Epidemiological studies show that subjects with elevated cholesterol levels
have
an increased risk of Alzheimer's disease (Notkola, et al., Neuroepidemiology
17(1),
14-20 (1998); Jarvik, et al., Neurology 45(6), 1092-96 (1995)). In addition to
the data
which suggests that elevated levels of A(3 are associated with Alzheimer's
disease, other
3o environmental and genetic risk factors have been identified. For example, a
relationship
exists between serum cholesterol levels and the incidence and the
pathophysiology of
Alzheimer's disease. The best studied of these is polymorphism of the
apolipoprotein E
("ApoE") gene: subjects homozygous for the s4 isoform of ApoE (apoE4) have
consistently been shown to have an increased risk for Alzheimer's disease
(Strittmatter,
et al., Proc. Nat'1 Acad. Sci. USA 90:1977-81 (1993). Because ApoE is a
cholesterol
transport protein, several groups have observed a correlation between the risk
of
developing Alzheimer's disease and circulating levels of cholesterol (Mahley,
Science
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240, 622-30 (1998); Saunders, et al., Neurology 43, 1467-72 (1993); Corder, et
al.,
Science 261, 921-23 (1993); Jarvik, et al., Ann. N.Y. Acad. Sci. 826, 128-46
(1997)).
Moreover, cholesterol loading increases the production of A(3 protein (Simons,
et al.,
Proc. Nat'1 Acad. Sci. USA 95, 6460-64 (1998)), while pharmacological
reduction of
cholesterol with the HMG CoA reductase inhibitor simvastatin decreases levels
of both
A(3 -40 and A(3 -42 (Fassbender, et al., Proc. Nat'1 Acad. Sci. USA 98, 5856-
61 (2001))
in vitro. Consistent with these data are the results of epidemiological
studies which have
shown that treatment with certain HMG CoA reductase inhibitors, commonly used
to
normalize cholesterol levels in humans, reduces the prevalence of Alzheimer's
disease
(Wolozin, et al., Arch. Neurol. 57, 1439-43 (2000); Jick, et al., Lancet 356,
1627-31
(2000). Taken together, these data suggest a link between regulation of
cholesterol levels
and Alzheimer's disease. In addition, a relationship with coronary disease has
been
demonstrated (discussed further below).
Amyloid-(3 peptide (Aj3) is a 39-43 amino acid peptide derived by proteolysis
from a large protein known as Beta Amyloid Precursor Protein ("(3APP").
Mutations in
(3APP result in familial forms of Alzheimer's disease, Down's syndrome,
cerebral
amyloid angiopathy, and senile dementia, characterized by cerebral deposition
of
plaques composed of A(3 fibrils and other components, which are described in
further
detail below. Known mutations in APP associated with Alzheimer's disease occur
proximate to the cleavage sites of 0 or -y-secretase, or within A(3. For
example, position
717 is proximate to the site of gamma-secretase cleavage of APP in its
processing to A(3,
and positions 670/671 are proximate to the site of (3-secretase cleavage.
Mutations at
any of these residues may result in Alzheimer's disease, presumably by causing
an
increase in the amount of the 42/43 amino acid form of A(3 generated from APP.
The
familial form of Alzheimer's disease represents only 10% of the subject
population.
Most occurrences of Alzheimer's disease are sporadic cases where APP and A(3
do not
possess any mutation.
The structure and sequence of Ap peptides of various lengths are well known in
the art. Such peptides can be made according to methods known in the art, or
extracted
from the brain according to known methods (e.g., Glenner and Wong, Biochem.
Biophys. Res. Comm. 129, 885-90 (1984); Glenner and Wong, Biochem. Biophys.
Res.
Comm. 122, 1131-35 (1984)). In addition, various forms of the peptides are
commercially available.
As used herein, the terms "j3 amyloid," "amyloid-(3," and the like refer to
amyloid (3 proteins or peptides, amyloid 0 precursor proteins or peptides,
intermediates,
and modifications and fragments thereof, unless otherwise specifically
indicated. In
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particular, "A(3" refers to any peptide produced by proteolytic processing of
the APP
gene product, especially peptides which are associated with amyloid
pathologies,
including A(31-39, A(31-40, A(31-41, A(31-42, and AP1-43. For convenience of
nomenclature, "Ap 1-42" may be referred to herein as "A j3(1-42)" or simply as
"A(342"
or "A(342" (and likewise for any other amyloid peptides discussed herein). As
used
herein, the terms "(3 amyloid," "amyloid-P," and "Ao" are synonymous. Unless
otherwise specified, the term "amyloid" refers to amyloidogenic proteins,
peptides, or
fragments thereof which can be soluble (e.g., monomeric or oligomeric) or
insoluble
(e.g., having fibrillary structure or in amyloid plaque). See, e.g., MP
Lambert, et al.,
z o Proc. Nat'lAcad. Sci. USA 95, 6448-53 (1998).
According to certain aspects of the invention, amyloid-(3 is a peptide having
39-43 amino-acids, or amyloid-(3 is an amyloidogenic peptide produced from
(3APP.
The amyloid-(3 diseases that are the subject of the present invention include
age-related
cognitive decline, early Alzheimer's disease as seen in Mild Cognitive
Impairment
("MCI"), vascular dementia, or Alzheimer's disease ("AD"), which may be
sporadic
(non-hereditary) Alzheimer's disease or familial (hereditary) Alzheimer's
disease. The
amyloid-(3 disease may also be cerebral amyloid angiopathy ("CAA") or
hereditary
cerebral hemorrhage. The amyloid-(3 disease may be senile dementia, Down's
syndrome, inclusion body myositis ("IBM"), or age-related macular degeneration
("ARMD").
The present invention relates to the use of certain compounds, denoted a
"first
agent," representative examples of which include substituted and unsubstituted
alkanesulfonic acids, in combination with a second agent that is biologically
active for
the treatment or prevention of amyloid-(3 diseases, including Alzheimer's
disease and
cerebral amyloid angiopathy. The invention also relates to pharmaceutical
compositions
for the prevention or treatment of such diseases and methods of preparing and
using
these compositions.
The invention pertains to pharmaceutical compositions and methods of use
thereof for the treatment of amyloid-P diseases. The pharmaceutical
compositions
comprise a first agent that treats or prevents an amyloid-(3 disease, e.g., by
preventing or
inhibiting amyloid-(3 fibril formation, neurodegeneration, or cellular
toxicity. The
pharmaceutical composition also comprises a second agent that is an active
pharmaceutical ingredient; that is, the second agent is therapeutic and its
function is
beyond that of an inactive ingredient, such as a pharmaceutical carrier (or
vehicle),
preservative, diluent, or buffer. The second agent may be useful in treating
or
preventing an amyloid-(3 disease or another neurological disease. The first
and second
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agents may exert their biological effects by similar or unrelated mechanisms
of action;
or either one or both of the first and second agents may exert their
biological effects by a
multiplicity of mechanisms of action. A pharmaceutical composition may also
comprise
a third compound, or even more yet, wherein the third (and fourth, etc.)
compound has
the same characteristics of a second agent.
It should be understood that the pharmaceutical compositions described herein
may have the first and second, third, or additional agents in the same
pharmaceutically
acceptable carrier or in a different pharmaceutically acceptable carrier for
each described
embodiment. It further should be understood that the first, second, third and
additional
agent may be administered simultaneously or sequentially within described
embodiments. Alternatively, a first and second agent may be administered
simultaneously, and a third or additional agent may be administered before or
after the
first two agents.
The term "com.bination" as in the phrase "a first agent in combination with. a
second agent" includes co-administration of a first agent and a second agent,
which for
example may be dissolved or intermixed in the same pharmaceutically acceptable
carrier, or administration of a first agent, followed by the second agent, or
administration
of the second agent, followed by the first agent. The present invention,
therefore, relates
to methods of combination therapeutic treatment and combination pharmaceutical
compositions.
The term "conco.m.itant" as in the phrase "concomitant therapeutic treatment"
includes administering an agent in the presence of a second agent. A
concomitant
therapeutic treatment method includes methods in which the first, second,
third, or
additional agents are co-administered. A concomitant therapeutic treatment
method also
includes methods in which the first or additional agents are administered in
the presence
of a second or additional agents, wherein the second or additional agents, for
example,
may have been previously administered. A concomitant therapeutic treatment
method
may be executed step-wise by different actors. For example, one actor may
administer
to a subject a first agent and a second actor may administer to the subject a
second agent,
and the administering steps may be executed at the same time, or nearly the
same time,
or at distant times, so long as the first'agent (and additional agents) are
after
administration in the presence of the second agent (and additional agents).
The actor
and the subject may be the same entity (e.g., human).
The combination of agents used within the methods and pharmaceutical
compositions described herein may have a therapeutic additive or synergistic
effect on
the condition(s) or disease(s) targeted for treatment. The combination of
agents used
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within the methods or pharmaceutical compositions described herein also may
reduce a
detrimental effect associated with at least one of the agents when
administered alone or
without the other agent(s) of the particular pharmaceutical composition. For
example,
the toxicity of side effects of one agent may be attenuated by another agent
of the
composition, thus allowing a higher dosage, improving patient compliance, and
improving therapeutic outcome. Physicians may achieve the clinical benefits of
previously recognized drugs while using lower dosage levels, thus minimizing
adverse
side effects. The additive or synergistic effects, benefits, and advantages of
the
compositions apply to classes of therapeutic agents, either structural or
functional
1 o classes, or to individual compounds themselves.
The present methods and compositions relate to the treatment of amyloid-(3
diseases and conditions. As explained elsewhere herein, the various diseases
and
conditions involve several biological processes that produce the clinically
recognized
disease or condition. The inventors believe that targeting more than one of
these
biological processes simultaneously by the concomitant methods described
herein
enhances the therapeutic benefits of the individual agents. For example,
potentiating the
activity of the acetylcholine secreted by the remaining cholinergic neurons by
administering cholinesterase inhibitors, while at the same time preventing
further
neuronal loss by enhancing clearance of A(3 from the brain, is clearly
desirable
compared to the use of only one individual treatment. Because the therapeutic
targets
outlined herein are independent, yet interconnected, it is desirable to act on
more than
one target at the same time. Two agents administered simultaneously and acting
on
different targets may act synergistically to modify or ameliorate disease
progression or
symptoms. Accordingly, one embodiment of the invention is concomitant therapy
with
a pharmaceutical composition described herein. In another embodiment, the
combination of the first agent of the invention with a second (therapeutic)
agent
produces an enhanced therapeutic profile, for example, a profile that is
greater than the
sum of the benefits of the treatment with each agent independently.
In addition, Alzheimer's disease patients often suffer from secondary
conditions
such as depression, delusions and psychosis, or sleep disturbance. From the
point of
view of ease of manufacture, patient compliance, and ease of administration,
it is
advantageous to combine multiple medicines that the Alzheimer's patient self-
administers into one combined medicament. Because of cognitive impairment,
patient
compliance among Alzheimer's disease patients is very low, and therefore the
methods
and pharmaceutical compositions of the present invention are especially
advantageously
applied to the treatment of this subject population because this combination
of medicines
is less likely to result in forgotten doses and may produce greater
compliance.
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Combination of the compounds of the invention (i.e., the first agents of the
compositions
discussed below) with other palliative medications, which may be for diseases
other than
Alzheimer's, is another beneficial application of the present invention.
In one embodiment, the pharmaceutical compositions disclosed herein prevent or
inhibit amyloid protein assembly into insoluble fibrils which, in vivo, are
deposited in
various organs, or it reverses or favors deposition in subjects already having
deposits. In
another embodiment, the compound may also prevent the amyloid protein, in its
soluble,
oligomeric form or in its fibrillar form, from binding or adhering to a cell
surface and
causing cell damage or toxicity. In yet another embodiment, the composition
may block
amyloid-induced cellular toxicity or microglial activation. In another
embodiment, the
compound may block amyloid-induced neurotoxicity.
The pharmaceutical compositions of the invention may be administered
therapeutically or prophylactically to treat diseases associated with amyloid-
(3 fibril
formation, aggregation or deposition. The pharmaceutical compositions of the
invention
may act to ameliorate the course of an amyloid-(3 related disease using any of
the
following mechanisms (this list is meant to be illustrative and not limiting):
slowing the
rate of amyloid-P fibril formation or deposition; lessening the degree of
amyloid-(3
deposition; inhibiting, reducing, or preventing amyloid-(3 fibril formation;
inhibiting
neurodegeneration or cellular toxicity induced by amyloid-(3; inhibiting
amyloid-(3
induced inflammation; or enhancing the clearance of amyloid-(3 from the brain.
The invention pertains to a pharmaceutical composition for the treatment of an
amyloid-(3 disease comprising a first agent and a second agent in a
pharmaceutically
acceptable carrier, where the first agent prevents or inhibits amyloid-(3
fibril formation,
neurodegeneration, or cellular toxicity; and the second agent is a therapeutic
drug or
nutritive supplement.
Similarly, the invention includes a pharmaceutical composition for the
treatment
of an amyloid-(3 disease comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein the first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and the
second agent
is a therapeutic drug or nutritive supplement, such that cognitive function is
stabilized or
further deterioration in cognitive function is prevented, slowed, or stopped.
In another embodiment, the invention is a pharmaceutical composition for the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and the
second agent
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is a therapeutic drug or nutritive supplement, such that activities of daily
living
otherwise impaired by an amyloid-(3 disease are improved or stabilized.
In yet another embodiment, the invention is a pharmaceutical composition for
the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and the
second agent
is a therapeutic drug or nutritive supplement, such that the pharmaceutical
composition
inhibits an interaction between an amyloidogenic protein and a glycoprotein or
proteoglycan constituent of a basement membrane to thereby prevent or inhibit
amyloid
1o deposition.
Further aspects of the invention include a pharmaceutical composition for the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and the
second agent
is a therapeutic drug or nutritive supplement, such that the concentration of
amyloid-(3
or tau in the CSF of the subject changes versus an untreated subject.
A pharmaceutical composition for the treatment of an amyloid-(3 disease is
also
within the scope of the invention in which the composition has a first agent
and at least
two second agents in a pharmaceutically acceptable carrier, wherein the first
agent
prevents or inhibits amyloid-(3 fibril formation, neurodegeneration, or
cellular toxicity;
and each of the second agent is a therapeutic drug or nutritive supplement.
Also included is a pharmaceutical composition for the treatment of an amyloid-
(3
disease comprising a first agent and a second agent in a pharmaceutically
acceptable
carrier, wherein the first agent binds amyloid-P; and the second agent is a
therapeutic
drug or nutritive supplement; such that amyloid-(3 fibril formation,
neurodegeneration,
or cellular toxicity in the subject is prevented or inhibited.
Another example of the invention is a pharmaceutical composition for the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent binds amyloid-(3;
and the
second agent is a therapeutic drug or nutritive supplement; such that
cognitive function.
is stabilized or further deterioration in cognitive function is prevented,
slowed, or
stopped in the subject.
In another aspect, the invention pertains to a pharmaceutical composition for
the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent binds amyloid-(3;
and the
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second agent is a therapeutic drug or nutritive supplement; such that
activities of daily
living otherwise impaired by the amyloid-(3 disease are improved or stabilized
in the
subject.
The invention also includes a pharmaceutical composition for the treatment of
an
amyloid-(3 disease comprising a first agent and a second agent in a
pharmaceutically
acceptable carrier, wherein the first agent binds amyloid-0; and the second
agent is a
therapeutic drug or nutritive supplement; such that the pharmaceutical
composition
inhibits an interaction between an amyloidogenic protein and a glycoprotein or
proteoglycan constituent of a basement membrane to thereby prevent or inhibit
amyloid
deposition in the subject.
Furthermore, the invention may be a pharmaceutical composition for the
treatment of an amyloid-(3 disease comprising a first agent and a second agent
in a
pharmaceutically acceptable carrier, wherein the first agent binds amyloid-0;
and the
second agent is a therapeutic drug or nutritive supplement; such that the
concentration of
amyloid-(3 or tau in the CSF of the subject changes versus an untreated
subject.
In another representation, the invention is a pharmaceutical composition for
the
treatment of an amyloid-(3 disease comprising a first agent and at least two
second
agents in a pharmaceutically acceptable carrier, wherein the first agent binds
amyloid-(3;
and the second agent is a therapeutic drug or nutritive supplement; such that
amyloid-(3
fibril formation, neurodegeneration, or cellular toxicity in the subject is
prevented or
inhibited.
The invention also relates to methods of making pharmaceutical compositions
for use in the therapeutic and prophylactic methods described herein. The
first agent and
the second agent are supplied as a pharmaceutical product, and they may be
packaged in
separate containers for sale or delivery to the consumer. The first agent and
the second
agent may be dissolved in a liquid pharmaceutically acceptable carrier, or
they may be
provided in a solid formulation, for example, as a homogenous mixture in a
capsule or
pill. The pharmaceutical compositions may further comprise a pharmaceutically
acceptable acid, base, buffering agent, inorganic salt, solvent, or
preservative.
Furthermore, the pharmaceutical compositions of the invention may also include
a
compound that increases the cerebral bioavailability of either the first agent
or the
second agent. The invention also relates to the use of a first agent and a
second agent in
the preparation of a pharmaceutical composition for the treatment or
prevention of an
amyloid-(3 disease comprising a first agent and a second agent in a
pharmaceutically
acceptable carrier, wherein the first agent prevents or inhibits amyloid-(3
fibril
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NB I-154CPPC
formation, neurodegeneration, or cellular toxicity; and the second agent is a
therapeutic
drug or nutritive supplement.
The term "container" includes any receptacle for holding the therapeutic
formulation. For example, in one embodiment, the container is the packaging
that
contains the formulation. In other embodiments, the container is not the
packaging that
contains the formulation, i.e., the container is a receptacle, such as a box
or vial that
contains the packaged formulation or unpackaged formulation and the
instructions for
use of the formulation. Moreover, packaging techniques are well known in the
art. It
should be understood that the instructions for use of the therapeutic
formulation may be
contained on the packaging containing the therapeutic formulation, and as such
the
instructions form an increased functional relationship to the packaged
product.
Pharmaceutical compositions of the invention may be effective in controlling
amyloid-(3 deposition either following their entry into the brain (following
penetration
of the blood brain barrier) or from the periphery. When acting from the
periphery, a
ls compound of a pharmaceutical composition may alter the equilibrium of A(3
between the
brain and the plasma so as to favor the exit of A(3 from the brain. An
increase in the exit
of A(3 from the brain would result in a decrease in Aj3 brain concentration
and therefore
favor a decrease in A(3 deposition. Alternatively, compounds that penetrate
the brain
could control deposition by acting directly on brain A(3 e.g., by maintaining
it in a non-
fibrillar form or favoring its clearance from the brain, or protecting brain
cells from the
detrimental effect of A(3. These compounds could also prevent A(3 in the brain
from
interacting with a cell surface and therefore prevent neurotoxicity or
inflammation.
In some aspects the pharmaceutical compositions of the invention contain a
first
agent that prevents or inhibits 0-amyloid fibril formation, either in the
brain or other
organ of interest (acting locally) or throughout the entire body (acting
systemically).
Without wishing to be bound by theory, the inventors believe that the first
agent as
described herein may inhibit or reduce an interaction between amyloid-(3 and a
cell
surface constituent, for example, a glycosaminoglycan or proteoglycan
constituent of a
basement membrane, and that inhibiting or reducing this interaction is
primarily
responsible for the observed neuroprotective effects. For example, the first
agent may
also prevent an amyloid-(3 peptide from binding or adhering to a cell surface,
a process
which is known to cause cell damage or toxicity. Similarly, the first agent
may block
amyloid-induced cellular toxicity or microglial activation or amyloid-induced
neurotoxicity, or inhibit amyloid-(3 induced inflammation. The first agent may
also
reduce the rate or amount of (3-amyloid aggregation, fibril formation, or
deposition, or
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the first agent lessens the degree of amyloid-(3 deposition. The first agent
may also
inhibit, reduce, or prevent amyloid-(3 fibril formation.
Additionally, the first agent may enhance the clearance of amyloid-(3 from the
brain; or the first agent may favorably alter the equilibrium of amyloid-(3
between the
brain and the plasma to decrease the amount of amyloid-(3 in the brain. The
first agent
may lower the levels of amyloid (3 peptides, e.g., both A(340 and A(342 in the
CSF and
the plasma, or the first agent may lower the levels of amyloid 0 peptides,
e.g., A(340 and
Aj342 in the CSF and increase it in the plasma.
Regardless of the particular mechanism by which the first agent exerts its
biological effects, the first agent prevents or treats amyloid-(3 diseases,
such as for
example Alzheimer's disease. The first agent may reverse or favor deposition
of
amyloid in a subject having amyloid deposits, or the first agent may favor
plaque
clearance or slow deposition in a subject having amyloid deposits. For
example, the first
agent decreases the amyloid-(3 concentration in the brain of a subject versus
an untreated
subject, and the first agent penetrates into the brain, that is, it crosses
the blood-brain
barrier ("BBB") where is exerts it biological effect. Therefore, the first
agent may
maintain soluble amyloid in a non-fibrillar form. Accordingly, the first agent
may
increase the rate of clearance of soluble amyloid from the brain of a subject
versus an
untreated subject.
The invention also includes a method of concomitant therapeutic treatment of a
subject, comprising administering to a subject in need thereof an effective
amount of a
pharmaceutical composition for treating or preventing an amyloid-(3 disease,
said
pharmaceutical composition comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein said first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and said
second
agent is a therapeutic drug or nutritive supplement.
Also within the purview of the invention is a method of concomitant
therapeutic
treatment of a subject, comprising administering to a subject in need thereof
an effective
amount of a pharmaceutical composition for treating or preventing an amyloid-
(3
3o disease, said pharmaceutical composition comprising a first agent and a
second agent in
a pharmaceutically acceptable carrier, wherein said first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and said
second
agent is a therapeutic drug or nutritive supplement, such that cognitive
function is
stabilized or further deterioration in cognitive function is prevented,
slowed, or stopped.
Similarly, the invention is a method of concomitant therapeutic treatment of a
subject, comprising administering to a subject in need thereof an effective
amount of a
CA 02582385 2006-12-18
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pharmaceutical composition for treating or preventing an amyloid-(3 disease,
said
pharmaceutical composition comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein said first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and said
second
agent is a therapeutic drug or nutritive supplement, such that activities of
daily living
otherwise impaired by said amyloid-(3 disease are improved or stabilized.
In another embodiment, the invention is a method of concomitant therapeutic
treatment of a subject, comprising administering to a subject in need thereof
an effective
amount of a pharmaceutical composition for treating or preventing an amyloid-
(3
disease, said pharmaceutical composition comprising a first agent and a second
agent in
a pharmaceutically acceptable carrier, wherein said first agent prevents or
inhibits
amyloid-j3 fibril formation, neurodegeneration, or cellular toxicity; and said
second
agent is a therapeutic drug or nutritive supplement, such that said
pharmaceutical
composition inhibits an interaction between an amyloidogenic protein and a
glycoprotein or proteoglycan constituent of a basement membrane to thereby
prevent or
inhibit amyloid deposition.
In yet another embodiment, the invention may be a method of concomitant
therapeutic treatment of a subject, comprising administering to a subject in
need thereof
an effective amount of a pharmaceutical composition for treating or preventing
an
amyloid-(3 disease, said pharmaceutical composition comprising a first agent
and a
second agent in a pharmaceutically acceptable carrier, wherein said first
agent prevents
or inhibits amyloid-(3 fibril formation, neurodegeneration, or cellular
toxicity; and said
second agent is a therapeutic drug or nutritive supplement, such that the
concentration of
amyloid-j3 or tau in the CSF of said subject changes versus an untreated
subject.
The invention also pertains to a method of concomitant therapeutic treatment
of a
subject, comprising administering to a subject in need thereof an effective
amount of a
pharmaceutical composition for treating or preventing an amyloid-(3 disease,
said
pharmaceutical composition comprising a first agent and at least two second
agents in a
pharmaceutically acceptable carrier, wherein said first agent prevents or
inhibits
amyloid-(3 fibril formation, neurodegeneration, or cellular toxicity; and each
of said
second agent is a therapeutic drug or nutritive supplement.
In other aspects, the invention is a method of concomitant therapeutic
treatment
of a subject, comprising administering to a subject in need thereof an
effective amount
of a pharmaceutical composition for treating or preventing an amyloid-(3
disease, said
pharmaceutical composition comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein said first agent binds amyloid-0;
and said
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NBI- I 54CPPC
second agent is a therapeutic drug or nutritive supplement; such that amyloid-
(3 fibril
formation, neurodegeneration, or cellular toxicity in said subject is
prevented or
inhibited.
In further aspects, the invention is a method of concomitant therapeutic
treatment
of a subject, comprising administering to a subject in need thereof an
effective amount
of a pharmaceutical composition for treating or preventing an amyloid-(3
disease, said
pharmaceutical composition comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein said first agent binds amyloid-
(3; and said
second agent is a therapeutic drug or nutritive supplement; such that
cognitive function
is stabilized or further deterioration in cognitive function is prevented,
slowed, or
stopped in said subject.
Another method of concomitant therapeutic treatment of a subject of the
invention comprises administering to a subject in need thereof an effective
amount of a
pharmaceutical composition for treating or preventing an amyloid-P disease,
said
pharmaceutical composition comprising a first agent and a second agent in a
pharmaceutically acceptable carrier, wherein said first agent binds amyloid-
(3; and said
second agent is a therapeutic drug or nutritive supplement; such that
activities of daily
living otherwise impaired by said amyloid-(3 disease are improved or
stabilized in said
subject.
Additionally, the invention pertains to a method of concomitant therapeutic
treatment of a subject, comprising administering to a subject in need thereof
an effective
amount of a pharmaceutical composition for treating or preventing an amyloid-
(3
disease, said pharmaceutical composition comprising a first agent and a second
agent in
a pharmaceutically acceptable carrier, wherein said first agent binds amyloid-
(3; and said
second agent is a therapeutic drug or nutritive supplement; such that said
pharmaceutical
composition inhibits an interaction between an amyloidogenic protein and a
glycoprotein or proteoglycan constituent of a basement membrane to thereby
prevent or
inhibit amyloid deposition in said subject.
A further example of the invention is a method of concomitant therapeutic
treatment of a subject, comprising administering to a subject in need thereof
an effective
amount of a pharmaceutical composition for treating or preventing an amyloid-
(3
disease, said pharmaceutical composition comprising a first agent and a second
agent in
a pharmaceutically acceptable carrier, wherein said first agent binds amyloid-
0; and said
second agent is a therapeutic drug or nutritive supplement; such that the
concentration of
amyloid-(3 or tau in the CSF of said subject changes versus an untreated
subject.
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NBI-154CPPC
In another embodiment, the invention is a method of concomitant therapeutic
treatment of a subject, comprising administering to a subject in need thereof
an effective
amount of a pharmaceutical composition for treating or preventing an amyloid-
(3
disease, said pharmaceutical composition comprising a first agent and at least
two
second agents in a pharmaceutically acceptable carrier, wherein said first
agent binds
amyloid-j3; and said second agent is a therapeutic drug or nutritive
supplement; such
that amyloid-P fibril formation, neurodegeneration, or cellular toxicity in
said subject is
prevented or inhibited.
As used herein, "coinbination therapy" or "tlierapeutic combination" means the
administration of two or more "first agents," e.g., compounds represented by
Formulae (I-X), or administration of one or more first agents, such as
compounds
represented by Formulae (I-X) with other Alzheimer's disease treatments
different from
the first agent, as discussed below, e.g., cholesterol biosynthesis inhibitors
or lipid-
lowering agents, to prevent or treat Alzheimer's Disease, by for example
reducing levels
of one or more amyloid (3 peptides, regulating production of amyloid (3
peptides or
regulating levels of ApoE isoform 4 in the bloodstream or the brain. Such
administration includes coadministration of these therapeutic agents in a
substantially
simultaneous manner, such as in a single tablet or capsule having a fixed
ratio of active
ingredients or in multiple, separate capsules for each therapeutic agent.
Also, such
administration includes use of each type of therapeutic agent in a sequential
manner. In
either case, the treatment using the combination therapy will provide
beneficial effects in
treating the condition. A potential advantage of the combination therapy
disclosed
herein may be a reduction in the required amount of an individual therapeutic
compound
or the overall total amount of therapeutic compounds that are effective in
treating the
2 5 condition. By using a combination of therapeutic agents, the side effects
of the
individual compounds can be reduced as compared to a monotherapy, which can
improve subject compliance. Also, therapeutic agents can be selected to
provide a
broader range of complimentary effects or complimentary modes of action.
According to the invention, "combination therapy" also includes simultaneous
co-administration of a first agent (e.g., an alkanesulfonic acid) and a second
agent; and
the term also includes methods comprising the steps of administration of the
first agent,
followed by the second agent, or treatment and administration of the second
agent,
followed by administration of the first agent.
In one embodiment of the present invention, the therapeutic value of the first
agent is enhanced or maximized by co-administration with a second agent. The
second
agent may facilitate and/or enhance the activity or efficacy of the first
agent by the same
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NBI-I54CPPC
and/or complementary mechanisms of action. For example, the first agent may
prevent
or inhibit amyloid-B fibril formation and the second agent may have a
complementary
effect of altering the biodistribution and/or the equilibrium amount of the
aggregation
forms for amyloid-B. Additionally or alternatively, the second agent may
alleviate one
or more symptoms of the diseases addressed herein, e.g., it may enhance
cognitive
function or memory, or treat depression.
Some general examples of compounds that may be used as a second agent
according to the invention include neuro-transmission enhancers;
psychotherapeutic
drugs; acetylcholineesterase inhibitors; calcium channel blockers; biogenic
amines;
benzodiazepine tranquilizers; acetylcholine synthesis, storage, or release
enhancers;
acetylcholine postsynaptic receptor agonists; monoamine oxidase-A or -B
inhibitors;
N-methyl-D-aspartate glutamate receptor antagonists; nonsteroidal anti-
inflammatory
drugs; antioxidants; and serotonergic receptor antagonists.
Additional examples of compounds that may be used as a second agent
according to the invention include agents that enhance acetylcholine
synthesis, storage,
or release, such as phosphatidylcholine, 4-aminopyridine, bifemelane,
3,4-diaminopyridine, choline, vesamicol, secoverine, bifemelane,
tetraphenylurea, and
nicotinamide; postsynaptic receptor agonists, such as arecoline, oxotremorine,
bethanechol, ethyl nipecotate, and levacecarnine;lV-methyl-D-aspartate
glutamate
receptor antagonists, such as milacemide and memantine; specific monoamine
oxidase A
inhibitors, such as moclobemide; monoamine oxidase B inhibitors, such as
selegiline;
thiamine and sulbutiamine; D-cycloserine; anfacine; linopirdine; deferoxamine
and
nonsteroidal anti-inflammatory drugs; serotoneregic receptor antagonists, such
as
ketanserin and mianserin; vasodilator or other nootropic direct brain
metabolic enhancer
drugs such as idebenone, bromvincamine, propentophylline, pentoxifylline,
citicoline,
piracetam, oxiracetam, aniracetam, pramiracetam, pyroglutamic acid,
tenilsetam,
rolziracetam, etiracetam, dupracetam, vinpocetine (CavintonTM, Chemical Works
of
Gedeon Richter, Ltd., Budapest, Hungary), ebiratide, P-carbolines (e.g., ethyl-
5-
isopropyloxy-4-methyl-(3-carboline-3-carboxylate and N'-methyl-(3-carboline-3-
carboximide, methyl-6,7-dimethoxy-4-ethyl-(3-carboline-3-carboxylate, and
ethyl 5-
methoxy-4-ethyl-(3-carboline-3-carboxylate), naloxone, ergoloid mesylates
(e.g.,
Hydergine), cyclandelate, isoxsuprene, nafronyl, papaverine, suloctidil,
vinburnine,
vincamine, vindeburnol, flunarizine, nimodipine, nicergoline, razobazam,
exifone,
rolipram, sabeluzole, phosphatidylserine, and ifenprodil; neurotransmission
enhancers,
such as amantadine, calcium hopantenate, lisuride, bifemelane, and
indeloxazine;
tiapride, a selective D2 antagonist; psychotherapeutic drugs, such as
haloperidol,
bromperidol, thioridazine, thiothixene, fluphenazine, perphenazine, and
molindone;
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NBI-154CPPC
antioxidants, such as tocopherols, ascorbic acid, and deferoxamine;
acetylcholinesterase
inhibitors, such as physostigmine (optionally with lecithin),
heptylphysostigmine,
tetrahydroaminoacridine (tacrine) and a the related compound 9-amino-
1,2,3,4-tetrahydroacridin-l-ol, metrifonate, velnacrine maleate, sulfonyl
fluorides (e.g.,
methanesulfonyl fluoride and phenylmethanesulfonyl fluoride), huperzines A and
B,
galanthamine, edrophonium and miotine and derivatives therof; calcium channel
blocker
agents, such as diltiazem, verapamil, nifedipine, nicardipine, isradipine,
amlodipine and
felodipine; biogenic amines and related compounds, such as clonidine (a
noradrenergic
a2-receptor agonist), guanfacine (an adrenergic agonist), alaproclate,
fipexide,
zimeldine, and citalopram; anti-rage drugs, such as propranolol,
carbamazepine, and
fluoxetine; minor tranquilizers such as benzodiazepine agents; and angiotensin-
converting enzyme inhibitors, such as captopril (CapotenTM and CapozideTM
(Bristol-
Myers Squibb Co., New York, New York). See, e.g., R. Anand, et al., Adv.
Neurol. 51,
261-68 (1990); W.G. Bradley, Muscle & Nerve 13, 833-42 (1990); V. Chan-Palay,
Psychopharmacology 106, S 137-S139 (1992); J.K. Cooper, et al., Arch. Intern.
Med.
151, 245-49 (1991); N.R. Cutler, et al., Ann. Pharmacother. 26, 1118-22
(1992);
P. Davies, Clin. Neuropharmacol. 14(Suppl. 1), S24-S33 (1991); M.W. Dysken, et
al., J.
Am. Geriatr. Soc. 40, 503-06 (1992); S.H. Ferris, Acta Neurol. Scand. Suppl.
129, 23-26
(1990); P.T. Francis, et a1., Ann. N.Y. Acad. Sci. 640, 184-88 (1991); D.
Groo, et al.,
Drug Dev. Res. 11, 29-36 (1987); A.L. Harvey, Adv. Neurol. 51, 227-33 (1990);
P.L. McGeer, et al., Neurology 42, 447-49 (1992); L. Parnetti, et al., Eur. J.
Clin.
Pharmacol. 42, 89-93 (1992); M. Shimizu, et al., Alzheimer's Dis. Assoc.
Disord.
5(Suppl. 1), S13-S24 (1991); J.E. Sweeney, et al., Psychopharmacology 102, 191-
200
(1990); P.J. Whitehouse, Alzheimer Dis. Assoc. Disord. 5(Suppl. 1), S32-S36
(1991);
and R.J. Wurtman, et al., Adv. Neurol. 51, 117-25 (1990).
In another aspect of the invention, the amyloid-(3 peptide is a peptide having
39-43 amino-acids, which is an amyloidogenic peptide produced from PAPP.
The "amyloid-(3 disease" (or "am.yloid-(3 related disease," which terms as
used
herein are synonymous) may be Mild Cognitive Impairment; vascular dementia;
Alzheimer's disease, including sporadic (non-hereditary) Alzheimer's disease
and
familial (hereditary) Alzheimer's disease; cerebral amyloid angiopathy or
hereditary
cerebral hemorrhage; senile dementia; Down's syndrome; inclusion body
myositis; or
age-related macular degeneration.
In another embodiment, the method is used to treat Alzheimer's disease (e.g.,
sporadic or familial Alzheimer's disease). The method can also be used
prophylactically
or therapeutically to treat other clinical occurrences of amyloid-(3
deposition, such as in
CA 02582385 2006-12-18
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Down's syndrome individuals and in subjects with cerebral amyloid angiopathy
("CAA") or hereditary cerebral hemorrhage.
Cerebral amyloid angiopathy ("CAA") refers to the specific deposition of
amyloid fibrils in the walls of leptomingeal and cortical arteries, arterioles
and in
capillaries and veins. It is commonly associated with Alzheimer's disease,
Down's
syndrome and normal aging, as well as with a variety of familial conditions
related to
stroke or dementia (see Frangione, et al., Amyloid: J. Protein Folding Disord.
8,
Suppl. 1, 36-42 (2001)). CAA can occur sporadically or be hereditary. Multiple
mutation sites in either A(3 or the APP gene have been identified and are
clinically
associated with either dementia or cerebral hemorrhage. Exemplary CAA
disorders
include, but are not limited to, hereditary cerebral hemorrhage with
amyloidosis of
Icelandic type (HCHWA-I); the Dutch variant of HCHWA (HCHWA-D; a mutation in
A(3); the Flemish mutation of A(3; the Arctic mutation of A(3; the Italian
mutation of A(3;
the Iowa mutation of A(3; familial British dementia; and familial Danish
dementia.
Additionally, abnormal accumulation of APP and of amyloid-P protein in
muscle fibers has been implicated in the pathology of sporadic inclusion body
myositis
("IBM") (Askanas, et al., Proc. Natl. Acad. Sci. USA 93, 1314-19 (1996);
Askanas,
et al., Current Opinion in Rheumatology 7, 486-96 (1995)). Accordingly, the
compounds of the invention can be used prophylactically or therapeutically in
the
treatment of disorders in which amyloid-(3 protein is abnormally deposited at
non-
neurological locations, such as treatment of IBM by delivery of the compounds
to
muscle fibers.
Additionally, it has been shown that A(3 is associated with abnormal
extracellular
deposits, known as drusen, that accumulate along the basal surface of the
retinal
,=
pigmented epithelium in individuals with age-related macular degeneration
(ARMD).
ARMD is a cause of irreversible vision loss in older individuals. It is
believed that Ap
deposition could be an important component of the local inflammatory events
that
contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis,
and the
pathogenesis of ARMD (Johnson, et al., Proc. Natl. Acad. Sci. USA 99(18),
11830-5
(2002)). Therefore, the invention also relates to the treatment or prevention
of age-
related macular degeneration.
The invention pertains to pharmaceutical compositions and methods of use
thereof for the treatment of amyloid-(3 diseases. The pharmaceutical
compositions
comprise a first agent that, e.g., prevents or inhibits amyloid-(3 fibril
formation,
neurodegeneration, or cellular toxicity. The pharmaceutical composition also
comprises
a second agent that is an active pharmaceutical ingredient; that is, the
second agent is
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NB I-154CPPC
therapeutic and its function is beyond that of an inactive ingredient, such as
a
pharmaceutical carrier, preservative, diluent, or buffer. The second agent may
be useful
in treating or preventing an amyloid-(3 disease or another neurological
disease. The first
and second agents may exert their biological effects by similar or unrelated
mechanisms
of action; or either one or both of the first and second agents may exert
their biological
effects by a multiplicity of mechanisms of action.
Accordingly, in particular embodiments, the invention pertains to
pharmaceutical
compositions and methods of use thereof for the treatment of amyloid diseases,
amyloid-
0 diseases, or Alzheimer's Disease. The pharmacei.utical composition comprises
a first
agent that modulates a first biological process and/or exerts a first
biological effect, and
a second agent that modulates a second biological process and/or exerts a
second
biological effect. The first agent and the second agent may modulate different
biological
processes in the pathogenesis of the disease and/or exert different biological
effects
and/or act on different targets. For example, the first agent may be
therapeutically
useful in the treatment of Alzheimer's disease, and the second agent may be
therapeutically useful in the treatment of CAA, dementia, ALS, or Parkinson's
Disease.
The first agent and the second agent may have different binding affinities or
specificities
for peptides, proteins, or enzymes involved in the pathogenesis of the amyloid
disease
(e.g., Alzheimer's disease). In preferred embodiments, the first agent and the
second
agent, when simultaneously present in a subject, act synergistically to
reduce, inhibit, or
ameliorate the symptoms or pathogenesis of Alzheimer's disease.
A pharmaceutical composition may also comprise a third compound, or even
more yet, wherein the third (and fourth, etc.) compound has the same
characteristics of a
second agent. The "second agent" is selected in accord with the following
therapeutic
principles.
Pharmacologic Treatment of Alzheimer's Disease and Other Am ly oid-J3 Diseases
The pathology of Alzheimer's disease includes a number of characteristic
components, including but not limited to (3-amyloid deposits, such as diffuse
plaques
and senile plaques; cytoskeletal pathology, such as hyperphosphorylated tau
and paired
helical filaments; cholinergic degeneration, such as basal cholinergic
neuronal loss and
reduced ChAT in cortex and septum; inflammation, such as gliosis; and
cognitive and
behavioral dysfunction, such as cognitive loss, apathy and aggression. To
reflect the
varied characteristics of the disease, a variety of therapeutic approaches to
the disease
have been taken. To date, clinically validated treatments for Alzheimer's
disease remain
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confined to symptomatic interventions such as treatment with enhancers of
cognitive
function, e.g., acetylcholinesterase, acetyl/ butyrylcholinesterase
inhibitors, or NMDA
receptor antagonists.
Several broad therapeutic strategies for disease-modifying agents are
currently
being approached. These include, for example, the following: inhibiting the 0
and
gamma- secretase enzymes that generate A(3 from APP; preventing
oligomerization or
fibrillogenesis of A(3 or enhancing its clearance from the brain, e.g. by
active or passive
immunization with A(3, by administering anti-fibrillogenic small molecule
compounds
or peptides, or by metal chelation; blocking or inhibiting inflammation and
neurodegeneration induced by A(3; reducing the formation of phosphorylated Tau
protein in the neurofibrillary tangles; and modulating cholesterol
homeostasis. A range
of compounds with antioxidant, neuroprotective or neurotrophic properties are
contemplated for treating Alzheimer's disease; numerous approaches such as
these and
others are intended to be within the scope of the invention. See, e.g., J.
Hardy, et al.,
Science 297, 353-56 (2002).
There are many different mechanisms by which these therapeutic approaches
could treat Alzheimer's disease. For example, vaccination therapy could
stimulate an
immune response against A(3 peptides, leading to clearance of the peptides
from the
body. J3 and gamma- secretase inhibitors could lead to decreased production of
A(3
peptides. Copper/zinc chelators such as clioquinol could decrease the
interaction of
copper and zinc with A(3 peptides, leading to the clearance of amyloid
plaques.
Activating a-secretase, which cleaves within A(3, would be expected to
decrease the
production of A(3 and is thus another target.
Pathways involved in neurodegeneration or apoptosis are also targets for
therapeutic intervention. For example, the phosphorylation of poly Q ataxin by
the Akt
kinase is required for neurodegeneration, suggesting that the Akt kinase could
be a
target. Orr, et al., Neuron 38(3), 375-87 (2003); Zoghbi, et al., Ce11113(4),
457-68
(2003). Tau is found in neurofibrillary tangles hyperphosphorylated and
inhibition of
the kinases involved in its phosphorylation, e.g., GSK-3, is also a target.
See, e.g.,
WO 96/35,126.
Many strategies for targeting amyloid include, inter alia, preventing
oxidative
damage with anti-oxidants (e.g., melatonin, curcumin); inhibiting amyloid
formation or
deposition with anti-aggregation agents (e.g., peptides, metal chelators,
glycosaminoglycan mimetics); altering APP metabolism (e.g., with wortmannin or
secretase inhibitors); shifting the equilibrium between levels of
amyloidogenic peptides
in the periphery and the central nervous system (e.g., with antibodies,
vaccines, gelsolin,
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GM1, IGF-1) and decreasing microglial activation leading to inflammation
(e.g., Fc,
TGF(31).
Therapeutic treatment strategies may employ anti-fibrillogenic agents. For
example, a therapeutic agent may bind to AR to prevent or inhibit its fibril
formation.
For example, the 16-21 region of the A(3 peptide, KLVFFA, is responsible for
the (3-
sheet formation and the intermolecular interactions of A(3 during
fibrillogenesis.
Peptides from this region have been extensively tested for their
antifibrillogenic activity
(Tjemberg LO, et al., J. Biol. Chem. 272, 12601-05 (1997); Findeis, et al.,
Biochemistry
38, 6791-6800 (1999); Findeis, et al., Amyloid, 231-41 (Dec 2001)). Agents,
including
non-peptidic agents, of the invention may be used as an anti-fibrillogenic
agent in this
way. The non-amyloidogenic pathway may be regulated through phosphorylation
processes. Alteration of PKC levels and activity is one of the most consistent
findings in
Alzheimer's disease brain tissue. In addition, altered signal transduction
mechanisms,
particularly PKC, are found consistently in peripheral tissues from
Alzheimer's disease
i s subjects suggesting that these changes are not secondary to neuronal loss
and may be
directly involved in Alzheimer's disease pathogenesis. Altered APP metabolism
is a key
event in the amyloid cascade hypothesis. The studies on the role of PKC in the
regulated APP processing have established that the A(3 forming amyloidogenic
pathway
and the a -secretase non-amyloidogenic pathway appear to be balanced. The
target of
PKC phosphorylation is not the APP molecule itself, yet the possibility that
PKC targets
directly the a-secretase or other key cellular factors possibly related to the
vesicular
trafficking of APP or the a-secretase, has not been resolved. M. Racchi, et
al.,
Experimental Gerontology 38, 145-57 (2003). Neurofibrillary tangles are
composed of
hyperphosphorylated tau proteins. One or more kinases are principally
responsible for
initiating the hyperphosphorylation of tau in vivo that leads to its apparent
dissociation
from microtubules and aggregation into insoluble paired helical filaments.
Hyperphosphorylation of tau may underlie tangle formation in Alzheimer's
disease.
Calpain is responsible for cleavage of p35 and treating cells with A(3
aggregates can
trigger p35 activation and the subsequent cdk5-mediated phosphorylation of
tau. and
perhaps other cytoplasmic substrates. D. Selkoe, Physiol. Rev. 81(2), 741-66
(2001).
Suitable agents for use in the invention may target any of these biological
processes.
In some cases, one drug may target more than one therapeutic approach. For
example, studies suggest that butyryl cholinesterase inhibitors which inhibit
the activity
of the cholinesterase enzyme are also associated with A(3 (Darvesh, et al.,
Cell. Mol.
Neurobiol. 21, 285-96 (2001)). Phenserine, an acetylcholinesterase inhibitor,
may
inhibit both the activity of the acetylcholinesterase enzyme and the
processing or
translation of the APP mRNA. Cholesterol-lowering drugs such as statins, e.g.
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avorstatin, could increase processing of amyloid precursor protein by alpha-
secretase,
leading to the decreased production of A(3 peptides. Nonsteroidal anti-
inflammatory
drugs such as ibuprofen, flurbiprofen, indomethacin, and sulindac sulphide,
could
selectively inhibit the production of the A042 peptide, in addition to
inhibiting the
inflammation induced by AD. The decrease in A042 peptide that occurs in
transgenic
mice when administered fluribuprofin, marketed as AnsaidTM (Upjohn, now
Pfizer, New
York, New York), which is in Phase II human clinical trials Myriad Genetics,
Inc. (Salt
Lake City, Utah), has been correlated with improved memory and special
learning.
The method relates to a method for treating or preventing an amyloid-(3
related
disease by administering at least two agents, each of which is a compound that
exerts a
therapeutic effect when so administered and is useful in treating or
preventing a
neurological or psychological condition or disease. The first compound of the
invention,
as described further below, may be an alkanesulfonic acid that is useful for
treating or
preventing an amyloid-(3 related disease. The second compound is therapeutic,
i.e., its
function is beyond that of an inactive ingredient, such as a pharmaceutical
carrier,
preservative, diluent, or buffer. The second compound may be useful in
treating or
preventing an amyloid-O related disease or another neurological disease. The
second
compound may also be useful in diminishing specific symptoms which are
characteristic
of Alzheimer's disease (e.g. memory loss, anxiety, etc.) The first and second
compounds
may exert their biological effects by similar or unrelated mechanisms of
action; or either
one or both of the first and second compounds may exert their biological
effects by a
multiplicity of mechanisms of action. A third compound, or even more yet,.may
likewise be used in a method of the invention, wherein the third (and fourth,
etc.)
compound has the same characteristics of a second compound.
23 In one embodiment, pharmaceutical compositions of the invention are
formulated to be orally administered to a subject. The first agent and said
second agent
may be simultaneously administered. The first agent and the second agent may
modulate different biological processes in the pathogenesis of Alzheimer's
disease. The
first agent and the second agent may act on different targets. For example,
the first
agent may be therapeutically useful in the treatment of Alzheimer's disease,
and the
second agent may be therapeutically useful in the treatment of CAA. The first
agent and
the second agent may have different binding affinities or specificities for
peptides,
proteins, or enzymes involved in the pathogenesis of Alzheimer's disease. The
first
agent and the second agent, when simultaneously present in a subject, act
synergistically
to reduce, inhibit, or ameliorate the symptoms or pathogenesis of Alzheimer's
disease.
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The term "subject" includes living organisms in which amyloidosis can occur,
or
which are susceptible to amyloid diseases, e.g., Alzheimer's disease. Examples
of
subjects include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats,
and
transgenic species thereof. Administration of the compositions of the present
invention
to a subject to be treated can be carried out using known procedures, at
dosages and for
periods of time effective to modulate amyloid aggregation or amyloid-induced
neurotoxicity in the subject as further described herein. An effective amount
of the
therapeutic compound necessary to achieve a therapeutic effect may vary
according to
factors such as the amount of amyloid already deposited at the clinical site
in the subject,
the age, sex, and weight of the subject, and the ability of the therapeutic
compound to
modulate amyloid aggregation in the subject. Dosage regimens can be adjusted
to
provide the optimum therapeutic response. For example, several divided doses
may be
administered daily or the dose may be proportionally reduced as indicated by
the
exigencies of the therapeutic situation.
In an exemplary aspect of the invention, the subject is a human. For example,
the subject may be a human over 40 years old, or a human over 50 years old, or
a human
over 60 years old, or even a human over 70 years old. The subject may be a
female
human, including a postmenopausal female human, who may be on hormone
(estrogen)
replacement therapy. The subject may also be a male human.
A subject may be a human at risk for Alzheimer's disease, e.g., being over the
age of 40 or having a predisposition for Alzheimer's disease. Alzheimer's
disease
predisposing factors identified or proposed in the scientific literature
include, among
others, a genotype predisposing a subject to Alzheimer's disease;
environmental factors
predisposing a subject to Alzheimer's disease; past history of infection by
viral and
bacterial agents predisposing a subject to Alzheimer's disease; and vascular
factors
predisposing a subject to Alzheimer's disease. A subject may also have one or
more risk
factors for cardiovascular disease (e.g., atherosclerosis of the coronary
arteries, angina
pectoris, and myocardial infarction) or cerebrovascular disease (e.g.,
atherosclerosis of
the intracranial or extracranial arteries, stroke, syncope, and transient
ischemic attacks),
such as hypercholesterolemia, hypertension, diabetes, cigarette smoking,
familial or
previous history of coronary artery disease, cerebrovascular disease, and
cardiovascular
disease. Hypercholesterolemia typically is defined as a serum total
cholesterol
concentration of greater than about 5.2 mmol/L (about 200 mg/dL).
Several genotypes are believed to predispose a subject to Alzheimer's disease.
These include the genotypes such as presenilin-1, presenilin-2, and amyloid
precursor
protein (APP) missense mutations associated with familial Alzheimer's disease,
and
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a-2-macroglobulin and LRP-1 genotypes, which are thought to increase the risk
of
acquiring sporadic (late-onset) Alzheimer's disease. E.van Uden, et al., J.
Neurosci.
22(21), 9298-304 (2002); J.J.Goto, et al., J. Mol. Neurosci. 19(1-2), 37-41
(2002).
Another genetic risk factor for the development of Alzheimer's disease are
variants of
ApoE, the gene that encodes apolipoprotein E (particularly the apoE4
genotype), a
constituent of the low-density lipoprotein particle. WJ Strittmatter, et al.,
Annu. Rev.
Neurosci. 19, 53-77 (1996). The molecular mechanisms by which the various ApoE
alleles alter the likelihood of developing Alzheimer's disease are unknown,
however the
role of ApoE in cholesterol metabolism is consistent with the growing body of
evidence
linking cholesterol metabolism to Alzheimer's disease. For example, chronic
use of
cholesterol-lowering drugs such as statins has recently been associated with a
lower
incidence of Alzheimer's disease, and cholesterol-lowering drugs have been
shown to
reduce pathology in APP transgenic mice. These and other studies suggest that
cholesterol may affect APP processing. Environmental factors have been
proposed as
predisposing a subject to Alzheimer's disease, including exposure to aluminum,
although the epidemiological evidence is ambiguous. In addition, prior
infection by
certain viral or bacterial agents may predispose a subject to Alzheimer's
disease,
including the herpes simplex virus and chlamydia pneumoniae. Finally, other
predisposing factors for Alzheimer's disease can include risk factors for
cardiovascular
or cerebrovascular disease, including cigarette smoking, hypertension and
diabetes. "At
risk for Alzheimer's disease" also encompasses any other predisposing factors
not listed
above or as yet identified and includes an increased risk for Alzheimer's
disease caused
by head injury, medications, diet, or lifestyle.
In certain embodiments of the invention, the subject is in need of treatment
by
the methods of the invention, and is selected for treatment based on this
need. A subject
in need of treatment is art-recognized, and includes subjects that have been
identified as
having a disease or disorder related to amyloid-deposition or amyloidosis, has
a
symptom of such a disease or disorder, or is at risk of such a disease or
disorder, and
would be expected, based on diagnosis, e.g., medical diagnosis, to benefit
from
treatment (e.g., curing, healing, preventing, alleviating, relieving,
altering, remedying,
ameliorating, improving, or affecting the disease or disorder, the symptom of
the disease
or disorder, or reducing the risk of the disease or disorder).
The methods of the present invention can be used for one or more of the
following: to prevent, to treat Alzheimer's disease, or ameliorate symptoms of
Alzheimer's disease, to regulate production of or levels of amyloid 0 (A(3)
peptides or
regulate the amount of ApoE isoform 4 in the bloodstream or brain of a
subject. In one
alternative embodiment, the human carries one or more mutations in the genes
that
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encode P-amyloid precursor protein, presenilin-1 or presenilin-2. In another
alternative
embodiment, the human carries the Apolipoprotein s4 gene. In another
alternative
embodiment, the human has a family history of Alzheimer's Disease or dementia
illness.
In another alternative embodiment, the human has trisomy 21 (Down's Syndrome).
In
another alternative embodiment, the subject has a normal or low serum total
blood
cholesterol level. In another embodiment, the serum total blood cholesterol
level is less
than about 200 mg/dL, or less than about 180, and it can range from about 150
to about
200 mg/dL. In another embodiment, the total LDL cholesterol level is less than
about
100 mg/dL, or less than about 90 mg/dL and can range from about 30 to about
100
mg/dL. Methods of measuring serum total blood cholesterol and total LDL
cholesterol
are well known to those skilled in the art and for example include those
disclosed in
WO 99/3 8498 at p.11, incorporated by reference herein. Methods of determining
levels
of other sterols in serum are disclosed in H. Gylling, et al., "Serum Sterols
During
Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid
Res. 40:
593-600 (1999).
In another alternative embodiment, the subject has an elevated serum total
blood
cholesterol level. In another embodiment, the serum total cholesterol level is
at least
about 200 mg/dL, or at least about 220 mg/dL and can range from about 200 to
about
1000 mg/dL. In another alternative embodiment, the subject has an elevated
total LDL
cholesterol level. In another embodiment, the total LDL cholesterol level is
greater than
about 100 mg/dL, or even greater than about 110 mg/dL and can range from about
100
to about 1000 mg/dL.
In another alternative embodiment, the human is at least about 40 years of
age. In
another alternative embodiment, the human is at least about 60 years of age.
In another
embodiment, the human is at least about 70 years of age. In one embodiment,
the
human is between about 60 and 100 years of age.
In still a further embodiment, the subject is shown to be at risk by a
diagnostic
brain imaging technique, for example, that measures brain activity, plaque
deposition, or
brain atrophy.
In another embodiment, the subject exhibits no symptoms of Alzheimer's
Disease. In another embodiment, the subject is a human who is at least 40
years of age
and exhibits no symptoms of Alzheimer's Disease. In another embodiment, the
subject
is a human who is at least 40 years of age and exhibits one or more symptoms
of
Alzheimer's Disease.
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By using the methods of the present invention, the levels of amyloid (3
peptides
in a subject's brain or blood can be reduced from levels prior to treatment
from about 10
to about 100 percent, or even about 50 to about 100 percent.
In an alternative embodiment, the subject can have an elevated level of
amyloid
A(340 and A(342 peptide in the blood and CSF prior to treatment, according to
the present
methods, of greater than about 10 pg/mL, or greater than about 20 pg/mL, or
greater
than about 35 pg/mL, or even greater than about 40 pg/mL. In another
embodiment, the
elevated level of amyloid A(342 peptide can range from about 30 pg/mL to about
200
pg/mL, or even to about 500 pg/mL. One skilled in the art would understand
that as
Alzheimer's disease progresses, the measurable levels of amyloid 0 peptide in
the CSF
may decrease slightly from elevated levels present before onset of the
disease. This
effect is attributed to increased deposition, i.e., trapping of A(3 peptide in
the brain
instead of normal clearance from the brain into the CSF.
In an alternative embodiment, the subject can have an elevated level of
amyloid
A(340 peptide in the blood and CSF prior to treatment, according to the
present methods,
of greater than about 5 pg A042/mL or greater than about 50 pg A(340/mL, or
greater than
about 400 pg/mL. In another embodiment, the elevated level of amyloid A(340
peptide
can range from about 200 pg/mL to about 800 pg/mL, to even about 1000 pg/mL.
In another embodiment, the subject can have an elevated level of amyloid A(342
peptide in the CSF prior to treatment, according to the present methods, of
greater than
about 5 pg/mL, or greater than about 10 pg/mL, or greater than about 200
pg/mL, or
greater than about 500 pg/mL. In another embodiment, the level of amyloid P
peptide
can range from about 10 pg/mL to about 1,000 pg/mL, or even about 100 pg/mL to
about 1,000 pg/mL.
In another embodiment, the subject can have an elevated level of amyloid A(340
peptide in the CSF prior to treatment according to the present methods of
greater than
about 10 pg/mL, or greater than about 50 pg/mL, or even greater than about 100
pg/mL.
In another embodiment, the level of amyloid (3 peptide can range from about 10
pg/mL
to about 1,000 pg/mL.
The amount of amyloid P peptide in the brain or blood of a subject can be
evaluated by enzyme-linked immunosorbent assay ("ELISA") or quantitative
immunoblotting test methods or by quantitative SELDI-TOF which are well known
to
those skilled in the art, such as is disclosed by Zhang, et al., J. Biol.
Chem. 274, 8966-72
(1999) and Zhang, et al., Biochemistry 40, 5049-55 (2001). See also,
A.K.Vehmas,
et al., DNA Cell Biol. 20(11), 713-21 (2001), P.Lewczuk, et al., Rapid Commun.
Mass
Spectrom. 17(12), 1291-96 (2003); B.M.Austen, et al., J. Peptide Sci. 6, 459-
69 (2000);
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and H.Davies, et aL, BioTechniques 27, 1258-62 (1999). These tests are
performed on
samples of the brain or blood which have been prepared in a manner well known
to one
skilled in the art. Another example of a useful method for measuring levels of
amyloid (3
peptides is by Europium immunoassay (EIA). See, e.g., WO 99/38498 at p.11.
In another embodiment, the amount of total ApoE in the bloodstream or brain of
a subject can be reduced from levels prior to treatment by about 5 to about 75
percent,
or, in another embodiment, by about 5 to about 50 percent. The amount of total
ApoE
can be measured in a manner well known to one skilled in the art, for example
using an
ELISA test kit such as Apo-Tek ApoE test kit that is available from Organon
Teknica.
The methods of the invention may be applied as a therapy for a subject having
Alzheimer's disease or a dementia, or the methods of the invention may be
applied as a
prophylaxis against Alzheimer's disease or dementia for subject with such a
predisposition, as in a subject, e.g., with a genomic mutation in the APP
gene, the ApoE
gene, or a presenilin gene. The subject may have (or may be predisposed to
developing
or may be suspected of having) vascular dementia, or senile dementia, or Mild
Cognitive
Impairment. In addition to Alzheimer's disease, the subject may have another
amyloid-
P related disease such as cerebral amyloid angiopathy, or the subject may have
amyloid
deposits, especially amyloid-j3 amyloid deposits in the subject's brain.
Definition of Dementia
The essential features of a dementia are multiple cognitive'deficits that
include
memory impairment and at least one of the following: aphasia, apraxia,
agnosia, or a
disturbance in executive functioning (the ability to think abstractly and to
plan, initiate,
sequence, monitor, and stop complex behavior). The order of onset and relative
prominence of the cognitive disturbances and associated symptoms vary with the
specific type of dementia, as discussed in the following.
Memory impairment is generally a prominent early symptom. Individuals with
dementia have difficulty learning new material and may lose valuables, such as
wallets
and keys, or forget food cooking on the stove. In more severe dementia,
individuals also
forget previously learned material, including the names of loved ones.
Individuals with
dementia may have difficulty with spatial tasks, such as navigating around the
house or
in the immediate neighborhood (where difficulties with memory are unlikely to
play a
role). Poor judgment and poor insight are common as well. Individuals may
exhibit little
or no awareness of memory loss or other cognitive abnormalities. They may make
unrealistic assessments of their abilities and make plans that are not
congruent with their
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deficits and prognosis (e.g., planning to start a new business). They may
underestimate
the risks involved in activities (e.g., driving).
In order to make a diagnosis of dementia, the cognitive deficits must be
sufficiently severe to cause impairment in occupational or social functioning
and must
represent a decline from a previous level of functioning. The nature and
degree of
impairment are variable and often depend on the particular social setting of
the
individual. For example, Mild Cognitive Impairment may significantly impair an
individual's ability to perform a complex job but not a less demanding one.
Cognitive or degenerative brain disorders are characterized clinically by
progressive loss of memory, cognition, reasoning, judgment and emotional
stability that
gradually leads to profound mental deterioration and ultimately death. It is
generally
believed that the disease begins a number of years before it manifests itself
in the mild
cognitive changes that are the early signs of Alzheimer's disease. "Dementia
of the
Alzheimer's Type" begins gradually, and is usually diagnosed after other
specific causes
have been ruled out. Diagnostic criteria for Dementia of the Alzheimer's Type
include
the development of multiple cognitive deficits manifested by both memory
impairment
(anterograde or retrograde, i.e., impaired ability to learn new information or
to recall
previously learned information); and one or more of the following cognitive
disturbances: aphasia (language disturbance), apraxia (impaired ability to
carry out
motor activities despite intact motor function), agnosia (failure to recognize
or identify
objects despite intact sensory function), disturbance in executive functioning
(i.e.,
planning, organizing, sequencing, and abstracting); where these cognitive
deficits each
cause significant impairment in social or occupational functioning and
represent a
significant decline froni a previous level of functioning. The course is
characterized by
gradual onset and continuing cognitive decline, and the cognitive deficits are
not due to
another condition that causes progressive deficits in memory and cognition
(e.g.,
cerebrovascular disease, brain tumor, hypothyroidism, vitamin B or folic acid
deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection, or
chemical
exposure). The cognitive disturbance may be accompanied by a behavioral
disturbance,
such as wandering, aggression, or agitation, or a psychological disturbance,
such as
depression or psychosis. See "Diagnostic and Statistical Manual of Mental
Disorders,"
4th Ed., Text Revision, by American Psychiatric Association (2000). For
example, the
National Institute of Neurological and Communicative Disorders and Stroke-
Alzheimer's Disease and the Alzheimer's Disease and Related Disorders
Association
(NINCDS-ADRDA) criteria can be used to diagnose Alzheimer's Disease (McKhann
et al., 1984, Neurology 34:939-944). The patient's cognitive function can be
assessed by
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the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; Rosen,
et al., 1984, Am. J. Psychiatry 141:1356-1364).
Alzheimer's Disease is the prototype of a cortical degenerative disease. A
major
component of the presenting symptoms is usually subjective complaints of
memory
difficulty, language impairment, dyspraxia, at which point diagnosis is
primarily based
on exclusion of other possible etiologies for dementia. No features of the
physical
examination or laboratory evaluation are pathognomonic for dementia of the
Alzheimer's type. Some studies have apparently discriminated patients with
dementia
of the Alzheimer's type from patients with dementia of other etiologies and
from normal
io controls by using techniques such as EEG, MRI, and SPECT, but these studies
have
been difficult to replicate consistently, and at present, brain-imaging
studies are' best
used to exclude other identifiable causes.
A variety of diagnostic tests have been developed for Alzheimer's disease.
Clinical criteria have been verified prospectively in autopsy studies and have
been found
to be highly specific although only moderately sensitive. Implementation of
the criteria
requires extensive evaluation, including an informant-based history,
neurological
examination, neuropsychological testing, and laboratory, and neuroimaging
data.
Alzheimer's disease is characterized pathologically by generalized atrophy of
the
cerebral cortex and by neurofibrillary tangles, neuritic (amyloid) plaques,
and
granulovacuolar degeneration. Although plaques and tangles may be detected in
the
brains of the elderly without Alzheimer's disease, they are more numerous in
patients
with dementia. Controversy remains whether brains with plaques from
individuals
without Alzheimer's diseasewere "normal variations" or early pathological
signs of
incipient disease. A definitive diagnosis ultimately requires both the
characteristic
dementia in life and the characteristic pathology after death.
The natural course of Alzheimer's disease is exacerbation and progression of
clinical symptomatology. Brain degeneration as measured by in vivo imaging
techniques such as MRI has not been found to correlate closely with the state
of clinical
disease. The final common clinical picture is of a bedridden patient, wholly
dependent
on others for all basic functions, even for turning in bed. Nutrition can
often be
provided only by nasogastric or gastrointestinal tubes.
The study of the pathobiology of Alzheimer's disease has identified at least
four
chromosomal loci associated with familial cases; the degeneration of central
neurochemical systems, especially basal forebrain structures related to
acetylcholine-
mediated neurotransmission; factors associated with the formation of plaques
and
tangles; and exogenous (e.g., infectious and toxic) processes that may
contribute to the
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development of sporadic cases. Although amyloid itself is a normal brain
product,
excessive amounts of oligomeric or fibrillar forms of A(3 may be neurotoxic.
For Alzheimer's disease, advanced age and a family history of the disease are
the
greatest important risk factor. A family history of Down's syndrome or of
hematological malignancies, such as leukemia, myelolymphoma, or Hodgkin's
disease,
is also associated with an increased risk for Alzheimer's disease. For
Alzheimer's
disease, other risk factors identified tentatively in recent years include
female sex, a past
history of head trauma, and lower education. Vascular dementias are highly
associated
with the risk factors for cerebrovascular disease. Those factors include
hypertension
(especially with systolic pressures greater than 160 mmHg), cardiac disease,
transient
ischemic attacks, diabetes mellitus, carotid bruits, and sickle cell disease.
Obesity, a
sedentary lifestyle, tobacco use, alcohol consumption, and elevated serum
cholesterol
and lipid levels may also be risk factors for cerebrovascular disease.
A general physical examination is a routine component of the workup for
Alzheimer's disease. It may reveal evidence of systemic disease causing brain
dysfunction, such as an enlarged liver and hepatic encephalopathy, or it may
demonstrate systemic disease related to particular CNS processes. Focal
neurological
findings, such as asymmetrical hyperreflexia or weakness, are seen more often
in
vascular than in degenerative diseases. Frontal release signs and primitive
reflexes,
while suggesting pathology in the frontal lobe, are present in many disorders
and often
point to a greater extent of progression. The first step in the diagnosis of
Alzheimer's
disease is to exclude delirium, which may be distinguished from dementia by
its cardinal
feature: disturbance of consciousness. Level of consciousness or arousal
should be
determined to be stable before a diagnosis of Alzheimer's diseasecan be made
with
confidence. It should also be distinguished from focal or specific cognitive
impairments, such as those seen in aphasic or amnestic patients. Mood
disorders can
present with cognitive symptoms, particularly in the dementia of depression or
pseudodementia. A history of a mood disorder or a current disturbance in
neurovegetative function indicates the possibility of a major depressive
disorder.
The course and prognosis of a dementia syndrome vary with its cause.
Alzheimer's disease does not necessarily equal progressive deterioration,
although many
of the pathobiological processes underlying dementia are degenerative. The
rate of
progression may vary within families. or from individual to individual. Age at
onset is
an important feature of Alzheimer's disease, the most common cause of dementia
in the
United States. Onset usually occurs after age 60 years and the prevalence
increases
exponentially with each siuccessive decade; although cases have been reported
in
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patients as young as 30 years. Familial forms of dementia of the Alzheimer's
type
appear to have an earlier age at onset. Cerebrovascular disease, the second
most
common cause of Alzheimer's disease, is associated with an earlier age at
onset overall.
As a class, the dementias can be distinguished to some extent by their course,
especially earlier in the disease process. Degenerative dementias are
insidious in onset
and gradually progressive. Despite the clinical rule of a steadily progressive
course in
dementia of the Alzheimer's type, some individuals may reach a plateau for
several
years in the overall functional impairment before progression resumes and
continues on
to death. Vascular dementias may follow a stepwise pattern, in which new
deficits
appear abruptly and are associated with new vascular events, but the vascular
dementias
also often have an insidious onset and a slow but steadily progressive course.
The first
step in the treatment of dementia is verification of the diagnosis. Preventive
pharmacological agents include antihypertensive, anticoagulant, or
antiplatelet agents.
Blood pressure control has been demonstrated to improve cognitive function in
patients
with vascular dementia, but it should be noted that antihypertensive beta-
blocking agents
have been associated with exaggeration of cognitive impairment. Angiotensin-
converting enzyme ("ACE") inhibitors and diuretics have not been linked to the
exaggeration of cognitive impairment and are thought to lower blood pressure
without
affecting cerebral blood flow (cerebral blood flow is presumed to correlate
with
cognitive function). Surgical removal of carotid plaques may prevent
subsequent
vascular events in carefully selected patients.
Numerous neurotransmitters, including acetylcholine, dopamine, norepinephrine,
GABA, and serotonin, and several neuropeptides, including somatostatin and
substance P, are decreased in dementia. Multiple neuropharmacological
strategies have
been devised in the hope of replenishing the deficient neurotransmitters.
Replacement
therapy for acetylcholine has been the most common and widely publicized
strategy.
Efforts at replenishment have included the use of acetylcholine precursors,
e.g., choline
salycilate (ArthropanTM, Purdue Pharma, L.P., Stamford, Connecticut) and
lecithin from
polyenylphosphatidylcholine (PhoscholTM, Nutrasal LLC, Oxford, Connecticut);
cholinergic agonists, e.g., arecoline (methyl N-methyltetrahydronicotinate,
and
cholinesterase inhibitors, such as described herein. Instead of targeting a
neurotransmitter defect, other strategies are directed toward neuronal
protection and
regeneration. Selegiline (EldeprylTM, Somerset, Tampa, Florida), a monoamine
oxidase
("MAO") type B ("MAO-B") inhibitor, slows the progression of Parkinson's
disease,
presumably by limiting endogenous generation of destructive oxidative
products, and the
same effect may be used therapeutically in the treatment of Alzheimer's
patients.
Similar antioxidant treatments are being used experimentally with other
dementias,
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NB I-154CPPC
includirig Huntington's disease and vascular dementia. Naloxone (Narcan), an
opiate
antagonist, is thought to have possible application in vascular dementia based
on animal
studies in which it was demonstrated to decrease the sequelae of cerebral
ischemia. See,
e.g., C.Stowe, et al., Ann. Pharmacother. 27, 447-48 (1993). Nerve growth
factor is
being studied as a means of promoting neural regeneration or sprouting.
As used herein, "treatment" of a subject includes the application or
administration, of a composition of the invention to a subject, or application
or
administration of a composition of the invention to a cell or tissue from a
subject, who
has a amyloid-(3 related disease or condition, has a symptom of such a disease
or
condition, or is at risk of (or susceptible to) such a disease or condition,
with the purpose
of curing, healing, alleviating, relieving, altering, remedying, ameliorating,
improving,
or affecting the disease or condition, the symptom of the disease or
condition, or the risk
of (or susceptibility to) the disease or condition. The term "treating" refers
to any
indicia of success in the treatment or amelioration of an injury, pathology or
condition,
including any objective or subjective parameter such as abatement; remission;
diminishing of symptoms or making the injury, pathology or condition more
tolerable to
the subject; slowing in the rate of degeneration or decline; making the final
point of
degeneration less debilitating; improving a subject's physical or mental well-
being; or,
in some situations, preventing the onset of dementia. The treatment or
amelioration of
symptoms can be based on objective or subjective parameters; including the
results of a
physical examination or a psychiatric evaluation. For example, the methods of
the
invention successfully treat a subject's dementia by slowing the rate of or
extent of
cognitive decline.
Also, the invention relates to a method for preventing or inhibiting amyloid
production in a subject. For example, such a method comprises administering to
a
subject a therapeutically effective amount of a pharmaceutical composition of
the
invention capable of reducing the concentration of Ap, such that amyloid
production or
accumulation is prevented or inhibited.
In another aspect, the invention relates to a method where at least the first
compound is for preventing, reducing, or inhibiting amyloid production in a
subject. For
example, such a method comprises administering to a subject a therapeutically
effective
amount of a pharmaceutical composition capable of inhibiting A(3 accumulation,
such
that A(3 amyloidosis is prevented, reduced, or inhibited.
"Inhibition" of amyloid deposition includes preventing or stopping of amyloid
formation, e.g., fibrillogenesis, clearance of soluble A(3 from brain,
inhibiting or slowing
down of further amyloid deposition in a subject with amyloidosis, e.g.,
already having
CA 02582385 2006-12-18
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amyloid deposits, and reducing or reversing amyloid fibrillogenesis or
deposits in a
subject with ongoing amyloidosis. Inhibition of amyloid deposition is
determined
relative to an untreated subject, or relative to the treated subject prior to
treatment, or,
e.g., determined by clinically measurable improvement, e.g., or in the case of
a subject
with brain amyloidosis, e.g., an Alzheimer's or cerebral amyloid angiopathy
subject,
stabilization of cognitive function or prevention of a further decrease in
cognitive
function (i.e., preventing, slowing, or stopping disease progression), or
improvement of
parameters such as the concentration of A(3 or tau in the CSF.
"Modulation" of amyloid deposition includes both inhibition, as defined above,
and enhancement of amyloid deposition or fibril formation. The term
"modulating" is
intended, therefore, to encompass prevention or stopping of amyloid formation
or
accumulation, inhibition or slowing down of further amyloid aggregation in a
subject
with ongoing amyloidosis, e.g., already having amyloid aggregates, and
reducing or
reversing of amyloid aggregates in a subject with ongoing amyloidosis; and
enhancing
amyloid deposition, e.g., increasing the rate or amount of amyloid deposition
in vivo or
in vitro. Amyloid-enhancing compounds may be useful in animal models of
amyloidosis, for example, to make possible the development of amyloid deposits
in
animals in a shorter period of time or to increase amyloid deposits over a
selected
period of time. Amyloid-enhancing compounds may be useful in screening assays
for
compounds which inhibit amyloidosis in vivo, for example, in animal models,
cellular
assays and in vitro assays for amyloidosis. Such compounds may be used, for
example,
to provide faster or more sensitive assays for compounds. In some cases,
amyloid
enhancing compounds may also be administered for therapeutic purposes, e.g.,
to
enhance the deposition of amyloid in the lumen rather than the wall of
cerebral blood
vessels to prevent CAA. Modulation of amyloid aggregation is determined
relative to an
untreated subject or relative to the treated subject prior to treatment.
In an embodiment, the method is used to treat Alzheimer's disease (e.g.,
sporadic
or familial Alzheimer's disease). The method may also be used prophylactically
or
therapeutically to treat other clinical occurrences of amyloid-(3 deposition,
such as in
Down's syndrome individuals and in subjects with hereditary or sporadic
cerebral
amyloid angiopathy ("CAA"), which lead to cerebral hemorrhage (or hemorrhagic
stroke).
Additionally, abnormal accumulation of APP and of amyloid-(3 protein in
muscle fibers has been implicated in the pathology of sporadic inclusion body
myositis
("IBM") (Askanas, et al., Proc. Natl. Acad. Sci. USA 93, 1314-19 (1996);
Askanas,
et al., Current Opinion in Rheumatology 7, 486-96 (1995)). Accordingly, the
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CA 02582385 2006-12-18
NB I-154CPPC
compounds of the invention can be used prophylactically or therapeutically in
the
treatment of disorders in which amyloid-(3 protein is abnormally deposited at
non-
neurological locations, such as treatment of IBM by delivery of the compounds
to
muscle fibers.
Additionally, it has been shown that A(3 is associated with abnormal
extracellular
deposits, known as drusen, that accumulate along the basal surface of the
retinal
pigmented epithelium in individuals with age-related macular degeneration
("ARMD").
ARMD is a cause of irreversible vision loss in older individuals. It is
believed that A(3
deposition could be an important component of the local inflammatory events
that
contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis,
and the
pathogenesis of ARMD (Johnson, et al., Proc. Natl. Acad Sci. USA 99(18), 11830-
5
(2002)).
The present invention therefore relates to the use of a first agent, e.g., an
alkanesulfonic acid compound, in the prevention or treatment of amyloid-j3
related
diseases, including, inter alia, Alzheimer's disease, cerebral amyloid
angiopathy,
inclusion body myositis, Down's syndrome, Mild Cognitive Impairment, and
macular
degeneration, in combination with a second therapeutic agent.
Accordingly, the invention relates to methods employing and compositions
including substituted or unsubstituted alkylsulfonic acids that are
substituted or
unsubstituted straight- chain alkylsulfonic acids, substituted or
unsubstituted
cycloalkylsulfonic acids, and substituted or unsubstituted branched- chain
alkylsulfonic
acids. Also, it is noted that the term "alkylsulfonic acid" as used herein is
to be
interpreted as being synonymous with the term "alkanesulfonic acid."
In another embodimerit, the subject has mild cognitive impairment (MCI), which
is a condition characterized by a state of mild but measurable impairment in
thinking
skills, but is not necessarily associated with the presence of dementia. MCI
frequently,
but not necessarily, precedes Alzheimer's disease. It is a diagnosis that has
most often
been associated with mild memory problems, but it can also be characterized by
mild
impairments in other thinking skills, such as language or planning skills.
However, in
general, an individual with MCI will have more significant memory lapses than
would
be expected for someone of their age or educational background. As the
condition
progresses, a physician may change the diagnosis to Mild-to-Moderate Cognition
Impairment, as is well understood in this art.
In one embodiment, the pharmaceutical compositions disclosed herein prevent or
inhibit amyloid protein assembly into insoluble fibrils which, in vivo, are
deposited in
various organs, or it reverses or favors deposition in subjects already having
deposits. In
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CA 02582385 2006-12-18
NBI-154CPPC
another embodiment, the agent may also prevent the amyloid protein, in its
soluble,
oligomeric form or in its fibrillar form, from binding or adhering to a cell
surface and
causing cell damage or toxicity. In yet another embodiment, the agent may
block
amyloid-induced cellular toxicity or microglial activation. In another
embodiment, the
agent may block amyloid-induced neurotoxicity.
The pharmaceutical compositions of the invention may be administered
therapeutically or prophylactically to treat diseases associated with amyloid-
(3 fibril
formation, aggregation or deposition. The pharmaceutical compositions of the
invention
may act to ameliorate the course of an amyloid-(3 related disease using any of
the
following mechanisms (this list is meant to be illustrative and not limiting):
slowing the
rate of amyloid-(3 fibril formation or deposition; lessening the degree of
amyloid-(3
deposition; inhibiting, reducing, or preventing amyloid-(3 fibril formation;
inhibiting
neurodegeneration or cellular toxicity induced by amyloid-p; inhibiting
amyloid-(3
induced inflammation; or enhancing the clearance of amyloid-(3 from the brain
;or
enhancing the catabolism or degradation of amyloid-f3; or lowering the levels
of
amyloid-(3 in the CSF; or modulating the levels of amyloid-(3 in the plasma..
Another
way of decreasing A(3 could be that these compounds act on secretases so that
A(3 levels
are reduced (as seen with proteoglycans).
Pharmaceutical compositions of the invention may be effective in controlling
amyloid-(3 deposition either following their entry into the brain (following
penetration
of the blood brain barrier) or from the periphery. When acting from the
periphery, an
agent of a pharmaceutical composition may alter the equilibrium of A(3 between
the
brain and the plasma so as to favor the exit of A(3 from the brain. An
increase in the exit
of A(3 from the brain would result in a decrease in A(3 brain concentration
and therefore
favor a decrease in A(3 deposition. Alternatively, agents that penetrate the
brain could
control deposition by acting directly on brain A(3, e.g., by maintaining it in
a non-
fibrillar form or favoring its clearance from the brain or enhancing its
degradation rate in
the brain or in the peripheral organs. These agents may also prevent A(3 in
the brain
from interacting with a cell surface and therefore prevent neurotoxicity or
inflammation.
.30 The compositions of the invention may be administered therapeutically or
prophylactically to treat diseases associated with amyloid-(3 fibril
formation,
aggregation, or deposition. The compositions of the invention may act to
ameliorate the
course of an amyloid-(3 related disease by a variety of mechanisms. In one
embodiment,
the pharmaceutical compositions disclosed herein prevent or inhibit amyloid
protein
assembly into insoluble fibrils which, in vivo, are deposited in various
organs, or it
favors plaque clearance or slows deposition in subjects already having
deposits. In
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CA 02582385 2006-12-18
NBI-154CPPC
another embodiment, the pharmaceutical compositions may also prevent the
amyloid
protein, in its soluble, oligomeric form or in its fibrillar form, from
binding or adhering
to a cell surface and causing cell damage or toxicity. In yet another
embodiment, the
pharmaceutical compositions may block amyloid toxicity. In other embodiments,
the
agent may act be slowing the rate of amyloid-O fibril formation or deposition.
In yet
another embodiment, the agent may lessen the degree of amyloid-(3 deposition.
Still
other examples include inhibiting, reducing, or preventing amyloid-(3 fibril
formation;
inhibiting neurodegeneration or cellular toxicity induced by amyloid-0;
inhibiting
amyloid-P induced inflammation; or enhancing the clearance of amyloid-O from
the
brain brain or enhancing its degradation rate in the brain or in the
peripheral organs.
At least one of the therapeutic agents of the invention may be effective in
controlling amyloid-(3 deposition either following their entry into the brain
(following
penetration of the blood brain barrier) or from the periphery. When acting
from the
periphery, an agent may alter the equilibrium of A(3 between the brain and the
plasma so
as to favor the exit of A(3 from the brain. An increase in the exit of Ap from
the brain
would result in a decrease in Ap brain concentration and therefore favor a
decrease in
AR deposition. Alternatively, agents that penetrate the brain could control
deposition by
acting directly on brain A(3, e.g., by maintaining it in a non-fibrillar form
or favoring its
clearance from the brain, or by favoring catabolism or acting on secretase so
that A(3
production is reduced.
In one aspect, the invention relates to pharmaceutical compositions comprising
two agents, each of which exerts a therapeutic effect when administered to a
subject in
need thereof, and is useful in treating or preventing a neurological disease.
The first
agent of a pharmaceutical composition of the invention is selected from
substituted and
unsubstituted alkanesulfonic acids and alkanesulfuric acids that are useful
for treating or
preventing an amyloid-(3 related disease. The second agent is therapeutic,
f.e., its
function is beyond that of an inactive ingredient, such as a pharmaceutical
carrier,
preservative, diluent, or buffer. The second agent may be useful in treating
or
preventing an amyloid-(3 related disease or another neurological disease. The
first and
second agents may exert their biological effects by similar or unrelated
mechanisms of
action; or either one or both of the first and second agents may exert their
biological
effects by a multiplicity of mechanisms of action. A pharmaceutical
composition may
also comprise a third agent, or even more yet, wherein the third (and fourth,
etc.) agent
has the same characteristics of a second agent.
The invention also relates to packaged pharmaceutical products containing two
agents, each of which exerts a therapeutic effect when administered to a
subject in need
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NBI-154CPPC
thereof, and is useful in treating or preventing a neurological disease. The
first agent of
a pharmaceutical composition of the invention may be selected from substituted
and
unsubstituted alkanesulfonic acids and alkanesulfuric acids that are useful
for treating or
preventing an amyloid-(3 related disease. The second agent is therapeutic,
i.e., its
function is beyond that of an inactive ingredient, such as a pharmaceutical
carrier,
preservative, diluent, or buffer. The second agent may be useful in treating
or
preventing an amyloid-(3 related disease or another neurological disease. The
agents
may exert their biological effects by similar or unrelated mechanisms of
action; or either
one or more than one of the agents may exert their biological effects by a
multiplicity of
mechanisms. A pharmaceutical composition may also comprise a third agent, or
even
more agents yet, wherein the third (and fourth, etc.) agent has the same
characteristics of
a second agent. In some cases, the individual agents may be packaged in
separate
containers for sale or delivery to the consumer. The agents of the invention
may be
supplied in a solution with an appropriate solvent or in a solvent-free form
(e.g.,
lyophilized). Additional components may include acids, bases, buffering
agents,
inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
The additional
kit components are present as pure compositions, or as aqueous or organic
solutions that
incorporate one or more additional kit components. Any or all of the kit
components
optionally further comprise buffers.
The present invention also includes packaged pharmaceutical products
containing a first agent in combination with (e.g., intermixed with) a second
agent. The
invention also includes a pharmaceutical product comprising a first agent
packaged with
instructions for using the first agent in the presence of a second agent or
instructions for
use of the first agent in a method of the invention. The invention also
includes a
pharmaceutical product comprising a second or additional agents packaged with
instructions for using the second or additional agents in the presence of a
first agent or
instructions for use of the second or additional agents in a method of the
invention.
Alternatively, the packaged pharmaceutical product may contain at least one of
the
agents and the product may be promoted for use with a second agent.
This invention also relates to a pharmaceutical composition for the treatment
of a
condition selected from mental retardation, developmental disorders,
disruptive
behavioral disorders, organic mental disorders (including dementia and
psychoactive
substance induced organic mental disorders), psychoactive substance abuse
disorders,
mood disorders, anxiety disorders, somatoform disorders, dissociative
disorders,
attention deficit disorder, schizophrenia and personality disorders in a
human,
comprising an acetylcholine esterase inhibitor. The second agent may also be a
neurotransmitter-release enhancer, i.e., they possess the ability to enhance
or stimulate
CA 02582385 2006-12-18
NBI-I54CPPC
the release of neurotransmitters such as acetylcholine, dopamine, and
serotonin in
humans. They are therefore able to function as therapeutic agents in the
treatment of a
variety of conditions in humans, the treatment or prevention of which can be
effected or
facilitated by the enhancement or stimulation of acetylcholine, dopamine, or
serotonin
release. Such conditions include Alzheimer's disease, age associated memory
impairment and Mild Cognitive Impairment, and Parkinson's disease. They also
include
mental retardation, developmental disorders, disruptive behavioral disorders,
organic
mental disorders (including dementia and psychoactive substance induced
organic
mental disorders), psychoactive substance abuse disorders, mood disorders,
anxiety
disorders, somatoform disorders, dissociative disorders, attention deficit
disorder,
schizophrenia, and personality disorders.
The invention is also ideally suited for the treatment of familiar or
hereditary
forms of Alzheimer's disease because, for example, therapeutic prophylactic
pharmaceutical treatment could be initiated earlier in a patient's life.
Presently, all
therapeutic regimens that are commercially available treat only the symptoms
of
Alzheimer's disease, as explairied elsewhere herein. The present invention
provides
methods and compositions, however, that treat the underlying etiology of the
disease
itself, and therefore may be used in a prophylactic manner. The biological
processes
that give rise to Alzheimer's disease may occur in a person for some time
before
clinically observable symptoms arise. Ordinarily, according to current medical
science,
such a period in a person's life would be undetectable and treatment with
current
medicines would be useless. For people with an identified predisposition for
developing
Alzheimer's disease compositions of the present invention may delay the onset
of
symptoms.
Furthermore, the invention pertains to any novel chemical agent described
herein. That is, the invention relates to novel agents, and novel methods of
their use as
described herein, including those coumpounds that may be within the scope of
the
Formulae disclosed herein, and which are not disclosed in the cited Patents
and Patent
Applications.
Example Therapeutic Drug Targets for the Treatment of Alzheimer's Disease
In the pharmaceutical compositions of the invention, an alkanesulfonic acid
compound may be combined with a second agent that is also useful in the
treatment of
Alzheimer's disease. In general, the second agent may be any therapeutic drug.
A
"therapeutic drug" is, a drug or medicine administered for legitimate or
medically-
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NBI-I 54CPPC
approved, therapeutic or diagnostic, purpose. Therapeutic drugs may be
available
over-the-counter or by prescription. Examples of therapeutic drugs include an
adrenergic, anti-adrenergic, anti-androgen, anti-anginal, anti-anxiety,
anticonvulsant,
antidepressant, anti-epileptic, antihyperlipidemic, antihyperlipoproteinemic,
antihypertensive, anti-inflammatory, antiobessional, antiparkinsonian,
antipsychotic,
adrenocortical steroids, adrenocortical suppressant, aldosterone antagonists,
amino acids,
anabolic steroids, analeptic agents; androgens; blood glucose regulators,
cardioprotectants; cardiovascular agents; cholinergic agonist and antagonists,
cholinesterase deactivators or inhibitors, cognition adjuvants and enhancers,
dopaminergic agents, enzyme inhibitors, estrogen and related steroid hormones,
free
oxygen radical scavengers, GABA agonists, glutamate antagonists, hormones,
antihypocholesterolemic agents, hypolipidemic agents, hypotensive agents,
immunizing
agents, immunostimulants, monoamine oxidase inhibitors, neuroprotective
agents,
NMDA antagonists, AMPA antagonists, competitive and non-competitive NMDA
antagonists, opioid antagonists, potassium channel openers, non-hormonal
sterol
derivatives, post-stroke and post-head trauma treatments, prostaglandins,
psychotropics,
relaxants, sedatives, sedative-hypnotics, selective adenosine antagonists,
serotonin
antagonists, serotonin inhibitors, selective serotonin uptake inhibitor,
serotonin receptor
antagonists, sodium and calcium channel blockers, steroids, stimulants,
thyroid
hormones and inhibitors, etc.
In one aspect, the invention pertains to a pharmaceutical composition
comprising
an alkanesulfonic acid and a second agent that is useful in the treatment or
prevention of
Alzheimer's disease. The second agent may be curative, i.e., modulate the
causative
agents of Alzheimer's disease, or it may be palliative, i.e., alleviate the
symptoms of the
disease, e.g., by enhancing memory or improving cognitive function. The second
agent
may be a drug that is useful in the treatment of Alzheimer's disease itself,
or it may be
used to treat a condition associated with Alzheimer's disease, e.g. a
secondary condition,
or it may be a drug commonly prescribed to Alzheimer's disease subjects.
According to current understanding of the natural history of Alzheimer's
disease,
several different drug targets have been identified. A pharmaceutical
composition of the
invention may comprise a second agent that is specific for any one of the
biological
processes giving rise to the clinical presentation of Alzheimer's disease. The
invention
is not to be considered bound by any particular theory of the etiology of
Alzheimer's
disease, and so the second agent according to the pharmaceutical compositions
of the
invention may be any agent that either by itself or in combination with an
alkanesulfonic
acid is empirically observed to be efficacious in the treatment or prevention
of
Alzheimer's disease. Nevertheless, a summary of the biological processes
believed to
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NBI-154CPPC
give rise to Alzheimer's disease itself or the symptoms thereof is useful
inasmuch as any
one of these biological processes may be modulated by a second agent in a
pharmaceutical composition of the invention.
The language "in combination with" a second agent or treatment includes
co-administration of an alkanesulfonic acid, administration of an
alkanesulfonic acid
first, followed by the second, or treatment and administration of the second
agent first,
followed by an alkanesulfonic acid.
The condition associated with Alzheimer's disease may be a symptom
characteristic of Alzheimer's disease, for example, hypothyroidism,
cerebrovascular or
cardiovascular disease, memory loss, anxiety, or a behavioral dysfunction
(e.g., apathy,
aggression, or incontinence); a psychological condition or a neurological
condition. The
neurological condition may be Huntington's disease, amyotrophic lateral
sclerosis,
acquired immunodeficiency, Parkinson's disease, aphasia, apraxia, agnosia,
Pick
disease, dementia with Lewy bodies, altered muscle tone, seizures, sensory
loss, visual
field deficits, incoordination, gait disturbance, transient ischemic attack or
stroke,
transient alertness, attention deficit, frequent falls, syncope, neuroleptic
sensitivity,
normal pressure hydrocephalus, subdural hematoma, brain tumor, posttraumatic
brain
injury, or posthypoxic damage. The psychological condition is depression,
delusions,
illusions, hallucinations, sexual disorders, weight loss, psychosis, a sleep
disturbance
such as insomnia, behavioral disinhibition, poor insight, suicidal ideation,
depressed
mood or irritability, anhedonia, social withdrawal, or excessive guilt.
The second agent, i.e., a therapeutic drug may be a psychotropic medication,
antidepressant (a selective serotonin reuptake inhibitor, atypical
antidepressant),
antipsychotic, appetite stimulants, or another drug used to treat a condition
associated
with Alzheimer's disease, or a a nutritive supplement that is a precursor of
acetylcholine
(lecithin or choline), Ginkgo biloba, acetyl-L-camitine, idebenone,
propentofylline, or a
xanthine derivative.
Antidepressants include selective serotonin reuptake inhibitors such as
citalopram (Celexa); escitalopram (Lexapro); fluoxetine (ProzacTM); alprazolam
(XanaxTM), triptolene, fluvoxamine (LuvoxTM); paroxetine (PaxilTM); sertraline
(ZoloftTM); mixed norepinephrine/dopamine reuptake inhibitors such as
bupropion
(WellbutrinTM); drugs with mixed serotonin effects such as nefazodone
(SerzoneTM) and
trazodone (DesyrelTM); mixed serotonin/norepinephrine reuptake inhibitors
venlafaxine
(EffexorTM); monoamine oxidase inhibitors including pheneizine (NardilTM) and
tranylcypromine (ParnateTM); and tetracyclic antidepressants such as
maprotiline,
mirtazapine (RemeronTM), amitriptyline (ElavilTM), amoxapine, clomipramine
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(AnafranilTM), desipramine (NorpraminTM), doxepin (SinequanTM), imipramine
(TofranilTM), nortriptyline (AventylTM, PamelorTM), protriptyline
(VivactilTM), and
trimipramine (SurmontilTM). Antidepressants: tricyclic and selective serotonin
reuptake
inhibitors; fluoxetine (ProzacTM); sertraline (ZoloftTM); paroxetine
(PaxilTM); citalopram
(CelexaTM); nortriptyline; moclobemide; miratazepine; NardilTM; ParnateTM;
ManerixTM;
TofranilTM; ElavilTM; SinequanTM; SurmontilTM; AnafranilTM; NorpramineTM;
AventylTM;
EffexorTM; SerzoneTM; WelbutrinTM; DesyrelTM; and RemeronTM.
Antipyschotics include aripiprazole (AbilifyTM), clozapine (ClozarilTM),
olanzapine (ZyprexaTM), quetiapine (SeroquelTM), risperidone (RisperdalTM),
and
ziprasidone (GeodonTM). Antipsychotics: conventional and atypical; olanzapine
(ZyprexaTM); quetiapine (SeroquelTM); haloperidol (HaldolTM); risperidone
(RisperidalTM); zuclopenhixol (ClopixolTM); ziprazidone; thioridazine
(MellarilTM,
Sandoz Pharmaceutical Corp., now Novertis, Basel, Switzerland); clozapine
(ClozarilTM); olanzapine; and lithium.
Still other examples of drugs that may be a second agent include:
cholinesterase
inhibitors: huperzine A; antidepressants: venlafaxine, desipramine,
nefazodone,
trazodone, citalopram, escitalopram, nortriptyline, paroxetine; anti-
agitation/mood-
stabilizing agents, or anti-epileptics for convulsions: carbamazepine,
gabapentin,
primidone, phenytoin, clonazepam, valproic acid; neuroleptics: ziprasidone,
haloperidol,
risperidone, olanzapine, quetiapine; anti-inflammatory/immunomodulating drugs:
colchicine, dapsone, meloxicam, nimesulide, flurbiprofen, cyclophosphamide,
methotrexate, 0-interferon, gamma-interferon, etanercept, infliximab;
chelators:
penicillamine; hormonal therapies: leuprolide; homocysteine reducing vitamins:
metafolin; antioxidants: lipoic acid, selegeline; anti-thrombotics: aspirin;
others:
carbidopa, levodopa (SinemetTM), folic acid; anxiolytics hypnotics, and
sedatives (anti-
anxiety drugs): clonazepan, lorazapam, oxazepam, bupropion., benzodiazepines
including diazepam (ValiumTM, Roche Products, Hoffmann-La Roche Inc. (Roche),
Nutley, N.J.), chlordiazepoxide (LibriumTM or LibritabsTM, F. Hoffman-LaRoche
Ltd.,
Basel, Switzerland), lorazepam (AtivanTM, Wyeth, Madison, New Jersey),
oxazepam
(SeraxTM, Wyeth, Madison, New Jersey), buspirone (BusparTM), zolpidem
(AmbienTM),
bromazepam (LectopamTM), alprazolam (XanaxTM), clonazepam (RivotrilTM),
flurazepam (DalmaneTM), temazepam (RestorilTM), triazolam (HalcionTM),
nitrazepam
(MogadonTM); and anti-Parkinson including benztopine (CogentinTM) and
procyclidine
(KernadrinTM); ACE inhibitors such as captopril (CapotenTM), captopril in
combination
with hydrochlorothiazide (CapozideTM), enalapril maleate (VasotecTM),
enalaprilat,
enalapril maleate/hydrochlorothiazide combination (VasereticTM), fosinopril
(MonoprilTM), lisinopril (ZestrilTM), ramipril (AltaceTM), epi-captopril,
alacepril,
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NB I-154CPPC
quinapril, perindopril, delapril, cilazapril, pivalopril, rentiapril,
zofenopril, zofenoprilat;
analgesics; anesthetics; antienemic and mineral or vitamin dietary
supplements;
antibiotics; antidiarrheal; antiepileptics; antigout; antihistamines;
antihypertensives;
antiinflammatory and antirheumatoid; antipruritics; antithrombotics; beta-
blockers;
calcium channel blockers; cardioactive glycosides; corticosteroids such as
prednisone
(DeltasoneTM) and dexamethasone (DecadronTM); antitussives; diuretics;
antidiabetes ;
antiseptics; antiinfectives; laxatives; psychoanaleptics and psycholeptics;
serum lipid-
reducing drugs; sex hormones; thyroid hormones; and urological drugs.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of Parkinson's Disease or its symptoms, which second agents include:
(a)
cabidopa and levodopa compositions; (b) dopamine agonists such as
bromocriptine
mesylate (ParlodelTM), pergolide mesylate (PermaxmTM), (+)-4-propyl-9-
hydroxynaphthoxazine, and apomorphine; (c) anticholinergic medications such as
benztropine mesylate (CogentinTM), and biperiden; (d) antihistamines such as
orphenadrine citrate (NorflexTM, NorgesicTM); (e) tricyclic antidepressants
such as
amitriptyline HCI (ElavilTM), amitriptyline HCl/perphenazine combinations
(EtrafonTM),
amitriptyline and chlordiazepoxide combinations (LimbitrolTM), nortriptyline
HCI
(PamelorTM), imipramine, and doxepin; (f) serotonin reuptake inhibitor
antidepressants
such as fluoxetine HCl (ProzacTM), and sertraline (ZoloftTM); (g) beta blocker
agents
such as propranolol HCI (InderalTM), pindolol (ViskenTM), metoprolol tartrate
(LopressorTM), metoprolol succinate (Toprol XLTM), and atenolol (TenorminTM);
(h)
selegiline (EldeprylTM) or selegiline in combination with tocopherol; (i) D-
cycloserine
with or without a cholinesterase inhibitor co-agent; (j) neurotransmission
enhancer
drugs such as lisuride; (k) peripheral decarboxylase inhibitors such as
benserazide used
in combination with levodopa; (1) N-methyl-D-aspartate glutamate receptor
antagonists
such as trihexyphenidyl (ArtaneTM), ethopropazine (ParidolTM), procyclidine
(KemadrinTM), diphenhydramine (BenadrylTM), dizocilpine (NeurogardTM),
amantadine
(SymmetrelTM), memantine, and milacemide; (m) tacrine (CognexTM), optionally
with
phosphatidylcholine co-agent; (n) (+/-)-9-amino-1,2,3,4-tetrahydroacridin-l-
ol; (o)
lazabemide; (p) tiapride; and(q) antioxidant agents which may be used in
combination
such as ascorbic acid, N-acetylcysteine, penicillamine, and cysteamine.
Suitable second agents further include therapeutic drugs -that are useful in
the
treatment of Alzheimer's Disease or its symptoms, which second agents include:
(a)
CA 02582385 2006-12-18
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vasodilators or other nootropic direct brain metabolic enhancer drugs such as
idebenone,
propentophylline, pentoxifylline, citicoline, ebiratide, vinpocetine
(CavintonTM),
bromvincamine, cyclandelate, isoxsuprene, nafronyl, papaverine, suloctidil,
vinburnine,
vincamine, vindeburnol, naloxone, ethyl 5-isopropyloxy-4-methyl-p-carboline-3-
carboxylate, N'-methyl-(3-carboline-3-carboxamide, methyl 6,7-dimethoxy-4-
ethyl-p-
carboline-3-carboxylate, ethyl 5-methoxy-4-ethyl-(3-carboline-3-carboxylate,
ifenprodil
tartrate, piracetam, aniracetam, pyroglutamic acid, tenilsetam, pramiracetam,
oxiracetam, rolziracetam, razobazam, exifone, rolipram, sabeluzole, nimodipine
(NimotopTM), flunarizine, nicergoline (SermionTM), phosphatidylserine,
etiracetam,
dupracetam, and ergoloid mesylates (HydergineTM); (b) neurotransmission
enhancer
drugs such as amantadine (SymmetrelTM), calcium hopantenate, lisuride, and
indeloxazine; (c) tiapride; (d) psychotherapeutic drugs such as haloperidol
(HaldolTM),
bromperidol, thioridazine (MellarilTM), thiothixene (NavaneTM), fluphenazine
(ProlixinTM), perphenazine in amitriptyline/perphenazine combinations
(EtrafonTM), and
molindone (MobanTM); (e) acetylcholinesterase inhibitors such as physostigmine
(AntiliriumTM), optionally with phosphatidylcholine co-agent,
heptylphysostigmine,
donepezil (AriceptTM), tacrine (CoanexTM), optionally with phosphatidylcholine
co-
agent, (+/-)-9-amino-1,2,3,4-tetrahydroacridin-l-ol, metrifonate, velnacrine
(MentaneTM), phenylmethylsulfonyl fluoride, methanesulfonyl fluoride,
huperzine A,
huperzine B, edrophonium chloride, galanthamine, and miotine; (f) calcium
channel
blocker agents such as diltiazem (CardizemTM), verapamil (CalanTM), nifedipine
(ProcardiaTM), nifedipine (Procardia, nicardipine (CardeneTM), isradipine
(DynaCircTM),
amlodipine (NorvascTM), felodipine (PlendilTM); (g) biogenic amines and agents
related
thereto such as clonidine (CatapresTM), guanfacine (TenexTM), alaproclate,
fipexide,
zimeldine, and citalopram; (h) antirage drugs such as propranolol (InderalTM),
carbamazepine (TegretolTM), and fluoxetine; (i) minor tranquilizers such as
benzodiazepine agents including diazepam (ValiumTM), lorazepam (AtivanTM),
prazepam (CentraxTM), chlordiazepoxide (LibritabsTM),
chlordiazepoxide/clidinium
combination (LibraxTM), chlordiazepoxide/amitriptyline combination
(LimbitrolTM),
chlordiazepoxide/esterified estrogen combination (MenriumTM), oxazepam
(SeraxTM),
and clorazepate dipotassium (TranxeneTM); (j) angiotensin-converting enzyme
inhibitors
such as captopril (CapotenTM), captopril in combination with
hydrochlorothiazide
(CapozideTM), enalapril maleate (VasotecTM), enalaprilat, enalapril
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NBI-154CPPC
maleate/hydrochlorothiazide combination (VasereticTM), fosinopril
(MonoprilTM),
lisinopril (ZestrilTM), ra.mipril (AltaceTM), epi-captopril, alacepril,
quinapril, perindopril,
delapril, cilazapril, pivalopril, rentiapril, zofenopril, zofenoprilat; (k)
agents which may
enhance acetylcholine synthesis, storage or release such as
phosphatidylcholine, 4-
aminopyridine, 3,4-diaminopyridine, choline chloride, choline bitartrate,
bifemelane,
vesamicol, secoverine, tetraphenylurea, nicotinamide; (1) postsynaptic
receptor agonists
such as arecoline, oxotremorine, ethyl nipecotate, bethanechol (UrecholineTM),
and
levacecarnine; (m) ganglioside GM1; (n) specific monoamine oxidase-A
inhibitors such
as moclobemide (AurorixTM); (o) N-methyl-D-aspartate glutamate receptor
antagonists
such as milacemide, trihexyphenidyl (ArtaneTM), ethopropazine (ParidolTM),
procyclidine (KemadrinTM), diphenhydramine (BenadrylTM), dizocilpine
(NeuroQardTM),
amantadine (SymmetrelTM), and memantine; (p) nonsteroidal anti-inflammatory
agents
such-as those recognized for treatment of rheumatoid arthritis, including
flurbiprofen
(AnsaidTM), aspirin, mesalamine (AsacolTM), phenylbutazone (ButazolidinTM),
sulindac
(ClinorilTM), penicillamine (CuprimineTM), oxaprozin (DayproTM), salsalate
(DisalcidTM),
diflunisal (DolobidTM), piroxicam (FeldeneTM), indomethacin (IndocinTM),
etodolac
(LodineTM), meclofenamate sodium (MeclomenTM), ibuprofen (MotrinTM, AdvilTM),
fenoprofen calcium (NalfonTM), naproxen sodium (AnaproxTM), naproxen,
ketoprofen
(OrudisTM), mefenamic acid (PonstelTM), nabumetone (RelafenTM), auranofin
(RidauraTM), tolmetin sodium (TolectinTM), ketorolac tromethamine (ToradolTM),
diclofenac sodium (VoltarenTM), and deferoxamine mesylate (DesferalTM); (q)
selegiline
(EldeprylTM); (r) thiamine; (s) anfacine; (t) sulbutiamine (ArcalionTM); (u)
antioxidant
agents which may be used in combination such as ascorbic acid, N-
acetylcysteine,
penicillamine, cysteamine, and deferoxamine mesylate (Desferal); (v) specific
monoamine oxidase-B inhibitors such as lazabemide; (w) linopirdine (AvivaTM);
(x) D-
cycloserine; and (y) serotonergic receptor antagonists such as ketanserin, and
mianserin
(MianTM).
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of aging or its symptoms, which second agents include: (a) monoamine
oxidase B inhibitors such as selegiline; (b) acetylcholinesterase inhibitors
such as
physostigmine (Antilirium InjectableTM), heptylphysostigmine, tacrine
(CognexTM),
optionally with phosphatidylcholine co-agent; (+/-)-9-amino-1,2,3,4-
tetrahydroacridin-1-
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NBI- I 54CPPC
ol, velnacrine maleate (MentaneTM), methanesulfonyl fluoride,
phenylmethylsulfonyl
fluoride, huperzine A, huperzine B, edrophonium chloride, galanthamine, and
miotine;
(c) angiotensin-converting enzyme inhibitors such as captopril (CapotenTM),
captopril in
combination with hydrochlorothiazide (CapozideTM), enalapril maleate
(VasotecTM),
enalaprilat, enalapril maleate/hydrochlorothiazide combination (VasereticTM),
fosinopril
(MonoprilTM), lisinopril (ZestrilTM), ramipril (AltaceTM), epi-captopril,
alacepril,
quinapril, perindopril, delapril, cilazapril, pivalopril, rentiapril,
zofenopril, and
zofenoprilat; (d) N-methyl-D-aspartate glutamate receptor antagonists such as
milacemide, trihexyphenidyl (ArtaneTM), ethopropazine (ParidolTM),
procyclidine
(KemadrinTM), diphenhydramine (BenadrylTM), dizocilpine (NeurogardTM),
amantadine
(SymmetrelTM), and memantine (NamendaTM); (e) the antioxidant co-agent
ascorbic
acid; (f) vasodilator and other nootropic direct brain metabolic enhancer
drugs such as
!.. flunarizine, nimodipine (NimotopTM), idebenone, ebiratide, vinpocetine
(CavintonTM),
pentoxifylline, citicoline, bromvincamine, cyclandelate, isoxsuprene,
nafronyl,
papaverine, suloctidil, vinburnine, vincamine, vindeburnol, nicergoline
(SermionTM),
razobazam, exifone, rolipram, naloxone, ethyl 5-isopropyloxy-4-methyl-(3 -
carboline-3-
carboxylate, N'-methyl-(3-carboline-3-carboxamide, methyl 6,7-dimethoxy-4-
ethyl-P -
carboline-3-carboxylate, ethyl5-methoxy-4-ethyl-(3-carboline-3-carboxylate,
sabeluzole,
phosphatidylserine, piracetam, aniracetam, pyroglutamic acid, tenilsetam,
pramiracetam,
oxiracetam, rolziracetam, etiracetam, propentophylline, dupracetam, and
ergoloid
mesylates (HydergineTM); (g) postsynaptic receptor agonists such as arecoline,
oxotremorine, bethanechol (UrecholineTM), levacecarnine (acetyl-L-carnitine or
A1carTM), and ethyl nipecotate; (h) biogenic amines and co-agents related
thereto such
as clonidine (CatapresTM), guanfacine (TenexTM), alaproclate, fipexide,
zimeldine, and
citalopram; (i) anfacine; (j) agents which may enhance acetylcholine
synthesis, storage
or release such as phosphatidylcholine, 4-aminopyridine, 3,4-diaminopyridine,
choline
chloride, choline bitartrate, bifemelane, vesamicol, secoverine,
tetraphenylurea, and
nicotinamide; (k) acetylhomocysteine thiolactone; (1) ganglioside GM1; (m)
sulbutiamine; and (n) serotonergic receptor antagonists such as ketanserin
(KetanTM),
3 0 and mianserin (MianTM)
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of tinnitus (nerve deafness) or its symptoms, which second agents
include:
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NBI-154CPPC
antidepressants or antianxiety medications such as amitriptyline (ElavilTM),
amitriptyline/perphenazine combinations (EtrafonTM), alprazolam (XanaxTM), and
triptolene; anticonvulsants such as primidone (MysolineTM), phenytoin
(DilantinTM), and
carbamazepine (TegQretolTM); lidocaine (XylocaineTM); tocainide; flecinide;
nicotinamide; aminooxyacetic acid; praxilene; aniracetam; piracetam; 13-cis-
retinoic
acid; and 13-trans-retinoic acid.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of multiple sclerosis or its symptoms, which second agents include:
(a)
azathioprine (ImuranTM); (b) copolymer-1 (random polymer of L-alanine, L-
glutamic
1 o acid, L-lysine and L-tyrosine, ratio of 6.0:1.9:4.7:1.0, of molecular
weight between
14,000 and 23,000 Daltons); (c) cyclosporine (SandimmuneTM); (d) interferons
such as
alfa-2a interferon (Roferon-ATM), alfa-2b interferon (Intron-ATM), alfa-N3
interferon
(Alferon N InjectionTM), beta interferon (BetaseronTM), and gamma-lb
interferon
(ActimmuneTM); (e) corticosteroids such as prednisone (DeltasoneTM), and
dexamethasone (DecadronTM); (f) cyclophosphamide (CytoxanTM); (g) 4-
aminopyridine; (h) baclofen (AtrofenTM); and (i) 3,4-diaminopyridine.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of amyotrophic lateral sclerosis or its symptoms, which second
agents include:
thyrotropin releasing factor (Relefact TRH); serine; L-threonine; N-methyl-D-
aspartate
glutamate receptor antagonists such as milacemide, trihexyphenidyl (ArtaneTM),
ethopropazine (ParidolTM), procyclidine (KemadrinTM), diphenhydramine
(BenadrylTM),
dizocilpine (NeurogardTM), amantadine (SymmetrelTM), and memantine
(NamendaTM).
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of Huntington's disease or its symptoms, which second agents
include: (a) N-
methyl-D-aspartate glutamate receptor antagonists such as milacemide,
trihexyphenidyl
(ArtaneTM), ethopropazine (ParidolTM), procyclidine (KemadrinTM),
diphenhydramine
(BenadrylTM), dizocilpine (NeurogardTM), amantadine (SymmetrelTM), and
memantine
(NamendaTM); (b) agents which may enhance acetylcholine synthesis, storage or
release
such as phosphatidylcholine, 3,4-diaminopyridine, choline chloride, and
choline
bitartrate; and (c) postsynaptic receptor agonists such as arecoline.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of olivopontocerebellar atrophy or its symptoms, which second agents
include:
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NBI-154CPPC
N-methyl-D-aspartate glutamate receptor antagonists such as milacemide,
trihexyphenidyl (ArtaneTM), ethopropazine (ParidolTM), procyclidine
(KemadrinTM),
diphenhydramine (BenadrylTM), dizocilpine (NeurogardTM), amantadine
(SymmetrelTM),
and memantine (NamendaTM).
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of alcoholic polyneuropathy or its symptoms, which second agents
include:
tiapride, physostigmine, optionally with pho sphatidylcho line co-agent,
piracetam, and
cyclandelate.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of hereditary motor and sensory neuropathies or its symptoms, which
second
agents include 3,4-diaminopyridine.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of urinary incontinence resulting from Alzheimer's senile dementia,
demyelinating diseases such as multiple sclerosis, peripheral nerve lesions,
diabetes
mellitus and alcoholic polyneuropathy or its symptoms, which second agents
include:
(a) cholinergics such as bethanechol (UrecholineTM), alone or in combination
with
prazosin; (b) anti-cholinergics such as hyoscyamine sulfate, atropine sulfate,
propantheline (Pro-BanthineTM), oxybutynin (DitropanTM), and dicyclomine
(BentylTM);
(c) a-adrenergics such as ephedrine and phenylpropanolamine; (d) tricyclic
agents such
2 o as imipramine (TofranilTM) and doxepin (AdapinTM); (e) flavoxate
(UripasTM); (f) (3-
adrenergic blockers such as propranolol (InderalTM), pindolol (ViskenTM),
metoprolol
tartrate (LopressorTM), metoprolol succinate (Toprol XLTM), and atenolol
(TenorminTM);
and (g) vasopressin analogues such as desmopressin (DDAVP Nasal SprayTM).
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of gastroesophageal reflux disease, hypoperistalsis and/or delayed
gastric
emptying or its symptoms, which second agents include: metoclopramide
(ReglanTM),
cisapride (PrepulsidTM), famotidine (PepcidTM), cimetidine (TagametTM),
ranitidine
(ZantacTM), omeprazole (PrilosecTM), and galanthamine.
Suitable second agents further include therapeutic drugs that are useful in
the
treatment of symptomology related to onset and development of atherosclerosis
or its
symptoms, which second agents include: (a) angiotensin-converting enzyme
inhibitor
CA 02582385 2006-12-18
NBI-154CPPC
free radical scavenging agents possessing sulfhydryl groups such as captopril
(CapotenTM), captopril in combination with hydrochlorothiazide (CapozideTM),
epi-
captopril, alacepril, pivalopril, and rentiapril; (b) fibric acid derivative
anti-
hyperlipidemia agents such as gemfibrozil (LopidTM), clofibrate (Atromid-STM),
bezafibrate, and fenofibrate; (c) metformin; (d) nicotinic acid (NicolarTM);
(e) natural
hydroscopic non-digestible edible plant carbohydrate polymers such as guar
gum; (f) 3-
hydroxy-3-methylglutaryl-CoA reductase inhibitors such as lovastatin
(MevacorTM),
pravastatin (PravacholTM), and simvastatin (ZocorTM); (g) acipimox; (h) bile
acid
sequestrants such as cholestyramine resin (Questran LightTM), and colestipol
(ColestidTM); (i) anti-hypertensive agents including oral diuretics such as
bendroflumethiazide (NaturetinTM), benzthiazide (ExnaTM), chlorothiazide
(DiurilTM),
chlorthalidone (HvqrotonTM), cyclothiazide (AnhydronTM), hydrochlorothiazide
(Hydro-
DiurilTM), hydroflumethiazide (SaluronTM), indapamide (LozolTM),
methylclothiazide
(EnduronTM), metolazone (ZaroxolynTM), polythiazide (ReneseTM), quinethazone
(HydromoxTM), trichlormethiazide (NaguaTM) and idebenone; loop diuretics such
as
bumetanide (BumexTM), ethacrynic acid (EdecrinTM), furosemide (LasixTM) and
torsemide (PresarilTM); potassium-sparing diuretics such as amiloride
(MidamorTM);
spironolactone (AldactoneTM), and triamterene (DyreniumTM); 0-adrenergic
antagonists
such as acebutolol (SectralTM), atenolol (TenorminTM), betaxolol (KerloneTM),
carteolol
(CartrolTM), labetalol (NormodyneTM), metoprolol (LopressorTM), nadolol
(CorgardTM),
penbutolol (LevatolTM), pindolol (ViskenTM), propranolol (InderalTM or Inderal
LATM),
timolol (BlocadrenTM) and bisoprolol (ZebetaTM); calcium antagonists such as
diltiazem
(CardizemTM or Cardizem SRTM), verapamil (CalanTM or Calan SRTM), nifedipine
(ProcardiaTM), nifedipine (Procardia XLTM), nicardipine (CardeneTM),
isradipine
(DynaCircTM), amlodipine (NorvascTM), felodipine (PlendilTM), nimodipine
(NimotopTM)
and flunarizine; angiotensin-converting enzyme inhibitors such as captopril
(CapotenTM), enalapril (VasotecTM), fosinopril (MonoprilTM), lisinopril
(ZestrilTM),
ramipril (AltaceTM), quinapril (AccuprilTM), quinapril/hydrochlorothiazide
combinations
(AccureticTM) and benazepril (LotensinTM); peptide-based renin inhibitors such
as [(2S)-
3-(4-methylpiperazin-ll-yl)sulfonyl-2-(phenylmethyl)-propionyl]-N-[( 1S,2R,3S)-
1-
(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-[3-(thiazol-4 -
yl)alaninamide];
centrally acting a-adrenergic agonists such as clonidine (CatapresTM),
clonidine TTS
(CatapresTM), guanabenz (WytensinTM), guanfacine (TenexTM) and methyldopa
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NBI-1 S4CPPC
(AldometTM); peripherally acting adrenergic antagonists such as guanadrel
(HylorelTM),
guanethidine (IsmelinTM), whole root Rauwolfia alkaloids (RaudixinTM) and
reserpine
(SerpasilTM); a-adrenergic antagonists such as prazosin (MinipressTM),
prazosin/polythiazide combination (MinizideTM), terazosin (HytrinTM) and
doxazosin
(CarduraTM); direct-acting vasodilators such as hydralazine (ApresolineTM) and
minoxidil (LonitenTM); and (j) drugs for use in treatment of ischemic heart
disease
including nitrates such as oral isosorbide dinitrate and sustained-release
trinitroglycerin;
P-adrenergic antagonists such as acebutolol (SectralTM), atenolol
(TenorminTM),
betaxolol (KerloneTM), carteolol (CartrolTM), labetalol (NormodyneTM),
metoprolol
(LopressorTM), nadolol (CorgardTM), penbutolol (LevatolTM), pindolol
(ViskenTM),
propranolol (InderalTM or Inderal LATM), timolol (BlocadrenTM) and bisoprolol
(ZebetaTM); and calcium channel antagonists such as diltiazem (CardizemTM or
Cardizem SRTM), verapamil (CalanTM or Calan SRTM), nifedipine (ProcardiaTM),
nifedipine (Procardia XLTM), nicardipine (CardeneTM), isradipine (DynaCircTM),
amlodipine (NorvascTM) and felodipine (PlendilTM); and (k) ventricular
antiarrhythmic
drugs such as sotalol (BetapaceTM), mexilitene (MexitilTM), propafenone
(RythmolTM),
quinidine (Quinaglute Dura-TabsTM), procainamide (Procan SRTM), and pirmenol
(PimavarTM)
2 o The First Agent
Compositions of certain alkanesulfur-oxides, including alkanesulfonic acids
and
alkanesulfuric acids, and more particularly including, for example, 3-amino-
1-propanesulfonic acid and certain salts thereof have been shown to be useful
in the
treatment of amyloid-(3 related diseases, including Alzheimer's disease and
cerebral
amyloid angiopathy. See WO 96/28187, WO 01/85093, and U.S. Pat. No. 5,840,294.
The anionic group of the composition is believed to inhibit an interaction
between an
amyloidogenic protein and a glycosaminoglycan (GAG) or proteoglycan
constituent of a
basement membrane to thus inhibit amyloid deposition.
The ability of a therapeutic compound of the invention to inhibit an
interaction
between an amyloidogenic protein and a glycoprotein or proteoglycan
constituent of a
basement membrane can be assessed by an in,vitro binding assay, such as that
described
herein or in U.S. Pat. No. 5,164,295. Briefly, a solid support such as a
polystyrene
microtiter plate is coated with an amyloidogenic protein (e.g., serum amyloid
A protein
52
CA 02582385 2006-12-18
NBI-154CPPC
or (3-amyloid precursor protein ((3-APP)) and any residual hydrophobic
surfaces are
blocked. The coated solid support is incubated with various concentrations of
a
constituent of basement membrane, for example HSPG, either in the presence or
absence
of a compound to be tested. The solid support is washed extensively to remove
unbound
material. The binding of the basement membrane constituent (e.g., HSPG) to the
amyloidogenic protein (e.g., (3-APP) is then measured using an antibody
directed against
the basement membrane constituent that is conjugated to a detectable substance
(e.g., an
enzyme, such as alkaline phosphatase) by detecting the detectable substance. A
compound which inhibits an interaction between an amyloidogenic protein and a
glycoprotein or proteoglycan constituent of a basement membrane will reduce
the
amount of substance detected (e.g., will inhibit the amount of enzyme activity
detected).
A therapeutic compound of the invention may interact with a binding site for a
basement
membrane glycoprotein or proteoglycan in an amyloidogenic protein and thereby
inhibit
the binding of the amyloidogenic protein to the basement membrane constituent.
Basement membrane glycoproteins and proteoglycans include laminin, collagen
type IV,
fibronectin and heparan sulfate proteoglycan (HSPG), perlecan, and agrin. In a
similar
embodiment, the therapeutic compound inhibits an interaction between an
amyloidogenic protein and HSPG. Consensus binding site motifs for HSPG in
amyloidogenic proteins have been described (see, e.g., Cardin and Weintraub,
2o Arteriosclerosis 9, 21-32 (1989)).
The method also relates to a method for treating or preventing an amyloid-(3
related disease by administering at least two agents, each of which exerts a
therapeutic
effect when so administered and is useful in treating or preventing a
neurological
disease. The first agent of the invention is selected from alkanesulfonic
acids that are
useful for treating or preventing an amyloid-(3 related disease. The second
agent is
therapeutic, i.e., its function is beyond that of an inactive ingredient, such
as a
pharmaceutical carrier, preservative, diluent, or buffer. The second agent may
be useful
in treating or preventing an amyloid-(3 related disease or another
neurological disease.
The second agent may also be useful in diminishing specific symptoms which are
characteristic of Alzheimer's disease (e.g., memory loss, anxiety, etc.). The
first and
second agents may exert their biological effects by similar or unrelated
mechanisms of
action; or either one or both of the first and second agents may exert their
biological
effects by a multiplicity of mechanisms of action. A third agent, or even more
yet, may
likewise be used in a method of the invention, wherein the third (and fourth,
etc.) agent
has the same characteristics of a second agent. The invention relates to a
method of
treating or preventing an amyloid-(3 related disease in a subject (for
example, a human)
comprising administering to the subject a therapeutic amount of a
alkanesulfonic acid,
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CA 02582385 2006-12-18
NBI-154CPPC
such that amyloid fibril formation or deposition, neurodegeneration, or
cellular toxicity
is reduced or inhibited. In another embodiment, the invention relates to a
method of
treating or preventing an amyloid-(3 related in a subject (for example, a
human)
comprising administering to the subject a therapeutic amount of an
alkanesulfonic acid,
such that cognitive function is stabilized or further deterioration in
cognitive function is
prevented, slowed, or stopped in subjects with brain amyloidosis, e.g.,
Alzheimer's
disease or cerebral amyloid angiopathy. In another embodiment, the invention
relates to
a method of treating or preventing an amyloid-(3 disease in a subject (for
example,
human) comprising administering to the subject a therapeutic amount of a
alkanesulfonic
lo acid, such that activities of daily living are improved or stabilized in
subjects with brain
amyloidosis, e.g., Alzheimer's disease.
The "first agent" according to the invention may be an alkanesulfonic acid or
an
alkanolsulfuric acid. The term "alkanesulfonic acid" includes substituted or
unsubstituted alkanesulfonic acids, and substituted or unsubstituted lower
alkanesulfonic
acids. Amino-substituted compounds are especially noteworthy and the invention
pertains to substituted- or unsubstituted-amino-substituted alkanesulfonic
acids, and
substituted- or unsubstituted-amino-substituted lower alkanesulfonic acids,
and example
of which is 3-amino-l-propanesulfonic acid.
The methods and pharmaceutical compositions of the invention are therefore
directed to a first agent that is a substituted or unsubstituted
alkanesulfonic acid,
substituted or unsubstituted alkanesulfuric acid (also known as an alkanol
sulfuric acid),
substituted or unsubstituted alkylthiosulfonic acid, substituted or
unsubstituted
alkylthiosulfuric acid, or an ester or amide thereof, including
pharmaceutically
acceptable salts thereof. For example, the invention relates to a first agent
that is a
substituted or unsubstituted alkanesulfonic acid, or an ester or amide
thereof, including
pharmaceutically acceptable salts thereof. In another embodiment, the
invention
pertains to a first agent that is a substituted or unsubstituted lower
alkanesulfonic acid, or
an ester or amide thereof, including pharmaceutically acceptable salts
thereof.
Similarly, the invention includes a first agent that is a (substituted- or
unsubstituted-
amino)-substituted alkanesulfonic acid, or an ester or amide thereof,
including
pharmaceutically acceptable salts thereof. In yet another embodiment, the
first agent is a
(substituted- or unsubstituted-amino)-substituted lower alkanesulfonic acid,
or an ester
or amide thereof, including pharmaceutically acceptable salts thereof.
As used herein, "alkyl" groups include saturated hydrocarbons having one or
more carbon atoms, including straight-chain alkyl groups (e.g., methyl, ethyl,
propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), cyclic alkyl groups
(or
54
CA 02582385 2006-12-18
NBI-154CPPC
"cycloalkyl" or "alicyclic" or "carbocyclic" groups) (e.g., cyclopropyl,
cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched-chain alkyl groups
(isopropyl,
tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkyl groups
(e.g., alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl
groups). The
term "aliphatic group" includes organic moieties characterized by straight or
branched-chains, typically having between 1 and 22 carbon atoms. In complex
structures, the chains may be branched, bridged, or cross-linked. Aliphatic
groups
include alkyl groups, alkenyl groups, and alkynyl groups.
Accordingly, the invention relates to substituted or unsubstituted
alkanesulfonic
acids that are substituted or unsubstituted straight-chain alkanesulfonic
acids, substituted
or unsubstituted cycloalkanesulfonic acids, and substituted or unsubstituted
branched-chain alkanesulfonic acids.
The structures of some of the compounds of this invention include stereogenic
carbon atoms. It is to be understood that isomers arising from such asymmetry
(e.g., all
enantiomers and diastereomers) are included within the scope of this invention
unless
indicated otherwise. That is, unless otherwise stipulated, any chiral carbon
center may
be of either (R)- or (S)-stereochemistry. Such isomers can be obtained in
substantially
pure form by classical separation techniques and by stereochemically-
controlled
synthesis. In addition, the compounds of the present invention may exist in
unsolvated
as well as solvated forms with acceptable solvents such as water, THF,
ethanol, and the
like. In general, the solvated forms are considered equivalent to the
unsolvated forms
for the purposes of the present invention. The term "solvate" represents an
aggregate
that comprises one or more molecules of a compound, with one or more molecules
of a
pharmaceutical solvent, such as water, ethanol, and the like.
In certain embodiments, a straight-chain or branched-chain alkyl group may
have
or fewer carbon atoms in its backbone, e.g., C1-C30 for straight-chain or C3-
C30 for
branched-chain. In certain embodiments, a straight-chain or branched-chain
alkyl group
may have 20 or fewer carbon atoms in its backbone, e.g., C1-C20 for straight-
chain or
C3-C20 for branched-chain, and more, for example, 18 or fewer. Likewise,
example
30 cycloalkyl groups have from 4-10 carbon atoms in their ring structure, or 4-
7 carbon
atoms in the ring structure.
The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbons in
the
chain, and to cycloalkyl groups having from 3 to 6 carbons in the ring
structure. Unless
the number of carbons is otherwise specified, "lower" as in "lower alkyl,"
means that the
moiety has at least one and less than about 8 carbon atoms. In certain
embodiments, a
straight-chain or branched-chain lower alkyl group has 6 or fewer carbon atoms
in its
CA 02582385 2006-12-18
NBI-154CPPC
backbone (e.g., C1-C6 for straight-chain, C3-C6 for branched-chain), and more
preferably
4 or fewer, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, and
tert-butyl. Likewise, cycloalkyl groups may have from 3-8 carbon atoms in
their ring
structure, for example, 5 or 6 carbons in the ring structure. The term "Ci-C6"
as in
"CI -C6 alkyl." means alkyl groups containing I to 6 carbon atoms.
Moreover, unless otherwise specified the term alkyl includes both
"unsubstituted
alkyls" and "substituted alkyls," the latter of which refers to alkyl groups
having
substituents replacing one or more hydrogens on one or more carbons of the
hydrocarbon backbone. Such substituents may include, for example, alkenyl,
alkynyl,
halogeno, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl,
alkoxyl,
phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
(including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino,
sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkanesulfinyl,
sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkylaryl, or
aromatic (including heteroaromatic) groups.
An "arylalkyl" group is an alkyl group substituted with an aryl group
(e.g., phenylmethyl (i.e., benzyl)). An "alkylaryl" moiety is an aryl group
substituted
with an alkyl group '(e.g., p-methylphenyl (i.e., p-tolyl)). The term "n-
alkyl" means a
straight-chain (i.e., unbranched) unsubstituted alkyl group. An "alkylene"
group is a
divalent analog of the corresponding alkyl group. The terms "alkenyl" and
"alkynyl"
refer to unsaturated aliphatic groups analogous to alkyls, but which contain
at least one
double or triple carbon-carbon bond respectively. Suitable alkenyl and alkynyl
groups
include groups having 2 to about 12 carbon atoms, preferably from 2 to about 6
carbon
atoms.
The term "aromatic group" or "aryl group" includes unsaturated and aromatic
cyclic hydrocarbons as well as unsaturated and aromatic heterocycles
containing one or
more rings. Aryl groups may also be fused or bridged with alicyclic or
heterocyclic
rings that are not aromatic so as to form a polycycle (e.g., tetralin). An
"arylene" group
is a divalent analog of an aryl group. Aryl groups can also be fused or
bridged with
alicyclic or heterocyclic rings which are not aromatic so as to form a
polycycle (e.g.,
tetralin).
The term "heterocycl'-c group" includes closed ring structures analogous to
carbocyclic groups in which one or more of the carbon atoms in the ring is an
element
56
CA 02582385 2006-12-18
NBI-154CPPC
other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic
groups may be
saturated or unsaturated. Additionally, heterocyclic groups (such as pyrrolyl,
pyridyl,
isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character, in
which case
they may be referred to as "heteroaryl" or "heteroaromatic" groups.
Unless otherwise stipulated, aryl and heterocyclic (including heteroaryl)
groups
may also be substituted at one or more constituent atoms. Examples of
heteroaromatic
and heteroalicyclic groups may have 1 to 3 separate or fused rings with 3 to
about 8
members per ring and one or more N, 0, or S heteroatoms. In general, the term
"heteroatom" includes atoms of any element other than carbon or hydrogen,
preferred
examples of which include nitrogen, oxygen, sulfur, and phosphorus.
Heterocyclic
groups may be saturated or unsaturated or aromatic.
Examples of heterocycles include, but are not limited to, acridinyl; azocinyl;
benzimidazolyl; benzofuranyl; benzothiofuranyl; benzothiophenyl; benzoxazolyl;
benzthiazolyl; benztriazolyl; benztetrazolyl; benzisoxazolyl;
benzisothiazolyl;
benzimidazolinyl; carbazolyl; 4aH-carbazolyl; carbolinyl; chromanyl;
chromenyl;
cinnolinyl; decahydroquinolinyl; 2H,6H-1,5,2-dithiazinyl;
dihydrofuro[2,3-b]tetrahydrofuran; furanyl; furazanyl; imidazolidinyl;
imidazolinyl;
imidazolyl; I H-indazolyl; indolenyl; indolinyl; indolizinyl; indolyl; 3H-
indolyl;
isobenzofuranyl; isochromanyl; isoindazolyl; isoindolinyl; isoindolyl;
isoquinolinyl;
isothiazolyl; isoxazolyl; methylenedioxyphenyl; morpholinyl; naphthyridinyl;
octahydroisoquinolinyl; oxadiazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl;
1,2,5-oxadiazolyl; 1,3,4-oxadiazolyl; oxazolidinyl; oxazolyl; oxazolidinyl;
pyrimidinyl;
phenanthridinyl; phenanthrolinyl; phenazinyl; phenothiazinyl; phenoxathiinyl;
phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; piperidonyl; 4-
piperidonyl;
piperonyl; pteridinyl; purinyl; pyranyl; pyrazinyl; pyrazolidinyl;
pyrazolinyl; pyrazolyl;
pyridazinyl; pyridooxazole; pyridoimidazole; pyridothiazole; pyridinyl;
pyridyl;
pyrimidinyl; pyrrolidinyl; pyrrolinyl; 2H-pyrrolyl; pyrrolyl; quinazolinyl;
quinolinyl;
4H-quinolizinyl; quinoxalinyl; quinuclidinyl; tetrahydrofuranyl;
tetrahydroisoquinolinyl;
tetrahydroquinolinyl; tetrazolyl; 6H-1,2,5-thiadiazinyl; 1,2,3-thiadiazolyl;
1,2,4-thiadiazolyl; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; thianthrenyl;
thiazolyl; thienyl;
thienothiazolyl; thienooxazolyl; thienoimidazolyl; thiophenyl; triazinyl;
1,2,3-triazolyl;
1,2,4-triazolyl; 1,2,5-triazolyl; 1,3,4-triazoiyl; and xanthenyl. Preferred
heterocycles
include, but are not limited to, pyridinyl; furanyl; thienyl; pyrrolyl;
pyrazolyl;
pyrrolidinyl; imidazolyl; indolyl; benzimidazolyl; 1H-indazolyl; oxazolidinyl;
benzotriazolyl; benzisoxazolyl; oxindolyl; benzoxazolinyl; and isatinoyl
groups. Also
included are fused ring and spiro compounds containing, for example, the above
heterocycles.
57
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NB I-1 S4CPPC
A common hydrocarbon aryl group is a phenyl group having one ring. Two-ring
hydrocarbon aryl groups include naphthyl, indenyl, benzocyclooctenyl,
benzocycloheptenyl, pentalenyl, and azulenyl groups, as well as the partially
hydrogenated analogs thereof such as indanyl and tetrahydronaphthyl. Exemplary
three-
ring hydrocarbon aryl groups include acephthylenyl, fluorenyl, phenalenyl,
phenanthrenyl, and anthracenyl groups.
Aryl groups also include heteromonocyclic aryl groups, i.e., single-ring
heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl,
pyrazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups; and oxidized
analogs thereof
such as pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl, and thiazolonyl
groups. The
corresponding hydrogenated (i.e., non-aromatic) heteromonocylic groups include
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl,
piperidyl and piperidino, piperazinyl, and morpholino and morpholinyl groups.
Aryl groups also include fused two-ring heteroaryls such as indolyl,
isoindolyl,
indolizinyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, chromenyl, isochromenyl, benzothienyl,
benzimidazolyl,
benzothiazolyl, purinyl, quinoliziny,l, isoquinolonyl, quinolonyl,
naphthyridinyl, and
pteridinyl groups, as well as the partially hydrogenated analogs such as
chromanyl,
isochromanyl, indolinyl, isoindolinyl, and tetrahydroindolyl groups. Aryl
groups also
include fused three-ring groups such as phenoxathiinyl, carbazolyl,
phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and
dibenzofuranyl groups.
Some typical aryl groups include substituted or unsubstituted 5- and 6-
membered single-ring groups. In another aspect, each Ar group may be selected
from
the group consisting of substituted or unsubstituted phenyl, pyrrolyl, furyl,
thienyl,
thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl,
oxazolyl, isooxazolyl,
pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl groups. Further examples
include
substituted or unsubstituted phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 1-
pyrrolyl, 2-
pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-
oxazolyl, 4-
oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-
thiazolyl, 5-
thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl, 2-
pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-
indolyl, 1-
isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-
quinolyl
groups.
The term "amine" or "amino," as used herein, refers to an unsubstituted or
substituted moiety of the formula -NRaRb, in which Ra and Rb are each
independently
58
CA 02582385 2006-12-18
NB T-154CPPC
hydrogen, alkyl, aryl, or heterocyclyl, or Ra and Rb, taken together with the
nitrogen
atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms
in the
ring. Thus, the term amino includes cyclic amino moieties such as piperidinyl
or
pyrrolidinyl groups, unless otherwise stated. Thus, the term "alkylamino" as
used herein
means an alkyl group having an amino group attached thereto. Suitable
alkylamino
groups include groups haviing 1 to about 12 carbon atoms, for example, l to
about 6
carbon atoms. The term amino includes compounds or moieties in which a
nitrogen
atom is covalently bonded to at least one carbon or heteroatom. The term
"dialkylainino" includes groups wherein the nitrogen atom is bound to at least
two alkyl
groups. The term "arylamino" and "di.arylami.no" include groups wherein the
nitrogen is
bound to at least one or two aryl groups, respectively. The term
"alkylarylami.no" refers
to an amino group which is bound to at least one alkyl group and at least one
aryl group.
The term "alkarninoalkyl" refers to an alkyl, alkenyl, or alkynyl group
substituted with
an alkylamino group. The term "amide" or "aminocarbonyl" includes compounds or
moieties which contain a nitrogen atom which is bound to the carbon of a
carbonyl or a
thiocarbonyl group.
The term "alkylthio" refers to an alkyl group, having a sulfliydryl group
attached
thereto. Suitable alkylthio groups include groups having I to about 12 carbon
atoms,
preferably from 1 to about 6 carbon atoms.
The term "alkylcarboxyl" as used herein means an alkyl group having a carboxyl
group attached thereto.
The term "alkoxy" as used herein means an alkyl group having an oxygen atom
attached thereto. Representative alkoxy groups include groups having I to
about 12
carbon atoms, preferably 1 to about 6 carbon atoms, e.g., methoxy, ethoxy,
propoxy,
tert-butoxy and the like. Examples of alkoxy groups include methoxy, ethoxy,
isopropyloxy, propoxy, butoxy, and pentoxy groups. The alkoxy groups can be
substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,
cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples
of halogen
substituted alkoxy groups include, but are not limited to, fluoromethoxy,
59
CA 02582385 2006-12-18
NBI-154CPPC
difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,
trichloromethoxy,
etc., as well as perhalogenated alkyloxy groups.
The term "acylamino" includes moieties wherein an amino moiety is bonded to
an acyl group. For example, the acylamino group includes alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido groups.
The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl
groups, as described above, which further include oxygen, nitrogen or sulfur
atoms
replacing one or more carbons of the hydrocarbon backbone.
The term "carbonv(" or "carboxy" includes compounds and moieties which
i o contain a carbon connected with a double bond to an oxygen atom. Examples
of
moieties which contain a carbonyl include aldehydes, ketones, carboxylic
acids, amides,
esters, anhydrides, etc.
The term "ether" or "ethereal" includes compounds or moieties which contain an
oxygen bonded to two carbon atoms. For example, an ether or ethereal group
includes
"alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl, group substituted
with an
alkoxy group.
The term "nitro" means -NOZ; the term "halogen" or "halogeno" or "halo"
designates -F, -C1, -Br or -I; the term "thiol," "thio," or "mercapto" means
SH; and the
term "hydroxyl" or "hydroxy" means -OH.
The term "acyl" refers to a carbonyl group that is attached through its carbon
atom to a hydrogen (i.e., a formyl), an aliphatic group (e.g., acetyl), an
aromatic group
(e.g., benzoyl), and the like. The term "substituted acyl" includes acyl
groups where one
or more of the hydrogen atoms on one or more carbon atoms are replaced by, for
example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), imino, sulfliydryl, alkylthio, arylthio,
thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,
cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
A "sulfonic acid" or "sulfonate" group is a-SO3H or -SO3-X+ group bonded to a
carbon atom, where X+ is a cationic counter ion group. Similarly, a "sulfonic
acid"
compound has a-SO3H or -SO3-X+ group bonded to a carbon atom, where X+ is a
CA 02582385 2006-12-18
NBI-I54CPPC
cationic group. A "sulfate" as used herein is a-OSO3H or -OSO3-X+ group (which
may
also be represented as -SO4H or -SO4"X+) bonded to a carbon atom, and a
"sulfuric
acid" compound has a-SO3H or -OSO3-X+ group bonded to a carbon atom, where X+
is
a cationic group. According to the invention, a suitable cationic group may be
a
hydrogen atom. In certain cases, the cationic group may actually be another
group on
the therapeutic compound that is positively charged at physiological pH, for
example an
amino group. A "counter ion" is required to maintain electroneutrality, and is
pharmaceutically acceptable in the compositions of the invention. Examples of
anionic
counter ions include halide, triflate, sulfate, nitrate, hydroxide, carbonate,
bicarbonate,
acetate, phosphate, oxalate, cyanide, alkylcarboxylate, N-hydroxysuccinimide ,
N-hydroxybenzotriazole, alkoxide, thioalkoxide, alkane sulfonyloxy,
halogenated alkane
sulfonyloxy, arylsulfonyioxy, bisulfate, oxalate, valerate, oleate, palmitate,
stearate,
laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate,
tartrate,
naphthylate mesylate, glucoheptonate, or lactobionate. Compounds containing a
cationic group covalently bonded to an anionic group may be referred to as an
"internal
salt."
Unless otherwise specified, the chemical moieties of the compounds of the
invention, including those groups discussed above, may be "substituted or
unsubstituted." In some embodiments, the term "substituted" means that the
moiety has
substituents placed on the moiety other than hydrogen (i.e., in most cases,
replacing a
hydrogen), which allow the molecule to perform its intended function. Examples
of
substituents include moieties selected from straight or branched alkyl
(e.g.,Cl-C5),
cycloalkyl (e.g., C3-C8), amino groups (including -NH2), -SO3H, -OSO3H, -CN, -
NO2,
halogen (e.g., -F, -Cl, -Br, or -I), -CHZOCH3, -OCH3, -SH, -SCH3, -OH, and -
CO2H,
alkoxy (preferably C1-C6), thioalkyl (preferably C1-C6), alkenyl (preferably
C2-C6),
alkynyl (preferably C2-C6), heterocyclic, carbocyclic, aryl (e.g., phenyl),
aryloxy (e.g.,
phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl),
arylacetamidoyl,
alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl
group,
heteroarylcarbonyl, and heteroaryl groups, as well as (CR'R")0-3NR'R" (e.g., -
NH2),
(CR'R")0-3CN (e.g., -CN), -NO2, halogen (e.g., -F, -Cl, -Br, or -I),
(CR'R")o-3C(halogen)3 (e.g., -CF3), (CR'R")0-3CH(halogen)2, (CR'R")0-
3CH2(halogen),
(CR'R")0-3CONR'R", (CR'R")0-3(CNH)NR'R", (CR'R")0-3S(O)1-2NR'R",
(CR'R")0-3CH0, (CR'R")o-30(CR'R")0-3H, (CR'R")o-3S(O)0-3R' (e.g., -SO3H),
(CR'R")0-30(CR'R")0-3H (e.g., -CH2OCH3 and -OCH3), (CR'R")o-3S(CR'R")o-3H
(e.g., -SH and -SCH3), (CR'R")0-30H (e.g., -OH), (CR'R")0.3COR',
(CR'R")0-3(substituted or unsubstituted phenyl), (CR'R")0-3(C3-C8 cycloalkyl),
(CR'R")0-3CO2R' (e.g., -CO2H), and (CR'R")0-30R' groups, wherein R' and R" are
each
61
CA 02582385 2006-12-18
NBI-154CPPC
independently hydrogen, a CI-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl
group; or
the side chain of any naturally occurring amino acid.
In another embodiment, a substituent may be selected from straight or branched
alkyl (preferably C1-C5), cycloalkyl (preferably C3-C8), alkoxy (preferably Ci-
C6),
thioalkyl (preferably C1-C6), alkenyl (preferably C2-C6), alkynyl (preferably
C2-C6),
heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy),
aralkyl (e.g.,
benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl,
heteroaralkyl,
alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl,
or
heteroaryl group, (CR'R")o.loNR'R" (e.g., -NH2), (CR'R")o-IOCN (e.g., -CN),
NO2,
halogen (e.g., F, Cl, Br, or I), (CR'R")o.loC(halogen)3 (e.g., -CF3),
(CR'R")o.1oCH(halogen)2, (CR'R")o.loCH2(halogen), (CR'R")o-ioCONR'R",
(CR'R")o.io(CNH)NR'R", (CR'R")o-loS(O)z.2NR'R", (CR'R")o.loCHO,
(CR'R")o-t00(CR'R")o-toH, (CR'R")o-ioS(O)o-3R' (e.g., -SO3H)>
(CR'R")o-loO(CR'R")o-loH (e.g., -CH2OCH3 and -OCH3), (CR'R")o.1oS(CR'R")0-3H
(e.g., -SH and -SCH3), (CR'R")o-IoOH (e.g., -OH), (CR'R")o-IoCOR',
(CR'R")o-to(substituted or unsubstituted phenyl), (CR'R")o.1o(C3-C8
cycloalkyl),
(CR'R")o-toC02R' (e.g., -COZH), or (CR'R")o_IOOR' group, or the side chain of
any
naturally occurring amino acid; wherein R' and R" are each independently
hydrogen, a
C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group, or R' and R" taken
together are
a benzylidene group or a -(CH2)20(CH2)2- group.
As used herein, the term "substituted" is meant to include all permissible
substituents of organic compounds. In a broad aspect, the permissible
substituents
include acyclic and cyclic, branched and unbranched, carbocyclic and
heterocyclic,
aromatic and nonaromatic substituents of organic compounds. The permissible
substituents can be one or more.
It will be understood that "substitution" or "substituted with" includes the
implicit proviso that such substitution is in accordance with permitted
valence of the
substituted atom and the substituent, and that the substitution results in a
stable
compound, e.g., which does not spontaneously undergo transformation such as by
rearrangement, cyclization, elimination, etc. As used herein, the term
"substituted" is
meant to include all permissible substituents of organic compounds. In a broad
aspect,
the permissible substituents include acyclic and cyclic, branched and
unbranched,
carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic
compounds. The permissible substituents can be one or more and the same or
different
for appropriate organic compounds.
62
CA 02582385 2006-12-18
NBI- I 54CPPC
In some embodiments, a"substituent" may be, selected from the group
consisting of, for example, halogeno, trifluoromethyl, nitro, cyano, Cl-C6
alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 alkylcarbonyloxy, arylcarbonyloxy,
C1-C6 alkoxycarbonyloxy, aryloxycarbonyloxy, C1-C6 alkylcarbonyl,
CI-C6 alkoxycarbonyl, CI-C6 alkoxy, CI-C6 alkylthio, arylthio, heterocyclyl,
aralkyl, and
aryl (including heteroaryl) groups.
One group of example alkanesulfonic acids have the following structure as
depicted in Formula I (see the Drawings, attached hereto) where Y is either an
amino
group (having the formula -NRaRb) or a sulfonic acid group (having the formula
-SO3-X*), n is an integer from 1 to 5, and X is hydrogen or a cationic group
(e.g., sodium). Some exemplary alkanesulfonic acids include the those depicted
within
Formula IIa, Formula IIb, Formula IIc, and Formula IId (see Figures).
One embodiment of the invention is the use of 3-amino-l-propanesulfonic acid
and pharmaceutically acceptable salts thereof as a first agent of the
pharmaceutical
compositions described herein and the methods of using them.
An "ageiit," as in a "first agent" or a "second agent" is generally intended
to
describe a chemical compound of suitable purity for use in a pharmaceutical
preparation.
In some cases, the agent is a"sma:ll molecule," that is, a compound that that
is not itself
the product of gene transcription or translation (e.g., protein, RNA, or DNA)
and has a
low molecular weight, e.g., less than about 2500. In other cases, the agent
may be a
biological product, such as an antibody or an immunogenic peptide.
In general, alkanesulfonic acids may be prepared by the methods illustrated in
the general reaction schemes as, for example, described in U.S. Pat. Nos.
5,643,562;
5,972,328; 5,728,375; 5,840,294; 4,657,704; and the U.S. Provisional Patent
Application
No. 60/482,058, filed 23 June 2003, entitled "Synthetic Process for Preparing
Compounds for Treating Amyloidosis", or by modifications thereof, using
readily
available starting materials, reagents and conventional synthesis procedures.
In these
reactions, it is also possible to make use of variants which are in themselves
known, but
are not mentioned. Functional and structural equivalents of the agents
described herein
and that have the same general properties, wherein one or more simple
variations of
substituents are made which do not adversely affect the essential nature or
the utility of
the agent may be prepared according to a variety of methods known in the art.
In general, the agents of the present invention may be prepared by the methods
illustrated in the general reaction schemes as, for example, described below,
or by
modifications thereof, using readily available starting materials, reagents
and
conventional synthesis procedures. In these reactions, it is also possible to
make use of
63
CA 02582385 2006-12-18
NBI-154CPPC
variants which are in themselves known, but are not mentioned here. Functional
and
structural equivalents of the agents described herein and which have the same
general
properties, wherein one or more simple variations of substituents are made
which do not
adversely affect the essential nature or the utility of the agent. The agents
of the present
invention may be readily prepared in accordance with the synthesis schemes and
protocols described herein, as illustrated in the specific procedures
provided. However,
those skilled in the art will recognize that other synthetic pathways for
forming the
agents of this invention may be used, and that the following is provided
merely by way
of example, and is not limiting to the present invention. See, e.g.,
"Comprehensive
Organic Transformations," 2 d Ed., by R.C. Larock, John Wiley & Sons, Ltd.
(1999);
"March's Advanced Organic Chemistry," 5'h Ed., by M.B. Smith and J. March,
John
Wiley & Sons, Ltd. (2000); and "Reagents for Organic Synthesis," Vol. I-XX, by
M. Fieser and L. Fieser, John Wiley & Sons (2000). It will be further
recognized that
various protecting and deprotecting strategies will be employed that are
standard in the
art (see, e.g., "Protective Groups in Organic Synthesis," 3'd Ed., by T.W.
Greene, John
Wiley & Sons, Ltd. (1999)). Those skilled in the relevant arts will recognize
that the
selection of any particular protecting group (e.g., amine and carboxyl
protecting groups)
will depend on the stability of the protected moiety with regards to the
subsequent
reaction conditions and will understand the appropriate selections. Further
illustrating
the knowledge of those skilled in the art is the following sampling of the
extensive
chemical literature: "Comprehensive Asymmetric Catalysis", by E.N. Jacobsen,
et al.,
Springer Verlag (1999) "Chemistry of the Amino Acids" by J.P. Greenstein and
M. Winitz, John Wiley & Sons, Inc., New York (1961); T.D. Ocain, et al., J.
Med.
Chem. 31, 2193-99 (1988); E.M. Gordon, et al., J. Med. Chem. 31, 2199-10
(1988);
"Practice of Peptide Synthesis" by M. Bodansky and A. Bodanszky, Springer-
Verlag,
New York (1984); "Asymmetric Synthesis: Construction of Chiral Molecules Using
Amino Acids" by G.M. Coppola and H.F. Schuster, John Wiley & Sons, Inc., New
York
(1987); "The Chemical Synthesis of Peptides" by J. Jones, Oxford University
Press,
New York (1991); and "Introduction of Peptide Chemistry" by P.D. Bailey, John
Wiley
& Sons, Inc., New York (1992).
The chemical structures herein are drawn according to the conventional
standards known in the art. Thus, where an atom, such as a carbon atom, as
drawn
appears to have an unsatisfied valency, then that valency is assumed to be
satisfied by a
hydrogen atom even though that hydrogen atom is not necessarily explicitly
drawn. The
structures of some of the compounds of this invention include stereogenic
carbon atoms.
It is to be understood that isomers arising from such asymmetry (e.g., all
enantiomers
and diastereomers) are included within the scope of this invention unless
indicated
64
CA 02582385 2006-12-18
NBI-154CPPC
otherwise. That is, unless otherwise stipulated, any chiral carbon center may
be of either
(R)- or (S')-stereochemistry. Such isomers can be obtained in substantially
pure form by
classical separation techniques and by stereochemically-controlled synthesis.
Furthermore, alkenes can include either the E- or Z- geometry, where
appropriate. In
addition, the compounds of the present invention may exist in unsolvated as
well as
solvated fonns with acceptable solvents such as water, THF, ethanol, and the
like. In
general, the solvated forms are considered equivalent to the unsolvated forms
for the
purposes of the present invention.
Further examples of compounds that may be used as a first agent according to
the present invention include those described in the US Provisional Patent
Application
No. 60/480,906, filed 23 June 2003, entitled "Methods and Compositions for
Treating
Amyloid-Related Diseases" and Application No. 60/480,928, also filed 23 June
2003
"Methods and Compositions for The Treatment of Amyloid- and Epileptogenesis-
Associated Diseases" .
In an embodiment, the invention pertains, at least in part to a pharmaceutical
composition having a first agent.that is a compound of Formula I-A (see the
Drawings
sheets attached hereto), wherein R' is a substituted or unsubstituted
cycloalkyl, aryl,
arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring
group, or a
substituted or unsubstituted C2-C10 alkyl group; R 2 is selected from a group
consisting
hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycioalkyl, aryl, arylalkyl,
thiazolyl,
triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; Y is SO3 X+, OSO3
X+, or
SSO3 X+; X+ is hydrogen, a cationic group, or an ester-forming group (i.e., as
in a
prodrug, which are described elsewhere herein); and each of L1 and L 2 is
independently
a substituted or unsubstituted CI-C5 alkyl group or absent, or a
pharmaceutically
acceptable salt thereof, provided that when R' is alkyl, L1 is absent.
In another embodiment, the invention pertains, at least in part a
pharmaceutical
composition having a first agent that is a compound of Formula II-A (see the
Drawings
sheets attached hereto) wherein R' is a substituted or unsubstituted cyclic,
bicyclic,
tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C2-Clo
alkyl
group; R2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl,
thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked
to Rl to form
a heterocycle; Y is SO3-X+, OSO3-X+, or SSO3-X+; X+ is hydrogen, a cationic
group, or
an ester forming moiety; m is 0 or 1; n is 1, 2, 3, or 4; L is substituted or
unsubstituted
C1-C3 alkyl group or absent, or a pharmaceutically acceptable salt thereof,
provided that
when Rl is alkyl, L is absent.
CA 02582385 2006-12-18
NBI-154CPPC
In yet another embodiment, the invention pertains, at least in part to a
pharmaceutical composition having a first agent that is a compound of Formula
III-A
(see the Drawings sheets attached hereto) wherein A is nitrogen or oxygen; R'
1 is
hydrogen, salt-forming cation, ester forming group, -(CH2),-Q, or when A is
nitrogen,
A and R11 taken together may be the residue of a natural or unnatural amino
acid or a
salt or ester thereof; Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or
benzoimidazolyl; x is 0, 1, 2, 3, or 4; n is 0, 1,2 ,3, 4, 5, 6, 7, 8, 9, or
10; R3, R3a, R4, R4a,
Rs, RSa, R6, R6a, R7 and R7a are each independently hydrogen, alkyl,
mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, cyano,
halogen, amino, amidino, tetrazolyl, or two R groups on adjacent ring atoms
taken
together with the ring atoms form a double bond, provided that one of R3, R3a,
R4, R4a~
R5, Rsa, R6, R68, R7 and R7a is a moiety of Formula IIla-A, as depicted in the
Drawings,
wherein m is 0, 1, 2, 3, or 4; RS, R9, R10, RI i, and R12 are independently
selected from a
group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl,
mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, cyano, amidino, thiazolyl, triazolyl,
imidazolyl,
tetrazolyl, benzothiazolyl, and benzoimidazoly; and pharmaceutically
acceptable salts
and esters thereof, provided that said compound is not 3-(4-phenyl-1, 2, 3, 6-
tetrahydro-
1-pyridyl)-1-propanesulfonic acid.
In yet another embodiment, the invention pertains at least in part to a
pharmaceutical composition having a first agent that is a compound of Formula
IV (see
the attached Drawings) wherein: A is nitrogen or oxygen; Rl 1 is hydrogen,
salt-forming
cation, ester forming group, -(CH2)X--Q, or when A is nitrogen, A and R11
taken
together may be the residue of a natural or unnatural amino acid or a salt or
ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl; x is
0, 1, 2, 3, or 4; n is 0, 1,2 ,3, 4, 5, 6, 7, 8, 9, or 10; R4, R4a, Rs, RSa,
R6, R6a, R7, and R7a
are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino,
amidino,
tetrazolyl, R4 and R5 are taken together, with the ring atoms they are
attached to, form a
double bond, or R6 and R7 are taken together, with the ring atoms they are
attached to,
form a double bond; m is 0, 1, 2, 3, or 4; RB, R9, R10, R", and R12 are
independently
selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl,
halogenated alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, amidino, thiazolyl,
triazolyl,
imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl, and
pharmaceutically
acceptable salts and esters thereof.
In another embodiment, the invention includes a pharmaceutical composition
having a first agent that is a compound of Formula V-A (see the attached
Drawings)
wherein A is nitrogen or oxygen; Rl 1 is hydrogen, salt-forming cation, ester
forming
66
CA 02582385 2006-12-18
NBI-154CPPC
group, -(CH2)X Q, or when A is nitrogen, A and R11 taken together may be the
residue
of a natural or unnatural amino acid or a salt or ester thereof; Q is
hydrogen, thiazolyl,
triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or
4; n is 0, 1,2
,3, 4, 5, 6, 7, 8, 9, or 10; aa is a natural or unnatural amino acid residue;
m is 0, 1, 2, or 3;
R14 is hydrogen or protecting group; R15 is hydrogen, alkyl or aryl, and
pharmaceutically
acceptable salts and prodrugs thereof.
In another embodiment, the invention includes a pharmaceutical composition
having a first agent that is a compound of the Formula VI-A (see the attached
Drawings)
wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is oxygen or nitrogen; Rt 1
is hydrogen, salt-
1 o forming cation, ester forming group, -(CH2)X-Q, or when A is nitrogen, A
and Rl l
taken together may be the residue of a natural or unnatural amino acid or a
salt or ester
thereof, Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl; x is 0, 1, 2, 3, or 4; R19 is hydrogen, alkyl or aryl; Y' is
oxygen, sulfur,
or nitrogen; Y2 is carbon, nitrogen, or oxygen; R20 is hydrogen, alkyl, amino,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl,
triazolyl,
tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; R21 is hydrogen,
alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl,
triazolyl,
tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent if Y2 is
oxygen; R22 is
hydrogen, alkyl, mercaptoallcyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, thiazolyl,
triazolyl, tetrazolyi, imidazolyl, benzothiazolyl, benzoimidazolyl; or R22 is
hydrogen,
hydroxyl, alkoxy or aryloxy if Y' is nitrogen; or R22 is absent if Y' is
oxygen or sulfur;
or R22 and R21 may be linked to form a cyclic moiety if Y' is nitrogen; or
pharmaceutically acceptable salts thereof.
In another embodiment, the invention includes a pharmaceutical composi-tion
having a first agent that is a compound of Formula VII-A (see the attached
Drawings)
wherein: n is 2, 3, or 4; A is oxygen or nitrogen; R' 1 is hydrogen, salt-
forming cation,
ester forming group, -(CHz)X Q, or when A is nitrogen, A and Rl l taken
together may
be the residue of a natural or unnatural amino acid or a salt or ester
thereof; Q is
hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl; x is 0, 1,
2, 3, or 4; G is a direct bond or oxygen, nitrogen, or sulfur; z is 0, 1, 2,
3, 4, or 5; m is 0
or 1; R24 is selected from a group consisting hydrogen, alkyl, mercaptoalkyl,
alkenyl,
alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl,
arylalkyl, thiazolyl,
triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; each R25 is
independently
selected from hydrogen, halogen, cyano, amidino, hydroxyl, alkoxy, thiol,
amino, nitro,
alkyl, aryl, carbocyclic, or heterocyclic, and pharmaceutically acceptable
salts thereof.
67
CA 02582385 2006-12-18
NBI-154CPPC
Such compounds of the invention include, for example, compounds of Formula
I-B (see the attached Drawings) wherein X is oxygen or nitrogen; Z is C=O,
S(O)Z, or
P(O)OR7; m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R'
and R7 are
each independently hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl,
alkynyl,
cycloalkyl, aryl, a moiety together with X to form natural or unnatural amino
acid
residue, or -(CH2)p Y; Y is hydrogen or a heterocyclic moiety selected from
the group
consisting of thiazolyl, triazolyl, tetrazolyl, amidino, imidazolyl,
benzothiazolyl, and
benzoimidazolyl; p is 0, 1, 2, 3, or 4; RZ is hydrogen, alkyl, mercaptoalkyl,
alkenyl,
alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; R3
is
lo hydrogen, amino; cyano, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic,
sunbstituted or unsubstituted aryl, heteroaryl, thiazolyl, triazolyl,
tetrazolyl, amidino,
imidazolyl, benzothiazolyl, or benzoimidazolyl, and pharmaceutically
acceptable salts,
esters, and prodrugs thereof.
In a further embodiment, in the compounds of Formula I-B, m is 0, 1, or 2. In
another further embodiment, n is 0, 1, or 2. In another further embodiment, R3
is aryl,
e.g.; heteroaryl or phenyl. In yet another embodiment, Z is S(O)2.
In another embodiment, the compound of the invention is of the Formula II-B
(see the attached Drawings) wherein: each R4 is independently selected from
the group
consisting of hydrogen, halogen, hydroxyl, thiol, amino, amidino, cyano,
nitro, alkyl,
aryl, carbocyclic or heterocyclic; J is absent, oxygen, nitrogen, sulfur, or a
divalent link-
moiety comsisting of, without limiting to, lower alkylene, alkylenyloxy,
alkylenylamino, alkylenylthio, alkylenyloxyalkyl, alkylenylamonialkyl,
alkylenylthioalkyl, alkenyl, alkenyloxy, alkenylamino, or alkenylthio; and q
is 1, 2, 3, 4,
or 5, and pharmaceutically acceptable salts, esters and prodrugs thereof.
In a further embodiment of compounds of Formula II-B, R4 is aryl, e.g.,
substituted or unsubstituted phenyl. In another embodiment, R4 is halogen
(e.g.,
chlorine, fluorine, bromine, or iodine). In yet another embodiment, R4 is
alkyl, e.g.,
methyl, ethyl, propyl, butyl, pentyl, trifluoromethyl, etc. In another
embodiment, J is
absent or oxygen. In a further embodiment, m is I or n is 1. In another
further
embodiment, the compound can be R- or S-isomer.
In yet a further embodiment, the compound may be selected from the group
consisting of those compounds depicted in either Table X or Table Y (see the
attached
Drawings) and pharmaceutically acceptable salts, prodrugs, and esters thereof.
In still a further embodiment, the compound is selected from the group
consisting
of those compounds depicted in either Table Z-1 or Table Z-2 (see the attached
Drawings) and pharmaceutically acceptable salts, prodrugs, and esters thereof.
68
CA 02582385 2006-12-18
NB I-154CPPC
In a further embodiment, the compound of the invention is of the Formula Ill-B
(see the attached Drawings) wherein: X is oxygen or nitrogen; m and n are each
independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q is 1, 2, 3, 4, or 5; R' is
hydrogen, metal
ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or a moiety
together with X
to form a natural or unnatural amino acid residue, or -(CH2)p Y; Y is hydrogen
or a
heterocyclic moiety selected from the group consisting of thiazolyl,
triazolyl, tetrazolyl,
amidino, imidazolyl, benzothiazolyl, and benzoimidazolyl; p is 0, 1, 2, 3, or
4; R2 is
hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl,
arylcarbonyl, or alkoxycarbonyl; R5 is selected from the group consisting of
hydrogen,
halogen, amino, nitro, hydroxy, carbonyl, thiol, carboxy, alkyl, alkoxy,
alkoxycarbonyl,
acyl, alkylamino, acylamino; q is an integer selected from 1 to 5; J is
absent, oxygen,
nitrogen, sulfur, or a divalent link-moiety comsisting of, without limiting
to, lower
alkylene, alkylenyloxy, alkylenylamino, alkylenylthio, alkylenyloxyalkyl,
alkylenylamonialkyl, alkylenylthioalkyl, alkenyl, alkenyloxy, alkenylamino, or
alkenylthio; and pharmaceutically acceptable salts, esters, and prodrugs
thereof.
In still yet another embodiment, the compound of the invention may be a
compound of Formula IV-B (see the attached Drawings). In a related embodiment,
m is
0.
Examples of compounds of the invention include those compounds depicted in
Table W (see the attached Drawings) and pharmaceutically acceptable salts,
esters, and
prodrugs thereof.
In another embodiment, the invention pertains to compounds of Formula V-B
(see the attached Drawings) wherein: R6 is a substituted or unsubstituted
heterocyclic
moiety. In a further embodiment, m is 0 or 1. In another embodiment, n is 0 or
1. In
another further embodiment, R6 is thiazolyl, oxazoylyl, pyrazolyl, indolyl,
pyridinyl,
thiazinyl, thiophenyl, benzothiophenyl, dihydroimidazolyl, dihydrothiazolyl,
oxazolidinyl, thiazolidinyl, tetrahydropyrimidinyl, or oxazinyl. In yet
another
embodiment, Z is S(O)2.
In a further embodiment, the invention pertains to the following compounds
depicted in Table V (see the attached Drawings) and pharmaceutically
acceptable salts,
esters, and prodrugs thereof.
In yet another embodiment, the invention pertains to compounds of Formula I-C:
69
CA 02582385 2006-12-18
NBI-154CPPC
R2
R~ I
L '/ L 2 (I-C)
wherein:
R' is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl,
arylcycloalkyl,
bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a
substituted or
unsubstituted C2-Cao alkyl group;
R2 is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl,
alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyi, imidazolyl,
benzothiazolyl, and
benzoimidazolyl;
Y iS SO3 X+, OSO3 X+, or SSO3lX+;
X+ is hydrogen, a cationic group, or ester-forming group; and
each of Ll and L2 is independently a substituted or unsubstituted Cl-C5 alkyl
group or absent, or a pharmaceutically acceptable salt thereof, provided that
when Rl is
alkyl, Lt is absent.
In a further embodiment, the invention pertains to compounds of Formula Il-C:
R2 O
1 II
RN-kC)m-(CH2)n-Y
(II-C)
wherein:
R' is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or
benzoheterocyclic group or a substituted or unsubstituted C2-Clo alkyl group;
W is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl,
thiazolyl, triazolyl, irnidazolyl, benzothiazolyl, benzoimidazolyl, or linked
to Ri to form
a heterocycle;
Y is SO3 X+, OSO3 X+, or SS03 X+;
X+ is hydrogen, a cationic group, or an ester fonning moiety;
mis0or1;
nis 1,2,3,or4;
L is substituted or unsubstituted CI-C3 alkyl group or absent, or a
pharmaceutically acceptable salt thereof, provided that when Rl is alkyl, L is
absent.
In a furtller embodiment, R2 is hydrogen. In another further embodiment, R1 is
straight chain alkyl., .for example, ethyl, n-pentyl, n-heptyl, or n-octyl. In
another
CA 02582385 2006-12-18
NBI-154CPPC
embodiment, R' is t-butyl. In yet another alternate embodiment, R' is C7-CIo
bicycloalkyl or tricycloalkyl, such as, for example, tricyclo[3.3.1.03'7
]decyl (or
adamantyl), bicyclo[2.1.2]heptyl, or indolyl. In another alternate embodiment,
R' is
tetrahydronaphthyl.
In one embodiment, L 2 is -(CH2)3-. In anotlier further embodiment, L2 is -
(CH2)4- or -(CHZ)5-. In yet another further embodiment, L2 is -(CH2)2-. In yet
another
fui-ther embodiment, L2 is substituted alkyl, e.g., -CH2-(CHOH)-CH2-.
In another embodiment, L1 is C:H2CH2 or absent.
In a further embodiment, R' is branched alkyl, e.g., t-butyl. In another
embodiment, Ri is adamanyl. In another embodiment, R' is cyclic alkyl, e.g.,
cyclopropyl, cyclohexyl, cycloheptyl, cyclo-octyl, etc. The cycloalkyl
moieties may be
substituted further, e.g., with additional alkyl groups or other groups which
allow the
molecule to perform its intended function. In another embodiment, R' is alkyl
substituted with a propargyl moiety (e.g., HC=C-). In another embodiment, R'
is
i5 cyclohexyl substituted withone or more methyl or propargyl groups.
In other embodiments, Lt is a Ci-Cz alkyl linker group (e.g., -CH(CH3)- or -
(CH2)2-/. In a further embodiment, Rl is phenyl. 'In certain embodiments, R'
is
substituted with a methoxy group. In other embodiments, Ll is C3, e.g., -
(CH2)3- or
C(CH3)2-. In certain embodiments, Ll is substituted, e.g., with an alkoxy,
carboxylate 20 COOH), benzyl , amido (-C=O--NH-), or ester (C=O-C-O) grou.p.
In certain
embodiment, the ester group is a methyl , ethyl, propyl, butyl, cyclohexyl, or
benzyl
ester. In other embodiments, the ester group may be propenyl. In other
embodiments,
L1 is substituted with a carboxylate group. In a further embodiment, R1 is
substituted
with a subsituted amido group, wherein the amido group is substituted with an
alkyl,
25 e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl group. In another
embodiment, the
alkyl Rl group is a substituted with a-C=O-NH-OH, C=O-NH2, or an amido group.
In
certain embodiments, the amido group is substituted with an alkyl (e.g.,
methyl, ethyl,
propyl, butyl, pentyl, hexyl, cyclohexyl, bezyl or aryl group. In another
embodiment,
the amido group is substituted with a -CH(CH2)2 group. R' itself may be
substituted
30 with a phenyl or may be branched or straight chain alkyl. In certain
embodiments, R'
may also be substituted with a thioether moiety. Examples of thioethers
include S-Me,
S-Et, etc. In certain embodiments, the alkyl R' moiety is substituted with
both an aryl or
a thioether moiety and an amido moiety. In other embodiments, the alkyl R1
moiety
may be substituted with both a thioether and a carboxylate moiety. In other
35 embodiments, alkyl R' groups are substituted with hydroxyl. R1 groups,
e.g., alkyl Rl
groups, may also be substituted with both thioether and hydroxyl groups. In
other
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CA 02582385 2006-12-18
NBI-154CPPC
embodiments, R' groups, e.g., alkyl R' groups are substituted with cyano
groups.
Examples of R' groups including -CN moieties include -C(CH3)2CN, cyclohexyl
substituted with one or more cyano groups, etc.
In other embodiments, alkyl Rl groups are substituted with aryl groups. The
aryl
groups may be substituted phenyl, for example. The substituted phenyl may be
substituted with one or more substituents such as hydroxy, cyano and alkoxy.
In other
embodiments, alkyl R1 groups are substituted with tetrazolyl or substituted or
unsubstituted benzyl.
In a further embodiment, L1 is -C(CH3)2-(CH2)-. In another embodiment, L1 is -
(C(CH3)2-CHOH-. In yet another embodiment, L1 is -(C(CH3)2CH(OMe)-. In another
embodiment, R' is substituted or unsubstituted phenyl. In a further
embodiment, R, is
para-substituted phenyl. Examples of substitutuents include but are not
limited to
fluorine, chlorine, bromine, iodine, methyl, t-butyl, alkoxy, methoxy, etc. ln
other
embodiment, R' is substituted at the meta position. Examples of substituents
include
methoxy, chloro, methyl, t-butyl, fluoro, alkyl, alkoxy, iodo, trifluoroalkyl,
methoxy,
etc. In another embodiment, R' is phenyl substituted in the ortho position,
with similar
substituents. In another embodiment, Ll comprises a cycloalkyl moiety, e.g.,
cyclopentyl. In another embodiment, Ll comprises an alkyenyl group and,
optionally, a
substituted aryl group, with substittuents similar to those described about.
In certain embodi.ments, Rl is cyclopropyl or cyclohexyl. In certain
embodiments, the cyclopropyl or cyclohexyl group is subsituted with an ether
group or
an alkyl group. In certain fitrther embodiments, the ether group is a benzyl
ether group.
In another embodiment, wherein R' is alkyl, it is substituted with groups such
as
phenyl, or hydroxy.
In another embodiment, the invention pertains to compounds of Formula III-C:
R=-a R5
R4 R5a
0
R3 II 11
R3a N-(CH2)n-S-A-R
R7 R6
R7a R6a
(III-C)
wherein:
A is nitrogen or oxygen;
R11 is hydrogen, salt-forming cation, ester forming group, -(CH2)X-Q, or when
A is nitrogen, A and R" taken together may be the residue of a natural or
u:nnatural
72
CA 02582385 2006-12-18
NBI-154CPPC
amino acid or a salt or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
xis0, 1,2,3,or4;
n is 0, 1,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
R3, R3a, R4 , R4a, R5, R' , R6, R6a, R7 and R7a are each independently
hydrogen,
alkyl, mercaptoalkyl, alkenyl, alkynyl., cycloalkyl, aryl, alkylcarbonyl,
arylcarbonyl,
alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent
ring
atoms taken together with the ring atoms form a double bond, provided that one
of R3,
R3a, Ra, Raa, R5, Rsa R6, R6a~ R7 and R7a is a moiety of the Formula IIIa-C:
RA .rw
RB ~ (CH2)m
RC RE
R (IIIa-C)
wherein:
mis0, 1,2,3,or4;
RA, RB, Ro, RD, and RE are independently selected from a group of hydrogen,
halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl,
alkynyl,
cycloalkyl, aryl., cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl,
benzothiazolyl, and
benzoimidazolyl; and pharmaceutically acceptable salts and esters thereof,
provided that
said compound is not 3-(4-phenyl-1, 2, 3, 6-tetrahydro-l-pyridyl)-1-
propanesulfonic
acid. In a further embodiment, n is 2, 3 or 4.
In another embodiment, R" is a salt-forming cation. Examples of salt forming
cations include pharmaceutically acceptable salts described herein as well as
lithium,
sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In
another
embodiment, R11 is an ester-forming group. An ester-forming group include
groups
when bound form an ester. Examples of such groups include substituted or
unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl. In another
embodiment, A is
oxygen.
In another embodiment, R3 and R4 are taken together with the carbon atoms to
which they are attached to form a double bond. In another embodiment, RA, RB,
Rc, RD,
and RE are each hydrogen. RA, RII, RD, and RE are each hydrogen and RC is a
halogen,
such as fluorine, chlorine, iodine, or bromine.
In another embodiment, R3 or R'a is a moiety of Formula IIIa-C.
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NBI-154CPPC
In another embodiment, R4, R5, R6, and R7 are each hydrogen. In another
further
embodiment, R4a, Rsa, R6a, and R7a are each hydrogen.
In another, R3a is hydroxyl, cyano, acyl., or hydroxyl.
In another further embodiment, R' 1 and A taken together are a natural or
unnatural amino acid residue or a pharmaceutically acceptable salt or ester
thereof.
Examples of amino acid residues include esters and salts of phenylalanine and
leucine.
In another embodiment, m is 0, 1, or 3.
In another embodiment, the invention pertains to compounds of Formula IV-C:
R9 R8 Raa R5
R4~4 R5a
O
11
Rto \ / (CHz)m-'N N-(CH2)n-S-A-R11
11
R7 )_+ R6a u
Rtt Rtz R7a R6 (IV-C)
wh.erein:
A is nitrogen or oxygen;
R' I is hydrogen, salt-forming cation, ester forming group, -(CH2)X Q, or when
A is nitrogen, A and Rt i taken together may be the residue of a natural or
unnatural
amino acid or a salt or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
x is 0, 1, 2, 3, or 4;
n is 0, 1,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
R4, Raa, Rs, Rsa, R6, R6a, R7 , and R7a are each independently hydrogen,
alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl,
arylcarbonyl,
alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R4 and RS taken together,
with the
ring atoms they are attached to, form a double bond, or R6 and R7 taken
together, with
the ring atoms they are attached to, form a double bond;
mis0, 1,2,3;or4;
R8, R9, Rlo, R11, and R12 are independently selected from a group of hydrogen,
halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl,
alkynyl,
cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl,
benzothiazolyl, and
benzoimidazolyl, and pharmaceutically acceptable salts and esters thereof.
In another embodiment, R" is a salt-forming cation. Examples of salt forming
cations include pharmaceutically acceptable salts described herein as well as
lithium,
sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In
another
74
CA 02582385 2006-12-18
NBI-154CPPC
embodiment, Rll is an ester-forming group. An ester-forming group include
groups
when bound form an ester. Examples of such groups include substituted or
unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl. In another
embodiment, A is
oxygen.
In another embodiment, m is 0 or 1. In another further embodiment, n is 2, 3,
or
4. In another further embodiment, R4, R5, R6 and R7 are each hydrogen. Rad,
R5a Rba~
and R7a also may be hydrogen. Examples of R8, R9, R10, R", and R12 include
hydrogen.
In other embodiment R8, R9, R11, R12 are each hydrogen, and R10 is a halogen,
(e.g.,
fluorine, chlorine, bromine, or iodine), nitro, or alkyl (e.g., methyl, ethyl,
butyl).
In another embodiment, A-R11 may be the residue of an amino acid, e.g., a
phenyl alanine residue. In another embodiment, R9, R10, R" and R1z are each
hydrogen,
and R8 is not hydrogen, e.g., halogen, e.g., fluorine, bromine, chlorine, or
iodine.
In another embodiment, the invention pertains to compounds of Formula V-C:
R15 0
R1a_(aa)m-N-(CH2)n'S-A-R11
II
u , (V-C)
wherein:
A is nitrogen or oxygen;
R' I is hydrogen, salt-forming cation, ester forming group, -(CH2),-Q, or when
A is nitrogen, A and Ri I taken together may be the residue of a natural or
unnatural
amino acid or a salt or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
xis0, 1,2,3,or4;
nis0,1,2,3,4,5,6,7,8,9,or10;
aa is a natural or unnatural amino acid residue;
mis0, 1,2,or3;
R'a is hydrogen or protecting group;
R15 is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and
prodrugs thereof.
In another embodiment, Rll is a salt-forming cation. Examples of salt forming
cations include pharmaceutically acceptable salts described herein as well as
lithium,
sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In
another
embodiment, R11 is an ester-forming group. An ester-forming group includes
groups
when bound form an ester. Examples of such groups include substituted or
unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl. ln another
embodiment, A is
oxygen.
CA 02582385 2006-12-18
NBI- I 54CPPC
In an embodiment, n is 2, 3 or 4. In certain embodiments, m is 0. In certain
embodiments, A-Rl 1 is a residue of a natural amino acid, or a salt or ester
thereof.
Examples of amino acid residues, include, but are not limited, to leucine or
phenylalanine residues, and pharmaceutically acceptable salts and esters
thereof.
Examples of possible esters include methyl, ethyl, and t-butyl.
In another embodiment, m is 1. Examples of aa include natural and unnatural
amino acid residues such as phenylalanine, glycine, and leucine.
In another embodiment, (aa)n, is a residue of phe-phe; and pharmaceutically
acceptable salts or an appropriate protecting group.
In certain embodiments, R15 is hydrogen or substituted alkyl, e.g., arylalkyl.
The term "unnatural amino acid" refers to any derivative of a natural amino
acid
including D forms, and a- and R-amino acid derivatives. It is noted that
certain amino
acids, e.g., hydroxyproline, that are classified as a non-natural amino acid
herein, may be
found in nature within a certain organism or a particular protein. Amino acids
with
many different protecting groups appropriate for immediate use in the solid
phase
synthesis of peptideS are commercially available. In addition to the twenty
most
common naturally occurring amino acids, the following examples of non-natural
amino
acids and amino acid derivatives may be used according to the invention
(common
abbreviations in parentheses): P-alanine (R-ALA), y-aminobutyric acid (GABA),
2-aminobutyric acid (2-Abu), a,(3-dehydro-2-aminobutyric acid (8-AU),
1-aminocyclopropane-l-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 2-
amino-
thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic
acid
(6-Ahx), 8-aininooctanoic acid (8-Aoc), 1 I-aminoundecanoic acid (11-Aun),
12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic
acid
(3:Abz), 4-aminobenzoic acid(4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid
(Statine, Sta), aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid
(ATC),
4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), para-aminophenylalanine
(4-NH2-Phe), biphenylalanine (Bip), para-bromophenylalanine (4-Br-Phe),
ortho-chlorophenylalanine] (2-Cl-Phe), meta-chiorophenylalanine (3-Cl.-Phe),
para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine (3-C1.-Tyr), para-
benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha),
cyclohexylglycine (Chg), 2,3-diaminopropioni.c acid (Dpr), 2,4-diaminobutyric
acid
(Dbu), 3,4-dichlorophenylalanine (3,4-C 12-Phe), 3,4-diflurorphenylalanine
(3,4-F2-Phe),
3,5-diiodotyrosine (3,5-I2-Tyr), ortho-t7uorophenylalanine (2-F-Phe),
meta-fluorophenylalanine (3-F-Phe), para-fluorophenylalanine (4-F-Phe),
meta-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe),
homotyrosine (Htyr), 5-hydroxytryptophan (5-OH-Trp), hydroxyproline (Hyp),
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CA 02582385 2006-12-18
NBI-154CPPC
para-iodophenylalanine (4-1-Phe), 3-iodotyrosine (3-1-Tyr), indoline-2-
carboxylic acid
(Idc), isonipecotic acid (Inp), meta-methyltyrosine (3-Me-Tyr), 1-
naphthylalanine
(1-Nal), 2-naphthylalanine (2-Nal), para-nitrophenylalanine (4-N02-Phe),
3-nitrotyrosine (3-N02-Tyr), norleucine (Nle), norvaline (Nva), ornithine
(Orn),
ortho-phosphotyrosine (H2:P03-Tyr), octahydroindole-2-carboxylic acid (Oic),
penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg),
pipecolic
acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar),
tetrahydroisoquinoli.ne-3-carboxylic acid (Tic), and thiazolidine-4-carboxylic
acid
(thioproline, Th). Additionally, N-alkylatd amino acids may be used, as well
as amino
acids having amine-containing side chains (such as Lys and Orn) in which the
amine has
been acylated or or alkylated.
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NBI-I54CPPC
In another embodiment, the invention pertains, at least in part, to compounds
of Formula VI-C:
R22
Yi 0
R2 II II
R20 y2-C- i -(CH2)n II-A-Rtt
IRj23 R19 O (VI-C)
wherein:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
A is oxygen or nitrogen;
Rl 1 is hydrogen, salt-forming cation, ester forming group, -(CH2),-Q, or
when A is nitrogen, A and R~ ~ taken together may be the residue of a natural
or
unnatural amino acid or a salt or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyi;
x is 0, 1, 2, 3, or 4;
R19 is hydrogen, alkyl or aryl;
Y' is oxygen, sulfur, or nitrogen;
y2 is carbon, nitrogen, or oxygen;
R20 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl,
or
benzoimidazolyl;
R21 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl,
benzoimidazolyl, or
absent if Y2 is oxygen;
R22 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, thiazolyl, triazolyl, tetr.azolyl., imidazolyl, ben.zothiazolyl,
benzoimidazolyl; or
R22 is .hydrogen, hydroxyl, alkoxy or aryloxy if Y' is nitrogen; or R22 is
absent if Yt is
oxygen or sulfur;or R22 and R21 may be linked to form a cyclic moiety if Y' is
nitrogen;
R23 is hydrogen, alkyl, amino> mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl,
or
3o benzoimidazolyl, or absent if Y2 is nitrogen or oxygen;
or pharmaceutically acceptable salts thereof.
In another embodiment, R11 is a salt-forming cation. Examples of salt forming
cations include pharmaceutically acceptable salts described herein as well as
lithium,
78
CA 02582385 2006-12-18
NBI-154CPPC
sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium. In a
further embodiment, the salt is a sodium salt. In a further, embodiment, A is
oxygen.
In another embodiment, Y' is oxygen or sulfur, and R22 is absent.
In another embodiment, Y2 is oxygen and R2' is absent. Examples of R20 include
benzyl, aryl (e.g., phenyl), alkyl, cycloalkyl (e.g., adamantyl), etc. In
other embodiment,
y2 is nitrogen and R21 is hydrogen. In other embodiment, R2i is benzyl. In
another
further embodiment, R2 and R21 are linked to form a pyridyl ring. In another
embodiment, Y' is sulfur.
In another embodiment, the invention pertains to compounds of Formula V II-C:
0
11
/ (CH2)m- i -(CHz)n_ ISI-A-R11
(R G)z R24 O (VL[-C)
wherein:
nis2,3,or4;
A is oxygen or nitrogen;
15 R11 is hydrogen, salt-forming cation, ester forming group, -(CH2)C Q; or
when
A is nitrogen, A and Rl I taken together may be the residue of a natural or
unnatural
amino acid or a salt or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
20 xis0, 1,2,3,or4;
G is a direct bond or oxygen, nitrogen, or sulfur;
z is 0, 1, 2, 3, 4, or 5;
mis0orl;
R.24 is selected from a group consisting of hydrogen, a.lkyl, mercaptoalkyl,
25 alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl,
aryl, arylalkyl,
thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
each R25 is independently selected from hydrogen, halogen, cyano, hydroxyl,
alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic, and
pharmaceutically acceptable salts thereof.
In one embodiment, R11 is hydrogen. In another, A is oxygen. For example, n
may be 3 and m may be 1. In other embodiments, R 24 is hydrogen or benzyl.
In certain embodiments, z is 0, 2, or 3. In others, R25 is hydroxyl or alkoxy,
e.g.,
methoxy, ethoxy, etc. In certain embodiments, two or more R2S substituents can
be
linked to form a fused ring (e.g., to form a methylendioxyphenyl moiety).
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NBI-154CPPC
The invention pertains to both salt forms and acid/base forms of the.compounds
of the invention. For example, the invention pertains not only to the
particular salt forms
of compounds shown herein as salts, but also the invention includes other
pharmaceutically acceptable salts, and the acid and/or base form of the
compound. The
invention also pertains to salt forms of compounds shown herein.
Exemplary compounds of the invention are shown in the Figures and Tables
attached hereto. Intended to be part of this invention are the exemplary
compounds and
selected groups and subsets thereof for any of the formulas recited herein,
e.g., Formula
I-C through VII-C, provided in the two U.S. Patent Applications filed June 18,
2004,
both entitled "Methods and Compositions for Treating Amyloid Related Diseases"
(Attorney Docket Nos. NBI-162A and NBI-162B), and the U.S. Patent Application
filed
June 18, 2004, entitled "Methods and Compositions for the Treatment of Amyloid-
and
Epileptogenesis-Associated Diseases" (Attorney Docket Nos. NBI- 163), which
are
expressly incorporated. by reference herein.
In one embodiment, the invention does not pertain to the compounds described
in
WO 00/64420, WO 97/023458 and WO 96/28187. In one embodiment, the invention
does not pertain to methods of using the compounds described in WO 00/64420,
WO
97/023458 and WO 96/28187 for the treatment of diseases or disorders described
therein.
In a further embodiment, the invention pertains to methods of using the
compounds
described in WO 00/64420, WO 97/023458 and WO 96/28187 for methods described
in
this application, which are not described. in WO 00/64420, WO 97/023458 and WO
96/28187. Moreover WO 00/64420, WO 97/023458 and WO 96/28187 are incorporated
by reference herein in their entirety.
In one embodiment the invention relates to the compounds in Table 2 (see
attached Drawings). Additionally or alternatively the invention relates to the
compounds in Table 2A (see attached Drawings). In one embodiment the invention
does not pertain to the compounds in Table 2A and/or Figures 15 through 32. In
one
embodiment, the invention does pertain to the compounds in Table 2A and/or
Figures 15
through 32.
Blockers of sodium or calcium ion channel activity are well known in the art
and
can be used as the A moiety in the compounds and methods of the present
invention.
Similarly, any compound that opens potassium or chloride ion channels can be
used as
the A moiety in the compounds and methods of the present invention.
Antagonists of
NMDA receptors and augmenters of endogenous GABA inhibition are also known to
one of skill in the art and can be used in the methods and compounds of the
invention.
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NBI-154CPPC
For example, 2,3-quinoxalinediones are reported to have NMDA receptor
antagonistic
activity (see, e.g., U.S. Pat. No. 5,721,234). Exemplary calcium and zinc
chelators
include moieties known in the art for chelation of divalent cations, including
(in addition
to those mentioned supra) ethylenediaminetetraacetic acid (EDTA), ethylene
glycol
bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and the like. Exemplary
iron
chelators include enterobactin, pyridoxal isonicotinyl hydrazones,
N,N'-bis(2-hydroxybenzoyl)-ethylenediamine-N,N'-diacetic acid (HBED), 1-
substituted-
2-alkyl-3-hydroxy-4-pyridones, including 1-(2'-carboxyethyl)-2-methyl-3-
hydroxy-
4-pyridone, and other moieties known in the art to chelate iron. Compounds
which
inhibit NO synthase activity are known in the art and include, e.g., Ny-
substituted
arginine analogs (especially of the L configuration), including L-Ny-nitro-
arginine (a
specific inhibitor of cerebral NO synthase), L-Ny-amino-arginine, and L-Ny-
alkyl-
arginines; or an ester (for example, the methyl ester) thereof. Exemplary
antioxidants
include ascorbic acid, tocopherols including alpha-tocopherol, and the like.
In another aspect, the invention relates to pharmaceutical compositions
comprising a first agent, e.g., an alkanesulfonic acid, and another drug that
targets
secondary symptoms of Alzheimer's disease, such as behavioral and emotional
difficulties. For example, some approved medications exist that appear to
improve
memory and cognition, but do not address the underlying pathology, as
discussed more
fully elsewhere herein.
The discussion below explains in more detail the various therapeutic
approaches
and classes of medications for Alzheimer's disease.
Cognitive Enhancers - Cholinesterase Inhibitors
Alzheimer's Disease is associated with degeneration of cholinergic neurons in
the basal forebrain that play a fundamental role in cognitive functions,
including
memory. Alzheimer's disease patients exhibit a marked reduction in
acetylcholinesterase activity and choline uptake. Becker, et al., Drug
Development
Research 12, 163-95 (1988). It has been observed that A(3 can inhibit
acetylcholine
release via its effects on, for example, choline transport, post-synaptic
events and
3o nicotinic acetylcholine receptors (a7, a2, 04) (Wang et al., J. Biol.
Chem., vol. 275, pp.
5626-32 (2000); Melo et al., Amyloid, vol. 9, pp. 221-8 (2002); Kar et al., J.
Neurosci.,
vol. 16, pp. 1034-1040 (1996)). By binding to A(3, an alkylsulfonic acid could
thus
normalize acetylcholine esterase (AChE) efflux levels (e.g. from the
hippocampus)
which are usually decreased in the presence of A(3 in the brain. In addition,
AChE has
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been found to be associated with senile plaques and has been shown to interact
with A(3,
promote amyloid fibril formation and increase its toxicity (De Ferrari et al.,
Biochemistry 40: 10447-10457, 2001). These findings suggest that in
combination with
a cholinesterase inhibitor or with an acetylcholine receptor agonist, an
alkylsulfonic acid
could act synergistically to treat an amyloid-(3 disease such as Alzheimer's
disease.
Accordingly, in one aspect, the present invention is related to increasing
levels of
acetylcholine by the administration of an inhibitor of choline esterase (e.g.,
acetylcholinesterase or butyrylcholinesterase), and a first agent alkyl
sulfonic acid which
acts synergistically to treat an amyloid, (e.g., amyloid-(3) disease.
Cholinergic neurons
make up a major neuronal system of the central and peripheral nervous systems.
Cholinergic neurons produce the neurotransmitter acetylcholine. In the central
nervous
system, acetylcholine is a neurotransmitter and is released by cholinergic
neurons in,
among other places, the hippocampus and frontal cortex of the brain. The
hippocampal
area of the brain, particularly those areas where acetylcholine is released,
is believed to
1 s have functions associated with cognition, learning, and memory.
Degenerative diseases
with symptoms such as loss of cognition, learning, and memory, have been
linked to a
loss in cholinergic neurons. Cholinergic dysfunction, characterized by marked
degeneration of cholinergic innervation in the basal forebrain, and reduction
of choline
acetyltransferase, acetylcholinesterase, and the nicotinic and muscarinic
receptors are
known to be very early features of Alzheimer's disease. Other neurotransmitter
systems,
such as glutamatergic, serotonergic, and dopaminergic, are also disrupted in
Alzheimer's
disease, but at a later stage of the disease.
The present invention also relates to the combination use of a nicotinic
acetylcholine receptor agonist or muscarinic agonist that results in cognition
enhancement. Nicotinic acetylcholine receptor agonists improve cognitive
function in
Alzheimer's patients. Wilson, et al., Pharmacol. Biochem. Behavior 51, 509-14
(1995);
Arneric, et al., Alzheimer Disease Assoc. Disorders 9(suppl. 2), 50-61 (1995);
Buccafusco, et al., Behav. Pharmacol. 10, 681-90 (1999). Muscarinic and
nicotinic
agonists have been reported to enhance cognitive tasks in animal models and in
humans.
Schwarz, et al., J. Pharmacol. Experim. Theraput. 291, 812-22 (1999); Veroff,
et al.,
Alzheimer Disease Assoc. Disorders 12, 304-12 (1998); Bodick, et al.,
Alzheimer
Disease Assoc. Disorders 11(Suppl. 4), S 16-22 (1997).
In subjects with Alzheimer's disease, the number of cholinergic neurons
innervating the hippocampus typically decreases, and the progressive loss of
these
cholinergic neurons mirrors the loss in memory and cognitive function in these
subjects.
Acetylcholine is synthesized by choline acetyltransferase ("ChAT"). Once
released by
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the neuron, it is degraded by cholinesterases, e.g., acetylcholinesterase
("AChE"). Thus
either potentiating the activity of ChAT or inhibiting the activity of a
cholinesterase,
e.g., AchE, may raise levels of the neurotransmitter. These medications alone
appear to
provide primarily symptomatic improvement.
Another therapeutic strategy for increasing levels of acetylcholine is based
on
up-regulating ChAT in the neurons. For example, estrogen increases the level
of
acetylcholine by up-regulating ChAT in the hippocampus of rats. Luine, et al.,
Brain
Res. 191, 273-77 (1980); Luine, Exp. Neurology 89, 484-90 (1985), Singh, et
al., Brain
Res. 644, 305-12 (1994). Also clinical information implies that post-
menopausal
women on hormone replacement therapy (estrogen with or without progestins) may
be
less likely to develop Alzheimer's disease and more likely to have existing
symptoms
alleviated. See, e.g., WO 93/014085 (indole derivatives as having the ability
to enhance
the release of acetylcholine); U.S. Pat. No. 5,278,162 (substituted polycyclic
compounds that enhance acetylcholine release).
Many choline esterase inhibitors are known. Certain cholinesterase inhibitors
are
approved for use in treatments for improving memory and learning in
Alzheimer's
subjects. Tacrine (CognexTM, Warner-Lambert Co., now Pfizer, New York, New
York)
was the first approved cholinesterase inhibitor but is rarely used because of
negative side
effects like stomach and liver problems. Donepezil (AriceptTM, Eisai Co, Ltd)
is more
selective for acetyl-cholinesterase and shows fewer side effects than tacrine.
Rivastigmine (ExelonTM, Novartis Pharma SA) targets a specific subtype of
acetyl-
cholinesterase that is present at high concentrations in the brains of
Alzheimer's
subjects. Galanthamine (ReminylTM, Janssen Pharmaceutica Products, LP) has a
dual
mode of action in the brain; in addition to working as an acetylcholinesterase
inhibitor,
galanthamine also appears to exert action on the nicotinic acetylcholine
receptors in the
brain. These cholinesterase inhibitors may be acetyl-cholinesterase or butyryl-
cholinesterase inhibitors or both. Another example is phenserine (currently in
advanced
clinical trials in the United States). In addition to its cholinergic effects,
phenserine may
inhibit (3-APP production by a separate and distinct mechanism of action at
the level of
the mRNA level. Another example is AIT-082 (also in advanced clinical trials).
The
degradation pathway of AchE may also be inhibited by inhibitors such as
physostigmine
(SynaptonTM, or (Antilirium InjectableTM, Forrest Laboratories, New York, New
York)),
quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine,
neostigmine, eseroline,
zifrosilone, mestinon, huperzine A and icopezil.
Phenserine, an acetylcholinesterase inhibitor, is in development (Axonyx, New
York, New York) for the treatment of Alzheimer's Disease. Phenserine, which
has been
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shown to increase memory and learning in the laboratory animals, works through
two
mechanisms: it inhibits the degradation of the neurotransmitter acetylcholine
in the
brains of animals, and it inhibits the production of a toxic form of the 0-
amyloid protein
in the brain that is thought to be a cause of the death of brain cells in
Alzheimer's
disease. Unlike other acetylcholinesterase inhibitors that simply suppress the
activity of
the enzyme, Phenserine's dual mechanism of action suggests that it not only
has the
potential to improve memory and cognition but also to slow the progression of
the
disease. Compared to currently marketed drugs for Alzheimer's, Phenserine is
more
brain-targeted versus the rest of the body and is more rapidly cleared from
the blood. In
preclinical studies, Phenserine demonstrated a brain-to-blood ratio of 10: l.
These
properties of Phenserine could potentially maximize the therapeutic effects of
the drug
in the brain and reduce side effects by clearing the drug from the blood
quickly. Since
undesirable side effects and drug interactions often arise due to the presence
of drugs in
the body for an extended period, Phenserine's rapid disappearance from the
blood
suggests that it will represent a more tolerable treatment option to existing
therapies.
Even though Phenserine is rapidly cleared from the body, the drug remains
bound to the
acetylcholinesterase enzyme in the brain allowing it to have a long duration
of
therapeutic action. Substituted phenserines and phenylcarbamates of eseroline,
noreseroline, and benzylnoreseroline are also specific inhibitors of
acetylcholinesterase
See, e.g., U.S. Pat. Nos. 5,171,750; 5,378,723; 5,409,948; 5,998,460;
5,948,763;
6,410,747; 6,462,171; and 6,495,700; as well as WO 93/06105.
Suitable cholinesterase inhibitors include galanthamine derivatives available
from Janssen, metrifonate available from Bayer Corp., ipidacrine available
from Nikken
Chemicals Co. Ltd., TAK-147, T-82 available from SS Pharmaceutical Co. Ltd.,
methanesulfonyl fluoride, CHF-2819, phenserine, physostigmine available from
Forest
Laboratories, Inc., huperzine, cymserine available from Axonyx Inc., tolserine
available
from National Institutes of Health, ER-127528 available from Eisai Co. Ltd.,
and
combinations thereof.
In addition, the present invention relates to a method for maintaining or
preventing a decrease in the levels of acetylcholine in the frontal cortex or
hippocampus
regions of the brain in mammals comprising administering to a mammal in need
thereof,
an effective amount of a first agent, e.g., an alkanesulfonic acid or a
pharmaceutically
acceptable salt thereof, and optionally a choline esterase inhibitor.
Further, the present invention relates to a method for inhibiting conditions
or
detrimental effects caused by a deficiency of choline acetyltransferase or
acetylcholine
in the frontal cortex or hippocampus regions of the brain in mammals
comprising
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administering to a mammal in need thereof, an effective amount of a first
agent, e.g., an
alkanesulfonic acid, or a pharmaceutically acceptable salt thereof, and
optionally a
choline esterase inhibitor.
Moreover, the present invention relates to a pharmaceutical formulation
comprising a first agent, e.g., an alkanesulfonic acid or a pharmaceutically
acceptable
salt thereof, and optionally a choline esterase inhibitor; and a
pharmaceutical carrier,
diluent, or excipient.
Another embodiment of the present invention is where the condition caused by a
decrease of choline acetyltransferase or acetylcholine in the frontal cortex
or
hippocampus regions of the brain is Alzheimer's disease.
As used herein, the term "effective amou:nt" means an amount of a first agent,
e.g., an alkanesulfonic acid, that is capable of maintaining brain cell
ability to produce
stable levels of acetylcholine in the brain, such as in the hippocampus and
frontal cortex
regions, or inhibiting conditions or detrimental effects caused by a decrease
of
acetylcholine in mammals. When an alkanesulfonic acid or other such first
agent is
co-administered with an AChE inhibitor the term "effective amount" also means
an
amount of such an agent capable of inhibiting AChE. An inhibitor of AChE may
be
represented as "AChEi."
In this context, the term "inhibiting" in the context of inhibiting conditions
or
detrimental effects caused by a deficiency of ChAT or acetylcholine in the
frontal cortex
or hippocampus regions of the brain includes its generally accepted meaning,
i.e.,
prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or
reversing the
progression or severity of a decrease in ChAT and acetylcholine and the
pathological
sequelae, i.e., symptoms, resulting from that event.
The term "up-regulating ChAT" refers to increasing the enzymatic activity of
ChAT, i.e., promoting the conversion of choline to acetylcholine. This
promotion would
include an increase in the efficiency or rate of reaction of ChAT and choline
or an
increase in the amount of ChAT present at the site of action. This increase in
the amount
of enzyme present may be due to gene regulation or another synthetic step in
the
enzyme's formation or a decrease in the enzyme's de-activation and metabolism.
It has been shown that A(3 can inhibit the efflux of acetylcholine from
neurons
upon new stimulation, and in addition that exogenous A(3 may inhibit high
affinity
choline uptake. Normally acetylcholine efflux levels (e.g. from hippocampus)
are
decreased in the presence of A(3 in the brain. A(3 may act in several
different ways to
exert these effects, such.as acting at the choline transporter, modulating
post synaptic
CA 02582385 2006-12-18
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events, or acting on neuronal acetyl cholinesterase receptors (e.g., nAChr
(a7, a2(34). It
has been shown that antibodies capable of binding to A(3 can normalize
acetylcholine
efflux levels, which are usually reduced in the presence of A(3 in the brain
(Bales, et al.,
Cholignergic dysfunction in APP V717F transgenic mice is normalized following
anti-
Ap antibody administration. See, Abstract from Neuroscience Meeting, New
Orleans,
Nov. 2003 program no. 133.9.). A first agent of the invention, e.g., an
alkanesulfonic
acid, may act similarly to normalize acetylcholine levels by binding to AP.
The
presence of an alkanesulfonic acid may thus prevent A(3 from inhibiting the
efflux of
acetylcholine, thereby leading to an increase in the amount of acetylcholine
at the
synapse. It is likely therefore that an alkanesulfonic acid and an
acetylcholinesterase
inhibitor will act synergistically to ameliorate cholinergic
neurotransmission, as both
agents act to potentiate the levels of acetylcholine.
Ester Neurosciences (Herzlia Pituach, Israel) antisense drug (EN 101) for the
treatment of myasthenia gravis, demonstrated for the first time effective and
safe use of
an orally-administered antisense therapy for a neurological condition that
lessened the
severity of symptoms of myasthenia gravis , with no cholinergic symptoms nor
significant adverse events based on balancing cholinergic transmission via
controlled
modulation of the company's novel target, a stress-response variant of
acetylcholinesterase. AChE is an enzyme that degrades the neurotransmitter
acetylcholine. EN101 selectively inhibits the production of the target at the
critical stage
of its biosynthesis, thereby allowing an effective treatment, while minimizing
side
effects and substantially improving upon the short-duration palliative relief
currently
observed with conventional inhibitors. EN101 is the lead compound in Ester's
disease-
modifying platform technology for the pre-expression control of a specific
variant of the
AChE protein, which is applicable to a wide range of neurological disorders.
Useful muscarinic receptor agonists include cevimeline, PD- 151832 available
from Pfizer Inc., YM-796 available from Yamanouchi Pharmaceutical Inc., and P-
58
available from Phytopharm plc. Suitable acetylcholine release stimulators
include
minaprine, and montirelin available from Grunenthal GmbH, T-588 available from
Toyama Chemical Co. Ltd., XE-991. Useful choline uptake stimulators include
MKC-
231 available from Mitsubishi-Tokyo Pharmaceuticals Inc. Suitable nicotinic
cholinergic receptor agonists include altinicline available from SIBIA
Neurosciences,
Inc., SIB-1553A, ABT-089 (U.S. Pat. No. 5,278,176, Abbott Laboratories),
nicotine
patch, GRS-21, and TC-2403.
In 1993, tacrine became the first agent approved specifically for the
treatment of
cognitive symptoms of Alzheimer's disease. Tacrine is a reversible
cholinesterase
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inhibitor and is thought to work by increasing the availability of
intrasynaptic
acetylcholine in the brains of Alzheimer's disease patients. The medication
may also
have other actions. Donepezil, another reversible cholinesterase inhibitor, is
now
available for the treatment of Alzheimer's disease. Another example of a
second agent
is xanomeline, which is a muscarinic selective m 1 and m4 (muscarinic)
acetylcholine
receptor agonist and shows moderate improvement in cognitive performance,
greater
efficacy in decreasing psychotic symptoms, and agitation. N.C.Bodick, et al.
"Effects of
xanomeline, a selective muscarinic receptor agonist, on cognitive function and
behavioral symptoms in Alzheimer disease." Arch. Neurol. 54, 465-73 (1997).
The
second agent may also be an ergot alkaloid or a vinca alkaloid, such as
HydergineTM
(Sandoz Pharmaceutical Corp., now Novartis, Basel, Switzerland) and
nicergolin; or it
may be a nootropic, such as piracetam, oxiracetam, pramiracetam, and
aniracetam;
which have cholinergic and dopaminergic properties as well as effects on
protein
processing. B.Saletu, et al., "Nicergoline in senile dementia of Alzheimer
type and
multi-infarct dementia: a double-blind, placebo-controlled, clinical and
EEG/ERP
mapping study." Psychopharmacology 117, 385-95 (1995). In yet another
embodiment,
the second agent may be a carbamate derivative of physostigmine, such as
eptastigmine,
which is an inhibitor of acetylcholinesterase. A.Norberg, et al.,
"Cholinesterase
inhibitors in the treatment of Alzheimer's disease: a comparison of
tolerability and
pharmacology." Drug Saf. 19, 465-80 (1998).
Cognitive Enhancers - NMDA Receptor Anta-aonists
Excessive excitation by neurotransmitters can cause the degeneration and death
of neurons. It is believed that this degeneration is in part mediated by the
excitotoxic
actions of the excitatory amino acids glutamate and aspartate at the N-methyl-
D-Aspartate (NMDA) receptor. An increased level of one or more glutamate-
related
compounds is associated with many neurodegenerative disorders and
neurodegeneration
associated with long term disease states such as Huntington's disease,
Alzheimer's
disease, amyotrophic lateral sclerosis (ALS, which is also known as motor
neuron
disease), Parkinson's disease and acquired immunodeficiency (AIDS). Excitatory
amino
acid receptor antagonists that block NMDA receptors are recognized for
usefulness in
the treatment of disorders. NMDA receptors are intimately involved in the
phenomenon
of excitotoxicity, which may be a critical determinant of outcome of several
neurological
disorders. Disorders known to be responsive to blockade of the NMDA receptor
include
acute cerebral ischemia (stroke or cerebral trauma, for example), muscular
spasm,
convulsive disorders, neuropathic pain and anxiety, and may be a significant
causal
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factor in chronic neurodegenerative disorders such as Parkinson's disease,
amyotrophic
lateral sclerosis (ALS), Alzheimer's disease and Huntington's disease.
Compounds that
effect the greatest protection of neurons from NMDA receptor-mediated injury,
e.g., that
injury resulting from stimulation of the NMDA receptor by glutamate or other
excitatory
amino acids or structurally similar compounds may be used in one embodiment of
the
invention.
Some examples of NMDA receptor antagonists are known and commercially
available. Memantine (EbixaTM or AxuraTM or NamendaTM recently available in
the U.S.
from Merz Pharmaceuticals, Frankfurt am Main, Germany), which operates by yet
another mechanism, appears to prevent or reduce the brain damage caused by
Alzheimer's disease by blocking NMDA receptors in the brain. See U.S. Pat.
No. 5,614,560. Memantine (1-amino-3,5-dimethyl adamantine) reduces neuronal
damage by blocking NMDA receptor-operated channel activation by excitatory
amino
acids (such as glutamate-related compounds) at concentrations that are readily
obtainable in human subjects taking the drug (Wesemann, et al., J. Neural
Transmission
(Supp.) 16, 143 (1980)). Others include ethopropazine (ParidolTM),
diphenhydramine
(BenadrylTM), dizocilpine (NeurogaurdTM), and amantadine (SymmetrelTM).
Several drugs have NMDA antagonist activity without causing hypofunction
because of activity at some other type of receptor. In the brains of healthy
lab animals,
such NMDA antagonists do not cause the vacuoles and other toxic side effects
that are
caused by NMDA antagonists such as PCP and MK-801, because of activity at the
additional neuronal receptors. Such drugs, and the receptors they interact
with in
addition to NMDA receptors, include the following: Ibogaine, which also
suppresses
excitatory activity at sigma receptors and which may also be active at
serotonin
receptors, and Eliprodil, which also increases inhibitory activity at sigma
receptors;
Certain anti-cholinergic drugs such as procyclidine, trihexyphenydyl, and
biperiden,
which also suppress excitatory activity at muscarinic acetylcholine receptors;
and
Certain quinoxalinediones, including NBQX, ACEA 1021, and ACEA 1031, which are
discussed below, and which suppress activity at non-NMDA receptors (i.e.,
kainic acid
receptors and AMPA receptors), in addition to NMDA receptors. As described in
Example 11, NBQX blocks non-NMDA receptors so strongly that it acts as a
safener
agent when co-administered with MK-801. Accordingly, these and other
quinoxalinediones are of great interest to pharmaceutical companies, and offer
strong
promise as inherently safened NMDA antagonists. Low-toxicity NMDA antagonists
offer good candidates both for treating Alzheimer's disease, and for
additional
developmental research to identify analogs having adjusted balances in their
dual or
multiple receptor binding affinities. For example, the anti-parkinsonian
agents
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procyclidine, trihexyphenydyl, and biperiden all have affinities for
muscarinic receptors
that are several times higher than for NMDA receptors. Further examples of
NMDA
receptor antagonists include those in U.S. Pat. No. 4,906,779, which discloses
disubstituted guanidines, e.g., N,N'-di-m-tolyl guanidine, N,N'-di-o-
ethylphenyl
guanidine, N,N'-di-m-ethylphenyl guanidine, and N,N'-di-o-iodophenyl-
guanidine; U.S.
Pat. No. 5,498,610, which discloses 5-(I-hydroxy-2-piperidino)-propyl-
2(1H,3H)-indolone analogs. A muscarinic agonist may also be used in this
invention. A
class of styryl amidine derivatives, which are antagonists of the human NMDA
receptor,
are selective for those containing the NR2B subunit, and may, in some
embodiments, be
used in the invention. U.S. Published Application No. 2003/0,119,871. Suitable
NMDA
receptor antagonists also include ipenoxazone, which is available from Nippon
Chemiphar Co. Ltd.
The term "agonist," as used herein, refers to a molecule which, when
interacting
with a biologically active molecule, causes a change (e.g., enhancement) in
the
biologically active molecule, or which positively modulates the activity of
the
biologically active molecule. An agonist interacts with a receptor and
initiates a
physiological or a pharmacological response characteristic of that receptor.
As known in
the art, agonists include, but are not limited to proteins, nucleic acids,
carbohydrates,
lipids or any other molecules which bind or interact with biologically active
molecules.
The terms "antagonist" or "inhibitor," as used herein, refer to a molecule
which, when
interacting with a biologically active molecule, blocks or negatively
modulates the
biological activity of the biologically active molecule. Antagonists oppose
the receptor-
associated responses normally induced by other bioactive agents (i.e.,
agonists).
Antagonists and inhibitors include, but are not limited to, proteins, nucleic
acids,
carbohydrates, lipids or any other molecules that bind or interact with
biologically active
molecules. Inhibitors and antagonists may effect the biology of entire cells,
organs, or
organisms (e.g., an inhibitor that slows or prevents neuronal degeneration and
death).
Estrogens
Estrogen plays a powerful, pleiotropic role in many neurodegenerative
conditions including Alzheimer's disease. Women have been shown to have
increased
risk, earlier onset, and more rapid progression of Alzheimer's Disease than
men,
although not gender-specific morbidity. Postmenopausal loss of estrogens leads
to
generally reversible decreases in memory that respond to estrogen replacement
therapy.
Besides mechanisms of blocking neurotoxicity directly, estrogen acts at
various levels of
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plasticity: axon sprouting, synaptogenesis, and promoting synaptic
transmission
(electrophysiologically and biochemically). These effects may be ascribed to
either
receptor-dependent mechanisms, primarily transcriptional, including direct
effects of ER
in transcription and indirect effects through other transcription factors like
CREB and
Akt, as well as their retrograde transport or receptor-independent (rapid)
mechanisms
involving activational effects of second messenger systems, coexisting
neurotransmission, or coordinated activation of both, as well as oxidative
effects of the
estrogen molecule. Estrogen replacement decreases the risk of Alzheimer's
disease in
postmenopausal women, delays the age of onset, and perhaps slows the decline.
Estrogenic agent include estrogen, lasofoxifene, droloxifene, tamoxifen, and
raloxifene
(EvistaTM, Eli Lilly, Indianapolis, Indiana).
Also useful with the present invention are compositions or therapeutic
combinations that further comprise hormone replacement agents and
compositions.
Useful hormone agents and compositions include androgens, estrogens,
progestins, their
pharmaceutically acceptable salts and derivatives. Combinations of these
agents and
compositions also are useful.
Examples of estrogens include, but are not limited to, androgen and estrogen
combinations such as the combination of esterified estrogens (sodium estrone
sulfate and
sodium equilin sulfate) and methyltestosterone available from Solvay
Pharmaceuticals,
Inc., Marietta, GA., as EstratestTM; the blend of nine synthetic estrogenic
substances
including sodium estrone sulfate, sodium equilin sulfate, sodium 17a-
dihydroequilin
sulfate, sodium 17a-estradiol sulfate, sodium 17(3-dihydroequilin sulfate,
sodium
17a-dihydroequilenin sulfate, sodium 170-dihydroequilenin sulfate, sodium
equilenin
sulfate and sodium 17(3-estradiol sulfate; available from Duramed
Pharmaceuticals, Inc.,
Cincinnati, Ohio, as CenestinTM; ethinyl estradiol, available by Schering
Plough
Corporation, Kenilworth, N.J., as EstinylTM; esterified estrogen combinations
such as
sodium estrone sulfate and sodium equilin sulfate; available from Solvay as
EstratabTM
and from Monarch Pharmaceuticals, Bristol, Tenn., as MenestTM; estropipate,
available
from Pharmacia & Upjohn, Peapack, N.J., as OgenTM and from Women First Health
Care, Inc., San Diego, Calif., as Ortho-EstTM; and conjugated estrogens (17a-
dihydroequilin, 17a-estradiol, and 17(3-dihydroequilin), available from Wyeth,
Philadelphia, Pa., as PremarinTM. Another estrogen example is disclosed in
U.S. Pat.
No. 6,610,706.
Progestins and estrogens may also be administered as combinations including
estradiol and norethindrone, available from Pharmacia & Upjohn, Peapack, N.J.,
as
ActivellaTM; levonorgestrel and ethinyl estradiol, from Wyeth as AlesseTM,
from Watson
CA 02582385 2006-12-18
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Laboratories, Inc., Corona, Calif., as LevoraTM and TrivoraTM, Monarch
Pharmaceuticals, as NordetteTM, and from Wyethas TriphasilTM; ethynodiol
diacetate
and ethinyl estradiolTM; available from G. D. Searle & Co., as DemulenTM and
WatsonTM
as ZoviaTM; desogestrel and ethinyl estradiolTM, from Organon as DesogenTM and
MircetteTM, and from Ortho-McNeil Pharmaceutical, Raritan, N.J., as Ortho-
CeptTM;
norethindrone and ethinyl estradiol; available from Parke-Davis, Morris
Plains, N.J.,
under the tradenames EstrostepTM and FemhrtTM, from Watson as MicrogestinTM,
NeconTM, and Tri-NorinylTM, from Ortho-McNeil as ModiconTM and Ortho-NovemTM,
and from Warner Chilcott Laboratories, Rockaway, N.J., under the tradename
OvconTM;
1 o the combination of norgestrel and ethinyl estradiol; available from Wyeth
under the
tradenames OvralTM and Lo/OvralTM, and from Watson under the tradenames
OgestrelTM
and Low-OgestrelTM; the combination of norethindrone, ethinyl estradiol, and
mestranol,
from Watson as BreviconTM and NorinylTM, the combination of 170-estradiol and
micronized norgestimate, from Ortho-McNeil under the tradename Ortho-
PrefestTM; the
combination of norgestimate and ethinyl estradiol; available from Ortho-McNeil
under
the tradenames Ortho CyclenTM and Ortho Tri-CcyclenTM; and the combination of
conjugated estrogens (sodium estrone sulfate and sodium equilin sulfate) and
medroxyprogesterone acetate, from Wyeth under the tradenames PremphaseTM and
Premp'roTM.
Examples of progestins include norethindrone; available from ESI Lederle,
Inc.,
Philadelphia, Pa., as AygestinTM, from Ortho-McNeil under the tradename
MicronorTM,
and from Watson as NOR-QDTM; norgestrel; available from Wyeth as OvretteTM;
micronized progesterone, from Solvay as PrometriumTM; and medroxyprogesterone
acetate; available from Pharmacia & Upjohn under the tradename ProveraTM
Non-Steroidal Anti-In ammatory Drujzs
Nonsteroidal anti-inflammatory drugs ("NSAIDs") appear to be associated with a
lower likelihood of developing Alzheimer's disease. Anti-inflammatory drugs
are
believed to interfere with aspects of the microglial, astrocytic, and cytokine
responses
that occur in Alzheimer's disease. NSAIDs, including ibuprofen, naproxen,
sulindac,
and indomethacin, have been shown to be selective A(342-lowering agents. A
subset of
NSAIDs lower amyloidogenic A(342 independently of cyclooxygenase activity.
S.Weggen, et al., "A subset of NSAIDs lower amyloidogenic A(342 independently
of
cyclooxygenase activity." Nature 414, 212-16 (2001). Although the mechanisms
by
which these NSAIDs lower A042 have not been established, the effect is
independent of
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cyclooxygenase inhibition, which is the primary anti-inflammatory target of
these
compounds. NSAIDs do not appear to change the total level of A(3 produced but
shift
cleavage from AP42 to a less toxic shorter 38-amino acid A(3 peptide (A(338),
which
suggests that they interact with y-secretase. One class of developmental
compounds are
inhibitors of PDE4, which act as anti-inflammatory drug in mice. These anti-
inflamatory agent, e.g., rolipram, appear to block the microglial inflammatory
response,
and may have toxic side effects, but newer analogs without such properties are
in
development. Wilcock, et al., "Intracranially Administered Anti-Abeta
Antibodies
Reduce Beta-Amyloid Deposition by Mechanisms Both Independent of and
Associated
with Microglial Activation. J. Neurosci. 23(9), 3745-51 (2003). For example,
Memory
Pharmaceutical's MEM 1414 is a PDE4 inhibitor currently in testing for
Alzheimer's
disease.
Suitable anti-inflammatory agents include COX-2 inhibitors (such as VioxxTM
and CelebrexTM), cytokine inhibitors (such as thalidomide disclosed in WO
95/04533
and dexanabinol) complement inhibitors, leukotriene receptor antagonists and
combinations thereof. Examples include acetic acid aerivatives sulindac
(ClinorilTM,
Merck & Co., Inc., Rahway, New Jersey), indomethacin (IndocinTM, Merck & Co.,
Inc.,
Rahway, New Jersey); etodolac (LodineTM, Wyeth, Madison, New Jersey),
nabumetone
(RelafenTM, GlaxoSmithKline, Middlesex, England), tolmetin sodium (TolectinTM,
McNeil Pharmaceuticals, Spring House, Pennsylvania); anthranilic acid
derivatives:
meclofenamate sodium (MeclomenTM, Pfizer, New York, New York), mefenamic acid
(PonstelTM, Pfizer, New York, New York); enolic acid derivatives: piroxicam
(FeldeneTM, Pfizer, New York, New York), mobic (meloxicam); phenylacetic acid
derivatives: arthrotec (diclofenac/misoprostol), VoltarenTM (diclofenac);
propionic acid
derivatives: naproxen sodium (AnaproxTM, NaprosynTM, Hoffmann-La Roche Inc.
(Roche), Nutley, N.J.), flurbiprofen (AnsaidTM, Upjohn, now Pfizer, New York,
New
York), oxaprozin (DayproTM, G.D Searle, now Pfizer, New York, New York);
ibuprofen
(MotrinTM, Upjohn, now Pfizer, New York, New York), fenoprofen calcium
(NalfonTM,
Dista, Ranbaxy, Princeton, NJ), ketoprofen (OruvailTM or OrudisTM, Wyeth,
Madison,
New Jersey), ketorolac tromethamine (ToradolTM, Syntex Laboratories, Hoffmann-
La
Roche Inc. (Roche), Nutley, N.J.); salicylic acid derivative: diflunisal
(DolobidTM,
Merck & Co., Inc., Rahway, New Jersey); and COX-2 selective inhibitors:
BextraTM
(valdecoxib), CelebrexTM (celecoxib, Pfizer, New York, New York), and VioxxTM
(rofecoxib, Merck & Co., Inc., Rahway, New Jersey). Flurbiprofen is currently
the
subject of clinical trials with Alzheimer's patients by Myriad Genetics.
Maas Bio1AB (Albuquerque, New Mexico) is developing cyclosporin as an anti-
inflammatory neuroprotection agent. EP 813,420 B 1. Cyclosporins, a class of
drugs
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best known as immunosuppressants, were discovered to have a new use as the
most
effective neuroprotectants across the spectrum of neurological disease models
when they
cross the blood-brain barrier. Cyclosporins protect the brain's mitochondria
and prevent
neuron death due to traumatic brain and spinal cord injury, stroke,
Alzheimer's,
Parkinson's, Huntington's diseases and amyotrophic lateral sclerosis (ALS)
animal
models.
Anti-Oxidants
As a lipid rich organ, the CNS is particularly susceptible to effects of lipid
peroxidation in modulating cellular signaling pathways, cell dysfunction, and
cell death
in the nervous system. In Alzheimer's disease, emerging evidence provides
strong
support for a role for oxidative stress in neurodegeneration, as multiple
indices of
oxidative stress have been observed, including protein oxidation, decreased
polyunsaturated fatty acids, mitochondrial and nuclear DNA damage.
Free radicals (e.g., superoxide radicals) are used by phagocytes to kill
bacteria
and to oxidatively destroy foreign matter. Ordinarily excess superoxide is
quenched by
superoxide dismutase, however if oxidative stress causes the overproduction of
radicals,
or if the production of the superoxide exceeds the capacity, of superoxide
dismutase, then
unintended oxidative damage may occur. B. Halliwell, Acta Neurol. Scand. 126,
23-3 3
(1989). In Alzheimer's subjects, protein oxidation, DNA oxidation, and lipid
peroxidation are greater than in age-matched controls. S.S. Pitchumoni, et
al., N. Engl.
J. Med. 46(12), 1566-72 (1998).
An "antioxidant" is any substance capable of protecting against the damages of
oxidative stress caused by reactive oxygen species such as free radicals.
Antioxidants
are generally desined so that they may be oxidized over other materials. In
addition to
superoxide dismutase, catalase and glutathione peroxidase react with hydrogen
peroxide
and convert it to water and diatomic oxygen. Other antioxidants include
vitamin E
(a-tocopherol), vitamin C (ascorbic acid), vitamin A (retinoic acid), co-
enzyme Q, and
selegiline.
Vitamin E and its derivitatives, e.g., a-tocopherol, quenches a free radical
by
donating a hydrogen atom thereby producing a tocopheroxy radical, which
scavenges
yet another peroxyl radical to produce a-tocopherol quinone, a stable
compound. Unlike
many other antioxidants, vitamin E is lipophilic and therefore soluble in the
central
nervous system and able to localize in a cell membrane thus preventing lipid
peroxidation. Suitable Vitamin E derivatives include but are not limited to a-
tocopherol
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[3-tocopherol , y-tocopheraol, 8-tocopheral, c-tocopherol, ~I-tocopherol, ~Z -
tocopherol
and rl-tocopherol, and pharmaceutically acceptable ester derivatives thereof,
e.g., the
corresponding acetate, succinate and nicotinate forms. Additional antioxidants
include
citric acid in its various forms, including its administration as a
combination of
potassium citrate monohydrate and citric acid monohydrate. Additionally or
alternatively, agents that supplement the chain-breaking antioxidant property
of Vitamin
E can be co-adminstered, e.g., ubiquinol, seleno-amino acids and sulfhydryl
compounds
(e.g., glutathione, sulfhydryl proteins, cysteine and methionine).
Also suitable as second or futher agents are butylated hydroxytoluene,
butylated
1 o hydroxyanisole, propyl gallate, dodecylgallate, tert-butylhydroquinone,
dihydrolipoic
acid, prostaglandin B1 oligomers (also known as polymeric 15-keto
prostaglandin B or
PGB,,), 2-aminomethyl-4-tert-butyl-6-iodophenol, 2-aminomethyl-4-tert-butyl-6-
propionylphenol, 2,6-di-tert-butyl-4-[2'-thenoyl]phenol, N,N'-diphenyl-p-
phenylenediamine, ethoxyquin, probucol, ebselen, 5-[[3,5-bis(l,l-
dimethylethyl)-4-
hydroxyphen-yl]methylene]-3-(dimethylamino )-4-thiazolidinone, 5-[[3,5-bis(1,1-
dimethylethyl)-4-hydroxyphenyl]meth-ylene]-3-(methylamino)- 4-thiazolidinone
(LY269415), D-myoinositol-1.2.6-trisphosphate, nordihydroguaiaretic acid,
deferoxamine mesylate, tirilazad mesylate, derivatives of tirilazad in which
the steroid
portion of the chemical structure has been replaced with the tetramethyl
chroman portion
of d-a-tocopherol, trimetazidine, N,N'-dimethylthiourea, 2-(2-hydroxy-4-
methylphenyl)aminothiazolehydrochloride, 2-L-oxothiazolidine, and combinations
of
these compouns or combinations with any other agents disclosed herein.
Additional antioxidants and free radical trapping substances that can be co-
administered in accordance with the invention include plant (e.g., vegetable)
active
ingredients. This category, includes dimethyl sulfoxide, parthenolide,
lycopene, daidzin,
genistein, quercetin, morin, curcumin, apigenin, sesamol, chlorogenic acid,
fisetin,
ellagic acid, quillaia saponin, capsaicin, ginsenoside, silymarin, kaempferol,
ginkgetin,
bilobetin, isoginkgetin, isorhamnetin, herbimycin, rutin, bromelain,
levendustin A, and.
erbstatin.
Glutamate and A(3 together have been shown to stimulate the production of free
radicals in cultured neurons, but this process is retarded by the addition of
catalase or
a-tocopherol and agents that increase catalase activity. H. Hara, et al.,
Brain Res. 510,
335-38 (1990). Vitamin E has been shown to slow cognitive decline in
Alzheimer's
disease and in rat models. Patients with Alzheimer's disease treated with
vitamin E
showed a decreased rate of functional decline. Although it is not clear what
causal
relation oxidation has to Alzheimer's disease etiology, e.g., whether it is a
secondary
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effect of the stress caused by synaptic or neuronal loss, antioxidant
therapies have shown
limited but promising efficacy in treating Alzheimer's disease. Vitamin E
lacks negative
medication interaction and may be used in combination with other Alzheimer's
disease
therapies. C.Behl, et al., "Vitamin E protects nerve cells from beta-amyloid
protein
toxicity." Biochem. Biophys. Res. Commun. 186, 944-50 (1992); M.Sano, et al.,
"Rationale and design of a multicenter study of selegiline and a-tocopherol in
the
treatment of Alzheimer disease using novel clinical outcomes." Alzheimer Dis.
Assoc.
Disord. 10, 132-40 (1996); H.Kappus, et al., "Tolerance and safety of vitamin
E: a
toxicological position report." Free Radic. Biol. Med. 13, 55-74 (1992)).
Selegiline inhibits monoamine oxidase, which may convert certain protoxins
into
toxins. L.S. Schneider, J. Clin. Psychiatry 57, 30-36 (1996). Selegiline and
other
monoamine oxidase type B inhibitors may protect neurons from oxidative damage
while
not interfering with the action of type A inhibitors, which metabolize
serotonin and
norepinephrine. Selegiline also inhibits oxidative deamination of dopamine,
which
prevents the formation of free radicals and subsequent neuronal damage. M.
Sano,
et al., Alzheimer Dis. Assoc. Disord. 10, 132-140 (1996). Selegiline, through
its anti-
oxidative and neuroprotective properties may slow progression of Alzheimer's
disease.
Selegiline effect on catecholamine metabolism may also contribute to the
efficacy of
selegiline in delaying the progression of Alzheimer's disease in patients with
moderate
impairment.
Other antioxidants include free radical scavengers (Egb-76 1, yuyu Industrial,
CP1-21, dexanabinol and iron chelators, which prevent iron from reacting to
form
hydroxyl radicals. Desferrioxamine prevents radical damage in vivo, and
clinical trial
shows that it may slow the progression of Alzheimer's disease. Yet another
example is
HCT- 1026 (NO-flurbiprofen), which is a nitric oxide-donating derivative of
flurbiprofen
presently being developed in human clinical trials by NicOx SA (Sophia
Antipolis,
France). The chronic use of certain NSAIDS may result in gastrointestinal
ulcers and
impaired kidney function. Nitric oxide is believed to prevent or reverse such
side-
effects, thus making HCT-1026 particularly noteworthy.
Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
Also useful in the present invention are compositions or therapeutic
combinations that further comprise at least one (one or more) activators for
peroxisome
proliferator-activated receptors ("PPAR"). The activators act as agonists for
the
peroxisome proliferator-activated receptors. Three subtypes of PPAR have been
CA 02582385 2006-12-18
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identified, and these are designated as peroxisome proliferator-activated
receptor alpha
("PPARa"), peroxisome proliferator-activated receptor gamma ("PPARy") and
peroxisome proliferator-activated receptor delta ("PPARS," which is also known
as
"PPAR(3" or "NUC 1 ").
Exposure of mammalian cells to PPAR agonists, particularly PPARa or PPARS
agonists, modulates, e.g., decreases the production or release of A(3,
particularly A042,
from the cells. See, U.S. Patent Application Publication No. 2003/0125338,
which
describes administrations of peroxisome proliferator-activated receptors for
the
treatment of amyloidosis and conditions and diseases associated therewidth.
The
lo peroxisome proliferator-activated receptors (PPARa, PPARS, PPAR(3, and
PPARy) are
a subfamily of the nuclear receptor gene family, Desvergne, et al., Endocrine
Rev. 20,
649-88 (1999)). PPARs are usually activated by fatty acids and similar
derivatives.
PPARS has been identified as being useful in increasing high density
lipoprotein (HDL)
levels in humans. See, e.g., WO 97/28149, which describes PPAR agonists that
are
useful for raising high density lipoprotein (HDL) plasma levels in mammals.
PPARa
activator compounds are useful for, among other things, lowering
triglycerides,
moderately lowering LDL levels and increasing HDL levels. Useful examples of
PPARa activators include fibrates.
In contrast to PPARa, the function of PPARS is not well understood. Although
PPARS is ubiquitously expressed the brain, adipose tissue and skin have higher
levels of
relative mRNA expression (J.M. Peters, et al., Mol. Cell. Biol. 20, 5119-28
(2000)). The
expression profile of PPAR6 suggests that it may be involved in brain
functions.
G. Xing, et al., Biochem. Biophys. Res. Commun. 217, 1015-25 (1995).
Furthermore,
PPAR6 may be implicated in reverse cholesterol transport, W.R. Oliver, et al.,
Proc.
Nat'1. Acad. Sci. USA 98, 5306-11 (2001). Examples ofPPAR8 agonists include
valproic Acid (Lampen, et al., Tox. Appl. Pharmacol. 160, 238-49 (1999)),
GW501516
(W.R. Oliver, et al., Proc. Nat'l Acad. Sci. USA 98, 5306-11 (2001)), L-
165041,
L-165461, L-783483, and L-796449 (Berger, et al., J. Biol. Chem. 274, 6718-25
(1999)).
Routine experimentation may be performed to determine if a composition affects
the release ofA(3 from at least one cell in vivo. A suitable assay involves SM-
4 cells,
which are stably transfected with Swedish mutant amyloid Precursor Protein,
and then
treated with a PPARa or PPARS agonist, such as pirinixic acid, or derivative
thereof.
After treatment, the media is collected and assayed for A(340 or A(342. A
statistically
significant decrease (p<0.05) in AP40 or A(342 concentration in the media
compared to
appropriate control(s) indicates that the treatment inhibited or prevented
A(340 or A(342
production or release from the cells. If a compound decreases A(342 production
or
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release by a statistically significant amount relative to control (absence of
the compound
or presence of vehicle) it is considered to be an A(342-modulating agent
according to the
invention.
An exemplary PPAR agonist is pirinixic acid, which has been -shown to induce a
decrease in A(342 production or release from SM-4 cells in a concentration-
dependent
manner. Pirinixic acid has been identified as a hypolipidemic agent, see, U.S.
Pat.
No. 3,814,761, which characterized it and related compounds as anti-lipidemic
agents.
Although it might be tempting to view the activity of pirinixic acid on A042
production
or release as being directly related to its hypolipidemic role, particularly
in view of the
1 o clinical correlation between hypercholesterolemia and Alzheimer's disease.
Wolozin,
Proc. Nat'1 Acad. Sci. USA 98, 5371-73 (2001)). Fibrates are known to act as
cholesterol-lowering agents but they generally are not known to reduce A(342
production
or release. For example, it has been reported that when SM-4 cells were
treated with
clofibrate and the culture media was collected in order to assay AP421evels,
clofibrate
was found to increase A(342 extracellular levels at a concentration range of
50-500 M.
Similar results were found with 5,8,11,14-eicosatetraynoic acid ("ETYA") at 20-
50 M
concentrations. The fact that three PPARa agonists (all of which are
cholesterol
lowering agents) have disparate effects on A(342 production or release from SM-
4 cells
implies that some PPARa agonists affect A042 production or release via a
mechanism
that is not strictly concomitant with their role as cholesterol lowering
agents. See, U.S.
Patent Application Publication No. 2003/0013699, which describes novel
heterocycles
designed to prevent, treat, or ameliorate symptoms of Alzheimer's Disease,
regulating
production or levels of amyloid-(3 peptides in the bloodstream or brain.
Non-limiting examples of suitable fibric acid derivatives ("fibrates") include
clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methylpropionate, for example
Atromid-STM capsules, which are commercially available from Wyeth, Madison,
New
Jersey); gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic
acid, for
example, LopidTM tablets, which are commercially available from Pfizer, New
York,
New York); ciprofibrate (C.A.S. Registry No. 52214-84-3, see, U.S. Pat. No.
3,948,973,
which describes the synthesis of such halocyclopropyl
substitutedphenoxyalkanoic acids
and esters); bezafibrate (C.A.S. Registry No. 41859-67-0, see, U.S. Pat. No.
3,781,328,
which describes the synthesis of novel phenoxy-alkyl-carboxylic acid compounds
and
their ability to lower the serum lipid and cholesterol level); clinofibrate
(C.A.S. Registry
No. 30299-08-2, see, U.S. Pat. No. 3,716,583, which describes the preparation
of novel
anti-atherosclerosis agents); binifibrate (C.A.S. Registry No. 69047-39-8);
lifibrol
(C.A.S. Registry No. 96609-16-4); fenofibrate (such as TricorTM micronized
fenofibrate
(2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid, 1-methylethyl ester),
which
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is available from Abbott Laboratories, Abbott Park, Illinois, or LipanthylTM
micronized
fenofibrate, available from Laboratoire Founier, Chenove, France).
Other examples of PPARa activators include suitable fluorophenyl compounds
as disclosed in U.S. Pat. No. 6,028,109, which describes the use of agnosts of
PPARa for the manufacture of a medicament for the treatment of obesity and the
methods of treating obesity; certain substituted phenylpropionic compounds as
disclosed
in WO 00/75103; which describes novel substituted phenylpropionic acid
derivatives
capable of binding as a ligand to PPARa to thereby activate the receptor and
thus show a
potent effect of lowering blood lipid; and PPARa activator compounds as
disclosed in
WO 98/4308 1, which describes methods and compositions for treating a host
having a
gastrointestinal disease by administering to the host a composition containing
a
pharmaceutically effective amount of a modulator of a PPAR. Non-limiting
examples of
suitable PPARy activators include derivatives of glitazones or
thiazolidinediones, such
as, troglitazone (such as RezulinTM 5[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-
tetramethyl-
2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione)
commercially
available from Pfizer, New York, New York); rosiglitazone (such as AvandiaTM
rosiglitazone maleate 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-
2,4-
thiazolidinedione, (Z)-2-butenedioate) available from GlaxoSmithKline,
Middlesex,
England) and pioglitazone (such as ActosTM pioglitazone hydrochloride
(5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-]-thiazolidine-dione
monohydrochloride) commercially available from Takeda Pharmaceuticals, Lincoln-
shire, Illinois). Other useful thiazolidinediones include ciglitazone,
englitazone,
darglitazone and BRL 49653, see, WO 98/05331, which relates such compounds for
the
prevention and treatment of type 2 diabetes and cardiovascular disease; PPARy
activator
compounds disclosed in WO 00/76488, which describes methods for delaying or
preventing the onset of Type 1 diabetes; and PPARy activator compounds
disclosed in
U.S. Pat. No.-5,994,554, which describes a method for determining whether a
compound does or does not interact directly with PPARy using radiolabeling.
Other useful PPARy activator compounds include certain acetylphenols, see,
e.g.,
U.S. Pat. No. 5,859,051, which describes acetylphenol and its analogues for
use as
antiobesity and antidiabetic compounds; certain quinoline phenyl compounds as
disclosed in WO 99/20275, which describes the use of such compounds for
mediating
the activity of PPAR receptors with such compounds; aryl compounds as
disclosed by
WO 99/38845, which describes such compounds for use as PPARy modulators for
the
treatment for conditions such as type 2 diabetes and obesity; certain 1,4-
disubstituted
phenyl compounds as disclosed in WO 00/63161, which describes such compounds
as
highly selective agonists for the PPAR receptor or prodrugs of agonists for
the PPARy
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receptor, and therefore useful in the treatment of type 2 diabetes; certain
aryl compounds
as disclosed in WO 01/00579, which describes such compounds as modulators of
PPARy activity which are useful in pharmaceutical compositions and methods for
the
treatment of conditions such as type 2 diabetes and obesity; benzoic acid
compounds as
disclosed in WO 01/12612 & WO 01/12187, which describe such compounds as PPAR
agonists, in particular PPARy, and so are useful in the treatment of states of
insulin
resistance, including type 2 diabetes mellitus; and substituted 4-hydroxy-
phenylalconic
acid compounds as disclosed in WO 97/31907, which describes such compounds as
exhibiting activation, including agonist activity, to PPARS, thereby enabling
them to
lo modulate the blood glucose levels in mammals.
PPARB compounds are useful for, among other things, lowering triglyceride
levels or raising HDL levels. Non-limiting examples of PPARS activators
include
suitable thiazole and oxazole derivatives, such as C.A.S. Registry No. 3 1 73
1 8-32-4, see,
e.g., WO 01/00603, which describes the use of pamoic acid or one of its
derivatives for
the preparation of a medicament for the treatment of diseases characterized by
deposits
of amyloid aggregates; suitable non-(3-oxidizable fatty acid analogues);
certain fluoro,
chloro or thio phenoxy phenylacetic acids; see, e.g., WO 97/28149, which
describes
such compounds as useful for raising high density lipoprotein (HDL) plasma
levels in
mammals and for preventing, halting or slowing the progresssion of
atherosclerotic
cardiovascular diseases and related conditions; see, e.g., U.S. Pat. No.
5,093,365, which
describes the ability of such fatty acid analogues to lower the concentration
of
cholesterol and triglyceride in the blood; and PPARS compounds as disclosed in
WO
99/04815, which describes medicinal compositions with a cholesterol-lowering
effect
containing, as the active ingredient, compounds having the effect of
activating a PPARS
receptor, thereby having an LDL-cholesterol-lowering effect.
Moreover, compounds that have multiple functionality for activating various
combinations of PPARa, PPARy and PPARS are also useful with the practice of
the
present invention. Non-limiting examples include certain substituted aryl
compounds as
disclosed in U.S. Pat. No.-6,248,781, which describes the ability of such
compounds in
the treatment or prevention of conditions mediated by nuclear receptors, in
particular
PPAR; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and
WO 00/63153, all of which describe compounds that may be utilized in the
treatment of
conditions mediated by PPARa or PPARy activator compounds, such as diabetes
and
obesity. Other non-limiting examples of useful PPARa or PPARy activator
compounds
include activator compounds as disclosed in WO 97/25042, which describes the
use of a
pharmaceutically effective amount of an agonist of PPARa and PPARy for the
treatment
or prophylaxis of Syndrome X; activator compounds as disclosed in WO 00/63190,
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which describes novel compounds that may be utilized in the treatment or
prevention of
conditions mediated by nuclear receptors, in particular PPAR; activator
compounds as
disclosed in WO 01/21181, which describes novel drugs efficacious against
diseases in
association with glycometabolism and lipid metabolibsm by inhibiting or
promoting
PPARa or PPARy; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120, in
which modulators of PPARs are useful in the treatment of type 2 diabetes and
of
cardiovascular diseases; compounds as disclosed in WO 00/63196, which
describes
compounds that are useful in the treatment of conditions mediated by nuclear
receptors,
in particular Retinoid X Receptor and PPARs families; and WO 00/63209, which
1o describes a pharmaceutical composition useful in the treatment or
prevention of
conditions mediated by PPARs; substituted 5-aryl-2,4-thiazolidinediones
compounds as
disclosed in U.S. Pat. No. 6,008,237, which describes substituted 5-aryl-2,4-
thiazolidinediones as potent agonists of PPAR, and are therefore useful in the
treatment,
control or prevention of diabetes, hyperglycemia, vacular restenosis, and
other PPAR
mediated diseases; arylthiazolidinedione and aryloxazolidinedione compounds as
disclosed in WO 00/78312 and WO 00/78313, which describe substituted 5-aryl-
2,4-
thiazolidinediones and oxazolidinediones as potent agonists of PPAR, and are
therefore
useful in the treatment, control or prevention of PPAR a or y mediated
diseases;
G W2331 or (2-(4-[difluorophenyl]-1-heptylureido)-ethyl]-phenoxy)-2-
methylbutyric
compounds, see, e.g., WO 98/05331, which describes such compounds for the
prevention and treatment of type 2 diabetes and cardiovascular disease with
diabetic or
pre-diabetic conditions or symptoms by behaving as both a PPARa agonist and a
PPARy agonsit, or activating both PPARa and PPARy; aryl compounds as disclosed
in
U.S. Pat. No. 6,166,049, which describes a method comprising the
administration of
PPARa and PPARS ; oxazole compounds as disclosed in WO 01/17994, which
describes chemical modification of a phosphorous-based PPAR agonist; and
dithiolane
compounds as disclosed in WO 01/25225, and WO 01/25226, which describes
methods
for synthesizing novel dithiolane derivatives with high affinity for PPARa or
PPARy.
Other useful PPAR activator compounds include substituted benzylthiazolidine-
2,4-dione compounds as disclosed in WO 01/14349, WO 0l/14350, and WO 01/04351,
all of which show how such a compound, as a ligand of human PPAR, enhances the
transcriptional activity of the receptor and effects the lowering of blood
sugar level and
lipid level; mercaptocarboxylic compounds as disclosed in WO 00/50392, which
demonstrates how such compounds exhibit excellent antihyperglycemic and PPAR-
activating effects; ascofuranone compounds as disclosed in WO 00/53563, which
demonstrates how such compounds are usable in preventing or treating diabetes,
chronic
inflammation, digestive cancers, etc.; carboxylic compounds as disclosed in WO
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99/46232, which have and effect of regulating PPARs; compounds as disclosed in
WO
99/12534, which describes aromatic compounds that exhibit control effects
against
PPAR; benzene compounds as disclosed in WO 99/15520, which describes compounds
that exhibit control effects against PPAR and therefore useful for the
treatment of related
diseases; o-anisamide compounds as disclosed in WO 01/21578, which describes
the
ability of such compounds to serve as PPAR agonists; and PPAR activator
compounds
as disclosed in WO 01/40192, which describes heterocyclic compounds that have
the
effects of lowering blood glucose level, lowering blood lipid level,
ameliorating insulin
resistance and activating PPAR.
Cholesterol-Lowering Agents
Since one aspect of the present invention relates to treating Alzheimer's
disease,
regulating production of or levels of amyloid P (A(3) peptides or regulating
the amount
of ApoE isoform 4 in the bloodstream or brain by treatment with a combination
of active
ingredients wherein the active ingredients may be administered separately, the
invention
also relates to combining separate pharmaceutical compositions in kit form.
That is, the
invention includes a kit wherein two separate units are combined: a
pharmaceutical
composition comprising at least a compound of any of the Formulae described
herein
and a separate pharmaceutical composition comprising at least one cholesterol
biosynthesis inhibitor or lipid-lowering agent as described above. In one
embodiment,
the kit may include directions for the administration of the separate
components. The kit
form is particularly advantageous when the separate components must be
administered
in different dosage forms (e.g., oral and parenteral) or are administered at
different
dosage intervals.
In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise one or more AcylCoA:Cholesterol 0-
acyltransferase ("ACAT") Inhibitors, which can reduce LDL and VLDL levels,
coadministered with or in combination with the compound(s) of the Formulae
herein
discussed above. ACAT is an enzyme responsible for esterifying excess
intracellular
cholesterol and may reduce the synthesis of VLDL, which is a product of
cholesterol
esterification, and overproduction of apo B-100-containing lipoproteins.
Non-limiting examples of useful ACAT inhibitors include avasimibe
([[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-
methylethyl)phenyl
ester, formerly known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082
(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-
heptylurea). See
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P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and
Atherosclerosis", Drugs 60(1), 55-93 (2000).
There is a complex relationship between Alzheimer's disease, cholesterol
homeostasis, and agents used for regulating cholesterol levels in the body. WO
00/28981
discloses the administration of an inhibitor of HMG CoA reductase (3-hydroxy-
3-methylglutaryl CoA reductase) to reduce the risk of onset of Alzheimer's
disease. The
inhibitors used were lovastatin, pravastatiii, or a combination thereof
However, a similar
correlation was not seen with simvastatin. WO 00/31548 also discloses
inhibitors of
HMG CoA reductase, particularly statins. Interestingly, simvastatin is a
suggested
inhibitor, contrasting with the results disclosed in WO 00/28981, which states
that the
prevalence of Alzheimer's disease in simvastatin-treated subjects was not
decreased.
More than half of the total body cholesterol in humans is derived from
intrinsic
biosynthesis. HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A ) reductase is
the
enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis,
i.e.,
conversion of HMG-CoA to mevalonate. Cholesterol and triglycerides circulate
in the
bloodstream as part of lipoprotein complexes. These complexes may be separated
by
density ultracentrifugation into high (HDL), intermediate (IDL), low (LDL),
and very
low (VLDL) density lipoprotein fractions. Triglycerides (TG) and cholesterol
synthesized in the liver are incorporated into VLDLs and released into the
plasma for
delivery to pheripheral tissues. In a series of subsequent steps, VLDLs are
transformed
into IDLs and cholesterol-rich LDLs. HDLs, containing apolipoprotein A, are
hypothesized to participate in the reverse transport of cholesterol from
tissues back to
the liver. Elevated levels of total cholesterol, i.e., hypercholesterolemia,
low LDL-
cholesterol (LDL-C), and apolipoprotein B (a membrane transport protein for
LDL)
promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol
(HDL-C) and its transport complex, apolipoprotein A are associated with the
development of atherosclerosis. Cardiovascular morbidity and mortality vary
directly
with the level of total cholesterol and LDL-C, and inversely with the level of
HDL-C.
HMG-CoA reductase inhibitors have been shown to reduce total serum cholesterol
levels, LDL-C, and apolipoprotein B, most likely by increasing the catabolism
of LDL
and hepatic extraction of LDL precursors, blocking enzymatic cholesterol
synthesis, and
simultaneously increasing HD levels. These lipid lowering drugs lower serum
cholesterol levels and reduce the incidence of both cardiovascular and
cerebrovascular
events. See, e.g., U.S. Pat. Nos. 5,831,115; 5,807,834; 5,801,143; 5,798,375;
and
5,786,485. Statins, well known for the treatment of prevention of coronary
heart
disease, block a rate-limiting step in the biosynthesis of cholesterol by HMG-
CoA
reductase. See U.S. Pat. No. 6,465,516.
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While Alzheimer's disease is typically characterized pathologically by the
presence of senile plaques and neurofibrillary tangles found at autopsy in the
brains of
subjects afflicted with the disease, vascular components of the disease have
also been
noted. These include lesions in the cerebral microcirculation and vascular
deposits of
A(3 protein, which is also a major constituent of the senile plaques found in
Alzheimer's
disease.
In addition to a relationship with coronary disease, it is known that there is
a
relationship between serum cholesterol levels and the incidence and the
pathophysiology
of Alzheimer's disease. Epidemiological studies show that subjects with
elevated
cholesterol have an increased risk of Alzheimer's disease. (Notkola et al.,
"Serum total
cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease,"
Neuroepidemiology; 17(1): 14-20 (1998); Jarvik et al., "Interactions of
apolipoprotein E
genotype, total cholesterol level, age and sex in prediction of Alzheimer's
disease: a
case-control study," Neurology 45(6):1092-6 (1995).) Other studies have
established that
subjects possessing the apolipoprotein s4 genotype ("apoE4") that codes for a
variant of
apolipoprotein, a cholesterol transport protein; have an increased risk for
Alzheimer's
disease, as well as for elevated levels of cholesterol and for heart disease.
R.Mahley,
"Cholesterol transport protein with expanding role in cell biology," Science
240, 622-30
(1988); Saunders, et al., "Association of apolipoprotein E allele s4 with late-
onset
familial and sporadic Alzheimer's disease," Neurology 43, 1467-72 (1993);
Corder,
et al., "Gene dose of apolipoprotein E type 4 allele and the risk of
Alzheimer's disease
in late-onset families," Science 261:921-923 (1993); Jarvik, et al., "Coronary
artery
disease, hypertension, ApoE and cholesterol: a link to Alzheimer's disease?"
Ann. N. Y.
Acad. Sci. 826:128-146 (1997). Both apoE4 and a second putative risk factor
for
Alzheimer's disease, a-2-macroglobulin, bind to a receptor, the lipoprotein
receptor
related protein, which is important for cellular uptake of cholesterol.
(Narita et al.,
"Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-
amyloid
peptide via cell surface low-density lipoprotein receptor-related protein," J.
Neurochem.
69(5):1904-11 (1997); and Blacker et al., "Alpha-2 macroglobulin is
genetically
associated with Alzheimer's disease," Nature Genetics 19:357-60 (1998).) Other
studies
have shown that cholesterol increases the production of A(3 protein, which
accumulates
in the brains of subjects with Alzheimer's disease and is thought by many
researchers to
cause the neurodegeneration underlying the disease. D.J.Selkoe, "Cell biology
of the
beta-amyloid precursor protein and the genetics of Alzheimer's disease," Cold
Spring
Harbor Symposia on Quantitative Biology, 61, 587-96 (1996); and Simons, et
al.,
"Cholesterol depletion inhibits the generation of (3-amyloid in hippocampal
neurons,"
Proc. Nat'l. Acad. Sci. USA, 95, 6460-04 (1998).
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The apolipoprotein E isoform 4 (ApoE isoform 4) is a major genetic risk factor
for Alzheimer's disease. PCT Patent Application No. WO 95/06470 discloses
administration of an HMG-CoA reductase inhibitor (statin) to regulate levels
of (ApoE
isoform 4) in humans to prevent and treat Alzheimer's Disease. A normal
cellular
function of ApoE is uptake and delivery of lipids. The ApoE isoform correlates
with an
increased risk for atherosclerosis, increased amyloid plaque deposition and
increased
risk of Alzheimer's disease. K.Fassbender, et al., "Simvastatin Strongly
Reduces Levels
of Alzheimer's Disease (3-amyloid peptides AP42 and A(340 in vitro and in
vivo", Proc.
Nat'Z Acacl. Sci. USA 98: 5856-5861 (2001). PCT Patent Application WO 00/28981
1 o discloses at page 3 that patients possessing the ApoE isoform 4 have an
increased risk
for Alzheimer's disease, as well as elevated levels of cholesterol and
increased risk for
heart disease.
Levels of cholesterol in the brain are critical for synapse formation and
maintenance and recent studies identify cholesterol as a limiting factor in
synaptogenesis. Reduced cholesterol may place a limit on plastic processes
thus
reducing tlie tendency to develop Alzheimer's disease. An issue for very long
axons is
the ability to supply sufficient cholesterol for rapid axonal growth,
especially in
regeneration. Alzheimer's disease brain contains less cholesterol, and this
contributes to
Alzheimer's disease-related alterations in membrane composition, membrane
fluidity,
and lipid bilayer structure and dynamics. Statins, as inhibitors of
cholesterol synthesis,
may reduce the prevalence of Alzheimer's disease. Long term potentiation is
inhibited
by cholesterol biosynthesis inhibitors and long term potentiation induction is
associated
with pathway-specific increases in lipid production. For example, axonal
growth ceases
when cholesterol synthesis is inhibited by pravastatin and could be
reactivated by
addition of cholesterol to either cell bodies or distal axons.
The term, "HMG CoA reductase inhibitor," refers to any compound which
inhibits the bioconversion of 3-hydroxy-3-methylglutaryl coenzyme A to
mevalonic acid
catalyzed by the enzyme HMG CoA reductase. The inhibiting effect of any such
compounds can be readily determined by those skilled in the art according to
standard
assays. HMG CoA reductase inhibitors will be known to those skilled in the
art. Non-
limiting examples of suitable cholesterol biosynthesis inhibitors include
competitive
inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol
biosynthesis,
squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures
thereof. The
HMG CoA reductase inhibitors suitable for use in the invention include, but
are not
limited to, pravastatin (for example PravacholTM which is available from
Bristol Meyers
Squibb) and related compounds, as disclosed in U.S. Pat. No. 4,346,227; and
lovastatin
and related compounds, as disclosed in U.S. Pat. Nos. 4,231,938 and 4,346,227.
In
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some embodiments, lovastatin and pravastatin are used as HMG CoA reductase
inhibitors in the invention. Lovastatin, marketed under the trade name
MevacorTM, is a
competitive inhibitor of HMG CoA reductase.
Other HMG CoA reductase inhibitors which may be employed in the invention
include atorvastatin (LipitorTM, Pfizer, New York, New York) and other
6-[2-(substituted-pyrrol-l-y1)alkyl]pyran-2-ones and derivatives, such as
disclosed in
U.S. Pat. No. 4,647,576; fluvastatin (LescolTM, Novartis, Basel, Switzerland);
fluindostatin (Sandoz XU-62-320); pyrazole analogs of inevalonolactone
derivatives as
disclosed in PCT application WO 86/03488; rivastatin and other
pyridyldihydroxyheptenoic acids as disclosed in European Patent 491226A;
Searle's
SC 45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate;
imidazole
analogs of inevalonolactone, as disclosed in PCT application WO 86/07054; 3-
carboxy-
2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Patent
No.
2,596,393; 2,3-di-substituted pyrrole, furan, and thiophene derivatives, as
disclosed in
i5 European Patent Application No. 0221025; naphthyl analogs of
mevalonolactone, as
disclosed in U.S. Pat. No. 4,686,237; octahydronaphthalenes, such as those
disclosed in
U.S. Pat. No. 4,499,289; keto analogs of mevinolin (lovastatin), as disclosed
in
European Patent Application No. 0,142,146 A2; as well as other HMG CoA
reductase
inhibitors.
Other examples of suitable HMG CoA reductase inhibitors include statins such
asfluvastatin, simvastatin (for example ZocorTM which is available from Merck
& Co.),
atorvastatin, cerivastatin, CI-981 and pitavastatin (such as NK-104 of Negma
Kowa of
Japan), rosuvastatin; HMG CoA synthetase inhibitors, for example L-659,699
((E,E)-11-
[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-tri- methyl-2,4-
undecadienoic
acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene
epoxidase
inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-
3-
[(3,3'-bithiophen-5-yl)me- thoxy]benzene-methanamine hydrochloride) and other
sterol
biosynthesis inhibitors such as DMP-565.
In addition, other compounds useful in inhibiting HMG-CoA reductase suitable
for use herein are disclosed in U.S. Pat. No. 4,904,646 and 5,091,378.
Examples of
statins include AdvicorTM (lovastatin/niacin); cerivastatin (BaycolTM, Bayer
Corp.,
withdrawn from U.S. market); MevacorTM (lovastatin, Merck & Co., Inc., Rahway,
New
Jersey); rivastatin; rosuvastatin; pitavastatin; mevastatin; velostatin; and
ZocorTM
(simvastatin, Merck & Co., Inc., Rahway, New Jersey). Further examples of HMG-
CoA
reductase inhibitors include pyrazole analogs of a mevalonolactone, indene
analogs of
mevalonolactone, 3-carboxy-2-hydroxy-propanephosphinic acid derivatives,
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6-[2-(substituted-pyrrol-1-yl)-alkyl]pyran-2-one, heterocyclic analogs of
mevalonolactone including imidazole analogs, naphthyl analogs of
mevalonolactone,
octahydro-naphthalene derivatives, keto analogs of lovastatin, and 2,3-di-
substituted
pyrrole, furan, or thiophene compounds.
In addition to their direct effects on lipid/cholesterol biosynthesis and
metabolism, statins in combination with substrates of nitric oxide synthase
are known to
facilitate transport of drugs across the blood brain barrier ("BBB"). Inasmuch
as
Alzheimer's disease is a disease of the brain, an especially useful
pharmaceutical
composition is a combination of a statin second agent and a nitric oxide
synthase
substrate second agent (e.g., L-Arg) as well as a first agent as described
herein. A
family of enzymes called Nitric Oxide Synthase ("NOS") form nitric oxide from
L-arginine, and the nitric oxide produced is responsible for the endothelium
dependent
relaxation and activation of soluble guanylate cyclase, neurotransmission in
the central
and peripheral nervous systems, and activated macrophage cytotoxicity. Nitric
Oxide
Synthase, occurs in many distinct isoforms which include a constitutive form
(cNOS)
and an inducible form (iNOS). The constitutive form is present in normal
endothelial
cells, neurons and some other tissues. Formation of nitric oxide by the
constitutive form
in endothelial cells is thought to play an important role in normal blood
pressure
regulation, prevention of endothelial dysfunction such as hyperlipodemia,
arteriosclerosis, thrombosis, and restenosis. The inducible form of nitric
oxide synthase
has been found to be present in activated macrophages and is induced in
vascular
smooth muscle cells, for example, by various cytokines or microbial products.
The
conversion of precursor substrates such as L-arginine into nitric oxide is
enzymatically
catalyzed by NOS and the resulting by-product of the conversion of L-arginine
is
L-citrulline. L-arginine as used herein includes all biochemical equivalents
(i.e. salts,
precursors, and its basic form).
In one embodiment, this invention provides a method to enhance delivery of a
first agent to brain tissue of an individual comprising introducing the
composition into
the blood stream of the individual substantially contemporaneously with a
blood flow
enhancing amount of L-arginine. In another embodiment, this invention provides
a
method to enhance delivery of a desired composition to brain tissue of an
individual
comprising introducing the composition into the blood stream of the individual
substantially contemporaneously with a blood flow enhancing amount of L-
arginine or a
blood flow-enhancing amount of a non-ecNOS NO-generating system.
In another alternative embodiment, the compositions used in the methods of the
present invention may further comprise one or more Cholesteryl Ester Transfer
Protein
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("CETP") Inhibitors coadministered with or in combination with the compound(s)
of the
Formulae described herein. CETP is responsible for the exchange or transfer of
cholesteryl ester carrying HDL and triglycerides in VLDL.
Non-limiting examples of suitable CETP inhibitors are disclosed in PCT Patent
Application No. WO 00/38721 and U.S. Pat. No. 6,147,090, which are
incorporated
herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors
such as
WAY-121898 also may be coadministered with or in combination with the fibric
acid
derivative(s) and sterol absorption inhibitor(s) discussed above.
In another alternative embodiment, the compositions used in the methods of the
present invention may further comprise probucol or derivatives thereof (such
as AGI-
1067 and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 and
6,147,250), which
may reduce LDL and HDL levels, coadministered with or in combination with the
compounds of the Formulae herein.
In another alternative embodiment, the compositions used in the methods of the
ls present invention may further comprise one or more low-density lipoprotein
(LDL)
receptor activators, coadministered with or in combination with a compound of
any
Formula discussed above. Non-limiting examples of suitable LDL-receptor
activators
include HOE-402, an imidazolidinyl-pyrimidine derivative that directly
stimulates LDL
receptor activity. See, M. Huettinger et al., "Hypolipidemic activity of HOE-
402 is
Mediated by Stimulation of the LDL Receptor Pathway." Arterioscler. Thromb.
13,
1005-12 (1993).
In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise plant sterols, plant stanols or fatty
acid esters of
plant stanols, such as sitostanol ester used in BenecolTM margarine, which can
reduce
cholesterol levels, coadministered with or in combination with a compound of
any
Formula herein. Generally, a total daily dosage of plant sterols, plant
stanols or fatty acid
esters of plant stanols can range from about 0.5 to about 20 grams per day in
single or 2-
4 divided doses.
In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise one or more antioxidants, such as
probucol,
tocopherol, ascorbic acid, j3-carotene and selenium, or vitamins such as
vitamin B6 or
vitamin B 12, coadministered with or in combination with a compound of any
Formula
herein. Generally, a total daily dosage of antioxidants or vitamins can range
from about
0.05 to about 10 grams per day in single or 2-4 divided doses.
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In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise monocyte and macrophage inhibitors such
as
polyunsaturated fatty acids (PUFA), thyroid hormones including throxine
analogues
such as CGS-26214 (a thyroxine compound with a fluorinated ring), gene therapy
and
use of recombinant proteins such as recombinant apo E, coadministered with or
in
combination with a compound of any Formula herein. Generally, a total daily
dosage of
these agents can range from about 0.01 to about 1000 mg/day in single or 2-4
divided
doses.
Fassbender et al. disclose that use of simvastatin and lovastatin, alone or in
combination with methyl-(3-cyclodextrin, can reduce intracellular and secreted
A(3 levels
in vitro and that treatment of animals with simvastatin reduces brain and
cerebrospinal
fluid levels of A(3 in vivo.
U.S. Pat. No. 6,071,899 discloses compounds, which may have a general
application in any disorder that involves endothelial dysfunction, such as
atherosclerosis,
or may have a general application in any disorder that involves lipid
peroxidation in
conjunction with enzyme activity, including inflammatory conditions of the
brain such
as Alzheimer's Disease (see col. 5, lines 16-29).
PCT Patent Application WO 99/38498 discloses methods for preventing or
treating Alzheimer's disease by administering a plasma-triglyceride level-
lowering agent
(e.g., fibrates), optionally in combination with a cholesterol level-lowering
agent such as
statins, bile acid sequestrants or agents that block intestinal cholesterol
absorption (e.g.,
0-sitosterol, SCH 48461 ((3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-
2-
azetidi- none), CP-148,623, saponins, neomycin and ACAT inhibitors).
U.S. Pat. Nos. 5,767,115, 5,624,920, 5,688,990, 5,656,624 and 5,688,787,
respectively, disclose hydroxy-substituted azetidinone compounds and
substituted (3-
lactam compounds useful for lowering cholesterol or in inhibiting the
formation of
cholesterol-containing lesions in mammalian arterial walls, but does not
disclose
treatment of Alzheimer's Disease.
Simvastatin has been used to reduce levels of 0-amyloid peptides A(342 and
A(34o
in vitro and in vivo, for example, in guinea pigs. Wolozin, B. et al., Arch.
Neurol.
57:1439-1443, 2000, describe the analysis of a subject population treated with
HMG-
CoA reductase inhibitors. The authors reported that the prevalence of
Alzheimer's
disease was 60-73% lower in these subjects than in subjects taking other
medications. In
this study, a causal relationship could not be established. Jick, H. et al.,
The Lancet
356:1627-1631, 2000, also reviewed subject records and found that in
individuals 50
years and older, statin administration was associated with a substantially
lowered risk of
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dementia, including Alzheimer's disease and other conditions. Similarly, Acyl-
CoA:
cholesterol acyltransferase (ACAT) inhibitors have been used to decrease
plasma
cholesterol in various animal models including rats, guinea pigs and rabbits
(Tanaka
et al., J. Med. Chem. 41:2390-2410, 1998; Junquero et al., Biochem. Pharmacol.
61:97-
108, 2001). Examples of ACAT inhibitors include but are not limited to
Glibenclamide,
CI-976 (PD128042), NTE-122, Fatty acid Anilides, F12511, Avasimibe, TS-962 (HL-
004), N-Chlorosulfonyl isocyanate and derivatives, SR-9223i, Pyripyropenes, PD-
132301, PD-132301-2, DUP-128, YM-17E, BW447A, Alzheimer's disease 6591, CL-
277,082, Melinamide, Hydroxyphenyl Urea derivatives, R- 106578, Indoline
derivatives
lo with amide or urea moiety, 57-118, 58-035, CI-999, CI-1011, N-alkyl-N-
[(fluorophenox-
y)benzyl]-N'-arylureas and derivatives, SKF-99085, EAB309, N-alkyl-N-
(heteraryl-
substituted benzyl)-N'-arylureas and derivatives, F-1394, N-alkyl-N-
biphenyllylmethyl-
N'-aryl ureas and derivatives, CL 277,082, CL 283,546, CL 283,796, CP-113,818,
CP-
105,191, Polyacetylene analogs-panaxynol, panaxydol, panaxydiol and
panaxytriol, T-
2591, 4,4-bis(trifluoromethyl)imidazolines and derivatives, FR145237,
FR186054,
FR129169, Naringenin, Ulmoidol, 23-hydroxyursolic acid, 27-trans-
p-coumaroyloxyursolic acid, 27-cis-p-coumaroyloxyursolic acid, Triterpenes and
derivatives, N-(4,5-diphenylthiazol-2-yl)-N'-aryl or alkyl (thio)ureas and
derivatives, N-
(4,5-diphenylthiazol-2-yl)alkanamide- s and derivatives, RP73163, RP64477,
Diaryl-
2 o substituted heterocyclic ureas and derivatives, Heterocyclic amides and
derivatives,
Cyclic sulfides derived from hetero-Diels-Alder reaction of thioaldehydes with
1,3-
dienes, E5324, Tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-p- henyl-N-
(2,4,6-
trimethoxyphenyl)-2H-tetrazole-5-acetamide, Epicochlioquinone A,
acyclic(diphenylethyl) diphenylacetamides, 2-(1,3-dioxan-2-yl)-4,5-diphenyl-IH-
2 5 imidazoles and derivatives, N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-
yl)amide
derivatives, FCE 27677, GERI-BP002-A, TMP-153, amides of 1,2-diarylethylamines
and derivatives, F-1394, N-(4-oxochroman-8-yl)amide derivatives, terpendoles,
short
chain ceramide and dihydroceramide, FY-087, 447C88, cyclandelate, 3-
quinolylurea
derivatives, N-phenyl-6,11-dihydrodibenz[b,e]oxepin-ll-carboxamides and
related
30 derivatives, Gypsetin, AS-183, AS-186, 2,6-disubstituted-3-
imidazolylbenzopyrane
derivatives, Lateritin, 2-(alkylthio)-4,5-diphenyl-IH-imidazoles derivatives,
glisoprenins, acaterin, U-73482, purpactins, and chlorpromazine.
Amyloid Inhibitors (Anti-Amyloid Therapeutic Approaches)
Other important targets for therapeutic intervention are the mechanisms which
35 convert APP into A(3. In particular, down-regulation of the 0 and gamma-
secretases and
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up-regulation of alpha-secretase (which cleaves within the AP peptide) would
inhibit the
production of A(3 peptide. (3-secretase or BACE has been identified by several
groups
and is an aspartyl protease enzyme. However the molecular identity of the
gamma-site
APP processing enzyme, gamma-secretase, still remains to be determined. It is
clear
that presenilins are required for y-secretase cleavage of APP. A(3 secretion
is almost
completely blocked in neurons lacking presenilin 1. There are a number of
possibilities
for the function of presenilins: (1) They could be required for intracellular
trafficking
and sorting of APP to the y-secretase compartment, or (2) They could serve as
a co-
factor for-y-secretase cleavage. (C. Haass, et al., Science 286, 916-19
(1999); MS Wolfe,
zo et al., Biochemistry 38, 4720-27 (1999); T. Bayer, et al., Brain Pathology
11, 1-11
(2001); B. De Strooper, et al., Nature 391, 387-91 (1998)). See also, WO
2003/103652
and WO 2003/103653.
y-Secretase cleaves at the C-terminus of A(3 and is primarily responsible for
generating the pathogenic 42-amino acid form of A(3, A042, which forms
insoluble toxic
fibrils and accumulates in senile plaques. M. Hutton, et al.; Essays Biochem.
33, 117-31
(1998); R.L. Nussbaum and C.E. Ellis, N. Engl. J. Med. 348(14), 1356-64
(2003);
T. Iwatsubo, et al., Neuron 13, 45-53 (1994), W.P. Esler and M.S. Wolfe,
Science 293,
1449-54 (2001). Although the normal function of APP is unknown, it is
predominantly
expressed in the brain and is suspected of participating in cell adhesion,
synaptic growth,
and neural repair.
Amyloid-(3 forms a continuum of aggregation species: monomeric amyloid-(3,
soluble oligomeric amyloid-(3, insoluble protofibrils, amyloid-0, diffuse
amyloid,
compact amyloid, and neuritic or senile amyloid, the latter two being the
pathologic and
diagnostic hallmarks of Alzheimer's disease. Independent of fibril or plaque
formation,
however, amyloid-(3 may alter membrane potential and firing, synaptic
transmission,
synaptic plasticity, and learning. Amyloid-(3, especially amyloid-(3 1-42, has
been
shown to be neurotoxic. Accordingly, amyloid-(3 itself represents a
significant drug
target. Recent evidence suggests that plaques per se are less toxic than
oligomers or
protofibrils. These oligomeric forms of A(3 could be responsible for the first
stage of the
disease when neuronal cell death is initiated. See also, WO 03/050073; WO
03/047576;
WO 03/045378; WO 03/043987; WO 03/043975; WO 03/043618; U.S. Pat.
No. 6,569,851; WO 03/040096; U.S. Pat. No. 6,552,013; WO 03/037325;
WO 03/030886; WO 03/029169; EP 1,298,436; WO 03/027068; U.S. Pat.
No. 6,528,505; WO 03/020370; U.S. Pat. No. 6,509,331; WO 03/006453;
WO 03/006423; WO 03/006021; WO 03/006013; U.S. Pat. No. 6,509,331; U.S. Pat.
No. 6,486,350; WO 03/002122; U.S. Pat. No. 6,476,263; WO 03/000261;
WO 02/100856; WO 02/100820; WO 02/100818; WO 02/100410; WO 02/100399;
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WO 02/098849; WO 02/094768; U.S. Pat. No. 6,476,263; WO 02/076440; U.S. Pat.
No. 2002/16320 A1; U.S. Pat. No. 6,329,163; WO 00/202520; WO 00/202518;
WO 00/202512; WO 00/202506; WO 00/202505; U.S. Pat. No. 6,284,221; U.S. Pat.
No. 6,221,645; WO 00/175165; WO 00/170672; U.S. Pat. No. 6,262,302; U.S. Pat.
No. 6,191,166; U.S. Pat. No. 6,262,302; U.S. Pat. No. 6,153,652; WO 96/40885;
U.S.
Pat. No. 5,942,400; U.S. Pat. No. 5,744,346; and WO 98/21589.
Dense microspheres or spherons may be turned into plaques when they are burst
in vitro or when injected into experimental animals. P. Averback, J.
Alzheimer's
Disease 1, 1-34 (1998). The compound NX-D2858 (Nymox Pharmaceutical Corp.,
1 o Dorval, Qudbec, Canada) blocks the transformation of spherons into senile
plaques and
may stop or slow the progress of Alzheimer's disease. U.S. published
application no.
2003-0083298. Another compound that may be used in the pharmaceutical
compositions
of the invention is AteroidTM (Hunter-Fleming,) and related
mucopolysaccharides, such
as glycosaminoglycans having an average molecular weight equal to 2,400 Da,
which
have been described as suitable for the treatment of Alzheimer's disease. EP
1,181,024
Another compound is indole-3-propionic acid (OxygonTM, Mindset), which is
described as preventing the cytotoxic effects of amyloid beta protein on
cells, as well as
blocking amyloid deposition and therefore useful in treating a fibrillogenic
disease, such
as Alzheimer's disease. U.S. Pat. No. 6,395,768 Bl. Suitable amyloid
aggregation
inhibitors also include reumacon available from Conpharm AB.
Additional examples include a variety of polysaccharide compounds. U.S. Pat.
No. 6,607,758, WO 03/013442, US 2002/197692, US 2002/150637, and CA 2,323,090
Yet another approach is exemplified by a new chelating agent. "Targeted
pharmacological depletion of serum amyloid P component for treatment of human
amyloidosis." M.B.Pepys, et al., Nature 417(6886), 254-59.
Amyloid-Formation Inhibitors
The present invention pertains to a method for treating or preventing a
disease
state associated with amyloidosis, the method comprising administering to a
subject a
therapeutically effective amount of an agent for reducing the concentration of
fibrillar or
soluble A(3, such that said disease state associated with amyloidosis is
treated or
prevented.
In an embodiment, the methods of the invention are based, at least in part, on
inhibiting an interaction between an amyloidogenic protein and a constituent
of
I11
CA 02582385 2006-12-18
NBI-! 54CPPC
basement membrane to inhibit amyloid deposition. The constituent of basement
membrane is a glycoprotein or proteoglycan, e.g., heparan sulfate
proteoglycan. A
therapeutic agent used in the method of the invention may interfere with
binding of a
basement membrane constituent to a target binding site on an amyloidogenic
protein,
thereby inhibiting amyloid deposition. In some aspects, the methods of the
invention
involve administering to a subject a therapeutic agent which inhibits amyloid
deposition.
"lnhibition of amyloid deposition" is intended to encompass prevention of
amyloid
formation, inhibition of further amyloid deposition in a subject with ongoing
amyloidosis and reduction of amyloid deposits in a subject with ongoing
amyloidosis.
Inhibition of amyloid deposition is determined relative to an untreated
subject or relative
to the treated subject prior to treatment. Amyloid deposition is inhibited by
inhibiting an
interaction between an amyloidogenic protein and a constituent of basement
membrane.
"Basement membrane" refers to an extracellular matrix comprising glycoproteins
and
proteoglycans, including laminin, collagen type IV, fibronectin and heparan
sulfate
proteoglycan ("HSPG"). In one embodiment, amyloid deposition is inhibited by
interfering with an interaction between an amyloidogenic protein and a
sulfated
glycosaminoglycan such as HSPG. Sulfated glycosaminoglycans are known to be
present in all types of amyloids (see Snow, et al. Lab. Invest. 56, 120-23
(1987)) and
amyloid deposition and HSPG deposition occur coincidentally in animal models
of
amyloidosis (see Snow, et al. Lab. Invest. 56, 665-75 (1987)).
The ability of a therapeutic compound of the invention to inhibit an
interaction
between an amyloidogenic protein and a glycoprotein or proteoglycan
constituent of a
basement membrane may be assessed by an in vitro binding assay, such as that
described
in U.S. Pat. No. 5,164,295. Alternatively, the ability of a compound to bind
to an
amyloidogenic protein or to inhibit the binding of a basement membrane
constituent
(e.g., HSPG) to an amyloidogenic protein (e.g., A(3) may be measured using a
mass
spectrometry assay where soluble protein, e.g., A(3, is incubated with the
compound. A
compound that binds to, e.g., Ap, will induce a change in the mass spectrum of
the
protein.
For example, a therapeutic agent of the invention may interact with a binding
site
for a basement membrane glycoprotein or proteoglycan in an amyloidogenic
protein and
thereby inhibits the binding of the amyloidogenic protein to the basement
membrane
constituent. Basement membrane glycoproteins and proteoglycans include
laminin,
collagen type IV, fibronectin and HSPG. In an embodiment, the therapeutic
agent
inhibits an interaction between an amyloidogenic protein and HSPG. Consensus
binding
site motifs for HSPG in amyloidogenic proteins have been described (see, e.g.,
Cardin
and Weintraub, Arteriosclerosis 9, 21-32 (1989)).
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Metal Chelators
Zn2+ mediates neurodegenerative processes observed in seizure, ischemia,
trauma, and Alzheimers disease. Zn2+ is observed in the extracellular plaque
and
degenerating neurons in Alzheimer's disease, which may contribute to neuronal
degeneration in Alzheimer's disease. Oxidative damage in the neocortex
associated
with Alzheimer's disease may be the result of gradual build up of metal ions
like zinc
and copper. Copper and zinc have particularly high concentrations in the (3-
amyloid
plaques in the brains of Alzheimer's subjects. Both metals are essential, but
normally
only small amounts are required and excess metals are excreted. It is
hypothesized that
0-amyloid converts dissolved oxygen to hydrogen peroxide, which in turn causes
cell
damage. Metal chelators may be used to diminish the oxidative burden. In APP
transgenic mice treated with clioquinol (an antibiotic and bioavailable Cu/Zn
chelator),
marked reduction in A(3 deposition occurred after several months of treatment.
Zinc and
other divalent cations appear necessary for A(3 aggregation. Thus, metal
chelation may
have some therapeutic benefit in the treatment of Alzheimer's disease, either
by
preventing A(3 aggregation or by disrupting preformed aggregates. In the
laboratory, the
copper-zinc chelator clioquinol may dissolve amyloid-beta deposits in
postmortem brain
tissue from Alzheimer's disease subjects. In APP transgenic mice treated with
clioquinol (an antibiotic and bioavailable Cu/Zn chelator), marked reduction
in A(3
deposition occurred after several months of treatment A new study extends
these results
to mice genetically prone to overproduce amyloid-P. Clioquinol cut amyloid
deposits in
half over a nine week period with no adverse effects. The mice treated with
clioquinol
also exhibited significantly improved scores on a behavioral rating scale. The
affinity of
clioquinol for Zn is in the nanomolar range, whereas the affinity of A(3 for
Zn2+ is in the
low micromolar range. Clioquinol had been approved by the FDA as an
antibiotic, but
was removed from the market about 30 years ago because of side effects
involving the
loss of Vitamin B-12. The antibiotic clioquinol, also known as 5-chloro-7-iodo-
8-hydroxyquinoline or iodochlorhydroxyquin, a known copper/zinc chelator is a
reasonably well tolerated drug in humans and is currently in a phase II
clinical trial for
Alzheimer's disease. T.E. Golde, J. Clin. Invest. 111, 11-18 (2003).
Clioquinol chelates
copper and zinc in vitro, and reduces A(3 deposition in a mouse model.
Moreover,
interim results from a randomized, double-blind, placebo-controiled clinical
trial in 32
subjects with Alzheimer's disease suggested that this drug slows the rate of
cognitive
decline in the most severely affected group.
Suitable copper/zinc chelators include clioquinol available from PN
Gerolymatos
SA. Preliminary positive results have been generated by a human clinical trial
in which
clioquinol, supplemented with B-12, appears to be helpful in humans with
Alzheimer's.
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NB I-154CPPC
Bush, et al., Proc. Nat'l Acad. Sci. USA 99, 7317-19 (1999), U.S. Publshed
Patent
Application No. 2002/0,025,944. See also, "Treatment with a copper-zinc
chelator
markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease
transgenic mice." R.A. Cherny, et al., Neuron 30, 665-76 (2001); and "The
galvanization of 0-amyloid in Alzheimer's disease" A.I. Bush and R.E. Tanzi
Proc.
Nat'l Acad. Sci. USA 99, 7317-19 (2002).
Phanquinone (4,7-phenanthroline-5,6-dione) has hitherto been used for the
treatment of various disorders, such as amoebiasis. However, its use for the
treatment or
prevention of memory improvement has been suggested. Phanquinone has been
marketed by Ciba-Geigy as EntobexTM. Phanquinone is also a metal chelator in
the
same family as clioquinol. According to the present invention the use of
phanquinone
for the manufacture of a pharmaceutical composition for the treatment or
prevention of
memory impairment is provided.
Behavioral Management ofAlzheimer's disease
Patients with Alzheimer's disease may also be treated for behavioral
disturbances associated with progression of the disease. Use of such
treatments is
intended to decrease psychotic symptoms such as paranoia, delusions and
hallucinations,
and associated or independent agitation, screaming, combativeness or violence,
and
thereby increase the comfort and safety of patients. Anti-psychotics and
antidepressants
can be used intermittently in patients with defined psychotic symptoms.
Benzodiazepines may be used briefly and judiciously for emergency sedation but
otherwise should be avoided because they can produce delirium and tend to
further
compromise residual cognitive capacities. Lithium (Eskalith), centrally active
P-adrenergic blockers, carbamazepine (TegretolTM, Ciba-Geigy Pharmaceuticals,
now
Novartis, Basel, Switzerland), and valproate (Depakene) have been used
empirically in
the treatment of affective lability and aggressive outbursts. Resperidone can
also be
used for psychoses associated with Alzheimer's disease. Olanzabine,
sertindole, and
quetiapine can also be used. Still other examples include trazodone; (3
blockers,
propranolol, metoprolol and pindotol (especially for some agitated patients
with
dementia). When male patients display intrusive disinhibited sexual behavior,
a
particular problem in patients with frontal lobe dementias,
medroxyprogesterone and
related hormonal agents may be employed. Glycosaminoglycan polysulfate
(AteroidTM)
can also improve depressive symptomatology in old-age dementia. Prog.
Neuropsychopharmacol. Biol. Psychiatry 13, 977-81 (1989).
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Treatment of apathy is also considered. Dopaminergic agents, such as
psychostimuiant CD-amphelamine, methylphemidate), amantadine (SymmetrelTM, Du
Pont Multi-Source Products, Wilmington, DE), bromocriptine and buproprion are
helpful in the treatment of severe apathy. A.E.Wallace, et al., "Double-blind,
placebo-
controlled trial of inethylphenidate in older, depressed, medically ill
patients." Am. J.
Psychiatry 152, 929-31 (1995).
SSRIs are often chosen as the initial treatment because of their better side
effect
profiles. Once-a-day dosing may be appropriate. Examples of SSRIs include
fluoxetine
(ProzacTM, Pulvules, Dista, Eli Lilly, Indianapolis, Indiana), paroxetine,
sertraline,
bupropion, and venlagaxin. Among the tricyclic and heterocyclic agents,
theoretical
reasoning and clinical experience suggest avoiding agents with prominent
anticholinergic activity (e.g., amitriptyline, imipramine). Among the
remaining agents,
sample dosing strategies are given here for nortriptyline. MAOIs are also
considered for
individuals unresponsive to or unable to take other agents (tranylcypromine
and
phenelzine are examples)
When sleep disturbances occur without other psychiatric symptoms beyond the
dementia itself, some clinicians prescribe trazodone or zolpidem.
Benzodiazepines (e.g.,
lorazepam or oxazepam) and chloral hydrate may be used. Triazolam in
particular is not
recommended for individuals with dementia because of its association with
amnesia.
Diphenhydramine, which is found in most over-the-counter sleep preparations,
is used
by some clinicians, but its anticholinergic properties make it suboptimal for
the
treatment of demented patients.
Some individuals with dementia show disinhibited behavior, including making
inappropriate jokes, neglecting personal hygiene, exhibiting undue familiarity
with
strangers, or disregarding conventional rules of social conduct. Occasionally,
they may
harm others by striking out. Suicidal behavior may occur, especially in mildly
impaired
individuals, who are more likely to have insight into their deficits and to be
capable of
formulating (and carrying out) a plan of action. Anxiety is fairly common, and
some
patients manifest "catastrophic reactions," overwhelming emotional responses
to
3 o relatively minor stressors, such as changes in routine or environment.
Depressed mood,
with or without neurovegetative changes, is quite common, as are sleep
disturbances
independent of depression. Delusions can occur, especially those involving
themes of
persecution (e.g., the belief that misplaced possessions have been stolen).
Misidentifications of familiar people as unfamiliar (or vice versa) frequently
occur.
Hallucinations can occur in all sensory modalities, but visual hallucinations
are most
common. Some patients exhibit a peak period of agitation (or other behavioral
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NBI-154CPPC
disturbances) during the evening hours, which is sometimes referred to as
"sundowning."
Delirium is frequently superimposed on dementia because the underlying brain
disease increases susceptibility to the effects of medications or concurrent
general
medical conditions. Individuals with dementia may also be especially
vulnerable to
psychosocial stressors (e.g., going to the hospital, bereavement), which may
exacerbate
their intellectual deficits and associated problems.
Dementia is sometimes accompanied by motor disturbances, which may include
gait difficulties, slurred speech, and a variety of abnormal movements. Other
neurological symptoms, such as myoclonus and seizures, may also occur.
When male patients display intrusive disinhibited sexual behavior, a
particular
problem in patients with frontal lobe dementias, medroxyprogesterone and
related
hormonal agents are sometimes recommended (H.Kyomen, et al., "The use of
estrogen
to decrease aggressive physical behavior in elderly men with dementia." J Am.
Geriatr.
Soc. 39, 1110-12 (1991); S.S.Rich, et al., "Leuprolide acetate for
exhibitionism in
Huntington's disease." Mov. Disord. 9, 3 53-57 (1994); P.G.Weiler, et al.,
"Propranolol
for the control of disruptive behavior in senile dementia." J. Geriatr.
Psychiatry Neurol.
1, 226-30 (1988)), but only case series support this recommendation at
present.
Glycosaminoglycan polysulfate (e.g., AteroidTM) in old-age dementias: effects
upon depressive symptomatology in geriatric patients. Prog.
Neuropsychopharmacol.
Biol. Psychiatry 13, 977-81 (1989)) The literature concerning the treatment of
apathy is
much sparser. There is minimal evidence that dopaminergic agents, such as
psychostimulants (d-amphetamine, methylphenidate), amantadine, bromocriptine,
and
bupropion, are helpful in the treatment of severe apathy, but promising case
reports
suggest that efficacy studies are warranted (A.E.Wallace, et al., "Double-
blind, placebo-
controlled trial of inethylphenidate in older, depressed, medically ill
patients." Am. J.
Psychiatry 152, 929-31 (1995)). Psychostimulants have also received some
support for
the treatment of depression in elderly individuals with severe general medical
disorders
(P.Pickett, et al., "Psychostimulant treatment of geriatric depressive
disorders secondary
to medical illness." J. Geriatr. Psychiatry Neurol. 3, 146-51 (1990);
L.W.Lazarus, et al.,
"Methylphenidate and nortriptyline in the treatment of poststroke depression:
a
retrospective comparison." Arch. Phys. Med. Rehabil. 75, 403-06 (1994);
T.R.Price, et
al., "Safety and efficacy of ECT in depressed patients with dementia: a review
of
clinical experience." Convulsive Ther. 5, 1-74 (1989)).
SSRIs are often chosen as the initial treatment because of their better side
effect
profiles. Once-a-day dosing is appropriate. Fluoxetine,. Paroxetine,.
Sertraline,
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NBI-154CPPC bupropion and venlagaxin are examples of SSRIs treatment. Among
the tricyclic and
heterocyclic agents, theoretical reasoning and clinical experience suggest
avoiding
agents with prominent anticholinergic activity (e.g., amitriptyline,
imipramine). Among
the remaining agents, sample dosing strategies are given here for
nortriptyline
Among the tricyclic and heterocyclic agents, theoretical reasoning and
clinical
experience suggest avoiding agents with prominent anticholinergic activity
(e.g.,
amitriptyline, imipramine). Among the remaining agents, sample dosing
strategies are
given here for nortriptyline, desipramine, and trazodone.
Depression is common in patients with dementia. Patients with depression
should be carefully evaluated for suicide potential. Depressed mood may
respond to
improvements in the living situation or stimulation-oriented treatments, but
patients with
severe or persistent depressed mood with or without a full complement of
neurovegetative signs should be treated with antidepressant medications.
Although
formal evaluation of the efficacy of antidepressants for demented patients is
limited,
is there is considerable clinical evidence supporting their use. The choice
among agents is
based on the side effect profile and the characteristics of a given patient.
MAOIs are also
considered for individuals unresponsive to or unable to take other agents
(tranylcypromine and phenelzine are examples).
Treatment of sleep disturbance in dementia is aimed at decreasing the
frequency
and severity of insomnia, interrupted sleep, and nocturnal confusion in
patients with
dementia. The goals are to increase patient comfort and to decrease the
disruption to
families and caregivers. Sleep disorder is common in dementia (Satlin A: Sleep
disorders in dementia. Psychaatr. Ann. 24, 186-90 (1994); C.C.Hoch, et al.,
"Sleep
patterns in Alzheimer, depressed, and healthy elderly." West J. Nurs. Res. 10,
239-56
(1988)) and is not always so disruptive that the risk of medication side
effects is
outweighed by the need for a pharmacologic trial. When sleep disturbances
occur
without other psychiatric symptoms beyond the dementia itself, some clinicians
prescribe trazodone or zolpidem. Benzodiazepines (e.g., lorazepam or oxazepam)
and
chloral hydrate may in some cases be used. Triazolam in particular is not
recommended
for individuals with dementia because of its association with amnesia.
Diphenhydramine, which is found in most over-the-counter sleep preparations,
is used
by some clinicians, but its anticholinergic properties make it suboptimal for
the
treatment of demented patients.
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NBI-154CPPC
Nutritional supplements: Vitamin B12, homoc sty eine
In another aspect of the invention, a first agent is co-administered with one
or
more nutritional supplements to improve the safety or efficacy of treatment.
For
example, treatment can be optimized by provision of nutrients depleted in the
subject.
Accordingly, suitable second agents include the following vitamins, some of
which have an antioxidant and/or anti-inflammatory effect: retinol, vitamin A
aldehyde
(retinal), vitamin A acid (retinoic acid), retinyl acetate, vitamin B1
(thiamine HCI),
thiamine propyl disulfide, thiamine disulfide, thiamine disulfide O,O-
diisobutyrate,
thiamine disulfide hydrochloride, thiamine disulfide phosphate, thiamine
mononitrate,
thiamine 1,5-sait, thiamine phosphoric acid ester chloride, thiamine
phosphoric acid
ester phosphate salt, thiamine triphosphoric acid ester, vitamin Bz
(riboflavin), riboflavin
tetrabutyrate, riboflavine 5'-phosphate ester monosodium salt, vitamin BS
(pantothenic
acid), pantothenic acid sodium salt, pantothenic acid calcium salt, vitamin B6
(pyridoxine HCI), pyridoxal, pyridoxal HCI, pyridoxal 5-phosphate, pyridoxal 5-
phosphate calcium salt, pyridoxamine, pyridoxamine dihydrochloride,
pyridoxamine
phosphate, vitamin B12 (cyanocobalamin), methyl vitamin B12 (co-
methylcobalamin),
vitamin D2, vitamin D3, vitamin D4, vitamin H (biotin), vitamin K1
(phytonadione),
diacetyl dihydro vitamin K1,
vitamin K1 oxide, vitamin(s) K2 (menaquinones), vitamin K2(35), vitamin K2(35)
dihydrodiacetate, vitamin K2(30), vitamin K2(30) dihydrodiacetate, vitamin K5,
vitamin K5
hydrochloride, N-acetyl vitamin K5, vitamin K6, vitamin K6 dihydrochloride,
vitamin K7,
vitamin K7 hydrochloride, vitamin K-S(II), vitamin L1, Vitamin L2, vitamin U,
methylmethioninesulfonium bromide (bromide analog of vitamin U), a-carotene,
(3-
carotene, y-carotene, w-carotene, yV-carotene (lycopene), phytofluene, L-
carnitine
(vitamin BT), acetyl-L-camitine, folic acid (vitamin Bc), folinic acid,
folinic acid
calcium salt pentahydrate, niacinamide, nicotinic acid (vitamin B3), nicotinic
acid
sodium salt sesquihydrate, nicotinic acid monoethanolamine salt, and
combinations
thereof.
Pyrrolidone or pyrrolidine derivatives for improving memory have been
suggested in EP 239500, EP 165919, BE 892942, U.S. Pat. No. 5,102,882, EP
296978,
EP 296979. Pyridine derivatives for the treatment of impairment of short-term
memory
are disclosed in U.S. Pat. No. 4,448,779. Choline derivatives for treating
mental decline
in the elderly are suggested in EP 201623. Indole or indolin derivatives for
the
improvement of processes involved in learning are disclosed in EP 241006, JP
6107544,
U.S. Pat. No. 5,494,928, WO 97/47598, and U.S. Pat. No. 4,778,812. Pilocardin
derivatives for improving memory functions are disclosed in U.S. Pat. No.
4,977,176.
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NB I-154CPPC
Glycine-containing compositions for enhancing cognitive functions are
disclosed in U.S.
Pat. No. 5,731,349. Peptide derivatives for treating mental decline and
improving mental
capacity are disclosed in U.S. Pat. No. 5,439,930, RU 2099078, and WO 95/153
10.
Xanthine derivatives for the treatment of age-related memory impairment are
disclosed
in WO 94/19349.
Compounds enhancing the stimulus-induced release of neurotransmitters,
especially acetylcholine, may also be used to treat memory impairment.
Examples are 2-
benzyl-2-propyl 2-amino-2-R-acetate derivatives disclosed in EP 293351,
1-(4-chlorophenyl)-2-methyl-2-propyl 2-amino-3-methyl-butanoate disclosed in
GB
2205097, polycyclic hetero-aromatic derivatives disclosed in U.S. Pat. No.
5,300,642, 5-
phenyl-4,4-dimethyl-3-oxo or hydroxy-pentylamine derivatives disclosed in EP
322391,
1-oxa-8-azaspiro(4.5)decane derivatives disclosed in EP 491562, derivatives of
azacyclic and azabicyclic hydroxylamine disclosed in WO 94/00448, halogenated
aromatic derivatives disclosed in EP 627400, derivatives of acyclic and cyclic
amides
disclosed in WO 95/29909, carbamoyloxypropylamine or carbamoyloxyethylamine
derivatives disclosed in WO 96/08468.
Compounds that modulate the function of the kainate receptor may be used to
improve memory, e.g., alkyl carboxy amino acids, such as (2S,4R)-4-methyl
glutamic
acid. WO 96/25387.
Hypothalamic hypophysiotropic hormones, such as somatostatin and growth-
hormone releasing factor, may improve learning abilities. EP 326381
Uronic acids improve cerebral efficiency in general, such as improvement of
memory. DE 2555010.
Improvement of memory occurs upon administering spiro(N'-methyl-4'-
piperidyl)-N-ethyl-succinimide, a parasympathicomimetic substance also having
cholinomimetic, analgetic and sedative activity. U.S. Pat. No. 4,481,206.
WO 98/33498 discloses the use of breflate or analogous compounds thereof for
the treatment of a mammal suffering from a cognitive dysfunction. Breflate or
analogous
compounds thereof enhance the long-term potential of nerve cells. Suitable
monoamine
3o reuptake inhibitors include NS-2330. Suitable nootropic agents include
oxiracetam
available from ISF Societa Per Azioni, pramiracetam available from Warner
Lambert
Co., idebenone available from Takeda Chemical Inds. Ltd., anapsos available
from
ASAC Pharmaceuticals International, nebracetam available from Boehringer
Ingelheim
Corp., JTP-2942 available from Japan Tobacco Inc., fasoracetam available from
Nippon
Shinyaku Co. Ltd., bacosides available from Central Drug Research Institute,
alzene
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available from Bar-IIan University, KA-672 availabie from Dr. Willmar Schwabe
GmbH & Co., alaptid available from VUFB, IQ-200, ALE-26015 available from
Allelix
Pharm-Eco LP and combinations thereof.
A useful dopamine receptor agonist is speramine. Useful AMPA receptor ligands
include CX-516, CX-691 available from Cortex Pharmaceuticals Inc. and
combinations
thereof. Suitable calcium channel blockers include tamolarizine available from
Nippon
Chemiphar Co., Ltd., nimodipine available from Bayer AG, PD-1 76078 available
from
Elan Pharmaceuticals, Inc., and combinations thereof. Suitable apoptosis
inhibitors
include acetyl-L-carnitine, CEP-1347 available from Cephalon, Inc., TCH-346
available
from Novartis AG and combinations thereof. A useful caspase inhibitor is
pralnacasan.
Suitable monoamine oxidase inhibitors include moclobemide available from Roche
Holding AG, selegiline, rasagiline available from Teva Pharmaceutical Inds.
Ltd., SL-
25.1188, Ro-41-1049 available from Roche Holding AG, and combinations thereof.
A
useful 5-HTIa receptor agonist is AP-159 available from Asahi Kasei Corp.; a
suitable
NGF stimulator is xaliprodene available from Sanofi-Synthelabo. Suitable
neuroprotective agents include citicholine, GS-1590 available from Leo
Pharmaceutical
Products Ltd. A/S, CPI-1189 available from Centaur Pharmaceuticals Inc., SR-
57667
available from Sanofi-Synthelabo and combinations thereof. Suitable H3
histamine
receptor antagonists include GT-2016 and GT-2331 (both available from
Gliatech, Inc.)
and combinations thereof.
Useful prolylendopeptidase inhibitors include ONO- 1603 available from Ono
Pharmaceutical Co. Ltd., Z-321 available from Zeria Pharmaceutical Co. Ltd.
and
combinations thereof. A useful calcium modulator includes neurocalc available
from
Apollo Biopharmaceuticals, Inc. A suitable corticortropin releasing factor
receptor
antagonist includes NBI-113 available from Neurocrine Biosciences, Inc. A
useful
GABA modulator includes NGD 97-1 available from Neurogen Corp. A suitable
sigma
receptor ligand is igmesine available from Pfizer Inc. A useful
imidazoline/alpha
adrenergic receptor antagonist is efaroxan available from Reckitt & Colman
PLC. A
suitable vasoactive intestinal peptide receptor agonist is stearyl-Nle-VIP. A
useful
benzodiazepine inverse agonist is S-8510 available from Shionogi & Co. Ltd. A
suitable
cannabinoid receptor agonist is dronabinol available from Unimed
Pharmaceuticals Inc.
Useful thyrotropin releasing hormone receptor agonists include taltireline
available from
Tanabe Seiyaku Co. Ltd. and protirelin available from Takeda Chemical Inds.,
Inc. A
suitable 5-HT3 antagonist is GYKI-46903. A useful topoisomerase II inhibitor
is
iododoxorubicin available from Pharmacia & Upjohn AB. A suitable steroid
receptor
agonist is GL-701 available from Leland Stanford Junior University. A useful
corticosteroid receptor antagonist is anticort. A suitable nitric oxide
modulator is GL-
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701. A suitable RAGE inhibitor is ALT-71 I available from Alteon Inc. RAGE is
a
multiligand receptor of the immunoglobulin superfamily that is implicated in
homeostasis and chronic disease. Bucciarelli, et al., Cell Mol Life Sci.
59(7), 1117-28
(2002).
The invention also relates to a pharmaceutical composition comprising at least
one compound selected from the group consisting of D-phosphoserine and L-
phosphoserine and a second therapeutic agent selected from the group
consisting of
antipsychotics, antidepressants, psychostimulants, and Alzheimer's disease
therapeutics.
In these pharmaceutical compositions, the second therapeutic agent is an
antipsychotic
selected from the group consisting of typical antipsychotics, atypical
antipsychotics, and
depot antipsychotics. Examples of second therapeutic agents include
Chlorpromazine,
Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine,
Thiothixene,
Haloperidol (HaldolTM, McNeil Pharmaceuticals, Spring House, Pennsylvania),
Loxapine, Molindone (MobanTM, Du Pont Multi-Source Products, Wilmington, DE),
Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate,
Fluphenazine
decanoate, Fluphenazine enanthate, Amitriptyline, Amoxapine, Bupropion,
Bupropion
SR, Clomipramine, Desipramine, Doxepin, Fluoxetine, Fluvoxamine, Imipramine,
Maprotiline, Mirtazapine, Nefazodone, Nortriptyline, Paroxetine, Phenelzine,
Protriptyline, Sertraline, Tranylcypromine, Trazodone, Trimipramine ,
Venlafaxine,
Velafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline,
Donepezil, TacrineTM, Acetoplenazine, Chlorprothixene, Droperidol, Pimozide,
Butaperazine, Carphenazine Remoxipride, Piperacetazine, Sulpiride, and
Ziprasidone:
In another alternative embodiment, the compositions used in the methods to
treat
or prevent a neuropsychiatric disorder characterized by attenuated NMDA
neurotransmission. The neuropsychiatric disorder may be Alzheimer's disease,
Down's
syndrome, depression, benign forgetfulness, cerebral amyloid angiopathy,
vascular
dementia, hemorrhagic stroke, Mild Cognitive Impairment ("MCI"), or close head
injury.
In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise one or more bile acid sequestrants
(insoluble
anion exchange resins), coadministered with or in combination with a compound
of any
Formula herein.
Bile acid sequestrants bind bile acids in the intestine, interrupting the
enterohepatic circulation of bile acids and causing an increase in the faecal
excretion of
steroids. Use of bile acid sequestrants is desirable because of their non-
systemic mode of
action. Bile acid sequestrants can lower intrahepatic cholesterol and promote
the
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synthesis of apo B/E (LDL) receptors which bind LDL from plasma to further
reduce
cholesterol levels in the blood.
Non-limiting examples of suitable bile acid sequestrants include
cholestyramine
(a styrene-divinylbenzene copolymer containing quaternary ammonium cationic
groups
capable of binding bile acids, such as QuestranTM cholestyramine which are
available
from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and
1-chloro-2,3-epoxypropane; such as ColestidTM tablets which are available from
Pharmacia), colesevelam hydrochloride (such as WelCholTM Tablets
(poly(allylamine
hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-
bromodecane and
(6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo),
water
soluble derivatives such as 3,3-ioene,lV (cycloalkyl) alkylamines and
poliglusam,
insoluble quaternized polystyrenes, saponins and mixtures thereof. Other
useful bile acid
sequestrants are disclosed in PCT Patent Applications Nos. WO 97/11345 and
WO 98/57652, and U.S. Pat. No. 3,692,895 and 5,703,188 which are incorporated
herein
i5 by reference. Suitable inorganic cholesterol sequestrants include bismuth
salicylate plus
montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
In an alternative embodiment, the compositions used in the methods of the
present invention can further comprise one or more ileal bile acid transport
("IBAT")
inhibitors (or apical sodium co-dependent bile acid transport ("ASBT")
inhibitors)
coadministered with or in combination with a compound of any Formula herein.
The
IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol
levels. Non-
Iimiting examples of suitable IBAT inhibitors include benzothiepines such as
therapeutic
compounds comprising a 2,3,4,5-tetrahydro-l-benzothie- pine 1,1-dioxide
structure such
as are disclosed in PCT Patent Application WO 00/38727 which is incorporated
herein
by reference.
In another alternative embodiment, the compositions used in the methods of the
present invention can further comprise nicotinic acid (niacin) or derivatives
thereof
coadministered with or in combination with a compound of any Formula herein.
As used herein, "nicotinic acid derivative" means a compound comprising a
pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure,
including acid
forms, salts, esters, zwitterions and tautomers, where available. Examples of
nicotinic
acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl
pyrazine-2-
carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit hepatic
production of
VLDL and its metabolite LDL and increases HDL and apo A-1 levels. An example
of a
suitable nicotinic acid product is NiaspanTM (niacin extended-release tablets)
which are
available from Kos.
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The compositions, therapeutic combinations or methods of the present invention
can further comprise one or more obesity control medications. Useful obesity
control
medications include, but are not limited to, drugs that reduce energy intake
or suppress
appetite, drugs that increase energy expenditure and nutrient-partitioning
agents.
Suitable obesity control medications include, but are not limited to,
noradrenergic agents
(such as diethylpropion, mazindol, phenylpropanolamine, phentermine,
phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and
tartrate);
serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine,
fluoxetine,
fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine,
theophylline, and selective P3-adrenergic agonists); an alpha-blocking agent;
a kainite or
AMPA receptor antagonist; a leptin-lipolysis stimulated receptor; a
phosphodiesterase
enzyme inhibitor; a compound having nucleotide sequences of the mahogany gene;
a
fibroblast growth factor- 10 polypeptide; a monoamine oxidase inhibitor (such
as
befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol,
toloxatone,
pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and
caroxazone); a compound for increasing lipid metabolism (such as evodiamine
compounds); and a lipase inhibitor (such as orlistat). Generally, a total
dosage of the
above-described obesity control medications can range from 1 to 3,000 mg/day,
desirably from about 1 to 1,000 mg/day and more desirably from about 1 to 200
.mg/day
in single or 2-4 divided doses.
The compositions, therapeutic combinations or methods of the present invention
can further comprise one or more blood modifiers. Useful blood modifiers
include but
are not limited to anti-coagulants (argatroban, bivalirudin, dalteparin
sodium, desirudin,
dicumarol, lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin
sodium,
warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin,
cilostazol,
dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran
sulfate,
enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium, lamifiban,
lotrafiban
hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban,
tinzaparin
sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogen receptor
antagonists
(roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride,
tirofiban,
xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors
(cilostazol,
clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine
hydrochloride,
aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate, droxicam,
diclofenac,
sulfinpyrazone, piroxicam, dipyridamole); platelet aggregation inhibitors
(acadesine,
beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine,
lotrafiban
hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban,
tirofiban,
xemilofiban); hemorrheologic agents (pentoxifylline); lipoprotein associated
coagulation
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NBI-154CPPC
inhibitor; Factor VIIa inhibitors (4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-
4-
thiones, quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4-ones,
imidazolyl-
boronic acid-derived peptide analogues TFPI-derived peptides, naphthalene-2-
sulfonic
acid { 1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrol- idin-3-(S)-yl} amide
trifluoroacetate, dibenzofuran-2-sulfonic acid { 1-[3-(aminomethyl)-berizyl]-5-
oxo-
pyrrolidin-3-yl}-amide, tolulene-4-sulfonic acid { 1-[3-(aminoiminomethyl)-
benzyl]-2-
oxo-pyrrolidi- n-3-(S)-yl}-amide trifluoroacetate, 3,4-dihydro-lH-isoquinoline-
2-
sulfonic acid {1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl}-amide
trifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines,
disubstituted
triazolines, substituted n-[(aminoiminomethyl)phenyl] propylamides,
substituted
N-[(aminomethyl)phenyl] propylamides, tissue factor pathway inhibitor (TFPI),
low
molecular weight heparins, heparinoids, benzimidazolines, benzoxazolinones,
benzopiperazinones, indanones, dibasic (amidinoaryl) propanoic acid
derivatives,
amidinophenyl-pyrrolidines, amidinophenyl-pyrrolines, amidinophenyl-
isoxazolidines,
1 s amidinoindoles, amidinoazoles, bis-arlysulfonylaminobenzamide derivatives,
peptidic
Factor Xa inhibitors).
The compositions, therapeutic combinations or methods of the present invention
can further comprise one or more cardiovascular agents. Useful cardiovascular
agents
include but are not limited to calcium channel blockers (clentiazem maleate,
amlodipine
2 o besylate, isradipine (DynaCircTM, Reliant Pharmaceuticals, Liberty Corner,
NJ),
nimodipine, felodipine (PlendilTM, Merck & Co., Inc., Rahway, New Jersey),
nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride
((CardizemTM
or Cardizem SRTM, Aventis, Strasbourg, France), belfosdil, verapamil
hydrochloride
(CalanTM or Calan SRTM, G.D. Searle LLC, Skokie, IL), fostedil); adrenergic
blockers
25 (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin
hydrochloride,
acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol,
bunolol
hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol
hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride,
diacetolol
hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol
hydrochloride,
30 flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride,
levobunolol
hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate,
nadolol,
pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride
(InderalTM,
Wyeth, Madison, New Jersey), sotalol hydrochloride, timolol, timolol maleate,
tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate,
nebivolol);
35 adrenergic stimulants; angiotensin converting enzyme (ACE) inhibitors
(benazepril
hydrochloride, benazeprilat, captopril (CapotenTM, Bristol-Myers Squibb Co.,
New
York, New York), delapril hydrochloride, fosinopril sodium, libenzapril,
moexipril
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hydrochloride, pentopril, perindopril, quinapril hydrochloride, quinaprilat,
ramipril
(AltaceTM, Hoechst Marion Roussel, Inc., now Aventis, Strasbourg, France),
spirapril
hydrochloride, spiraprilat, teprotide, enalapril maleate (VasotecTM, Merck &
Co., Inc.,
Rahway, New Jersey), lisinopril (ZestrilTM, Stuart, AstraZenica, Wilmington,
Delaware),
zofenopril calcium, perindopril erbumine); antihypertensive agents
(althiazide,
benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine
hydrochloride
(CatapresTM, Boehringer Ingelheim, Ridgefield, Connecticut), cyclothiazide,
delapril
hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,
guanfacine hydrochloride (TenexTM, Robins, ESP Pharmaceuticals, Flanders, NJ),
1 o methyidopa, metoprolol succinate, moexipril hydrochloride, monatepil
maleate,
pelanserin hydrochloride, phenoxybenzamine hydrochloride, prazosin
hydrochloride,
primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin
hydrochloride,
candesartan, candesartan cilexetil, telmisartan, amiodipine besylate,
amlodipine maleate
(NorvascTM, Pfizer, New York New York), bevantolol hydrochloride); angiotensin
II
receptor antagonists (candesartan, irbesartan, losartan potassium, candesartan
cilexetil,
telmisartan); anti-anginal agents (amlodipine besylate, amlodipine maleate,
betaxolol
hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride,
carvedilol,
cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate,
primidolol,
ranolazine hydrochoride, tosifen, verapamil hydrochloride); coronary
vasodilators
(fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate,
diltiazem
hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate,
isosorbide dinitrate,
isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine,
molsidomine,
nicorandil, nifedipine (ProcardiaTM, Pfizer, New York, New York), nisoldipine,
nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate,
prenylamine,
- 25 propatyl nitrate, terodiline hydrochloride, tolamolol, verapamil);
diuretics (the
combination product of hydrochlorothiazide and spironolactone and the
combination
product of hydrochlorothiazide and triamterene).
Blood-Brain Barrier
Nitric oxide is a vasodilator of the peripheral vasculature in normal tissue
of the
body. Increasing generation of nitric oxide by nitric oxide synthase causes
vasodilation
without loss of blood pressure. The blood-pressure-independent increase in
blood flow
through brain tissue increases cerebral bioavailability of blood-born
compositions. This
increase in nitric oxide may be stimulated by administering L-arginine. As
nitric oxide
is increased, cerebral blood flow is consequently increased, and drugs in the
blood
stream are carried along with the increased flow into brain tissue. Therefore,
L-arginine
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NBI-154CPPC
may be used in the pharmaceutical compositions of the invention to enhance
delivery of
agents to brain tissue after introducing a pharmaceutical composition into the
blood
stream of the subject substantially contemporaneously with a blood flow
enhancing
amount of L-arginine. WO 00/56328
Agents of the invention that exert their physiological effect in vivo in the
brain
may be more useful if they gain access to target cells in the brain. Non-
limiting
examples of brain cells are neurons, glial cells (astrocytes,
oligodendrocytes, microglia),
cerebrovascular cells (rnuscle cells, endothelial cells), and cells that
comprise the
meninges. The blood brain barrier ("BBB") typically restricts access to brain
cells by
acting as a physical and functional blockade that separates the brain
parenchyma from
the systemic circulation (see, e.g., Pardridge, et al., J. Neurovirol. 5(6),
556-69 (1999);
Rubin, et al., Rev, Neurosci. 22, 11-28 (1999)). Circulating molecules are
normaIly able
to gain access to brain cells via one of two processes: lipid-mediated
transport through
the BBB by free diffusion, or active (or catalyzed) transport.
The agents of the invention may be formulated to improve distribution in vivo,
for example as powdered or liquid tablet or solution for oral administration
or as a nasal
spray, nose drops, a gel or ointment, through a tube or catheter, by syringe,
by packtail,
by pledget, or by submucosal infusion. For example, the blood-brain barrier
(BBB)
excludes many highly hydrophilic agents. To ensure that the more hydrophilic
therapeutic agents of the invention cross the BBB, they may be formulated, for
example,
in liposomes. For methods of manufacturing liposomes, see, e.g., U.S. Pat.
Nos.
4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more
moieties which are selectively transported into specific cells or organs
("targeting
moieties" or "targeting groups" or "transporting vectors"), thus providing
targeted drug
delivery (see, e.g., V.V. Ranade J Clin. Pharmacol. 29, 685 (1989)). Likewise,
the
agents may be linked to targeting groups that facilitate penetration of the
blood brain
barrier. In one embodiment, the method of the present invention employs a
naturally
occurring polyamine linked to an agent that is a small molecule and _is useful
for
inhibiting A(3 deposition.
To facilitate transport of agents of the invention across the BBB, they may be
coupled to a BBB transport vector (for review of BBB transport vectors and
mechanisms, see, Bickel, et al., Adv. Drug Delivery Reviews 46, 247-79
(2001)).
Exemplary transport vectors include cationized albumin or the OX26 monoclonal
antibody to the transferrin receptor; these proteins undergo absorptive-
mediated and
receptor-mediated transcytosis through the BBB, respectively. Natural cell
metabolites
that may be used as targeting groups, include, inter alia, putrescine,
spermidine,
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NBI-I54CPPC
spermine, or DHA. Other exemplary targeting moieties include folate or biotin
(see,
e.g., U.S. Pat. No. 5,416,016); mannosides (Umezawa, et al., Biochem. Biophys.
Res.
Commun. 153, 1038 (1988)); antibodies (P.G. Bloeman, et al., FEBSLett. 357,
140
(1995); M. Owais, et al., Antimicrob. Agents Chemother. 39, 180 (1995));
surfactant
protein A receptor (Briscoe, et al., Am. J. Physiol. 1233, 134 (1995)); gp 120
(Schreier,
et al., J. Biol. Chem. 269, 9090 (1994)); see also, K. Keinanen and M.L.
Laukkanen,
FEBS Lett. 346, 123 (1994); J.J. Killion and I.J. Fidler, Immunomethods 4, 273
(1994).
Examples of other BBB transport vectors that target receptor-mediated
transport
systems into the brain include factors such as insulin, insulin-like growth
factors
("IGF-I," and "IGF-II"), angiotensin II, atrial and brain natriuretic peptide
("ANP," and
"BNP"), interleukin I("IL-1 ") and transferrin. Monoclonal antibodies to the
receptors
that bind these factors may also be used as BBB transport vectors. BBB
transport
vectors targeting mechanisms for absorptive-mediated transcytosis include
cationic
moieties such as cationized LDL, albumin or horseradish peroxidase coupled
with
polylysine, cationized albumin or cationized immunoglobulins. Small basic
oligopeptides such as the dynorphin analogue E-2078 and the ACTH analogue
ebiratide
may also cross the brain via absorptive-mediated transcytosis and are
potential transport
vectors.
Other BBB transport vectors target systems for transporting nutrients into the
brain. Examples of such BBB transport vectors include hexose moieties, e.g.,
glucose
and monocarboxylic acids, e.g., lactic acid and neutral amino acids, e.g.,
phenylalanine
and amines, e.g., choline and basic amino acids, e.g., arginine, nucleosides,
e.g.,
adenosine and purine bases, e.g., adenine, and thyroid hormone, e.g.,
triiodothyridine.
Antibodies to the extracellular domain of nutrient transporters may also be
used as
transport vectors. Other possible vectors include angiotensin II and ANP,
which may be
involved in regulating BBB permeability.
In some cases, the bond linking the therapeutic agent to the transport vector
may
be cleaved following transport into the brain in order to liberate the
biologically active
agent. Exemplary linkers include disulfide bonds, ester-based linkages,
thioether
linkages, amide bonds, acid-labile linkages, and Schiff base linkages.
Avidin/biotin
linkers, in which avidin is covalently coupled to the BBB drug transport
vector, may
also be used. Avidin itself may be a drug transport vector.
Transcytosis, including receptor-mediated transport of compositions across the
blood brain barrier, may also be suitable for the agents of the invention.
Transferrin
receptor-mediated delivery is disclosed in U.S. Pat. Nos. 5,672,683;
5,383,988;
5,527,527; 5,977,307; and 6,015,555. Transferrin-mediated transport is also
known.
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P.M. Friden, et al., Pharmacol. Exp. Ther. 278, 1491-98 (1996); H.J. Lee, J.
Pharmacol.
Exp. Ther. 292, 1048-52 (2000). EGF receptor-mediated delivery is disclosed in
Y. Deguchi, et al., Bioconjug. Chem. 10, 32-37 (1999), and transcytosis is
described in
A. Cerletti, et al., J. Drug Target. 8, 435-46 (2000). Insulin fragments have
also been
used as carriers for delivery across the blood brain barrier. M. Fukuta, et
al., Pharm.
Res. 11. 1681-88 (1994). Delivery of agents via a conjugate of neutral avidin
and
cationized human albumin has also been described. Y.S. Kang, et al., Pharm.
Res. 1,
1257-64 (1994).
Other modifications in order to enhance penetration of the agents of the
invention across the blood brain barrier may be accomplished using methods and
derivatives known in the art. For example, U.S. Pat. No. 6,024,977 discloses
covalent
polar lipid conjugates for targeting to brain and central nervous system. U.S.
Pat. No.
5,017,566 discloses cyclodextrin derivatives comprising inclusion complexes of
lipoidal
forms of dihydropyridine redox targeting moieties. U.S. Pat. No. 5,023,252
discloses
the use of pharmaceutical compositions comprising a neurologically active drug
and a
compound for facilitating transport of the drug across the blood-brain barrier
including a
macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioester,
dithioester,
thioamide, ketone or lactone. U.S. Pat. No. 5,024,998 discloses parenteral
solutions of
aqueous-insoluble drugs with cyclodextrin derivatives. U.S. Pat. No. 5,039,794
discloses the use of a metastatic tumor-derived egress factor for facilitating
the transport
of compounds across the blood-brain barrier. U.S. Pat. No. 5,112,863 discloses
the use
of 1V-acyi amino acid derivatives as antipsychotic drugs for delivery across
the blood-
brain barrier. U.S. Pat. No. 5,124,146 discloses a method for delivery of
therapeutic
agents across the blood-brain barrier at sites of increase permeability
associated with
brain lesions. U.S. Pat. No. 5,153,179 discloses acylated glycerol and
derivatives for
use in a medicament for improved penetration of cell membranes. U.S. Pat. No.
5,177,064 discloses the use of lipoidal phosphonate derivatives of nucleoside
antiviral
agents for delivery across the blood-brain barrier. U.S. Pat. No. 5,254,342
discloses
receptor-mediated transcytosis of the blood-brain barrier using the
transferrin receptor in
corimbination with pharmaceutical compounds that enhance or accelerate this
process.
U.S. Pat. No. 5,258,402 discloses treatment of epilepsy with imidate
derivatives of
anticonvulsive sulfamate. U.S. Pat. No. 5,270,312 discloses substituted
piperazines as
central nervous system agents. U.S. Pat. No. 5,284,876 discloses fatty acid
conjugates
of dopamine drugs. U.S. Pat. No. 5,389,623 discloses the use of lipid
dihydropyridine
derivatives of anti-inflammatory steroids or steroid sex hormones for delivery
across the
blood-brain barrier. U.S. Pat. No. 5,405,834 discloses prodrug derivatives of
thyrotropin
releasing hormone. U.S. Pat. No. 5,413,996 discloses acyloxyalkyl phosphonate
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conjugates of neurologically-active drugs for anionic sequestration of such
drugs in
brain tissue. U.S. Pat. No. 5,434,137 discloses methods for the selective
opening of
abnormal brain tissue capillaries using bradykinin infused into the carotid
artery. U.S.
Pat. No. 5,442,043 discloses a peptide conjugate between a peptide having a
biological
activity and incapable of crossing the blood-brain barrier and a peptide which
exhibits
no biological activity and is capable of passing the blood-brain barrier by
receptor-
mediated endocytosis. U.S. Pat. No. 5,466,683 discloses water soluble
analogues of an
anticonvulsant for the treatment of epilepsy. U.S. Pat. No. 5,525,727
discloses
compositions for differential uptake and retention in brain tissue comprising
a conjugate
of a narcotic analgesic and agonists and antagonists thereof with a lipid form
of
dihydropyridine that forms a redox salt upon uptake across the blood-brain
barrier that
prevents partitioning back to the systemic circulation.
Still further examples of modifications that enhance penetration of the blood
brain barrier are described in International (PCT) Application Publication
Number
WO 85/02342, which discloses a drug composition comprising a glycerolipid or
derivative thereof. PCT Publication Number WO 089/11299 discloses a chemical
conjugate of an antibody with an enzyme which is delivered specifically to a
brain lesion
site for activating a separately-administered neurologically-active prodrug.
PCT
Publication Number WO 91/04014 discloses methods for delivering therapeutic
and
diagnostic agents across the blood-brain barrier by encapsulating the drugs in
liposomes
targeted to brain tissue using transport-specific receptor ligands or
antibodies. PCT
Publication Number WO 91/04745 discloses transport across the blood-brain
barrier
using cell adhesion molecules and fragments thereof to increase the
permeability of tight
junctions in vascular endothelium. PCT Publication Number WO 91/14438
discloses
the use of a modified, chimeric monoclonal antibody for facilitating transport
of
substances across the blood-brain barrier. PCT Publication Number WO 94/01131
discloses lipidized proteins, including antibodies. PCT Publication Number
WO 94/03424 discloses the use of amino acid derivatives as drug conjugates for
facilitating transport across the blood-brain barrier. PCT Publication Number
WO
94/06450 discloses conjugates of neurologically-active drugs with a
dihydropyridine-
type redox targeting moiety and comprising an amino acid linkage and an
aliphatic
residue. PCT Publication Number WO 94/02178 discloses antibody-targeted
liposomes
for delivery across the blood-brain barrier. PCT Publication Number WO
95/07092
discloses the use of drug-growth factor conjugates for delivering drugs across
the blood-
brain barrier. PCT Publication Number WO 96/00537 discloses polymeric
microspheres
as injectable drug-delivery vehicles for delivering bioactive agents to sites
within the
central nervous system. PCT Publication Number WO 96/04001 discloses omega-
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3-fatty acid conjugates of neurologically-active drugs for brain tissue
delivery. PCT
WO 96/22303 discloses fatty acid and glycerolipid conjugates of neurologically-
active
drugs for brain tissue delivery.
In general, it is well within the ordinary skill in the art to prepare an
ester, amide
or hydrazide derivative of an agent of the invention, for example, from the
corresponding carboxylic acid and a suitable reagent. For instance, a
carboxylic acid-
containing compound, or a reactive equivalent thereof, may be reacted with a
hydroxyl-
containing compound, or a reactive equivalent thereof, so as to provide the
corresponding ester. See, e.g., "Comprehensive Organic Transformations," 2 d
Ed., by
lo R.C. Larock, VCH Publishers John Wiley & Sons, Ltd. (199989); "March's
Advanced
Organic Chemistry," 5 th Ed., by M.B. Smith and J. March, John Wiley & Sons,
Ltd.
(2000).
The compound may also act from the periphery, causing a change in the
equilibrium of the amyloid protein concentration in the two compartments i.e.
(systemic
vs central). In this case a compound may not be required to penetrate the
brain to induce
or decrease the concentration of A(3 in the brain (a "sink" effect)
Prodruy-s
The present invention is also related to prodrugs of the agents of the
Formulae
disclosed herein. Prodrugs are agents which are converted in vivo to active
forms (see,
e.g., R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug
Action,"
Academic Press, Chp. 8). Prodrugs can be used to alter the biodistribution
(e.g., to allow
agents which would not typically enter the reactive site of the protease) or
the
pharmacokinetics for a particular agent. For example, a carboxylic acid group,
can be
esterified, e.g., with a methyl group or an ethyl group to yield an ester.
When the ester is
administered to a subject, the ester is cleaved, enzymatically or non-
enzymatically,
reductively, oxidatively, or hydrolytically, to reveal the anionic group. An
anionic
group can be esterified with moieties (e.g., acyloxymethyl esters) which are
cleaved to
reveal an intermediate agent which subsequently decomposes to yield the active
agent.
The prodrug moieties may be metabolized in vivo by esterases or by other
mechanisms
to carboxylic acids.
Examples of prodrugs and their uses are wel l known in the art (see, e.g.,
Berge,
et al., "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977)). The prodrugs
can be
prepared in situ during the final isolation and purification of the agents, or
by separately
reacting the purified agent in its free acid form with a suitable derivatizing
agent.
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Carboxylic acids can be converted into esters via treatment with an alcohol in
the
presence of a catalyst.
Examples of cleavable carboxylic acid prodrug moieties include substituted and
unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., ethyl
esters,
propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexyl esters,
cyclohexyl
esters), lower alkenyl esters, dilower alkyl-amino lower-alkyl esters (e.g.,
dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl
esters
(e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl
esters (e.g.,
benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents)
aryl and
aryl-lower alkyl esters, amides, lower-alkyl amides, dilower alkyl amides, and
hydroxy
amides.
Pharmaceutical Preparations
In another embodiment, the present invention relates.to pharmaceutical
compositions comprising agents according to any of the Formulae herein for the
treatment of an amyloid-(3 related disease, as well as methods of
manufacturing such
pharmaceutical compositions.
In general, the agents of the present invention may be prepared by the methods
illustrated in the general reaction schemes as, for example, in the patents
and patent
applications refered to herein, or by modifications thereof, using readily
available
starting materials, reagents and conventional synthesis procedures. In these
reactions, it
is also possible to make use of variants which are in themselves known, but
are not
mentioned here. Functional and structural equivalents of the agents described
herein and
which have the same general properties, wherein one or more simple variations
of
substituents are made which do not adversely affect the essential nature or
the utility of
the agent.
The agents of the invention may be supplied in a solution with an appropriate
solvent or in a solvent-free form (e.g., lyophilized). In another aspect of
the invention,
the agents and buffers necessary for carrying out the methods of the invention
may be
packaged as a kit. The kit may be commercially used according to the methods
described herein and may include instructions for use in a method of the
invention.
Additional kit components may include acids, bases, buffering agents,
inorganic salts,
solvents, antioxidants, preservatives, or metal chelators. The additional kit
components
are present as pure compositions, or as aqueous or organic solutions that
incorporate one
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or more additional kit components. Any or all of the kit components optionally
further
comprise buffers.
The therapeutic agent may also be administered parenterally,
intraperitoneally,
intraspinally, or intracerebrally. Dispersions can be prepared in glycerol,
liquid
polyethylene glycols, and mixtures thereof and in oils. Under ordinary
conditions of
storage and use, these preparations may contain a preservative to prevent the
growth of
microorganisms.
To administer the therapeutic agent by other than parenteral administration,
it
may be necessary to coat the agent with, or co-administer the agent with, a
material to
prevent its inactivation. For example, the therapeutic agent may be
administered to a
subject in an appropriate carrier, for example, liposomes, or a diluent.
Pharmaceutically
acceptable diluents include saline and aqueous buffer solutions. Liposomes
include
water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan
et al., J.
Neuroimmunol. 7, 27 (1984)).
Pharmaceutical compositions suitable for injectable use include sterile
aqueous
solutions (where water soluble) or dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions or dispersion. In
all cases, the
composition must be sterile and must be fluid to the extent that easy
syringability exists.
It must be stable under the conditions of manufacture and storage and must be
preserved
against the contaminating action of microorganisms such as bacteria and fungi.
Suitable pharmaceutically acceptable carriers include, without limitation, any
non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal,
mucosal,
transdermal, intravascular (IV), intraarterial (IA), intramuscular (IM), and
subcutaneous
(SC) administration routes, such as phosphate buffer saline (PBS).
The vehicle can be a solvent or dispersion medium containing, for example,
water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid
polyethylene
glycol, and the like), suitable mixtures thereof, and vegetable oils. The
proper fluidity
can be maintained, for example, by the use of a coating such as lecithin, by
the
maintenance of the required particle size in the case of dispersion and by the
use of
3.0 surfactants. Prevention of the action of microorganisms can be achieved by
various
antibacterial and antifungal agents, for example, parabens, chlorobutanol,
phenol,
ascorbic acid, thimerosal, and the like. In many cases, isotonic agents are
included, for
example, sugars, sodium chloride, or polyalcohols such as mannitol and
sorbitol, in the
composition. Prolonged absorption of the injectable compositions can be
brought about
by including in the composition an agent which delays absorption, for example,
aluminum monostearate or gelatin.
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Sterile injectable solutions can be prepared by incorporating the therapeutic
agent in the required amount in an appropriate solvent with one or a
combination of
ingredients enumerated above, as required, followed by filtered sterilization.
Generally,
dispersions are prepared by incorporating the therapeutic agent into a sterile
vehicle
which contains a basic dispersion medium and the required other ingredients
from those
enumerated above. In the case of sterile powders for the preparation of
sterile injectable
solutions, the methods of preparation are vacuum drying and freeze-drying
which yields
a powder of the active ingredient (i.e., the therapeutic agent) plus any
additional desired
ingredient from a previously sterile-filtered solution thereof.
The therapeutic agent can be orally administered, for example, with an inert
diluent or an assimilable edible carrier. The therapeutic agent and other
ingredients may
also be enclosed in a hard or soft shell gelatin capsule, compressed into
tablets, or
incorporated directly into the subject's diet. For oral therapeutic
administration, the
therapeutic agent may be incorporated with excipients and used in the form of
ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups,
wafers, and the
like. The percentage of the therapeutic agent in the compositions and
preparations may,
of course, be varied. The amount of the therapeutic agent in such
therapeutically useful
compositions is such that a suitable dosage will be obtained.
It is especially advantageous to formulate parenteral compositions in dosage
unit
form for ease of administration and uniformity of dosage. Dosage unit form as
used
herein refers to physically discrete units suited as unitary'dosages for the
subjects to be
treated; each unit containing a predetermined quantity of therapeutic agent
calculated to
produce the desired therapeutic effect in association with the required
pharmaceutical
vehicle. The specification for the dosage unit forms of the invention are
dictated by and
directly dependent on (a) the unique characteristics of the therapeutic agent
and the
particular therapeutic effect to be achieved, and (b) the limitations inherent
in the art of
compounding such a therapeutic agent for the treatment of amyloid deposition
in
subjects.
The present invention therefore includes pharmaceutical formulations
comprising
the agents of the Formulae described herein, including pharmaceutically
acceptable salts
thereof, in pharmaceutically acceptable carriers for aerosol, oral and
parenteral
administration. Also, the present invention includes such agents, or salts
thereof, which
have been lyophilized and which may be reconstituted to form pharmaceutically
acceptable formulations for administration, as by intravenous, intramuscular,
or
subcutaneous injection. Administration may also be intradermal or transdermal.
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In accordance with the present invention, an agent of the Formulae described
herein, and pharmaceutically acceptable salts thereof, may be administered
orally or
through inhalation as a solid, or may be administered intramuscularly or
intravenously as
a solution, suspension or emulsion. Alternatively, the agents or salts may
also be
administered by inhalation, intravenously or intramuscularly as a liposomal
suspension.
Pharmaceutical formulations are also provided which are suitable for
administration as an aerosol, by inhalation. These formulations comprise a
solution or
suspension of the desired agent of any Formula herein, or a salt thereof, or a
plurality of
solid particles of the agent or salt. The desired formulation may be placed in
a small
chamber and nebulized. Nebulization may be accomplished by compressed air or
by
ultrasonic energy to form a plurality of liquid droplets or solid particles
comprising the
agents or salts. The liquid droplets or solid particles should have a particle
size in the
range of about 0.5 to about 5 microns. The solid particles can be obtained by
processing
the solid agent of any Formula described herein, or a salt thereof, in any
appropriate
manner known in the art, such as by micronization. The size of the solid
particles or
droplets will be, for example, from about 1 to about 2 microns. In this
respect,
commercial nebulizers are available to achieve this purpose.
A pharmaceutical formulation suitable for administration as an aerosol may be
in
the form of a liquid, the formulation will comprise a water-soluble agent of
any Formula
described herein, or a salt thereof, in a carrier which comprises water. A
surfactant may
be present which lowers the surface tension of the formulation sufficiently to
result in
the formation of droplets within the desired size range when subjected to
nebulization.
Peroral compositions also include liquid solutions, emulsions, suspensions,
and
the like. The pharmaceutically acceptable carriers suitable for preparation of
such
2.5 compositions are well known in the art. Typical components of carriers for
syrups,
elixirs, emulsions and suspensions include ethanol, glycerol, propylene
glycol,
polyethylene glycol, liquid sucrose, sorbitol. and water. For a suspension,
typical
suspending agents include methyl cellulose, sodium carboxymethyl cellulose,
tragacanth, and sodium alginate; typical wetting agents include lecithin and
polysorbate
80; and typical preservatives include methyl paraben and sodium benzoate.
Peroral
liquid compositions may also contain one or more components such as
sweeteners,
flavoring agents and colorants disclosed above.
Pharmaceutical compositions may also be coated by conventional methods,
typically with pH or time-dependent coatings, such that the subject agent is
released in
the gastrointestinal tract in the vicinity of the desired topical application,
or at various
times to extend the desired action. Such dosage forms typically include, but
are not
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limited to, one or more of cellulose acetate phthalate, polyvinylacetate
phthalate,
hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, and shellac.
Other compositions useful for attaining systemic delivery of the subject
agents
include sublingual, buccal and nasal dosage forms. Such compositions typically
comprise one or more of soluble filler substances such as sucrose, sorbitol
and mannitol;
and binders such as acacia, microcrystalline cellulose, carboxymethyl
cellulose and
hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants,
antioxidants and flavoring agents disclosed above may also be included.
The compositions of this invention can also be administered topically to a
subject, e.g., by the direct laying on or spreading of the composition on the
epidermal or
epithelial tissue of the subject, or transdermally via a "patch". Such
compositions
include, for example, lotions, creams, solutions, gels and solids. These
topical
compositions may comprise an effective amount, usually at least about 0.1 %,
or evan
from about 1% to about 5%, of an agent of the invention. Suitable carriers for
topical
administration typically remain in place on the skin as a continuous film, and
resist
being removed by perspiration or immersion in water. Generally, the carrier is
organic
in nature and capable of having dispersed or dissolved therein the therapeutic
agent. The
carrier may include pharmaceutically acceptable emolients, emulsifiers,
thickening
agents, solvents and the like.
Active agents are administered at a therapeutically effective dosage
sufficient to
inhibit amyloid deposition in a subject. A "therapeutically effective" dosage
inhibits
amyloid deposition by, for example, at least about 20%, or by at least about
40%, or
even by at least about 60%, or by at least about 80% relative to untreated
subjects. In
the case of an Alzheimer's subject, a "therapeutically effective" dosage
stabilizes
cognitive function or prevents a further decrease in cognitive function (i.e.,
preventing,
slowing, or stopping disease progression). The present invention accordingly
provides
therapeutic drugs. By "therapeutic" or "drug" is meant an agent having a
beneficial
ameliorative or prophylactic effect on a specific disease or condition in a
living human
or non-human animal.
Furthermore, active agents are administered at a therapeutically effective
dosage
sufficient to decrease deposition in a subject of amyloid protein, e.g., A040
or AR42. A
therapeutically effective dosage inhibits amyloid deposition by, for example,
at least
about 15%, or by at least about 40%, or even by at least 60%, or at least by
about 80%
relative to untreated subjects.
In another embodiment, active agents are administered at a therapeutically
effective dosage sufficient to increase or enhance amyloid protein, e.g.,
AC340 or Af342,
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in the.blood of a subject A therapeutically effective dosage increases the
concentration
by, for example, at least about 15%, or by at least about 40%, or even by at
least 60%, or
at least by about 80% relative to untreated subjects.
In yet another embodiment, active agents are administered at a therapeutically
effective dosage sufficient to improve ADAS-cog test scores by, e.g., at least
about 1
point, at least about 2 points, at least about 3 points, at least about 4
points, at least about
5 points, at least about 10 points, at least about 12 points, at least about
15 points, or at
least about 20 points relative to untreated subjects.
. Toxicity and therapeutic efficacy of such agents can be determined by
standard
pharmaceutical procedures in cell cultures or experimental animals, e.g., for
determining
the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose
therapeutically effective in 50% of the population). The dose ratio between
toxic and
therapeutic effects is the therapeutic index and can be expressed as the ratio
LD50/ED50, and usually a larger therapeutic index are more efficacious. While
agents
that exhibit toxic side effects may be used, care should be taken to design a
delivery
system that targets such agents to the site of affected tissue in order to
minimize
potential damage to uninfected cells and, thereby, reduce side effects.
It is understood that appropriate doses depend upon a number of factors within
the ken of the ordinarily skilled physician, veterinarian, or researcher. The
dose(s) of the
small molecule will vary, for example, depending upon the identity, size, and
condition
of the subject or sample being treated, further depending upon the route by
which the
composition is to be administered, if applicable, and the effect which the
practitioner
desires the small molecule to have upon the nucleic acid or polypeptide of the
invention.
Exemplary doses include milligram or microgram amounts of the small molecule
per
kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to
about
500 milligrams per kilogram, about 100 micrograms per kilogram to about 5
milligrams
per kilogram, or about 1 microgram per kilogram to about 50 micrograms per
kilogram).
It is furthermore understood that appropriate doses depend upon the potency
with
respect to the expression or activity to be modulated. Such appropriate doses
may be
determined using the assays described herein. When one or more of these small
molecules is to be administered to an animal (e.g., a human) in order to
modulate
expression or activity of a polypeptide or nucleic acid of the invention, a
physician,
veterinarian, or researcher may, for example, prescribe a relatively low dose
at first,
subsequently increasing the dose until an appropriate response is obtained. In
addition,
it is understood that the specific dose level for any particular animal
subject will depend
upon a variety of factors including the activity of the specific agent
employed, the age,
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body weight, general health, gender, and diet of the subject, the time of
administration,
the route of administration, the rate of excretion, any drug combination, and
the degree
of expression or activity to be modulated.
The ability of an agent to inhibit amyloid deposition can be evaluated in an
animal model system that may be predictive of efficacy in inhibiting amyloid
deposition
in human diseases, such as a transgenic mouse expressing human APP 'or other
relevant
animal models where Ap deposition is seen. Likewise, the ability of an agent
to prevent
or reduce cognitive impairment in a model system may be indicative of efficacy
in
humans. Alternatively, the ability of an agent can be evaluated by examining
the ability
of the agent to inhibit amyloid fibril formation in vitro, e.g., using a
fibrillogenesis assay
such as that described herein, including a ThT, CD, or EM assay. Also the
binding of an
agent to amyloid fibrils may be measured using a MS assay as described herein.
Pharmaceutically Acceptable Salts
Certain embodiments of the present agents can contain a basic functional
group,
such as amino or alkylamino, and are, thus, capable of forming
pharmaceutically
acceptable salts with pharmaceutically acceptable acids. The term
"pharmaceutically
acceptable salts" in this respect, refers to the relatively non-toxic,
inorganic and organic
acid addition salts of agents of the present invention. These salts can be
prepared in situ
during the final isolation and purification of the agents of the invention, or
by separately
2 o reacting a purified agent of the invention in its free base form with a
suitable organic or
inorganic acid, and isolating the salt thus formed.
Representative salts include the hydrohalide (including hydrobromide and
hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate,
oleate, palmitate,
stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, Inaleate,
fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate,
2-hydroxyethanesulfonate, and laurylsulphonate salts and the like. See, e.g.,
Berge
et al., "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977).
In other cases, the agents of the present invention may contain one or more
acidic
functional groups and, thus, are capable of forming pharmaceutically
acceptable salts
with pharmaceutically acceptable bases. The term "pharmaceutically acceptable
salts"
in these instances refers to the relatively non-toxic, inorganic and organic
base addition
salts of agents of the present invention.
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These salts can likewise be prepared in situ during the final isolation and
purification of the agents, or by separately reacting the purified agent in
its free acid
form with a suitable base, such as the hydroxide, carbonate or bicarbonate of
a
pharmaceutically acceptable metal cation, with ammonia, or with a
pharmaceutically
acceptable organic primary, secondary or tertiary amine. Representative alkali
or
alkaline earth salts include the lithium, sodium, potassium, calcium,
magnesium, and
aluminum salts and the like. Representative organic amines useful for the
formation of
base addition sAlts include ethylamine, diethylamine, ethylenediamine,
ethanolamine,
diethanolamine, piperazine and the like.
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments and
methods
described herein. Such equivalents are intended to be encompassed by the scope
of the
following claims. All patents, patent applications, and literature references
cited herein
are hereby expressly incorporated by reference in their entirety. This
invention is further
illustrated by the following examples which should not be construed as
limiting.
"Phannaceutically acceptable salts" also includes, for example, derivatives of
agents modified by making acid or base salts thereof, as described further
below and
elsewhere in the present application. Examples of pharmaceutically acceptable
salts
include mineral or organic acid salts of basic residues such as amines; and
alkali or
organic salts of acidic residues such as carboxylic acids. Pharmaceutically
acceptable
salts include the conventional non-toxic salts or the quaternary ammonium
salts of the
parent agent formed, for example, from non-toxic inorganic or organic acids.
Such
conventional non-toxic salts include those derived from inorganic acids such
as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid;
and the salts
prepared from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic,
malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic,
phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic acid.
Pharmaceutically
acceptable salts may be synthesized from the parent agent which contains a
basic or
acidic moiety by conventional chemical methods. Generally, such salts may be
prepared
by reacting the free acid or base forms of these agents with a stoichiometric
amount of
the appropriate base or acid in water or in an organic solvent, or in a
mixture of the two.
It is to be understood that wherever values and ranges are provided herein,
e.g.,
in ages of subject populations, dosages, and blood levels, all values and
ranges
encompassed by these values and ranges, are meant to be encompassed within the
scope
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of the present invention. Morover, all values in between these values and
ranges may
also be the upper or lower limits of a range.
Examples
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, numerous equivalents to the specific procedures,
embodiments,
claims, and examples described herein. Such equivalents were considered to be
within
the scope of this invention and covered by the claims appended hereto. The
contents of
all references, issued patents, and published patent applications cited
throughout this
application are hereby incorporated by reference. The invention is further
illustrated by
the following example, which should not be construed as further limiting.
Binding and Antifibrillogenic Assays
Test compounds were purchased from commercial sources or synthesized and
screened by mass spectroscopy ("MS") assays. The MS assay gives data on the
ability
of compounds to bind to an amyloid.
In the mass spectroscopy ("MS") assay, samples were prepared as aqueous
solutions containing 20% ethanol, 200 M of a test compound and 20 M of
solubilized
A(340. The pH value of each sample was adjusted to 7.4 (10.2) by addition of
0.1%
aqueous sodium hydroxide. The solutions were then analyzed by electrospray
ionization
mass spectroscopy using a Waters ZQ 4000 mass spectrometer. Samples were
introduced by direct infusion at a flow-rate of 25 L/min within 2 hr. after
sample
preparation. The source temperature was kept at 70 C and the cone voltage was
20 V
for all the analysis. Data were processed using Masslynx 3.5 software. The MS
assay
gives data on the ability of compounds to bind to soluble A(3, whereas the
ThT, EM and
CD assays give data on inhibition of fibrillogenesis. The results from the
assay for
binding to Ap are summarized in Table 2. "+++" indicates strong binding; "++"
indicates moderate binding; "+" indicates weak binding; "-" indicates no
detectable
binding; and entries left blank were not determined.
An ultraviolet absorption assay is also available, and this assay gives an
indication of the ability of test compounds to bind to (fibrillar) A(3. The
experiments
were carried out in a blinded fashion. Test compound at 20 M was incubated
with 50
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M Aj3(1-40) fibers for I h at 37 C in Tris buffered saline (20 mM Tris, 150 mM
NaCI,
pH 7.4 containing 0.01 sodium azide). Following incubation, the solution was
centrifuged for 20 min at 21,000 g to sediment the A(3(1-40) fibers along with
any bound
test compound. The amount of test compound remaining in the supernatant was
determined by reading the absorbance. The fraction of test compound bound was
then
calculated by comparing the amount remaining in the supernatants of
incubations with
A(3 to the amount remaining in control incubations which do not contain A(3
fibers.
Thioflavin T and Congo Red, both of which are known to bind to A(3 fibers, are
included
in each assay run as positive controls. Before assaying, test compounds were
diluted to
1 o 40 M, which is twice the concentration in the final test, and then
scanned using the
Hewlett Packard 8453 UV/VIS spectrophotometer to determine if the absorbance
was
sufficient for detection.
Observed Synergistic Effects of Combination Therapy in Human Patients
In this example, mild and moderate patients have been treated with an
alkanesulfonic acid, namely 3-amino-l-propanesulfonic acid, in combination
with other
therapeutic compounds used to diminish symptoms characteristic of Alzheimer's
disease
(e.g., loss of cognitive functions). The examples comprise the use of an
alkanesulfonic
acid in combination with cognitive enhancers such as acetylcholine esterase
inhibitors
("AChEi"). The effect of these combination therapies on the change in ADAS-cog
score
in the patients was determined.
Patients were treated with the test alkanesulfonic acid for a period of 9
months.
A group of patients received the test compound alone while another group were
treated
with the test compound in combination with an AChEi, namely donepezil.
Effect on ADAS-Cog. Upon entering the study, Alzheimer's patients were
categorized as being "mild" or "moderate" according to their MMSE ("Mini
Mental
State Examination") score. B.W.Rover, et al., "Mini-mental state exam in
clinical
practice." Hospital Practice 22(1A), 99 et seq. (1987). (According to this
examination a
MMSE score in the range of 19 to 26 was considered "mild," and a score in the
range 13
to 18 was considered "moderate"). Then, the change in mental function of these
patients
was analyzed by using their ADAS-Cog scores, which were recorded periodically
over a
nine month period. During this time, certain of the patients received the test
alkanesulfonic acid compound, and others received the same alkanesulfonic acid
concomitantly with donepezil, an acetylcholinesterase inhibitor. The average
change in
ADAS-Cog score for each group of patients was compared to the standard
reported
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change in similar Alzheimer's disease patients who have been treated with
donepezil
alone. The reference and experimental data are tabulated below, according to
the
particular therapeutic regimen and the patient population:
AD Patient Treatment Change in ADAS-Cog
Group(s) over 9 months
Mild +5.0 reference
AchEi alone
Moderate +2.5 reference
Mild + Moderate Test compound alone -0.5 observed
combined
Mild + Moderate Test compound + AchEi -3.0 observed
combined
A positive change in ADAS-Cog score reflects a deterioration of cognitive
function of a "mild AD" patient; stabilization is seen by a change of f 1; and
a negative
change shows an improvement in cognitive function. The medical literature
predicts
that patients with Alzheimer's disease who do not receive any treatment will,
on
average, have a change in ADAS-cog score over nine months varying from +2.5
(for
"mild" patients) to +5 (for "moderate" patients).
As the results indicate, patients who were treated with the test compound
alone
had a stable ADAS-Cog score (-0.5 on average, both the mild and moderate
groups are
considered together for convenience), and therefore the test compound appears
to have
limited a further decrease in the cognitive function of patients in this group
over the test
period.
The quantitative effects for each therapeutic drug regimen when administered
separately are known. An additive effect for the combined mild plus moderate
patient
group would therefore be in the range of (+5.0 to +2.5) + (-0.5), which
calculates to a
deterioration on the ADAS-Cog scale of +4.5 to +2.0 points. Surprisingly, the
opposite
effect is observed. The effect of concomitant administration of the test
alkanesulfonic
acid compound with the acetylcholinesterase inhibitor led to an improvement of
cognitive function (-3.0), whereas the predicted result is a decline. These
results show
an example of the benefit of having combination therapy for Alzheimer's
disease
patients.
The alkanesulfonic acid used in the study is known to have an effect on the
concentration of Ap in the brain. We also determined the effect of test
compound on the
change in Ap CSF levels of patients with mild to moderate Alzheimer's disease
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NBI-154CPPC compared to that seen in patients treated with a triple
combination of test compound
with AChEi and statin.
Patients treated with alkanesulfonic acid test compound in the presence or
absence of AChEi and statin were evaluated for their A(3 CSF concentration at
time 0
and 3 months following the initiation of treatment with the alkanesulfonic
acid. The
change in Aj342 CSF concentration was compared to the respective placebo
group.
Patients treated with the test compound had a decrease of 34% in A(3 CSF
concentration. The test compound was previously shown to decrease the levels
of both
soluble and insoluble A(342 in the brain of transgenic mice. Based on the mice
studies
lo the test compound is hypothesized to favor the clearance of A(3 from the
brain and CSF
prior to its deposition. The decrease in A(3 CSF concentration seen in
patients treated
with the test compound is greater than that seen in the placebo group, where
patients
showed a non-significant increase of 15% in their A(3 CSF concentration. This
result
demonstrates a difference of 49% between the two groups. Patients treated with
the
triple therapy (test compound and AchEi and statin) showed a decrease of 31 %
while
patients on AChEi and statin showed an increase of 45% in their A(342 CSF
levels. This
triple therapy showed a greater effect on the change (-76%) of A(342 CSF
concentration
when compared to the appropriate controls.
In sum, when compared to the respective placebo group, the combination of test
compound with AchEi and statin showed a much greater effect on the Ap CSF
concentration than test compound alone.
Methodology. CSF was obtained from patients before and after treatment with
the test compound at daily doses of 100 mg, 200 mg, or 300 mg. CSF was
fractionated
by FPLC following treatment with formic acid, and then the A(3 containing
fraction was
lyophilised. The amount of A(3 peptide was measured using an ELISA assay
(Biosource). The test alkanesulfonic acid-containing composition was found to
reduce
the CSF level of A(3 when patients were treated with 200 or 300 mg daily
doses. A
majority of patients on placebo and on 100 mg daily doses showed stable A(3
CSF levels
over a 3-month period, whereas the greatest reduction of Ap occurred in
patients
receiving 200 or 300 mg daily doses. The presence of a drug in the
cerebrospinal fluid
suggests that the drug crosses the blood brain barrier to penetrate the brain.
The
presence of the alkanesulfonic acid in the CSF was determined in patients who
had
received treatment for three months. In these patients, CSF was collected five
hours
following dosing, and levels of alkanesulfonic acid were determined by LC-
MS/MS.
The test alkanesulfonic acid was found to be present in CSF of patients in a
dose-
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dependent manner, e.g., patients receiving 200 or 300 mg daily dosing had a
greater
concentration than that seen in patients with 100 mg daily dosing.
Cognitive function with combination therapy - alkanesulfonic acid plus an
acetyl
cholenesterase inhibitor. Mild to moderate Alzheimer's disease patients who
had been
on cognition enhancers (AriceptTM or ExelonTM) were co-medicated with daily
doses of
test drug (300 mg alkanesulfonic acid) for six months. At the time the
experiments were
undertaken the peer-reviewed medical literature indicated that patients who
had been on
AChE inhibitors for more than twelve months would be expected to show a
decline in
cognitive functions of at least two to three points on the ADAS-Cog scale over
a six
month period. In order to determine whether the drug could potentiate or even
stabilize
the benefits of AChE inhibitors, patients were treated with both AChE and the
test drug
for a period of six months. Although the expectation was that the cognitive
functions of
patients receiving only AChE inhibitors would inevitably decline, the study
shows that
patients receiving co-medication had stable or improved ADAS-Cog, as
illustrated in
Graph A of the Figures, attached hereto. These results show that the test drug
given
concomitantly with AChE inhibitors is able to maintain and even improve the
cognitive
function of patients.
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