NZ504733A - Method of treating tic disorders in non-human mammals - Google Patents

Abstract

A method of treating Tourette's syndrome, obsessive compulsive disorder, chronic motor or vocal tic disorder in a non-human mammal comprising the administration of a pharmaceutically acceptable form of a piperazinyl-heterocyclic compound of formula (I) as outlined in NZ Patent Application 331742.

Description

New Zealand Paient Spedficaiion for Paient Number 504733 NEW ZEALAND PATENTS ACT, 1953 No. Divided out of NZ 331742 Date: Dated 4 September 1998 COMPLETE SPECIFICATION METHOD OF TREATING TOURETTE'S SYNDROME We, PFIZER PRODUCTS INC., a corporation organized under the laws of the A State of Connecticut, USA of Eastern Point Road, Groton, Connecticut 06340, USA, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) PC10001ABTC $0'■ ? 3 j -la- METHOD OF TREATING TOURETTE'S SYNDROME 5 Background of the Invention This application is a divisional of parent application no. 331742 The present invention relates to a method for treating Tourette's syndrome, obsessive compulsive disorder, chronic motor or vocal tic disorder by administering to a non-human patient in need thereof a piperazinyl-heterocyclic compound of formula I, defined below 10 Tourette's syndrome is a chronic neuropsychiatry diiorder of childhood causes that is characterized by multiple motor and vocal ties, somatosensory urges, and behavior problems such as attention deficit hyperactivity disorder, learning disabilities, obsessive compulsive disorder, anxiety and depression gestures and utterances A typical bout is usually of a brief duration that rarely lasts more than a second Motor tics vary from abrupt movements (eye blinking, sudden head jerks and shoulder shrugs) to more complex behaviors such as gestures of the hands or face or a slow sustained head tilt Vocal tics range from simple sniffinq to throat clearing to fragments of words or phrases . The piperazinyl-heterocyclic compounds of formula I of this invention, useful in the treatment of psychotic disorders, are referred to in United States 4,831,031 and 4,883,795, both of which are assigned in common with the present application compulsive disorder, chronic motor or vocal tic disorder in a non-human mammal comprising administering to said mammal an effective amount of a compound of the formula or a pharmaceutical^ acceptable acid addition salt thereof, wherein Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one 30 fluoro, chloro trifluoromethyl, methoxy, cyano, nitro or naphthyl optionally substituted by fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro, quinolyl, 6-hydroxy-8-quinolyl, isoquinolyl, quinazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxazolyl, benzoxazolonyl, indolyl, indanyl optionally substituted by one or two fluoro, 3-indazolyl optionally substituted by 1-trifluoromethylphenyl, or phthalazinyl, n is 1 or 2, and X and Y together with the phenyl to which they are attached form quinolyl, 2-hydroxyquinolyl, benzothiazolyl, 2-aminobenzothiazolyl, benzoisothiazolyl, indazolyl, 2- The range of tic symptoms is enormous and includes sudden repetitive movements, Summary of the Invention The present invention relates to a method for treating Tourette's syndrome, obsessive (I) INTELLECTUAL PROPERTY OFFICE OF NZ. 2 8 SEP 2001 RECEIVED hyaroxymaazolyl inaolyl spiro oxindolyI optionally substituted by one to three of (C ,-C3(ialkyI or ore of cnioro fluoro or phenyl, said phenyl optionally substituted by one chloro or fluoro benzoxazolyl 2-aminobenzoxazolyl, benzoxazolonyl 2-aminobenzoxazolinyl benzothiazolonyl bezoimidazolonyl, or benzotriazolyl The term 'treating", as used herein refers to reversing alleviating, inhibiting the progress 10 of or preventing the disorder or condition to which such term applies or one or more symptoms of such disorders or condition The term 'treatment" as used herein, refers to the act of treating as treating is defined immediately above A preferred embodiment of this invention relates to the above method wherein the cc~pounc administered is used for treating Tourette s synarome 15 Another preferred embodiment of this invention re'ates to the above method wherem the conpounc administered is used for treating obsessive comoulsive disorder Another preferred embodiment of this invents re'ates 'o the above method wherein the ccHDOund administered is used for treating chronic motor tic discraer Another preferred embodiment of this invention re'ates tc the above method wherein the 20 compound administered is used for treating vocal tic disorder Another preferred embodiment of this invention relates to the above method wherein the comDound administered is one wherein X and Y together with the ohenyl to which they are attached form benzoxazolonyl Another preferred embodiment of this invention re'ates to the above method wnerein the 25 comoouno administered is one wherein Ar is Denzoisoth'azolyi and n is 1 Another preferred embodiment of this invention relates to the above method wherein the cornocund administered is one wherein X and Y together with the phenyl to which they are attached form oxindcle optionally substituted by chloro, fluoro or phenyl Another preferred embodiment of this invention relates to the above method wherein the 30 concound administered is one wherein Ar is naohthyl and n is 1 Detailed Description of the Invention The oiperazinyl-heterocyclic compounds of formula I can oe prepared by one or more of the synthetic methods described and referred to in United States Patents 4 831,031 and 4 883 795 United States Patents 4 831 031 and 4 883 7S5 are incorporated herein by reference 35 in t^eir entirety The compounds of formula I may be prepared by reacting piperazines of formula II with compounds of formula III as follows II III wherein Hal is fluoro chloro bromo or lodo This coupling reaction is generally conducted in a pclar solvent sucn as a lower alccnol, for instance ethanol dimethylformamide or methylisobutylketone and in the presence of a weak base such as a tertiary amine base for instance triethylamine or dnsopropylethylamine Preferably, the reaction is in the further presence of a catalytic amount of sodium iodide and a neutralizing agent for hydrochloride such as sodium carbonate The reaction is preferably conducted at the reflux temperature of the solvent used The piperazine derivatives of formula II may be prepared by methods known in the an For instance preparation may be by reacting an arylhalide of the formula ArHal wherein Ar is as defined above and Hal is flucro chloro bromo or lodo with piDerazine in a hydrocarbon sc vent sucn as 'oluene at aDout room temperature to reflux iemoerature for about half an hour to 24 hours Alternatively the compounds cf formula II may be precared by heating an amino-suostituted aryl compound of the formula ArNH; wnerein Ar -s as defined above with a secondary amine to allow cyclization to form the piperaz.ne ring attached to the an/I group Ar Tne compounds of formula III may be preparea by known methods For instance compounds (III) may be preparea by reacting a helo-acetic acid or halo-butyric acid wherein the halogen substituted is fluoro chloro bromo or lodo with a compound of the formula IV as follows wherein X and Y are as defined aDove and m is 1 or 3 The compounds (V) are then reduced e g with tnethylsilane and trifluoroacetic acid m a nitrogen atmosphere to form compounds (III) When Ar is the oxiae or dioxide of benzoisothiazolyl the corresponding benzoisothiazolyl is oxidized unaer acid conditions at low temperatures The acid used is advantageously a mixture of sulphuric acid and nitric acid The pharmaceutical^ acceptable ac.d addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base (I) with aoout one chemical equivalent of a pharmaceutical^ acceptable acid Conventional concentration and recrystallization techniques are employed in isolating the salts Illustrative of suitable acids are acetic lactic succinic maleic, tartaric citric gluconic ascorbic benzoic, IV V cinnamic fumaric sulfuric phosphoric hydrochloric hydrobromic hydroiodic sulfamic sulfonic such as methanesulfonic benzenesulfonic and related acids Compounds of formula I and their pharmaceutical^ acceptable salt (referred to collectvely hereinafter as the active compounds of this invention') can be administered to a human suoject either aione or, preferably in combination with pharmaceutically-acceptable 10 carriers or diluents in a pharmaceutical practice Such compounds can be administered orally or parenterally Parenteral administration includes especially intravenous and intramuscular administration Additionally in a pharmaceutical composition comprising an active compound of this invention the weight ratio of active ingredient to carrier will normally be in the range from 1 6 to 2 1 ana preferably 1 4 to 1 1 However in any given case the ratio chosen will decend on 15 such factors as the solubility of the active component the dosage contemplated and the precise route cf administration For oral use in treating Tourettes syndrome chronic motor or vocal tic disorder the active compounds of this invention can be admimste'ed for example in the form of tablets or capsuies or as an aqueous solution or suscension in the case of taDlets for oral use carriers 20 which can be used include lactose and corn starch and lubricating agents such as magnesium stearate can oe aaded For oral administration in cacsule form useful diluents are lactose and dried corn starch When aaueous suspensions are required for oral use the active ingredient can be combined with emulsifying ana suspending agents If desired certain sweetening and/or flavoring agents can be added For intramuscular and intravenous use sterile solutions of the 25 active .ngredient can be prepared and fhe oH of the solutions should be suitably adjusted and buffered For intravenous use the total concentration of solutes should be controlled to render the preoaration isotonic When an active compound cf this invention is to be used in a human subject to treat Tourettes syndrome obsessive comDulsive disorder chronic motor or vocal tic disorder the 30 daily dosage will normally be determined by the prescribing physician Moreover the dosage will vary according to the age weight and response of the individual Datient as well as the severity of the patient's symptoms However in most instances an effective amount for treating Tourette's syndrome obsessive compulsive disorder chronic motor or vocal tic disorder will be 3 daily dosage ,n the range from 5 to 500 mg and preferably 10 mg a day to 80 mg a day in single or 35 divided doses orally or parenterally In some instances it may oe necessary to use dosages outside these limits The following examples are provided solely for the purpose of further illustration • • EXAMPLE 1 -(2-M-( l-Naphthynpiperazinyl)ethyl)-benzoxazolone A To a 500 Til three-necked round-bottomed flask equipped with mechanical stirrer and nitrogen inlet were added 200 grams of polyphosphoric acid 13 51 grams (0 1 mole) of benzoxazolone and 13 8S g (0 1 mole) of bromoacetic acid The reaction was heated with a* stirring at 115° C for 2 5 hours and poured into 1 kg ice The mixture was stirred mechanically for 1 hour to form a purple scud which was then filtered off and washed with water The solid was slurried with acetone for 30 minutes, a small amount of purple solid filtered off and the brown filtrate evaporated The resulting dark brown gum was slurried with 150 ml ethanol for 30 minutes and the brown sclid filtered off and washed with ethanol This solid had a m p of '92°" 15 194s C The solid (6 6 gratis 0 0257 mole) was placed in a 100 ml three-necked round-bottomed flask equipped with magnetic stirrer dropping funnel thermometer, and nitrogen inlet and 19 15 ml (0 257 mole) of tnfluorcacetic acid added Triethyisilane (9 44 ml 0 0591 mole) was added dropwise to the stirring s jrry over 30 minutes Tne reaction was stirred overnight at room 20 temperature then poured .nto 150 grams ice The mixture was stirred for 15 minutes ana the brown gum filtered off The gum was dissolved in 100 ml ethyl acetate ana 125 ml cyciohexane added giving a brown precioitate which was filtered and washed with cvclohexane The titrate was evaporated and the resulting /ellow solid slurried with 50 ml isopropyi ether the paie yellow solid was filtered off and c;ed to give 2 7 g 5-(2-bromoethyl)-benzoxazolcne (11% yield for two 25 steps) m p 148° 151°C B To a 100 ml rouna-oottomed flask equipped with magnetic stirrer condenser and nitrogen inlet were added 0 618 g (2 10 mmol) of N-(1-naphthyl)piperazine 0 472 g (1 95 mmol) of 6-(2-bromoethvl)-benzoxazoione 0 411 ml (2 92 mmol) of tnethylamine 50 ml ethanol and a catalytic amount of sodium -odioe The reaction was refluxed for 3 days cooled and evaporated 30 to a brown gum The gum was partitioned between 50 ml water and 75 ml methylene chloride the pH adjusted with aqueous 1N sodium hydroxide solution and a little methanol added to facilitate phase separation Tne methylene chloride layer was dried over sodium sulfate and evaporated, then chromatograohed on silica gel Fractions containing the product were combined and evaporated the residue taken ud in ethyi acetate treated with hydrochloride gas, 35 and the resulting hydrocnionoe salt of the oroduct filtered off to give the while solid title compound mp 282° 285;C 213 mg (23% yield) EXAMPLE 2 6-(2-(4-( 1 -NaphthyppiperazinyDethyQ-benzimidazolone A To a 500 ml three-necked round-bottomed flasK equipped with mechanical stirrer and nitrogen inlet were adaed 100 grams of polyprospnoric acid 6 7 grams (0 05 molej of benzoxazoione ana 6 95 grams (0JD5 mole; of bromoacetic acid The reaction was heated with 10 stirring at 115° C for 1 5 hours and poured into 1 kg ice The mixture was stirred mechanically for 1 hour to form a gray solid which was then filtered off and washed with water The solid was slurried with acetone for 30 minutes a small amount of purple solid filtered off, and the brown filtrate evaporated The resulting dark brown gum was taken ud in ethyl acetate/water and the organic layer washed with water and brine dried ard evaporated to solid 6 5 grams (51%) 15 NMR (d DMSO-ds) 5 05 (s 2H), 7 4 (m 1Hj 7 7-8 05 im 2H) Tne solid i6 0 grams 0 0235 mole) //as placed in a 100 ml three-necked round-bottomed f:ask equiDpea witn magnetic stirrer dropping funnel trermome'er and nitrogen inlet and 18 2 ml (0 235 mole) of tr.fuoroacetic acid acdea Tnethyis .ane .3 64 mi 0 0541 mole) was added cropwise to the stirring slurry over 30 mirjtes Trs reaction was stirrea overnight at room 20 temperature then ocured into 150 grams ice The r- xture was stirred for 14 minutes and the pink solid 5-(2-brcmoethyl)-benzimidazolone filtered cf to give 5 0 grams (42% yield for two s'eos) mD 226° 220°C B To a 100 ml round-bottomed flask equipped with magnetic stirrer condenser and nitrogen inlet were aadea 2 64 grams "2 4 mmc of N-( 1 -naphthyD-piperazine 3 0 grams 25 (12 4 mmol; of 6-(2-Dromoethyl)-benz'midazcione 1 2' grams (12 4 mmol) sodium carbonate 50 mi methylisooLtylketcne and a catalyfic amcunt cf see „rr odice The reaction was refiuxed for 3 days cooled and evaporated to a brown gum The gum was oartiticned between 50 ml water and 75 ml ethyl acetate and the ethyl acetate layer wasned with orine dried over sodium sulfate and evaporated, then chromatographed on silica ge1 Fractions containing the product were 30 combined and evaporated the residue taken oo in tetranydrofuran treated with hydrochloric acid gas and the resulting hydrochloride salt of the product Altered off to give a white solid m p 260° 262°C 716 mg (14% yield) EXAMPLE 3 6-(2-;4-< 8-Quinoly 'Oiperazir. >eth /li-cenzoxazolone 35 To a 35 ml round-oottomed fask equicced with condenser and nitrogen inlet were addea 0 36 grams (1 5 mmol) of 6-bromoethyl be^zoxazolore 0 32 grams (1 5 mmol) of 8-piperazinyl quinoline 0 2 grams (1 9 mmol) of sodium carbonate 50 mg of sodium iodide and 5 ml of ethanol The reaction was refiuxed for 20 hours cooled diluted with water and the pH adjusted to 4 with 1N Sodium hydroxide and the product extracted into ethyl acetate The ethyl 40 acetate layer was washed with brine dried and evaporated to give 0 3 grams of a yellow oil Trte oil was dissolved in ethyl acetate ethyl acetate saturated with hydrochloric acid gas added and the mixture concentrated to c^ness The residue was crystallized from jsopropanol to give 3 18 grams (32%) of a yellow salt mp 20C; NMR id CDCI-J 2 74 (m 2H) 2 89 (m, 6H) 3 44 <m 4H) 6 76-7 42 (m 7H) 8 07 > m 1H) 8 83 (m 1H) EXAMPLE 4 6-(2-(4-.6-Quinolyl)piperazinyl)ethyl)-benzoxazolone To a 35 ml round-bottomed flask equipped with condenser and nitrogen inlet were added C 36 grams (15 mmol) of 6-bromoethylbenzoxazolone, 0 32g (15 mmol) of 8-Ciperazinylaumazoline 0 85 grams (8 0 mmol) of sodium carbonate 2 mg of sodium iodide and 35 ml of ethanol The reaction was refiuxed for 3 days cooled diluted with water and the pH adjusted to 4 with 1N HCI The aqueous -ayer was separated the pH aajusted to 7 with 1N Scaium hydroxide and the proc-ct extracted into ethyl acetate The ethyl acetate layer was washed with brine, dried and evaporated to give 1 3 grams of a yeilow oil The oil was crystallized form chloroform (1 " g) dissolved in ethyl acetate ethyl acetate saturated with r/drochlcnc acid gas added anc the mixture concentrated to dryness The residue gave 0 9 grams (58%) of a yellow salt, m p 200° C NMR (d CDCI3) 2 72 (m 6H) 2 86 (m 2H) 3 83 (m 4h; 6 9-7 9 (m 7H) 8 72 (s 1Hi EXAMPLE 5 6-(2-;4-4-Phthalaz nynoiperazinyliethyn-benzoxazo one To a 35 mi round-oottomec flask ecuipped witn condenser and nitrogen inlet were added 1 13 grams (4 7 mmol) or 6-bror_oethyl benzoxazoione 1 0 gram (4 7 mmol) of 4-piperazinyl phthalazine 0 64 grams (6 0 mmc 1 of sodiLm carbonate and 30 ml of ethanol The reaction was refiuxed for 20 hours cooled, diluted with water and the pH adjusted to 4 with IN HCI The aqueous layer was separated, the dH adjusted to 7 with 1N Sodium hydroxide, and the product extracted into ethyl acetate T~e ethyl acetate layer was washed with brine dried and evaporated to give 0 5 grams of a red oil The oil was chromatographec on silica gel using chloroforrrvmethanol as eluent to give 0 2 grams of a pink oil The oil was dissolved in ethyl acetate ethyl acetate saturated witn hydrochloric acid gas added and the mixture concentrated to give 0 37 grams (11%) of a yellow salt mp 200° C NMR (d CDCI3) 2 78 (m 2H), 2 88 (m 6H) 3 65 (m 4H), 7 0-8 1 (m 7H) 9 18 (s 1H) EXAMPLE 6 6-(2-(4-(4-MeLnoxy-1-naphthyl)piperazinyl)ethyl)-benzoxazolone To a 35 ml round-bottomeo flask equipped with condenser and nitrogen inlet were added 0 24 grams (1 0 mmol) of 6-bromcethylbenzoxazolone 0 24 grams (1 0 mmol) of 4-methoxy-1-piperazinylnaphthalene 0 13 grams (1 2 mmol) of sodium carbonate and 25 ml of ethanol The reaction was refiuxed for 36 hours cooled diluted with water and the product extracted into ethyl acetate The ethyl acetate layer was washed with brine dried and evaporated to give 0 49 grams of a yellow oil The oil was chromatographea on silica gel using chloroform as eluent to give 0 36 grams of yellow crystals The solid was dissolved in ethyl acetate ethyl acetate saturated witn hydrochloric acia gas added and the mixture concentrated to dryness to give 0 26 grams (55%' of white salt crystals jn p 200'C NMR (d CDCI3) 2 8-3 2 (m 12H), 4 01 (s 3H), 10 6 7-7 6 (m 7H; 8 25 (m 2H) EXAMPLE 7 6-(2-(4-(5-Tetralinyl)piperazmyl)ethyl)-benzoxazolone To a 35 ml round-bottomed flask equipped with condenser and nitrogen inlet were added 10 gram (3 9 mmol) of 6-Dromoethylbenzoxazolone 0 85 grams (3 9 mmol) of 5-15 piperazinvitetrahn C 4 grams (3 9 mmol) of sodium carDonate 2 mg of sodium iodide and 30 ml of isopropanc: Tne reaction was refiuxed for 18 hours cooled evaporated to dryness and the residue dissolved in ethyl acetate'water Tne pH was adjusted to 2 0 with 1N HCI and the precipitate wmch had formea collected by filtration The precipitate was suspended in ethyl acetate/water the cH adjusted to 8 5 with IN Sodium hydroxide and the ethyl acetate layer 20 separated T^e ethyl acetate laver was washed wit" brine aried ana evaporated to give 0 7 grams of a solid The scud //as dissolved in etH/l acetate ethyl acetate saturated with hydrochloric acid gas added ana the mixture concentrated to dryness to give 0 70 grams (40%) of a yellow sa t m p 200° C NMR'd CDCI-j 1 9 (m 4H) 2 95 m 16H) 6 8-7 2 (m 6H) EXAMPLE 8 5-i 2-(4- 6-Hydroxy-8-quinolyl)piperazinyi)ethyO-benzoxazolone To a 25 ml rcund-bottomed flask equ'pped wit.n conaenser and nitrogen inlet were added 0 84 grams '3 5 mmol) of 6-Dromoethylbenzoxazolore 0 80 grams (3 5 mmol) of 6-hydroxy-8-piperazinyl qumoline 0 37 grams >3 5 mmol) of sodium carbonate 2 mg of sodium iodide and 30 ml of isopropanol Tne reaction was refiuxed for 18 hours cooled evaporated and the residue 30 dissolved in ethyl acetate/water The pH was adjusted to 2 0 with 1N HCI and the phases separated T~e aqueous pnase was adjusted to pH 8 5 and extracted with ethyl acetate The ethyl acetate ayer was washed with brine dried and evaporated to give 0 33 grams of a yellow solid The soi>d was dissolved in ethyl acetate ethyl acetate saturated with hydrochloric acid gas added and tne mixture concentrated to dryness The residue was crystallized from isopropanol 35 to give 0 32 grams |20%) of a yellow salt mp 200° C NMR (d CDCI3) 2 8 im 8H) 3 4 (m 4H) 6 7-7 3 (m 7H) 7 7-7 9 (m 1H) EXAMPLE 9 6-(2-(4-(1-(6-Fluoro)naphthyl)piperazinyl)ethyl)-benzoxazolone A To a round-bottomed flask equipped with condenser and nitrogen inlet were added 345 ml (3 68 mol) of fluorebenzene and 48 grams (0 428 mol) of furoic ac:d To the stirring suspension was added in .portion 120 grams (0 899 mol) of aluminum chloride The reaction was then stirred at 95° C for 16 hours and then quenched by addition to ice'water/1N HCI After stirring 1 hour the aqueous layer was decanted off and benzene and a saturated aqueous solution of sodium bicarbonate added After stirring 1 hour the layers were separated the aqueous layer washed with benzene acidified and extracted into ethyl acetate The ethyl acetate layer was washed with water and brine dried over sodium sulfate and evaporated to a solid The solid was triturated with isopropvl ether to give 5 0 grams (6 1%) of white solid 6-fluoro-1-naphthoic acid, NMR (d DMSO-ds) " 0-8 0 (m 5H) 8 6 (m 1H) B To a 125 ml round-bottomec flask equipped with condenser addition funnel and nitrogen inlet were added 5 0 grams (26 3 mmol) of 6-fluoro-1-naphthoic acid and 50 ml acetone To the stirring suspension were added dropwise 6 25 ml (28 9 mmol) of diphenyl pnosphoryl azide and 4 ml ;23 9 mmol) of tnethylamine The reaction was refiuxed 1 hour poured into water/ethyl acetate and filtered The filtrate was washed with water and brine dried over sodium sulfate ana evaporated The residue was further treated with hydrochloric acid tc form the hydrochloriae salt ana then liberated with scaium hydroxide to affora the £ree base S-fluoro-1-ammo-naphthalene as an oil 1 0 gram 124% C To a 125 ml round-bottomec flasK equipDed with condenser and nitrogen inlet were added 1 0 gram (6 21 mmol) of 6-fluoro-1-amino naphthalene 1 8 grams (7 76 mmol) of N-benzyl bis(2-chioroethyl)amine hydrocnlonde 3 3 ml (19 2 mmol) of dnsopropylethylamine and 50 ml isopropanol The reaction was refluxea 24 hours cooled and evaporated to an oil The oil was taken up in ethyl acetate, washed with water and brine dried over sodium sulfate and evaporated to an oil The oil was chromatcgraphed on silica gel using methylene chloride as eiuent to afford 1 5 grams (75 5%) of an oil " -benzyl-4-!,6-fluoronaphthyl)-piperazine D To a 125 ml round-bottomea flask eauipped with nitrogen >nlet were added 1 5 grams (4 69 mmol) of 1-benzyl-4-(6-fluoronaphthyl)-oiperazine 1 2 ml (31 3 mmol) of formic acid 3 0 grams 5% palladium on carbon 50 ml ethanol The reaction was stirred at room temperature for 16 hours, the catalyst filtered under N2 and the solvent evaporated The oil N-(1-.'6-fluoro)naphthyl)-piperazine (0 420 grams 39%), was used directly in the following steo E To a 100 ml round-bottomed flask equipped with magnetic stirrer condenser and nitrogen inlet were added 0 420 grams (1 83 mmol) of N-(1-naDhthyl)piperazine 0 440 grams (1 83 mmol) of 6-(2-bromoethvl)-benzoxazolone 194 mg (1 83 mmol) of sodium carbonate 50 ml methyiisobutylketone and a catalytic amount of sodium iodide The reaction was refiuxed for 3 days coolea and evaoorated to a drown gum The gum was partitioned between 50 mi water and 75 mi ethyl acetate the pH adjusted with aqueous 1N Sodium hydroxide solution the layers separated and the ethyl acetate layer washed with water ana brine The ethyl acetate layer was dried over sodium sulphate and evaporated then chromatographed on silica gel Fractions containing the proauct were combiq^d and evaporated the residue taken up in ether/methylene chloriae treated with hydrochloric ac.d gas and the resulting hydrochloride salt of the product filtered off :c give a white solid mp 2S5°-300° C 214 mg (22% yield) EXAMPLE 10 6-(4-(4-( 1-Naphthyl)piperazinyl)butyn-benzoxazolone A To a 500 ml rouna-bottomed flask eauDpea with mechanical stirrer and nitrogen inlet were added 290 grams polypnosphoric acid 16 7 grams (0 1 mol) 4-bromobutyric acid and 13 51 grams (0 1 mol) benzoxazoione The react'on was heated at 115c C for 1 hour and 50° C for 1 5 nours It was men oourea onto ice stirred for 45 minutes and the solid filtered and washed witn water The solid was suspended in acetone st red for 20 minutes filtered washed with petroieum etner and dried tc give 12 3 grams (43% of white solid 6-\4-bromobutyryl)-benzoxazolone NMR (d DMSO-ds) 1 77 duin 2H) 3 CO (t 2H) 3 45 (t 2H) 7 0-7 8 (m 3H) B Tc a 100 ml three-decked rouna-cottcmed ""ask equipced with dropping funnel thermometer ana nitrogen inlet were adaed 10 grams (0 035 moi) 6-(4-bromocutyryh-benzoxazoicne arc 25 08 ml (0 35 mol) frifluorcscetic acic To the stirring suspension was added drocwise 12 93 ml ,0 080 mcl tnethylsilane ana the 'eaction stirred at room temoerature for 16 hours The reaction was then soured into water and "he resulting white solid filtered and wasnea with water It was then suscended in isoDroDyl ether stirred and filtered to afford /vnite solid 6-i.4-tr*iuorcacetoxybutvl)-benzcxazolone mo 100=-103= C 10 47 grams (98 7%) C To a 250 ml round-bottomed flasK ecuippea with nitrogen inlet were added 5 0 grams (0 0164 mol) 6-(trifluoroacetoxybutyl)-benzoxazolone 100 ml methanol and > gram sodium carponate The reaction was stirred at room temperature for 1 hour evaporated and the residue taken up in methylene chloriae'methancl wasned wth aaueous HCI dried over sodium sulfate ana evaporated to white solid 6-(4-chlorobutyD-benzcxazolone m p 130°-133° C 2 57 grams (75 7%) E To a 100 ml round-bottom flask eauiDped with condenser and nitrogen iniet were aaded 0 658 grams (3 10 mmol) of 6-.4-chlorobutyl)-benzoxazolone 0 7 grams (3 10 mmol) of N-(1-naphthyDpiperazine 0 328 grams sodium carbonate 2 mg sodium iodide and 50 ml isopropanol The reaction was refiuxed for 3 days evaporated taken up in methylene chloride washed witn water dried over sodium sulfate and evaporated The residue was chromatograDhed on silica gel using ethyl acetate as eluent and the product dissolved in acetone precipitated with ethereal HCI and the white solid filtered washed with acetone and dried to afford 6 76 grams (46 0%) of a white solid m p 231°-233° C EXAMPLE 11 6-(2-(4-(3-(N-(3-Trifluoromethyl)pheny0indazolyl)-piperazinyl)ethynbenzoxazolone To a 125 ml round-bottomed flask equipped with condenser were added 1 0 gram (2 89 10 mmol) of N-(3-tri-fluoromethylphenyl)indazolyi'DiDerazine 0 70 grams (2 89 mol) of 6-(2-bromoethyl)benzoxazoione 0 31 grams (2 89 mmol) of sodium carbonate and 50 ml of methyl isooutyl ketone and the mixture refiuxed 18 hours The reaction was cooled and partitioned between ethyl acetate and water The ethyl acetate layer was isolated washed with water and saturated aqueous sodium chloride solution dried over sodium sulfate and evaporated to an oil 15 The oil was chromatogracned on silica gel using ethyl acetate/methylene chloride as eluent and the croduct fractions collection and dissolved ir ether precipitated with hydrochloride gas and the solid collected to give the hydrochloride sat of the title compound m o 280=-282; C 0 75 grams (47%) EXAMPLE 12 5-^2-(4-(1-Naphthy npiperazinyl)ethyl)oxindole A To a 250 ml round-bottomed flask eauioped with condenser and nitrogen inlet were added 30 7 grams (230 mmol) aluminum chloride 150 ml carbon disulfide and 3 8 ml (48 mmol) chioroacetyl cnioride To the stirring mixture was added 5 0 grams (37 mmol) of oxindole pcrt.onwise over 15 minutes The reaction was stirred a further 1Q minutes then refiuxed 2 25 hours The reaction was cooleo added *o ice stirred thoroughly and 'he beige precipitate filtered washed with water and dried to affcra 7 57 grams (97%) of 5-chloroacetyl-oxindole NMR \d DMSO-d6) 3 40 is 2H) 5 05 (s 2H) 6 S-7 9 (m 3H) B To a 100 ml round-bottomed flask eauipped with condenser and nitrogen inlet were added 5 0 grams (23 9 mmol) of 5-chloroacetyl oxindole and 18 5 ml triflouroacetic acid To the 30 stirring solution was added 8 77 ml (54 9 mmol) of triethyIsilane while cooling to prevent exotherm and the reaction stirred 16 hours at room temperature The reaction was then ooured into ice water stirred and the beige solid filtered washed with water and hexane and dried to give 5-(2-chloroethyl)oxindole mp 168C-170;C 3 0 grams (64%) C To a 50 ml round bottomed flask eouipped with condenser and nitrogen inlet were 35 added 370 mg (1 69 mmol) 5-(2-chloroethyl)oxindole 400 mg (1 69 mmol) N-(1-naphthyl)piperazine hydrochloride 200 mg (1 69 mmol) sodium carbonate 2 mg sodium iodide, and 50 ml methylisobutylketone The reaction was refiuxed 24 hours cooled and evaporated The residue was taken up in ethyl acetate washed with water and brine dried over sodium sulfate and evaporated The residue was chromatographed on silica gel with ethyl acetate and 40 the product fractions collected and evaoorated to give a foam The foam was dissolved in ether treated with hydrochloric acid gas and the precioitate collected washed with ether and dried to afford a white solid m p 303;-305° C , 603 mg (84%) EXAMPLE 13 6-(2-i4-(4-(2- 1 3-Benzothi3diazolyl)piperazinyl)ethyl)-benzoxazolone A To a 125 ml round-bottpmed flask equipped with condenser and nitrogen inlet were addec 2 0 grams (13 2 mmol) 4-amino-2,1 3-benzothiadiazole 2 54 grams (13 2 mmol) mecPiorethamine hydrccnloride 4 19 grams (39 6 mmol) sodium carbonate 2 mg sodium iodide and 50 mi etnanoi Tne react'on was refiuxed 2 days cooled and evaporated The residue was taker jp in methylene cmorioe washed in water dried over sodium sulfate and evaporated The residue was cnromatographed on silica gel using ethyl acetate/methanol as eluent and the product fractions collected and evaporated to an oil of 4-(2 1 3-benzothiadiazolyl)-N-methylpiperazme 628 mg (20%) NMR (d CDCUj 2 5 (s 3H), 2 8 (m 4H), 3 6 (m 4H) 6 8 (m 1H) 7 5 (m 2H) B To a 25 ml round-Dottomed flask equiDced with condenser and nitrogen inlet were addec 620 mg (2 64 mmol) of 4-(2 1 3-benzothiadiazolyl)-N-methylpiperazine 0 224 ml \2 64 mmoi; vinyi cnloroformate and 15 ml dichloroethane The reaction was refiuxed 16 hours cooled and evaporated The residue was chromatographed on silica gel using methylene chlorice/ethyl acetate as eluent and the product fractions collected to give yellow solid 4-<2 1 3-benzothiadiazolyl)-N-vmyioxycarbonylpiperaz:ne 530 mg (69%) NMR (d CDCU) 3 6 (m 4H) 3 8 <m 4H) 4 4-5 0 (m 2H) 6 6-7 6 (m 4H) C To a 50 ml 'ound-bottomed flask equipoed with condenser and nitrogen inlet were addec 530 mg ■ 1 83 mmol) 4-*2 1 3-benzothiadiazoiyli-N-vinyloxycarbonylpiperazine and 25 ml ethanol and rne suspension saturated with hyarochlcric acid gas The reaction was refiuxed 2 75 nours cooled and evaoorated The residue was triturated with acetone to give a yellow solid N-(2 1 3-oenzothiaoiazoly')-piperazine m d 240"-2443C 365 mg (62%) D To a 125 ml rouna-bottomed flask equiDced with condenser and nitrogen inlet were added 365 mg (1 13 mmol) N-(2,1 3-benzothiadiazolyl)-piperazine 275 mg (1 13 mmol) 6-(2-bromoethyl)benzoxazolone 359 mg (3 39 mmol) sodium carbonate 2 mg sodium iodide and 40 ml ethanol The reaction was heated at reflux for 2 days cooled and evaporated The residue was taken up in methylene chloride, washed with water dried over sodium sulfate and evaporated The residue was chromatographed on silica gel using ethyl acetate/methanol as eluent and the product fractions collected dissolved in methylene chloride/methanol precipitated by addition of and ethereal solution of HCI and the solid filtered washed with ether and dried to give 228 mg (45%) m p 166°-170° C EXAMPLE 14 S-(2-(4-t 1 -Naphth/l)-piperazinyl)ethyi)benzothiazolone To a 100 ml round-bottomed flask with condenser and nitrogen inlet were added 1 0 gram (3 88 mmol) cf 6-(2-bromoethyiibenzothiazolone 822 mg (3 88 mmol) N-(1-"aphthyUpiperazine 410 mg (3 88 mmol) sodium carbonate and 50 ml methylisobutlyketone Tne reaction was 'efluxed for 24 flours cooled and evaporated The residue was taken up in ethyl acetate wawshed with water and br ne dried over sodium sulfate and evaporated The -esulting solid was treated with hot ethyl acetate to afford a white solic mp 198'-220°C 540 mg 36 %) EXAMPLE 15 6-,2-'4-(3-benzoisotr,azolyl)piperazinyi)ethyl)benzoxazolone To a 125 ml rcund-bottomed flas* equipped with condenser were added 4 82 grams S 022 mol) of N- 3-benzoisothiazolyl)piperazine ^prepared according to the procedure given in j S Pat No 4 41* 901) 5 32 grams (0 022 mol) of 6-(2-bromo)ethyibenzoxazolone 2 33 grams . 3 022 mol) of sod um carbonate and 50 rr cf methyl isobutyl ketone The mixture was refiuxed *cr 18 hours The 'eacticn was cooled arc oartitic.ned between ethyl acetate and water The e:nyI acetate layer was isolated washed with water and saturated acueous sodium chloride solution dried over sodium sulfate and evaoorated to an oil The oil was chromatographed on s ica gel using ethyl acetate as eluent and the product fractions collected and triturated with "ethylene chloride soprcoyl ether to give a .vmte solid 1 m d 185:-'37=C NMR (CDCI;) 1 7 :s 1H) 2 8 (m 5H 36'm 4H) 5 9-8 0(°~ 7H) EXAMPLE 16 - 2-'4-d 2-cenzisc" azci-3-yli-piperazinyl)etr.iioxirdole To a 125 r rounc-oottom flask ec<- ccec wth nitrogen inlet a~d condenser were added 3 52 grams (3 20 mmol) 5-'2-cnlorcethyl)-ox "dole 0 70 grams (3 20 mmol) sodium carbonate 2 ""9 sodium iodide and 30 ml methylisobutyl <etone The reaction was refluxed 40 hours cooled " tered and evapcated Tne residue was chromatographed on silica gel e'uting the byproducts a :h ethyl acetate 11 1) and the product witn 4% methanol m ethyl acetate (15 1) The product ''actions (R, =0 2 n 5% methanol in ethyl acetate) were evaporated taken up in methylene cioride and prec.citated oy addition of etber saturated with HCI fhe solid was filtered and washed with ether dried and wasned with acetore The latter was done by slurrying the solid acetone and filtering The title compound was obtained as a high melting non-hygroscoDic solid product, m p 288°-288 5° C 0 78(59%) In a manner analogous to that for preparing 5-'2-(4-M 2-benzisothiazol-3-y piperazinyl)ethyh-oxindole the following compounds were made -(2-(4-(1 2-Denzisothiazol-3-yl)piperazinyl)ethyl)-1-ethyloxindoie hydrochloride 25% rr d 278:-279c C -(2-(4-( 1 2-benzisothiazol-3-yi)piperazinyl)ethyl)-1-methyloxindolehydrochloride hemih/drate 42% mp 283°-285= C MS(%) 392(1) 232(100) 177(31), Anal for C22H2,N4OS HCI „,H20 C 60 33, H 5 98 N 12 79 Found C 60 37, H 5 84 N 12 77, -(2-(4-(1 2-benzisothiazol-3-yl)piperazinyl)ethyl)-1-(3-chlorophenyl)oxindole hydrccnloride hydrate, 8%, m p 22J°- 223° C MS(%) 488(1), 256(4) 232(100), 177 (15), Anal for C2-H25CIN40S HCI H20 C 59 67 H 5 19 N 10 31 Found C 59 95 H 5 01 N 10 14, -(2-i4-(1 2-benzisothiazol-3-yl)piperazinyl)ethyl)-3 3-dimethyloxindole hydrochloride heminydrate 40% mp 289c- 291s C MS(%) 406(1), 232(100), 177(42), Anal for C23H;5N4OS HCI ,H20 C 61 11 H 6 24 12 39 Found C 61 44 H 6 22 N 12 01 -(2-(4-( 1 2-benzisothiazol-3-yl)piperazmyl)ethyl)-1 3-dimethyloxindole 76%, mp 256" C '-(2-(4-(1 2-benzisothiazol-3-yl)piperazinyl)ethyl)-spiro[cyclopentane-1 3'-indoline-]-2'-one hydrochloride hemihydrate 50% mp 29T-293" C (dec), MS(%) 432(1) 232(100) 200(1 1) 177(36), Anal for C25H2aN4OS HCI ,H20 C 62 81 H 6 33 N 11 72 Found C 63 01 H 6 32 N 11 34 -(2-(4-(1 2-benzisothiazol-3-yl)piperazmyl)ethyl)-1 3 3-trimethyloxindole hydrochloride heminydrate 63% mp 225=-2573 C MS(%) 420(1) 232(100) 177(37), Anal for C24H;3N4OS HCI ,H20 C 61 85 H 6 49 N 12 02 Found C 61 97 H 6 34 N 11 93 -(2-/4-(1 2-benzisothiazol-3-yl)piperazinyl)ether)-6-flucrooxindole hydrochloride nydrate 18% tip 291 "-293: C MS(%) 3S6(1) 232'100) 177(53) Anal for C; H2 H.FOS HCI H,0 C 55 93 H 5 36 N 12 42 Found C 56 39 H 5 30 N 12 19 -(2-i4-(1 2-benzisothiazol-3-yl)piperazinyl)ethyl)-7-fluorooxindcle hydrocnlorioe 9% m p 253C C -12-14-^1 2-benzisothiazol-3-yl)piperazinyliethyl)-6-chlorooxindole hydrochloride 20% mp >300JC MS(%) 488(1) 256(4), 232(100) 177(15) Analysis for C: H2 CIN4OS HCI .,H20 C 52 50 H 4 71 N 11 39 Found C 52 83 H 4 93 N 11 42 -(2-(4-(1 2-benzisothiazol-3-yl)piperazinyljethyl)-6-fluoro-3 3-dimethyloxindole hydrochloride 35% m p 284*-286= C Anal for C23H25FN4OS HCI H20 C 57 67, H 5 89 N 11 70 Found C 58 03 H 5 79, N 11 77, -(2-(4-(1 2-benzisothiazol-3-yl)piperazmyl)butyl)oxindole hemihydrate 26%, mp 131=-135= C MS(%) 406(2) 270(8), 243(65), 232(23), 177(45) 163(100), Anal for C23H25N4OS ,;H20 C 66 48 H 6 55 N 13 48 Found C 66 83 H 6 30, N 13 08 -(2-(4-(1 2-benzisothiazol-3-yl)piperazinyl)butyl)-7-fluorooxindole hydrate 7% mp 1263-129° C MS(%) 424(3), Anal for C;2H;5FN4OS H;0 C 57 67 H 5 89 N 11 70 Found C 57 96 H 5 62 N 11 47 -(2-(4-( 1,2-benzisothiazol-3-yl)piperazinyl)butyl -1 -ethyloxindole hemihydrate 25% mp 126"-128° C, MS(%) 434(2), 298(10) 271(55) 232(34), 177(53), 163(100) Anal for C;5H30N4OS _H20 C 67 69 H 7 04, N 12 63 Found C 6~ 94 H 6 73 N 12 21, -(2-(4-(naphthalen-1-yl)piperazinyl)ethyl)-1-ethyloxindole hydrochloride hydrate 21% mp >300° C MS(%) 399(1), 225^96), 182(30) 70(100 Anal for C;5H29N30 HCI H20 C 68 78, H 7 10, N 9 26 Found C 69 09 H 6 72 N 9 20 -(2-\4-(naphthalen-1-yl)piperazinyl)ethyl)-6-fluorooxindole hydrochloride, 23% mp 289°-291° C MS(%; 389(1), 232(3) 225(*Z0) 182(32) 70(84), Anal for C24H24FN30 HCI ^CH2CI2 C 62 82 H 5 60 N 8 97 Founc C 62 42, H 5 82, N 8 77 -(2-i4-(naphthalen-1-yl)piperazinyl)ethyl)-7-f!uorooxindole hydrochloride, 22% mp 308= C (dec i MS(%j 389(1), 225(100) Anal for C;4H;.FN30 HCI CH2CI2, C 58 78 H 5 93 N 8 23 Found C 58 82 H 5 80 N 8 27, EXAMPLE 17 6-(4-<'2- 3-Benz sothiazolyhpiperazmyi ethyl)phenyl;benzothiazolone To a 100 ml round-bottomed flasK equipped w :h condenser and nitrogen inlet were added 103 grams (4 mmol) 6-<2-bromoethyl)-benzo:hiazolone 0 88 grams (4 mmol) N-Denzisothiazolylpiperazine 0 84 grams (8 mmol) soaium carbonate, 2 mg sodium iodide and 40 ml methylisobutyl ketone The reaction was refiuxed 36 hours cooled filtered and the filtrate evaporated The residue was chnomatograDhed on silica gel using ethyl acetate as eluent to afford an oil which was taken uc in methylene chloride and precipitated by addition of ether saturated with HCI The solid was filtered washed w th ether dred briefly washed with a minimal amount of acetone and eried tc afford a wnite solid m p 288°-290= C 1 44 grams (76 7%) EXAMPLE A A Following the general crocedure for the precaration of 5-(chloroacetyl)oxindoie in Example 12A the following intermediates were Drepared f^om the appropriate oxindoles -(chloroacetyl)-1-ethyl-oxindole (81% mp 15~c-159° C NMR(CDCI3), 1 30(t 3H), 3 50(s 2H) 3 85(q 2H) 4 70(s 2H ■ 5 85-8 15(m 2H) -(chloroacetyl)-1-methylcx:ndole(C H ;CIN02 52% mp 201;-202°C 1-(3-chlorophenyl)-5(Chlorcacetyl)oxindole 98% mp 143=-145° C NMR(DMSO-ds) 3 85(br s 2H) 510(s2H) 6 8(d 1 H), 7 4-7 6(m 4H) 7 9 (s+d 2H), MS(%) 319(17,270(100), 179(46), 178(38) 1 3-dimethyl-5-(chloroacetyl)oxindole 97% m p 206° - 207° C -(chloroacetyl)-spirocyclopentane[1 3']-indol2'one 99% mp 203° -204° C (dec) NMR(DMSO-dc) 2 0(br s 8H), 4 95(s 2H) 6 9(d 1H), 7 8(d+s 2H), 10 6(br s, 1H), -(ch)oroacetyl)-1 3 3-trimethyloxindole 82% mp 182° -185° C NMR(CDCI3) 1 45is 6H) 3 25(s 3H) 4 65(s 2H) 6 S(d 1H) 7 9(s 1H) 8 0(d 1H) 6-fluoro-5-(chloroacetyl)oxindo!e 96% mp 178c -180° C NMR(DMSO-ds) 3 5< s 2H; 4 8(d 2H), 6 7-7 2(m 2H) 7 8fd 1H), 7-fiuoro5-(Ch!oroacety!)oxiq£ic!e 91% mp 194°-196° C NMR(DMSO-ds) 3 68(s 2H) 13(s 2H) 7 65-7 9(dd 2H) 6-chloro-5-(chloroacetyl)oxindole 99% m p 206° -207° C 5-(cnloroacetyl)-3 3-dimethyl-c-fluorooxindole 89% mp 185°- 188° C 5-(y-chlorobutyryl)oxindole 84% oil MS(%) 239 237(55) 1-ethyl-5-<y-chlorobutyryl)oxirdole 99% oil NMR CDCI-j 1 2(t 3H) 15-2 7fm5H' 3 0-3 2(m 2H) 3 5-4 0(m 3H) 6 8-7 0(d IHi 7 9^s 1H) 7 95ia 1H) and 5-(y-cnloroDutyryl)-7-fluorooxirdole 53% mp 156~-160;C EXAMPLE B By the same procedure as thar used to prepare 5-(2-chlorethyl)oxindole in Example "2B the following were prepared -(2-chloroethyl)-1-ethyloxindole 93% mp 120° - 122° C NMR (CDCI3) 130(t2H) 3 55is 2H) 3 65-4 0(m 4H) 6 8-7 3(m 3H), -(2-chloroethyl)-1-methyloxindc.'e 99% mp 127c - 130s C NMR (CDCU) 3 1 (t 2H) 3 2(5 2H) 3 5(S 2H) 3 75(t2H) 6 8(d"H) 7 15is1H) 7 3td 1H) -i2-chloroethyl)-1-(3-cnloropne'"yl)oxindole 83% mo 75°-~6"C 5-(2-chloroethyl)-1,3-dimethylox,"dole 58% mp "3° - 75° c NMR CDCI3) 145-1 55td 3H) 3 03-3 2(t 2H) 3 25(s3H) 3 30-3 60(qiH) 3 65-3 90(t2H) 6 85-6 90(d*H) 7 15(S 1H) 7 15-7 30(d 1H) -\2-chloroethyl)-spiro[cyclopen:ane-1 3'-indoline]-2'-one 92% mp 140° -142= C NMRiDMSO-ds) 2 8(brs8H) 2 90(t2H> 3 7(t2H) 6 6-7 1(m3H) 10 2(brs1H) -(2-chloroethyl)- 3 3-tnmethylox ndole 83% oil -(2-chloroethyl)-6-fiuorooxindole 62% mo 188° -190° C NMR(DMSO-ds) 3 05(t2H) 3 5(2 2H) 3 35(t 2H) 6 6-7 3(m2H), -(2-cnloroethyl)-7-fluorooxindole 79% mp 176° -179° C MS(%), 213(50), 180(20) 164(100) 136(76), -(2-chloroethyi)-6-chlorooxindole 94% mp 210°-211°C -(2-chloroethyl)-3,3-dimethyl-6-fluorooxindole (C12H.3CIFNO, 84% mp 195° -196° C, NMR(DMSO-ds) 1 3(s 6H), 3 05(t.2H) 3 7(t 2H), 6 65(d 1H) 7 1 (d 1H), 10 1 (br s,1H), -(4-chlorobutyl)oxindole 40% oil NMR(CDCI3) 1 6-2 0(m 4H) 2 6(m 2H) 3 6(m 4H) 6 3-7 15(m 3H), 9 05(br s 1H), 5-(4-chlorobutyl)-eth/ioxindole 48% oil NMR(CDCI3) 1 25(t,3H) 1 5-1 95(m,4H) 2 6(m 2H) 3 5(s 2H) 3 55':2H) 3 75(q,2H) 6 7-7 2(m3H) and 5-(4-chlorobutyl)-7-^uorooxindole 71% mp 168°-173° C ••

Claims (10)

WHAT WE CLAIM IS: 10 15 20 25 30 35

1 A method for treating Tourettes syndrome obsessive compulsive disorder, chronic motor or vocal tic disorder in a non-human mammal comprising administering to said mammal an effective amount of a compound of the formula / \ Ar— N N—(C2H4)„- (I) or a pharmaceutical^ acceptable acid addition salt thereof, wherein Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one fluoro chloro tnfluorome"~/l methoxy cyano nitro or napnthyl optionally substituted by fluoro chloro trifluoromethyl methoxy cyano or nitro quincyl 6-hyaroxy-8-quinolyl isoquinolyl quinazolyl benzothiazolyl oenzothiadiazolyl benzotriazolyl cenzoxazolyl benzoxazolonyl indoiyl indanyl optionally substituted by one or two fluoro 3-mdazolyl optionally substituted by 1-trifluoromethylphenyl, or phtnalazinyl, n is 1 or 2 and X and Y together with the phenyl to which they are attached form quinolyl 2-hydroxyquinolyl benzothiazolyl, 2-aminobenzothiazolyl benzoisothiazolyl indazolyl 2-hydroxymdazolyl indoiyl soiro oxindolyl optionally substituted by one to three of (C .-C2)alkyl, or one of chloro fluoro or onenyl said phenyl optionally substituted by one chloro or fluoro benzoxazolyl 2-aminoberzoxazolyl benzoxazolonyl 2-arrinobenzoxazolinyl benzothiazolonyl bezoimidazolonyl or benzotriazolyl

2 A method according to claim 1, wherein said method is for treating Tourettes syndrome

3 A method according to claim 1 wherein said method is for treating obsessive compulsive disorder

4 A method according to claim 1 wherein sa.c method is for treating chronic motor tic disorder

5 disorder

6 A method according to claim 1 wherein said method is for treating vocal tic A method according to claim 1 wherein x and y together with the phenyl to which they are attached form benzoxazolonyl

7 A method according to claim 2, wherein Ar is benzoisothiazolyl and n is 1

8 A method according to claim 1, wherein x and y together with the phenyl to which they are attached form oxindole optionally substituted by chloro fluoro or phenyl

9 A method according to claim 1 wherein Ar is naphthyl and n is 1

10. A method as claimed in claim 1 substantially as herein described. ^ — intellectual property office of n.z. 2 8 SEP 2001 RECEIVED