US 20090042939A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0042939 A1 Ieni et al. (43) Pub. Date: Feb. 12, 2009

(54) METHODS AND COMPOSITIONS USING Publication Classification CHOLINESTERASE INHIBITORS (51) Int. Cl. A6II 3/445 (2006.01) (75) Inventors: John Ieni, Bloomfield, NJ (US); Raymond Pratt, Baltimore, MD (52) U.S. Cl...... S14/319 (US) (57) ABSTRACT The invention provides methods for treating and/or prevent Correspondence Address: ing Alzheimer's disease, psychiatric illnesses, encephalitis, VENABLE LLP meningitis, fetal alcohol Syndrome, Karsakoff's syndrome, P.O. BOX 34385 anoxic brain injury, cardiopulmonary resuscitation injuries, WASHINGTON, DC 20043-9998 (US) diabetes, Sjogren's syndrome, mental retardation, develop mental delay, menopause, strokes, macular degeneration, (73) Assignee: Eisai Co., Ltd., Tokyo (JP) neuronal loss associated with macular degeneration, sleep disorders, severe Alzheimer's disease, jet lag, post-traumatic (21) Appl. No.: 12/192,826 stress disorder, anxiety disorders, panic attacks, obsessive compulsive disorder, amnesia, and other disorders by admin Filed: Aug. 15, 2008 istering to a patient in need thereofat least one cholinesterase (22) inhibitor. The invention also provides novel pharmaceutical Related U.S. Application Data compositions that can be administered to the eyes or to the nose of patients. In one embodiment, the cholinesterase (60) Division of application No. 10/988,600, filed on Nov. inhibitor is , a stereoisomer thereof and/or a phar 16, 2004, now abandoned, which is a continuation of maceutically acceptable salt thereof. In other embodiments, application No. PCT/US03/15279, filed on May 16, the can be one or more of , 2003. tolserine, phenethylnorcymserine, gainstigmine, epastigmine, , , , , (60) Provisional application No. 60/447,724, filed on Feb. , , citicoline, Velnacrine, huperzine, 19, 2003, provisional application No. 60/380,852, , heptastigmine, , TAK-147, T-82, filed on May 17, 2002. and upreazine. US 2009/0042939 A1 Feb. 12, 2009

METHODS AND COMPOSITIONS USING 0010 "Cognitive impairment” refers to an acquired deficit CHOLINESTERASE INHIBITORS in one or more of memory function, problem solving, orien tation and/or abstraction that impinges on a patient’s ability to RELATED APPLICATIONS function independently. 0001. This application is a divisional of U.S. Non-Provi 0011 “” refers to a global deterioration of intel sional application Ser. No. 10/988,600 filed Nov. 16, 2004, lectual functioning in clear consciousness, and is character which is a continuation of PCT Application No. PCT/US03/ ized by one or more symptoms of disorientation, impaired 15279 filed May 16, 2003, which claims priority to U.S. memory, impaired judgment, and/or impaired intellect. The Application No. 60/447,724 filed Feb. 19, 2003, and U.S. symptoms of "dementia” are generally worse than, and can Application No. 60/380,852 filed May 17, 2002. encompass, the symptoms of “cognitive impairment.” 0012. The invention provides methods for treating and FIELD OF THE INVENTION preventing cognitive impairments and/or dementia caused by 0002 The invention provides methods for treating and/or radiation in a patient in need thereof by administering athera preventing cognitive impairments, dementia, and other disor peutically effective amount of at least one cholinesterase ders by administering a therapeutically effective amount of at inhibitor. The radiation may be, for example, a radiation least one cholinesterase inhibitor. A preferred cholinesterase treatment used for cancer oran accidental exposure to radio inhibitor is donepezil, a stereoisomer thereof, and/or a phar active materials. maceutically acceptable salt thereof. 0013 The invention provides methods for treating and preventing visuospatial deficits in a patient in need thereof by BACKGROUND OF THE INVENTION administering a therapeutically effective amount of at least 0003 Cholinesterase inhibitors are described in U.S. Pat. one cholinesterase inhibitor. Visuospatial deficits refer to No. 4,895,841 and WO 98/39000, the disclosures of which problems with perceiving, processing and/or interpreting are incorporated by reference herein in their entirety. The information through the visual system. Visuospatial deficits cholinesterase inhibitors described in U.S. Pat. No. 4,895,841 can include impairments in visuoperceptual abilities and include donepezil hydrochloride or ARICEPTR), which has visuoconstructive abilities. proven to be a highly successful drug for the treatment of 0014. The invention provides methods for treating and Alzheimer's disease. There is a need in the art for new and preventing Williams syndrome in a patient in need thereof by improved treatments for other diseases, disorders, and Syn administering a therapeutically effective amount of at least dromes that may be characterized by symptoms of cognitive one cholinesterase inhibitor. Williams syndrome is a devel impairments. The invention is directed to these, as well as opmental disorder that is characterized by visuospatial defi other, important ends. cits. Most patients with Williams syndrome have mild or moderate mental retardation (mean IQ ranging from 55-60), SUMMARY OF THE INVENTION but some have borderline normal intelligence or severe men 0004. The invention provides methods for treating and/or tal retardation. preventing Alzheimer's disease, vascular dementia, dementia 0015 The invention provides methods for treating and associated with Parkinson's disease, visuospatial deficits, preventing cognitive impairments and/or dementia associated Williams syndrome, encephalitis, meningitis, fetal alcohol with or caused by encephalitis by administering to a patient in syndrome, Korsakoff’s syndrome, anoxic brain injury, car need thereof at least one cholinesterase inhibitor. “Encepha diopulmonary resuscitation injuries, diabetes, Sjogren's Syn litis' refers to an inflammation of the brain. Symptoms can drome, mental retardation, developmental delay, menopause, include a Sudden fever, headache, vomiting, photophobia, pre-menstrual syndrome, strokes, macular degeneration, stiff neck and back, confusion, drowsiness, clumsiness, sleep disorders, cognitive impairments caused by high cho unsteady gait, and irritability. Other symptoms include loss of lesterol levels, jet lag, post-traumatic stress disorder, anxiety disorders, panic attacks, obsessive-compulsive disorder, consciousness, poor responsiveness, seizures, muscle weak amnesia and other disorders by administering to a patient at ness, Sudden severe dementia, memory loss, withdrawal from least one cholinesterase inhibitor. Social interaction, and impaired judgment. 0005. The invention provides novel nasally administrable 0016. The invention provides methods for treating and pharmaceutical compositions comprising at least one cho preventing cognitive impairments and/or dementia associated linesterase inhibitor and a nasal delivery system. with or caused by meningitis by administering to a patient in 0006. The invention provides methods of treating need thereofatherapeutically effective amount of at least one migraines in a patient in need thereof by the nasal adminis cholinesterase inhibitor. “Meningitis” refers to an infection of tration of a pharmaceutical composition comprising at least the membranes that Surround the brain and spinal cord. one cholinesterase inhibitor and a nasal delivery system. Symptoms can appear Suddenly and can include a high fever, 0007. The invention provides ophthalmic compositions severe and persistent headache, stiffneck, nausea, and Vom comprising at least one cholinesterase inhibitor. The oph iting. Other symptoms can include confusion, sleepiness, and thalmic compositions of the invention can be used, for difficulty waking up. Symptoms of meningitis in infants can example, to treat macular degeneration, Sjogren's syndrome, include irritability or tiredness, poor feeding and fever. and glaucoma. 0017. The invention provides methods for treating and 0008. The invention is described in more detail below. preventing Sjogren's syndrome by administering to a patient in need thereof a therapeutically effective amount of at least DETAILED DESCRIPTION OF THE INVENTION one cholinesterase inhibitor. “Sjogren's syndrome' refers to a 0009. “Patient” refers to animals, preferably mammals, chronic autoimmune disorder in which immune cells attack more preferably humans. The term “patient' includes adults and destroy the glands that produce tears and saliva. The and children, and men and women. Children includes neo symptoms of Sjogren's syndrome can include dry eyes and a nates, infants, and adolescents. dry mouth. Additional symptoms can include skin, nose, and/ US 2009/0042939 A1 Feb. 12, 2009

or vaginal dryness. Sjogren's syndrome can be associated need thereof at least one cholinesterase inhibitor. “Diabetes’ with rheumatic disorders, such as rheumatoid arthritis, and refers to a disease of high blood sugar caused by too little can affect other organs of the body including the kidneys, insulin, resistance to insulin, or both. “Type I diabetes’ occurs blood vessels, lungs, liver, pancreas, and brain. In the meth when the body makes little or no insulin and daily injections ods of the invention, the cholinesterase inhibitors can be used of insulin are required to live. “Type 2 diabetes’ occurs when systemically or by topical application to the eyes to treat the pancreas does not make enough insulin to keep blood Sjogren's syndrome. glucose levels normal. Symptoms of Type 1 diabetes can 0018. The invention provides methods for treating and include increased thirst, increased urination, weight loss in preventing cognitive impairments and/or dementia associated spite of increased appetite, fatigue, nausea and Vomiting. with or caused by fetal alcohol syndrome by administering to Symptoms of Type 2 diabetes can include increased thirst, a patient in need thereofatherapeutically effective amount of increased urination, increased appetite, fatigue, blurred at least one cholinesterase inhibitor. “Fetal alcohol syn vision, slow healing infections, and sexual dysfunctions. Pos drome' refers to the manifestation of specific growth, mental, sible complications of diabetes can include heart disease, and physical birth defects associated with a mother's high stroke, eye diseases (such as cataracts, glaucoma, or blind level of alcohol use during pregnancy. Symptoms of fetal ness), kidney disease leading to kidney failure, and nervous alcohol syndrome can include slow intrauterine and neonatal system disease. Cognitive impairments resulting from diabe growth with occasional diagnosis of failure to thrive, delayed tes can include the loss of mental agility, poor concentration, development and evidence of mild to moderate mental retar disruptive behavior, fatigue, anxiety, tension, confusion, dis dation, facial abnormalities, skeletal abnormalities, tremorin orientation, aggression, memory problems, and mood the newborn infant, agitation and crying by the newborn changes. infant, simian crease or other abnormal creases on the palm, 0023 The invention provides methods for treating and growth deficiency, heart defects, vision difficulties, abnormal preventing mental retardation by administering to a patient in behavior Such as short attention span, hyperactivity, poor need thereofatherapeutically effective amount of at least one impulse control, extreme nervousness and anxiety, and limb cholinesterase inhibitor. “Mental retardation” refers to the abnormalities. below-average general intellectual function with associated 0019. The invention provides methods for treating and deficits in adaptive behavior that occurs before age 18. Symp preventing cognitive impairments (e.g., memory impairment) toms of mental retardation can include failure to meet intel associated with or caused by Korsakoff’s syndrome by lectual developmental markers, persistence of infantile administering to a patient in need thereof at least one cho behavior, lack of curiosity, decrease learning ability, and linesterase inhibitor. “Korsakoff’s syndrome' is a syndrome inability to meet educational demands of school. in which the impairment of memory is out of proportion to 0024. The invention provides methods for treating and other cognitive functions. Symptoms can include memory preventing developmental delay by administering to a patient impairment (e.g., loss of memory, inability to form new in need thereof a therapeutically effective amount of at least memories), vision changes (such as double vision), loss of one cholinesterase inhibitor. “Developmental delay” refers to muscle coordination, symptoms that indicate alcohol with a child who fails to achieve certain skills as quickly as drawal, and fabrication of stories. expected, i.e., a child not reaching developmental bench 0020. The invention provides methods for treating and marks at the usual age. Signs of developmental delay can preventing cognitive impairments and/or dementia associated include the delay in walking and other motor skills, the inabil with or caused by anoxic brain injury by administering to a ity to walk, language delay or inability to learn, abnormalities patient in need thereof at least one cholinesterase inhibitor. of vision or hearing, behavioral problems, and seizures. Anoxic brain injury” refers to the injury to the brain caused 0025. The invention provides methods for treating and by an absence or complete lack of oxygen Supply to the preventing cognitive impairments (e.g., memory loss) caused brain's tissues. Symptoms can include seizures, muscle by or associated with menopause by administering to a spasms or twitches, short-term memory loss, word-finding patient in need thereof at least one cholinesterase inhibitor. difficulties, visual disturbances, incoordination, inability to “Menopause' refers to the transition period in a woman's life follow a sequence of commands, spasticity, weakness or when the ovaries stop producing eggs, menstrual activity paralysis, and neck stiffness. Severe symptoms include coma decreases and eventually ceases, and the body decreases the or unconsciousness for hours to days, weeks or months. production of the female hormones, estrogen and progester 0021. The invention provides methods for treating and one. The symptoms of menopause can include memory loss, preventing cognitive impairments and/or dementia caused by hot flashes, skin flushing, mood changes, decreased libido, cardiopulmonary resuscitation by administering to a patient irregular menstrual periods, and vaginal dryness. in need thereof a therapeutically effective amount of at least 0026. The invention provides methods for treating and one cholinesterase inhibitor. “Cardiopulmonary resuscita preventing cognitive impairments (e.g., language develop tion” refers to the administration of heart compression and ment) and/or dementia caused by or associated with strokes artificial respiration to restore circulation and breathing. Pos by administering to a patient in need thereof at least one sible post-resuscitation complications can include cognitive cholinesterase inhibitor. In another embodiment, the inven impairments, cardiovascular dysfunction, microcirculatory tion provides methods of treating post-stroke aphasia in a dysfunction, hypoxia and the release of toxic enzymes and patient in need thereof by administering at least one cho free radicals, multiple organ dysfunction syndrome, seizures, linesterase inhibitor. A “stroke' refers to the loss of brain systemic inflammatory response syndrome, septic shock, and functions caused by a loss of blood circulation to areas of the sepsis syndrome. brain. Symptoms of a stroke can include loss of movement 0022. The invention provides methods for treating and (paralysis) of a body area, weakness, decreased sensation, preventing cognitive impairments and/or dementia caused by numbness, decreased vision, language difficulties (aphasia) or associated with diabetes by administering to a patient in (such as slurred, thick or difficult speech, or the inability to US 2009/0042939 A1 Feb. 12, 2009

speak), inability to understand speech and difficulty with level greater than 200; about 215 or higher; about 225 or reading or writing, inability to recognize or identify sensory higher; or about 235 or higher. stimuli, loss of memory, vertigo, loss of coordination, Swal 0031. The invention provides methods for treating and lowing difficulties, personality changes, mood/emotion preventing jetlag by administering to a patient in need thereof changes, consciousness changes, urinary incontinence, and at least one cholinesterase inhibitor. “Jet lag” refers to a cognitive decline Such as dementia, impaired judgment and physical reaction to a rapid change in time Zones. Symptoms limited attention. Additional symptoms can include tongue of jet lag can include disorientation, irritability, fatigue, Swol problems, seizures, jerky movement, uncontrollable and/or len limbs and eyes, headaches, cold-like symptoms, and dysfunctional movement, fainting, drooling, temporary irregular bowels. absent breathing, and lack of Sweating. 0032. The invention provides methods for treating and 0027. The invention provides methods for treating and preventing post-traumatic stress disorders by administering preventing macular degeneration by administering to a to a patient in need thereof at least one cholinesterase inhibi patient in need thereofat least one cholinesterase inhibitor. In tor. “Post-traumatic stress disorder is a psychiatric illness another embodiment, the invention provides methods for pre that can occur following a traumatic event in which there is venting the neuronal loss associated with macular degenera the threat of injury or death to the patient or someone else. tion by administering to a patient in need thereof at least one Symptoms can include recurrent distressing memories of the cholinesterase inhibitor. “Macular degeneration” refers to a event, recurrent dreams of the event, flashback episodes, disorder that affects the macula or the central part of the retina bodily reactions to situations that remind the person of the causing decreased visual acuity and possible loss of central traumatic event, the inability to remember important aspects vision. Symptoms of macular degeneration can include of the trauma, lack of interest in normal activities, feelings of blurred, distorted, dim or absent central vision. In the meth detachment, reduced expression of moods, irritability or out ods of the invention, the cholinesterase inhibitors can be used burst of anger, sleeping difficulties, difficulty concentrating, systemically or by topical application of the eyes to treat hypervigilance, paleness, heart palpitations, headache, fever, macular degeneration or neuronal loss associated with macu fainting, dizziness, and agitation. Some possible complica lar degeneration. tions can include depression, anxiety, unusual phobia to 0028. The invention provides methods for treating and things that are not usually frightening to other people, alcohol preventing sleep disorders by administering to a patient in abuse and/or drug abuse. need thereof at least one cholinesterase inhibitor. “Sleep dis 0033. The invention provides methods for treating and orders, refer to a disruptive pattern of sleep that can include preventing anxiety disorders or panic attacks by administer difficulty falling or staying asleep, falling asleep at inappro ing to a patient in need thereof at least one cholinesterase priate times, excessive total sleep time, or abnormal behav inhibitor. iors associated with sleep. Sleep disorders include, for 0034) "Panic attacks” refer to unexpected and repeated example, REM (rapid eye movement) disorders, sleep onset episodes of intense fear accompanied by physical symptoms with depression, age-related sleep disorders, narcolepsy, that can include chest pain, heart palpitations, shortness of sleep deprivation, and REM-deprived sleep disorders. Symp breath, dizziness or abdominal distress. Other symptoms can toms of sleep disorders can include awakening in the night, include terror, nausea, tingling or numbness in the hands, difficulty falling asleep, excessive daytime drowsiness, loud flushes or chills, sense of unreality, fear of losing control, Snoring, episodes of stopped breathing, sleep attacks during going "crazy, or doing something embarrassing, and fear of the day, daytime fatigue, depressed mood, anxiety, difficulty dying. concentrating, apathy, irritability, loss of memory or 0035. The invention provides methods for treating and decreased memory, and lower leg movements during sleep. preventing obsessive-compulsive disorder by administering “REM sleep’ refers to the occasional periods of active dream to a patient in need thereof at least one cholinesterase inhibi ing during sleep. “Age related sleep disorders' refer to the tor. “Obsessive-compulsive disorder refers to an anxiety increased difficulty of falling asleep, the increase of awaken disorder characterized by the presence of obsessions or com ings, the less time spent in deep dreamless sleep, which can pulsions. An “obsession” refers to a recurrent or persistent lead to confusion and other metal changes. “Narcolepsy thought that is intrusive or inappropriate. A "compulsion' is a refers to a sleep disorder associated with uncontrollable repetitive behavior a patient feels driven to perform such as a sleepiness and frequent daytime sleeping. physical action (i.e., handwashing) or a mental action (i.e., 0029. In another embodiment, the invention provides praying, repeating words, counting). Symptoms of the disor methods for enhancing REM sleep by administering to a der include obsessions or compulsions that cause significant patient in need thereof at least one cholinesterase inhibitor. distress or interference with every day life, and are not due to Enhancing REM sleep includes, for example, increasing the medical illness or drug use. number of REM sleep episodes and/or increasing the duration 0036. The invention provides methods for treating and of REM sleep episodes. Without intending to be bound by any preventing cognitive impairments associated with patients theory of the invention, enhancing REM sleep may enhance who ingest or are exposed to MTPT by administering a thera memory consolidation and learning, and may improve a peutically effective amount of at least one cholinesterase patient's mood. inhibitor. MTPT is a designer drug that can produce symp 0030. In another embodiment, the invention provides toms of Parkinson's disease in a patient who uses it or makes methods for treating and/or preventing cognitive impairments it. and/or dementia associated with or caused by high choles 0037. The invention provides methods for treating and terol levels in a patient. Without intending to be bound by any preventing amnesia by administering to a patient in need theory of the invention, it is believed that high cholesterol thereof at least one cholinesterase inhibitor. “Amnesia' refers levels cause cognitive impairments, such as impaired to a disturbance in memory manifested by total or partial memory. High cholesterol generally refers to a cholesterol inability to recall past experiences. Symptoms of amnesia can US 2009/0042939 A1 Feb. 12, 2009

include memory gaps, confusion, changes in emotion, diffi inhibitor. In another embodiment, the invention provides for culty in remembering recent events and/or events in the past, methods treating psychiatric disorders by administering to a and disorientation. Cognitive impairments associated with patient in need thereofatherapeutically effective amount of at amnesia can include difficulty thinking/concentrating, drops least one cholinesterase inhibitor and at least one psychiatric in IQ, and problems with fine/gross motor coordination. medicine. 0038. The invention provides methods for treating Alzhe 0043 Any psychiatric medicine in the art can be used imer's disease and/or delaying the onset of Alzheimer's dis depending on the psychiatric illness that is being treated. ease in a patient in need thereof by administering a therapeu Psychiatric medicines include, for example, antidepressant; tically effective amount of at least one cholinesterase anti-psychotic medications (e.g., pimozide, chlorpromazine, inhibitor and at least one statin. In another embodiment, the phenothiazines, butyrophenone, thioxanthines, haloperidol. invention provides methods for treating Alzheimer's disease Suipride, clozapine, Sulpiride, tiapride, , amisul and/or delaying the onset of Alzheimer's disease by admin pride, risperidone, olanzapine, quetiapine, polycarbophil. istering a therapeutically effective amount of at least two Ziprasidone, aripiprazole, illoperidone, trifluoperazine, loxap cholinesterase inhibitors. In another embodiment, the inven ine, molindone, fluiphenazine, thiothixene, perphenazine, tion provides methods for treating Alzheimer's disease and/or prochlorperizine, perphenazine/amitryptiline, mesoridazine, delaying the onset of Alzheimer's disease by administering a thioridazine); mood stabilizers (e.g., lithium, divalproex, therapeutically effective amount of at least two cholinesterase gabapentin, carbamazepine, lamotrigine, topiramate); anti inhibitors and at least one statin. The statin can be any in the anxiety medications (e.g., hydroxy Zine, doxepin, Venlafax art. Exemplary statins include fluvastatin, atorvastatin, simv ine, paroxetine, meprobamate. NGD 91-3, and benzodiaz astatin, pravastatin, lovastatin, cerivastatin, rosuvastatin, and epines (such as alprazolam, flurazepam, oxazepam, the like. The cholinesterase inhibitor and statin can be admin triazolam, estazolam, chlordiazepoxide, lorazepam, istered separately or in the form of a composition. quaZepam, diazepam, tamazepam, clonazepam); stimulants 0039. The invention provides methods for treating and/or (e.g., methylphenidate, dextroamphetamine, pemoline, dex delaying the onset of vascular dementia (also known as cere troamphetamine/levoamphetamine), and the like. brovascular dementia) or dementia associated with Parkin 0044 Antidepressants include, for example, tricyclic anti son's disease in a patient in need thereof by administering a depressants (e.g., amitriptyline, desipramine, imipramine, therapeutically effective amount of at least one cholinesterase nortirptyline); serotonin-specific reuptake inhibitors (e.g., inhibitor and at least one statin. In another embodiment, the fluoxetine, paroxetine, Sertraline, citalopram, fluvoxamine); invention provides methods for treating and/or delaying the monoamine oxidase inhibitors (e.g., pheneizine, tranyl onset of vascular dementia or dementia associated with Par cypromine, isocarboxazid); other antidepressants (e.g., ven kinson's disease by administering a therapeutically effective lafaxine, nefazodone, bupropion, mirtazapine, traZodone, amount of at least two cholinesterase inhibitors. In another thioridazine, protriptyline), and the like. The psychiatric dis embodiment, the invention provides methods for treating and/ order can be any known in the art. Exemplary psychiatric or delaying the onset of vascular dementia or dementia asso disorders include obsessive-compulsive disorder, post-trau ciated with Parkinson's disease by administering a therapeu matic stress disorder, anxiety, panic attacks, Schizophrenia, tically effective amount of at least two cholinesterase depression, mania, manic-depression (bipolar disorder), inhibitors and at least one statin. The cholinesterase inhibitor autism, dyslexia, apathy, delirium, attention deficit hyperac and statin can be administered separately or in the form of a tivity disorder, phobias, eating disorders (e.g., bulimia, anor composition. exia), and the like. 0040. The invention provides methods for treating and/or 0045. The invention provide methods for treating and/or delaying the onset of Alzheimer's disease, vascular dementia, delaying the onset of Alzheimer's disease, vascular dementia, Parkinson's disease, or cognitive impairments by administer or dementia associated with Parkinson's disease by adminis ing to a patient in need thereof a therapeutically effective tering to a patient in need thereof at least one cholinesterase amount of at least one cholinesterase inhibitor and at least one inhibitor and at least one NMDA receptor blocker. In another anti-oxidant. The anti-oxidant can be any in the art. Exem embodiment, the invention provides methods for treating and/ plary anti-oxidants include vitamin E. BHA (i.e., butylated ordelaying the onset of Alzheimer's disease, vascular demen hydroxyanisole), BHT (i.e., butylated hydroxytoluene), vita tia, or dementia associated with Parkinson's disease by min C, budralazine, cadralazine, dihydralazine, endralazine, administering to a patient in need thereof at least two cho hydralazine, pildralazine, todralazine, glutathione, cysteine, linesterase inhibitors and at least one NMDA receptor N-acetyl-cysteine, P-carotene, ubiquinone, ubiquinol-10, blocker. Any NMDA receptor blocker in the art can be used. tocopherols, coenzyme Q, Superoxide dismutase, catalase, Exemplary NMDA receptor blockers include , glutathione peroxidase, and the like. A preferred anti-oxidant remacemide, dizocilipine, dextromethorphan, dextorphan, is vitamin E. The anti-oxidants can be synthetic or natural. AP5, AP7 and the like. In one embodiment, the NMDA recep The cholinesterase inhibitor and the anti-oxidant can be tor blocker is memantine. The cholinesterase inhibitor and administered separately or in the form of a composition. NMDA blocker can be administered separately or in the form 0041. The invention provides methods for treating and/or of a composition. delaying the onset of Alzheimer's disease by administering a 0046. The invention provide methods for treating memory therapeutically effective amount of at least one cholinesterase loss, cognitive impairments or dementia; and for treating inhibitor and an Alzheimer's vaccine. The Alzheimer's vac and/or delaying the onset of Alzheimer's disease, vascular cine can be any in the art. In one embodiment, the Alzheimer's dementia, or dementia associated with Parkinson's disease by vaccine comprises an amyloid. administering to a patient in need thereof at least one cho 0042. The invention provides methods for treating psychi linesterase inhibitor and at least one calcium channel blocker. atric disorders by administering to a patient in need thereof a In another embodiment, the invention provides methods for therapeutically effective amount of at least one cholinesterase treating and/or delaying the onset of Alzheimer's disease, US 2009/0042939 A1 Feb. 12, 2009

vascular dementia, or dementia associated with Parkinson's oxymorphone, papaveretum, pentazocine, phenadoxone, disease by administering to a patient in need thereof at least phenomorphan, phenazocine, phenoperidine, piminodine, two cholinesterase inhibitors and at least one calcium channel piritramide, propheptazine, promedol, properidine, propi blocker. Any calcium channel blocker in the art can be used. ram, propoxyphene, Sufentanil, tramadol, tilidine and the Exemplary calcium channel blockers include amlodipine, like. The MAID can be any in the art. Exemplary NSAIDs, aranidipine, barnidipine, benidipine, cilnidipine, clentiazem, include COX-1 and COX-2 inhibitors, such as celecoxib, diltiazen, efonidipine, fantofarone, felodipine, isradipine, rofecoxib, Valdecoxib, ibuprofen, acetaminophen, aspirin, lacidipine, lercanidipine, manidipine, mibefradil, nicar ketorolac, ketoprofen, diflunisal, Salsalate, Salicylates, salicy dipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, lamide, thiosalicylates, mesalamine, SulfaSalazine, methyl semotiadil, and Veraparmil. The cholinesterase inhibitor and salicylate, phenylbutaZone, oxyphenbutaZone, antipyrine, calcium channel blocker can be administered separately or in aminopyrine, dipyrone, azapropaZone, phenacetin, the form of a composition. indomethacin, Sulindac, mefenamic, meclofenamic, flufe 0047. The invention provide methods for treating memory namic, tolfenamic, etofenamic, tolmetin, naproxen, flurbi loss, cognitive impairments or dementia; and for treating profen, fenoprofen, fenbufen, pirprofen, oxaprozin, indopro and/or delaying the onset of Alzheimer's disease, vascular fen, tiaprofenic acid, piroXicam, ampiroxicam, tenoxicam, dementia, or dementia associated with Parkinson's disease by tenidap, diclofenac, etodolac, nabumentone, and the like. The administering to a patient in need thereof at least one cho cholinesterase inhibitor and analgesic can be administered linesterase inhibitor and atherapeutically effective amount of separately or in the form of a composition. . In another embodiment, the invention provides 0050. The invention provides methods for treating incon methods for treating and/or delaying the onset of Alzheimer's tinence in a patient in need thereof by administering a thera disease, vascular dementia, or dementia associated with Par peutically effective amount of at least one cholinesterase kinson's disease by administering to a patient in need thereof inhibitor. “Incontinence' is the inability to prevent the dis at least two cholinesterase inhibitors and a therapeutically charge of , such as urine or feces. In one embodi effective amount of caffeine. The cholinesterase inhibitor and ment, the invention provides methods for treating urinary caffeine (or caffeine-containing compound) can be adminis incontinence in a patient in need thereof by administering a tered separately or in the form of a composition. therapeutically effective amount of at least one cholinesterase 0048. The invention provides methods for treating and/or inhibitor. In one embodiment, the invention provides methods delaying the onset of Alzheimer's disease or vascular demen for treating fecal incontinence in a patient in need thereof by tia by administering to a patient in need thereof at least one administering a therapeutically effective amount of at least cholinesterase inhibitor and at least one GABA inverse ago one cholinesterase inhibitor. nist. Any GABA inverse agonist in the art can be used. In one 0051. The invention provides methods for treating consti embodiment, the GABA inverse agonist is NGD 97-1. The pation in a patient in need thereof by administering a thera cholinesterase inhibitor and GABA inverse agonist can be peutically effective amount of at least one cholinesterase administered separately or in the form of a composition. inhibitor. 0049. The invention provides methods for potentiating the 0.052 The invention provides methods for treating wasting effect of analgesics by administering to a patient in need in a patient in need thereof by administering a therapeutically thereof a therapeutically effective amount of at least one effective amount of at least one cholinesterase inhibitor. cholinesterase inhibitor and at least one analgesic. The use of “Wasting is the involuntary loss of more than 10% of body a cholinesterase inhibitor in combination with the analgesic weight, and can also be accompanied by more than thirty days allows for the use of a lower dose of the analgesic to achieve of either diarrhea, or weakness and fever. The critical com the same results. The invention provides methods for treating ponent of weight loss in wasting is the loss of body cell mass. one or more side-effects of analgesics by administering to a Body cell mass contains the metabolically active tissues of patient in need thereofatherapeutically effective amount of at the body, including muscle cells, organ cells, and cells of the least one cholinesterase inhibitor. The invention also provides immune system. In wasting, the muscles waste away and the methods for preventing emergence reactions (e.g., hallucina immune system is weakened. Wasting is often a problem for tions) by administering to a patient in need thereof a thera people living with AIDS (HIV disease) or cancer. Wasting can peutically effective amount of at least one cholinesterase also be referred to as wasting syndrome. inhibitor and at least one narcotic. The analgesic can be any in 0053. The invention provides methods for treating or pre the art. Exemplary analgesics include narcotics, NSAIDs, venting chronic fatigue syndrome in a patient in need thereof meperidine, propoxyphene and the like. The narcotic can be by administering atherapeutically effective amount of at least any in the art. Exemplary narcotics include alfentanil, allyl one cholinesterase inhibitor. Chronic fatigue syndrome can prodine, alphaprodine, anilleridine, benzylmorphine, bezitra be characterized by having severe chronic fatigue for six mide, buprenorphine, butorphanol, clonitaZene, codeine, months or longer with other known medical conditions cyclazocine, desomorphine, dextromoramide, dezocine, excluded by clinical diagnosis, and also having four or more diampromide, dihydrocodeine, dihydromorphine, dimenoxa of the following symptoms: Substantial impairment in short dol, dimepheptanol, dimethylthiambutene, dioxaphetyl term memory or concentration, Sore throat, tender lymph butyrate, dipipanone, eptazocine, ethoheptazine, ethylmeth nodes, muscle pain, multijoint pain without Swelling or red ylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, ness, headaches of a new type, pattern or severity, unrefresh hydrocodone, hydromorphone, hydroxypethidine, isometha ing sleep, and/or post-exertion malaise lasting more than 24 done, ketobemidone, levallorphan, levorphanol, levophena hours. cylmorphan, lofentanil, meperidine, meptazinol, metazocine, 0054 The invention also provides veterinary uses for cho methadone, metopon, morphine, myrophine, nalbuphine, linesterase inhibitors. In one embodiment, the invention pro narceline, nicomorphine, norlevorphanol, normethadone, vides methods for treating memory loss or anxiety inapatient nalorphine, normophine, norpipanone, opium, oxycodone, in need thereof by administering an effective amount of at US 2009/0042939 A1 Feb. 12, 2009 least one cholinesterase inhibitor and a veterinarily-accept tuted benzyl; R is hydrogen, lower alkyl or phenyl; r is zero able carrier. The patient can be any mammal. Such as cats and oran integer of about 1 to about 10: R’ is hydrogen or methyl dogs. In another embodiment, the invention provides meth so that one alkylene group can have no methyl branch or one ods for treating excessive barking in a dog in need thereof by or more methyl branches; b is an integer of about 1 to about 3: administering an effective amount of at least one cholinest c is Zero or an integer of about 1 to about 9; d is zero or an erase inhibitor and a veterinarily-acceptable carrier. integer of about 1 to about 5: 0055. The cholinesterase inhibitor used in the methods 0065 T is nitrogen or carbon; and compositions of the invention can be any in the art. The cholinesterase inhibitor can be, for example, an acetylcho linesterase inhibitor or abutyrylcholinesterase inhibitor. Ace tylcholinesterase inhibitors are preferred. Exemplary cho -o linesterase inhibitors include donepezil, phenserine, tolserine, phenethylnorcymserine, ganstigmine, epastigmine, 0.066 Q is nitrogen, carbon or tacrine, physostigmine, pyridostigmine, neostigmine, 0067 q is an integer of about 1 to about 3: rivastigmine, galantamine, citicoline, Velnacrine, huperzine 0068 K is hydrogen, phenyl, substituted phenyl, arylalkyl (e.g., ), metrifonate, heptastigmine, edropho in which the phenyl can have a Substituent, cinnamyl, a lower nium, TAK-147 (i.e., 3-1-(phenylmethyl)-4-piperidinyl)-1- alkyl, pyridylmethyl, cycloalkylalkyl, adamantanemethyl, (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone furylmenthyl, cycloalkyl, lower alkoxycarbonyl or an acyl: fumarate or other salts thereof), T-82, upreazine, and the like. and In each of the methods described herein, one or more cho 0069 "r is a single bond or a double bond. linesterase inhibitors can be used. In one embodiment, one 0070. In the compound of formula I, J is preferably (a) or cholinesterase inhibitor is used. In another embodiment, (b), more preferably (b). In the definition of (b), a monovalent donepezil, a stereoisomer thereof and/or a pharmaceutically group (2), (3) and (5) and a divalent group (2) are preferred. acceptable salt thereof and a second cholinesterase inhibitor The group (b) preferably includes, for example, the groups are used in the methods or compositions of the invention. having the formulae shown below: 0056. In one embodiment, the cholinesterase inhibitor can be a compound of formula I, a stereoisomer thereof, and/or a O pharmaceutically acceptable salt thereof: N N s-H 21 (S)-H 2 JBT Q-K indanyl tetralonyl \ (CH), O O N N 0057 wherein J is 0.058 (a) a substituted or unsubstituted group selected (S)- from the group consisting of (1) phenyl, (2) pyridyl, (3) 21 A4 pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl, and indanonyl (S), (7) furyl; benzoSuberonyl 0059 (b) a monovalent or divalent group, in which the O OH phenyl can have one or more Substituents selected from (1)indanyl. (2) indanonyl, (3) indenyl, (4) indenonyl, (5) N N indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8) (S)- it (S)- it indanolyl, and (9) C6H5-CO-CH(CH3)-; 21 2 0060 (c) a monovalent group derived from a cyclic indanonylidenyl indanolyl amide compound; 0061 (d) a lower alkyl group; or 1N 0062 (e) a group of R-CH=CH-, in which R’ is (S)- it hydrogen or a lower alkoxycarbonyl group; 2 0063 Bis-(CHR)r , CO (CHR)r , NR indenyl (CHR)r , CO. NR (CHR)r CH-CH N CO-CH(CH)- (CHR’) OCOO (CHR’)r OOC NH (S)- it (CHR’)r , NH CO-(CHR’)r , -CH, CO 2 NH-(CHR)r (CH), NH. (CHR)r CH O O (OH) (CHR’)r =(CH-CH=CH) , —CH (CH)c — —(CH-CH)—, —CO CH=CH-CH . 1N 1n CO CH-CH(OH)—CH2—, CH(CH) CO (S)- (S)- it NH-CH , -CH=CH=CO. NH-(CH) , 2 21 —NH-, —O— —S , a dialkylaminoalkyl-carbonyl or a O lower alkoxycarbonyl: indanedionyl indenonyl 0064 wherein R is hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl, substituted phenyl, benzyl, or substi US 2009/0042939 A1 Feb. 12, 2009

0071 whereint is an integer of about 1 to about 4; and each 0079 R2 is a substituted or unsubstituted phenyl group; a S is independently hydrogen or a Substituent, Such as a lower Substituted or unsubstituted arylalkyl group; a cinnamyl alkyl having 1 to 6 carbon atoms or a lower alkoxy having 1 group; a lower alkyl group; a pyridylmethyl group; a to 6 carbon atoms. Among the Substituents, methoxy is most cycloalkylalkyl group; an adamantanemethyl group; or a preferred. The phenyl is most preferred to have 1 to 3 methoxy furoylmethyl group; and groups thereon. (S), can form methylene dioxy groups or 0080 r is a single bond or a double bond. ethylene dioxy groups on two adjacent carbon atoms of the I0081. The term “lower alkyl group’ as used herein means phenyl group. Of the above groups, indanonyl, indanedionyl a straight or branched alkyl group having 1 to 6 carbonatoms. and indenyl, optionally having Substituents on the phenyl, are Exemplary “lower alkyl groups' include methyl, ethyl, pro the most preferred. pyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl 0072. In the definition of B, -(CHR), , -CO (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, (CHR), , =(CH-CH=CH) , —CH-(CH) and 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-meth =(CH-CH)—are preferable. The group of (CHR)r- ylpentyl, 2-methyl-pentyl, 3-methylpentyl, 1,1-dimethylbu in which R’ is hydrogen and r is an integer of 1 to 3, and the tyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimthyl-butyl, group of CH (CH)c- are most preferable. The preferable 2,3-dimethylbutyl, 3.3-dimethylbutyl, 1-ethylbutyl, 2-ethyl groups of B can be connected with (b) of J, in particular butyl, 1,1,2-trimethylpropyl, 1.2.2-trimethylpropyl, 1-ethyl (b)(2). 1-methylpropyl, 1-ethyl-2-methylpropyl, and the like. The 0073. The ring containing T and Q in formula I can be 5-, lower alkyl group is preferably methyl, ethyl, propyl or iso 6- or 7-membered. It is preferred that Q is nitrogen, T is propyl; more preferably methyl. carbon or nitrogen, and q is 2; or that Q is nitrogen, T is I0082 Specific examples of the substituents for the substi carbon, and q is 1 or 3; or that Q is carbon, T is nitrogen and tuted or unsubstituted phenyl, pyridyl, pyrazyl, quinolyl, q is 2. indanyl, cyclohexyl, quinoxalyl and furyl groups in the defi 0074. It is preferable that K is a phenyl, arylalkyl, cin nition of R' include lower alkyl groups having 1 to 6 carbon namyl, phenylalkyl or a phenylalkyl having a Substituent(s) atoms, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, on the phenyl. isobutyl, and tert-butyl groups; lower alkoxy groups corre 0075. In another embodiment, the cyclic amine com sponding to the above-described lower alkyl groups, such as pounds of formula I are the piperidine compounds of formula methoxy and ethoxy groups; a nitro group; halogen atoms, II, a stereoisomer thereof, and/or a pharmaceutically accept Such as chlorine, fluorine and bromine; a carboxyl group; able salt thereof: lower alkoxycarbonyl groups corresponding to the above described lower alkoxy groups. Such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl, II and n-butyloxycarbonyl groups; an amino group; a lower monoalkylamino group; a lower dialkylamino group; a car RIX -O -R2 bamoyl group; acylamino groups derived from aliphatic Satu rated monocarboxylic acids having 1 to 6 carbonatoms. Such as acetylamino, propionylamino, butyrylamino, isobutyry I0076 wherein R' is a (1) substituted or unsubstituted phe lamino, Valerylamino, and pivaloylamino groups; cycloalky nyl group; (2) a Substituted or unsubstituted pyridyl group; (3) oxycarbonyl groups, such as a cyclohexyloxycarbonyl group; a Substituted or unsubstituted pyrazyl group; (4) a Substituted lower alkylaminocarbonyl groups, such as methylaminocar or unsubstituted quinolyl group; (5) a Substituted or unsub bonyl and ethylaminocarbonyl groups; lower alkylcarbony stituted indanyl group; (6) a Substituted or unsubstituted loxy groups corresponding to the above-defined lower alkyl cyclohexyl group; (7) a Substituted or unsubstituted quinox groups, such as methylcarbonyloxy, ethylcarbonyloxy, and alyl group; (8) a substituted or unsubstituted furyl group; (9) n-propylcarbonyloxy groups; halogenated lower alkyl a monovalent or divalent group derived from an indanone groups, such as a trifluoromethyl group; a hydroxyl group; a having a Substituted or unsubstituted phenyl ring; (10) a formyl group; and lower alkoxy lower alkyl groups, such as monovalent group derived from a cyclic amide compound; ethoxymethyl, methoxymethyl and methoxyethyl groups. (11) a lower alkyl group; or (12) a group of the formula The “lower alkyl groups' and “lower alkoxy groups in the R CH=C , where R is a hydrogen atom or a lower above description of the substituent include all the groups alkoxycarbonyl group; derived from the above-mentioned groups. The substituent 0.077 X is -(CH), , –C(O)–(CH), , – N(R) can be one to three of them, which can be the same or differ (CH), , C(O) N(R)-(CH), , CH -CH ent (CH), , O—C(O)—O—(CH), , O C(O) I0083. When the substituent is a phenyl group, the follow NH-(CH), , -CH=CH-CH=CO , -NH C ing group is within the scope of the Substituted phenyl group: (O)—(CH2). , CH2—C(O)—NH-(CH), , —(CH2) C(O) NH-(CH), , —CH(OH)—(CH), , —C(O) CH=CH-CH , C(O) CH-CH(OH)—CH2—, D —CH(CH) C(O) NH-CH , -CH=CH-C(O)– 21 == NH-(CH) , a dialkylaminoalkylcarbonyl group, a lower --G alkoxycarbonyl group; 0078 where n is an integer of 0 to 6: R is a hydrogenatom, s! \ / a lower alkyl group, an acyl group, a lower alkylsulfonyl group, a Substituted or unsubstituted phenyl group, or a Sub I0084 wherein G is C(O)— —O C(O)— —O—, stituted or unsubstituted benzyl group; and R is a hydrogen CH-NH C(O) , CH2—O , CH2—SO , atom a lower alkyl group or a phenyl group; CH(OH)—, or —CH2—S(->O)—; E is a carbon or nitro US 2009/0042939 A1 Feb. 12, 2009

gen atom; and D is a substituent. Preferred examples of the preferably a methyl group, or a lower alkoxy group having 1 substituents (i.e., “D) for the phenyl group include lower to 6 carbon atoms, preferably a methoxy group. alkyl, lower alkoxy, nitro, halogenated lower alkyl, lower 0090 Preferred examples of the monovalent group alkoxycarbonyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups, halogenatoms, and benzyol and benzylsulfonyl include the following: groups. The substituent can be two or more of them, which can be the same or different. (a) I0085 Preferred examples of the substituent for the pyridyl group include lower alkyl and amino groups and halogen atOmS. I0086 Preferred examples of the substituent for the pyrazyl group include lower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, and cycloalkyOxycarbonyl groups. With respect to R', the pyridyl group is preferably a 2-pyridyl, 3-pyridyl, or (b) 4-pyridyl group; the pyrazyl group is preferably a 2-pyrazinyl group; the quinolyl group is preferably a 2-quinolyl or 3-quinolyl group; the quinoxalinyl group is preferably a 2-quinoxalinyl or 3-quinoxalinyl group; and the furyl group is preferably a 2-furyl group. 0087 Specific examples of preferred monovalent or diva (c) lent groups derived from an indanone having an unsubstituted or substituted phenyl ring include those represented by for mulas (A) and (B):

(A) O (d) N (A)m 21 (B) O

N (A)n it 21

0088 where m is an integer of from 1 to 4, and each A is independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a halogen atom, a carboxyl (f) group, a lower alkoxycarbonyl group, an amino group, a lower monoalkylamino group, a lower dialkylamino group, a carbamoyl group, an acylamino group derived from aliphatic saturated monocarboxylic acids having 1 to 6 carbonatoms, a cycloalkyloxycarbonyl group, a lower alkylaminocarbonyl (g) group, a lower alkylcarbonyloxy group, a halogenated lower alkyl group, a hydroxyl group, a formyl group, or a lower alkoxy lower alkyl group; preferably a hydrogen atom, a lower alkyl group or a lower alkoxy group; most preferably O the indanone group is unsubstituted or substituted with 1 to 3 (h) methoxy groups. 0089. Examples of the monovalent group derived from a cyclic amide compound include quinazolone, tetrahydroiso quinolinone, tetrahydrobenzodiazepinone, and hexahy (i) drobenzazocinone. However, the monovalent group can be any one having a cyclic amide group in the structural formula thereof, and is not limited to the above-described specific examples. The cyclic amide group can be one derived from a monocyclic or condensed heterocyclic ring. The condensed heterocyclic ring is preferably one formed by condensation with a phenyl ring. In this case, the phenyl ring can be Sub Cl stituted with a lower alkyl group having 1 to 6 carbon atoms, US 2009/0042939 A1 Feb. 12, 2009

0096 Specific examples of the pyridylmethyl group -continued include 2-pyridylmethyl 3-pyridylmethyl, and 4-pyridylm () ethyl groups. N O 0097. Preferred examples of R include benzyl and phen ethyl groups. The symbol 'rimeans a double or single bond. The bond is a double bond only when R' is the divalent group rA-4 (B) derived from an indanone having an unsubstituted or U Substituted phenyl ring, while it is a single bond in other (k) CaSCS. O 0098. In another embodiment, the compound of formula II N is a compound of formula III, a stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof: rA4 V III (l)

N O N (CHR22)-C N-K (S)- 2 Q- ch, N Y 0099 wherein r is an integer of about 1 to about 10: each (m) O R’ is independently hydrogen or methyl; K is a phenalkyl or a phenalkyl having a Substituent on the phenyl ring; each S is W independently a hydrogen, a lower alkyl group having 1 to 6 NH carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms; t is an integer of 1 to 4: q is an integer of about 1 to W2 about 3; with the proviso that (S), can be a methylenedioxy (n) O group or an ethylenedioxy group joined to two adjacent car bon atoms of the phenyl ring. W 0100. In other embodiments, the compound of formula III N-W3 is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpip eridine: 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-ylidenyl) W2 methylpiperidine: 1-benzyl-4-((5-methoxy-1-indanon)-2-yl) methylpiperidine: 1-benzyl-4-((5,6-diethoxy-1-indanon)-2- 0091. In the above formulae, Y is a hydrogen atom or a yl)methylpiperidine: 1-benzyl-4-((5.6-methnylenedioxy-1- lower alkyl group; V and U are each a hydrogen atom or a indanon)-2-yl)methylpiperidine: 1-(m-nitrobenzyl)-4-((5.6- lower alkoxy group (preferably dimethoxy); W and W are dimethoxy-1-indanon)-2-yl)methylpiperidine; each a hydrogenatom, a lower alkyl group, or a lower alkoxy 1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl) group; and W is a hydrogenatom or a lower alkyl group. The methylpiperidine: 1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1- right hand ring in formulae () and (1) is a 7-membered ring, indanon)-2-yl)methylpiperidine; 1-benzyl-4-((5.6- while the right hand ring in formula (k) is an 8-membered dimethoxy-1-indanon)-2-yl)propylpiperidine: 1-benzyl-4- r1ng. ((5-isopropoxy-6-methoxy-1-indanon)-2-yl) 0092. The most preferred examples of the above-defined methylpiperidine; 1-benzyl-4-((5,6-dimethoxy-1- R' include a monovalent group derived from an indanone oXoindanon)-2-yl)propenylpiperidine, or a stereoisomer and/ having an unsubstituted or Substituted phenyl group and a or a pharmaceutically acceptable salt thereof. monovalent group derived from a cyclic amide compound. 0101. In still other embodiments, the compound of for 0093. The most preferred examples of the above-defined mula III is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)me X include —(CH), , an amide group, or groups repre thylpiperidine, a stereoisomer thereof and/or a pharmaceuti sented by the above formulae where n is 2. Thus, it is most cally acceptable salt thereof, which is represented by formula preferred that any portion of a group represented by the for IV: mula R'" X have a carbonyl or amide group. 0094. The substituents involved in the expressions “a sub stituted or unsubstituted phenyl group' and “a substituted or IV unsubstituted arylalkyl group” in the above definition of R2 are the same substituents as those described for the above definitions of a phenyl group, a pyridyl group, a pyrazyl CHO group, a quinolyl group, an indanyl group, a cyclohexyl group, a quinoxalyl group or a furyl group in the definition of CH2 -O -CH -( ) R. CHO 0095. The term “arylalkyl group' is intended to mean an unsubstituted benzyl or phenethyl group or the like. US 2009/0042939 A1 Feb. 12, 2009

0102. In still other embodiments, the compound of for which can be in the form of a pharmaceutically acceptable mula III is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)me salt, such as a hydrochloride salt; and compounds of formula thylpiperidine hydrochloride or a stereoisomer thereof, VIII: which is also known as donepezil hydrochloride or ARI CEPTOR (Eisai Inc., Teaneck, N.J.), and which is represented by formula IVa: VIII O IVa. CHO O s-cis-K) oHC CHO CHO CH2 N-CH oHC.

CHO 0105. As described above, the cholinesterase inhibitors and other medications described herein can be administered in the form of a pharmaceutically acceptable salt. Pharma 0103) The compounds of the invention can have an asym ceutically acceptable salts are well known in the art and metric carbon atom(s), depending upon the Substituents, and include those of inorganic acids, such as hydrochloride, Sul can have stereoisomers, which are within the scope of the fate, hydrobromide and phosphate; and those of organic invention. For example, donepezil or pharmaceutically acids, such as formate, acetate, trifluoroacetate, methane acceptable salts thereof can be in the forms described in sulfonate, benzenesulfonate and toluenesulfonate. When cer Japanese Patent Application Nos. 4-187674 and 4-2 1670, the tain Substituents are selected, the compounds of the invention disclosures of which are incorporated by reference herein in can form, for example, alkali metal salts. Such as Sodium or their entirety. potassium salts; alkaline earth metal salts, such as calcium or 0104 Japanese Patent Application No. 4-187674 magnesium salts; organic amine salts, such as a salt with describes a compound of formula V: trimethylamine, triethylamine, pyridine, picoline, dicyclo hexylamine or N,N'-dibenzylethylenediamine. One skilled in the art will recognize that the compounds of the invention can V be made in the form of any other pharmaceutically acceptable O salt. 0106 The cholinesterase inhibitors can be prepared by CHO processes that are known in the art and described, for example, in U.S. Pat. No. 4,895.841, WO 98/39000, and -et-() Japanese Patent Application Nos. 4-187674 and 4-2 1670, the CHO disclosures of each of which are incorporated by reference herein in their entirety. Donepezil hydrochloride, a preferred cholinesterase inhibitor for use in the methods described which can be in the form of a pharmaceutically acceptable herein, is commercially available as ARICEPTR) from Eisai salt, Such as a hydrochloride salt. Japanese Patent Application Inc., Teaneck, N.J. The other medications described herein No. 4-21670 describes compounds of formula VI: (e.g., statins, vaccines, anti-oxidants, psychiatric medica tions, NMDA receptor blockers, calcium channel blockers, caffeine, analgesics, GABA inverse agonists) are commer VI cially available, are in development, and/or can be prepared O by processes described in the literature. The cholinesterase inhibitors and other medications described herein can be CHO CH2 administered as pharmaceutical combinations. A pharmaceu w N-CH tical combination is a pharmaceutical formulation compris ing both active ingredients or separate pharmaceutical dosage CHO forms. 0107 The dosage regimen for treating and preventing the which can be in the form of a pharmaceutically acceptable diseases described herein with the cholinesterase inhibitors salt, such as a hydrochloride salt; and compounds of formula and other medications can be selected in accordance with a VII: variety of factors, including the age, weight, sex, and medical condition of the patient, the severity of the migraines, the , pharmacological considerations such VII as the activity, efficacy, pharmacokinetic and toxicology pro files of the drugs, whether a drug delivery system is used and O whether the cholinesterase inhibitor is administered as part of CHO CH a drug combination. N-CH 0108. When more than one cholinesterase inhibitor is administered to a patient and/or when the cholinesterase CHO inhibitor(s) is administered in conjunction with another medi cation, the compounds can be separately administered about the same time as part of an overall treatment regimen, i.e., as US 2009/0042939 A1 Feb. 12, 2009

a drug cocktail or combination therapy. About the same used in the preparation of injectables. The preparations can be time' includes administering the compounds at the same lyophilized by methods known in the art. time, at different times on the same day, or on different days, 0113 Solid dosage forms for oral administration of the as long as they are administered as part of an overall treatment cholinesterase inhibitors can include chewing gum, capsules, regimen. tablets, Sublingual tablets, powders, granules, and gels; pref 0109 The cholinesterase inhibitors can be administered to erably tablets. In Such solid dosage forms, the active com treat or prevent the diseases described herein in doses of about pound can be admixed with one or more inert diluents such as 0.01 milligrams to about 300 milligrams per day, preferably lactose or starch. As is normal practice. Such dosage forms about 1 milligram to about 100 milligrams per day, more can also comprise other Substances including lubricating preferably about 5 milligrams to about 10 milligrams per day. agents such as magnesium Stearate. In the case of capsules, The doses can be administered in one to four portions over the tablets, and pills, the dosage forms can also comprise buffer course of a day, preferably once a day. One skilled in the art ing agents. The tablets can be prepared with enteric or film will recognize that when the cholinesterase inhibitors are coatings, preferably film coatings. administered to children, the dose can be smaller than the 0114 Sublingual administration refers to the administra dose administered to adults, and that the dose can be depen tion of the cholinesterase inhibitors in the mouth (e.g., under dent upon the size and weight of the patient. A child can be the tongue, between the cheek and gum, between the tongue administered the cholinesterase inhibitors in doses of about and roof of the mouth). The highly vascular mucosal lining in 0.1 milligrams to about 15 milligrams per day, preferably the mouth is a convenient location for the cholinesterase about 0.5 milligrams to about 10 milligrams per day, more inhibitors to be administered into the body. To make tablets, preferably about 1 milligram to about 3 milligrams per day. the cholinesterase inhibitors can be admixed with pharma 0110. In other embodiments of the methods described ceutically acceptable carriers known in the art Such as, for herein, donepezil hydrochloride, which is commercially example, vehicles (e.g., lactose, white Sugar, mannitol, glu available as ARICEPTOR (Eisai Inc., Teaneck, N.J.), can be cose, starches, calcium carbonate, crystalline cellulose, administered as tablets containing either 5 milligrams done silicic acid, and the like), binders (e.g., water, ethanol, myra pezil hydrochloride or 10 milligrams donepezil hydrochlo nol, glucose solution, starch Solution, gelatin Solution, poly ride. The tablets can be administered one to about four times vinylpyrrolidone, and the like), disintegrators (e.g., dry a day. In preferred embodiments, one 5 milligram or one 10 starch, Sodium, alginate, sodium hydrogen carbonate, cal milligram ARICEPTR tablet is administered once a day for cium carbonate, polyoxyethylene Sorbitan fatty acid esters, the methods described herein. One skilled in the art will Sodium laurylsulfate, Stearic monoglyceride, Starches, lac appreciate that when donepezil hydrochloride is administered tose, and the like), absorption promoters (e.g., quaternary to children, the dose can be smaller than the dose that is ammonium base, sodium laurylsulfate, and the like), wetting administered to adults. agents (e.g. glycerin, starches, and the like), lubricants (e.g., 0111. The cholinesterase inhibitors and other medications Stearates, polyethylene glycol, and the like), and flavoring of the invention can be administered orally, topically, agents (e.g., Sweeteners). The tablets can be in the form of a parenterally, by inhalation (nasal or oral), or rectally in dos conventional tablet, a molded tablet, a wafer and the like. age unit formulations containing conventional nontoxic phar 0.115. In other embodiments, the solid dosage form can be maceutically acceptable carriers, adjuvants, and vehicles as packaged as granules or a powder in a pharmaceutically desired. The term parenteral includes subcutaneous, intrave acceptable carrier, where the granules or powder are removed nous, intramuscular, intrathecal, intrasternal injection, or from the packaging and sprinkled on food or mixed with a infusion techniques. Preferably, the cholinesterase inhibitors liquid, Such as water or juice. In this embodiment, the cho are orally administered as tablets. When administered to chil linesterase inhibitors can be mixed with flavoring or sweet dren, the cholinesterase inhibitors are preferably orally ening agents. The packaging material can be plastic, coated administered in a liquid dosage form. paper, or any material that prevents water or moisture from 0112 Injectable preparations, for example, sterile inject reaching the granules and/or powder. able aqueous or oleaginous Suspensions, of the cholinesterase 0116. Liquid dosage forms for oral administration of the inhibitors can be formulated according to the art using Suit cholinesterase inhibitors can include pharmaceutically able dispersing or wetting agents, Suspending agents (e.g., acceptable emulsions, Solutions, Sublingual Solutions, Sus methylcellulose, Polysorbate 80, hydroxyethylcellulose, aca pensions, and syrups containing inert diluents commonly cia, powdered tragacanth, sodium carboxymethylcellulose, used in the art, such as water. Such compositions can also polyoxytehylene Sorbitan monolaurate and the like), pH comprise adjuvants, such as wetting agents, emulsifying and modifiers, buffers, solubilizing agents (e.g., polyoxyethylene Suspending agents, and Sweetening, flavoring, and perfuming hydrogenated castor oil, Polysorbate 80, nicotinamide, poly agents. To make Sublingual solutions, the cholinesterase oxyethylene Sorbitan monolaurate, Macrogol, an ethyl ester inhibitors can be admixed with various carriers, excipients, of castor oil fatty acid, and the like) and preservatives. The pH adjusters, and the like (e.g., water, Sugar, lactic acid, acetic sterile injectable preparation can also be a sterile injectable acid, fructose, glucose, saccharin, polyethylene glycol, pro Solution or Suspension in a nontoxic parenterally acceptable pylene glycol, alcohol, bentonite, tragacanth, gelatin, algi diluent or solvent, for example, as a solution in 1,3-butane nates, aspartame, Sorbitol, methylparaben, propylparaben, diol. Among the acceptable vehicles and solvents that can be Sodium benzoate, artificial flavoring and coloring agents). used are water, Ringer's solution, and isotonic sodium chlo 0117 For administration by inhalation, the cholinesterase ride solution. In addition, sterile, fixed oils are conventionally inhibitors can be delivered from an insufflator, a nebulizer or used as a solvent or Suspending medium. For this purpose any a pressured pack or other convenient mode of delivering an bland fixed oil can be used including synthetic mono- or aerosol spray. Pressurized packs can include a Suitable pro diglycerides, in addition, fatty acids, such as oleic acid, can be pellant. Alternatively, for administration by inhalation, the US 2009/0042939 A1 Feb. 12, 2009

cholinesterase inhibitors can be administered in the form of a I0122) When administered in the form of eye drops, the dry powder composition or in the form of a liquid spray. cholinesterase inhibitors can be topically administered to the 0118 Suppositories for rectal administration of the cho patient's eye in a concentration of about 0.00001% (e.g., 0.01 linesterase inhibitors can be prepared by mixing the active milligram cholinesterase inhibitor per 100 ml H2O) to about compounds with Suitable nonirritating excipients such as 1% (e.g., 1 gram cholinesterase inhibitor per 100 ml H2O): cocoa butter and polyethylene glycols that are solid at room preferably in a concentration of about 0.0001% to about temperature and liquid at body temperature. Alternatively, an 0.25%, and even more preferably in a concentration of about enema can be prepared by for rectal administration of the 0.001% to about 0.125%, most preferably in a concentration cholinesterase inhibitors. of about 0.01% to about 0.1%. One to four drops can be 0119 For topical administration to the epidermis, the cho administered to the patient's eye(s) over the course of a day, linesterase inhibitors can be formulated as ointments, creams preferably one or two drops per day, most preferably one drop or lotions, or as the active ingredient of a transdermal patch. per day. In yet another embodiment, the cholinesterase inhibi The cholinesterase inhibitors can also be administered via tors can be administered in a concentration of about 0.125% iontophoresis or osmotic pump. Ointments, creams and to about 0.25% administered in one or two drops daily, pref lotions can be formulated with an aqueous or oily base with erably one drop daily. the addition of Suitable thickening and/or gelling agents. Alternatively, ointments, creams and lotions can be formu I0123. The cholinesterase inhibitors can be topically lated with an aqueous or oily base and can also contain one or administered to the affected eye(s) in the form of an oph more emulsifying agents, stabilizing agents, dispersing thalmic composition. The ophthalmic composition can be in agents, Suspending agents, thickening agents, and/or coloring the form of a gel, a solution, a Suspension, an emulsion agents. As creams or lotions, the cholinesterase inhibitors can (dispersion), or an erodible solid ocular insert. The oph be mixed to form a smooth, homogeneous cream or lotion thalmic compositions can comprise liposomes or with, for example, one or more of a preservative (e.g., benzyl microbubbles. Alternatively, the ophthalmic compositions alcohol 1% or 2% (wit/wt)), emulsifying wax, glycerin, iso can be administered in the form of non-aqueous formulations, propyl palmitate, lactic acid, purified water, Sorbitol Solution. Such as Substantially non-aqueous liquids, Substantially non Such topically administrable compositions can contain poly aqueous semi-solid compositions, and Solid compositions or ethylene glycol 400. To form ointments, the cholinesterase devices. The methods of treating or preventing glaucoma inhibitors can be mixed with one or more of a preservative and/or intraocular pressure typically comprise the topical (e.g., benzyl alcohol 2% (wt/wt)), petrolatum, emulsifying application of one or two drops (or an equivalent amount of a wax, and Tenox (II) (e.g., butylated hydroxyanisole, propyl solid or semi-solid dosage form) to the affected eye one to gallate, citric acid, propylene glycol). Woven pads or rolls of four times per day, preferably once per day. bandaging material, e.g., gauze, can be impregnated with the 0.124 Informing compositions for topical administration, transdermally administrable compositions for topical appli the ophthalmic compositions are generally formulated at a pH cation. between about 4.5 and about 8.0. The topical compositions 0120. The cholinesterase inhibitors can also be topically can also comprise other ingredients that are known to be used applied using a transdermal system, Such as one of an acrylic in ophthalmic compositions including, for example, preser based polymer adhesive with a resinous crosslinking agent Vatives, Surfactants and co-solvents, tonicity agents, and vis impregnated with the cholinesterase inhibitors and laminated cosity building agents. to an impermeable backing. For example, the cholinesterase 0.125 Ophthalmic compositions are typically packaged in inhibitors can be administered in the form of a transdermal multidose form, which generally requires the addition of patch, Such as a Sustained-release transdermal patch. Trans preservatives to prevent microbial contamination during use. dermal patches can include any conventional form Such as, Suitable preservatives include, for example, benzalkonium for example, an adhesive matrix, a polymeric matrix, a reser chloride, thimerosal, chlorobutanol, methyl paraben, propyl Voir patch, a matrix- or monolithic-type laminated structure, paraben, phenylethyl alcohol, edetate disodium, Sorbic acid, and are generally comprised of one or more backing layers, ONAMERM(R), and the like. Such preservatives are typically adhesives, penetration enhancers, and/or rate-controlling used at a concentration of about 0.001% to about 1.0% by membranes. Transdermal patches generally have a release weight. liner which is removed to expose the adhesive/active ingre 0.126 Surfactants or co-solvents that can be used in the dient(s) prior to application. Transdermal patches are ophthalmic compositions of the invention include polysor described in, for example, U.S. Pat. Nos. 5.262,165, 5.948, bate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Plu 433, 6,010,715 and 6,071,531, the disclosures of which are ronic F-84, Pluronic P-103, TYLOXAPOLOR), CREMO incorporated by reference herein in their entirety. PHORR) EL, sodium dodecyl sulfate, glycerol, PEG 400, 0121 For the methods of treating and/or preventing, for propylene glycol, cyclodextrins, and the like. Surfactants or example, Sjogren's syndrome (e.g., with respect to problems co-solvents are typically used at a concentration of about associated with the eyes), neuronal loss in the eyes, and/or 0.01% to about 2% by weight. macular degeneration, the cholinesterase inhibitors can be I0127. A viscosity greater than that of simple aqueous solu topically administered to the affected eye(s) in the form of an tions can be desirable to increase ocular absorption of the ophthalmic composition. The cholinesterase inhibitors can be active compounds, to decrease variability in dispensing the administered in doses of about 0.00001 milligrams to about compositions, to decrease physical separation of components 300 milligrams per day to the affected eye(s), preferably of a Suspension or emulsion of the compositions and/or to about 0.0001 milligrams to about 100 milligrams per day, otherwise improve the ophthalmic composition. Viscosity more preferably about 0.0001 milligrams to about 10 milli building agents include polyvinyl alcohol, polyvinyl pyrroli grams per day. The doses can be administered in one to four done, methyl cellulose, hydroxy propyl methylcellulose, portions over the course of a day, preferably once per day. hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy US 2009/0042939 A1 Feb. 12, 2009 propyl cellulose and the like. Viscosity building agents are example, aqueous gels, aqueous Suspensions, aqueous lipo typically used at a concentration of about 0.01% to about 2% Somal dispersions, aqueous emulsions, aqueous microemul by weight. sions and combinations thereof. Non-aqueous solutions 0128 Suitable agents which can be used to adjust the include, for example, non-aqueous gels, non-aqueous Sus tonicity or osmolality of the ophthalmic compositions include pensions, non-aqueous liposomal dispersions, non-aqueous Sodium chloride, potassium chloride, mannitol, dextrose, emulsions, non-aqueous microemulsions and combinations glycerin, propylene glycol and the like. Tonicity agents are thereof. typically used at a concentration of about 0.1% to about 10% by weight. I0135) In other embodiments, the nasal delivery system can 0129. Substantially non-aqueous liquids comprise at least be a powder formulation. Powder formulations include, for one of the cholinesterase inhibitors of the invention dissolved example, powder mixtures, powder microspheres, coated or Suspended in one or more of the following: Vegetable and powder microspheres, liposomal dispersions and combina mineral oils, such as liquid petrolatum, corn oil, castor oil, tions thereof. Preferably, the powder formulation is powder sesame oil and peanut oil; triglycerides, such as the capric/ microspheres. The powder microspheres are preferably caprylic triglycerides commonly used in foods and cosmet formed from various polysaccharides and celluloses selected ics; liquid lanolin and lanolin derivatives; and perfluorohy from starch, methylcellulose, Xanthan gum, carboxymethyl drocarbons. cellulose, hydroxypropyl cellulose, carbomer, alginate poly 0130. Substantially non-aqueous semi-solid compositions vinyl alcohol, acacia, chitosans, and mixtures of two or more comprise at least one of the cholinesterase inhibitors of the thereof. invention dissolved or suspended in or more of the following: 0.136. In certain embodiments, the particle size of the various types of petrolatum, Such as white, yellow and red; droplets of the aqueous and/or non-aqueous solution or of the lanolin and lanolin derivatives; gelled mineral oil having a powders delivered to the nasal mucosa can be, for example, hydrocarbon base, such as PLASTIBASE(R); petrolatum and about 0.1 micron to about 100 microns; from about 1 micron ethylene carbonate mixtures; petrolatum in combination with to about 70 microns; from about 5 microns to about 50 Surfactants and polyglycol. Such as polyoxyl 40 Stearate and microns; or from about 10 microns to about 20 microns. The polyethylene glycol. particle sizes can be obtained using Suitable containers or 0131 Solid compositions or devices include non-erodible metering devices known in the art. Exemplary devices devices which are inserted into the conjunctival sac of the eye include mechanical pumps in which delivery is made by and later removed, such as the Alza-type diffusion or osmotic movement of a piston; compressed air mechanisms in which pressure controlled polymer membranes; and bioerodible delivery is made by hand pumping air into the container; polymers which do not have to be removed from the conjunc compressed gas (e.g., nitrogen) techniques in which delivery tival sac, Such as essentially anhydrous but water soluble is made by the controlled release of a compressed gas in the polymers and resins (e.g., celluloses, polycarboxylic acids). sealed container, liquefied propellant techniques in which a 0132) The invention provides for the cholinesterase inhibi low boiling liquid hydrocarbon (e.g., butane) is vaporized to tors to be administered nasally to a patient to treat the diseases exert a pressure and force the composition through the and disorders described herein and those described, for metered valve; and the like. Powders may be administered, example, in PCT/US02/29734, WO 01/661 14, and U.S. Pat. for example, in Such a manner that they are placed in a capsule Nos. 6,482,838, 6,458,807 and 6,455,544, the disclosures of that is then set in an inhalation or insufflation device. A needle which are incorporated by reference herein in their entirety. is penetrated through the capsule to make pores at the top and “Administered nasally” or “nasal administration' is intended the bottom of the capsule and air is sent to blow out the to mean that at least one cholinesterase inhibitor is combined powder particles. Powder formulation can also be adminis with a suitable delivery system for absorption across the nasal tered in a jet-spray of an inert gas or Suspended in liquid mucosa of a patient, preferably a human. Generally, lower organic fluids. doses of the cholinesterase inhibitor can be used for nasal 0.137 In one embodiment, the invention provides a nasally administration when compared, for example, to the dose administrable pharmaceutical composition comprising at required for the oral administration of the cholinesterase least one cholinesterase inhibitor dispersed in a nasal delivery inhibitor. system that improves the solubility of the cholinesterase 0133. The cholinesterase inhibitors of the invention can be inhibitor. The nasal delivery system that improves solubility administered, for example, as nasal sprays, nasal drops, nasal can include one of the following or combinations thereof: (i) Suspensions, nasal gels, nasal ointments, nasal creams or a glycol derivative (e.g., propylene glycol, polyethylene gly nasal powders. The cholinesterase inhibitors can also be col, mixtures thereof); (ii) a system that improves its solubil administered using nasal tampons or nasal Sponges. The cho ity. linesterase inhibitors of the invention can be brought into a 0.138. In yet another embodiment, the invention provides a Viscous basis via systems conventionally used, for example, nasally administrable pharmaceutical composition compris natural gums, methylcellulose and derivatives, acrylic poly ing at least one cholinesterase inhibitor and a nasal delivery mers (carbopol) and vinyl polymers (polyvinylpyrrolidone). system, where the nasal delivery system comprises at least In the compositions, many other excipients known in the art one pharmaceutically acceptable thickening agent, at least can be added such as water, preservatives, Surfactants, Sol one humectant, at least one surfactant, and at least one solu vents, adhesives, antioxidants, buffers, bio-adhesives, viscos bilizing agent. The nasal delivery system can optionally fur ity enhancing agents and agents to adjust the pH and the ther comprise buffers, pH adjusting agents, isotonicity osmolarity. agents, preservatives, antioxidants, bio-adhesives, and/or 0134. The nasal delivery systems can take various forms other pharmaceutically acceptable excipients. The cholinest including aqueous Solutions, non-aqueous solutions and erase inhibitor can optionally be dispersed in a nasal delivery combinations thereof. Aqueous solutions include, for system that improves its solubility. US 2009/0042939 A1 Feb. 12, 2009

0.139. In yet another embodiment, the invention provides a thereof. The concentration of the humectant will vary nasally administrable pharmaceutical composition compris depending upon the agent selected. In one embodiment, the ing at least one cholinesterase inhibitor and a nasal delivery humectant can be present in the nasal delivery system in a system, where the nasal delivery system comprises at least concentration ranging from about 0.01% to about 20% by one buffer to maintain the pH of the cholinesterase inhibitor, weight of the composition. at least one pharmaceutically acceptable thickening agent, at 0146 In other embodiments, the nasal delivery system can least one humectant, at least one Surfactant, and at least one further comprise surfactants which enhance the absorption of solubilizing agent. The nasal delivery system can optionally the cholinesterase inhibitor. Suitable surfactants include non further comprise buffers, pH adjusting agents, isotonicity ionic, anionic and cationic Surfactants. Exemplary Surfactants agents, preservatives, antioxidants, bio-adhesives, and/or include oleic acid, polyoxyethylene derivatives offatty acids, other pharmaceutically acceptable excipients. The cholinest partial esters of Sorbitol anhydride, Such as for example, erase inhibitor can optionally be dispersed in a nasal delivery Tweens (e.g., Tween 80, Tween 40, Tween 20), Spans (e.g., system that improves its solubility. Span 40, Span 80, Span 20), polyoxyl 40 stearate, polyoxy 0140. The nasally administrable pharmaceutical composi ethylene 50 Stearate, fusieates, bile salts, octoxynol, and mix tions of the invention preferably provide a peak plasma con tures of two or more thereof. Exemplary anionic Surfactants centration of the cholinesterase inhibitorinless than one hour, include salts of long chain hydrocarbons (e.g., Co or Co preferably within about 5 minutes to about 30 minutes, more 20) having one or more of the following functional groups: preferably within about 5 minutes to about 20 minutes, after carboxylates; Sulfonates; and Sulfates. Salts of long chain administration to the patient. hydrocarbons having Sulfate functional groups are preferred, 0141. The buffer has a pH that is selected to optimize the Such as sodium cetostearyl Sulfate, sodium dodecyl Sulfate absorption of the cholinesterase inhibitor across the nasal and sodium tetradecyl sulfate. One particularly preferred mucosa. The particular pH of the buffer can vary depending anionic Surfactant is sodium lauryl Sulfate (i.e., Sodium dode upon the particular nasal delivery formulation as well as the cyl Sulfate). The Surfactants can be present in an amount from specific cholinesterase inhibitor selected. Buffers that are about 0.001% to about 50% by weight, or from about 0.001% Suitable for use in the invention include acetate (e.g., sodium to about 20% by weight. acetate), citrate (e.g., sodium citrate dihydrate), phthalate, 0147 The pharmaceutical compositions of the invention borate, prolamine, trolamine, carbonate, phosphate (e.g., may further comprise an isotonicity agent, Such as sodium monopotassium phosphate, disodium phosphate), and mix chloride, dextrose, boric acid, sodium tartrate or other inor tures of two or more thereof. ganic or organic Solutes. 0142. The pH of the compositions should be maintained 0.148. The nasal pharmaceutical compositions of the from about 3.0 to about 10.0. Compositions having a pH of invention can optionally be used in combination with a pH less than about 3.0 or greater than about 10.0 can increase the adjusting agent. Exemplary pH adjusting agents include Sul risk of irritating the nasal mucosa of the patient. Further, it is furic acid, Sodium hydroxide, hydrochloric acid, and the like. preferable that the pH of the compositions be maintained 0149. To extend shelf life, preservatives can be added to from about 3.0 to about 9.0. With respect to the non-aqueous the nasally administrable compositions. Suitable preserva nasal formulations, Suitable forms of buffering agents can be tives that can be used include benzyl alcohol, parabens, selected such that when the formulation is delivered into the thimerosal, chlorobutanol, benzalkonium chloride, or mix nasal cavity of a mammal, selected pH ranges are achieved tures of two or more thereof. Preferably benzalkonium chlo therein upon contact with, e.g., a nasal mucosa. ride is used. Typically, the preservative will be present in a 0143. The solubilizing agent for use in the compositions of concentration of up to about 2% by weight. The exact con the invention can be any known in the art, such as carboxylic centration of the preservative, however, will vary depending acids and salts thereof. Exemplary carboxylic acid salts upon the intended use and can be easily ascertained by one include acetate, gluconate, ascorbate, citrate, fumurate, lac skilled in the art. tate, tartrate, maleate, maleate. Succinate, or mixtures of two 0150. Other ingredients which extend shelf life can be or more thereof. added such as for example, antioxidants. Some examples of 0144. The viscosity of the compositions of the present antioxidants include Sodium metabisulfite, potassium met invention can be maintained at a desired level using a phar abisulfite, ascorbyl palmitate and the like. Typically, the anti maceutically acceptable thickening agent. For example, the oxidant will be present in the compositions in a concentration viscosity may be at least 1000 cps; from about 1000 to about of from about 0.001% up to about 5% by weight of the total 10,000 cps; from about 2000 cps to about 6500 cps; or from composition. about 2500 cps to about 5000 cps. Thickening agents that can 0151. Other optional ingredients can also be incorporated be used in accordance with the present invention include, for into the nasal delivery system provided that they do not inter example, methyl cellulose, Xanthan gum, carboxymethyl cel fere with the action of the cholinesterase inhibitor or signifi lulose, hydroxypropyl cellulose, carbomer, polyvinyl alco cantly decrease the absorption of the cholinesterase inhibitor hol, alginates, acacia, chitosans, and mixtures of two or more across the nasal mucosa. thereof. The concentration of the thickening agent will 0152 The nasal delivery systems can be made following depend upon the agent selected and the Viscosity desired. the processes described in, for example, U.S. Pat. Nos. 6,451, Such agents can also be used in a powder formulation. 848, 6,436,950, and 5,874,450, and WO 00/00199, the dis 0145 The nasally administrable compositions can also closures of which are incorporated by reference herein in their include a humectant to reduce or prevent drying of the mucus entirety. membrane and to prevent irritation thereof. Suitable humec 0153. In another embodiment, the invention provides tants that can be used include, for example, Sorbitol, mineral methods for treating and/or preventing migraines by nasally oil, vegetable oil and glycerol; soothing agents; membrane administering to a patient the nasally administrable pharma conditioners; Sweeteners; and mixtures of two or more ceutical composition comprising at least one cholinesterase US 2009/0042939 A1 Feb. 12, 2009

inhibitor of the invention. The migraines can be classic wherein R is hydrogen, lower alkyl, acyl, lower alkylsul migraines, common migraines, complicated migraines, and/ fonyl, phenyl, substituted phenyl, benzyl, or substituted or cluster headaches. In other embodiments, the migraines benzyl; R is hydrogen, lower alkyl orphenyl: ris zero or can be menstrual migraines, premenstrual migraines, oph an integer of about 1 to about 10: R’ is hydrogen or thalmic migraines, and/or opthalmoplegic migraines. In other methyl so that one alkylene group can have no methyl embodiments, the migraines can be fulgurating migraines, branch or one or more methyl branches; b is an integer of Harris' migraines, and/or hemiplegic migraines. In still other about 1 to about 3; c is Zero or an integer of about 1 to embodiments, the migraines can be abdominal migraines. about 9; d is Zero or an integer of about 1 to about 5: 0154 Each of the patents, patent applications, and publi T is nitrogen or carbon; cations cited herein are incorporated by reference herein in their entirety. 0155. It will be apparent to one skilled in the art that various modifications can be made to the invention without departing from the spirit or scope of the appended claims. Q is nitrogen, carbon or 1. (canceled) q is an integer of about 1 to about 3, 2. (canceled) K is hydrogen, phenyl, Substituted phenyl, arylalkyl in 3. (canceled) which the phenyl can have a Substituent, cinnamyl, a 4. (canceled) lower alkyl, pyridylmethyl, cycloalkylalkyl, adaman 5. (canceled) tanemethyl, furylmenthyl, cycloalkyl, lower alkoxycar 6. (canceled) bonyl or an acyl; and 7. (canceled) ris a single bond or a double bond. 8. A method for treating a cognitive impairment or demen 17. The method of claim 8, wherein the cholinesterase tia caused by a stroke, in a patient in need thereof comprising inhibitor is a compound of formula II, a stereoisomer thereof, administering a therapeutically effective amount of at least and/or a pharmaceutically acceptable salt thereof: one cholinesterase inhibitor. II 9. (canceled) 10. (canceled) 11. (canceled) rx-O- 12. (canceled) 13. (canceled) wherein R' is a substituted or unsubstituted phenyl group; 14. (canceled) 15. The method of claim 8, wherein the cholinesterase inhibitor is donepezil, phenserine, tolserine, phenethylnor , gainstigmine, epastigmine, tacrine, physostig mine, pyridostigmine, neostigmine, rivastigmine, galan (O)—(CH), , CH C(O) NH (CH), , tamine, citicoline, Velnacrine, huperzine, metrifonate, (CH) C(O)—NH-(CH2), , CH(OH) heptastigmine, edrophonium, 3-(1-(phenylmethyl)-4-pip (CH) , —C(O)—CH=CH-CH , —C(O)— eridinyl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1- CH-CH(OH)-CH , —CH(CH) C(O) NH propanone, T-82 or upreazine. CH , —CH=CH-C(O) NH-(CH) , a 16. The method of claim 8, 9, 10, 12, 13 or 14, wherein the dialkylaminoalkylcarbonyl group, a lower alkoxycarbo cholinesterase inhibitor is a compound of formula I, a stere nyl group: oisomer thereof, and/or a pharmaceutically acceptable salt where n is an integer of 0 to 6: R is a hydrogen atom, a thereof: lower alkyl group, an acyl group, a lower alkylsulfonyl group, a Substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; and R is a hydrogen atom a lower alkyl group or a phenyl group; JBT Q-K R’ is a substituted or unsubstituted phenyl group; a substi N(CH/ tuted or unsubstituted arylalkyl group; a cinnamyl group; a lower alkyl group; a pyridylmethyl group; a wherein J is cycloalkylalkyl group; an adamantanemethyl group; or a substituted or unsubstituted a furoylmethyl group; and B is -(CHR), , –CO (CHR’). , NR ris a single bond or a double bond. (CHR’). CO. NR (CHR’), , CH-CH 18. The method of claim 8, wherein the cholinesterase (CHR’?). , OCOO (CHR’), OOC NH inhibitor is a compound of formula III, a stereoisomer -(CHR), NH CO (CHR), CH, CO thereof, and/or a pharmaceutically acceptable salt thereof: NH (CHR), , —(CH). NH-(CHR’), , III -CH(OH)–(CHR’), , =(CH-CH=CH) , O =CH-(CH2) , —(CH-CH)—, —CO— CH=CH-CH , —CO CH-CH(OH)—CH , —CH(CH) CO. NH-CH , N (CHR22)-C N-K -CH=CH=CO. NH-(CH) , – NH-, - O , (S)- —S— a dialkylaminoalkyl-carbonyl or a lower alkoxy 2 Q- ch, carbonyl: US 2009/0042939 A1 Feb. 12, 2009 16

wherein r is an integer of about 1 to about 10; each R’ is 21. The method of claim 8, wherein the cholinesterase independently hydrogen or methyl; K is a phenalkyl or a inhibitor is phenalkyl having a substituent on the phenyl ring; each S is independently a hydrogen, a lower alkyl group hav IVa. ing 1 to 6 carbon atoms or a lower alkoxy group having O 1 to 6 carbonatoms; tisan integer of 1 to 4: q is an integer CHO of about 1 to about 3; with the proviso that (S), can be a CH2 N-CH oHC. methylenedioxy group or an ethylenedioxy group joined to two adjacent carbon atoms of the phenyl ring. CHO 19. The method of claim 8, wherein the cholinesterase inhibitor is 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanon)- 22. The method of claim 8, wherein the cholinesterase 2-yl idenyl)methylpiperidine: 1-benzyl-4-((5-methoxy-1-in inhibitor is a compound of formula VI or a pharmaceutically danon)-2-yl)methylpiperidine: 1-benzyl-4-((5,6-diethoxy-1- acceptable salt thereof: indanon)-2-yl)methylpiperidine; 1-benzyl-4-((5.6- methnylenedioxy-1-indanon)-2-yl)methylpiperidine: 1-(m- VI nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl) O methylpiperidine: 1-cyclohexylmethyl-4-((5,6-dimethoxy 1-indanon)-2-yl)methylpiperidine: 1-(m-fluorobenzyl)-4- CHO CH2 ((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine; w N-CH 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)propylpiperi dine: 1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanon)-2- CHO yl)methylpiperidine: 1-benzyl-4-((5,6-dimethoxy-1-oxoin danon)-2-yl)propenylpiperidine; or a stereoisomer and/or a 23. The method of claim 8, wherein the cholinesterase pharmaceutically acceptable salt thereof. inhibitor is a compound of formula VII or a pharmaceutically 20. The method of claim 8, wherein the cholinesterase acceptable salt thereof: inhibitor is a compound of formula IV or a pharmaceutically acceptable salt thereof: VII O

IV CHO CH2 N-CH CHO CH -O-et-K) CHO 24. The method of claim 8, wherein the cognitive impair CHO ment includes post-stroke aphasia.

c c c c c