N-(2-ARYLETHYL)BENZYLAMINES AS ANTAGONISTS OF THE 5-HT6RECEPTOR
The present invention relates to the field of pharmaceutical and organic chemistry and is concerned with compounds which are antagonists of the 5-HT6 receptor.
The 5-HT6 receptor is a member of the G-protein coupled receptor superfamily of serotonin receptors, and, like the 5-HT4 and 5-HT7 receptors, it is positively coupled to adenylate cyclase.1 The rat 5-HT6 receptor was first cloned in 19932,3 and the cloning of the human homologue, to which it shares a 89% sequence identity, was reported in 1996.4 The localization of 5-HT6 receptors in rat brain has been studied using mRNA quantification by Northern analysis and RT-PCR, immunohistochemistry, and autoradiography.2,3,5,6,7,8 These methods have consistently found high levels of the receptor in olfactory tubercle, hippocampus, striatum, nucleus accumbens, and cortical regions. 5-HT6, receptors are either absent or present in very low levels in peripheral tissues.2,3
To date, there are no known high affinity, selective agonists at the 5-HT6 receptor. Serotonin itself has only moderate affinity for the 5-HT6 receptor (Ki = 65 nM) and the most selective agonist reported to date, N,N-dimethyl-2-ethyl-5-methoxytryptamine, has Ki = 81 nM and only 3.5-fold selectivity versus the 5-HT2A receptor.9
Much of the recent interest in the 5-HT6 receptor is due to the observation that several psychotropic agents are high affinity antagonists at the human 5-HT6 receptor.4,10 These compounds include amitriptyline (Ki = 65 nM) and the atypical antipsychotics clozapine (Ki = 9.5 nM), olanzapine (Ki = 10 nM), and quetiapine (33 nM). None of these compounds, however, are selective. The first selective 5-HT6 receptor antagonists reported are Ro 04-6790 and Ro 63-0563. Their usefulness is limited by their moderate affinity (Ki = 50nM and 12 nM, respectively) and poor pharmacokinetics.11 A series of 5-HT6 receptor antagonists, culminating in SB-271,046, has been reported.12 This compound has high affinity (Ki = 1.2 nM) and selectivity (>200-fold versus >55 receptors, enzymes and ion channels) and is 80% bioavailable. A selective radioligand [125I]-SB-25S,585 has been used for radioligand binding and autoradiographic studies.13'14 These compounds are useful tools for preclinical studies on the 5-HT6 receptor.
The rationale for the use of selective 5-HT6 receptor antagonists to treat cognitive dysfunction is based on three lines of reasoning: the ability of selective 5-HT6 receptor antagonists to modulate cholinergic and glutamatergic neuronal function, clinical studies of the atypical antipsychotics clozapine and olanzapine on cognitive function, the activity of selective 5-HT6 receptor antagonists in animal models of cognitive function.
Selective 5-HT6 receptor antagonists modulate cholinergic and glutamatergic neuronal function. Cholinergic and glutamatergic neuronal systems play important roles in cognitive function. Cholinergic neuronal pathways are known to be important to memory formation and consolidation. Centrally acting anticholinergic agents impair cognitive function in animal and dimcal studies and loss of cholinergic neurons is one of the hallmarks of Alzheimer's disease Conversely, stimulation of cholinergic function has been known to improve cognitive performance and the only two agents currently approved for the treatment of cognitive deficit in Alzheimer's disease, tacrine and donepezil, are both acetylcholinesterase inhibitors. The glutamatergic system in the prefrontal cortex is also known to be involved in cognitive function.26'27
form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention may be determined by a person skilled in the art.
The tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations typically contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 90% of the weight thereof. The amount of the compound of

formula I and II present in such compositions is such that a suitable dosage will be obtained. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations are able to be determined by one skilled in the art.
The compounds of the present invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment, or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bees wax, mineral oil, diluents such as water and alcohol, and emulsifiers, and stabilizers. Topical formulations may contain a concentration of the formula I and II or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).
The compounds of formula I and II are antagonists of 5-HT6 receptors. Such antagonism can be identified by the methods below.
Example A Assay for 5HT6 binding
The assay buffer used is 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl, 5 mM MgC12, 1 mM EDTA. The radioligand used is 3H - LSD from New England Nuclear Cat. # NET 638 -75.9 Ci/mmol. The membranes used are from Receptor Biology, Cat. No. RB-HS6. These are membranes from HEK-293 cells expressing the Human 5HT6 receptor.
Test compounds are obtained as 10 mM stocks in 100% DMSO. They are diluted to 1 mM in 100% DMSO by adding 180 ?l DMSO to 20 ?l of stock in 96 well plates using a multidrop. The 1 mM stocks are then diluted to make an 11 point concentration range from 125 ?M down to 1.25 nM in half log increments using 10% DMSO as diluent. This is done using a TECAN robot. The final DMSO at this stage is 21.25%.
Radioligand is diluted in assay buffer to make a 125 nM solution and each vial of membranes is diluted up to 92 mL in assay buffer. The final assay volume is 250 ?l consisting of 210 ?l of diluted membranes, 20 ?l of compound or 21.25% DMSO for total binding, and 20 ?l of diluted radioligand. The compounds are transferred from drug dilution plates into coming 96 well assay plates using a 96 well Multimek pipettor.

Radioligand and membranes are added to assay plates using multidrop pipettors. Nonspecific binding is determined in wells containing a final serotonin concentration of 10 ?M. In the final assay volume the radioligand is 10 nM and the membrane protein is approximately 25 fig/well. The final drug concentration range in half logs is from 10 ?M down to 0.1 nM. The final DMSO in the assay is 1.7%.
After addition of drug, membrane, and ligand, the plates are incubated for one hour at room temperature. During this time 96 well Millipore filter plates (MAFBNOB50) are soaked for a least 30 minutes with 200 ul per well of 0.5% polyethyleneimine.
The 0.5% PEI is removed from filterplate wells using a TiterTek MAP aspirator and 200 ul of the incubation mixture is transferred from the incubation plate to the filterplate after mixing. This transfer is done using the 96 tip Mutimek pipettor. After transfer to the filterplate filterplates are extracted and washed twice with 220 ?l per well of cold buffer on the MAP aspirator. The peel away bottoms are removed from the filterplates and 100 ?l per well of microscint 20 scintillation fluid is added per well using a multidrop. Plates are placed into suitable holders and are left at room temperature for three hours and are counted for 3H in either a Wallac Microbeta counter or on a Packard Topcount.
In one embodiment, the present invention provides methods of treating disorders associated with the 5-HT6 receptor, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Thus, the present invention contemplates the various disorders described to be treated herein and others which can be treated by such antagonists as arc appreciated by those skilled in the art
In particular, because of their ability to antagonize the 5-HT6 receptor, it is recognized that the compounds of the present invention are useful for treating cognitive disorders, that is, disorders involving cognitive deficits. A number of the disorders which can be treated by 5-HT6 antagonists are known according to established and accepted classifications, while others are not.
Some of the disorders to be treated according to the present invention are not well categorized and classified because cognition is a complicated and sometimes poorly defined phenomenon. It is, however, widely recognized that cognition includes various "domains." These domains include short term memory, long term memory, working memory, executive function, and attention.
While many of the disorders which can be treated according to the present invention are not uniformly described and classified in the art, it is understood that the compounds of the present invention are useful for treatment of disorders characterized by a deficit in any of the cognitive domains listed above or in other aspects of cognition. Thus the term "cognitive disorders" is meant to encompass any disorder characterized by

a deficit in one or more cognitive domain, including but not limited to short term memory, long term memory, working memory, executive function, and attention.
One cognitive disorder to be treated by the present invention is age-related cognitive decline. This disorder is not well defined, but includes decline in the cognitive domains, particularly the memory and attention domains, which accompany aging. Another is mild cognitive impairment. Again, this disorder is not well defined in the art, but involves decline in the cognitive domains, and is believed to represent a group of patients the majority of which have incipient Alzheimer's disease. Also, a wide variety of insults, including stroke, ischemia, hypoxia, inflammation, and infectious processes can result in cognitive deficits as a sequella which can be treated according to the present invention.
Where the disorders which can be treated by 5-HT6 antagonists are, at present, known according to established and accepted classifications, these classifications can be found in various sources. For example, at present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-TV™) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool for identifying many of the disorders described herein. Also, the International Classification of Diseases, Tenth Revision, (1CD-10) provides classifications for many of the disorders described herein. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for disorders described herein, including those not well characterized by the art and those described in the DMS-IV and ICD-10, and that terminology and classification systems evolve with medical scientific progress.
In one embodiment, the present invention provides methods of treating disorders selected from the group consisting of: age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's Chorea, cognitive deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac aiTest, and hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic lateral sclerosis, and multiple sclerosis, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or n. That is, the present

invention provides for the use of a compound of formula I and II or pharmaceutical composition thereof for the treatment disorders associated with the 5-HT6 receptor.
It is recognized that the terms "treatment" and "treating" are intended to include improvement of the cognitive deficit associated with each of the disorders associated with the 5-HT6 receptor described herein. Also, it is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient believed to be susceptible to such disorders with an effective amount of the compound of formula I. Thus, the terms "treatment" and "treating" are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all symptoms, and is intended to include prophylactic treatment of such disorders. For example, the present invention specifically encompasses the treatment of the cognitive deficits associated with schizophrenia, stroke, Alzheimer's disease, and the other disorders described herein. Thus, it is understood that the present invention includes adjunctive treatment of the disorders described herein. More specifically, the compounds of formula I and II are useful to treat cognition disorders in combination with a wide variety of therapeutic agents, in particular, in combination with AMP A potentiators; with typical and atypical antipsychotics, including olanzapine; with a variety of agents such as mGluR agonists, with NMDA antagonists, with IL 1-6 inhibitors, and the like; with cholinergics, including cholinesterase inhibitors, such as tacrine and donepezil, and compounds that inhibit amyloid protein processing, including inhibitors of amyloid precursor protein processing and antibodies directed against amyloid proteins; with antidepressants, including SSRIs; and with anxiolytic agents; etc. It is believed that the combinations above are synergistically beneficial providing efficacy at doses that are a small fraction of those required to produce the same effect with the individual components.
As used herein, the term "patient" refers to a warm blooded animal such as a mammal which is afflicted with one or more disorders associated with the 5-HT6 receptor. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, pigs, and humans are examples of animals within the scope of the meaning of the term.
As used herein, the term "effective amount" of a compound of formula I or II refers to an amount, that is, the dosage which is effective in treating the disorders described herein.
An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining an effective amount, the dose of a compound of formula I, a number of factors are considered by the attending

diagnostician, including, but not limited to: the compound of formula I or II to be administered; the co-administration of other therapies, if used; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.
An effective amount of a compound of formula I and II is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are able to be determined by one skilled in the art.
Of the disorders to be treated according to the present invention a number are particularly preferred.
In a preferred embodiment the present invention provides a method of treating cognitive disorders, comprising: administering to a patient in need thereof an effective amount of a compound of Claim 1.
In another preferred embodiment the present invention provides a method for treating Alzheimer's disease, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
In a preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including schizophrenia and related disorders, all of which are understood to be specifically included in the scope of this invention.
In a preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or II or a pharmaceutical composition thereof.
In one of the available sources of diagnostic tools, Dorland's Medical Dictionary (23rd Ed., 1982, W. B. Saunders Company, Philadelphia, PA), migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia. As used herein the term "migraine" includes to these periodic headaches, both temporal and unilateral, the associated irritability, nausea, vomiting, constipation or diarrhea, photophobia, and other associated symptoms. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric

disorders, including migraine, and that these systems evolve with medical scientific progress.
In a preferred embodiment the present invention provides a method for treating anxiety disorders, including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, D.C), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein the term "anxiety" includes treatment of those anxiety disorders and related disorders as specifically described in the DSM-IV and the term "anxiety" is intended to include like disorders that are described in other diagnostic sources.
A number of preclinical laboratory animal models have been described for the disorders described herein.
Example B Fear Potentiated Startle Paradigm
Male Sprague-Dawley rats weighing 325-400 g were purchased from Harlan Sprague-Dawley, Inc. (Cumberland, IN) and given a one week acclimation period before testing. Rats were individually housed with food and water ad libitum in an animal room on a 12-hour light/dark cycle with lights on between 6:00 AJM. and 6:00 P.M. The compound of Example 16 was prepared in a suspension of 5% ethanol, 0.5% CMC, 0.5% Tween 80 and 99% water. 2S-2-amino-2-(lS,2S-2-carboxvcyclopropan-l-yl)-3-(xanth-9-yl) propionic acid was prepared in sterile water. Control rats were given the respective vehicle.
The fear potentiated startle paradigm is conducted over three consecutive days. All three days begin with a 5-minute adaptation period before the trial starts. On day one (baseline startle) after the adaptation period, the animal receives 30 trials of 120dB auditory noise. The mean startle amplitude (Vmax) is used to assign animals to groups with similar means before conditioning begins. Day two consists of conditioning the animals. Each animal receives 0.5 mA of shock for 500 msec preceded by a 5 second presentation of light which remains on for the duration of the shock. Ten presentations of the light and

shock are administered. Day three is the testing trial where drug administration occurs prior to testing. Twenty-four hours after conditioning, startle testing sessions are conducted. Ten trials of acoustic startle (120 dB), non-light paired, are presented at the beginning of the session. This is followed by 20 random trials of the noise alone and 20 random trials of noise preceded by light. Excluding the first 10 trials, the startle response amplitudes for each trial type are averaged for each animal. Data is presented as the difference between light + noise and noise-alone. Differences in startle response amplitudes were analyzed by Jmp statistical software using a One-way Anova (analysis of variance, t-test). Group differences were considered to be significant at p<0.05.
The radial arm maze model can be used as a model of cognition and can be used to evaluate the present compounds.
Example C Radial Arm Maze
The delayed non-match to sample task has been used to study the effect of drugs on memory retention (Pussinen, R. and Sirvio, J. J of Psychopharm 13:171-179(1999); Staubli, U., et al. Proc Natl Acad Sci 91:777-781(1994)) in the eight arm radial maze.
Well-trained rats were allowed to retrieve food rewards from four randomly selected arms of the maze (sampling phase). Some time later, the rats were exposed to eight open arms and were tested for their ability to remember and avoid the arms they had previously entered to obtain food. Re-entry into an arm that was baited during the sampling session was counted as a reference error, whereas entry into the same arm more than once during the retention session was counted as working error. The total (reference + working) number of errors made during the retention test increases with increasing delay periods. For example, young male rats made 0.66 (+ 0.4) errors at a 1 minute delay, 2 (+ 0.5) errors at a one hour delay, and 3.95 (+ 0.2) errors at a seven hour delay (observations of this lab).
Male Sprague-Dawley rats were individually housed and maintained on a 12h light-dark cycle (lights on at 6 am). The rats were given free access to water and maintained at 85% of their free-feeding weight by supplemental feedings of Purina Lab Chow.
The rats were initially trained to search for food at the end of each of the eight arms. Once the rats had reached the criteria of no more than two errors (i.e. entering the same arm more than once during a session) on three consecutive days, a delay of one minute was imposed between the fourth and the fifth arm choices. This training ensured that the rats were thoroughly familiar with the procedural aspects of the task before any drugs were administered. Once stable performance had been obtained on the delay task

(i.e. no more than one error was made on three consecutive days), drug and vehicle tests commenced using a seven hour delay period. A novel set of arms was baited each day for each rat and the maze was thoroughly cleaned during the delay period.
During the sampling session, each rat was placed on the center platform with access to all eight arms of the maze blocked. Four of the eight arms were randomly selected and baited with food. The gates of the baited arms were raised and the rat was allowed five minutes to obtain the food at the end of each of the four arms. As soon as the rat had obtained the food, it was removed, administered vehicle or various doses of compounds, and placed back in its home cage. Seven hours later (retention session), the rat was placed back onto the center platform with access to all eight arms blocked. The four arms that were previously baited during the sampling session, were baited and the gates to all eight arms were raised. The rat was allowed five minutes to obtain the remaining four pieces of food. An entry into a non-baited arm or a re-entry into a previously visited arm was counted as an error. Significance (p<0.05) was determined using a repeated measure ANOVA followed by a Dunnett's test for comparison with control.
In order to compare test compounds with standards, scopolamine and tacrine were administered s.c. immediately after the sampling phase. The effects of scopolamine, a known amnesic, were tested after a three-hour delay, whereas the effect of tacrine, a cholinesterase inhibitor used in the treatment of Alzheimer's disease was tested after a six-hour delay. Scopolamine disrupted retention after a three-hour delay in a dose-related fashion. Tacrine significantly improved retention after a six-hour delay at 10, but not at 3 mg/kg.
Example D Acquisition in the Radial Maze 8-arm radial maze acquisition
A prominent early feature of Alzheimer's disease (AD) symptomology is a pronounced deficit in declarative memory (R.W. Parks, R.F. Zee & R.S. Wilson (Eds.), Neuropsychology of Alzheimer's disease and other dementias. NY: Oxford University Press pp. 3-80 (1993).
As the disease progresses, other domains of cognition become severely affected as well. Among the brain regions affected early in the progression of AD is the hippocampus, which is a critical neural substrate for declarative memory (West M.J., Coleman P.D., Flood D.G. & Troncoso J.C.. Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer's disease. Lancet, 344: 769-772(1994). One behavioral test that is often used to assess hippocampal function in animal models is the

8-ann radial maze (Olton D.S. The radial arm maze as a tool in behavioral pharmacology. Physiology & Behavior, 40: 793-797 (1986)).
Lesions or pharmacological blockade of the hippocampus disrupt performance of this task. Moreover, aged animals generally show deficits in this task (Porsolt R.D., Roux S. & Wettstein J.G. Animal models of dementia. Drug Development Research, 35:214-229(1995)).
In this test of spatial learning and memory, a hungry rat is placed in the center of the maze and allowed to traverse the maze in search of food located at the end of each runway arm. In this version of the maze, the rat learns a win-shift strategy in which a visited arm is not replaced. Therefore, the most efficient foraging strategy is to visit each arm once. The version of the maze also taps into general learning processes as the rat is naive to the maze on day one of the four day experiment.
Upon arrival, male Sprague Dawley®, rats were individually housed in a regular light-cycle colony room and allowed to acclimate for at least 4 days prior to testing. Each rat was reduced to and maintained at 85% of their target body weight throughout the experiment. Proper body weight was maintained by adjusting the allotment of lab chow based on a combination of age and the rat's daily bodyweight reading.
A session began with an individual rat being placed into the hub of the maze and then all guillotine doors were raised, allowing free access to all areas of the maze. A food hopper was located at the end of each of the 8 runway arms and a single food pellet was placed in each food hopper. Each daily session terminated when either all 8 food-hoppers had been visited or when the rat timed out (15 min on Day 1:5 min on Days 2-4). The number of arm entries was recorded. Errors were counted as repeat arm entries or failures to visit an arm in the session period. An animal was excluded from the study if it failed to visit at least one arm on Day 1,2 arms on Day 2, and at least 4 arms on Days 3 & 4.
Each rat was pseudo-randomly assigned to either a vehicle or drug group and received the same treatment throughout the experimental period. Vehicle consisted of 5% acacia within sterile water. Injections were administered subcutaneously 20-30 minutes prior to each daily session.
In this acquisition task, vehicle-treated animals do not consistently show significant acquisition of maze learning as compared to the number of errors committed on Day 1. We have found that in compounds that facilitate acquisition of maze learning, the effects are often not observed until the fourth day of training- Therefore, results consisted of total Day 4 errors across treatment groups.

We Claim:
A compound of the formula
formula I wherein
X is selected from the group consisting of-O-, -NH-, -S-, -SO2-, -CH2-, -CH(F)-, -CH(OH)-, and -C(O)-;
R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused;
R2 is selected from the group consisting of hydrogen and C1-C3 alkyl; R3 is selected from the group consisting of hydrogen, fluoro, and methyl;
R4 is selected from the group consisting of hydrogen, allyl, C2-C4 alkyl, fluorinated C2-C4 alkyl, optionally substituted phenyl, napthyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that R4 is not optionally substituted phenylsulfonyl when X is -SO2-, -CH2-, CH(F)-, -CH(OH)-, or -C(O)-;
wherein
"optionally substituted phenyl" means a radical of the formula
wherein Ra is from 1 to 3 groups independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, halogen, benzyloxy, carboxy, C1-C4 alkoxycarbonyl, amido, N-(C1-C4 alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl;

"optionally substituted naphthyl" means a radical of the formula
wherein Rc is from 1 to 2 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, and nitro;
"optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused" means radicals of the formula
wherein Q1 is selected from the group consisting of-O-, -S-, and -NRg- wherein Rg is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q2 is -N=, Rd, each Re, and Rf are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyaho, and trifluoromethyl, or Rj and Re (or one of Re) are taken together with the atoms to which they are attached to form an benzo ring which benzo ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen, carboxy, C1-C4 alkoxycarbonyl, amido, N-(C1-C4 alkyl)amido, amino, (C1-C4 alkyl)amino, acylamino wherein the acyl group is selected from the group consisting of C1-C4 alkyl and phenyl; cyano, nitro, sulfonylamido, phenyl unsubstituted or substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; phenoxy, benzyloxy, -NHS(O)2Rh, wherein Rh is selected from the group consisting of C1-C4 alkyl and phenyl; and -S(O)pRi, wherein p is 0, 1, or 2 and Rj is selected from the group consisting of C1-C4 alkyl and phenyl unsubstituted or substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; and Rf is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, and halogen;
"optionally substituted phenylsulfonyl" means a radical of the formula
wherein Rj is from 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, nitro, and phenyl;
"optionally substituted benzyl" means a radical of the formula
wherein Rk is from 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro, trifluoromethyl, and halogen;
"optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur" refers to radicals of the formula
wherein Q3 is selected from the group consisting of -O-,-S-, and -NRg- wherein Rg- is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q4 and Q5 ate -CRm, wherein each Rm is independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and trifluoromethyl or one or both of Q4 and Q5 is -N=; and wherein one or two of Q6 are -N=, while the others are -CRn; wherein each Rn is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitra, and trifluoromethyl.
and pharmaceutically acceptable salts thereof; other than 3-ethoxybenzyl-[2-(4-ethoxyphenyl)ethyl]amine, 3-ethoxybenzyl-[2-(3-ethoxyphenyl)ethyl]amine, 3-ethoxybenzyl-[2-(2-ethoxyphenyl)ethyl]amine and N-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenoxybenzylamine.
2. A compound as claimed in claim 1, wherein X is selected from the group consisting
of-O-and-NH-.
3. A compound as claimed in claim 2, wherein X is -O-
4. A compound as claimed in claim 3, wherein R3 is hydrogen.
2.
5. A compound as claimed in claim 4, wherein R4 is selected from the group consisting of
C2-C4 fluorinated alkyl and optionally substituted phenyl.
6. A compound as claimed in claim 5, wherein R1 is selected from the group consisting of
optionally substituted phenyl and optionally substituted 5 to 6 membered monocyclic aromatic
heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and
sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused.
7. A compound as claimed in claim 6, wherein Ri is optionally substituted phenyl.
8. A compound as claimed in claim 6, wherein Rj is optionally substituted 5 to 6 membered
monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of
nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is
benzofused.
9. A compound as claimed in claim 8, wherein the benzofused 5 to 6 membered monocyclic
aromatic heterocycle is optionally substituted indol-3.
10. A compound as claimed in any one of claims 7 to 9, wherein R4 is optionally substituted
phenyl.
11. A compound as claimed in any one of claims 7 to 9, wherein R4 is C2-C4 fluorinated
alkyl.
12. A compound as claimed in claim 1, wherein the compound is N-(2-(6-Fluoro-IH-indol-3-
yl)ethyl)3-(2,2,3,3 -tetrafluoropropoxy)benzylamine.
13. A compound as claimed in claim 1, wherein the compound is N-(2-(6-Fluoro-1H-indol-
3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride.
14. A pharmaceutical composition comprising a compound as claimed in anyone of claims 1-
13 and a pharmaceutically acceptable diluent.
N-(2-ARYLETHYL) BENZYLAMINES AS ANTAGONISTS OF THE 5-HT6
RECEPTOR
The present invention provides compounds of formula (I), which are antagonists of the 5-HT6 Receptor.