U.S. patent application number 09/947086 was filed with the patent office on 2002-04-04 for methods for treating vascular dementia.
Invention is credited to Pratt, Raymond.
Application Number | 20020040038 09/947086 |
Document ID | / |
Family ID | 27497683 |
Filed Date | 2002-04-04 |
United States Patent
Application |
20020040038 |
Kind Code |
A1 |
Pratt, Raymond |
April 4, 2002 |
METHODS FOR TREATING VASCULAR DEMENTIA
Abstract
The invention describes novel methods for treating and
preventing dementia caused by vascular diseases; dementia
associated with Parkinson's disease; Lewy Body dementia; AIDS
dementia; mild cognitive impairments; age-associated memory
impairments; cognitive impairments and/or dementia associated with
neurologic and/or psychiatric conditions, including epilepsy, brain
tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's
syndrome, progressive supranuclear palsy, frontal lobe syndrome,
and schizophrenia and related psychiatric disorders; cognitive
impairments caused by traumatic brain injury, post coronary artery
by-pass graft surgery, electroconvulsive shock therapy, and
chemotherapy, administering a therapeutically effective amount of
at least one of the cholinesterase inhibitor compounds described
herein. The invention also describes novel methods for treating and
preventing delirium, Tourette's syndrome, myasthenia gravis,
attention deficit hyperactivity disorder, autism, dyslexia, mania,
depression, apathy, and myopathy associated with diabetes by
administering a therapeutically effective amount of at least one of
the cholinesterase inhibitor compounds described herein. The
invention also describes novel methods for delaying the onset of
Alzheimer's disease, for enhancing cognitive functions, for
treating and preventing sleep apnea, for alleviating tobacco
withdrawal syndrome, and for treating the dysfunctions of
Huntington's Disease by administering a therapeutically effective
amount of at least one of the cholinesterase inhibitor compounds
described herein. A preferred cholinesterase inhibitor for use in
the methods of the invention is donepezil hydrochloride or
ARICEPT.RTM..
Inventors: |
Pratt, Raymond; (Leonia,
NJ) |
Correspondence
Address: |
Edward D. Grieff, Esq.
Hale and Dorr LLP
1455 Pennsylvania Avenue, NW
Washington
DC
20004
US
|
Family ID: |
27497683 |
Appl. No.: |
09/947086 |
Filed: |
September 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60259226 |
Jan 3, 2001 |
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60220783 |
Jul 25, 2000 |
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60197610 |
Apr 18, 2000 |
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60186744 |
Mar 3, 2000 |
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Current U.S.
Class: |
514/319 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/00 20180101; A61K 31/445 20130101; A61P 25/28 20180101 |
Class at
Publication: |
514/319 |
International
Class: |
A61K 031/445 |
Claims
What is claimed is:
1. A method for treating vascular dementia in a patient in need
thereof comprising administering a therapeutically effective amount
of a compound of formula (IV) or a pharmaceutically acceptable salt
thereof: 15or a stereoisomer thereof.
2. The method of claim 1, wherein the compound of formula (IV) is
16or a stereoisomer thereof.
3. The method of claim 1, wherein the compound of formula (IV) is a
compound of formula (VI) or a pharmaceutically acceptable salt
thereof: 17
4. The method of claim 1, wherein the compound of formula (IV) is a
compound of formula (VII) or a pharmaceutically acceptable salt
thereof: 18
5. The method of claim 1, wherein the compound of formula (IV), the
stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is administered in an amount of about 1 mg to about 100
mg.
6. The method of claim 5, wherein the compound of formula (IV), the
stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is administered in an amount of about 5 mg to about 10
mg.
7. The method of claim 1, wherein the compound of formula (IV), the
stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is administered in an amount of about 5 milligrams.
8. The method of claim 1, wherein the compound of formula (IV), the
stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is administered in an amount of about 10 milligrams.
9. The method of claim 1, wherein the compound of formula (IV), the
stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is orally administered.
10. The method of claim 9, wherein the compound of formula (IV),
the stereoisomer thereof, or the pharmaceutically acceptable salt
thereof is orally administered in the form of a tablet.
11. The method of claim 1, further comprising administering a
pharmaceutically acceptable carrier.
Description
RELATED APPLICATIONS
[0001] This application claims priority to PCT Application No.
PCT/US01/07027 filed Mar. 5, 2001, which claims priority to U.S.
Provisional Application No. 60/259,226 filed Jan. 3, 2001, U.S.
Provisional Application No. 60/220,783 filed Jul. 25, 2000, U.S.
Provisional Application No. 60/197,610 filed Apr. 18, 2000, and
U.S. Provisional Application No. 60/186,744 filed Mar. 3, 2000.
FIELD OF THE INVENTION
[0002] The invention describes novel methods for treating and
preventing dementia caused by vascular diseases; dementia
associated with Parkinson's disease; Lewy Body dementia; AIDS
dementia; mild cognitive impairments; age-associated memory
impairments; cognitive impairments and/or dementia associated with
neurologic and/or psychiatric conditions, including epilepsy, brain
tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's
syndrome, progressive supranuclear palsy, frontal lobe syndrome,
and schizophrenia and related psychiatric disorders; cognitive
impairments caused by traumatic brain injury, post coronary artery
by-pass graft surgery, electroconvulsive shock therapy, and
chemotherapy, by administering a therapeutically effective amount
of at least one of the cholinesterase inhibitor compounds described
herein. The invention also describes novel methods for treating and
preventing delirium, Tourette's syndrome, myasthenia gravis,
attention deficit hyperactivity disorder, autism, dyslexia, mania,
depression, apathy, and myopathy associated with or caused by
diabetes by administering a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein. The invention also describes novel methods for delaying the
onset of Alzheimer's disease, for enhancing cognitive functions,
for treating and preventing sleep apnea, for alleviating tobacco
withdrawal syndrome, and for treating the dysfunctions of
Huntington's Disease by administering a therapeutically effective
amount of at least one of the cholinesterase inhibitor compounds
described herein. A preferred cholinesterase inhibitor for use in
the methods of the invention is donepezil hydrochloride or
ARICEPT.RTM..
BACKGROUND OF THE INVENTION
[0003] Novel cholinesterase inhibitors are described in U.S. Pat.
No. 4,895,841 and WO 98/39000, the disclosures of which are
incorporated by reference herein in their entirety. The
cholinesterase inhibitors described in U.S. Pat. No. 4,895,841
include donepezil hydrochloride or ARICEPT.RTM., which has proven
to be a highly successful drug for the treatment of Alzheimer's
disease.
[0004] There is a need in the art for new and improved treatments
for other diseases, disorders, and syndromes that are characterized
by symptoms of dementia and/or cognitive impairments. The invention
is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
[0005] The invention describes novel methods for treating and
preventing dementia associated with or caused by vascular diseases
by administering to a patient a therapeutically effective amount of
at least one of the cholinesterase inhibitor compounds described
herein.
[0006] The invention describes novel methods for treating and
preventing dementia associated with or caused by Parkinson's
disease by administering to a patient a therapeutically effective
amount of at least one of the cholinesterase inhibitor compounds
described herein.
[0007] The invention describes novel methods for treating and
preventing the dementia associated with or caused by Lewy Body
dementia by administering to a patient a therapeutically effective
amount of at least one of the cholinesterase inhibitor compounds
described herein.
[0008] The invention describes novel methods for treating and
preventing AIDS dementia by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0009] The invention describes novel methods for treating and
preventing mild (minor) cognitive impairments, age-associated
memory impairments, and/or for delaying the onset of Alzheimer's
disease by administering to a patient a therapeutically effective
amount of at least one of the cholinesterase inhibitor compounds
described herein.
[0010] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with
neurologic and/or psychiatric conditions by administering to a
patient a therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0011] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with
epilepsy (including cognitive impairments and/or dementia caused by
or associated with the treatments for epilepsy) by administering to
a patient a therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0012] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by brain tumors by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0013] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by brain lesions or other inflammatory brain diseases by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0014] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by multiple sclerosis by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0015] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by Down's syndrome by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0016] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by Rett's syndrome by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0017] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by progressive supranuclear palsy by administering to a
patient a therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0018] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by frontal lobe syndrome by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0019] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia associated with or
caused by schizophrenia and related psychiatric disorders by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0020] The invention describes novel methods for treating and
preventing cognitive impairments and/or dementia caused by
antipsychotic medications by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0021] The invention describes novel methods for treating and
preventing cognitive impairments caused by traumatic brain injury
(e.g., post head trauma) by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0022] The invention describes novel methods for treating and
preventing cognitive impairments caused by post coronary artery
by-pass graft surgery or by ischemic vascular disease by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0023] The invention describes novel methods for treating and
preventing cognitive impairments associated with or caused by
electroconvulsive shock therapy (including cognitive impairments
caused by the seizures which can be a side-effect of
electroconvulsive shock therapy) by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0024] The invention describes novel methods for treating and
preventing cognitive impairments associated with or caused by
chemotherapy by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0025] The invention describes novel methods for treating and
preventing delirium by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0026] The invention describes novel methods for treating and
preventing Tourette's syndrome by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0027] The invention describes novel methods for treating and
preventing myasthenia gravis (including Lambert-Eaton syndrome) by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0028] The invention describes novel methods for treating and
preventing the cognitive impairments and/or attentional symptoms
associated with or caused by attention deficit hyperactivity
disorder (ADHD) by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0029] The invention describes novel methods for treating and
preventing autism by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0030] The invention describes novel methods for treating and
preventing dyslexia by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0031] The invention describes novel methods for treating and
preventing mania and/or depression in patients by administering to
a patient a therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0032] The invention describes novel methods for treating and
preventing apathy by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0033] The invention describes novel methods for treating and
preventing myopathy associated with or caused by diabetes by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0034] The invention also describes novel methods for enhancing
cognitive functions by administering to a patient a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0035] The invention also describes novel methods of treating and
preventing sleep apnea by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0036] The invention also describes novel methods for alleviating
tobacco withdrawal syndrome by administering to a patient a
therapeutically effective amount of at least one of the
cholinesterase inhibitor compounds described herein.
[0037] The invention also provides novel methods for treating the
cognitive and/or behavioral dysfunctions in Huntington's disease by
administering to a patient a therapeutically effective amount of at
least one of the cholinesterase inhibitor compounds described
herein.
[0038] The invention is described in more detail below.
DETAILED DESCRIPTION OF THE INVENTION
[0039] "Patient" refers to animals, preferably mammals, more
preferably humans. The term "patient" includes adults and children,
and includes men and women. Children includes neonates, infants,
and adolescents.
[0040] "Cognitive impairment" refers to an acquired deficit in one
or more of memory function, problem solving, orientation and/or
abstraction that impinges on an individual's ability to function
independently.
[0041] "Dementia" refers to a global deterioration of intellectual
functioning in clear consciousness, and is characterized by one or
more symptoms of disorientation, impaired memory, impaired
judgment, and/or impaired intellect. The symptoms of "dementia" are
generally worse than, and can encompass, the symptoms of "cognitive
impairment."
[0042] "Dementia associated with or caused by vascular diseases,"
also referred to as vascular dementia, generally refers to
cerebrovascular diseases (e.g., infarctions of the cerebral
hemispheres), which generally have a fluctuating course with
periods of improvement and stepwise deterioration. "Vascular
dementia" can include one or more symptoms of disorientation,
impaired memory and/or impaired judgment. Early markers of vascular
dementia can include urinary dysfunction and/or gait disturbances.
Vascular dementia can be caused by discrete multiple infarctions,
or other vascular causes including, for example, autoimmune
vasculitis, such as that found in systemic lupus erythematosus;
infectious vasculitis, such as Lyme's disease; recurrent
intracerebral hemorrhages; and/or strokes. "Vascular dementia" can
also be referred to as cerebrovascular dementia.
[0043] "Parkinson's disease" is a neurological syndrome usually
resulting from deficiency of the neurotransmitter dopamine as the
consequence of degenerative, vascular or inflammatory changes in
the basal ganglia, and is characterized by rhythmical muscular
tremors, rigidity of movement, fesination, droopy posture and/or
masklike facies. In preferred embodiments, the invention is
directed to methods of treating and preventing dementia, as defined
herein, that is caused by or associated with Parkinson's
disease.
[0044] "Lewy body dementia" is characterized by one or more
symptoms of the development of dementia with features overlapping
those of Alzheimer's disease; development of features of
Parkinson's disease; and/or early development of hallucinations.
Lewy body dementia is generally characterized by day-to-day
fluctuations in the severity of the symptoms. The name for the
disease comes from the presence of abnormal lumps which develop
inside nerve cells called Lewy bodies.
[0045] "AIDS dementia" is caused by the complications associated
with HIV disease or AIDS. Symptoms associated with AIDS dementia
can include one or more of the following: headaches, retro-orbital
pain, photophobia, depression, mania, irritability, psychosis,
mental slowing, inattention, apathy, reduced concentration,
forgetfulness, motor abnormalities, gait abnormalities (ataxia),
altered personality, disorientation, impaired memory, impaired
judgment, and/or impaired intellect.
[0046] "Mild cognitive impairments" refer to one or more minor
symptoms of disorientation, impaired memory, impaired judgment,
and/or impaired intellect. The elderly often suffer from mild
cognitive impairments, usually memory impairments, that do not rise
to the level of an Alzheimer's disease diagnosis. The invention
also describes methods of delaying the onset of Alzheimer's disease
(including preventing the onset of Alzheimer's disease) by
administering to a patient the cholinesterase inhibitor compounds
described herein, preferably by administering the cholinesterase
inhibitor compounds to a patient suffering from age-associated
memory impairments.
[0047] "Cognitive impairments and/or dementia associated with
epilepsy" refers to cognitive impairments, as defined herein,
and/or dementia, as defined herein, that are associated with or
caused by epilepsy. The cholinesterase inhibitors described herein
are also useful in methods for treating the side-effects (e.g.,
cognitive impairments and/or dementia) that are caused by the drugs
that are used to treat epilepsy.
[0048] "Cognitive impairments associated with brain tumors" refers
to cognitive impairments, as defined herein, that are caused by or
associated with brain tumors.
[0049] "Cognitive impairments associated with brain lesions" refers
to cognitive impairments, as defined herein, that are caused by or
associated with brain lesions or inflammatory diseases of the
brain.
[0050] "Multiple sclerosis" is a disease caused by the occurrence
of patches of sclerosis (e.g., plaques) in the brain and spinal
cord, and is characterized by some degree of paralysis, tremor,
nystagmus and/or disturbances of speech. The symptoms of multiple
sclerosis are dependent upon the location of the lesions on the
brain. The invention is preferably directed to methods of treating
and preventing cognitive impairments, as defined herein, and/or
dementia, as defined herein, that are associated with or caused by
multiple sclerosis.
[0051] "Down's syndrome" is a syndrome of mental retardation
associated with a plethora of abnormalities caused by
representation of chromosome 21 (or a critical portion thereof)
three times instead of twice in some or all cells. In preferred
embodiments, the invention is directed to methods of treating and
preventing cognitive impairments, as defined herein, and/or
dementia, as defined herein, that are associated with or caused by
Down's syndrome.
[0052] "Rett's syndrome" or cerebroatrophic hyperammonemia is a
progressive syndrome characterized by symptoms of autism, dementia,
cognitive impairments, ataxia, and/or purposeless hand movements.
In preferred embodiments, the invention is directed to methods of
treating and preventing cognitive impairments, as defined herein,
and/or dementia, as defined herein, that are associated with or
caused by Rett's syndrome.
[0053] "Progressive supranuclear palsy," also known as
Steele-Richardson-Olszewksi syndrome, is a rare brain disorder
characterized by problems with control of gait and/or balance. The
most obvious sign of the disease is an inability to aim the eyes
properly, which occurs because of lesions in the area of the brain
that coordinates eye movements. Other symptoms of progressive
supranuclear palsy include alterations of mood and behavior (e.g.,
depression, apathy, cognitive impairments, and/or progressive mild
dementia). In preferred embodiments, the invention is directed to
methods of treating and preventing cognitive impairments, as
defined herein, and/or dementia, as defined herein, that are
associated with or caused by progressive supranuclear palsy.
[0054] "Frontal lobe syndrome" can arise from a variety of causes,
including, for example, stroke, head injury, multi-infarct
dementia, tumors affecting the frontal lobe, and/or
post-encephalitis syndrome. Symptoms of frontal lobe syndrome
include mood lability, decrease or loss of judgment and insight,
inappropriate or disinhibited behavior, memory deficit, decrease in
attention span, inability to shift set of thinking, difficulties in
planning and execution of tasks, and/or motor or sensory deficits
specific to other brain areas that may be concomitantly impaired.
In preferred embodiments, the invention is directed to methods of
treating and preventing cognitive impairments, as defined herein,
and/or dementia, as defined herein, that are associated with or
caused by frontal lobe syndrome.
[0055] "Schizophrenia" is a psychosis characterized by a disorder
in the thinking processes, such as delusions and hallucinations,
and extensive withdrawal of the patient's interest from other
people and the outside world, and the investment of it in his own.
Patients diagnosed with schizophrenia often have cognitive
impairments and/or dementia caused by the underlying disease
process and/or as a side-effect of the treatments with
antipsychotic medications. In preferred embodiments, the invention
is directed to methods of treating and preventing cognitive
impairments, as defined herein, and/or dementia, as defined herein,
that are associated with or caused by schizophrenia and related
psychiatric/psychological disorders (including, for example,
schizoaffective disorders). In alternative embodiments, the
invention is directed to methods of treating and preventing
cognitive impairments, as defined herein, and/or dementia, as
defined herein, that are a side-effect of antipsychotic
medications. As used herein, the term "schizophrenia" refers to
reactive and process schizophrenias, including, for example,
chronic schizophrenia, ambulatory schizophrenia, catatonic
schizophrenia, disorganized schizophrenia, latent schizophrenia,
paranoid schizophrenia, pseudoneurotic schizophrenia, residual
schizophrenia, and simple schizophrenia.
[0056] "Cognitive impairments caused by traumatic brain injury"
refers to cognitive impairments, as defined herein, that are
associated with or caused by traumatic brain injury, including
post-head trauma and other traumas to the head, such as, for
example, traumas caused by accidents and/or sports injuries.
"Cognitive impairments caused by traumatic brain injury" includes
dementia pugilistica, which is severe brain damage caused by
repeated blows to the head (e.g., from boxing). Dementia
pugilistica is a chronic and progressive clinical syndrome
characterized by neurological evidence of damage to pyramidal,
extrapyramidal, and cerebellar systems with associated psychosis,
dementia, personality change and impaired social functioning and/or
prominent signs/symptoms of Parkinsonism (e.g., tremors,
dysarthria, rigidity, bradykinesia, other extrapyramidal
signs).
[0057] "Cognitive impairments caused by post coronary artery
by-pass graft surgery" refers to cognitive impairments, as defined
herein, that are caused by or associated with post coronary artery
by-pass graft surgery or ischemic vascular disease.
[0058] "Cognitive impairments associated with electroconvulsive
shock therapy" refers to cognitive impairments, as defined herein,
that are caused by or associated with electroconvulsive shock
therapy. In other embodiments, the invention is directed to
alleviating (e.g., reducing or eliminating) the cognitive
impairments caused by the seizures that follow electroconvulsive
shock therapy by administering a therapeutically effective amount
of at least one of the cholinesterase inhibitor compounds described
herein.
[0059] "Cognitive impairments associated with chemotherapy" refers
to cognitive impairments, as defined herein, that are caused by or
associated with chemotherapy. In other embodiments, the invention
is directed to alleviating (e.g., reducing or eliminating) the
cognitive impairments that are associated with chemotherapy by
administering a therapeutically effective amount of at least one of
the cholinesterase inhibitor compounds described herein. In a
preferred embodiment, the invention describes novel methods for
treating or preventing cognitive impairments in breast cancer
patients undergoing chemotherapy by administering a therapeutically
effective amount of at least one of the cholinesterase inhibitor
compounds described herein.
[0060] "Delirium" refers to a clouded state of consciousness and
confusion that is marked by difficulty in sustaining attention to
stimuli, disordered thinking, defective perceptions, illusions,
hallucinations, disordered sleep-wakefulness cycles, and/or motor
disturbances. There are various categories of delirium covered by
the invention, including, for example, post-operative delirium
(where the onset of the delirium is after an operation) anxious
delirium (in which the predominating symptom is an incoherent
apprehension or anxiety); collapse delirium (caused by extreme
physical depression induced by a shock, profuse hemorrhage,
exhausting labor, and the like); low delirium (in which there is
little excitement, either mental or motor, where ideas are confused
and incoherent but follow each other slowly); muttering delirium
(common in low fevers in which the patient is unconscious but
constantly muttering incoherently); posttraumatic delirium (a
posttraumatic neuropsychologic disorder of the brain with disturbed
consciousness, agitation, hallucinations, delusions and/or
disorientation); toxic delirium (caused by a poison); and tremens
delirium (a form of acute organic brain syndrome due to alcoholic
withdrawal and marked by sweating, tremor, atonic dyspepsia,
restlessness, anxiety, precordial distress, mental confusion, and
hallucinations).
[0061] "Tourette's syndrome" is characterized by motor
incoordination, echolalia (i.e., repetition of what is said by
other people) and/or coprolalia (i.e., involuntary utterances of
vulgar or obscene words). Tourette's syndrome is a form of tic.
[0062] "Myasthenia gravis" refers to any chronic progressive
muscular weakness. Myasthenia gravis includes Goldflam or
Hoppe-Goldflam disease. Myasthenia gravis is thought to be caused
by a defect in myoneural conduction. As used herein, "myasthenia
gravis" includes Lambert-Eaton syndrome or carcinomatous myopathy,
which is a progressive proximal muscle weakness in patients with
carcinoma, generally in the absence of dermatomyositis
orpolymyositis. Lambert-Eaton syndrome is thought to be caused by
antibodies directed against motor-nerve axon terminals.
[0063] "Attention deficit hyperactivity disorder" (ADHD) is a
neurological condition where the patient, including adults and
children, has a reduced ability to maintain attention without
distraction, has a reduced ability to control doing or saying
something due to impulsivity, has a lack of appropriate
forethought, and/or is restless. In preferred embodiments, the
invention is directed to methods of treating and preventing
cognitive impairments, as defined herein, that are associated with
or caused by attention deficit hyperactivity disorder. In
alternative embodiments, the invention is directed to methods of
treating the attentional symptoms associated with or caused by
attention deficit hyperactivity disorder.
[0064] "Autism" is a complex developmental disability that affects
the functioning of the brain, and typically appears in a patient by
the age of three. Autism impacts the normal development of the
brain in the areas of social interaction and communication skills.
Patients with autism typically have difficulties in verbal and
non-verbal communication, social interactions, and/or leisure or
play activities. The disorder makes it hard for them to communicate
with others and relate to the outside world. In some cases,
aggressive and/or self-injurious behavior may be present. Patients
with autism may experience sensitivities in the senses, exhibit
repeated body movements (e.g., hand flapping, rocking), have
unusual responses to people or attachments to objects and/or
resistance to changes in routines.
[0065] "Dyslexia" is characterized by one or more of the following:
a memory instability for letters, words, or numbers; tendency to
skip over or scramble letters, words, and sentences; poor reading
ability; poor concentration; distractibility; photophobia; tunnel;
vision, delayed visual and phonetic processing; poor handwriting
prone to size, spacing, and letter-sequencing errors; memory
instability for spelling, grammar, math, names, dates, and lists;
speech disorders such as slurring, stuttering, minor articulation
errors, poor word recall, and auditory-input and motor-output
speech lags; impaired concentration, distractibility,
hyperactivity, or overactivity; difficulties with balance and
coordination functions; headaches, nausea, dizziness, vomiting,
motion sickness, abdominal complaints, excessive sweating, and
bed-wetting; and/or poor self-esteem.
[0066] "Mania" is an emotional disorder characterized by symptoms
of euphoria, increased psychomotor activity, rapid speech, flight
of ideas, decreased need for sleep, distractibility, irritability,
increased sexual desire, increased energy, grandiosity, and/or poor
judgment. "Hypomania" refers to a mild form of mania. Mania and
hypomania often occur in bipolar disorder.
[0067] "Depression" refers to and includes major depression,
dysthymia and bioplar disorder. Major depression is characterized
by a persistent sad, anxious and/or empty mood; feelings of
hopelessness, pessimism, guilt, worthlessness, and/or helplessness;
a loss of interest or pleasure in hobbies and activities, including
sex; decreased energy or fatigue; difficulty concentrating,
remembering and/or making decisions; insomnia, early-morning
awakening or oversleeping; increased or decreased appetite;
thoughts of suicide or death; suicide attempts; restlessness and/or
irritability; and/or persistent physical symptoms that do not
respond to treatment, such as headaches, digestive disorders and/or
chronic pain. Major depression can be characterized by a few or
many symptoms which can vary over time. Dysthymia refers to a less
severe (sometimes chronic) form of major depression. Bipolar
disorder, also called manic-depressive illness, is characterized by
cycling mood changes from highs (e.g., mania) to lows (e.g., major
depression or dysthymia).
[0068] "Apathy" refers to a slowing of cognitive processes and/or a
lack of motivation as manifested by one or more of the following:
lack of productivity, lack of initiative, lack of perseverance,
diminished socialization or recreation, lack of interest in
learning new things, lack of interest in new experiences, lack of
emotional responsivity to positive or negative events, unchanging
or flat affect, and/or absence of excitement or emotional
intensity.
[0069] "Enhancing cognitive functions" refers to increasing or
improving a patient's normal level of cognitive functioning,
including, for example, learning and recall of newly learned
information. In the methods of enhancing cognitive functions
described herein, the patient is administered at least one of the
cholinesterase inhibitors described herein for about 1 to about 7
days prior to the time when improved cognitive function is required
or desired.
[0070] "Sleep apnea" can be characterized by sleep symptoms and
daytime symptoms. Sleep symptoms can include, for example, snoring,
restless sleep, sleep disruptions, choking, esophageal reflux,
nocturia, heavy sweating and the like. Day time symptoms can
include, for example, hypersomnolence, morning headaches, mood
alterations, sexual dysfunctions, hearing loss, automatic behavior,
short term memory loss and hypnogenic hallucinations. "Sleep apnea"
includes obstructive sleep apnea syndrome and central sleep apnea,
both of which are characterized by repetitive episodes of upper
airway obstruction that occur during seep.
[0071] "Alleviating tobacco withdrawal syndrome" refers to reducing
or eliminating at least one symptom that occurs when a person stops
using a product containing nicotine. The symptoms that generally
occur in tobacco withdrawal syndrome include one or more of
cravings for tobacco or nicotine, irritability, insomnia,
impatience, restlessness, difficulty concentrating, increased
appetite (which can include weight gain), and/or decreased heart
rate. The phrase "stops using a product containing nicotine" refers
to a patient who ceases or attempts to cease, either permanently or
temporarily, from smoking cigarettes, cigars, pipes, other forms of
tobacco, and/or other nicotine-containing products, and/or using
chewing tobacco, or other nicotine-containing products.
[0072] Huntington's disease is a genetic degenerative brain
disorder. The "behavioral dysfunctions in Huntington's disease"
includes one or more symptoms of aggressive outbursts,
impulsiveness, mood swings and/or social withdrawal. The "cognitive
dysfunctions in Huntington's disease" includes one or more symptoms
of the "cognitive impairments" defined herein. The cholinesterase
inhibitors of the invention can also be used to treat the motor
dysfunctions in Huntington's disease, including, for example,
nervous activity, fidgeting, twitching, excessive restlessness,
reduced coordination and the like. The cholinesterase inhibitors of
the invention can also be used to treat the emotional dysfunctions
in Huntington's disease including, for example, depression,
irritability, anxiety, apathy and the like.
[0073] In another embodiment, the cholinesterase inhibitors of the
invention are used to treat the dysfunctions caused by Juvenile
Huntington's Disease, also known as the Westphal variant, that
affects children. Symptoms of Juvenile Huntington's Disease include
slow, stiff and awkward walking and talking, choking, clumsiness
and falling, and also include the "cognitive impairments" defined
herein.
[0074] In each of the methods described herein, the cholinesterase
inhibitors of the invention alleviate (e.g., reduce or eliminate)
at least one (preferably two, three, or all) symptom of the
disease, disorder or syndrome being treated. Preferably, the
cholinesterase inhibitors are alleviating the symptoms of cognitive
impairments and/or dementia.
[0075] As described and defined herein, the invention is directed
to novel methods for treating and preventing dementia caused by
vascular diseases; dementia associated with Parkinson's disease;
Lewy Body dementia; AIDS dementia; mild cognitive impairments;
age-associated memory impairments; cognitive impairments and/or
dementia associated with neurologic and/or psychiatric conditions,
including epilepsy, brain tumors, brain lesions, multiple
sclerosis, Down's syndrome, Rett's syndrome, progressive
supranuclear palsy, frontal lobe syndrome, and schizophrenia and
related psychiatric disorders; cognitive impairments caused by
traumatic brain injury, post coronary artery by-pass graft surgery,
electroconvulsive shock therapy, and chemotherapy; and to novel
methods for treating and preventing delirium, Tourette's syndrome,
myasthenia gravis, attention deficit hyperactivity disorder,
autism, dyslexia, mania, depression, apathy, and myopathy
associated with diabetes; and to novel methods for delaying the
onset of Alzheimer's disease; for enhancing cognitive functions;
for treating and preventing sleep apnea, and for alleviating
tobacco withdrawal syndrome, and for treating the dysfunctions of
Huntington's disease by administering to a patient in need thereof
a therapeutically effective amount of at least one cholinesterase
inhibitor of formula I or a pharmaceutically acceptable salt
thereof: 1
[0076] wherein J is
[0077] (a) a substituted or unsubstituted group selected from the
group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4)
quinolyl, (5) cyclohexyl, (6) quinoxalyl, and (7) furyl;
[0078] (b) a monovalent or divalent group, in which the phenyl may
have one or more substituents selected from (1) indanyl, (2)
indanonyl, (3) indenyl, (4) indenonyl, (5) indanedionyl, (6)
tetralonyl, (7) benzosuberonyl, (8) indanolyl, and (9)
C.sub.6H.sub.5--CO--CH(CH.sub.3)--- ;
[0079] (c) a monovalent group derived from a cyclic amide
compound;
[0080] (d) a lower alkyl group; or
[0081] (e) a group of R.sup.21--CH.dbd.CH--, in which R.sup.21 is
hydrogen or a lower alkoxycarbonyl group;
[0082] B is --(CHR.sup.22).sub.r--, --CO--(CHR.sup.22).sub.r--,
--NR.sup.4--(CHR.sup.22).sub.r--,
--CO--NR.sup.5--(CHR.sup.22).sub.r--,
--CH.dbd.CH--(CHR.sup.22).sub.r--, --OCOO--(CHR.sup.22).sub.r--,
--OOC--NH--(CHR.sup.22).sub.r--, --NH--CO--(CHR.sup.22).sub.r--,
--CH.sub.2--CO--NH--(CHR.sup.22).sub.r--,
--(CH.sub.2).sub.2--NH--(CHR.su- p.22).sub.r--,
--CH(OH)--(CHR.sup.22).sub.r--, .dbd.(CH--CH.dbd.CH).sub.b-- -,
.dbd.CH--(CH.sub.2).sub.c--, .dbd.(CH--CH).sub.d.dbd.,
--CO--CH.dbd.CH--CH.sub.2--, --CO--CH.sub.2--CH(OH)--CH.sub.2--,
--CH(CH.sub.3)--CO--NH--CH.sub.2--,
--CH.dbd.CH.dbd.CO--NH--(CH.sub.2).su- b.2--, --NH--, --O--, --S--,
a dialkylaminoalkylcarbonyl or a lower alkoxycarbony;
[0083] wherein R.sup.4 is hydrogen, lower alkyl, acyl, lower
alkylsulfonyl, phenyl, substituted phenyl, benzyl, or substituted
benzyl; R.sup.5 is hydrogen, lower alkyl or phenyl; r is zero or an
integer of about 1 to about 10; R.sup.22 is hydrogen or methyl so
that one alkylene group may have no methyl branch or one or more
methyl branches; b is an integer of about 1 to about 3; c is zero
or an integer of about 1 to about 9; d is zero or an integer of
about 1 to about 5;
[0084] T is nitrogen or carbon;
[0085] Q is nitrogen, carbon or 2
[0086] q is an integer of about 1 to about 3;
[0087] K is hydrogen, phenyl, substituted phenyl, arylalkyl, in
which the phenyl may have a substituent, cinnamyl, a lower alkyl,
pyridylmethyl, cycloalkalkyl, adamantanemethyl, furylmenthyl,
cycloalkyl, lower alkoxycarbonyl or an acyl; and
[0088] is a single bond or a double bond.
[0089] In the compound of formula I, J is preferably (a) or (b),
more preferably (b). In the definition of (b), a monovalent group
(2), (3) and (5) and a divalent group (2) are preferred. The group
(b) preferably includes, for example, the groups having the
formulae shown below: 3
[0090] wherein t is an integer of about 1 to about 4; and each S is
independently hydrogen or a substituent, such as a lower alkyl
having 1 to 6 carbon atoms or a lower alkoxy having 1 to 6 carbon
atoms. Among the substituents, methoxy is most preferred. The
phenyl is most preferred to have 1 to 3 methoxy groups thereon.
(S).sub.t may form methylene dioxy groups or ethylene dioxy groups
on two adjacent carbon atoms of the phenyl group. Of the above
groups, indanonyl, indanedionyl and indenyl, optionally having
substituents on the phenyl, are the most preferred.
[0091] In the definition of B, --(CHR.sup.22).sub.r--,
--CO--(CHR.sup.22).sub.r--, .dbd.(CH--CH.dbd.CH).sub.b--,
.dbd.CH--(CH.sub.2).sub.c-- and .dbd.(CH--CH).sub.d.dbd. are
preferable. The group of --(CHR.sup.22).sub.r-- in which R.sup.22
is hydrogen and r is an integer of 1 to 3, and the group of
.dbd.CH--(CH.sub.2).sub.c-- are most preferable. The preferable
groups of B can be connected with (b) of J, in particular
(b)(2).
[0092] The ring containing T and Q in formula I can be 5-, 6- or
7-membered. It is preferred that Q is nitrogen, T is carbon or
nitrogen, and q is 2; or that Q is nitrogen, T is carbon, and q is
1 or 3; or that Q is carbon, T is nitrogen and q is 2.
[0093] It is preferable that K is a phenyl, arylalkyl, cinnamyl,
phenylalkyl or a phenylalkyl having a substituent(s) on the
phenyl.
[0094] In preferred embodiments, the cyclic amine compounds of
formula I are the piperidine compounds of formula II or a
pharmaceutically acceptable salt thereof: 4
[0095] wherein R.sup.1 is a (1) substituted or unsubstituted phenyl
group; (2) a substituted or unsubstituted pyridyl group; (3) a
substituted or unsubstituted pyrazyl group; (4) a substituted or
unsubstituted quinolyl group; (5) a substituted or unsubstituted
indanyl group; (6) a substituted or unsubstituted cyclohexyl group;
(7) a substituted or unsubstituted quinoxalyl group; (8) a
substituted or unsubstituted furyl group; (9) a monovalent or
divalent group derived from an indanone having a substituted or
unsubstituted phenyl ring; (10) a monovalent group derived from a
cyclic amide compound; (11) a lower alkyl group; or (12) a group of
the formula R.sup.3--CH.dbd.C--, where R.sup.3 is a hydrogen atom
or a lower alkoxycarbonyl group;
[0096] X is --(CH.sub.2).sub.n--, --C(O)--(CH.sub.2).sub.n--,
--N(R.sup.4)--(CH.sub.2).sub.n--,
--C(O)--N(R.sup.5)--(CH.sub.2).sub.n--,
--CH.dbd.CH--(CH.sub.2).sub.n--, --O--C(O)--O--(CH.sub.2).sub.n--,
--O--C(O)--NH--(CH.sub.2).sub.n--, --CH.dbd.CH--CH.dbd.CO--,
--NH--C(O)--(CH.sub.2).sub.n--,
--CH.sub.2--C(O)--NH--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.2--C(O)--NH--(CH.sub.2).sub.n--,
CH(OH)--(CH.sub.2).sub.- n--, --C(O)--CH.dbd.CH--CH.sub.2--,
--C(O)--CH.sub.2--CH(OH)--CH.sub.2--,
CH(CH.sub.3)--C(O)--NH--CH.sub.2--,
--CH.dbd.CH--C(O)--NH--(CH.sub.2).sub- .2--, a
dialkylaminoalkylcarbonyl group, a lower alkoxycarbonyl group;
[0097] where n is an integer of 0 to 6; R.sup.4 is a hydrogen atom,
a lower alkyl group, an acyl group, a lower alkylsulfonyl group, a
substituted or unsubstituted phenyl group, or a substituted or
unsubstituted benzyl group; and R.sup.5 is a hydrogen atom a lower
alkyl group or a phenyl group;
[0098] R is a substituted or unsubstituted phenyl group; a
substituted or unsubstituted arylalkyl group; a cinnamyl group; a
lower alkyl group; a pyridylmethyl group; a cycloalkylalkyl group;
an adamantanemethyl group; or a furoylmethyl group; and
[0099] is a single bond or a double bond.
[0100] The term "lower alkyl group" as used herein means a straight
or branched alkyl group having 1 to 6 carbon atoms. Exemplary
"lower alkyl groups" include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl,
neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,
1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimthylbutyl,
2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, and the like. The
lower alkyl group is preferably methyl, ethyl, propyl or isopropyl;
more preferably methyl.
[0101] Specific examples of the substituents for the substituted or
unsubstituted phenyl, pyridyl, pyrazyl, quinolyl, indanyl,
cyclohexyl, quinoxalyl and furyl groups in the definition of
R.sup.1 include lower alkyl groups having 1 to 6 carbon atoms, such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and
tert-butyl groups; lower alkoxy groups corresponding to the
above-described lower alkyl groups, such as methoxy and ethoxy
groups; a nitro group; halogen atoms, such as chlorine, fluorine
and bromine; a carboxyl group; lower alkoxycarbonyl groups
corresponding to the above-described lower alkoxy groups, such as
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
n-propoxycarbonyl, and n-butyloxycarbonyl groups; an amino group; a
lower monoalkylamino group; a lower dialkylamino group; a carbamoyl
group; acylamino groups derived from aliphatic saturated
monocarboxylic acids having 1 to 6 carbon atoms, such as
acetylamino, propionylamino, butyrylamino, isobutyrylamino,
valerylamino, and pivaloylamino groups; cycloalkyloxycarbonyl
groups, such as a cyclohexyloxycarbonyl group; lower
alkylaminocarbonyl groups, such as methylaminocarbonyl and
ethylaminocarbonyl groups; lower alkylcarbonyloxy groups
corresponding to the above-defined lower alkyl groups, such as
methylcarbonyloxy, ethylcarbonyloxy, and n-propylcarbonyloxy
groups; halogenated lower alkyl groups, such as a trifluoromethyl
group; a hydroxyl group; a formyl group; and lower alkoxy lower
alkyl groups, such as ethoxymethyl, methoxymethyl and methoxyethyl
groups. The "lower alkyl groups" and "lower alkoxyl groups" in the
above description of the substituent include all the groups derived
from the above-mentioned groups. The substituent may be one to
three of them, which may be the same or different.
[0102] When the substituent is a phenyl group, the following group
is within the scope of the substituted phenyl group: 5
[0103] wherein G is --C(O)--, --O--C(O)--, --O--,
--CH.sub.2--NH--C(O)--, --CH.sub.2--O--, --CH.sub.2--SO.sub.2--,
--CH(OH)--, or --CH.sub.2-S(.fwdarw.O)--; E is a carbon or nitrogen
atom; and D is a substituent.
[0104] Preferred examples of the substituents (i.e., "D") for the
phenyl group include lower alkyl, lower alkoxy, nitro, halogenated
lower alkyl, lower alkoxycarbonyl, formyl, hydroxyl, and lower
alkoxy lower alkyl groups, halogen atoms, and benzyol and
benzylsulfonyl groups. The substituent may be two or more of them,
which may be the same or different.
[0105] Preferred examples of the substituent for the pyridyl group
include lower alkyl and amino groups and halogen atoms.
[0106] Preferred examples of the substituent for the pyrazyl group
include lower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, and
cycloalkyloxycarbonyl groups.
[0107] With respect to R.sup.1, the pyridyl group is preferably a
2-pyridyl, 3-pyridyl, or 4-pyridyl group; the pyrazyl group is
preferably a 2-pyrazinyl group; the quinolyl group is preferably a
2-quinolyl or 3-quinolyl group; the quinoxalinyl group is
preferably a 2-quinoxalinyl or 3-quinoxalinyl group; and the furyl
group is preferably a 2-furyl group.
[0108] Specific examples of preferred monovalent or divalent groups
derived from an indanone having an unsubstituted or substituted
phenyl ring include those represented by formulas (A) and (B):
6
[0109] where m is an integer of from 1 to 4, and each A is
independently a hydrogen atom, a lower alkyl group, a lower alkoxy
group, a nitro group, a halogen atom, a carboxyl group, a lower
alkoxycarbonyl group, an amino group, a lower monoalkylamino group,
a lower dialkylamino group, a carbamoyl group, an acylamino group
derived from aliphatic saturated monocarboxylic acids having 1 to 6
carbon atoms, a cycloalkyloxycarbonyl group, a lower
alkylaminocarbonyl group, a lower alkylcarbonyloxy group, a
halogenated lower alkyl group, a hydroxyl group, a formyl group, or
a lower alkoxy lower alkyl group; preferably a hydrogen atom, a
lower alkyl group or a lower alkoxy group; most preferably the
indanone group is unsubstituted or substituted with 1 to 3 methoxy
groups.
[0110] Examples of the monovalent group derived from a cyclic amide
compound include quinazolone, tetrahydroisoquinolinone,
tetrahydrobenzodiazepinone, and hexahydrobenzazocinone. However,
the monovalent group may be any one having a cyclic amide group in
the structural formula thereof, and is not limited to the
above-described specific examples. The cyclic amide group may be
one derived from a monocyclic or condensed heterocyclic ring. The
condensed heterocyclic ring is preferably one formed by
condensation with a phenyl ring. In this case, the phenyl ring may
be substituted with a lower alkyl group having 1 to 6 carbon atoms,
preferably a methyl group, or a lower alkoxy group having 1 to 6
carbon atoms, preferably a methoxy group.
[0111] Preferred examples of the monovalent group include the
following: 7
[0112] In the above formulae, Y is a hydrogen atom or a lower alkyl
group; V and U are each a hydrogen atom or a lower alkoxy group
(preferably dimethoxy); W.sup.1 and W.sup.2 are each a hydrogen
atom, a lower alkyl group, or a lower alkoxy group; and W.sup.3 is
a hydrogen atom or a lower alkyl group. The right hand ring in
formulae (j) and (l) is a 7-membered ring, while the right hand
ring in formula (k) is an 8-membered ring.
[0113] The most preferred examples of the above-defined R.sup.1
include a monovalent group derived from an indanone having an
unsubstituted or substituted phenyl group and a monovalent group
derived from a cyclic amide compound.
[0114] The most preferred examples of the above-defined X include
--(CH.sub.2).sub.r--, an amide group, or groups represented by the
above formulae where n is 2. Thus, it is most preferred that any
portion of a group represented by the formula
[0115] 8
[0116] have a carbonyl or amide group.
[0117] The substituents involved in the expressions "a substituted
or unsubstituted phenyl group" and "a substituted or unsubstituted
arylalkyl group" in the above definition of R.sup.2 are the same
substituents as those described for the above definitions of a
phenyl group, a pyridyl group, a pyrazyl group, a quinolyl group,
an indanyl group, a cyclohexyl group, a quinoxalyl group or a furyl
group in the definition of R.sup.1.
[0118] The term "arylalkyl group" is intended to mean an
unsubstituted benzyl or phenethyl group or the like.
[0119] Specific examples of the pyridylmethyl group include
2-pyridylmethyl, 3-pyridylmethyl, and 4-pyridylmethyl groups.
[0120] Preferred examples of R.sup.2 include benzyl and phenethyl
groups. The symbol means a double or single bond. The bond is a
double bond only when R.sup.1 is the divalent group (B) derived
from an indanone having an unsubstituted or substituted phenyl
ring, while it is a single bond in other cases.
[0121] In preferred embodiments, the compound of formula II is a
compound of formula III or a pharmaceutically acceptable salt
thereof: 9
[0122] wherein r is an integer of about 1 to about 10; each
R.sup.22 is independently hydrogen or methyl; K is a phenalkyl or a
phenalkyl having a substituent on the phenyl ring; each S is
independently a hydrogen, a lower alkyl group having 1 to 6 carbon
atoms or a lower alkoxy group having 1 to 6 carbon atoms; t is an
integer of 1 to 4; q is an integer of about 1 to about 3; with the
proviso that (S)t can be a methylenedioxy group or an ethylenedioxy
group joined to two adjacent carbon atoms of the phenyl ring.
[0123] In preferred embodiments, the compound of formula III
is:
[0124]
1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,
[0125]
1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-ylidenyl)methylpiperidine,
[0126] 1-benzyl-4-((5-methoxy-1-indanon)-2-yl)methylpiperidine,
[0127]
1-benzyl-4-((5,6-diethoxy-1-indanon)-2-yl)methylpiperidine,
[0128]
1-benzyl-4-((5,6-methnylenedioxy-1-indanon)-2-yl)methylpiperidine,
[0129]
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidin-
e,
[0130]
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidi-
ne,
[0131]
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidi-
ne,
[0132]
1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)propylpiperidine,
[0133]
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanon)-2-yl)methylpiperidin-
e,
[0134]
1-benzyl-4-((5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine;
or pharmaceutically acceptable salts thereof.
[0135] In more preferred embodiments, the compound of formula II is
1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine or a
pharmaceutically acceptable salt thereof. In the most preferred
embodiment, the compound of formula III is
1-benzyl-4-((5,6-dimethoxy-1-i- ndanon)-2-yl)methylpiperidine
hydrochloride, which is also known as donepezil hydrochloride or
ARICEPT.RTM. (Eisai Inc., Teaneck, N.J.), and which has formula IV:
10
[0136] The compounds of the invention may have an asymmetric carbon
atom(s), depending upon the substituents, and can have
stereoisomers, which are within the scope of the invention. For
example, donepezil hydrochloride can be in the forms described in
Japanese Patent Application Nos. 4-187674 and 4-21670, the
disclosures of which are incorporated by reference herein in their
entirety. Japanese Patent Application No. 4-187674 describes a
compound having formula V: 11
[0137] which can be in the form of a pharmaceutically acceptable
salt, such as a hydrochloride salt. Japanese Patent Application No.
4-21670 describes compounds having formula VI: 12
[0138] which can be in the form of a pharmaceutically acceptable
salt, such as a hydrochloride salt; and compounds of formula VII:
13
[0139] which can be in the form of a pharmaceutically acceptable
salt, such as a hydrochloride salt; and compounds of formula VIII:
14
[0140] As described above, the compounds of the invention can be
administered in the form of a pharmaceutically acceptable salt.
Pharmaceutically acceptable salts are known in the art and include
those of inorganic acids, such as hydrochloride, sulfate,
hydrobromide and phosphate; and those of organic acids, such as
formate, acetate, trifluoroacetate, methanesulfonate,
benzenesulfonate and toluenesulfonate. When certain substituents
are selected, the compounds of the invention may form, for example,
alkali metal salts, such as sodium or potassium salts; alkaline
earth metal salts, such as calcium or magnesium salts; organic
amine salts, such as a salt with trimethyl-amine, triethylamine,
pyridine, picoline, dicyclohexylamine or
N,N'-dibenzylethylene-diamine. One skilled in the art will
recognize that the compounds of the invention can be made in the
form of any other pharmaceutically acceptable salt.
[0141] The compounds of the invention can be prepared by processes
that are known in the art and described, for example, in U.S. Pat.
No. 4,895,841, WO 98/39000, and Japanese Patent Application Nos.
4-187674 and 4-21670, the disclosures of each of which are
incorporated by reference herein in their entirety. Donepezil
hydrochloride, a preferred cholinesterase inhibitor for use in the
methods described herein, is commercially available as ARICEPT.RTM.
from Eisai Inc., Teaneck, N.J.
[0142] The dosage regimen for treating the diseases described
herein with the cholinesterase inhibitors described herein is
selected in accordance with a variety of factors, including the
age, weight, sex, and medical condition of the patient, the
severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular
cholinesterase inhibitor used, whether a drug delivery system is
used and whether the cholinesterase inhibitor is administered as
part of a drug combination. Thus, the dosage regimen actually used
may vary widely and may deviate from the preferred dosage regimen
described herein.
[0143] In preferred embodiments, the cholinesterase inhibitors of
the invention are administered to treat the diseases described
herein in doses of about 0.1 milligram to about 300 milligrams per
day, preferably about 1 milligram to about 100 milligrams per day,
more preferably about 5 milligrams to about 10 milligrams per day.
The doses can be administered in one to four portions over the
course of a day, preferably once a day. One skilled in the art will
recognize that when the cholinesterase inhibitors of the invention
are administered to children, the dose may be smaller than the dose
administered to adults, and that the dose can be dependent upon the
size and weight of the patient. In preferred embodiments, a child
can be administered the cholinesterase inhibitors of the invention
in doses of about 0.5 milligrams to about 10 milligrams per day,
preferably about 1 milligram to about 3 milligrams per day.
[0144] In preferred embodiments of the methods described herein, a
physician can administer patients donepezil hydrochloride, which is
commercially available as ARICEPT.RTM. (Eisai Inc., Teaneck, N.J.),
as film-coated tablets containing 5 milligrams donepezil
hydrochloride or 10 milligrams donepezil hydrochloride. The tablets
can be administered one to about four times a day. In preferred
embodiments, one 5 milligram or one 10 milligram ARICEPT.RTM.
tablet is administered once a day for the methods described herein.
One skilled in the art will appreciate that when donepezil
hydrochloride is administered to children, the dose may be smaller
than the dose that is administered to adults. In preferred
embodiments, a child can be administered donepezil hydrochloride in
doses of about 0.5 milligrams to about 10 milligrams per day,
preferably about 1 milligram to about 3 milligrams per day.
[0145] The cholinesterase inhibitors of the invention can be
administered orally, topically, parenterally, by inhalation (nasal
or oral), or rectally in dosage unit formulations containing
conventional nontoxic pharmaceutically acceptable carriers,
adjuvants, and vehicles as desired. The term parenteral as used
herein includes subcutaneous, intravenous, intramuscular,
intrasternal injection, or infusion techniques. Preferably, the
cholinesterase inhibitors of the invention are orally administered
as tablets. When administered to children, the cholinesterase
inhibitors of the invention are preferably orally administered in a
liquid dosage form. It will also be preferable to orally administer
the cholinesterase inhibitors in a liquid dosage form to patients,
such as those being treated for schizophrenia or related
psychiatric disorders, who are unable to take a solid dosage form.
In the methods of alleviating tobacco withdrawal syndrome described
herein, the cholinesterase inhibitors can preferably be
administered topically, most preferably in the form of a
transdermal patch.
[0146] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents,
suspending agents (e.g., methylcellulose, Polysorbate 80,
hydroxyethylcellulose, acacia, powdered tragacanth, sodium
carboxymethylcellulose, polyoxytehylene sorbitan monolaurate and
the like), pH modifiers, buffers, solubilizing agents (e.g.,
polyoxyethylene hydrogenated castor oil, Polysorbate 80,
nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an
ethyl ester of castor oil fatty acid, and the like) and
preservatives. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be used are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally used as a solvent or suspending medium. For this
purpose any bland fixed oil may be used including synthetic mono-
or diglycerides, in addition, fatty acids such as oleic acid find
use in the preparation of injectables. The preparations can be
lyophilized by methods known in the art.
[0147] Solid dosage forms for oral administration may include
chewing gum, capsules, tablets, sublingual tablets, powders,
granules and gels; most preferably tablets. In such solid dosage
forms, the active compound may be admixed with one or more inert
diluents such as lactose or starch. As is normal practice, such
dosage forms may also comprise other substances including
lubricating agents such as magnesium stearate. In the case of
capsules, tablets, and pills, the dosage forms may also comprise
buffering agents. The tablets can be prepared with enteric or film
coatings, preferably film coatings.
[0148] In addition to the active ingredient, the tablets preferably
comprise lactose monohydrate, corn starch, microcrystalline
cellulose, hydroxypropyl cellulose, and magnesium stearate; while
the film-coating on the tablet preferably comprises talc,
polyethylene glycol, hydroxpropyl methylcellulose, titanium
dioxide, and, optionally, other coloring agents, such as yellow
iron oxide.
[0149] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions, and
syrups containing inert diluents commonly used in the art, such as
water. Such compositions can also comprise adjuvants, such as
wetting agents, emulsifying and suspending agents, and sweetening,
flavoring, and perfuming agents.
[0150] For administration by inhalation, the compositions of the
invention can be delivered from an insufflator, a nebulizer or a
pressured pack or other convenient mode of delivering an aerosol
spray. Pressurized packs can include a suitable propellant.
Alternatively, for administration by inhalation, the compositions
can be administered in the form of a dry powder composition or in
the form of a liquid spray.
[0151] Suppositories for rectal administration can be prepared by
mixing the active compounds with suitable nonirritating excipients
such as cocoa butter and polyethylene glycols that are solid at
room temperature and liquid at body temperature.
[0152] For topical administration to the epidermis, the
cholinesterase inhibitors of the invention can be formulated as
ointments, creams or lotions, or as the active ingredient of a
transdermal patch. Ointments and creams may, for example, be
formulated with an aqueous or oily base with the addition of
suitable thickening and/or gelling agents. Lotions may be
formulated with an aqueous or oily base and can also generally
contain one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, and/or
coloring agents. The cholinesterase inhibitors can also be
administered via iontophoresis.
[0153] While the cholinesterase inhibitors of the invention can be
administered as the sole active pharmaceutical agent in the methods
described herein, they can also be used in combination with one or
more compounds which are known to be therapeutically effective
against the specific disease that one is targeting for
treatment.
[0154] Each of the patents and publications cited herein are
incorporated by reference herein in their entirety.
[0155] It will be apparent to one skilled in the art that various
modifications can be made to the invention without departing from
the spirit or scope of the appended claims.
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