U.S. patent application number 14/317754 was filed with the patent office on 2014-10-23 for combinations of eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders.
The applicant listed for this patent is SUNOVION PHARMACEUTICALS INC.. Invention is credited to Roger P. Bakale, Judy Caron, Zhengxu Han, Stefan G. Koenig, Karim LALJI, Surendra P. Singh, Xiping Su, Mark Varney, Thomas Wessel, H. Scott Wilkinson.
Application Number | 20140315910 14/317754 |
Document ID | / |
Family ID | 37605221 |
Filed Date | 2014-10-23 |
United States Patent
Application |
20140315910 |
Kind Code |
A1 |
Caron; Judy ; et
al. |
October 23, 2014 |
Combinations of Eszopiclone and Trans
4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine
or Trans
4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine, and
Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive
Disorders
Abstract
One aspect of the present invention relates to pharmaceutical
compositions containing two or more active agents that when taken
together can be used to treat, e.g., menopause, mood disorders,
anxiety disorders, or cognitive disorders. The first component of
the pharmaceutical composition is a sedative eszopiclone. The
second component of the pharmaceutical composition is trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. The
present invention also relates to a method of treating menopause,
perimenopause, mood disorders, anxiety disorders, and cognitive
disorders.
Inventors: |
Caron; Judy; (Westwood,
MA) ; Wessel; Thomas; (Lenox, MA) ; LALJI;
Karim; (West Vancouver, CA) ; Varney; Mark;
(Laguna Niguel, CA) ; Bakale; Roger P.; (Malvern,
PA) ; Singh; Surendra P.; (Shrewsbury, MA) ;
Wilkinson; H. Scott; (Westborough, MA) ; Su;
Xiping; (Woodbridge, CT) ; Han; Zhengxu;
(Shrewsbury, MA) ; Koenig; Stefan G.; (Shrewsbury,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUNOVION PHARMACEUTICALS INC. |
Marlborough |
MA |
US |
|
|
Family ID: |
37605221 |
Appl. No.: |
14/317754 |
Filed: |
June 27, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13673076 |
Nov 9, 2012 |
|
|
|
14317754 |
|
|
|
|
13358155 |
Jan 25, 2012 |
8329950 |
|
|
13673076 |
|
|
|
|
11994644 |
Jun 20, 2008 |
|
|
|
PCT/US2006/026361 |
Jul 6, 2005 |
|
|
|
13358155 |
|
|
|
|
60697013 |
Jul 6, 2005 |
|
|
|
Current U.S.
Class: |
514/249 |
Current CPC
Class: |
A61K 31/4985 20130101;
C07C 211/42 20130101; A61P 15/12 20180101; A61P 25/16 20180101;
A61P 25/14 20180101; C07C 2602/10 20170501; A61P 25/22 20180101;
A61K 31/4985 20130101; A61K 31/135 20130101; A61P 25/18 20180101;
A61K 31/135 20130101; A61P 25/24 20180101; A61K 2300/00 20130101;
A61P 25/28 20180101; A61K 2300/00 20130101; A61P 25/00
20180101 |
Class at
Publication: |
514/249 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61K 31/135 20060101 A61K031/135 |
Claims
1. (canceled)
2. A pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
3-25. (canceled)
26. A method of treating a patient suffering from a CNS disorder of
Axis I, comprising the step of co-administering to a patient in
need thereof a therapeutically effective amount of eszopiclone, and
a therapeutically effective amount of trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a
pharmaceutically acceptable salt of either.
27. The method according to claim 26, wherein the CNS disorder of
Axis I is selected from attention deficit disorder (ADD) and
attention deficit/hyperactivity disorder (ADHD).
28. The method according to claim 27, wherein the CNS disorder of
Axis I is attention deficit/hyperactivity disorder (ADHD).
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions and methods
for the treatment of menopause and mood, anxiety, and cognitive
disorders.
BACKGROUND OF THE INVENTION
[0002] Menopause, which is caused by a lowering of the production
of female sex hormones that typically occurs at around age 50, but
can occur at much earlier or later ages, can generate disorders
such as edema, hot flushes (or flashes), attacks of sweating,
muscle and possibly joint pain, sleep disturbances, dysphoria,
nervousness, mood swings, headache, palpitations (enhanced
frequency of heart rate), dry mucous membranes, pain during
intercourse and urinary disturbances. Hot flashes or flushing are
characterized by a sudden onset of warmth in the face and neck,
often progressing to the chest. Episodes generally last several
minutes and are evidenced by a visible flushing of the skin. Often
such episodes are accompanied by sweating, dizziness, nausea,
palpitations and diaphoresis. Such symptoms can disrupt sleep and
interfere with quality of life.
[0003] Although the cause of hot flashes is not completely
understood, they are thought to be a disorder of thermoregulation
within the hypothalamus that is a consequence of declining estrogen
levels. The administration of female sex hormones, such as
estrogen, is effective in palliating these symptoms, but hormone
therapy is fraught with undesirable side effects. Four out of five
women have disturbing menopause disorders for at least one year and
25% of women have menopause disorders for more than 5 years. Half
of all women have severe disorders. Men may also have hot flashes
following androgen deprivation therapy (from bilateral orchiectomy
or treatment with a gonadotrophin-releasing-hormone agonist) for
metastatic prostate cancer. Menopause and perimenopause may also be
associated with mood disorders such as depression and anxiety.
[0004] Clinicians recognize a distinction among central nervous
system illnesses, and there have been many schemes for categorizing
mental disorders. The Diagnostic and Statistical Manual of Mental
Disorders, Fourth Ed., Text Revision, (hereinafter, the
"DSM-IV-TR.TM."), published by the American Psychiatric
Association, and incorporated herein by reference, provides a
standard diagnostic system upon which persons of skill rely.
According to the framework of the DSM-IV-TR.TM., the CNS disorders
of Axis I include: disorders diagnosed in childhood (such as, for
example, attention deficit disorder or "ADD" and attention
deficit/hyperactivity disorder or "ADHD") and disorders diagnosed
in adulthood. CNS disorders diagnosed in adulthood include (1)
schizophrenia and psychotic disorders; (2) cognitive disorders; (3)
mood disorders; (4) anxiety related disorders; (5) eating
disorders; (6) substance related disorders; (7) personality
disorders; and (8) "disorders not yet included" in the scheme.
[0005] Mood disorders are a group of heterogeneous, typically
recurrent illnesses including unipolar (depressive) and bipolar
(manic-depressive) disorders that are characterized by pervasive
mood disturbances, psychomotor dysfunction, and vegetative
symptoms.
[0006] In its full syndromal expression, clinical depression
manifests as major depressive disorder, with episodic course and
varying degrees of residual manifestations between episodes. The
mood is typically depressed, irritable, and/or anxious. The patient
may appear miserable, with furrowed brows, downturned corners of
the mouth, slumped posture, poor eye contact, and monosyllabic (or
absent) speech. The morbid mood may be accompanied by preoccupation
with guilt, self-denigrating ideas, decreased ability to
concentrate, indecisiveness, diminished interest in usual
activities, social withdrawal, helplessness, hopelessness, and
recurrent thoughts of death and suicide. Sleep disorders are
common. In some, the morbid mood is so deep that tears dry up; the
patient complains of an inability to experience usual
emotions--including grief, joy, and pleasure--and of a feeling that
the world has become colorless, lifeless, and dead.
[0007] Melancholia (formerly endogenous depression) is
characterized by marked psychomotor slowing (of thinking and
activity) or agitation (eg, restlessness, wringing of the hands,
pressure of speech), weight loss, irrational guilt, and loss of the
capacity to experience pleasure. Mood and activity vary diurnally,
with a nadir in the morning. Most melancholic patients complain of
difficulty falling asleep, multiple arousals, and insomnia in the
middle of the night or early morning. Sexual desire is often
diminished or lost. Amenorrhea can occur. Anorexia and weight loss
may lead to emaciation and secondary disturbances in electrolyte
balance.
[0008] In atypical depression, reverse vegetative features dominate
the clinical presentation; they include anxious-phobic symptoms,
evening worsening, initial insomnia, hypersomnia that often extends
into the day, and hyperphagia with weight gain. Unlike patients
with melancholia, those with atypical depression show mood
brightening to potentially positive events but often crash into a
paralyzing depression with the slightest adversity. A typical
depressive and bipolar II disorders overlap considerably.
[0009] In dysthymic disorder, depressive symptoms typically begin
insidiously in childhood or adolescence and pursue an intermittent
or low-grade course over many years or decades; major depressive
episodes may complicate it (double depression). In pure dysthymia,
depressive manifestations occur at a subthreshold level and overlap
considerably with those of a depressive temperament: habitually
gloomy, pessimistic, humorless, or incapable of fun; passive and
lethargic; introverted; skeptical, hypercritical, or complaining;
self-critical, self-reproaching, and self-derogatory; and
preoccupied with inadequacy, failure, and negative events.
[0010] Thorough evaluation of many persons with depression reveals
bipolar traits, and as many as one in five patients with a
depressive disorder also develops frank hypomania or mania. Most
switches from unipolar to bipolar disorder occur within 5 years of
the onset of depressive manifestations. Predictors of a switch
include early onset of depression (<25 years old), postpartum
depression, frequent episodes of depression, quick brightening of
mood with somatic treatments (eg, antidepressants, phototherapy,
sleep deprivation, electroconvulsive therapy), and a family history
of mood disorders for three consecutive generations.
[0011] Between episodes, patients with bipolar disorder exhibit
depressive moodiness and sometimes high-energy activity; disruption
in developmental and social functioning is more common than in
unipolar disorder. In bipolar disorder, episodes are shorter (3 to
6 months), age of onset is younger, onset of episodes is more
abrupt, and cycles (time from onset of one episode to that of the
next) are shorter than in unipolar disorder. Cyclicity is
particularly accentuated in rapid-cycling forms of bipolar disorder
(usually defined as >=4 episodes/year).
[0012] In bipolar I disorder, full-fledged manic and major
depressive episodes alternate. Bipolar I disorder commonly begins
with depression and is characterized by at least one manic or
excited period during its course. The depressive phase can be an
immediate prelude or aftermath of mania, or depression and mania
can be separated by months or years.
[0013] In bipolar II disorder, depressive episodes alternate with
hypomanias (relatively mild, nonpsychotic periods of usually <1
week). During the hypomanic period, mood brightens, the need for
sleep decreases, and psychomotor activity accelerates beyond the
patient's usual level. Often, the switch is induced by circadian
factors (eg, going to bed depressed and waking early in the morning
in a hypomanic state). Hypersomnia and overeating are
characteristic and may recur seasonally (eg, in autumn or winter);
insomnia and poor appetite occur during the depressive phase. For
some persons, hypomanic periods are adaptive because they are
associated with high energy, confidence, and supernormal social
functioning. Many patients who experience pleasant elevation of
mood, usually at the end of a depression, do not report it unless
specifically questioned.
[0014] Patients with major depressive episodes and a family history
of bipolar disorders (unofficially called bipolar III) often
exhibit subtle hypomanic tendencies; their temperament is termed
hyperthymic (ie, driven, ambitious, and achievement-oriented).
[0015] In cyclothymic disorder, less severe hypomanic and
mini-depressive periods follow an irregular course, with each
period lasting a few days. Cyclothymic disorder is commonly a
precursor of bipolar II disorder. But it can also occur as extreme
moodiness without being complicated by major mood disorders. In
such cases, brief cycles of retarded depression accompanied by low
self-confidence and increased sleep alternate with elation or
increased enthusiasm and shortened sleep. In another form,
low-grade depressive features predominate; the bipolar tendency is
shown primarily by how easily elation or irritability is induced by
antidepressants. In chronic hypomania, a form rarely seen
clinically, elated periods predominate, with habitual reduction of
sleep to <6 hours. Persons with this form are constantly
overcheerful, self-assured, overenergetic, full of plans,
improvident, overinvolved, and meddlesome; they rush off with
restless impulses and accost people.
[0016] Anxiety disorders are more common than any other class of
psychiatric disorder. Panic attacks are common, affecting >1/3
of the population in a single year. Most persons recover without
treatment; a few develop panic disorder. Panic disorder is
uncommon, affecting <1% of the population in a 6-month period.
Panic disorder usually begins in late adolescence or early
adulthood and affects women two to three times more often than men.
Phobic disorders involve persistent, unrealistic, yet intense
anxiety that, unlike the free-floating anxiety of panic disorder,
is attached to external situations or stimuli. Persons who have a
phobia avoid such situations or stimuli or endure them only with
great distress. However, they retain insight and recognize the
excessiveness of their anxiety. In agoraphobia, anxiety about or
avoidance of being trapped in situations or places with no way to
escape easily if panic develops. Agoraphobia is more common than
panic disorder. It affects 3.8% of women and 1.8% of men during any
6-month period. Peak age of onset is the early 20s; first
appearance after age 40 is unusual. In specific phobias, clinically
significant anxiety is induced by exposure to a specific situation
or object, often resulting in avoidance. Specific phobias are the
most common anxiety disorders but are often less troubling than
other anxiety disorders. They affect 7% of women and 4.3% of men
during any 6-month period.
[0017] One form of anxiety disorder is social phobia, which is a
clinically significant anxiety induced by exposure to certain
social or performance situations, often resulting in avoidance.
Social phobias affect 1.7% of women and 1.3% of men during any
6-month period. However, more recent epidemiologic studies suggest
a substantially higher lifetime prevalence of about 13%. Men are
more likely than women to have the most severe form of social
anxiety, avoidant personality disorder.
[0018] Yet another anxiety disorder is Obsessive-Compulsive
Disorder (OCD), a disorder characterized by recurrent, unwanted,
intrusive ideas, images, or impulses that seem silly, weird, nasty,
or horrible (obsessions) and by urges to do something that will
lessen the discomfort due to the obsessions (compulsions).
Obsessive-compulsive disorder occurs about equally in men and women
and affects 1.6% of the population during any 6-month period.
[0019] Posttraumatic Stress Disorder is another anxiety disorder.
It is a disorder in which an overwhelming traumatic event is
reexperienced, causing intense fear, helplessness, horror, and
avoidance of stimuli associated with the trauma. The stressful
event involves serious injury or threatened death to the person or
others or actual death of others; during the event, the person
experiences intense fear, helplessness, or horror. Lifetime
prevalence is at least 1%, and in high-risk populations, such as
combat veterans or victims of criminal violence, prevalence is
reported to be between 3% and 58%.
[0020] Acute stress disorder resembles posttraumatic stress
disorder in that the person has been traumatized, reexperiences the
trauma, avoids stimuli that remind him of the trauma, and has
increased arousal. However, by definition, acute stress disorder
begins within 4 weeks of the traumatic event and lasts a minimum of
2 days but no more than 4 weeks. A person with this disorder has
three or more of the following dissociative symptoms: a sense of
numbing, detachment, or absence of emotional responsiveness;
reduced awareness of surroundings (eg, being dazed); a feeling that
things are not real; a feeling that he is not real; and amnesia for
an important part of the trauma. The prevalence of acute stress
disorder is unknown but is presumably proportionate to the severity
of the trauma and the extent of exposure to the trauma.
[0021] Generalized Anxiety Disorder is an excessive, almost daily,
anxiety and worry for .gtoreq.6 months about a number of activities
or events. Generalized anxiety disorder is common, affecting 3 to
5% of the population within a 1-year period. Women are twice as
likely to be affected as men. The disorder often begins in
childhood or adolescence but may begin at any age.
[0022] Anxiety may be secondary to physical disorders, such as
neurologic disorders (eg, brain trauma, infections, inner ear
disorders), cardiovascular disorders (eg, heart failure,
arrhythmias), endocrine disorders (eg, overactive adrenal or
thyroid glands), and respiratory disorders (eg, asthma, chronic
obstructive pulmonary disease). Anxiety may be caused by use of
drugs, such as alcohol, stimulants, caffeine, cocaine, and many
prescription drugs. Also, drug withdrawal is commonly associated
with anxiety.
[0023] An estimated 4 to 5 million Americans (about 2% of all ages
and 15% of those >age 65) have some form and degree of cognitive
failure (cognitive disorder). Cognitive failure (dysfunction or
loss of cognitive functions--the processes by which knowledge is
acquired, retained, and used) is most commonly due to delirium
(sometimes called acute confusional state) or dementia. It may also
occur in association with disorders of affect, such as
depression.
[0024] Delirium (Acute Confusional State) is a clinical state
characterized by fluctuating disturbances in cognition, mood,
attention, arousal, and self-awareness, which arises acutely,
either without prior intellectual impairment or superimposed on
chronic intellectual impairment. Some practitioners use the terms
delirium and acute confusional state synonymously; others use
delirium to refer to a subset of confused people with
hyperactivity. Still others use delirium to refer to full-blown
confusion and confusional state to refer to mild
disorientation.
[0025] Dementia is a chronic deterioration of intellectual function
and other cognitive skills severe enough to interfere with the
ability to perform activities of daily living. Dementia may occur
at any age and can affect young people as the result of injury or
hypoxia. However, it is mostly a disease of the elderly, affecting
>15% of persons >65 years old and as many as 40% of persons
>80 years old. It accounts for more than half of nursing home
admissions and is the condition most feared by aging adults.
[0026] Alzheimer's Disease is a progressive, inexorable loss of
cognitive function associated with an excessive number of senile
plaques in the cerebral cortex and subcortical gray matter, which
also contains .beta.-amyloid and neurofibrillary tangles consisting
of tau protein.
[0027] Lewy body dementia may be the second most common dementia
after Alzheimer's disease. Lewy bodies are hallmark lesions of
degenerating neurons in Parkinson's disease and occur in dementia
with or without features of Parkinson's disease. In Lewy body
dementia, Lewy bodies may predominate markedly or be intermixed
with classic pathologic changes of Alzheimer's disease. Symptoms,
signs, and course of Lewy body dementia resemble those of
Alzheimer's disease, except hallucinations (mainly visual) are more
common and patients appear to have an exquisite sensitivity to
antipsychotic-induced extrapyramidal adverse effects.
[0028] Cerebrovascular disease can destroy enough brain tissue to
impair function. Vascular dementia, which includes impairment due
to single, strategically located infarcts or to multiple small
infarcts from small or medium-sized vessel disease, is more common
in men and generally begins after age 70. It occurs more often in
persons who have hypertension and/or diabetes mellitus or who abuse
tobacco. Progressive vascular dementia can generally be slowed by
controlling blood pressure, regulating blood sugar (90 to 150
mg/dL), and stopping smoking. Some degree of vascular damage is
found in up to 20% of autopsies of patients with dementia.
[0029] Binswanger's dementia (subcortical arteriosclerotic
encephalopathy) is uncommon and involves multiple infarcts in deep
hemispheric white matter associated with severe hypertension and
systemic vascular disease. Although clinically similar to vascular
dementia, Binswanger's dementia may be characterized by more focal
neurologic symptoms associated with acute strokes and a more rapid
course of deterioration. MRI and CT show areas of
leukoencephalopathy in the cerebrum semiovale adjacent to the
cortex.
[0030] More than 25% of patients with Parkinson's disease have
dementia; some estimates are as high as 80% (see Ch. 179). At
autopsy, patients with Parkinson's disease may have some of the
neuropathologic brain findings and many of the biochemical changes
seen in patients with Alzheimer's disease. A less severe
subcortical dementia is also associated with Parkinson's
disease.
[0031] The dementia associated with progressive supranuclear palsy
is commonly preceded by other neurologic symptoms, eg, multiple
falls, dystonic axial rigidity, retrocollis, supranuclear
ophthalmoplegia, dysphagia, and dysarthria.
[0032] Patients with Huntington's disease (chorea) may also present
with symptoms of dementia, but the diagnosis is usually clarified
by the family history, younger age at onset, and the disease's
characteristic motor abnormalities. In case of doubt, genetic
analysis can be diagnostic.
[0033] Pick's disease is a less common form of dementia, affecting
the frontal and temporal regions of the cortex. Patients have
prominent apathy and memory disturbances; they may show increased
carelessness, poor personal hygiene, and decreased attention span.
Although the clinical presentation and CT findings in Pick's
disease can be quite distinctive, definitive diagnosis is possible
only at autopsy. The Kluver-Bucy syndrome can occur early in the
course of Pick's disease, with emotional blunting, hypersexual
activity, hyperorality (bulimia and sucking and smacking of lips),
and visual agnosias.
[0034] Frontal lobe dementia syndromes may result from intrinsic
pathology, a primary or metastatic tumor, previous surgical
manipulation, irradiation to the brain, or severe head trauma. The
repeated head trauma in dementia pugilistica, which occurs in
professional fighters, appears to link genetically to the 4 allele
of apo E.
[0035] Normal-pressure hydrocephalus is characterized by a triad of
progressive dementia, incontinence, and an unsteady, slow, and
wide-based gait. Onset is usually insidious and occurs mostly in
late middle or old age. The disease is more common in men and
occasionally is related to prior meningitis, subarachnoid
hemorrhage, head injury, or neurosurgical interventions. In most
cases, evidence of precedent injury is lacking. Normal-pressure
hydrocephalus may result from scarring of arachnoid villi over
convexities of the brain, which results in slowed absorption of CSF
(ceresbrospinal fluid), ventricular dilatation, and frontal lobe
motor abnormalities. The laboratory diagnosis is based on
high-normal CSF pressure (150 to 200 mm Hg) and CT evidence of
ventricular dilatation and narrowed cerebral sulci at the brain's
apex without widening of the subarachnoid space. The results of
treatment with CSF shunting are inconsistent. The dementia is
sometimes reversible; some experts recommend a therapeutic lumbar
puncture to remove about 30 mL of CSF. Improvement in gait and
cognition for hours or several days suggests the value of shunt
placement.
[0036] Subdural hematoma can cause a change in mental status,
producing coma, delirium, or a dementia syndrome. Cognitive changes
may begin any time after blood begins to accumulate and can
progress rapidly or slowly, according to the size and location of
the hematoma. This chronic syndrome may resemble vascular dementia,
with focal neurologic signs and cognitive changes. Removing the
hematoma may restore function or prevent further loss of
intellectual function. However, some experts believe that after
hematomas have exerted pressure on the brain for a long time
(perhaps a year or more), removing them does little to improve
cognitive function.
[0037] The most well-known infectious cause of dementia is
Creutzfeldt-Jakob disease, in which memory deficits,
electroencephalographic changes, myoclonus, and sometimes ataxia
are prominent. The infectious agent is a corrupted protein called a
prion that can be acquired genetically, by tissue transplantation,
by cannibalism, and apparently by eating products from infected
cattle (with mad-cow disease). Most cases occur sporadically. It
produces a characteristic spongiform encephalopathy quite different
from the changes of Alzheimer's disease. The course is more rapid
than that of Alzheimer's disease and usually lasts from 6 to 12
months.
[0038] Patients with Gerstmann-Strussler-Scheinker disease, another
dementia with a prion-related cause, typically present with ataxia,
followed later by cognitive decline. This syndrome affects younger
persons and has a longer duration than Creutzfeldt-Jakob
disease.
[0039] General paresis, a form of neurosyphilis, was once a common
cause of dementia in Western societies. It is still prevalent in
developing countries. In addition to intellectual decline, tremors
and pupillary changes can occur. The CSF is tested using the
fluorescent treponemal antibody (FTA) test. A positive FTA test for
syphilis establishes the diagnosis.
[0040] AIDS dementia can complicate the later stages of HIV
infection. Dementia may be caused by HIV, by the JC virus that
causes progressive multifocal leukoencephalopathy, or by a variety
of other opportunistic infectious agents, including fungi,
bacteria, viruses, or protozoa that can be identified at autopsy.
Early manifestations include slowed thinking and expression,
difficulty in concentration, and apathy, with preserved insight and
few manifestations of depression. Motor movements are slowed;
ataxia and weakness may be evident. Reflexes, including the
extensor plantar responses, become abnormal. Treatment with
zidovudine often induces improvement sometimes verging on the
dramatic.
[0041] Therefore, there exists a need to develop effective and
minimally adverse therapies for the above listed disorders.
SUMMARY OF THE INVENTION
[0042] The present invention generally relates to pharmaceutical
compositions comprising eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof, and trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. The
pharmaceutical compositions of the invention are useful in the
treatment of menopause, perimenopause, mood disorders, anxiety
disorders, and cognitive disorders.
[0043] In addition, the present invention relates to a method for
augmentation of antidepressant therapy in a patient comprising
administering to the patient a therapeutically effective amount of
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof. The present invention
also relates to a method for eliciting a dose-sparing effect in a
patient undergoing treatment with trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
comprising administering to the patient a therapeutically effective
amount of eszopiclone, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof.
[0044] Furthermore, the present invention relates to a method for
reducing depression relapse in a patient who received trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
treatment comprising administering to the patient a therapeutically
effective amount eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0045] Co-administration of eszopiclone, a sedative agent, together
with an trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenam-
ine or trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is
beneficial in treatment of such disorders as menopause,
perimenopause, mood disorders, anxiety disorders, and cognitive
disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention relates generally to pharmaceutical
compositions containing two or more active agents that when taken
together have benefit in treatment of menopause, perimenopause,
mood disorder, anxiety disorder, or cognitive disorder. In certain
embodiments, the present invention relates to a pharmaceutical
composition comprising eszopiclone and trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. In one
embodiment, eszopiclone of the above listed embodiments is present
as a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof. In another embodiment, trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
is present as a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0047] Another aspect of the present invention relates to a method
of treating a patient suffering from menopause, perimenopause, mood
disorder, anxiety disorder, or cognitive disorder comprising the
step of administering to said patient a therapeutically effective
dose of a pharmaceutical composition containing two or more active
agents that when taken together improve the quality of sleep or
sleep disorders for said patient.
[0048] Further aspect of the present invention relates to a method
of treating a patient suffering from menopause, perimenopause, mood
disorder, anxiety disorder, or cognitive disorder comprising the
step of administering to said patient a therapeutically effective
dose of a pharmaceutical composition containing two or more active
agents that when taken together improve the treatment of the
patient.
[0049] In another embodiment, the present invention relates to a
method for augmentation of trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
therapy in a patient comprising administering to the patient a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0050] The present invention also relates to a method for eliciting
a dose-sparing effect in a patient undergoing treatment with trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
comprising administering to the patient a therapeutically effective
amount of eszopiclone, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof.
[0051] Furthermore, the present invention relates to a method for
reducing depression relapse in a patient who received trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
treatment comprising administering to the patient a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof
Eszopiclone
[0052] Eszopiclone is a cyclopyrrolone that has the chemical name
(+)
6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-di-
hydro-5H-pyrrolo[3-4-b]pyrazine or (+)
6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl4-
-methylpiperazine-1-carboxylate. The chemical structure of
eszopiclone is shown below:
##STR00001##
[0053] Eszopiclone is the S-(+)-optical isomer of the compound
zopiclone, which is described in U.S. Pat. Nos. 6,319,926 and
6,444,673. Racemic zopiclone is described in Goa and Heel, [Drugs,
32:48-65 (1986)] and in U.S. Pat. Nos. 3,862,149 and 4,220,646.
S-(+)-zopiclone, which will hereinafter be referred to by its
USAN-approved generic name, eszopiclone, includes the optically
pure and the substantially optically pure (e.g., 90%, 95% or 99%
optical purity)S-(+)-zopiclone isomer.
[0054] Zopiclone was the first of a chemically distinct class of
hypnotic and anxiolytic compounds that offers a psychotherapeutic
profile of efficacy and side effects similar to the
benzodiazepines. Some members of this class of compounds, the
cyclopyrrolones, appear to cause less residual sedation and less
slowing of reaction times than the benzodiazepines, and it offers
the promise of an improved therapeutic index over benzodiazepines.
Recently, the USFDA approved use of eszopiclone (LUNESTA.TM.) for
the treatment of insomnia.
[0055] Eszopiclone possesses potent activity in treating sleep
disorders such as insomnia. Eszopiclone also possess potent
activity in treating sleep disorders while avoiding the usual
adverse effects including but not limited to drowsiness, next day
effects tiredness in the morning, inability to concentrate and
headache. U.S. Pat. No. 5,786,357 relates to methods of using
eszopiclone also to treat convulsive disorders such as
epilepsy.
[0056] The size of a prophylactic or therapeutic dose of
eszopiclone in the acute or chronic management of disease will vary
with the severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight, and response of the
individual patient. In general, the total daily dose ranges, for
the conditions described herein, is from about 0.25 mg to about 10
mg. Preferably, a daily dose range should be between about 0.5 mg
to about 5 mg. Most preferably, a daily dose range should be
between about 0.5 mg to about 3.0 mg. In one embodiment, the daily
dose is 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, or 3.0 mg. In
managing the patient, the therapy may be initiated at a lower dose,
perhaps about 0.5 mg to about 2 mg and increased depending-on the
patient's global response. It is further recommended that children
and patients over 65 years, and those with impaired renal or
hepatic function, initially receive low doses, and that they be
titrated based on global response and blood level. It may be
necessary to use dosages outside these ranges in some cases.
[0057] In the case where an oral composition is employed, a
suitable dosage range for use is from about 0.25 mg to about 10.0
mg with, in the usual case, the lower doses serving more common
insomnia, and the higher doses, presented in divided dosing,
reserved for control of psychiatric disorders. Preferably, a dose
range of between about 0.5 mg to about 5 mg is given as a once
daily administration or in divided doses if required; most
preferably, a dose range of from about 0.5 mg to about 3 mg is
given, either as a once daily administration or in divided doses if
required. Patients may be upward titrated from below to within this
dose range to a satisfactory control of symptoms as
appropriate.
trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
[0058] Sertraline, whose chemical name is (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine,
is approved for the treatment of depression by the United States
Food and Drug Administration, and is available under the trade name
ZOLOFT.RTM. (Pfizer Inc., NY, NY, USA). The use of sertraline,
(1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
and (1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
for the treatment of psychoses, psoriasis, rheumatoid arthritis and
inflammation are disclosed in U.S. Pat. No. 4,981,870. The receptor
pharmacology of the individual (1S,4R) and (1R,4S) enantiomers of
trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine,
is described by Welch et al., J. Med. Chem., 27:1508-1515
(1984).
[0059] The present invention utilizes (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
(A); and (1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
(B):
##STR00002##
[0060] Compounds A or B are useful in treatment of menopause,
perimenopause, and mood, anxiety, and cognitive disorders. The
magnitude of a prophylactic or therapeutic dose of A or B will vary
with the nature and severity of the condition to be treated and the
route of administration. The dose, and perhaps the dose frequency,
will also vary according to the age, body weight and response of
the individual patient. In general, the total daily dose ranges of
A and B are from about 25 mg per day to about 1000 mg per day,
preferably about 100 mg per day to about 600 mg per day, in single
or divided doses.
[0061] Preparation of the compounds A and B is illustrated below in
Scheme 1 and its accompanying narrative.
##STR00003## ##STR00004##
[0062] In the compound
##STR00005##
of Scheme 1, R is
##STR00006##
[0063] wherein R.sup.1, R.sup.2 and R.sup.3 are each independently
alkyl. In a preferred embodiment of the compounds, R is
t-butyl.
[0064] Synthesis of 2-methyl-propane-2-sulfinic acid
[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydro-naphthalen-y-yl]-amide
(Tetralone t-butanesulfinimine): To a solution of
4-((3,4-dicholorophenyl)-3,4-dihydro-1-naphthalenone (12 g) in THF
(40 mL) was added (R)-t-butanesulfinamide (5.2 g) and Ti(OEt).sub.4
(85 mL 20%) in EtOH. The reaction mixture was heated to 60.degree.
C. for 13 h. The reaction mixture was cooled to rt, and poured to a
brine solution (100 mL) with stirring. The suspension was then
added EtOAc (300 mL) and stirred to 10 min. The suspension was
filtered and the filtrate was concentrated to ca 50 mL. It was then
added EtOAc (100 mL), the organic phase was then separated and
concentrated to give a crude reaction mixture. The final products
were isolated from the crude products by careful flash column using
EtOAc and hexane (3:7 to 1:1) to give ca 3 g starting ketone, and
(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
tert-butanesulfinimine (2.5 g, first product) as an oil that
solidified on standing. .sup.1H NMR (CDCl.sub.3) .delta. 1.33 (S,
9H), 2.10-2.20 (m, 1H), 2.28-2.38 (m, 1H) 2.88-2.98 (m, 1H),
3.34-3.44 (m 1H), 4.12-4.24 (m, 1H), 6.84-6.88 (m, 2H), 7.20 (s,
1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).
[0065] The other product (1R,4R)-4-(3,4-dichloro
phenyl)-3-4-dihydro-1-naphthalenone t-butanesulfinimine (3.0 g,
second product, lower R.sub.f) was isolated also as oil that
solidified on standing. .sup.1H NMR (CDCl.sub.3) .delta. 1.34 (S,
9H), 2.05-2.18 (m, 1H), 2.28-2.38 (m, 1H), 3.15-3.25 (m, 2H),
4.16-4.22 (m, 1H), 6.84-6.88 (m, 2H), 7.20 (s, 1H), 7.25-7.40 (m,
3H), 8.22-8.28 (m, 1H).
[0066] Synthesis of
(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone:
(1R,4R)-4-(3,4-dichlorophenyl)3,4-dihydro-1-naphthalenone
t-butanesulfinimine (3.0 g, second product) was dissolved in MeOH
(20 mL) and concentrated HCl (4 mL) at rt. The reaction mixture was
stirred at rt to give a suspension. It was filtered and the solids
were washed with hexane to give 1.2 g product. The enantiomeric
purity was determined to be >99.3% by HPLC analysis with a
ChiralPak AS 10:m, 4.6.times.250 mm, Hexane/IPA (90:10), UV 220 nm,
R-isomer 8.23 min. S-isomer 12.25 min. .sup.1H NMR (CDCl.sub.3)
.delta. 2.20-2.32 (m, 1H), 2.42-2.53 (m, 1H) 2.57-2.78 (m, 2H),
4.28 (dd=4.6, 8.1 Hz, 1H), 6.95 (dd, J=2.1, 7.6 Hz, 2H), 7.23 (d
J=2.0 Hz, 1H), 7.37-50 (m, 3H), 8.13 (d, J=7.6 Hz, 1H).
[.alpha.]=-66.degree. (c=1, acetone).
[0067] Synthesis of
(S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone. The
previous procedure was used, starting from
(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
t-butanesulfinimine. 1.7 g of product (>99% ee) was obtained.
[.alpha.]=+62, c=1, acetone). .sup.1H NMR spectrum of the product
is the same as that of its enantiomer.
[0068] Synthesis of (1S,4R) and
(1R,4R)--N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-fo-
rmamide: (R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
(1.2 g) was added formic acid (3 mL) and formamide (3 mL). The
reaction mixture was heated to 160-165.degree. C. for 15 h under
nitrogen atmosphere. The reaction mixture was cooled to rt and
decanted the solvent.
[0069] The residue solids was passed through flash column using
EtOAc:Hexane (3:7 to 1:1) to give and (1R,4R)-Norsertralaine
formamide (400 mg, first spot), and (1S,4R)-Norsertraline formamide
(360 mg). .sup.1H NMR of the first product [(1R,4R)-isomer]:
(CDCl.sub.3) .delta. 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H),
4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90
(M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H). M+320.
.sup.1H NMR of the second product [(1S,4R)-isomer: .delta.
1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m,
1H), 5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28
(s, 1H). Mass Spec. M.sup.+ 320.
The products were reduced to the corresponding A and B by
borane.
[0070] Synthesis of (1S*,4R*)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
HCl(racemic mixture of A and B HCl): (1S*,4R*) formamide (1.0 g)
was dissolved in THF (7 mL), and added BH.sub.3 THF (1M, 9.3 mL, 3
eq. The reaction mixture was heated to 75-80.degree. C. for 3 h and
stirred at rt overnight. The reaction mixture was quenched with
MeOH (20 mL). The mixture was concentrated to give a residue, which
was dissolved in 10% HCl (20 mL). The solution was heated to
80-90.degree. C. for 9 h, and basified with potassium carbonate,
and extracted with EtOAc (25 mL). The organic phase was separated
and washed with water, brine, dried over Na.sub.2SO.sub.4.
Concentrated to give the free base. It was converted to its HCl
salt in TBME with HCl/Et2O to give the product (0.75 g). .sup.1H
MNR (CD.sub.3OD) .delta. 1.86-1.96 (m, 1H), 2.04-2.12 (m, 1H),
2.18-2.28 (m, 1H), 2.30-2.42 (m, 1H), 2.78 (s, 3H), 4.34 (m, 1H),
4.60 (m, 1H), 6.93-7.00 (m, 2H), 7.15 (s, 1H), 7.34-7.44 (m, 3H),
7.57-7.59 (d, J=7.2 Hz, 1H). Mass Spec. M.sup.+ 305.
[0071] Synthesis of (1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
HCl by Resolution with (S)-Mandelic Acid: Racemic trans-sertraline
(3 g) was dissolved in anhydrous ethanol (30 g) and added
(S)-mandelic acid (1.5 g). The reaction mixture was heated to
reflux for 30 min. and cooled to rt. The reaction solution was
concentrated to give oil (ca 3 mL ethanol left). To it was added
EtOAc (30 mL) and stirred for 1 h at rt. The solid formed from the
solution was collected by filtration and dried (1.73 g). The solid
was dissolved in hot EtOAc (35 mL), and cooled to rt in 30 min, and
stirred for 1 h. The solid was collected by filtration and dried to
give (1S,4R)-sertraline-(S)-mandelate (1.3 g). Ee of the product
was >99% by HPLC. The solid (1.1 g) was converted to its free
base with potassium carbonate, and treated with HCl/ether in MeOH
to give the HCl salt (0.73 g). .sup.1H NMR spectrum was identical
to its racemate. (1R,4S)-sertraline HCl was prepared from the
mother liquor, after enriched with (R)-mandelic acid. Mass Spec
M.sup.+ 305.
[0072] The commercial form of sertraline [(S,S)-cis] and its
isomeric analogues were tested for their inhibition of functional
uptake of serotonin (5-HT), norepinephrine (NE), or dopamine (DA),
in synaptosomes prepared from rat whole brain, hypothalamus, or
corpus striatum, respectively. Compounds were tested initially at
10 .mu.M in duplicate, and if .gtoreq.50% inhibition of uptake was
observed, they were tested further at 10 different concentrations
in duplicate in order to obtain full inhibition curves. IC.sub.50
values (concentration inhibiting control activity by 50%) was then
determined by nonlinear regression analysis of the inhibition
curves and tabulated below in the Examples sections.
trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
[0073] (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine (P) and
(1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine (Q) are
useful in the treatment of menopause, perimenopause, and mood,
anxiety, and cognitive disorders. The magnitude of a prophylactic
or therapeutic dose of P or Q will vary with the nature and
severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight and response of the
individual patient. In general, the total daily dose ranges of
compounds P or Q will be from about 25 mg per day to about 1000 mg
per day, preferably about 100 mg per day to about 600 mg per day,
in single or divided doses.
Compounds P and Q are represented by the formulae:
##STR00007##
[0074] Preparation of compounds P and Q is illustrated below in
Scheme 2 and its accompanying narrative.
##STR00008## ##STR00009##
In the compound
##STR00010##
of Scheme 1,
R is
##STR00011##
[0075] wherein R.sup.1, R.sup.2 and R.sup.3 are each independently
alkyl. In a preferred embodiment of the compounds, R is
tert-butyl.
[0076] Synthesis of 2-methyl-propane-2-sulfinic acid
[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-y-yl]-amide(tetralo-
ne t-butanesulfinimine): To a solution of
4-((3,4-dicholorophenyl)-3,4-dihydro-1-naphthalenone (12 g) in THF
(40 mL) was added (R)-t-butanesulfinamide (5.2 g) and Ti(OEt).sub.4
(85 mL 20%) in EtOH. The reaction mixture was heated to 60.degree.
C. for 13 h. The reaction mixture was cooled to rt, and poured into
a brine solution (100 mL) with stirring. The suspension was then
added to EtOAc (300 mL) and stirred for 10 min. The suspension was
filtered and the filtrate was concentrated to ca 50 mL. One hundred
milliliters of EtOAc was added and the organic phase was separated
and concentrated to give a crude reaction mixture. The final
products were isolated from the crude products by careful flash
column chromatography using EtOAc and hexane (3:7 to 1:1) to give
ca 3 g starting ketone, and
(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
tert-butanesulfinimine (2.5 g, first product) as an oil that
solidified on standing. .sup.1H NMR (CDCl.sub.3) .delta. 1.33 (S,
9H), 2.10-2.20 (m, 1H), 2.28-2.38 (m, 1H) 2.88-2.98 (m, 1H),
3.34-3.44 (m 1H), 4.12-4.24 (m, 1H), 6.84-6.88 (m, 2H), 7.20 (s,
1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H). The other product
(1R,4R)-4-(3,4-dichloro phenyl)-3-4-dihydro-1-naphthalenone
tert-butanesulfinimine (3.0 g, second product, lower R.sub.f) was
isolated also as an oil that solidified on standing. .sup.1H NMR
(CDCl.sub.3) .delta. 1.34 (S, 9H), 2.05-2.18 (m, 1H), 2.28-2.38 (m,
1H), 3.15-3.25 (m, 2H), 4.16-4.22 (m, 1H), 6.84-6.88 (m, 2H), 7.20
(s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).
[0077] Synthesis of
(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone:
(1R,4R)-4-(3,4-dichlorophenyl)3,4-dihydro-1-naphthalenone
t-butanesulfinimine (3.0 g, second product) was dissolved in MeOH
(20 mL) and concentrated HCl (4 mL) at rt. The reaction mixture was
stirred at rt to give a suspension. It was filtered and the solids
were washed with hexane to give 1.2 g product. The enantiomeric
purity was determined to be >99.3% by HPLC analysis with a
ChiralPak AS 10 .mu.m, 4.6.times.250 mm, Hexane/IPA (90:10), UV 220
nm, R-isomer 8.23 min. S-isomer 12.25 min. .sup.1H NMR (CDCl.sub.3)
.delta. 2.20-2.32 (m, 1H), 2.42-2.53 (m, 1H) 2.57-2.78 (m, 2H),
4.28 (dd=4.6, 8.1 Hz, 1H), 6.95 (dd, J=2.1, 7.6 Hz, 2H), 7.23 (d
J=2.0 Hz, 1H), 7.37-50 (m, 3H), 8.13 (d, J=7.6 Hz, 1H).
[.alpha.]=-66.degree. (c=1, acetone).
[0078] Synthesis of
(S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone. The
previous procedure was used, starting from
(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
tert-butanesulfinimine. 1.7 g of product (>99% ee) was obtained.
[.alpha.]=+62 (c=1, acetone). .sup.1H NMR spectrum of the product
is the same as that of its enantiomer.
[0079] Synthesis of (1S,4R) and
(1R,4R)--N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-fo-
rmamide: (R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone
(1.2 g) was added formic acid (3 mL) and formamide (3 mL). The
reaction mixture was heated to 160-165.degree. C. for 15 h under
nitrogen atmosphere. The reaction mixture was cooled to rt and
decanted the solvent. The residue solids was passed through flash
column using EtOAc:Hexane (3:7 to 1:1) to give the
(1R,4R)-formamide (400 mg, first spot), and the (1S,4R)-formamide
(360 mg). .sup.1H NMR of the first product [(1R,4R)-isomer]:
(CDCl.sub.3) .delta. 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H),
4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90
(M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H). M+320.
.sup.1H NMR of the second product [(1S,4R)-isomer: .delta.
1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m,
1H), 5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28
(s, 1H). Mass Spec. M.sup.+ 320.
[0080] Synthesis of (1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl:
(1S,4R) formamide (ca 300 mg) was dissolved in MeOH (5 mL) followed
by addition of 6N HCl (6 mL). The reaction mixture was heated to
80.degree. C. for 2 h. The reaction mixture was cooled to rt for 1
h and filtered to collect the solid. It was washed with acetone (3
mL) and dried to give the product (280 mg). Enantiomeric purity was
determined to be >99.8% by HPLC analysis with a ChiralPak AD 10
.mu.m, 4.6.times.250 mm, Hexane/IPA/DEA (99:1:0.1), UV 220 nm,
(1R,4S)-isomer, 11.00 min. (1S,4R)-isomer 11.70 min
[.alpha.]=-51.degree. (C=1, MeOH). .sup.1H NMR (CD.sub.3OD) .delta.
1.86-1.97 (m, 2H), 2.20-2.42 (m, 2H), 4.30 (broad s, 1H), 4.67
(broad s, 1H), 4.87 (s, 3H), 6.95-6.99 (m, 2H), 7.18 (s, 1H),
7.28-7.50 (m, m, 4H). M' 293.
[0081] Synthesis of (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It
was obtained similarly from (1R,4S) formamide with HCl hydrolysis.
Ee of the product is >99.8% based on HPLC analysis with a
ChiralPak AD 10 .mu.m, 4.6.times.250 mm, Hexane/IPA/DEA (99:1:0.1),
UV 220 nm, (1R,4S)-isomer 11.00 min. (1S,4R)-isomer 11.70 min.
[0082] Synthesis of (1R,4R)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It
was obtained similarly from (1R,4R) formamide with HCl hydrolysis.
Enantiomeric purity was determined to be 96.8% by HPLC analysis
with a ChiralPak AD 10 .mu.m, 4.6.times.250 mm, Hexane/IPA/DES
(99:1:0.1), UV 220 nm, (1R,4R)-isomer 11.84 min. (1S,4S)-isomer
9.80 min. .sup.1H NMR (CD.sub.3OD) .delta. 1.96-2.26 (m, 4H),
4.14-4.22 (m, 1H), 4.54-4.63 (m, 1H), 4.87 (s, 3H), 7.88-7.94 (m,
1H), 7.18-7.20 (m, 1H), 7.30-7.50 (m, 5H). Mass Spec M.sup.+
292.
[0083] Synthesis of (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It
was obtained similarly from (1S,4S) formamide. Ee of the product
was 98.5% by HPLC analysis. .sup.1H NMR spectrum is the same as the
enantiomer. Mass Spec M.sup.+ 292.
[0084] Alternatively, compound P may be prepared as illustrated
below in Scheme 3 and its accompanying narrative.
##STR00012##
[0085] Charge
4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naphthalen-1-one (1 kg,
3.4 mol) and (R)-tert-butylsulphinamide (TBSA, 464 g, 3.8 mol) to a
suitable reactor and dissolved in about 7 L THF. Add a 20% wt
solution of Titanium ethoxide in ethanol (about 7.8 kg, 6.9 mol)
and heat the mixture to about 70.degree. C. for about 24 h. The
reaction is monitored by HPLC, and after the reaction is complete,
cool the mixture to room temperature and added a 24% wt aqueous
solution of NaCl to the mixture. The resultant slurry was filtered
and washed multiple times with about 1 L total of ethyl acetate.
The mother liquors and washes were concentrated to a minimum
volume. The aqueous phase was extracted with about 5 L of ethyl
acetate and evaporated to dryness.
[0086] The contents were then dissolved in about 7 L of THF and
cooled to about -10.degree. C. About 9 kg, (.about.5 mol) of a 0.5
M solution of 9-borabicyclononane (9-BBN) in THF, was added slowly
(about 3 h) and the mixture was stirred at 0.degree. C. until
reaction completion. A 6N HCl/methanol (.about.2 L) was added to
the mixture and stirred until the hydrolysis reaction was complete.
After neutralization with about 2 L of 6N aqueous NaOH, the mixture
was distilled to remove THF and the residue (aqueous phase) was
extracted twice with methyl t-butyl ether (2.times.6 L). The
organic phase was then washed with water. The organic phase was
concentrated, then cooled to 0.degree. C. followed by addition of
2N HCl in methyl t-butyl ether (3 L). The product slowly
precipitated as the HCl salt during the addition. The slurry was
filtered and washed with methyl t-butyl ether (2.times.2 L). The
product was dried under vacuum at about 45.degree. C. to afford
about 850 g of Re-Crystallization of crude
(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamine
HCl.
[0087] The resulting
(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamine
HCl (850 g) was charged to a suitable reactor and about 30 L of
denatured ethanol was added. The mixture was heated to reflux, the
volume was reduced to about 50% via distillation, and then cooled
to 50.degree. C. About 30 L of Hexane was added to the slurry to
complete the product crystallization and then the slurry was cooled
to about 0.degree. C. The product was isolated by filtration, the
cake was washed with about 2 L of ethanol/hexane (1/3 v/v) and then
about 2 L of ethyl acetate, followed by about 3 L of hexane. The
wet cake was dried under vacuum at about 45.degree. C. to afford
630 g of product.
[0088] Another alternative process for preparation of compound P is
presented below.
[0089] 4-(S)-(3,4-dichloro-phenyl)-3,4-dichloro-2H-naphthalen-1-one
(4.11 kg) and (R)-tert-butylsulphinamide (TBSA, 1.9 kg) were
charged to a suitable reactor and dissolved in 29 L THF. A 20% wt
solution of titanium ethoxide in ethanol (31.6 kg) was added and
the mixture was heated to 70.degree. C. with stirring. The reaction
is monitored by HPLC, and after the reaction was complete (20-24 h)
the mixture was cooled to room temperature and added to 20 L of a
24 wt % aqueous solution of NaCl. The resultant slurry was filtered
and washed 3 times with ethyl acetate (4.1 L). The mother liquors
and washes were concentrated to a minimum volume. The aqueous phase
was extracted with about 20 L of a 1:1 mix of ethyl acetate and
toluene. The organic phases were combined and concentrated to half
volume to give a solution of 2. A purified sample of 2 was
analyzed: m.p. 104.degree. C., .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ppm) 8.23 (dd, 1H, J=7.9, 0.9 Hz), 7.38 (ddd, 1H, J=14.7,
7.3, 1.5 Hz), 7.37 (d, 1H, J=8.4 Hz), 7.33 (d, 1H, J=7.7 Hz), 7.17
(d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=7.7 Hz), 6.89 (dd, 1H, J=8.4, 2.2
Hz), 4.18 (dd, 1H, J=7.3, 4.8 Hz), 3.36 (ddd, 1H, J=17.5, 8.8, 4.4
Hz), 2.93 (ddd, 1H, J=17.6, 8.3, 4.2 Hz), 2.33 (m, 1H), 2.15 (m,
1H), 1.34 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
175.8, 144.2, 142.7, 132.6, 130.8, 130.7, 129.7, 128.1, 127.6,
127.4, 57.8, 44.3, 31.1, 29.4, 22.8. HRMS calc for
C.sub.20H.sub.21Cl.sub.2NOS 394.0799. found 394.0767.
[0090] The solution of imine (2) was cooled to -10.degree. C. and
36.3 kg of a 0.5 M solution of 9-borabicyclononane (9-BBN) in THF,
was added slowly (over 3 h) and the mixture was stirred at
0.degree. C. until reaction completion. A 4N HCl/methanol (8 L) was
added to the mixture and stirred until the hydrolysis reaction was
complete. After neutralization with about 15 kg of 6N aqueous NaOH
(pH 8), the mixture was distilled to remove THF and methanol. The
residue (aqueous phase) was extracted twice with methyl t-butyl
ether (2.times.16 L). The organic phase was then washed with water.
The organic phase was concentrated, then cooled to 0.degree. C.
followed by addition of 2N HCl in methyl t-butyl ether (5.4 kg).
The product precipitated as the HCl salt. The slurry was filtered,
washed with methyl t-butyl ether (2.times.8 L) and dried under
vacuum at 45.degree. C. to afford about 3.73 kg of crude
(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamine
HCl (compound P). A purified sample of P was analyzed: m.p.
152-154.degree. C., .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm)
7.58 (d, 1H, J=7.7 Hz), 7.29 (m, 2H), 7.18 (br. t, 1H, J=7.5 Hz),
7.09 (d, 1H, J=1.8 Hz), 6.87 (d, 1H, J=7.7 Hz), 6.80 (dd, 1H,
J=8.3, 2.0 Hz), 4.65 (dd, 1H, J=4.4, 4.4 Hz), 4.15 (t, 1H, J=5.5
Hz), 3.30 (d, 1H, J=3.7 Hz), 2.35 (m, 1H), 1.95 (m, 1H), 1.85 (m,
1H), 1.75 (m, 1H), 1.23 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 147.1, 138.4, 138.0, 132.6, 130.8, 130.6, 130.5, 129.8,
128.3, 127.9, 55.8, 53.3, 44.0, 28.2, 27.7, 22.9. HRMS calc for
C.sub.20H.sub.23Cl.sub.2NOS 396.0956. found 396.0968.
[0091] The crude
(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamine
HCl (3.63 kg) was charged to a suitable reactor and 128 L of
denatured ethanol was added. The mixture was stirred at reflux and
polish filtered. The volume was reduced to about 50% via
distillation, and then cooled to 50.degree. C. 80 L of heptane was
added to the slurry to complete the product crystallization and
then the slurry was cooled to -5.degree. C. The product was
filtered, the cake was washed twice with 5.7 L of ethanol/heptane
(1/1 v/v) and then washed with 6 L of hexane. The wet cake was
dried under vacuum at about 45.degree. C. to afford 2.57 kg of
product. The product had a chemical purity of 99.65 A % and a
diastereomeric purity in excess of 99%.
[0092] Thus, the invention is also directed to a novel method of
preparation of compound P as a free base or as an acid addition
salt. In one embodiment, the process for preparation of compound
P
##STR00013##
comprises: [0093] a) reacting a compound of formula 1
##STR00014##
[0093] with
##STR00015##
[0094] wherein Z is chosen from aryl, aryl substituted by alkyl,
alkyl substituted by aryl, and --CR.sup.4R.sup.5R.sup.6, wherein
R.sup.4 is C.sub.1-C.sub.6 alkyl, R.sup.5 is C.sub.1-C.sub.6 alkyl,
and R.sup.6 is C.sub.1-C.sub.6 alkyl,
[0095] in presence of a dehydrating agent to obtain compound of
formula 2a
##STR00016##
and [0096] b) reducing the compound of formula 2a with a hydride
reducing agent followed by solvolysis.
[0097] In one embodiment, Z is tert-butyl, wherein each of R.sup.4,
R.sup.5, and R.sup.6 is methyl.
[0098] In one embodiment, the solvolysis is catalyzed by acid. In
an optional further step, the process further comprises
crystallizing an acid addition salt of the compound of formula
P.
[0099] In another embodiment, the process further involves
recrystallizing an acid addition salt of the compound of formula P
from a solvent selected from an alcohol and a mixture of alcohol
and hydrocarbon solvent. An example of hydrocarbon solvent is
toluene.
[0100] At any point, when an acid addition salt of compound P is
obtained, a further step may be performed of converting of an acid
addition salt to a free base of compound P. The converting step may
comprise treating with a base.
[0101] The dehydrating agent may be selected from titanium
alkoxide, boron trifluoride etherate, boron trifluoride etherate
with magnesium sulfate, and molecular sieves. The titanium alkoxide
may be selected from titanium ethoxide and titanium
isopropoxide.
[0102] The reducing agent may selected from 9-borabicyclononane,
sodium borohydride, catechol borane, borane, and diisobutylaluminum
hydride with zinc halide. The reducing step may be carried out in a
solvent comprising tetrahydrofuran.
[0103] The acid that may be used in the solvolysis step may be a
hydrochloric acid. The solvolysis step may be a hydrolysis
reaction, or may be performed under non-aqueous conditions, for
example, by use of methanol/acid mixture.
[0104] The compounds P and Q were tested for their inhibition of
functional uptake of serotonin (5-HT), norepinephrine (NE), or
dopamine (DA), in synaptosomes prepared from rat whole brain,
hypothalamus, or corpus striatum, respectively. Compounds were
tested initially at 10 .mu.M in duplicate, and if .gtoreq.50%
inhibition of uptake was observed, they were tested further at 10
different concentrations in duplicate in order to obtain full
inhibition curves. IC.sub.50 values (concentration inhibiting
control activity by 50%) were then determined by nonlinear
regression analysis of the inhibition curves and tabulated below in
the Examples section.
Combination Therapy
[0105] One aspect of the present invention relates to combination
therapy. This type of therapy is advantageous because the
co-administration of active ingredients achieves a therapeutic
effect that is greater than the therapeutic effect achieved by
administration of only a single therapeutic agent. In one
embodiment, the co-administration of two or more therapeutic agents
achieves a synergistic effect, i.e., a therapeutic affect that is
greater than the sum of the therapeutic effects of the individual
components of the combination. In another embodiment, the
co-administration of two or more therapeutic agents achieves an
augmentation effect.
[0106] The active ingredients that comprise a combination therapy
may be administered together via a single dosage form or by
separate administration of each active agent. In certain
embodiments, the first and second therapeutic agents are
administered in a single dosage form. The agents may be formulated
into a single tablet, pill, capsule, or solution for parenteral
administration and the like.
[0107] Alternatively, the first therapeutic agent and the second
therapeutic agents may be administered as separate compositions,
e.g., as separate tablets or solutions. The first active agent may
be administered at the same time as the second active agent or the
first active agent may be administered intermittently with the
second active agent. The length of time between administration of
the first and second therapeutic agent may be adjusted to achieve
the desired therapeutic effect. In certain instances, the second
therapeutic agent may be administered only a few minutes (e.g., 1,
2, 5, 10, 30, or 60 min) after administration of the first
therapeutic agent. Alternatively, the second therapeutic agent may
be administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr)
after administration of the first therapeutic agent. In certain
embodiments, it may be advantageous to administer more than one
dosage of the second therapeutic agent between administrations of
the first therapeutic agent. For example, the second therapeutic
agent may be administered at 2 hours and then again at 10 hours
following administration of the first therapeutic agent.
Alternatively, it may be advantageous to administer more than one
dosage of the first therapeutic agent between administrations of
the second therapeutic agent. Importantly, it is preferred that the
therapeutic effects of each active ingredient overlap for at least
a portion of the duration of each therapeutic agent so that the
overall therapeutic effect of the combination therapy is
attributable in part to the combined or synergistic effects of the
combination therapy.
[0108] The dosage of the active agents will generally be dependent
upon a number of factors including pharmacodynamic characteristics
of each agent of the combination, mode and route of administration
of active agent(s), the health of the patient being treated, the
extent of treatment desired, the nature and kind of concurrent
therapy, if any, and the frequency of treatment and the nature of
the effect desired. In general, dosage ranges of the active agents
often range from about 0.001 to about 250 mg/kg body weight per
day. For example, for a normal adult having a body weight of about
70 kg, a dosage in the range of from about 0.1 to about 25 mg/kg
body weight is typically preferred. However, some variability in
this general dosage range may be required depending upon the age
and weight of the subject being treated, the intended route of
administration, the particular agent being administered and the
like. Since two or more different active agents are being used
together in a combination therapy, the potency of each agent and
the interactive effects achieved using them together must be
considered. Importantly, the determination of dosage ranges and
optimal dosages for a particular mammal is also well within the
ability of one of ordinary skill in the art having the benefit of
the instant disclosure.
[0109] In certain embodiments, it may be advantageous for the
pharmaceutical combination to have a relatively large amount of the
first component compared to the second component. In certain
instances, the ratio of the first active agent to second active
agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. In
certain embodiments, it may be preferable to have a more equal
distribution of pharmaceutical agents. In certain instances, the
ratio of the first active agent to the second active agent is 4:1,
3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. In certain embodiments, it may be
advantageous for the pharmaceutical combination to have a
relatively large amount of the second component compared to the
first component. In certain instances, the ratio of the second
active agent to the first active agent is 30:1, 20:1, 15:1, 10:1,
9:1, 8:1, 7:1, 6:1, or 5:1. Importantly, a composition comprising
any of the above-identified combinations of first therapeutic agent
and second therapeutic agent may be administered in divided doses
1, 2, 3, 4, 5, 6, or more times per day or in a form that will
provide a rate of release effective to attain the desired results.
In a preferred embodiment, the dosage form contains both the first
and second active agents. In a more preferred embodiment, the
dosage form only has to be administered one time per day and the
dosage form contains both the first and second active agents.
[0110] For example, a formulation intended for oral administration
to humans may contain from 0.1 mg to 5 g of the first therapeutic
agent and 0.1 mg to 5 g of the second therapeutic agent, both of
which are compounded with an appropriate and convenient amount of
carrier material varying from about 5 to about 95 percent of the
total composition. Unit dosages will generally contain between from
about 0.5 mg to about 1500 mg of the first therapeutic agent and
0.5 mg to about 1500 mg of the second therapeutic agent. In a
preferred embodiment, the dosage comprises 0.5 mg, 1 mg, 2 mg, 3
mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400
mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the
first therapeutic agent. In a preferred embodiment, the dosage
comprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50
mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000
mg, etc., up to 1500 mg of the second therapeutic agent. The
optimal ratios of the first and second therapeutic agent can be
determined by standard assays known in the art.
[0111] The toxicity and therapeutic efficacy of compositions of the
invention can be determined by standard pharmaceutical procedures
in cell cultures or experimental animals, e.g., for determining the
LD.sub.50 (the dose lethal to 50% of the population) and the
ED.sub.50 (the dose therapeutically effective in 50% of the
population). The dose ratio between toxic and therapeutic effects
is the therapeutic index and it can be expressed as the ratio
LD.sub.50/ED.sub.50. Compounds which exhibit large therapeutic
indices are preferred. The data obtained from these cell culture
assays and animal studies can be used in formulating a range of
dosage for use in humans. The dosage of such compounds lies
preferably within a range of circulating concentrations that
include the ED.sub.50 with little or no toxicity. The dosage may
vary within this range depending upon the dosage form employed and
the route of administration utilized. For any compound used in the
method of the invention, the therapeutically effective dose can be
estimated initially from cell culture assays. A dose may be
formulated in animal models to achieve a circulating plasma
concentration range that includes the IC.sub.50 (i.e., the
concentration of the test compound which achieves a half-maximal
inhibition of RT production from infected cells compared to
untreated control as determined in cell culture. Such information
can be used to more accurately determine useful doses in humans.
Levels in plasma may be measured, for example, by high performance
liquid chromatography (HPLC).
Synergism and Augmentation
[0112] The term "synergistic" refers to a combination which is more
effective than the additive effects of any two or more single
agents. A synergistic effect permits the effective treatment of a
disease using lower amounts (doses) of either individual therapy.
The lower doses result in lower toxicity without reduced efficacy.
In addition, a synergistic effect can result in improved efficacy,
e.g., improved antidepressant activity. Finally, synergy may result
in an improved avoidance or reduction of disease as compared to any
single therapy.
[0113] Combination therapy can allow for the use of lower doses of
the first therapeutic or the second therapeutic agent (referred to
as "apparent one-way synergy" herein), or lower doses of both
therapeutic agents (referred to as "two-way synergy" herein) than
would normally be required when either drug is used alone.
[0114] In certain embodiments, the synergism exhibited between the
second therapeutic agent and the first therapeutic agent is such
that the dosage of the first therapeutic agent would be
sub-therapeutic if administered without the dosage of the second
therapeutic agent. Alternatively, the synergism exhibited between
the second therapeutic agent and the first therapeutic agent is
such that the dosage of the second therapeutic agent would be
sub-therapeutic if administered without the dosage of the first
therapeutic agent.
[0115] The terms "augmentation" or "augment" refer to combination
where one of the compounds increases or enhances therapeutic
effects of another compound or compounds administered to a patient.
In some instances, augmentation can result in improving the
efficacy, tolerability, or safety, or any combination thereof, of a
particular therapy.
[0116] In certain embodiments, the present invention relates to a
pharmaceutical composition comprising a therapeutically effective
dose of a first therapeutic agent together with a dose of a second
therapeutic agent effective to augment the therapeutic effect of
the first therapeutic agent. In other embodiments, the present
invention relates to methods of augmenting the therapeutic effect
in a patient of a first therapeutic agent by administering the
second therapeutic agent to the patient. In other embodiments, the
present invention relates to a pharmaceutical composition
comprising an therapeutically effective dose of a second
therapeutic agent together with a dose of a first therapeutic agent
effective to augment the therapeutic effect of the second
therapeutic agent. In other embodiments, the present invention
relates to methods of augmenting the therapeutic effect in a
patient of a second therapeutic agent by administering the first
therapeutic agent to the patient.
[0117] In certain preferred embodiments, the invention is directed
in part to synergistic combinations of the first therapeutic agent
in an amount sufficient to render a therapeutic effect together
with a second therapeutic agent. For example, in certain
embodiments a therapeutic effect is attained which is at least
about 2 (or at least about 4, 6, 8, or 10) times greater than that
obtained with the dose of the first therapeutic agent alone. In
certain embodiments, the synergistic combination provides a
therapeutic effect which is up to about 20, 30 or 40 times greater
than that obtained with the dose of first therapeutic agent alone.
In such embodiments, the synergistic combinations display what is
referred to herein as an "apparent one-way synergy", meaning that
the dose of second therapeutic agent synergistically potentiates
the effect of the first therapeutic agent, but the dose of first
therapeutic agent does not appear to significantly potentiate the
effect of the second therapeutic agent.
[0118] In certain embodiments, the combination of active agents
exhibit two-way synergism, meaning that the second therapeutic
agent potentiates the effect of the first therapeutic agent, and
the first therapeutic agent potentiates the effect of the second
therapeutic agent. Thus, other embodiments of the invention relate
to combinations of a second therapeutic agent and a first
therapeutic agent where the dose of each drug is reduced due to the
synergism between the drugs, and the therapeutic effect derived
from the combination of drugs in reduced doses is enhanced. The
two-way synergism is not always readily apparent in actual dosages
due to the potency ratio of the first therapeutic agent to the
second therapeutic agent. For instance, two-way synergism can be
difficult to detect when one therapeutic agent displays much
greater therapeutic potency relative to the other therapeutic
agent.
[0119] The synergistic effects of combination therapy may be
evaluated by biological activity assays. For example, the
therapeutic agents are be mixed at molar ratios designed to give
approximately equipotent therapeutic effects based on the EC.sub.90
values. Then, three different molar ratios are used for each
combination to allow for variability in the estimates of relative
potency. These molar ratios are maintained throughout the dilution
series. The corresponding monotherapies are also evaluated in
parallel to the combination treatments using the standard primary
assay format. A comparison of the therapeutic effect of the
combination treatment to the therapeutic effect of the monotherapy
gives a measure of the synergistic effect. Further details on the
design of combination analyses can be found in B E Korba (1996)
Antiviral Res. 29:49. Analysis of synergism, additivity, or
antagonism can be determined by analysis of the aforementioned data
using the CalcuSyn.TM. program (Biosoft, Inc.). This program
evaluates drug interactions by use of the widely accepted method of
Chou and Talalay combined with a statistically evaluation using the
Monte Carlo statistical package. The data are displayed in several
different formats including median-effect and dose-effects plots,
isobolograms, and combination index [CI] plots with standard
deviations. For the latter analysis, a CI greater than 1.0
indicates antagonism and a CI less than 1.0 indicates
synergism.
[0120] Compositions of the invention present the opportunity for
obtaining relief from moderate to severe cases of disease. Due to
the synergistic and/or additive effects provided by the inventive
combination of the first and second therapeutic agent, it may be
possible to use reduced dosages of each of therapeutic agent. By
using lesser amounts of other or both drugs, the side effects
associated with each may be reduced in number and degree. Moreover,
the inventive combination avoids side effects to which some
patients are particularly sensitive.
FORMULATIONS AND DEFINITIONS
[0121] Pharmaceutical compositions of the present invention may be
administered by any suitable route of administration that provides
a patient with a therapeutically effective dosage of the active
ingredients. Typically, the pharmaceutical compositions described
herein will be formulated for oral administration or for
inhalation. Suitable dosage forms include tablets, troches,
cachets, caplets, capsules, including hard and soft gelatin
capsules, and the like. Tablet forms, however, remain a preferred
dosage form because of advantages afforded both the patient (e.g.,
accuracy of dosage, compactness, portability, blandness of taste
and ease of administration) and to the manufacturer (e.g.,
simplicity and economy of preparation, stability and convenience in
packaging, shipping and dispensing).
[0122] The pharmaceutical compositions may further include a
"pharmaceutically acceptable inert carrier" and this expression is
intended to include one or more inert excipients, which include
starches, polyols, granulating agents, microcrystalline cellulose,
diluents, lubricants, binders, disintegrating agents, and the like.
If desired, tablet dosages of the disclosed compositions may be
coated by standard aqueous or nonaqueous techniques. In one
embodiment, coating with hydroxypropylmethylcellulose (HPMC) is
employed. "Pharmaceutically acceptable carrier" also encompasses
controlled release means. Compositions of the present invention may
also optionally include other therapeutic ingredients, anti-caking
agents, preservatives, sweetening agents, colorants, flavors,
desiccants, plasticizers, dyes, and the like. However, any such
optional ingredient must be compatible with combination of active
ingredients to insure the stability of the formulation.
[0123] The term "pharmaceutically acceptable salt" refers to salts
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic acids and bases and organic acids and bases.
When the compounds of the present invention are basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids including
inorganic and organic acids. Suitable pharmaceutically acceptable
acid addition salts for the compounds of the present invention
include acetic, benzenesulfonic (besylate), benzoic,
camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic,
glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic, and the like. When the compounds contain an
acidic side chain, suitable pharmaceutically acceptable base
addition salts for the compounds of the present invention include
metallic salts made from aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc or organic salts made from lysine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. In one embodiment, eszopiclone is formulated as a
succinate salt. In another embodiment, eszopiclone is formulated as
a fumarate salt.
[0124] Eszopiclone, trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine,
and trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine are
chiral compounds that can exist as a racemic mixture, a non-equal
mixture of enantiomers, or as a single enantiomer. Importantly, the
recitation of a compound that can exist as a racemic mixture, a
non-equal mixture of enantiomers, or a single enantiomer is meant
to encompass all three aforementioned forms, unless stated
otherwise. The term "enantiomeric excess" is well known in the art
and is defined for a resolution of ab into a+b as:
ee a = ( conc . of a - conc . of b conc . of a + conc . of b )
.times. 100 ##EQU00001##
[0125] The term "enantiomeric excess" is related to the older term
"optical purity" in that both are measures of the same phenomenon.
The value of e.e. will be a number from 0 to 100, zero being
racemic and 100 being pure, single enantiomer. A compound which in
the past might have been called 98% optically pure is now more
precisely described as 96% e.e.; in other words, a 90% e.e.
reflects the presence of 95% of one enantiomer and 5% of the other
in the material in question. In instances when a specific
enantiomer is recited (e.g., eszopiclone) for use in the
compositions or methods of the present invention, this indicates
that the composition contains a significantly greater proportion of
the specified enantiomer in relation to the non-specified
enantiomer. In a preferred embodiment, compositions comprising a
specified enantiomer contain the specified enantiomer in at least
90% e.e. More preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 95% e.e.
Even more preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 98% e.e.
Most preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 99%
e.e.
[0126] For example, compositions comprising eszopiclone contain the
S-enantiomer of zopiclone in at least 90% e.e. More preferably,
compositions comprising eszopiclone contain the S-enantiomer of
zopiclone in at least 95% e.e. Even more preferably, such
compositions comprising eszopiclone contain the S-enantiomer of
zopiclone in at least 98% e.e. Most preferably, such compositions
comprising eszopiclone contain the S-enantiomer of zopiclone in at
least 99% e.e.
[0127] The graphic representations of racemic, ambiscalemic and
scalemic or enantiomerically pure compounds used herein are taken
from Maehr, J. Chem. Ed., 62:114-120 (1985): solid and broken
wedges are used to denote the absolute configuration of a chiral
element; wavy lines indicate disavowal of any stereochemical
implication which the bond it represents could generate; solid and
broken bold lines are geometric descriptors indicating the relative
configuration shown but not implying any absolute stereochemistry;
and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
[0128] The term "antagonist" refers to a compound that binds to a
receptor binding site, but does not activate the receptor, a
compound that binds to a receptor and blocks receptor binding site,
or a compound that binds to an allosteric site on a receptor
(non-competitive antagonist) resulting in prevention of activation
of the receptor by its ligand. The resulting inhibition of the
receptor may vary in degree and duration.
[0129] The term "patient" refers to a mammal in need of a
particular treatment. In a preferred embodiment, a patient is a
primate, canine, feline, or equine. In another preferred
embodiment, a patient is a human.
[0130] The terms "co-administration" and "co-administering" refer
to both concurrent administration (administration of two or more
therapeutic agents at the same time) and time varied administration
(administration of one or more therapeutic agents at a time
different from that of the administration of an additional
therapeutic agent or agents), as long as the therapeutic agents are
present in the patient to some extent at the same time.
[0131] The term "solvate" refers to a pharmaceutically acceptable
form of a specified compound, with one or more solvent molecules,
that retains the biological effectiveness of such compound.
Examples of solvates include compounds of the invention in
combination with solvents such, for example, water (to form the
hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl
acetate, acetic acid, ethanolamine, or acetone. Also included are
formulations of solvate mixtures such as a compound of the
invention in combination with two or more solvents.
[0132] The term "disorders" as used herein includes menopause,
perimenopause, mood disorders, anxiety disorders, and cognitive
disorders.
[0133] The term "menopause" as used herein includes various
symptoms of menopause and perimenopause, such as hot flashes,
awakenings due to hot flashes, nocturnal awakenings, and mood
disorders associated with menopause or perimenopause, such as
depression and anxiety.
[0134] The term "mood disorder" as used herein includes major
depression, major depressive disorder, mild depression, severe
depression without psychosis, severe depression with psychosis,
melancholia (formerly endogenous depression), atypical depression,
dysthymic disorder, manic depression, bipolar disorder, bipolar I
disorder, bipolar II disorder, bipolar III disorder, cyclothymic
disorder, and chronic hypomania.
[0135] The term "mood disorder" as used herein also includes
premenstrual syndrome (PMS), premenstrual dysphoric disorder
(PMDD), prenatal depression, and postpartum depression.
[0136] The term "anxiety disorder" as used herein refers to panic
attacks, panic disorder, phobic disorders (such as agoraphobia,
specific phobias, social phobia, avoidant personality disorder),
obsessive-compulsive disorder (OCD), posttraumatic stress disorder,
acute stress disorder, and generalized Anxiety Disorder.
[0137] The term "cognitive disorder" as used herein refers to
delirium (acute confusional state), dementia, Alzheimer's Disease,
Lewy body dementia, vascular dementia, Binswanger's dementia
(subcortical arteriosclerotic encephalopathy), Parkinson's disease,
progressive supranuclear palsy, Huntington's disease (chorea),
Pick's disease, Kluver-Bucy syndrome, frontal lobe dementia
syndromes, normal-pressure hydrocephalus, subdural hematoma,
Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease,
general paresis, and AIDS dementia. The term "cognitive disorder"
as used herein also includes decreased cognitive function and
memory loss.
[0138] The term "treating" when used in connection with the
disorders means amelioration, prevention or relief from the
symptoms and/or effects associated with these disorders and
includes the prophylactic administration of the compositions of the
invention, or pharmaceutically acceptable salt thereof, to
substantially diminish the likelihood or seriousness of the
condition.
[0139] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Examples
Example 1
Formulations
[0140] The following formulations are exemplary of eszopiclone and
trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
combination tablet or capsule formulations:
TABLE-US-00001 TABLE 1 Eszopiclone and trans
4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-1-napthalenamine compositions Combo Strengths
(Eszopiclone/trans 4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-N-
Ingredient methyl-1-napthalenamine, mg/unit) (Tablet and Capsule)
3.0/25.0 3.0/50.0 3.0/100.0 Eszopiclone 3.00 3.00 3.00 trans 4-(3,4
-dichlorophenyl)- 28.00 56.00 112.00 1,2,3,4-tetrahydro-N-methyl-1-
napthalenamine HCl.sup.1 Microcrystalline Cellulose, NF 198.90
198.90 198.90 (Avicel .RTM. PH102) Dibasic Calcium Phosphate 90.00
90.00 90.00 Anhydrous USP Croscarmellose Sodium, NF 6.00 6.00 6.00
Colloidal Silicon Dioxide, NF 0.60 0.60 0.60 Magnesium Stearate, NF
1.50 1.50 1.50 Total tablet wt. or capsule fill wt. 328.00 356.00
412.00 Empty Size 0 hard gelatin 90.00 90.00 90.00 capsule wt.
Total weight of filled capsule 418.00 446.00 502.00 .sup.1trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
HCl potency is expressed in terms of free base. 1.12 mg trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
HCl is equivalent to 1.00 mg of free base.
TABLE-US-00002 TABLE 2 Eszopiclone and trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine
compositions Combo Strengths (Eszopiclone/trans 4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-1- Ingredient napthalenamine,
mg/unit) (Tablet and Capsule) 3.0/25.0 3.0/50.0 3.0/100.0
Eszopiclone 3.00 3.00 3.00 trans 4-(3,4-dichlorophenyl)- 28.00
56.00 112.00 1,2,3,4-tetrahydro-1- napthalenamine HCl.sup.1
Microcrystalline Cellulose, NF 198.90 198.90 198.90 (Avicel .RTM.
PH102) Dibasic Calcium Phosphate 90.00 90.00 90.00 Anhydrous USP
Croscarmellose Sodium, NF 6.00 6.00 6.00 Colloidal Silicon Dioxide,
NF 0.60 0.60 0.60 Magnesium Stearate, NF 1.50 1.50 1.50 Total
tablet wt. or capsule fill wt. 328.00 356.00 412.00 Empty Size 0
hard gelatin 90.00 90.00 90.00 capsule wt. Total weight of filled
capsule 418.00 446.00 502.00 .sup.1trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl
potency is expressed in terms of free base. 1.12 mg trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl is
equivalent to 1.00 mg of free base.
[0141] The above-presented formulations may be prepared by
performing the following steps: [0142] 1. Screen eszopiclone
through 80 mesh. [0143] 2. Screen trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
through 40 mesh. [0144] 3. Screen remaining ingredients through #20
or #30 mesh screen. [0145] 4. Blend eszopiclone with a portion of
MCC (microcrystalline cellulose). [0146] 5. Blend trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
with the blend from Step 4. [0147] 6. Blend the mixture from Step 5
with remaining MCC in three steps. [0148] 7. Blend mixture from
Step 6 with dicalcium phosphate. [0149] 8. Mix croscarmellose with
silicon dioxide, then blend with the mixture from Step 7. [0150] 9.
Blend mixture from Step 8 with magnesium stearate. [0151] 10. For
tablets, compress on a suitable tablet press machine. [0152] 11.
For capsules, fill into Size 0 hard gelatin capsules on a suitable
capsule filling machine. [0153] 12. For tablets, coat the tablet
cores from Step 10 with Opadry II in a suitable conventional tablet
coating machine.
Example 2
Clinical Study on Treatment of Menopause or Perimenopause with
Eszopiclone
[0154] The study was aimed at observing efficacy of eszopiclone 3
mg compared to placebo in the treatment of insomnia secondary to
perimenopause or menopause.
[0155] The study was a multicenter, randomized, double-blind,
placebo-controlled, parallel-group study. The study had a one-week
single-blind placebo run-in period, followed by four weeks of
double blind treatment, and one week of single blind placebo
wash-out. The primary method of analysis compared the
post-randomization results between the two treatment groups.
[0156] Subjects were women with insomnia secondary to perimenopause
or menopause. Subjects were perimenopausal or menopausal and had
insomnia symptoms including .gtoreq.45 minutes sleep latency (SL)
and total sleep time (TST) .ltoreq.6 hours.
Perimenopausal/menopausal symptoms predated the onset of sleep
disturbance symptoms. The patient population was predominately
Caucasian (77.2%). The mean age was 49, with a range of 40-60.
[0157] A total of 410 subjects were randomized. Among them, 201
received 3 mg of eszopiclone (ESZ) nightly (at bedtime) for four
weeks and 209 received matching placebo (PBO). The discontinuation
rates were moderate, 11.9% in the ESZ group and 12.9% in the PBO
group.
[0158] The ESZ group had significantly fewer nocturnal awakenings
due to hot flashes during Week 1 compared with PBO (LS means of 0.3
and 0.5 per night for ESZ and PBO, respectively; p=0.0016). This
effect was not significant for the other weeks, but was marginally
significant for the DB average (p=0.059). When change from baseline
was analyzed, ESZ significantly reduced the number of nocturnal
awakenings due to hot flashes in Week 1 compared with PBO
(p<0.0001). The difference was not significant for Week 2, but
was marginally significant for Weeks 3 and 4 (p=0.094 and 0.055,
respectively) and was significant for the DB average (p=0.0045).
See Table 3.
TABLE-US-00003 TABLE 3 Number of Nocturnal Awakenings due to Hot
Flashes (Intent-to-Treat Population) Placebo Eszopiclone 3 mg
Change Change Time Observed from Observed from Point Statistic
Value Baseline [1] Value Baseline [1] Baseline N 171 150 Mean (SD)
1.1 (1.2) 1.3 (1.2) 25th Percentile 0.0 0.3 Median 1.0 1.0 75th
Percentile 1.5 2.0 Minimum, Maximum 0.0, 10.0 0.0, 6.0 Week 1 N 179
157 175 140 Mean (SD) 0.8 (1.0) -0.2 (0.9) 0.5 (0.7) -0.7 (1.0)
25th Percentile 0.0 -0.7 0.0 -1.2 Median 0.5 0.0 0.2 -0.5 75th
Percentile 1.3 0.2 1.0 0.0 Minimum, Maximum 0.0, 5.0 -5.0, 2.3 0.0,
3.0 -6.0, 0.8 Least Squares Means 0.8 (0.1) 0.5 (0.1) (SE) [2]
p-value vs. placebo [2] <.0001 Least Squares Means -0.3 (0.1)
-0.7 (0.1) (SE) [3] p-value vs. placebo [3] <.0001 Week 2 N 174
153 170 139 Mean (SD) 0.6 (0.8) -0.5 (1.0) 0.5 (0.7) -0.7 (1.0)
25th Percentile 0.0 -1.0 0.0 -1.0 Median 0.3 -0.4 0.0 -0.6 75th
Percentile 1.0 0.0 1.0 0.0 Minimum, Maximum 0.0, 4.3 -6.8, 1.3 0.0,
3.0 -6.0, 2.0 Least Squares Means 0.6 (0.1) 0.5 (0.1) (SE) [2]
p-value vs. placebo [2] 0.2137 Least Squares Means -0.5 (0.1) -0.6
(0.1) (SE) [3] p-value vs. placebo [3] 0.1963 Week 3 N 162 147 164
129 Mean (SD) 0.6 (0.8) -0.5 (1.0) 0.5 (0.7) -0.7 (1.1) 25th
Percentile 0.0 -0.8 0.0 -1.0 Median 0.3 -0.3 0.0 -0.4 75th
Percentile 1.0 0.0 1.0 0.0 Minimum, Maximum 0.0, 4.6 -6.2, 2.7 0.0,
3.0 -6.0, 1.5 Least Squares Means 0.6 (0.1) 0.5 (0.1) (SE) [2]
p-value vs. placebo [2] 0.1583 Least Squares Means -0.5 (0.1) -0.6
(0.1) (SE) [3] p-value vs. placebo [3] 0.2408 Week 4 N 151 135 154
121 Mean (SD) 0.6 (0.9) -0.5 (1.0) 0.4 (0.7) -0.8 (1.2) 25th
Percentile 0.0 -1.0 0.0 -1.3 Median 0.0 -0.3 0.0 -0.7 75th
Percentile 1.0 0.0 1.0 0.0 Minimum, Maximum 0.0, 5.3 -4.8, 4.0 0.0,
3.6 -6.0, 2.1 Least Squares Means 0.6 (0.1) 0.4 (0.1) (SE) [2]
p-value vs. placebo [2] 0.0786 Least Squares Means -0.5 (0.1) -0.7
(0.1) (SE) [3] p-value vs. placebo [3] 0.0683 DB N 192 165 188 146
Average Mean (SD) 0.7 (0.8) -0.4 (0.9) 0.5 (0.6) -0.7 (1.0) 25th
Percentile 0.0 -0.8 0.0 -1.1 Median 0.4 -0.2 0.2 -0.5 75th
Percentile 1.0 0.0 0.9 0.0 Minimum, Maximum 0.0, 4.6 -6.0, 1.5 0.0,
2.7 -6.0, 1.5 Least Squares Means 0.7 (0.1) 0.5 (0.1) (SE) [2]
p-value vs. placebo [2] 0.0057 Least Squares Means -0.4 (0.0) -0.7
(0.1) (SE) [3] p-value vs. placebo [3] 0.0016 [1] Week 1 = First
week of double-blind treatment, Week 2 = Second week of
double-blind treatment, etc. DB Average includes all scheduled
assessments obtained after Visit 3 up to and including Visit 5.
Baseline is the average of all pre-DB observations. [2] The
pairwise comparison is a two-sided test performed using an ANOVA
model, using the MIXED procedure with treatment and site as fixed
effects. [3] The pairwise comparison is a two-sided test performed
using an ANCOVA model, using the MIXED procedure with treatment and
site as fixed effects and baseline as the covariate.
[0159] A Physician Global Assessment was administered at Week 4,
the end of the double-blind treatment period. ESZ patients had
significantly better scores at this time compared with PBO (LS
means of 2.7 and 3.3 for ESZ and PBO, respectively; p<0.0001).
See Table 4.
TABLE-US-00004 TABLE 4 Menopause and Perimenopause Study, Physician
Global Assessment (Intent- to-Treat Population) Placebo Eszopiclone
3 mg Observed Change from Observed Change from Visit (Week)
Statistic Value Baseline Value Baseline 3 (Baseline) N 202 195 Mean
(SD) 3.6 (1.0) 3.7 (1.0) 25th Percentile 3.0 4.0 Median 4.0 4.0
75th Percentile 4.0 4.0 Minimum, Maximum 0.0, 6.0 0.0, 7.0 5 (Week
4) N 191 188 189 185 Mean (SD) 3.3 (1.1) -0.3 (1.4) 2.6 (1.2) -1.0
(1.4) 5th Percentile 2.0 -1.0 2.0 -2.0 Median 4.0 0.0 2.0 -1.0 75th
Percentile 4.0 0.0 4.0 0.0 Minimum, Maximum 1.0, 6.0 -4.0, 5.0 1.0,
6.0 -4.0, 6.0 Least Squares Means 3.3 (0.1) 2.7 (0.1) (SE) [1]
p-value vs. placebo [1] <.0001 Least Squares Means -0.3 (0.1)
-0.9 (0.1) (SE) [2] p-value vs. placebo [2] <.0001 [1]The
pairwise comparison is a two-sided test performed using an ANOVA
model, using the MIXED procedure with treatment and site as fixed
effects. [2]The pairwise comparison is a two-sided test performed
using an ANCOVA model, using the MIXED procedure with treatment and
site as fixed effects and baseline as the covariate. Note(s): The
responses to the assessment question: Overall the subject's
perimenopausal or menopausal symptoms since the last assessment
are: 0 = Not assessed, 1 = Very much improved, 2 = Much improved, 3
= Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much
worse, 7 = Very much worse.
[0160] The results of the study will change slightly because data
from one site, consisting of 11 of the 410 subjects analyzed above
will be excluded due to negative findings during a site audit. It
is expected that the conclusions of the study will not change after
exclusion of these 11 subjects.
Example 3
trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
Activity Assays
Experimental Conditions for Monoamine Uptake Assays
Serotonin Functional Uptake Assay
[0161] Characterization of serotonin uptake is performed using
synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar
rat cortex. The uptake of radiolabelled serotonin by synaptosomes
(100 .mu.g of proteins/point) is allowed by incubating them in a
deep well for 15 minutes at 37.degree. C. in presence of test
compounds and [3H]5-hydroxytryptamin (0.1 .mu.Ci/point).
[0162] Synaptosomes and [.sup.3H]5-hydroxytryptamine are prepared
in a Krebs buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM
glucose and 50 .mu.M ascorbic acid. This incubation buffer is
oxygenated during 5 minutes before incubation. Basal control is
incubated for 15 minutes at 4.degree. C. in order to avoid any
uptake. Following this incubation the uptake is stopped by
filtration through an "unifilter 96-wells GFB "Packard plate washed
with Krebs buffer containing 25 mM NaHCO.sub.3 in order to
eliminate the free [.sup.3H]5-hydroxytryptamine. The radioactivity
associated to the synaptosomes retained onto the unifilter
corresponding to the uptake is then measured with a microplate
scintillation counter Topcount, Packard using a scintillation
liquid microscint 0, Packard.
[0163] The reference compound is imipramine tested at 10
concentrations ranging from 10.sup.-11 M to 10.sup.-5 M in order to
obtain an 10.sub.50 value. See, Perovics and Muller,
"Pharmacological profile of hypericum extract: effect on serotonin
uptake by postsynaptic receptors," Arzeim. Forsch./Drug Res.,
45:1145-1148 (1995).
Dopamine Functional Uptake Assay
[0164] Characterization of dopamine uptake is performed using
synaptosomes isolated at Cerep in a 0.32 M sucrose buffer from a
male Wistar rat striatum. The uptake of radiolabelled dopamine by
synaptosomes (20 .mu.g of proteins/point) is allowed by incubating
them in a deep well for 15 minutes at 37.degree. C. in presence of
test compounds and [.sup.3H]-dopamine (0.1 .mu.Ci/point).
[0165] Synaptosomes and [.sup.3H]-dopamine are prepared in a Krebs
buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM glucose and 50
.mu.M ascorbic acid. This incubation buffer is oxygenated during 5
minutes before incubation. Basal control is incubated for 15
minutes at 4.degree. C. in order to avoid any uptake. Following
this incubation the uptake is stopped by filtration through an
"unifilter 96-wells GFB "Packard plate washed with Krebs buffer
containing 25 mM NaHCO.sub.3 in order to eliminate the free
[.sup.3H]-dopamine. The radioactivity associated to the
synaptosomes retained onto the unifilter corresponding to the
uptake is then measured with a microplate scintillation counter
Topcount, Packard using a scintillation liquid microscint 0,
Packard. The reference compound is GRB12909 tested at 8
concentrations ranging from 10.sup.-11 M to 10.sup.-6 M in order to
obtain an IC.sub.50 value. Jankowsky et al., "Characterization of
sodium-dependent [.sup.3H] GBR-12935 binding in brain: a
radioligand for selective labeling of the dopamine transport
complex," J. Neurochem., 46:1272-1276 (1986).
Norepinephrine Functional Uptake Assay
[0166] Characterization of norepinephrine uptake is performed using
synaptosomes isolated at Cerep in a 0.32 M sucrose buffer from a
male Wistar rat hypothalamus. The uptake of radiolabeled
norepinephrine by synaptosomes (100 .mu.g of proteins/point) is
allowed by incubating them in a deep well for 20 minutes at
37.degree. C. in presence of test compounds and
[.sup.3H]-norepinephrine (0.1 .mu.Ci/point).
[0167] Synaptosomes and [.sup.3H]-norepinephrine are prepared in a
Krebs buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM glucose and
50 .mu.M ascorbic acid. This incubation buffer is oxygenated during
5 minutes before incubation. Basal control is incubated for 20
minutes at 4.degree. C. in order to avoid any uptake. Following
this incubation the uptake is stopped by filtration through an
"unifilter 96-wells GFB "Packard plate washed with Krebs buffer
containing 25 mM NaHCO.sub.3 in order to eliminate the free
[.sup.3H]-norepinephrine. The radioactivity associated to the
synaptosomes retained onto the unifilter corresponding to the
uptake is then measured with a microplate scintillation counter
Topcount, Packard using a scintillation liquid microscint 0,
Packard.
[0168] The reference compound is imipramine tested at 13
concentrations ranging from 10.sup.-11 M to 10.sup.-5 M in order to
obtain an IC.sub.50 value. See, Perovics and Muller,
"Pharmacological profile of hypericum extract: effect on serotonin
uptake by postsynaptic receptors," Arzeim. Forsch./Drug Res.,
45:1145-1148 (1995).
TABLE-US-00005 TABLE 5 IC.sub.50 Values (.mu.M) for Sertraline and
Analogues in Functional Monoamine Uptakes Assays 5-HT NE DA
sertraline 0.0016 0.31 0.048 (R,R) cis 0.11 0.11 0.039 A* 0.0075
0.012 0.0046 B** 0.33 0.024 0.026 A + B 0.0070 0.0056 0.0073
imipramine 0.054/0.051 -- -- protriptyline -- 0.0036 -- GBR 12909
-- -- 0.0028/0.0051/0.0034 *A (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
**B (1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine
/separates multiple determinations -- <50% inhibition
[0169] The IC.sub.50 value for (R,R) had to be estimated because
the lowest plateau of the inhibition curve (corresponding to 100%
inhibition) was not reached at the highest concentration tested or
100% or control activity was not apparent with the lowest
concentration.
[0170] As shown in Table 5, A and B exhibit similar inhibitory
potency on the neuronal uptake of NE, DA, and 5HT. Currently, the
therapeutic approach to treating affective disorders in man is the
selective inhibition of a single monoamine uptake mechanism or the
dual inhibition of two of these molecular targets. The equipotent
inhibition of neuronal uptake of NE, DA and 5HT provides the
clinician with the ability to more effectively treat the disorders
mentioned specifically herein by elevating all of the monoamine
levels in the brain simultaneously and over the same dose-range
without the need to titrate separate drugs.
Example 4
trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
Activity Assays
[0171] Monoamine uptake assays were performed according to
protocols provided in Example 3 above. Results are tabulated
below.
TABLE-US-00006 TABLE 6 IC.sub.50 Values (.mu.M) for Compounds of
the Invention in Functional Monoamine Uptake Assays 5-HT NE DA
sertraline 0.0016 0.31 0.048 P 0.0077 0.0096 0.0064 Q 0.088 0.035
0.019 P + Q 0.041 0.0088 0.0071 imipramine 0.054/0.051 -- --
(standard) protriptyline -- 0.0036 -- (standard) GBR 12909 -- --
0.0028/0.0051/0.0034 (standard) /separates multiple determinations
-- <50% inhibition
[0172] As shown in Table 6, P and Q exhibit similar inhibitory
potency on the neuronal uptake of NE, DA, and 5HT. Currently, the
therapeutic approach to treating affective disorders in man is the
selective inhibition of a single monoamine uptake mechanism or the
dual inhibition of two of these molecular targets. The equipotent
inhibition of the neuronal uptake of NE, DA and 5HT provides the
clinician with the ability to more effectively treat affective
disorders and eating disorders by elevating all of the monoamine
levels in the brain simultaneously and over the same dose-range
without the need to titrate separate drugs. For those CNS disorders
that are presently treated with dopaminergic, norepinephrine or
mixed DA-NE uptake inhibitors (e.g. OCD, ADD, ADHD, sexual
dysfunction and substance abuse), the equipotent inhibition of the
neuronal uptake of NE, DA and 5HT provides more effective treatment
by adding the serotonergic effect.
[0173] Table 7 below presents data on effect of intraperitoneal
administration of
(1R,4S)--N-[4-(3,4-dichlorophenyl-1,2,3,4-tetrahydro-1-naphthalenamine
(Compound P) in the Behavioral Despair Test in mice.
TABLE-US-00007 TABLE 7 Effect of Intraperitoneal Administration of
(1R,4S)-N-[4-
(3,4-dichlorophenyl-1,2,3,4-tetrahydro-1naphthalenamine (P) in the
Behavioral Despair Test.sup.1 in Mice (N = 10) Imipramine P P P P P
Compound Vehicle 10 mg/kg 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3
mg/kg Immobility 130 63 128 119 114 29 12 Duration 82 28 120 96 109
66 49 (sec) 129 33 96 85 115 87 0 172 89 129 100 93 34 3 162 85 99
103 23 51 17 148 73 107 76 102 35 5 154 37 159 109 110 51 0 118 74
102 56 106 19 40 133 95 115 98 98 81 0 153 5 122 62 120 50 26 Mean
.+-. sem 138 58 118 90 99 50 15 8 10 6 6 9 7 6 Dunnett P < 0.05
* ns * * * * .sup.1The Behavioral Despair Test is also known as the
Porsolt swim test (Porsolt, et al., 1977, Nature 266: 730-732).
.sup.2Vehicle = saline * indicates a significant difference vs
vehicle for P < 0.05 (Dunnett test)
[0174] The contents of each of the references cited herein,
including the contents of the references cited within the primary
references, are herein incorporated by reference in their
entirety.
[0175] The invention being thus described, it is apparent that the
same can be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the present
invention, and all such modifications and equivalents as would be
obvious to one skilled in the art are intended to be included
within the scope of the following claims.
* * * * *