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US20020099076A1 - Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis - Google Patents

Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis Download PDF

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Publication number
US20020099076A1
US20020099076A1 US09/861,980 US86198001A US2002099076A1 US 20020099076 A1 US20020099076 A1 US 20020099076A1 US 86198001 A US86198001 A US 86198001A US 2002099076 A1 US2002099076 A1 US 2002099076A1
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ethyl
fluorophenyl
dimethoxyphenyl
acid
dementia
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Scheyer Richard
Stephen Sorensen
Janice Hitchcock
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Priority to US10/217,843 priority patent/US20030036553A1/en
Priority to US10/838,035 priority patent/US7132433B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Dementias are neurodegenerative diseases characterized by learning and cognitive deficiencies and are typically accompanied by Behavioral Symptoms, Psychological Symptoms and Motor Symptoms. Dementias include Alzheimer's disease, Lewy Body Dementia, Vascular Dementia, Dementia in Parkinson's Disease, Fronto-Temporal Dementia, Pick's Disease and Corticobasal Degeneration.
  • Alzheimer's disease accounting for 50-60% of cases, is the most common form of dementia.
  • the second most common form was believed to be vascular dementia.
  • Dementia with Lewy bodies (DLB) is a recently identified form that may account for a substantial number of cases, and now is proposed to be the second most common type of dementia ( Pharmacotherapy (1999) 19(7): 795-803 at 795; J Neural Transm (1998)[Suppl] 54:107-116 at 107).
  • Lewy bodies are spherical inclusion bodies seen in the brain stem nuclei of patients with Parkinson's disease. Recently, they were identified in cerebral and limbic cortices as well. Lewy bodies predominantly contain neurofilaments and other proteins such as ubiquitin. The origin of their development is unknown.
  • Alzheimer's disease and DLB can be distinguished at the molecular level and through clinical observation.
  • Alzheimer's disease is characterized by deposits of amyloid protein and hyperphosphorylation of the microtubular associated protein tau, and DLB by neurofilament abnormalities including phosphorylation, ubiquitination, proteolysis, and cross-linking of constitutent proteins.
  • the two diseases appear therefore to be distinct at an ultrastructural and molecular level, a conclusion which is consistent with the fact that the clinical syndromes associated with DLB and Alzheimer's disease are sufficiently differentiated to allow for accurate antemortem diagnosis ( J Neural Transm (1998)[Suppl] 54:107-116 at 107).
  • Parkinsonian motor features are typically mild, spontaneous features such as bradykinesia and rigidity. Masked faces, hypophonia and a slow shuffling gait are also common. Patients treated with levodopa respond poorly and the drug can exacerbate or cause hallucinations ( Pharmacotherapy 1999: 19(7) 795-803 at 796).
  • Parkinson's disease patients with Parkinson's disease often develop dementia as the disease progresses, and hallucinations are a common side effect of levodopa therapy (“dopamine induced psychosis”). If the onsets of dementia and Parkinson's symptoms occur within 12 months of each other, a diagnosis of DLB can be made. The symptoms of myoclonus, absence of rest tremor, lack of response to levodopa, or no perceived need to administer levodopa are 10 times more likely in DLB than in Parkinson's disease Id. at 798. Since the compounds of the present invention have very little activity at the dopamine receptor (unlike some other 5HT 2A antagonists), these compounds are useful in treating patients susceptible to dopamine induced psychosis.
  • Pick's Disease is a dementing disorder primarily involving the frontal and temporal lobes. It is characterized clinically by an insidious mid-life onset (50-65 years of age) of personality and behavioral changes, disinhibition, impairment of language function and decline in memory and intellect. NEUROPATHY OF DEMENTING DISORDERS, Wm. R. Markesberry, MD, editor, Arnold, Hodder Headline.
  • Fronto-Temperoral dementia is a dementing disorder characterized by degeneration of the frontal and anterior temporal lobe.
  • Corticobasal degeneration is a dementing disorder which is predominantly an extrapyramidal motor disorder.
  • Behavioral symptoms such as sleep disturbances, delirium (including fluctuations), aggression and agitation;
  • d) Learning and cognitive impairment for example, impaired ability to learn new information or to recall previously learned information (e.g., impaired social memory), aphasia, apraxia, agnosia, disturbance in executive functioning, etc.
  • a compound of the present invention (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, or its pharmaceutically acceptable salt, is a potent antagonist at the serotonin 5HT 2A receptor ( J. Pharm. Exp. Ther. (1996) 277:968-9881) incorporated herein by reference. It was described in U.S. Pat. No. 5,134,149, incorporated herein by reference.
  • compositions of the present invention include prodrugs of (+)- ⁇ -(2,3-dimethoxyphenyl)- 1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, or its pharmaceutically acceptable salt, which mean that a compound is administered which is different from (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol but (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol becomes available in the body after metabolism.
  • Prodrug has the specific meaning of the compounds disclosed in U.S. Pat. No. 6,028,083, incorporated herein by reference, shown hereafter as Formula II:
  • R is C 1 -C 20 alkyl, or a stereoisomer or a pharmaceutically acceptable salt thereof.
  • Alkyl means a branched or straight chain alkyl group specified by the amount of carbons in the alkyl group, e.g., C 1 -C 20 alkyl means one, two, three, four, five, six, seven, eight, nine, ten eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty carbon branched or straight chain alkyl or ranges thereof, for example, but not limited to C 1 -C 15 , C 5 -C 20 , C 3 -C 15 , C 5 -C 15 , C 7 -C 15 and C 7 to C 9 .
  • (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol antagonizes the effects of serotonin at the 5HT 2A receptor and thus is useful for treating a variety of conditions.
  • Some of the uses for (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol have been disclosed in patents and patent applications.
  • 5,169,096 claimed compounds having a generic scope which encompassed the (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and disclosed uses of the treatment of anorexia nervosa, variant angina, Raynaud's phenomenon, coronary vasospasms, prophylactic treatment of migraine, cardiovascular diseases such as hypertension, peripheral vascular disease, thrombotic episodes, cardiopulmonary emergencies and arrythmias, and has anesthetic properties. See also U.S. Pat. Nos. 4,783,471; 4,912,117; and 5,021,428, which are divisions of U.S. Pat. No. 5,169,096.
  • “Pharmaceutically acceptable salts” means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the present invention.
  • “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points.
  • “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides
  • ammonia and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline.
  • the selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • “Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
  • Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • “Therapeutically effective amount” means an amount of the compound which is effective in treating the named disorder or condition.
  • “Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
  • a pharmaceutical composition i.e., a dosage form capable of administration to the patient.
  • a pharmaceutically acceptable oil typically used for parenteral administration.
  • “Sleep Disturbances” means fragmented sleep, narcolepsy and “REM” or “Rapid Eye Movement” behavior disorder, restless legs and/or periodic limb movements.
  • EPS EPS
  • Extrapyramidal symptoms are symptoms which may manifest upon administration of neuroleptic drugs.
  • the symptoms include a parkinsonian-like syndrome wherein the patient experiences muscular rigidity and tremors. Some experience akathesia and acute dystonic reactions.
  • Stepoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • M100907 means (+)-isomer of -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
  • (+)-isomer of -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be prepared by methods described in U.S. Pat. No. 5,134,149. One suitable method follows.
  • Step A of Reaction Scheme I an esterification reaction is carried out between racemic alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (structure 1) and the (+)-isomer of alphamethoxyphenylacetic acid (structure 2).
  • This esterification produces the diastereomeric mixture identified as structure 3.
  • These diastereomers are subjected to silica gel chromatography which separates the two diastereomers, thereby isolating the (+,+) diastereomer as is depicted in Step B.
  • Step C the (+,+) diastereomer is hydrolyzed which produces the (+)-isomer of alpha(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
  • the esterification reaction can be carried out using techniques known in the art. Typically approximately equivalent amounts of racemic alpha-(2,3-dimethoxyphenyl)- 1 -[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and the (+)-isomer of alpha-methoxyphenylacetic acid are contacted in an organic solvent such as methylene chloride, THF, chloroform, or toluene and heated to reflux for a period of time ranging from 5 to 24 hours.
  • the esterification is typically carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP).
  • DCC dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • the diastereomers are then subjected to silica gel chromatography which separates the (+,+) and the ( ⁇ ,+) diastereomers. This chromatographic separation may be carried out as is known in the art. A 1:1 mixture of hexane and ethyl acetate is one suitable eluent.
  • the resulting (+,+) diastereomer is then subjected to a hydrolysis reaction which produces the (+)-enantiomer of alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
  • the hydrolysis is carried out by contacting the diastereomer with an excess of a base such as potassium carbonate in an aqueous alcoholic solution.
  • the hydrolysis is carried out at a temperature of about 15 to 30° C. for a period of time ranging from 2 to 24 hours.
  • the resulting (+)-isomer of alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol may then be recovered by dilution with water and extraction with methylene chloride. It is then purified by recrystallization from a solvent system such as cyclohexane/hexane or ethyl acetate/hexane.
  • 4-hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4-hydroxy-1-[2-(4-fluorophenyl)ethyl]-piperidine.
  • This compound is brominated with Ph 3 P ⁇ Br 2 which produces 4-bromo-1-[2-(4-fluorophenyl)ethyl]piperidine.
  • This compound is contacted with Mg thereby forming a Grignard Reagent which is then reacted with 2,3-dimethoxybenzaldehyde which produces the desired product ( ⁇ )-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
  • the (+)-isomer of alphamethoxyphenylacetic acid is known in the art.
  • Scheme II shows the synthesis of the compounds of Formula II, Prodrugs.
  • the alcohol (5) is reacted with an acid halide (RC(O)X), RCO 2 H or acid anhydride (RCO) 2 O in the presence of an a sufficient amount of an appropriate base.
  • An appropriate base is one that permits ester formation from the acid halide or anhydride.
  • Examples of appropriate bases are trialkylamines, pyridine such as dimethylamino pyridine, diisopropyl ethyl amines, N-methyl morpholines, with triethylamine being preferred.
  • a sufficient amount of the base can be ascertained by one skilled in the art which permits the formation of the compounds of Formula I.
  • the base is added to the alcohol (5) and that mixture added dropwise to the acid halide or acid anhydride in an appropriate solvent.
  • appropriate solvents are chloroform, methylene chloride, or toluene, all of which are readily available, with chloroform being preferred.
  • the temperature of the reaction may be at a range of about 0-25° C.
  • the reaction mixture may be stirred for from a few hours to overnight to enhance the reaction.
  • Catalysts may also be added for enhancement of reaction times, e.g., 4-dimethylaminopyridine or the like.
  • the starting materials for the acid halide are readily available for those skilled in the art.
  • Aldrich Chemical company provides stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, myristoyl chloride, isovaleryl chloride, valeryl chloride, hexanoyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride and lauroyl chloride.
  • those acid halides not readily available, one skilled in the art may prepare the acid halide desired.
  • a carboxylic acid may be mixed with a halide donor to produce the desired acid halide.
  • a halide donor for example, a carboxylic acid may be mixed with a halide donor to produce the desired acid halide.
  • carboxylic acid (0.17 mol), methylene chloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogen atmosphere.
  • oxalyl chloride 0.2 mol
  • Another method is to dissolve the carboxylic acid (10 mmol) in methylene chloride (50 mL). Cool to 0° C., place under a nitrogen atmosphere and add, by dropwise addition, thionyl chloride (11 mmol). Stir at room temperature for several hours and evaporate the volatiles in vacuo to give the acid chloride.
  • the carboxylic acids are readily available or can be easily made by those skilled in the art.
  • the starting materials for the acid anhydrides (RCO) 2 O are readily available for those skilled in the art.
  • Aldrich Chemical company provides butryic anhydride, isobutyric anhydride, valeric anhydride, 2-2,dimethylglutaric anhydride, and phthalic anhydride.
  • acid anhydrides may be synthesized by methods well known in the art.
  • RCO 2 H The starting materials for the acids (RCO 2 H) are readily available or may be synthesized by methods well know in the art. For example, see Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons,, New York 1992, incorporated herein by reference.
  • Aldrich Chemical Company also provides isovaleric acid, valeric acid, tert-butylacetic acid, 2, 2dimethylbutyric acid, 2-ethylbutyric acid, hexanoic acid, 3-methylvaleric acid, 4-methylvaleric acid, heptanoic acid, octanoic acid, 2-propylpentanoic acid, nanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristoleic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid.
  • Example 1 demonstrates the preparation of the starting material ( ⁇ )-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, structure 1, Scheme I.
  • Example 2 demonstrate an alternative manner of preparing ( ⁇ )-alpha(2,3-dimethoxyphenyl)- 1 - [2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol, structure 1.
  • the compound of the present invention can be shown to be effective by clinical trials in humans and certain behavioral tests in animals.
  • SDASD Senile Dementia Associated Sleep Disorder
  • Cacabelos Cacabelos
  • Laredo Laredo
  • Couceiro Alvarez 1 999(incorporated herein by reference).
  • sleep disturbances such as initial insomnia, nocturnal sleep disruption, delayed insomnia, fragmented sleep patterns, etc.
  • Locomotor activity was recorded for 60 min in the activity counter, which was equipped with 15 photoelectric light sources spaced at 2 cm intervals and 1 cm above the floor. Each interruption of a photoelectric light beam was recorded as a single activity count by a microprocessor-based control system. Testing took place between 10:00 a.m. and 5:00 p.m., with all groups counterbalanced for time of testing. The experimenter was blind to treatment group during the experiment.
  • M100907 Group means of 60 min activity count totals +/ ⁇ SEM Treatment n MEAN +/ ⁇ SEM VEH + VEH 6 1687 457 VEH + SOOP 0.75 6 5753 1386 # M100907 0.03 + SCOP 0.75 6 3181 804 * M100907 0.1 + SCOP 0.75 6 2378 306 * M100907 0.3 + SCOP 0.75 6 2087 752 * M100907 1 + SCOP 0.75 6 2231 737 *
  • M100907 (0.1 and 1 mg/kg) significantly enhanced social memory in mice.
  • vehicle or M100907 (0.01, 0.1 or 1 mg/kg p.o.) 2 hours prior to their baseline test.
  • unfamiliar pairs of mice were placed into a test chamber (plexiglas mouse cage with sawdust bedding). The duration of social interaction of the two mice (sniffing, anogenital exploration, nosing, grooming, licking, pawing, playing copulatory attempts) was observed and recorded for a period of five minutes and was registered cumulatively as total seconds of contact. Twenty-four hours later, the animals were given a retest without any drug treatment.
  • the dosage range at which the compounds of Formula I exhibit their ability treat patients with DLB depends upon the severity of the disease, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally, the compounds of Formula I will exhibit their therapeutic activities between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
  • the dosage of the compounds of the present invention may be determined by administering the compound to an animal and determining the plasma level of the active ingredient by known procedures.
  • the compound of the present invention can be formulated into pharmaceutical dosage forms using techniques well known in the art.
  • the compound can be formulated into solid or liquid preparation such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions.
  • the compound or its salts may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetable, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art.

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US09/861,980 2000-05-25 2001-05-18 Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis Abandoned US20020099076A1 (en)

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Application Number Priority Date Filing Date Title
US09/861,980 US20020099076A1 (en) 2000-05-25 2001-05-18 Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis
US10/217,843 US20030036553A1 (en) 2000-05-25 2002-08-13 Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis
US10/838,035 US7132433B2 (en) 2000-05-25 2004-05-03 Use of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol or its prodrug in the treatment of behavioral or psychological symptoms associated with a disease

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US09/861,980 US20020099076A1 (en) 2000-05-25 2001-05-18 Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis

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US10/217,843 Abandoned US20030036553A1 (en) 2000-05-25 2002-08-13 Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis
US10/838,035 Expired - Fee Related US7132433B2 (en) 2000-05-25 2004-05-03 Use of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol or its prodrug in the treatment of behavioral or psychological symptoms associated with a disease

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US10/838,035 Expired - Fee Related US7132433B2 (en) 2000-05-25 2004-05-03 Use of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol or its prodrug in the treatment of behavioral or psychological symptoms associated with a disease

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WO2001089498A2 (en) 2001-11-29
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US20040204457A1 (en) 2004-10-14
NO20025630D0 (no) 2002-11-22
AU2001264842B2 (en) 2005-01-27
CN1436078A (zh) 2003-08-13
EP1289527B1 (de) 2008-03-26
KR100784655B1 (ko) 2007-12-12
IL152908A0 (en) 2003-06-24
JP2003535058A (ja) 2003-11-25
KR20030034078A (ko) 2003-05-01
MXPA02011511A (es) 2003-04-25
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DE60133385D1 (de) 2008-05-08
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EP1289527A2 (de) 2003-03-12
US20030036553A1 (en) 2003-02-20
AR029666A1 (es) 2003-07-10
TWI299001B (en) 2008-07-21
US7132433B2 (en) 2006-11-07
BR0111102A (pt) 2003-03-11
AU6484201A (en) 2001-12-03
PL359176A1 (en) 2004-08-23
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