US 20060018839A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0018839 A1 leni et al. (43) Pub. Date: Jan. 26, 2006

(54) METHODS AND COMPOSITIONS USING Publication Classification CHOLINESTERASE INHIBITORS (51) Int. Cl. A6IL 9/04 (2006.01) (75) Inventors: John Ieni, Bloomfield, NJ (US); A6IK 9/70 (2006.01) Raymond Pratt, Baltimore, MD (US) A6IK 3III.3 (2006.01) (52) U.S. Cl...... 424/45; 424/449; 514/662 Correspondence Address: (57) ABSTRACT VENABLE LLP The invention provides methods for treating and/or prevent P.O. BOX 34385 ing Alzheimer's disease, psychiatric illnesses, encephalitis, WASHINGTON, DC 20045-9998 (US) meningitis, fetal alcohol Syndrome, Karsakoff's Syndrome, anoxic brain injury, cardiopulmonary resuscitation injuries, diabetes, Sjogren's Syndrome, mental retardation, develop (73) Assignee: Eisai Co., Ltd., Tokyo (JP) mental delay, menopause, Strokes, macular degeneration, neuronal loSS associated with macular degeneration, Sleep disorders, Severe Alzheimer's disease, jet lag, post-traumatic (21) Appl. No.: 10/988,600 StreSS disorder, anxiety disorders, panic attacks, obsessive compulsive disorder, amnesia, and other disorders by administering to a patient in need thereof at least one (22) Filed: Nov. 16, 2004 . The invention also provides novel pharmaceutical compositions that can be administered to the Related U.S. Application Data eyes or to the nose of patients. In one embodiment, the cholinesterase inhibitor is , a Stereoisomer thereof and/or a pharmaceutically acceptable Salt thereof. In other (63) Continuation of application No. PCT/US03/15279, embodiments, the cholinesterase inhibitor can be one or filed on May 16, 2003. more of , tolserine, phenethylnorcymSerine, gan , epastigmine, , , pyridoStig (60) Provisional application No. 60/447,724, filed on Feb. mine, , , , citicoline, 19, 2003. Provisional application No. 60/380,852, Velnacrine, huperzine, , heptastigmine, edropho filed on May 17, 2002. nium, TAK-147, T-82, and upreazine. US 2006/0018839 A1 Jan. 26, 2006

METHODS AND COMPOSITIONS USING 0008. The invention is described in more detail below. CHOLINESTERASE INHIBITORS DETAILED DESCRIPTION OF THE RELATED APPLICATIONS INVENTION 0001. This application is a continuation of PCT Applica 0009. “Patient” refers to animals, preferably mammals, tion No. PCT/US03/15279 filed May 16, 2003, which claims more preferably humans. The term “patient” includes adults priority to U.S. Application No. 60/447,724 filed Feb. 19, and children, and men and women. Children includes neo 2003, and U.S. Application No. 60/380,852 filed May 17, nates, infants, and adolescents. 2002. 0010) “Cognitive impairment” refers to an acquired defi cit in one or more of memory function, problem Solving, FIELD OF THE INVENTION orientation and/or abstraction that impinges on a patient's ability to function independently. 0002 The invention provides methods for treating and/or preventing cognitive impairments, , and other dis 0011 “Dementia” refers to a global deterioration of intel orders by administering a therapeutically effective amount lectual functioning in clear consciousness, and is character ized by one or more Symptoms of disorientation, impaired of at least one cholinesterase inhibitor. A preferred cholinest memory, impaired judgment, and/or impaired intellect. The erase inhibitor is donepezil, a Stereoisomer thereof, and/or a Symptoms of “dementia” are generally worse than, and can pharmaceutically acceptable Salt thereof. encompass, the Symptoms of “cognitive impairment.” BACKGROUND OF THE INVENTION 0012. The invention provides methods for treating and preventing cognitive impairments and/or dementia caused 0003) Cholinesterase inhibitors are described in U.S. Pat. by radiation in a patient in need thereof by administering a No. 4,895,841 and WO 98/39000, the disclosures of which therapeutically effective amount of at least one cholinest are incorporated by reference herein in their entirety. The erase inhibitor. The radiation may be, for example, a radia cholinesterase inhibitors described in U.S. Pat. No. 4,895, tion treatment used for cancer or an accidental exposure to 841 include donepezil hydrochloride or ARICEPT(F), which radioactive materials. has proven to be a highly Successful drug for the treatment 0013 The invention provides methods for treating and of Alzheimer's disease. There is a need in the art for new and preventing visuospatial deficits in a patient in need thereof improved treatments for other diseases, disorders, and Syn by administering a therapeutically effective amount of at dromes that may be characterized by Symptoms of cognitive least one cholinesterase inhibitor. Visuospatial deficits refer impairments. The invention is directed to these, as well as to problems with perceiving, processing and/or interpreting other, important ends. information through the Visual System. Visuospatial deficits can include impairments in Visuoperceptual abilities and SUMMARY OF THE INVENTION Visuoconstructive abilities. 0004. The invention provides methods for treating and/or 0014. The invention provides methods for treating and preventing Alzheimer's disease, vascular dementia, demen preventing Williams Syndrome in a patient in need thereof tia associated with Parkinson's disease, visuospatial deficits, by administering a therapeutically effective amount of at Williams Syndrome, encephalitis, meningitis, fetal alcohol least one cholinesterase inhibitor. Williams syndrome is a Syndrome, Korsakoff's Syndrome, anoxic brain injury, car developmental disorder that is characterized by Visuospatial diopulmonary resuscitation injuries, diabetes, Sjogren's Syn deficits. Most patients with Williams syndrome have mild or drome, mental retardation, developmental delay, meno moderate mental retardation (mean IQ ranging from 55-60), pause, pre-menstrual Syndrome, Strokes, macular but Some have borderline normal intelligence or Severe degeneration, Sleep disorders, cognitive impairments caused mental retardation. by high cholesterol levels, jet lag, post-traumatic StreSS 0015 The invention provides methods for treating and disorder, anxiety disorders, panic attacks, obsessive-com preventing cognitive impairments and/or dementia associ pulsive disorder, amnesia and other disorders by adminis ated with or caused by encephalitis by administering to a tering to a patient at least one cholinesterase inhibitor. patient in need thereof at least one cholinesterase inhibitor. 0005 The invention provide novel nasally administrable “Encephalitis” refers to an inflammation of the brain. Symp pharmaceutical compositions comprising at least one cho toms can include a Sudden fever, headache, vomiting, pho linesterase inhibitor and a nasal delivery System. tophobia, Stiff neck and back, confusion, drowsiness, clum SineSS, unsteady gait, and irritability. Other Symptoms 0006 The invention provides methods of treating include loSS of consciousness, poor responsiveness, Seizures, migraines in a patient in need thereof by the nasal admin muscle weakness, Sudden Severe dementia, memory loSS, istration of a pharmaceutical composition comprising at withdrawal from Social interaction, and impaired judgment. least one cholinesterase inhibitor and a nasal delivery Sys tem. 0016. The invention provides methods for treating and preventing cognitive impairments and/or dementia associ 0007. The invention provides ophthalmic compositions ated with or caused by meningitis by administering to a comprising at least one cholinesterase inhibitor. The oph patient in need thereof a therapeutically effective amount of thalmic compositions of the invention can be used, for at least one cholinesterase inhibitor. “Meningitis” refers to example, to treat macular degeneration, Sjogren's Syn an infection of the membranes that Surround the brain and drome, and glaucoma. Spinal cord. Symptoms can appear Suddenly and can include US 2006/0018839 A1 Jan. 26, 2006

a high fever, Severe and persistent headache, Stiff neck, 0021. The invention provides methods for treating and nausea, and vomiting. Other Symptoms can include confu preventing cognitive impairments and/or dementia caused Sion, Sleepiness, and difficulty waking up. Symptoms of by cardiopulmonary resuscitation by administering to a meningitis in infants can include irritability or tiredness, patient in need thereof a therapeutically effective amount of poor feeding and fever. at least one cholinesterase inhibitor. “Cardiopulmonary resuscitation” refers to the administration of heart compres 0.017. The invention provides methods for treating and Sion and artificial respiration to restore circulation and preventing Sjogren's Syndrome by administering to a patient breathing. PoSSible post-resuscitation complications can in need thereof a therapeutically effective amount of at least include cognitive impairments, cardiovascular dysfunction, one cholinesterase inhibitor. “Sjogren's syndrome' refers to microcirculatory dysfunction, hypoxia and the release of a chronic autoimmune disorder in which immune cells toxic enzymes and free radicals, multiple organ dysfunction attack and destroy the glands that produce tears and Saliva. Syndrome, Seizures, Systemic inflammatory response Syn The Symptoms of Sjogren's Syndrome can include dry eyes drome, Septic shock, and Sepsis Syndrome. and a dry mouth. Additional Symptoms can include skin, nose, and/or vaginal dryneSS. Sjogren's Syndrome can be 0022. The invention provides methods for treating and asSociated with rheumatic disorders, Such as rheumatoid preventing cognitive impairments and/or dementia caused arthritis, and can affect other organs of the body including by or associated with diabetes by administering to a patient the kidneyS, blood vessels, lungs, liver, pancreas, and brain. in need thereof at least one cholinesterase inhibitor. “Dia In the methods of the invention, the cholinesterase inhibitors betes’ refers to a disease of high blood Sugar caused by too can be used Systemically or by topical application to the eyes little insulin, resistance to insulin, or both. “Type 1 diabetes' to treat Sjogren's Syndrome. occurs when the body makes little or no insulin and daily injections of insulin are required to live. “Type 2 diabetes' 0.018. The invention provides methods for treating and occurs when the pancreas does not make enough insulin to preventing cognitive impairments and/or dementia associ keep blood glucose levels normal. Symptoms of Type 1 ated with or caused by fetal alcohol syndrome by adminis diabetes can include increased thirst, increased urination, tering to a patient in need thereof a therapeutically effective weight loSS in Spite of increased appetite, fatigue, nausea and amount of at least one cholinesterase inhibitor. "Fetal alco Vomiting. Symptoms of Type 2 diabetes can include hol Syndrome' refers to the manifestation of specific growth, increased thirst, increased urination, increased appetite, mental, and physical birth defects associated with a mother's fatigue, blurred vision, Slow healing infections, and Sexual high level of alcohol use during pregnancy. Symptoms of dysfunctions. Possible complications of diabetes can include fetal alcohol Syndrome can include slow intrauterine and heart disease, Stroke, eye diseases (such as cataracts, glau neonatal growth with occasional diagnosis of failure to coma, or blindness), kidney disease leading to kidney fail thrive, delayed development and evidence of mild to mod ure, and nervous System disease. Cognitive impairments erate mental retardation, facial abnormalities, skeletal abnor resulting from diabetes can include the loSS of mental agility, malities, in the newborn infant, agitation and crying poor concentration, disruptive behavior, fatigue, anxiety, by the newborn infant, Simian crease or other abnormal tension, confusion, disorientation, aggression, memory creases on the palm, growth deficiency, heart defects, vision problems, and mood changes. difficulties, abnormal behavior Such as short attention Span, hyperactivity, poor impulse control, extreme nervousness 0023 The invention provides methods for treating and and anxiety, and limb abnormalities. preventing mental retardation by administering to a patient in need thereof a therapeutically effective amount of at least 0019. The invention provides methods for treating and one cholinesterase inhibitor. “Mental retardation” refers to preventing cognitive impairments (e.g., memory impair the below-average general intellectual function with asso ment) associated with or caused by Korsakoff’s Syndrome ciated deficits in adaptive behavior that occurs before age by administering to a patient in need thereof at least one 18. Symptoms of mental retardation can include failure to cholinesterase inhibitor. “Korsakoff's syndrome' is a syn meet intellectual developmental markers, persistence of drome in which the impairment of memory is out of pro portion to other cognitive functions. Symptoms can include infantile behavior, lack of curiosity, decrease learning abil memory impairment (e.g., loss of memory, inability to form ity, and inability to meet educational demands of School. new memories), vision changes (Such as double vision), loss 0024. The invention provides methods for treating and of muscle coordination, Symptoms that indicate alcohol preventing developmental delay by administering to a withdrawal, and fabrication of stories. patient in need thereof a therapeutically effective amount of at least one cholinesterase inhibitor. “Developmental delay” 0020. The invention provides methods for treating and refers to a child who fails to achieve certain skills as quickly preventing cognitive impairments and/or dementia associ as expected, i.e., a child not reaching developmental bench ated with or caused by anoxic brain injury by administering marks at the usual age. Signs of developmental delay can to a patient in need thereof at least one cholinesterase include the delay in walking and other motor skills, the inhibitor. “Anoxic brain injury” refers to the injury to the inability to walk, language delay or inability to learn, brain caused by an absence or complete lack of oxygen abnormalities of vision or hearing, behavioral problems, and Supply to the brain's tissues. Symptoms can include Sei Seizures. Zures, muscle Spasms or twitches, short-term memory loSS, word-finding difficulties, Visual disturbances, incoordina 0025 The invention provides methods for treating and tion, inability to follow a Sequence of commands, Spasticity, preventing cognitive impairments (e.g., memory loss) weakneSS or paralysis, and neck StiffneSS. Severe Symptoms caused by or associated with menopause by administering to include coma or unconsciousness for hours to days, weeks a patient in need thereof at least one cholinesterase inhibitor. or months. “Menopause” refers to the transition period in a woman's US 2006/0018839 A1 Jan. 26, 2006 life when the ovaries Stop producing eggs, menstrual activity increase of awakenings, the less time spent in deep dream decreases and eventually ceases, and the body decreases the leSS Sleep, which can lead to confusion and other metal production of the female hormones, estrogen and progest changes. "Narcolepsy refers to a sleep disorder associated erone. The Symptoms of menopause can include memory with uncontrollable sleepineSS and frequent daytime sleep loss, hot flashes, Skin flushing, mood changes, decreased Ing. libido, irregular menstrual periods, and vaginal dryneSS. 0029. In another embodiment, the invention provides 0026. The invention provides methods for treating and methods for enhancing REM sleep by administering to a preventing cognitive impairments (e.g., language develop patient in need thereof at least one cholinesterase inhibitor. ment) and/or dementia caused by or associated with strokes Enhancing REM sleep includes, for example, increasing the by administering to a patient in need thereof at least one number of REM sleep episodes and/or increasing the dura cholinesterase inhibitor. In another embodiment, the inven tion of REM sleep episodes. Without intending to be bound tion provides methods of treating post-Stroke aphasia in a by any theory of the invention, enhancing REM sleep may patient in need thereof by administering at least one cho enhance memory consolidation and learning, and may linesterase inhibitor. A “stroke” refers to the loss of brain improve a patient's mood. functions caused by a loSS of blood circulation to areas of the brain. Symptoms of a stroke can include loss of movement 0030. In another embodiment, the invention provides (paralysis) of a body area, weakness, decreased Sensation, methods for treating and/or preventing cognitive impair numbness, decreased vision, language difficulties (aphasia) ments and/or dementia associated with or caused by high (Such as slurred, thick or difficult speech, or the inability to cholesterol levels in a patient. Without intending to be bound Speak), inability to understand speech and difficulty with by any theory of the invention, it is believed that high reading or writing, inability to recognize or identify Sensory cholesterol levels cause cognitive impairments, Such as Stimuli, loSS of memory, vertigo, loss of coordination, Swal impaired memory. High cholesterol generally refers to a lowing difficulties, personality changes, mood/emotion cholesterol level greater than 200; about 215 or higher; changes, consciousness changes, urinary incontinence, and about 225 or higher; or about 235 or higher. cognitive decline Such as dementia, impaired judgment and 0031. The invention provides methods for treating and limited attention. Additional Symptoms can include tongue preventing jet lag by administering to a patient in need problems, Seizures, jerky movement, uncontrollable and/or thereof at least one cholinesterase inhibitor. “Jet lag” refers dysfunctional movement, fainting, drooling, temporary to a physical reaction to a rapid change in time Zones. absent breathing, and lack of Sweating. Symptoms of jet lag can include disorientation, irritability, 0027. The invention provides methods for treating and fatigue, Swollen limbs and eyes, headaches, cold-like Symp preventing macular degeneration by administering to a toms, and irregular bowels. patient in need thereof at least one cholinesterase inhibitor. 0032. The invention provides methods for treating and In another embodiment, the invention provides methods for preventing post-traumatic StreSS disorders by administering preventing the neuronal loSS associated with macular degen to a patient in need thereof at least one cholinesterase eration by administering to a patient in need thereof at least inhibitor. “Post-traumatic stress disorder” is a psychiatric one cholinesterase inhibitor. “Macular degeneration” refers illness that can occur following a traumatic event in which to a disorder that affects the macula or the central part of the there is the threat of injury or death to the patient or Someone retina causing decreased visual acuity and possible loss of else. Symptoms can include recurrent distressing memories central vision. Symptoms of macular degeneration can of the event, recurrent dreams of the event, flashback include blurred, distorted, dim or absent central vision. In episodes, bodily reactions to situations that remind the the methods of the invention, the cholinesterase inhibitors perSon of the traumatic event, the inability to remember can be used Systemically or by topical application of the eyes important aspects of the trauma, lack of interest in normal to treat macular degeneration or neuronal loSS associated activities, feelings of detachment, reduced expression of with macular degeneration. moods, irritability or outburst of anger, sleeping difficulties, 0028. The invention provides methods for treating and difficulty concentrating, hypervigilance, paleness, heart pal preventing Sleep disorders by administering to a patient in pitations, headache, fever, fainting, dizziness, and agitation. need thereof at least one cholinesterase inhibitor. “Sleep Some possible complications can include depression, anxi disorders,” refer to a disruptive pattern of Sleep that can ety, unusual phobia to things that are not usually frightening include difficulty falling or staying asleep, falling asleep at to other people, alcohol abuse and/or drug abuse. inappropriate times, excessive total sleep time, or abnormal 0033. The invention provides methods for treating and behaviors associated with sleep. Sleep disorders include, for preventing anxiety disorders or panic attacks by adminis example, REM (rapid eye movement) disorders, sleep onset tering to a patient in need thereof at least one cholinesterase with depression, age-related Sleep disorders, narcolepsy, inhibitor. “Panic attacks” refer to unexpected and repeated sleep deprivation, and REM-deprived sleep disorders. episodes of intense fear accompanied by physical Symptoms Symptoms of Sleep disorders can include awakening in the that can include chest pain, heart palpitations, shortneSS of night, difficulty falling asleep, excessive daytime drowsi breath, dizzineSS or abdominal distreSS. Other Symptoms can neSS, loud Snoring, episodes of Stopped breathing, Sleep include terror, nausea, tingling or numbness in the hands, attacks during the day, daytime fatigue, depressed mood, flushes or chills, Sense of unreality, fear of losing control, anxiety, difficulty concentrating, apathy, irritability, loss of going "crazy,' or doing Something embarrassing, and fear of memory or decreased memory, and lower leg movements dying. during sleep. “REM sleep” refers to the occasional periods of active dreaming during Sleep. “Age related Sleep disor 0034. The invention provides methods for treating and ders' refer to the increased difficulty of falling asleep, the preventing obsessive-compulsive disorder by administering US 2006/0018839 A1 Jan. 26, 2006

to a patient in need thereof at least one cholinesterase Statin. The cholinesterase inhibitor and Statin can be admin inhibitor. “Obsessive-compulsive disorder” refers to an istered Separately or in the form of a composition. anxiety disorder characterized by the presence of obsessions 0039 The invention provides methods for treating and/or or compulsions. An "obsession” refers to a recurrent or delaying the onset of Alzheimer's disease, Vascular demen persistent thought that is intrusive or inappropriate. A "com tia, Parkinson's disease, or cognitive impairments by admin pulsion' is a repetitive behavior a patient feels driven to istering to a patient in need thereof a therapeutically effec perform Such as a physical action (i.e., handwashing) or a tive amount of at least one cholinesterase inhibitor and at mental action (i.e., praying, repeating Words, counting). least one anti-oxidant. The anti-oxidant can be any in the art. Symptoms of the disorder include obsessions or compul Exemplary anti-oxidants include Vitamin E, BHA (i.e., buty Sions that cause Significant distress or interference with lated hydroxyanisole), BHT (i.e., butylated hydroxytolu every day life, and are not due to medical illness or drug use. ene), Vitamin C, budralazine, cadralazine, dihydralazine, 0035. The invention provides methods for treating and endralazine, hydralazine, pildralazine, todralazine, glu preventing cognitive impairments associated with patients tathione, cysteine, N-acetyl-cysteine, P-caroteine, who ingest or are exposed to MTPT by administering a ubiquinone, ubiquinol-10, tocopherols, coenzyme Q, Super therapeutically effective amount of at least one cholinest oxide dismutase, catalase, glutathione peroxidase, and the erase inhibitor. MTPT is a designer drug that can produce like. A preferred anti-oxidant is vitamin E. The anti-oxidants Symptoms of Parkinson's disease in a patient who uses it or can be Synthetic or natural. The cholinesterase inhibitor and makes it. the anti-oxidant can be administered Separately or in the form of a composition. 0.036 The invention provides methods for treating and preventing amnesia by administering to a patient in need 0040. The invention provides methods for treating and/or thereof at least one cholinesterase inhibitor. “Amnesia” delaying the onset of Alzheimer's disease by administering refers to a disturbance in memory manifested by total or a therapeutically effective amount of at least one cholinest partial inability to recall past experiences. Symptoms of erase inhibitor and an Alzheimer's vaccine. The Alzheimer's amnesia can include memory gaps, confusion, changes in vaccine can be any in the art. In one embodiment, the emotion, difficulty in remembering recent events and/or Alzheimer's vaccine comprises an amyloid. events in the past, and disorientation. Cognitive impairments 0041. The invention provides methods for treating psy asSociated with amnesia can include difficulty thinking/ chiatric disorders by administering to a patient in need concentrating, drops in IQ, and problems with fine/groSS thereof a therapeutically effective amount of at least one motor coordination. cholinesterase inhibitor. In another embodiment, the inven tion provides for methods treating psychiatric disorders by 0037. The invention provides methods for treating Alzhe administering to a patient in need thereof a therapeutically imer's disease and/or delaying the onset of Alzheimer's disease in a patient in need thereof by administering a effective amount of at least one cholinesterase inhibitor and therapeutically effective amount of at least one cholinest at least one psychiatric medicine. erase inhibitor and at least one Statin. In another embodi 0042 Any psychiatric medicine in the art can be used ment, the invention provides methods for treating Alzhe depending on the psychiatric illness that is being treated. imer's disease and/or delaying the onset of Alzheimer's Psychiatric medicines include, for example, antidepressant; disease by administering a therapeutically effective amount anti-psychotic medications (e.g., pimozide, chlorpromazine, of at least two cholinesterase inhibitors. In another embodi phenothiazines, butyrophenone, thioxanthines, haloperidol, ment, the invention provides methods for treating Alzhe Sulpride, clozapine, Sulpiride, tiapride, , amisul imer's disease and/or delaying the onset of Alzheimer's pride, risperidone, olanzapine, quetiapine, polycarbophil, disease by administering a therapeutically effective amount Ziprasidone, aripiprazole, illoperidone, trifluoperazine, lox of at least two cholinesterase inhibitors and at least one apine, molindone, fluphenazine, thiothixene, perphenazine, Statin. The Statin can be any in the art. Exemplary Statins prochlorperizine, perphenazine/amitryptiline, meSoridazine, include fluvastatin, atorvastatin, Simvastatin, pravastatin, thioridazine); mood Stabilizers (e.g., lithium, divalproex, lovastatin, cerivastatin, rosuvastatin, and the like. The cho gabapentin, carbamazepine, lamotrigine, topiramate); anti linesterase inhibitor and Statin can be administered Sepa anxiety medications (e.g., hydroxyzine, doxepin, Venlafax rately or in the form of a composition. ine, paroxetine, meprobamate, NGD 91-3, and benzodiaz epines (Such as alprazolam, flurazepam, oxazepam, 0.038. The invention provides methods for treating and/or triazolam, estaZolam, chlordiazepoxide, lorazepam, delaying the onset of vascular dementia (also known as quazepam, diazepam, tamazepam, clonazepam), Stimulants cerebrovascular dementia) or dementia associated with Par (e.g., methylphenidate, dextroamphetamine, pemoline, dex kinson's disease in a patient in need thereof by administer troamphetamine/levoamphetamine), and the like. ing a therapeutically effective amount of at least one cho linesterase inhibitor and at least one Statin. In another 0043 Antidepressants include, for example, tricyclic embodiment, the invention provides methods for treating antidepressants (e.g., amitriptyline, desipramine, imi and/or delaying the onset of vascular dementia or dementia pramine, nortirptyline); Serotonin-specific reuptake inhibi asSociated with Parkinson's disease by administering a tors (e.g., fluoxetine, paroxetine, Sertraline, citalopram, flu therapeutically effective amount of at least two cholinest voxamine); monoamine oxidase inhibitors (e.g., phenelzine, erase inhibitors. In another embodiment, the invention pro tranylcypromine, isocarboxazid); other antidepressants vides methods for treating and/or delaying the onset of (e.g., Venlafaxine, nefazodone, bupropion, mirtazapine, tra vascular dementia or dementia associated with Parkinson's Zodone, thioridazine, protriptyline), and the like. disease by administering a therapeutically effective amount 0044) The psychiatric disorder can be any known in the of at least two cholinesterase inhibitors and at least one art. Exemplary psychiatric disorders include obsessive-com US 2006/0018839 A1 Jan. 26, 2006

pulsive disorder, post-traumatic StreSS disorder, anxiety, used. In one embodiment, the GABA inverse agonist is panic attacks, Schizophrenia, depression, mania, manic-de NGD 97-1. The cholinesterase inhibitor and GABA inverse pression (bipolar disorder), autism, dyslexia, apathy, agonist can be administered Separately or in the form of a delirium, attention deficit hyperactivity disorder, phobias, composition. eating disorders (e.g., bulimia, anorexia), and the like. 0049. The invention provides methods for potentiating 004.5 The invention provide methods for treating and/or the effect of analgesics by administering to a patient in need delaying the onset of Alzheimer's disease, vascular demen thereof a therapeutically effective amount of at least one tia, or dementia associated with Parkinson's disease by cholinesterase inhibitor and at least one analgesic. The use administering to a patient in need thereof at least one of a cholinesterase inhibitor in combination with the anal cholinesterase inhibitor and at least one NMDA receptor gesic allows for the use of a lower dose of the analgesic to blocker. In another embodiment, the invention provides achieve the same results. The invention provides methods methods for treating and/or delaying the onset of Alzhe for treating one or more side-effects of analgesics by admin imer's disease, vascular dementia, or dementia associated istering to a patient in need thereof a therapeutically effec with Parkinson's disease by administering to a patient in tive amount of at least one cholinesterase inhibitor. The need thereof at least two cholinesterase inhibitors and at invention also provides methods for preventing emergence least one NMDA receptor blocker. Any NMDA receptor reactions (e.g., hallucinations) by administering to a patient blocker in the art can be used. Exemplary NMDA receptor in need thereof a therapeutically effective amount of at least blockers include , remacemide, dizocilipine, dex one cholinesterase inhibitor and at least one narcotic. The tromethorphan, dextorphan, AP5, AP7 and the like. In one analgesic can be any in the art. Exemplary analgesics embodiment, the NMDA receptor blocker is memantine. include narcotics, NSAIDS, meperidine, propoxyphene and The cholinesterase inhibitor and NMDA blocker can be the like. The narcotic can be any in the art. Exemplary administered Separately or in the form of a composition. narcotics include alfentanil, allylprodine, alphaprodine, 0046) The invention provide methods for treating anilleridine, benzylmorphine, beZitramide, buprenorphine, memory loSS, cognitive impairments or dementia; and for butorphanol, clonitaZene, codeine, cyclazocine, desomor treating and/or delaying the onset of Alzheimer's disease, phine, dextromoramide, dezocine, diampromide, dihydroco vascular dementia, or dementia associated with Parkinson's deine, dihydromorphine, dimenoxadol, dimepheptanol, dim disease by administering to a patient in need thereof at least ethylthiambutene, dioxaphetyl butyrate, dipipanone, one cholinesterase inhibitor and at least one calcium channel eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl blocker. In another embodiment, the invention provides morphine, etonitazine, fentanyl, heroin, hydrocodone, methods for treating and/or delaying the onset of Alzhe hydromorphone, hydroxypethidine, isomethadone, ketobe imer's disease, vascular dementia, or dementia associated midone, levallorphan, levorphanol, levophenacylmorphan, with Parkinson's disease by administering to a patient in lofentanil, meperidine, meptazinol, metazocine, methadone, need thereof at least two cholinesterase inhibitors and at metopon, morphine, myrophine, nalbuphine, narceline, nico least one calcium channel blocker. Any calcium channel morphine, norlevorphanol, normethadone, nalorphine, nor blocker in the art can be used. Exemplary calcium channel mophine, norpipanone, opium, oxycodone, oxymorphone, blockers include amlodipine, aranidipine, barnidipine, beni papaveretum, pentazocine, phenadoxone, phenomorphan, dipine, cilnidipine, clentiazem, diltiazen, efonidipine, fanto phenazocine, phenoperidine, piminodine, piritramide, farone, felodipine, isradipine, lacidipine, lercanidipine, propheptazine, promedol, properidine, propiram, pro manidipine, mibefradil, nicardipine, nifedipine, nilvadipine, poxyphene, Sufentanil, tramadol, tilidine and the like. The nisoldipine, nitrendipine, Semotiadil, and Veraparmil. The NSAID can be any in the art. Exemplary NSAIDs include COX-1 and COX-2 inhibitors, Such as celecoxib, rofecoxib, cholinesterase inhibitor and calcium channel blocker can be Valdecoxib, ibuprofen, acetaminophen, aspirin, ketorolac, administered Separately or in the form of a composition. ketoprofen, diflunisal, Salsalate, Salicylates, Salicylamide, 0047 The invention provide methods for treating thiosalicylates, meSalamine, SulfaSalazine, methylsalicylate, memory loSS, cognitive impairments or dementia; and for phenylbutaZone, oxyphenbutaZone, antipyrine, aminopy treating and/or delaying the onset of Alzheimer's disease, rine, dipyrone, azapropaZone, phenacetin, indomethacin, vascular dementia, or dementia associated with Parkinson's Sulindac, mefenamic, meclofenamic, flufenamic, tolfe disease by administering to a patient in need thereof at least namic, etofenamic, tolmetin, naproxen, flurbiprofen, feno one cholinesterase inhibitor and a therapeutically effective profen, fenbufen, pirprofen, Oxaprozin, indoprofen, tiapro amount of . In another embodiment, the invention fenic acid, piroXicam, ampirOXicam, tenoxicam, tenidap, provides methods for treating and/or delaying the onset of diclofenac, etodolac, nabumentone, and the like. The cho Alzheimer's disease, vascular dementia, or dementia asso linesterase inhibitor and analgesic can be administered Sepa ciated with Parkinson's disease by administering to a rately or in the form of a composition. patient in need thereof at least two cholinesterase inhibitors and a therapeutically effective amount of caffeine. The 0050. The invention provides methods for treating incon cholinesterase inhibitor and caffeine (or caffeine-containing tinence in a patient in need thereof by administering a compound) can be administered separately or in the form of therapeutically effective amount of at least one cholinest a composition. erase inhibitor. “Incontinence” is the inability to prevent the discharge of excretions, Such as urine or feces. In one 0.048. The invention provides methods for treating and/or embodiment, the invention provides methods for treating delaying the onset of Alzheimer's disease or vascular urinary incontinence in a patient in need thereof by admin dementia by administering to a patient in need thereof at istering a therapeutically effective amount of at least one least one cholinesterase inhibitor and at least one GABA cholinesterase inhibitor. In one embodiment, the invention inverse agonist. Any GABA inverse agonist in the art can be provides methods for treating fecal incontinence in a patient US 2006/0018839 A1 Jan. 26, 2006 in need thereof by administering a therapeutically effective 0056. In one embodiment, the cholinesterase inhibitor amount of at least one cholinesterase inhibitor. can be a compound of formula I, a Stereoisomer thereof, 0051. The invention provides methods for treating con and/or a pharmaceutically acceptable Salt thereof: Stipation in a patient in need thereof by administering a therapeutically effective amount of at least one cholinest erase inhibitor. 0.052 The invention provides methods for treating wast JBT O -K ing in a patient in need thereof by administering a thera peutically effective amount of at least one cholinesterase Sc. g l inhibitor. “Wasting” is the involuntary loss of more than 10% of body weight, and can also be accompanied by more than thirty days of either diarrhea, or weakness and fever. wherein J is The critical component of weight loSS in wasting is the loSS of body cell mass. Body cell mass contains the metabolically 0057 (a) a substituted or unsubstituted group selected active tissueS of the body, including muscle cells, organ from the group consisting of (1) phenyl, (2) pyridyl, (3) cells, and cells of the immune System. In wasting, the pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl, muscles waste away and the immune System is weakened. and (7) furyl; Wasting is often a problem for people living with AIDS 0.058 (b) a monovalent or divalent group, in which the (HIV disease) or cancer. Wasting can also be referred to as phenyl can have one or more Substituents Selected from wasting Syndrome. (1) indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl, 0053. The invention provides methods for treating or (5) indanedionyl, (6) tetralonyl, (7) benzoSuberonyl, (8) preventing chronic fatigue Syndrome in a patient in need indanolyl, and (9) CH-CO-CH(CH)-; thereof by administering a therapeutically effective amount of at least one cholinesterase inhibitor. Chronic fatigue 0059 (c) a monovalent group derived from a cyclic Syndrome can be characterized by having Severe chronic amide compound; fatigue for six months or longer with other known medical 0060) (d) a lower alkyl group; or conditions excluded by clinical diagnosis, and also having four or more of the following Symptoms: Substantial impair 0061 (e) a group of R-CH=CH-, in which R' is ment in short-term memory or concentration, Sore throat, hydrogen or a lower alkoxycarbonyl group; tender lymph nodes, muscle pain, multi-joint pain without Swelling or redness, headaches of a new type, pattern or Severity, unrefreshing sleep, and/or post-exertion malaise lasting more than 24 hours. –OOC-NH-(CHR)-, -NH-CO 0.054 The invention also provides veterinary uses for (CHR’)-, -CH-CO-NH-(CHR), cholinesterase inhibitors. In one embodiment, the invention -(CH-)-NH-(CHR’), -CH(OH)– provides methods for treating memory loSS or anxiety in a (CHR’)-, =(CH-CH=CH) , =CH patient in need thereof by administering an effective amount (CH)-, =(CH-CH)=, -CO-CH=CH of at least one cholinesterase inhibitor and a veterinarily CH-, CO-CH-CH(OH)-CH-, acceptable carrier. The patient can be any mammal, Such as -CH(CH-)-CO-NH-CH-, cats and dogs. In another embodiment, the invention pro CH=CH=CO-NH-(CH), -NH-, -O-, vides methods for treating excessive barking in a dog in need -S-, a dialkylaminoalkyl-carbonyl or a lower thereof by administering an effective amount of at least one alkoxycarbonyl, cholinesterase inhibitor and a veterinarily-acceptable carrier. 0063) wherein R is hydrogen, lower alkyl, acyl, lower 0.055 The cholinesterase inhibitor used in the methods alkylsulfonyl, phenyl, Substituted phenyl, benzyl, or and compositions of the invention can be any in the art. The substituted benzyl; R is hydrogen, lower alkyl or cholinesterase inhibitor can be, for example, an acetylcho phenyl, r is Zero or an integer of about 1 to about 10; linesterase inhibitor or a inhibitor. Rf is hydrogen or methyl So that one alkylene group inhibitors are preferred. Exemplary can have no methyl branch or one or more methyl cholinesterase inhibitors include donepezil, phenserine, branches; b is an integer of about 1 to about 3, c is Zero tolserine, phenethylnorcymSerine, gainstigmine, epastig or an integer of about 1 to about 9; d is Zero or an mine, tacrine, phySOStigmine, , neostigmine, integer of about 1 to about 5; rivastigmine, galantamine, citicoline, Velnacrine, huperzine (e.g., ), metrifonate, heptastigmine, edropho 0064. T is nitrogen or carbon; nium, TAK-147 (i.e., 3-1-(phenylmethyl)-4-piperidinyl)-1- (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone 0065 Q is nitrogen, carbon or fumarate or other salts thereof), T-82, upreazine, and the like. In each of the methods described herein, one or more cholinesterase inhibitors can be used. In one embodiment, one cholinesterase inhibitor is used. In another embodiment, donepezil, a Stereoisomer thereof and/or a pharmaceutically acceptable Salt thereof and a Second cholinesterase inhibitor are used in the methods or compositions of the invention. US 2006/0018839 A1 Jan. 26, 2006

0066 q is an integer of about 1 to about 3; 0.071) In the definition of B, -(CHR’)-, -CO (CHR)-, =(CH-CH=CH)-, =CH-(CH)- and 0067 K is hydrogen, phenyl, substituted phenyl, ary =(CH-CH) = are preferable. The group of lalkyl in which the phenyl can have a Substituent, -(CHR’)- in which R’ is hydrogen and r is an integer cinnamyl, a lower alkyl, pyridylmethyl, cycloalkyla of 1 to 3, and the group of =CH-(CH) - are most lkyl, adamantanemethyl, furylmenthyl, cycloalkyl, preferable. The preferable groups of B can be connected lower alkoxycarbonyl or an acyl, and with (b) of J, in particular (b)(2). 0068) ------is a single bond or a double bond. 0072 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 0069. In the compound of formula I, J is preferably (a) or carbon or nitrogen, and q is 2; or that Q is nitrogen, T is (b), more preferably (b). In the definition of (b), a monova carbon, and q is 1 or 3; or that Q is carbon, T is nitrogen and lent group (2), (3) and (5) and a divalent group (2) are q is 2. preferred. The group (b) preferably includes, for example, 0073. It is preferable that K is a phenyl, arylalkyl, cin the groups having the formulae shown below: namyl, phenylalkyl or a phenylalkyl having a Substituent(s) on the phenyl. O 0074. In another embodiment, the cyclic amine com pounds of formula I are the piperidine compounds of for N N mula II, a Stereoisomer thereof, and/or a pharmaceutically (S)-i- (S), -- acceptable Salt thereof: 2 21

indanyl tetralonyl II O O 1N N sax-O- (S)-i- 21 A 21 (S), 0075 wherein R is a (1) Substituted or unsubstituted phenyl group; (2) a Substituted or unsubstituted pyridyl indanonyl benzosuberonyl group; (3) a Substituted or unsubstituted pyrazyl group; O OH (4) a Substituted or unsubstituted quinolyl group; (5) a Substituted or unsubstituted indanyl group; (6) a Sub N N Stituted or unsubstituted cyclohexyl group; (7) a Sub (S), -H (S)-i- Stituted or unsubstituted quinoxalyl group; (8) a Sub 2 2 Stituted or unsubstituted furyl group; (9) a monovalent or divalent group derived from an indanone having a indanonylidenyl indanolyl Substituted or unsubstituted phenyl ring; (10) a monovalent group derived from a cyclic amide com N S-CO-CHCH.) pound; (11) a lower alkyl group; or (12) a group of the (S)-i- (S)-i- formula R-CH=C-, where R is a hydrogen atom 2 2 or a lower alkoxycarbonyl group; indenyl 0076 X is (CH), , C(O)-(CH), , O O N(R)-(CH), , C(O)-N(R)-(CH), , CH=CH-(CH), , -O-C(O)-O-(CH), , N N

(S)- 21 O "Ne indanedionyl indenonyl CH=CH-C(O)-NH-(CH), a dialkylami 0070 whereint is an integer of about 1 to about 4; and noalkylcarbonyl group, a lower alkoxycarbonyl group; each S is independently hydrogen or a Substituent, Such 0077 where n is an integer of 0 to 6; R" is a hydrogen as a lower alkyl having 1 to 6 carbon atoms or a lower atom, a lower alkyl group, an acyl group, a lower alkoxy having 1 to 6 carbon atoms. Among the Sub alkylsulfonyl group, a Substituted or unsubstituted phe Stituents, methoxy is most preferred. The phenyl is nyl group, or a Substituted or unsubstituted benzyl most preferred to have 1 to 3 methoxy groups thereon. group; and R is a hydrogen atom a lower alkyl group (S), can form methylene dioxy groups or ethylene dioxy or a phenyl group; groups on two adjacent carbon atoms of the phenyl group. Of the above groups, indanonyl, indanedionyl 0078 R is a substituted or unsubstituted phenyl group; and indenyl, optionally having Substituents on the a Substituted or unsubstituted arylalkyl group; a cin phenyl, are the most preferred. namyl group; a lower alkyl group; a pyridylmethyl US 2006/0018839 A1 Jan. 26, 2006

group; a cycloalkylalkyl group; an adamantanemethyl SO-, -CH(OH)-, or -CH-S(->O)-; E is a group, or a furoylmethyl group; and carbon or nitrogen atom; and D is a Substituent. 0079) - is a single bond or a double bond. 0084) Preferred examples of the substituents (i.e., “D”) 0080. The term “lower alkyl group” as used herein means for the phenyl group include lower alkyl, lower alkoxy, a Straight or branched alkyl group having 1 to 6 carbon nitro, halogenated lower alkyl, lower alkoxycarbonyl, atoms. Exemplary “lower alkyl groups include methyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, halogen atoms, and benzyol and benzylsulfonyl groups. The pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methyl Substituent can be two or more of them, which can be the butyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, Same or different. 1-methylpentyl, 2-methyl-pentyl, 3-methylpentyl, 1,1-dim 0085 Preferred examples of the substituent for the ethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- pyridyl group include lower alkyl and amino groupS and dimthyl-butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-eth halogen atoms. ylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2- trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- 0086 Preferred examples of the substituent for the pyra methylpropyl, and the like. The lower alkyl group is Zyl group include lower alkoxycarbonyl, carboxyl, acy preferably methyl, ethyl, propyl or isopropyl; more prefer lamino, carbamoyl, and cycloalkyloxycarbonyl groups. ably methyl. 0087. With respect to R', the pyridyl group is preferably 0.081 Specific examples of the substituents for the Sub a 2-pyridyl, 3-pyridyl, or 4-pyridyl group; the pyrazyl group Stituted or unsubstituted phenyl, pyridyl, pyrazyl, quinolyl, is preferably a 2-pyrazinyl group; the quinolyl group is indanyl, cyclohexyl, quinoxalyl and furyl groups in the preferably a 2-quinolyl or 3-quinolyl group; the quinoxalinyl definition of R' include lower alkyl groups having 1 to 6 group is preferably a 2-quinoxalinyl or 3-quinoxalinyl carbon atoms, Such as methyl, ethyl, n-propyl, isopropyl, group, and the furyl group is preferably a 2-furyl group. n-butyl, isobutyl, and tert-butyl groups, lower alkoxy groups 0088 Specific examples of preferred monovalent or diva corresponding to the above-described lower alkyl groups, lent groups derived from an indanone having an unsubsti Such as methoxy and ethoxy groups, a nitro group; halogen tuted or Substituted phenyl ring include those represented by atoms, Such as chlorine, fluorine and bromine; a carboxyl group; lower alkoxycarbonyl groups corresponding to the formulas (A) and (B): above-described lower alkoxy groups, Such as methoxycar bonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycar (A) bonyl, and n-butyloxycarbonyl groups, an amino group; a O lower monoalkylamino group; a lower dialkylamino group; a carbamoyl group, acylamino groups derived from aliphatic N Saturated monocarboxylic acids having 1 to 6 carbon atoms, (A)n it Such as acetylamino, propionylamino, butyrylamino, isobu 2 tyrylamino, Valerylamino, and pivaloylamino groups, (B) cycloalkyloxycarbonyl groups, Such as a cyclohexyloxycar O bonyl group; lower alkylaminocarbonyl groups, Such as methylaminocarbonyl and ethylaminocarbonyl groups, N lower alkylcarbonyloxy groups corresponding to the above (A)n it defined lower alkyl groups, Such as methylcarbonyloxy, 2 ethylcarbonyloxy, and n-propylcarbonyloxy groups, haloge nated 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 0089 where m is an integer of from 1 to 4, and each methoxyethyl groups. The “lower alkyl groups” and “lower A is independently a hydrogen atom, a lower alkyl alkoxyl groups' in the above description of the Substituent group, a lower alkoxy group, a nitro group, a halogen include all the groups derived from the above-mentioned atom, a carboxyl group, a lower alkoxycarbonyl group, groups. The Substituent can be one to three of them, which an amino group, a lower monoalkylamino group, a can be the same or different. lower dialkylamino group, a carbamoyl group, an acy lamino group derived from aliphatic Saturated mono 0082) When the substituent is a phenyl group, the fol carboxylic acids having 1 to 6 carbon atoms, a lowing group is within the Scope of the Substituted phenyl cycloalkyloxycarbonyl group, a lower alkylaminocar group: bonyl group, a lower alkylcarbonyloxy group, a halo genated lower alkyl group, a hydroxyl group, a formyl group, or a lower alkoxy lower alkyl group; preferably D a hydrogen atom, a lower alkyl group or a lower alkoxy 21 == group; most preferably the indanone group is unsub --G stituted or substituted with 1 to 3 methoxy groups. s! \ / 0090. Examples of the monovalent group derived from a cyclic amide compound include quinazolone, tetrahydroiso quinolinone, tetrahydrobenzodiazepinone, and hexahy 0083 wherein G is -C(O)-, -O-C(O)-, -O-, drobenzazocinone. However, the monovalent group can be CH-NH-C(O), CH-O-, CH any one having a cyclic amide group in the Structural US 2006/0018839 A1 Jan. 26, 2006

formula thereof, and is not limited to the above-described Specific examples. The cyclic amide group can be one -continued derived from a monocyclic or condensed heterocyclic ring. (i) The condensed heterocyclic ring is preferably one formed by condensation with a phenyl ring. In this case, the phenyl ring N can 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. () 0.091 Preferred examples of the monovalent group include the following: CON N O (k)

O N

(b) (T)

N O

N

Y

O W (d) NH

W2 (n) O W (e) N-W3

W2

0092. 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 and W are each a hydrogen atom, a lower alkyl group, or a lower (f) alkoxy group; and W is a hydrogen atom or a lower alkyl group. The right hand ring in formulae () and (l) is a 7-membered ring, while the right hand ring in formula (k) is an 8-membered ring. (g) 0093. The most preferred examples of the above-defined R' 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. (h) 0094. The most preferred examples of the above-defined X include -(CH2), , an amide group, or groups repre sented by the above formulae where n is 2. Thus, it is most preferred that any portion of a group represented by the formula R'rer X - have a carbonyl or amide group. US 2006/0018839 A1 Jan. 26, 2006

0.095 The substituents involved in the expressions 66“a ethylpiperidine, a Stereoisomer thereof and/or a pharmaceu Substituted or unsubstituted phenyl group' and "a Substi tically acceptable Salt thereof, which is represented by tuted or unsubstituted arylalkyl group” in the above defini formula IV: tion of Rare 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 cyclo IV hexyl group, a quinoxalyl group or a furyl group in the O definition of R". CHO 0096. The term “arylalkyl group” is intended to mean an CH2 N -CH unsubstituted benzyl or phenethyl group or the like. CHO 0097 Specific examples of the pyridylmethyl group include 2-pyridylmethyl, 3-pyridylmethyl, and 4-pyridylm ethyl groups. 0103) In still other embodiments, the compound of for mula III is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)m- 0098 Preferred examples of R include benzyl and phen ethylpiperidine hydrochloride or a Stereoisomer thereof, ethyl groups. The symbol means a double or single which is also known as donepezil hydrochloride or ARI bond. The bond is a double bond only when R is the CEPTE) (Eisai Inc., Teaneck, N.J.), and which is represented divalent group (B) derived from an indanone having an by formula IVa: unsubstituted or Substituted phenyl ring, while it is a single bond in other cases. Va. 0099. In another embodiment, the compound of formula II is a compound of formula III, a Stereoisomer thereof, and/or a pharmaceutically acceptable Salt thereof: CHO CH2 N-CH OHC1.

III CHO

N (CHR22)-g N-K 0104. The compounds of the invention can have an (S)-H asymmetric carbon atom(s), depending upon the Substitu 21 Sc.- ents, and can have Stereoisomers, which are within the Scope of the invention. For example, donepezil or pharmaceuti cally acceptable Salts thereof can be in the forms described 0100 wherein r is an integer of about 1 to about 10; in Japanese Patent Application Nos. 4-187674 and 4-21670, each R’ is independently hydrogen or methyl; K is a the disclosures of which are incorporated by reference phenalkyl or a phenalkyl having a Substituent on the herein in their entirety. phenyl ring; each S is independently a hydrogen, a lower alkyl group having 1 to 6 carbon atoms or a lower 0105 Japanese Patent Application No. 4-187674 alkoxy group having 1 to 6 carbon atoms; t is an integer describes a compound of formula V: of 1 to 4; q is an integer of about 1 to about 3; with the proviso that (S) can be a methylenedioxy group or an V ethylenedioxy group joined to two adjacent carbon atoms of the phenyl ring. O 0101. In other embodiments, the compound of formula CHO III is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)meth ylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2- -a-() ylidenyl)methylpiperidine, 1-benzyl-4-((5-methoxy-1-in CHO danon)-2-yl)methylpiperidine, 1-benzyl-4-((5,6-diethoxy-1- indanon)-2-yl)methylpiperidine; 1-benzyl-4-((5,6- methnylenedioxy-1-indanon)-2-yl)methylpiperidine, 1-(m- which can be in the form of a pharmaceutically acceptable nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2- Salt, Such as a hydrochloride Salt. Japanese Patent Applica yl)methylpiperidine; 1-cyclohexylmethyl-4-((5,6- tion No. 4-21670 describes compounds of formula VI: dimethoxy-1-indanon)-2-yl)methylpiperidine; 1-(m- fluorobenzyl)-4-((5,6-dimethoxy-1-indanon)-2- yl)methylpiperidine; 1-benzyl-4-((5,6-dimethoxy-1- VI indanon)-2-yl)propylpiperidine, 1-benzyl-4-((5-isopropoxy 6-methoxy-1-indanon)-2-yl)methylpiperidine, 1-benzyl-4- O ((5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine; or CHO CH2 a Stereoisomer and/or a pharmaceutically acceptable Salt w N-CH thereof. CHO 0102) In still other embodiments, the compound of for mula III is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)m- US 2006/0018839 A1 Jan. 26, 2006 which can be in the form of a pharmaceutically acceptable 0108. The dosage regimen for treating and preventing the Salt, Such as a hydrochloride Salt, and compounds of formula diseases described herein with the cholinesterase inhibitors VII: and other medications can be Selected in accordance with a variety of factors, including the age, weight, Sex, and medical condition of the patient, the Severity of the VII migraines, the route of administration, pharmacological con siderations Such as the activity, efficacy, pharmacokinetic O and toxicology profiles of the drugs, whether a drug delivery CHO CH2 System is used and whether the cholinesterase inhibitor is N-CH administered as part of a drug combination. CHO 0109 When more than one cholinesterase inhibitor is administered to a patient and/or when the cholinesterase inhibitor(s) is administered in conjunction with another medication, the compounds can be separately administered which can be in the form of a pharmaceutically acceptable about the same time as part of an overall treatment regimen, Salt, Such as a hydrochloride Salt, and compounds of formula i.e., as a drug cocktail or combination therapy. "About the VIII: Same time' includes administering the compounds at the Same time, at different times on the same day, or on different days, as long as they are administered as part of an overall VIII treatment regimen. O 0110. The cholinesterase inhibitors can be administered CHO to treat or prevent the diseases described herein in doses of about 0.01 milligrams to about 300 milligrams per day, s-cis-( ) OHC. preferably about 1 milligram to about 100 milligrams per CHO day, more preferably about 5 milligrams to about 10 milli grams per day. The doses can be administered in one to four portions over the course of a day, preferably once a day. One 0106 AS described above, the cholinesterase inhibitors skilled in the art will recognize that when the cholinesterase and other medications described herein can be administered inhibitors are administered to children, the dose can be in the form of a pharmaceutically acceptable Salt. Pharma Smaller than the dose administered to adults, and that the ceutically acceptable Salts are well known in the art and dose can be dependent upon the size and weight of the include those of inorganic acids, Such as hydrochloride, patient. A child can be administered the cholinesterase Sulfate, hydrobromide and phosphate, and those of organic inhibitors in doses of about 0.1 milligrams to about 15 acids, Such as formate, acetate, trifluoroacetate, methane milligrams per day, preferably about 0.5 milligrams to about Sulfonate, benzenesulfonate and toluenesulfonate. When 10 milligrams per day, more preferably about 1 milligram to certain Substituents are Selected, the compounds of the about 3 milligrams per day. invention can form, for example, alkali metal Salts, Such as Sodium or potassium Salts, alkaline earth metal Salts, Such as 0111. In other embodiments of the methods described calcium or magnesium Salts, organic amine Salts, Such as a herein, donepezil hydrochloride, which is commercially Salt with trimethylamine, triethylamine, pyridine, picoline, available as ARICEPTE) (Eisai Inc., Teaneck, N.J.), can be dicyclohexylamine or N,N'-dibenzylethylenediamine. One administered as tablets containing either 5 milligrams done skilled in the art will recognize that the compounds of the pezil hydrochloride or 10 milligrams donepezil hydrochlo invention can be made in the form of any other pharmaceu ride. The tablets can be administered one to about four times tically acceptable Salt. a day. In preferred embodiments, one 5 milligram or one 10 milligram ARICEPTOR tablet is administered once a day for 0107 The cholinesterase inhibitors can be prepared by the methods described herein. One skilled in the art will processes that are known in the art and described, for appreciate that when donepezil hydrochloride is adminis example, in U.S. Pat. No. 4,895.841, WO 98/39000, and tered to children, the dose can be Smaller than the dose that Japanese Patent Application Nos. 4-187674 and 4-21670, is administered to adults. the disclosures of each of which are incorporated by refer ence herein in their entirety. Donepezil hydrochloride, a 0112 The cholinesterase inhibitors and other medications preferred cholinesterase inhibitor for use in the methods of the invention can be administered orally, topically, described herein, is commercially available as ARICEPTOR parenterally, by inhalation (nasal or oral), or rectally in from Eisai Inc., Teaneck, N.J. The other medications dosage unit formulations containing conventional nontoxic described herein (e.g., Statins, vaccines, anti-oxidants, psy pharmaceutically acceptable carriers, adjuvants, and chiatric medications, NMDA receptor blockers, calcium vehicles as desired. The term parenteral includes Subcuta channel blockers, caffeine, analgesics, GABA inverse ago neous, intravenous, intramuscular, intrathecal, intrasternal nists) are commercially available, are in development, and/ injection, or infusion techniques. Preferably, the cholinest or can be prepared by processes described in the literature. erase inhibitors are orally administered as tablets. When The cholinesterase inhibitors and other medications administered to children, the cholinesterase inhibitors are described herein can be administered as pharmaceutical preferably orally administered in a liquid dosage form. combinations. A pharmaceutical combination is a pharma 0113 Injectable preparations, for example, Sterile inject ceutical formulation comprising both active ingredients or able aqueous or oleaginous Suspensions, of the cholinest Separate pharmaceutical dosage forms. erase inhibitors can be formulated according to the art using US 2006/0018839 A1 Jan. 26, 2006

Suitable dispersing or Wetting agents, Suspending agents 0117 Liquid dosage forms for oral administration of the (e.g., methylcellulose, Polysorbate 80, hydroxyethylcellu cholinesterase inhibitors can include pharmaceutically lose, acacia, powdered tragacanth, Sodium carboxymethyl acceptable emulsions, Solutions, Sublingual Solutions, Sus cellulose, polyoxytehylene Sorbitan monolaurate and the pensions, and Syrups containing inert diluents commonly like), pH modifiers, buffers, Solubilizing agents (e.g., poly used in the art, Such as water. Such compositions can also oxyethylene hydrogenated castor oil, PolySorbate 80, nico comprise adjuvants, Such as wetting agents, emulsifying and tinamide, polyoxyethylene Sorbitan monolaurate, Macrogol, Suspending agents, and Sweetening, flavoring, and perfum ing agents. To make Sublingual Solutions, the cholinesterase an ethyl ester of castor oil fatty acid, and the like) and inhibitors can be admixed with various carriers, excipients, preservatives. The Sterile injectable preparation can also be pH adjusters, and the like (e.g., water, Sugar, lactic acid, a Sterile injectable Solution or Suspension in a nontoxic acetic acid, fructose, glucose, Saccharin, polyethylene gly parenterally acceptable diluent or Solvent, for example, as a col, propylene glycol, alcohol, bentonite, tragacanth, gelatin, Solution in 1,3-butanediol. Among the acceptable vehicles alginates, aspartame, Sorbitol, methylparaben, propylpara and Solvents that can be used are water, Ringer's Solution, and isotonic Sodium chloride Solution. In addition, Sterile, ben, Sodium benzoate, artificial flavoring and coloring fixed oils are conventionally used as a Solvent or Suspending agents). medium. For this purpose any bland fixed oil can be used 0118 For administration by inhalation, the cholinesterase including Synthetic mono- or diglycerides, in addition, fatty inhibitors can be delivered from an insufflator, a nebulizer or acids, Such as oleic acid, can be used in the preparation of a pressured pack or other convenient mode of delivering an injectables. The preparations can be lyophilized by methods aeroSol Spray. PreSSurized packs can include a Suitable known in the art. propellant. Alternatively, for administration by inhalation, 0114 Solid dosage forms for oral administration of the the cholinesterase inhibitors can be administered in the form cholinesterase inhibitors can include chewing gum, cap of a dry powder composition or in the form of a liquid spray. Sules, tablets, Sublingual tablets, powders, granules, and 0119 Suppositories for rectal administration of the cho gels, preferably tablets. In Such Solid dosage forms, the linesterase inhibitors can be prepared by mixing the active active compound can be admixed with one or more inert compounds with Suitable nonirritating excipients Such as diluents Such as lactose or Starch. AS is normal practice, Such cocoa butter and polyethylene glycols that are Solid at room dosage forms can also comprise other Substances including temperature and liquid at body temperature. Alternatively, lubricating agents Such as magnesium Stearate. In the case of an enema can be prepared by for rectal administration of the capsules, tablets, and pills, the dosage forms can also cholinesterase inhibitors. comprise buffering agents. The tablets can be prepared with enteric or film coatings, preferably film coatings. 0120 For topical administration to the epidermis, the cholinesterase inhibitors can be formulated as ointments, 0115 Sublingual administration refers to the administra creams or lotions, or as the active ingredient of a transdermal tion of the cholinesterase inhibitors in the mouth (e.g., under patch. The cholinesterase inhibitors can also be administered the tongue, between the cheek and gum, between the tongue via iontophoresis or osmotic pump. Ointments, creams and and roof of the mouth). The highly vascular mucosal lining lotions can be formulated with an aqueous or oily base with in the mouth is a convenient location for the cholinesterase the addition of Suitable thickening and/or gelling agents. inhibitors to be administered into the body. To make tablets, Alternatively, ointments, creams and lotions can be formu the cholinesterase inhibitors can be admixed with pharma lated with an aqueous or oily base and can also contain one ceutically acceptable carriers known in the art Such as, for or more emulsifying agents, Stabilizing agents, dispersing example, Vehicles (e.g., lactose, white Sugar, mannitol, glu agents, Suspending agents, thickening agents, and/or color cose, Starches, calcium carbonate, crystalline cellulose, ing agents. AS creams or lotions, the cholinesterase inhibi Silicic acid, and the like), binders (e.g., water, ethanol, tors can be mixed to form a Smooth, homogeneous cream or myranol, glucose Solution, Starch Solution, gelatin Solution, lotion with, for example, one or more of a preservative (e.g., polyvinylpyrrolidone, and the like), disintegrators (e.g., dry benzyl alcohol 1% or 2% (wit/wt)), emulsifying wax, glyc Starch, Sodium, alginate, Sodium hydrogen carbonate, cal erin, isopropyl palmitate, lactic acid, purified water, Sorbitol cium carbonate, polyoxyethylene Sorbitan fatty acid esters, Solution. Such topically administrable compositions can Sodium laurylsulfate, Stearic monoglyceride, Starches, lac contain polyethylene glycol 400. To form ointments, the tose, and the like), absorption promoters (e.g., quaternary cholinesterase inhibitors can be mixed with one or more of ammonium base, Sodium laurylsulfate, and the like), wetting a preservative (e.g., benzyl alcohol 2% (wit/wt)), petrolatum, agents (e.g. glycerin, Starches, and the like), lubricants (e.g., emulsifying wax, and Tenox (II) (e.g., butylated hydroxya Stearates, polyethylene glycol, and the like), and flavoring nisole, propyl gallate, citric acid, propylene glycol). Woven agents (e.g., Sweeteners). The tablets can be in the form of pads or rolls of bandaging material, e.g., gauze, can be a conventional tablet, a molded tablet, a wafer and the like. impregnated with the transdermally administrable composi tions for topical application. 0116. In other embodiments, the solid dosage form can be packaged as granules or a powder in a pharmaceutically 0121 The cholinesterase inhibitors can also be topically acceptable carrier, where the granules or powder are applied using a transdermal System, Such as one of an removed from the packaging and Sprinkled on food or mixed acrylic-based polymer adhesive with a resinous crosslinking with a liquid, Such as water or juice. In this embodiment, the agent impregnated with the cholinesterase inhibitors and cholinesterase inhibitors can be mixed with flavoring or laminated to an impermeable backing. For example, the Sweetening agents. The packaging material can be plastic, cholinesterase inhibitors can be administered in the form of coated paper, or any material that prevents water or moisture a transdermal patch, Such as a Sustained-release transdermal from reaching the granules and/or powder. patch. Transdermal patches can include any conventional US 2006/0018839 A1 Jan. 26, 2006 form Such as, for example, an adhesive matrix, a polymeric preservatives to prevent microbial contamination during use. matrix, a reservoir patch, a matrix- or monolithic-type Suitable preservatives include, for example, benzalkonium laminated Structure, and are generally comprised of one or chloride, thimerosal, chlorobutanol, methyl paraben, propyl more backing layers, adhesives, penetration enhancers, and/ paraben, phenylethyl alcohol, edetate disodium, Sorbic acid, or rate-controlling membranes. Transdermal patches gener ONAMER M(R), and the like. Such preservatives are typi ally have a release liner which is removed to expose the cally used at a concentration of about 0.001% to about 1.0% adhesive/active ingredient(s) prior to application. Transder by weight. mal patches are described in, for example, U.S. Pat. Nos. 5,262,165, 5,948,433, 6,010,715 and 6,071,531, the disclo 0127 Surfactants or co-solvents that can be used in the Sures of which are incorporated by reference herein in their ophthalmic compositions of the invention include polySor entirety. bate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P-103, TYLOXAPOLR), CREMO 0122) For the methods of treating and/or preventing, for PHOR(R) EL, sodium dodecyl sulfate, glycerol, PEG 400, example, Sjogren's Syndrome (e.g., with respect to problems propylene glycol, cyclodextrins, and the like. Surfactants or associated with the eyes), neuronal loss in the eyes, and/or co-Solvents are typically used at a concentration of about macular degeneration, the cholinesterase inhibitors can be 0.01% to about 2% by weight. topically administered to the affected eye(s) in the form of an ophthalmic composition. The cholinesterase inhibitors 0128. A viscosity greater than that of simple aqueous can be administered in doses of about 0.00001 milligrams to Solutions can be desirable to increase ocular absorption of about 300 milligrams per day to the affected eye(s), prefer the active compounds, to decrease variability in dispensing ably about 0.0001 milligrams to about 100 milligrams per the compositions, to decrease physical Separation of com day, more preferably about 0.0001 milligrams to about 10 ponents of a Suspension or emulsion of the compositions milligrams per day. The doses can be administered in one to and/or to otherwise improve the ophthalmic composition. four portions over the course of a day, preferably once per Viscosity building agents include polyvinyl alcohol, poly day. Vinyl pyrrolidone, methyl cellulose, hydroxy propyl meth ylcellulose, hydroxyethyl cellulose, carboxymethyl cellu 0123. When administered in the form of eye drops, the lose, hydroxy propyl cellulose and the like. Viscosity cholinesterase inhibitors can be topically administered to the building agents are typically used at a concentration of about patient's eye in a concentration of about 0.00001% (e.g., 0.01% to about 2% by weight. 0.01 milligram cholinesterase inhibitor per 100 ml HO) to about 1% (e.g., 1 gram cholinesterase inhibitor per 100 ml 0129 Suitable agents which can be used to adjust the HO); preferably in a concentration of about 0.0001% to tonicity or OSmolality of the ophthalmic compositions about 0.25%, and even more preferably in a concentration of include Sodium chloride, potassium chloride, mannitol, dex about 0.001% to about 0.125%, most preferably in a con trose, glycerin, propylene glycol and the like. Tonicity centration of about 0.01% to about 0.1%. One to four drops agents are typically used at a concentration of about 0.1% to can be administered to the patient's eye(s) over the course of about 10% by weight. a day, preferably one or two drops per day, most preferably 0.130. Substantially non-aqueous liquids comprise at least one drop per day. In yet another embodiment, the cholinest one of the cholinesterase inhibitors of the invention dis erase inhibitors can be administered in a concentration of Solved or Suspended in one or more of the following: about 0.125% to about 0.25% administered in one or two vegetable and mineral oils, Such as liquid petrolatum, corn drops daily, preferably one drop daily. oil, castor oil, Sesame oil and peanut oil, triglycerides, Such 0.124. The cholinesterase inhibitors can be topically as the capric/caprylic triglycerides commonly used in foods administered to the affected eye(s) in the form of an oph and cosmetics, liquid lanolin and lanolin derivatives, and thalmic composition. The ophthalmic composition can be in perfluorohydrocarbons. the form of a gel, a Solution, a Suspension, an emulsion (dispersion), or an erodible Solid ocular insert. The oph 0131 Substantially non-aqueous semi-solid composi thalmic compositions can comprise liposomes or tions comprise at least one of the cholinesterase inhibitors of microbubbles. Alternatively, the ophthalmic compositions the invention dissolved or Suspended in or more of the can be administered in the form of non-aqueous formula following: Various types of petrolatum, Such as white, yel tions, Such as Substantially non-aqueous liquids, Substan low and red; lanolin and lanolin derivatives, gelled mineral tially non-aqueous Semi-Solid compositions, and Solid com oil having a hydrocarbon base, such as PLASTIBASE(R); positions or devices. The methods of treating or preventing petrolatum and ethylene carbonate mixtures, petrolatum in glaucoma and/or intraocular preSSure typically comprise the combination with Surfactants and polyglycol, Such as poly topical application of one or two drops (or an equivalent oxyl 40 Stearate and polyethylene glycol. amount of a Solid or semi-solid dosage form) to the affected 0132) Solid compositions or devices include non-erodible eye one to four times per day, preferably once per day. devices which are inserted into the conjunctival Sac of the 0.125 Informing compositions for topical administration, eye and later removed, Such as the Alza-type diffusion or the ophthalmic compositions are generally formulated at a oSmotic pressure controlled polymer membranes, and bio pH between about 4.5 and about 8.0. The topical composi erodible polymers which do not have to be removed from the tions can also comprise other ingredients that are known to conjunctival Sac, Such as essentially anhydrous but water be used in ophthalmic compositions including, for example, Soluble polymers and resins (e.g., celluloses, polycarboxylic preservatives, Surfactants and co-Solvents, tonicity agents, acids). and Viscosity building agents. 0133. The invention provides for the cholinesterase 0.126 Ophthalmic compositions are typically packaged in inhibitors to be administered nasally to a patient to treat the multidose form, which generally requires the addition of diseases and disorders described herein and those described, US 2006/0018839 A1 Jan. 26, 2006

for example, in PCT/US02/29734, WO 01/66114, and U.S. metered valve; and the like. Powders may be administered, Pat. Nos. 6,482,838, 6,458,807 and 6,455,544, the disclo for example, in Such a manner that they are placed in a Sures of which are incorporated by reference herein in their capsule that is then Set in an inhalation or insufflation device. entirety. “Administered nasally” or “nasal administration” is A needle is penetrated through the capsule to make pores at intended to mean that at least one cholinesterase inhibitor is the top and the bottom of the capsule and air is sent to blow combined with a suitable delivery system for absorption out the powder particles. Powder formulation can also be acroSS the nasal mucosa of a patient, preferably a human. administered in a jet-spray of an inert gas or Suspended in Generally, lower doses of the cholinesterase inhibitor can be liquid organic fluids. used for nasal administration when compared, for example, 0.138. In one embodiment, the invention provides a to the dose required for the oral administration of the nasally administrable pharmaceutical composition compris cholinesterase inhibitor. ing at least one cholinesterase inhibitor dispersed in a nasal 0134) The cholinesterase inhibitors of the invention can delivery system that improves the solubility of the cholinest be administered, for example, as nasal Sprays, nasal drops, erase inhibitor. The nasal delivery System that improves nasal Suspensions, nasal gels, nasal ointments, nasal creams Solubility can include one of the following or combinations or nasal powders. The cholinesterase inhibitors can also be thereof: (i) a glycol derivative (e.g., propylene glycol, poly administered using nasal tampons or nasal Sponges. The ethylene glycol, mixtures thereof); (ii) a Sugar alcohol (e.g., cholinesterase inhibitors of the invention can be brought into mannitol, xylitol, mixtures thereof); (iii) glycerin; (iv) a a Viscous basis via Systems conventionally used, for glycol derivative (e.g., propylene glycol, polyethylene gly example, natural gums, methylcellulose and derivatives, col or mixtures thereof) and glycerin; (V) ascorbic acid and acrylic polymers (carbopol) and vinyl polymers (polyvi water; (vi) Sodium ascorbate and water, or (vii) Sodium nylpyrrolidone). In the compositions, many other excipients metabisulfite and water. known in the art can be added Such as water, preservatives, 0.139. In another embodiment, the invention provides a Surfactants, Solvents, adhesives, antioxidants, buffers, bio nasally administrable pharmaceutical composition compris adhesives, Viscosity enhancing agents and agents to adjust ing at least one cholinesterase inhibitor and a nasal delivery the pH and the osmolarity. System, where the nasal delivery System comprises at least 0135 The nasal delivery systems can take various forms one buffer to maintain the pH of the cholinesterase inhibitor, including aqueous Solutions, non-aqueous Solutions and at least one pharmaceutically acceptable thickening agent combinations thereof. Aqueous Solutions include, for and at least one humectant. The nasal delivery System can example, aqueous gels, aqueous Suspensions, aqueous lipo optionally further comprise Surfactants, preservatives, anti Somal dispersions, aqueous emulsions, aqueous microemul oxidants, bio-adhesives, pH adjusting agents, isotonicity Sions and combinations thereof. Non-aqueous Solutions agents, Solubilizing agents, and/or other pharmaceutically include, for example, non-aqueous gels, non-aqueous Sus acceptable excipients. The cholinesterase inhibitor can pensions, non-aqueous liposomal dispersions, non-aqueous optionally be dispersed in a nasal delivery System that emulsions, non-aqueous microemulsions and combinations improves its solubility. thereof. 0140. In another embodiment, the invention provides a 0136. In other embodiments, the nasal delivery system nasally administrable pharmaceutical composition compris can be a powder formulation. Powder formulations include, ing at least one cholinesterase inhibitor and a nasal delivery for example, powder mixtures, powder microSpheres, coated System, where the nasal delivery System comprises at least powder microSpheres, liposomal dispersions and combina one Solubilizing agent, at least one pharmaceutically accept tions thereof. Preferably, the powder formulation is powder able thickening agent and at least one humectant. The nasal microSpheres. The powder microSpheres are preferably delivery System can optionally further comprise buffers, pH formed from various polysaccharides and celluloses Selected adjusting agents, isotonicity agents, Surfactants, preserva from Starch, methylcellulose, Xanthan gum, carboxymethyl tives, antioxidants, bio-adhesives, and/or other pharmaceu cellulose, hydroxypropyl cellulose, carbomer, alginate poly tically acceptable excipients. The cholinesterase inhibitor Vinyl alcohol, acacia, chitosans, and mixtures of two or more can optionally be dispersed in a nasal delivery System that thereof. improves its solubility. 0.141. In another embodiment, the invention provides a 0.137 In certain embodiments, the particle size of the nasally administrable pharmaceutical composition compris droplets of the aqueous and/or non-aqueous Solution or of ing at least one cholinesterase inhibitor and a nasal delivery the powders delivered to the nasal mucosa can be, for System, where the nasal delivery System comprises at least example, about 0.1 micron to about 100 microns; from about one buffer to maintain the pH of the cholinesterase inhibitor, 1 micron to about 70 microns; from about 5 microns to about at least one pharmaceutically acceptable thickening agent, at 50 microns; or from about 10 microns to about 20 microns. least one humectant, and at least one Surfactant. The nasal The particle sizes can be obtained using Suitable containers delivery System can optionally further comprise pH adjust or metering devices known in the art. Exemplary devices ing agents, isotonicity agents, Solubilizing agents, preserva include mechanical pumps in which delivery is made by tives, antioxidants, bio-adhesives, and/or other pharmaceu movement of a piston; compressed air mechanisms in which tically acceptable excipients. The cholinesterase inhibitor delivery is made by hand pumping air into the container; can optionally be dispersed in a nasal delivery System that compressed gas (e.g., nitrogen) techniques in which delivery improves its solubility. is made by the controlled release of a compressed gas in the Sealed container, liquefied propellant techniques in which a 0142. In yet another embodiment, the invention provides low boiling liquid hydrocarbon (e.g., butane) is vaporized to a nasally administrable pharmaceutical composition com exert a pressure and force the composition through the prising at least one cholinesterase inhibitor and a nasal US 2006/0018839 A1 Jan. 26, 2006 delivery System, where the nasal delivery System comprises include, for example, methyl cellulose, Xanthan gum, car at least one pharmaceutically acceptable thickening agent, at boxymethyl cellulose, hydroxypropyl cellulose, carbomer, least one humectant, at least one Surfactant, and at least one polyvinyl alcohol, alginates, acacia, chitosans, and mixtures Solubilizing agent. The nasal delivery System can optionally of two or more thereof. The concentration of the thickening further comprise buffers, pH adjusting agents, isotonicity agent will depend upon the agent Selected and the Viscosity agents, preservatives, antioxidants, bio-adhesives, and/or desired. Such agents can also be used in a powder formu other pharmaceutically acceptable excipients. The cholinest lation. erase inhibitor can optionally be dispersed in a nasal deliv ery System that improves its Solubility. 014.9 The nasally administrable compositions can also include a humectant to reduce or prevent drying of the 0143. In yet another embodiment, the invention provides mucus membrane and to prevent irritation thereof. Suitable a nasally administrable pharmaceutical composition com humectants that can be used include, for example, Sorbitol, prising at least one cholinesterase inhibitor and a nasal mineral oil, vegetable oil and glycerol, Soothing agents, delivery System, where the nasal delivery System comprises membrane conditioners, Sweeteners, and mixtures of two or at least one buffer to maintain the pH of the cholinesterase more thereof. The concentration of the humectant will vary inhibitor, at least one pharmaceutically acceptable thicken depending upon the agent Selected. In one embodiment, the ing agent, at least one humectant, at least one Surfactant, and humectant can be present in the nasal delivery System in a at least one Solubilizing agent. The nasal delivery System can concentration ranging from about 0.01% to about 20% by optionally further comprise buffers, pH adjusting agents, weight of the composition. isotonicity agents, preservatives, antioxidants, bio-adhe Sives, and/or other pharmaceutically acceptable excipients. 0150. In other embodiments, the nasal delivery system The cholinesterase inhibitor can optionally be dispersed in a can further comprise Surfactants which enhance the absorp nasal delivery System that improves its Solubility. tion of the cholinesterase inhibitor. Suitable Surfactants include non-ionic, anionic and cationic Surfactants. Exem 0144. The nasally administrable pharmaceutical compo plary Surfactants include oleic acid, polyoxyethylene deriva Sitions of the invention preferably provide a peak plasma tives of fatty acids, partial esters of Sorbitol anhydride, Such concentration of the cholinesterase inhibitor in less than one as for example, Tweens (e.g., Tween 80, Tween 40, Tween hour, preferably within about 5 minutes to about 30 minutes, 20), Spans (e.g., Span 40, Span 80, Span 20), polyoxyl 40 more preferably within about 5 minutes to about 20 minutes, Stearate, polyoxyethylene 50 Stearate, fusieates, bile Salts, after administration to the patient. Octoxynol, and mixtures of two or more thereof. Exemplary anionic Surfactants include Salts of long chain hydrocarbons 0145 The buffer has a pH that is selected to optimize the (e.g., Cao or Co-o) having one or more of the following absorption of the cholinesterase inhibitor acroSS the nasal functional groups: carboxylates, Sulfonates, and Sulfates. mucosa. The particular pH of the buffer can vary depending Salts of long chain hydrocarbons having Sulfate functional upon the particular nasal delivery formulation as well as the groups are preferred, Such as Sodium cetoStearyl Sulfate, specific cholinesterase inhibitor selected. Buffers that are Suitable for use in the invention include acetate (e.g., Sodium Sodium dodecyl Sulfate and Sodium tetradecyl Sulfate. One acetate), citrate (e.g., Sodium citrate dihydrate), phthalate, particularly preferred anionic Surfactant is Sodium lauryl borate, prolamine, trolamine, carbonate, phosphate (e.g., Sulfate (i.e., Sodium dodecyl Sulfate). The Surfactants can be monopotassium phosphate, disodium phosphate), and mix present in an amount from about 0.001% to about 50% by tures of two or more thereof. weight, or from about 0.001% to about 20% by weight. 0151. The pharmaceutical compositions of the invention 0146 The pH of the compositions should be maintained may further comprise an isotonicity agent, Such as Sodium from about 3.0 to about 10.0. Compositions having a pH of chloride, dextrose, boric acid, Sodium tartrate or other inor less than about 3.0 or greater than about 10.0 can increase ganic or organic Solutes. the risk of irritating the nasal mucosa of the patient. Further, it is preferable that the pH of the compositions be maintained 0152 The nasal pharmaceutical compositions of the from about 3.0 to about 9.0. With respect to the non-aqueous invention can optionally be used in combination with a pH nasal formulations, Suitable forms of buffering agents can be adjusting agent. Exemplary pH adjusting agents include Selected Such that when the formulation is delivered into the Sulfuric acid, Sodium hydroxide, hydrochloric acid, and the nasal cavity of a mammal, Selected pH ranges are achieved like. therein upon contact with, e.g., a nasal mucosa. 0153. To extend shelf life, preservatives can be added to 0147 The solubilizing agent for use in the compositions the nasally administrable compositions. Suitable preserva of the invention can be any known in the art, Such as tives that can be used include benzyl alcohol, parabens, carboxylic acids and Salts thereof. Exemplary carboxylic thimerosal, chlorobutanol, benzalkonium chloride, or mix acid Salts include acetate, gluconate, ascorbate, citrate, tures of two or more thereof. Preferably benzalkonium fumurate, lactate, tartrate, maleate, maleate, Succinate, or chloride is used. Typically, the preservative will be present mixtures of two or more thereof. in a concentration of up to about 2% by weight. The exact concentration of the preservative, however, will vary 0.148. The viscosity of the compositions of the present depending upon the intended use and can be easily ascer invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent. For example, tained by one skilled in the art. the viscosity may be at least 1000 cps; from about 1000 to 0154) Other ingredients which extend shelf life can be about 10,000 cps; from about 2000 cps to about 6500 cps; added Such as for example, antioxidants. Some examples of or from about 2500 cps to about 5000 cps. Thickening agents antioxidants include Sodium metabisulfite, potassium met that can be used in accordance with the present invention abisulfite, ascorbyl palmitate and the like. Typically, the US 2006/0018839 A1 Jan. 26, 2006 antioxidant will be present in the compositions in a concen 8. A method for treating a cognitive impairment or demen tration of from about 0.001% up to about 5% by weight of tia caused by radiation, encephalitis, meningitis, fetal alco the total composition. hol Syndrome, Korsakoff's Syndrome, an anoxic brain 0.155) Other optional ingredients can also be incorporated injury, cardiopulmonary resuscitation, diabetes, menopause, into the nasal delivery System provided that they do not pre-menstrual Syndrome, a Stroke, or a high cholesterol level interfere with the action of the cholinesterase inhibitor or in a patient in need thereof comprising administering a Significantly decrease the absorption of the cholinesterase therapeutically effective amount of at least one cholinest inhibitor acroSS the nasal mucosa. erase inhibitor. 0156 The nasal delivery systems can be made following 9. A method for treating a visuospatial deficit, Williams the processes described in, for example, U.S. Pat. Nos. Syndrome, Sjogren's Syndrome, mental retardation, a devel 6,451,848, 6,436,950, and 5,874.450, and WOOO/OO199, the opmental delay, post-Stroke aphasia, macular degeneration, disclosures of which are incorporated by reference herein in a sleep disorder, jet lag, a post-traumatic StreSS disorder, an their entirety. anxiety disorder, a panic attack, an obsessive-compulsive O157. In another embodiment, the invention provides disorder, amnesia, incontinence, constipation, wasting, or methods for treating and/or preventing migraines by nasally chronic fatigue Syndrome in a patient in need thereof com administering to a patient the nasally administrable pharma prising administering a therapeutically effective amount of ceutical composition comprising at least one cholinesterase at least one cholinesterase inhibitor. inhibitor of the invention. The migraines can be classic migraines, common migraines, complicated migraines, and/ 10. A method for treating a psychiatric disorder in a or cluster headaches. In other embodiments, the migraines patient in need thereof comprising administering a thera can be menstrual migraines, premenstrual migraines, oph peutically effective amount of at least one cholinesterase thalmic migraines, and/or ophthalmoplegic migraines. In inhibitor at least on psychiatric medication. other embodiments, the migraines can be fulgurating 11. The method of claim 10, wherein the psychiatric migraines, Harris' migraines, and/or hemiplegic migraines. disorder is an obsessive-compulsive disorder, a post-trau In Still other embodiments, the migraines can be abdominal matic StreSS disorder, anxiety, panic attack, Schizophrenia, migraines. depression, mania, manic-depression, autism, dyslexia, apa 0158 Each of the patents, patent applications, and pub thy, delirium, attention deficit hyperactivity disorder, a pho lications cited herein are incorporated by reference herein in bia or an eating disorder. their entirety. 12. A method for treating Alzheimer's disease, Parkin 0159. It will be apparent to one skilled in the art that Son's disease, or vascular dementia in a patient in need various modifications can be made to the invention without thereof comprising administering a therapeutically effective departing from the Spirit or Scope of the appended claims. amount of at least one cholinesterase inhibitor and at least one compound Selected from the group consisting of a Statin, What is claimed is: an anti-oxidant, an NMDA receptor blocker, a calcium 1. A nasally administrable pharmaceutical composition channel blocker, caffeine, and a GABA inverse agonist. comprising a therapeutically effective amount of at least one 13. A method for potentiating the effect of an analgesic in cholinesterase inhibitor and a nasal delivery System. 2. The nasally administrable pharmaceutical composition a patient in need thereof comprising administering a thera of claim 1, wherein the nasal delivery System comprises (i) peutically effective amount of at least one cholinesterase a glycol derivative; (ii) a Sugar alcohol; (iii) glycerin; (iv) a inhibitor and at least one analgesic. glycol derivative and glycerin; (V) ascorbic acid and water; 14. A method for enhancing REM sleep in a patient in (vi) Sodium ascorbate and water; (vii) Sodium metabisulfite need thereof comprising administering a therapeutically and water; or (viii) a mixture of two or more thereof. effective amount at least one cholinesterase inhibitor 3. A method of treating a migraine in a patient in need 15. The nasally administrable pharmaceutical composi thereof comprising administering the nasally administrable tion of claim 1, the transdermal patch of claim 4, the pharmaceutical composition of claim 1. pharmaceutical combination of claim 6, or the method of 4. A transdermal patch comprising a therapeutically effec claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase tive amount of at least one cholinesterase inhibitor and a inhibitor is donepezil, phenserine, tolserine, phenethylnor transdermal patch System. cymserine, gainstigmine, epastigmine, tacrine, phySoStig 5. The transdermal patch of claim 4, wherein the trans dermal patch System comprises a backing layer, a penetra mine, pyridostigmine, neostigmine, rivastigmine, galan tion enhancer, an adhesive, a rate-controlling membrane, a tamine, citicoline, Velnacrine, huperzine, metrifonate, polymeric matrix, an emulsifying agent, a Stabilizing agent, heptastigmine, , 3-(1-(phenylmethyl)-4-pip a dispersing agent, a Suspending agent, a thickening agent, eridinyl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1- a coloring agent, an adhesive, or a mixture of two or more propanone, T-82 or upreazine. thereof. 16. The nasally administrable pharmaceutical composi 6. A pharmaceutical combination comprising a therapeu tion of claim 1, the transdermal patch of claim 4, the tically effective amount of at least one cholinesterase inhibi pharmaceutical combination of claim 6, or the method of tor and at least one Statin. claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase 7. The pharmaceutical combination of claim 6, wherein inhibitor is a compound of formula I, a Stereoisomer thereof, the Statin is memantine. and/or a pharmaceutically acceptable Salt thereof: US 2006/0018839 A1 Jan. 26, 2006 17

17. The nasally administrable pharmaceutical composi tion of claim 1, the transdermal patch of claim 4, the pharmaceutical combination of claim 6, or the method of J. T O claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase inhibitor is a compound of formula II, a Stereoisomer (CH2) l thereof, and/or a pharmaceutically acceptable Salt thereof:

II wherein J is (a) a Substituted or unsubstituted group Selected from the group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, sax-O- (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl, and (7) furyl; wherein R' is a (1) substituted or unsubstituted phenyl (b) a monovalent or divalent group, in which the phenyl group; (2) a Substituted or unsubstituted pyridyl group; can have one or more Substituents selected from (1) (3) a Substituted or unsubstituted pyrazyl group; (4) a indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl, (5) Substituted or unsubstituted quinolyl group; (5) a Sub indanedionyl, (6) tetralonyl, (7) benzoSuberonyl, (8) Stituted or unsubstituted indanyl group; (6) a Substi indanolyl, and (9) CH-CO-CH(CH)-; tuted or unsubstituted cyclohexyl group; (7) a Substi (c) a monovalent group derived from a cyclic amide tuted or unsubstituted quinoxalyl group; (8) a compound; Substituted or unsubstituted furyl group; (9) a monova lent or divalent group derived from an indanone having (d) a lower alkyl group; or a Substituted or unsubstituted phenyl ring; (10) a monovalent group derived from a cyclic amide com (e) a group of R-CH=CH-, in which R is hydro pound; (11) a lower alkyl group; or (12) a group of the gen or a lower alkoxycarbonyl group; formula R-CH=C-, where R is a hydrogen atom or a lower alkoxycarbonyl group;

-OOC-NH-(CHR’), , -NH-CO (CHR’)-, -CH-CO-NH-(CHR’)-, (CHR).(CH-NH-(CHR.) , =(CH-CH=CH) ,-CH(OH)– =CH (CH) , =(CH-CH)=, CO-CH=CH CH-, CO-CH-CH(OH)-CH-, CH-CH(OH)-CH-, -CH(CH-)-C(O)NH -CH(CH-)-CO-NH-CH-, CH-, CH=CH-C(O)NH-(CH), a CH=CH=CO-NH-(CH), -NH-, -O-, dialkylaminoalkylcarbonyl group, a lower alkoxycar -S-, a dialkylaminoalkyl-carbonyl or a lower bonyl group; alkoxycarbonyl, where n is an integer of 0 to 6; R is a hydrogen atom, a wherein R" is hydrogen, lower alkyl, acyl, lower alkyl lower alkyl group, an acyl group, a lower alkylsulfonyl Sulfonyl, phenyl, Substituted phenyl, benzyl, or Substi group, a Substituted or unsubstituted phenyl group, or a tuted benzyl; R is hydrogen, lower alkyl or phenyl; r substituted or unsubstituted benzyl group; and R is a is zero or an integer of about 1 to about 10; R’ is hydrogen atom a lower alkyl group or a phenyl group; hydrogen or methyl So that one alkylene group can have no methyl branch or one or more methyl branches, R is a Substituted or unsubstituted phenyl group; a b is an integer of about 1 to about 3, c is Zero or an Substituted or unsubstituted arylalkyl group; a cin integer of about 1 to about 9; d is Zero or an integer of namyl group; a lower alkyl group; a pyridylmethyl about 1 to about 5; group; a cycloalkylalkyl group; an adamantanemethyl group; or a furoylmethyl group; and T is nitrogen or carbon; - - - - - F is a single bond or a double bond. Q is nitrogen, carbon or 18. The nasally administrable pharmaceutical composi tion of claim 1, the transdermal patch of claim 4, the pharmaceutical combination of claim 6, or the method of claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase inhibitor is a compound of formula III, a Stereoisomer thereof, and/or a pharmaceutically acceptable Salt thereof:

q is an integer of about 1 to about 3, III O K is hydrogen, phenyl, Substituted phenyl, arylalkyl in which the phenyl can have a Substituent, cinnamyl, a lower alkyl, pyridylmethyl, cycloalkylalkyl, adaman N (CHR)-g N-K tanemethyl, furylmenthyl, cycloalkyl, lower alkoxycar (S)-i- Q- l bonyl or an acyl; and 21 (CH2). ------is a single bond or a double bond. US 2006/0018839 A1 Jan. 26, 2006

wherein r is an integer of about 1 to about 10; each Rf pharmaceutical combination of claim 6, or the method of is independently hydrogen or methyl, K is a phenalkyl claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase or a phenalkyl having a Substituent on the phenyl ring, inhibitor is 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 Va. to 4, q is an integer of about 1 to about 3, with the proviso that (S) can be a methylenedioxy group or an O ethylenedioxy group joined to two adjacent carbon CHO atoms of the phenyl ring. CH2 N-CH OHC1. 19. The nasally administrable pharmaceutical composi tion of claim 1, the transdermal patch of claim 4, the CHO pharmaceutical combination of claim 6, or the method of claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase 22. The nasally administrable pharmaceutical composi inhibitor is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)m- tion of claim 1, the transdermal patch of claim 4, the ethylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2- pharmaceutical combination of claim 6, or the method of ylidenyl)methylpiperidine, 1-benzyl-4-((5-methoxy-1-in claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase danon)-2-yl)methylpiperidine, 1-benzyl-4-((5,6-diethoxy-1- inhibitor is a compound of formula VI or a pharmaceutically indanon)-2-yl)methylpiperidine; 1-benzyl-4-((5,6- acceptable Salt thereof: methnylenedioxy-1-indanon)-2-yl)methylpiperidine, 1-(m- nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2- yl)methylpiperidine; 1-cyclohexylmethyl-4-((5,6- VI dimethoxy-1-indanon)-2-yl)methylpiperidine; 1-(m- fluorobenzyl)-4-((5,6-dimethoxy-1-indanon)-2- yl)methylpiperidine; 1-benzyl-4-((5,6-dimethoxy-1- CHO CH2 indanon)-2-yl)propylpiperidine, 1-benzyl-4-((5-isopropoxy w N-CH 6-methoxy-1-indanon)-2-yl)methylpiperidine, 1-benzyl-4- ((5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine; or CHO a stereoisomer and/or a pharmaceutically acceptable Salt thereof. 23. The nasally administrable pharmaceutical composi 20. The nasally administrable pharmaceutical composi tion of claim 1, the transdermal patch of claim 4, the tion of claim 1, the transdermal patch of claim 4, the pharmaceutical combination of claim 6, or the method of pharmaceutical combination of claim 6, or the method of claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase claim 8, 9, 10, 12, 13 or 14, wherein the cholinesterase inhibitor is a compound of formula VII or a pharmaceuti inhibitor is a compound of formula IV or a pharmaceutically cally acceptable Salt thereof: acceptable Salt thereof:

IV VII O CHO CHO CH2 CH2 N-CH N-CH

CHO CHO

21. The nasally administrable pharmaceutical composi tion of claim 1, the transdermal patch of claim 4, the