1-(3-(6-FLUORO-1,2-BENZISOXASOL-3-YL)PROPYL)-4-HYDROXY-4-PHENYLPIPERIDINES, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS

Abstract: 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy­ -4-penylpiperidines, of formula: wherein X is hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl; Y is hydrogen or trifluoromethyl with the proviso that Y is hydrogen when X is hydrogen, loweralkyl, loweralkoxy or trifluoromethyl and Y is hy­ drogen, trifluoromethyl when X is halogen; the optical antipodes thereof, or pharmaceutically acceptable ad­ dition salts thereof, processes and intermediates for the preparation thereof, a process for the preparation of the intermediate, and the use of the title compounds as medicaments are disclosed.

Description: DESCRIPTION OF THE INVENTION The The present invention relates to novel l-[3-(1,2 enzisoxazoi-3-yi)propyi3-4-hydroxy-4-phenylpiperidinese More articularly, the present invention relates to 1-[3-(6-fluoro Ih,2-benzisoxazoi-3-yi)propyi]-4-phenyl-4-hydroxypiperidines of formula 1, EMI1.1 therein X is hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl; Y is hydrogen or trifluoromethyl with the proviso that Y is hydrogen when X is hydrogen, loweralkyl, loweralkoxy or trifluoromethyl and Y is hydrogen, trifluoromethyl when X is halogen; the optical antipodes thereof, or pharmaceutically acceptable addition salts thereof, whIch are usefui for treating psychoses and alleviating pain, alone or in combination with inert psychoses treating and pain alleviating aujuvants. Preferred 1-[3-(1, 2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 phenylpiperidines are those wherein X is halogen and Y is hydrogen Most preferred are those wherein the halogen is bond to the 4-position of the benzene rng. As at used through the specification and appended claims, the tcrm "alkyl" refers to a straight or branched chain hydrocarbon radicai containing no unsaturation and having 1 to 7 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, l-butyl, l-pentyl, 2-pentyl, 3-hexyi, 4-heptyl and the like; the term "alkoxy" refers to a monovaient substituent which consists of an alkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen such as methoxy, ethoxy, propoxy, butoxy, 1, 1-dimethylethoxy, pentoxy, 3-methylpentoxy, 2-ethylpentoxy and the like; the term "haiogen" refers to a member of a family consisting of chlorine; fluorine, bromine or iodine. The term "lower" as applied to any of the aforementioned grbups refers to a group having a carbon skeieton containing up to and including 5 carbon atoms. The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the raceme forms thereof. The optical antipode may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diastereomeric salts of those instant compounds characterized by the presence of a basic amino group and an optical active acid, or by the synthesis from optically active precursors. The present invention comprehends all optical isomers and racemic forms thereof. The formuias of the compounds shown herein are intended to encompass all possibe optical isomers of the compounds so depicted. The novel 1-[3-(6-fluoro-1, 2-benzisoxazol-3-yl)propyl)-4xy-4-phenylpiperidines of formula 1, the compounds of the present invention, are prepared by condensing a Grignard reagent of formula 2 EMI3.1 wherein X and Y are as before, prepared by conventional method from a bromobenzene of formula 3 EMI3.2 wherein X and Y are as before with magnesium (see, for example, M.S. Kharasch, "Grignard Reactions of Nonmetallic Substances", Prentice Haii, New York, i954, Chapter II), with 1-[3-(6-fluoro-1, 2-benzisoxazol-3-yl)propyl]-4-piperidone of formula 4 EMI4.1 The condensation is conveniently performed by treating the piperidone 4 with the Grignard reagent 2 in a suitable solvent. Among suitable solvents there may be mentioned ethereal solvents such as, for example, diethyi ether, dimethoxyethane, dimethoxyethoxyethane, dioxane, tetrahydropyran and tetrahydrofuran. Tetrahydrofuran is preferred. The condensation temperature is not narrowly critical. it is desirable1 however, to conduct the condensation at a temperature within the range of about -10 C to about 4 C to assure a reasonable rate of conversion. A condensation temperature of about ambient temperature is preferred. Alternatively, the compounds of the present invention, the 1[3-(6-fluoro-1, 2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines of formula I, are prepared by condensing 3-(3-chioro- propyi)-6-fiuoro-1,2-benzisoxazoie of formula 5 EMI4.2 the synthesis of which is described in U.S. Patent Application Serial No. 257,698, filed April 27, 1981, with readily available 4-hydroxy-4-phenyipiperidines of formula 6 EMI5.1 wherein X and Y are as above. The condensation is conveniently performed by treating the halide 5 with the piperidine 6 in the presence cf an acid acceptor, a displacement promotor and a suitable solvent. Among acid acceptors, there may be mentioned alkali metal carbonates and alkali metal bicarbonates such as, for example, iithium carbonate, sodium carbonate and potassium carbonate, and iithium bicarbonate, sodium bicarbonate and potassium bicarbonate. Potassium carbonate and sodium bicarbonate are preferred. Among displacement promotors, there may be mentioned alkali metal haiides such as, for example, sodium iodide and potassium iodide, and sodium bromide and potassium bromide. Potassium iodide is preferred. Among suitable solvents, there may be mentioned polar aprotic substances such as, for example, dimethylformamide, dimethylacetamide and hexamethylphosphoramide. Dimethylformamide is preferred The temperature at which the condensation is conducted is not narrowly critical. Itis desirable however1 to perform the condensation at a temperature within the range of about 50 G to about 130 C to assure a reasonable rate cf conversion. A reaction temperature within the range of about 70 C to 110 C is preferred. The compound of the formula 4 above can be prepared by con denying a compound of th formula 5 above with the readily available piperidone of the formula EMI6.1 The condensation is conveniently performed by treating the compound of the formula 4 with the piperidone in the presence of an acid acceptor, a displacement promoter and a suitable solvent. Among acid acceptors, there may be mentioned alkali metal carbonates and alkali metal bicarbonates such as, for example, lithium carbonate, sodium carbonate and potassium carbonate, and lithium bicarbonate, sodium bicarbonate and potassium bicarbonate. Potassium carbonate and sodium bicarbonate are preferred. Among displacement promoters, there may be mentioned alkali metal halides such as, for example, sodium iodide and potassium iodide, and sodium bromide and potassium bromide. Potassium iodide is preferred. Among suitable solvents, there may be mentioned polar aprotic substances such as, for example, dimethylformamide, dimethylacetamide and hexamethylphosphoramide. Dimethylformamide is preferred. The temperature at which the condensation is conducted is not narrowly critical. It is desirable, however to perform the condensation at a temperature within the range of about 50 C to about 1300C to assure a reasonable rate of conversion. A reaction temperature within the range of about 70C to llOC is preferred. The 3-(F-chloropropyl)-6-fluoro-1,2-benzisoxazole of the formula 5 EMI6.2 is an important intermediate for the preparation of neuroleptics, and particularly, of the compounds of the formula 1 above. Japanese patent publication J5 1136-666 discloses a broad class of compounds of the formula I as starting materials for drugs exhibiting action on the central nervous system, EMI7.1 were R1 is hydrogen, halogen atom. lower alkoxy, or hydroxy; X is a reactive ester residue of an alcohol (e.g., chlorine, bromine, iodine, an aryl sulfonyloxy group, such as p-toluene-sulfonyloxy or benzene sulfonyloxy, or an alkyl sulfonyloxy group, such as methanesulfonyloxy; and n is an -integer 1 - 3. This disclosure, however, does not reveal or hint that 3-( chloropropyl)-6-fluoro-1 ,2-benzisoxazole is especially useful in the synthesis of neuroleptics, nor does it reveal or hint at the preparation of this precursor or a method by which to do so. Japanese patent publication J4 9070 963 describes the preparation of 1,2-benzisoxazole derivatives of formula II, EMI7.2 where R1 is hydrogen, hydroxy, alkoxy, alkyl, halogen, nitro; R2 is halogen; R3 is hydrogen, halogen; R4 is hydro gen, halogen, carboxyl, alkoxyearbonyl by balogenating 1,2-benzisoxazole-3-acetic acid derivatives III, EMI8.1 where R is hydroxy, alkoxy, halogen; and R1 is as shown under II. No method, however, is revealed or hinted at which would yield 3-(g-chloropropyl)-6-fluoro-1,2-benzisoxazole of this invention or even closely related analogs or next adjacent homologs. A process for preparation. of a 3-(g-substituted propyl)6-fluoro-1,2-benzisoxazole is described. The process comprises cyclizing an oxime having the formula EMI8.2 where X is a leaving group in organic nucleophilic displacement reactions. Typical leaving groups are a halide group, comprising C1 and Br, a tosyl group, a mesyl group, etc. A preferred halide is C1. R is a substituent selected from EMI8.3 where alkyl is a straigth or branched chain hydrocarbon of 1 to 6 carbon atoms, and EMI8.4 The starting compound for the preparation of 3-(Psub- stit;uted- propyl)-6-fluoro-l ,2-benzisoxazole is 9- substituted -4-fluoro-2-hydroxybutyrophenone. A preferred compound is &gamma;-chloro-4-fluoro-2-hydrobutyrophenone having a formula, EMI9.1 A butyrophenone precursor to this benzisoxazole is prepared by reacting 3-fluorophenol, with an acid chloride, such as the aicd chloride EMI9.2 EMI9.3 in the manner described in Belgian patent 839,097. The resultant butyrophenone, e.g. g-chloro-4-fluoro- 2-hydroxybutyrophenone, is then converted into its oxime, e.g. EMI9.4 by reaction with a salt of hydroxylamine, utilizing conventional techniques and conditions. Typically hydroxylarnine hydrochloride is employed in the presence of an acid acceptor, such as pyrldine. The resulting oxime, &gamma;-chloro-4-fluoro-2-hydrobutyrophenone phenone oxime, is predominantly the E-oxime in respect to its position relative to the benzene ring. This reasoning is deduced from the fact that after acetylation to E-&gamma;-chloro-4 fluoro-2-hydroxybutyrophenone-0-acetyl oxime, the acetylated oxime gives a high yield (80 %) of 3-(&gamma;-chloropropyl)-6- fluoro-1, 2-benzisoxazole on cyclization. The resulting oxime, e.g. EMI10.1 is reacted with an acyl anhydride, acetyl halide, e.g., chloride, or benzoic anhydride or halide to form an O-acetyl or O-benzoyl compound e.g. EMI10.2 where R is selected from EMI10.3 alkyl, where alkyl is a straight or branched chain hydrocarbon substituent having 1 to 6 carbon atoms, and EMI10.4 It is to be understood that other reagents reacting with the -OH group of the oxime may be employed to form O-alkanoyl or O-aroyl derivatives, as for example, propionic anhydride, butyric anhydride, acetic benzoic anhydride, propionyl chloride, butyroyl chloride, and benzoyl chloride. The resulting O-alkanoyl or O-aroyl-derivative is then'cyclized in the presence of a base to form the desired compound EMI10.5 3-(g-chloroprepyl)-6-fluoro--1,2-benzisoxazole. Typically the cyclization is carried out in the presence of potassium carbonate. Alternate reagents of. potassium carbonate to effect cyclization of the O-acyl oxime, e.g., E-&gamma;-chloro-4-fluoro- 2-hydroxybutyrophenon-O-acetyl oxime, include alkaline reagents such as sodium bicabonate, sodium carbonate, calcium carbonate, magnesium carbonate, calcium oxide, magnesium oxide and potassium hydroxide. Because of the necessity to avoid excess alkali with its potential for reaction with the chlorine atom of the chloropropyl side chain attached to the benzisoxazole ring, it is desirable to limit any alkali present to a slight excess over that required to react with the phenol group. Desirably, alkali remaining after reaction with the acetylated oxime should not cause a pH greater than 9 after dilution with water. Cyclization with reagents yielding a pH after reaction and dilution with water below 8 are preferred. It is understood that the above-identified reactions of the reaction sequence are carried out in-a conventional solvent system typically employed therefor and well known to those skilled in the art. The overall reaction sequence 'from &gamma;-chloro-4-fluoro- 2-hydroxy-butyrophenone to its oxime to its acetylated oxime to 3-(&gamma;-chloropropyl)-6-fluoro-1, 2-benzisoxazole is remarkable for its high yield of desired product. This yield is the more remarkable in that the g-chloropropyl group survives intact and is available for subsequent use in reactions to prepare compounds having neuroleptic utility, such as for example 4-(,-C-chlorophenyl )-1- r3-(6-fluoro-I ,2-ben- zisoxazole-3-yl)propyl]-4-hydroxypiperidine. The 1-[3-(6-fluoro-1, 2-benzisoxazol-3-yl)propyl]-4-hydroxy4-phenylpiperidines of the present invention are useful as analgesic agents due to their ability to alleviate pain in mammals which is demonstrated in the phenyi-para-quinone writhing assay in mice, a standard assay for analgesia [Proc. Soc. Expti. Biol. Med., 95, 729 (i953)]. Presented in Tabie i is the anaigesic activity of representative compounds of the invention and two standards, expressed as the estimated subcutaneous dose at which the' mice experience a 50% reduction in phenyl-para-quinone induced writhes, i.e., the ED5-value. TABLE 1 Analgesic Activity Compound (ED5(3 mg/kg) 1-[3-(6-Fluoro-1,2-benzisoxazol 3-yl)propyl]-4-hydroxy-4-phenylpiperidine 5.9 1-[3-(6-Fluoro-1,2-benzisoxazol 3-yl)propyil--(3-chiorophenyl)- 4-hydroxypiperidine hydrochloride 1-[3-(6-Fluoro-1,2-benzisoxazol 3-yl)propyi]-4-hydroxy-4-(4-meth- oxypheny piperidine hydrochioride 3.8 1-[3-(6-Fluoro-1,2-benzisoxazol 3-yi)propyi]-4-(4-fiuorophenyi)- 4-hydroxypiperidine 6.2 1-[3-(6-Fluoro-1,2-benzisoxazol3-yl)propyl]-4-hydroxy-4-(3-tri fluoromethylphenyi)piperidine hydrochloride 1.0 propoxyphene (standard) 3.9 pentazocin (standard) 1.3 Anaigesia production is achieved when the present 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidines are administered to a subject requiring such treatment as an effective orai, parenterai or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professionai judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the.dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention. The 1-(3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl)-4-hydroxy- 4-phenylpiperidines of the present invention are useful for treating psychoses by virtue of their ability to block apomorphine-induced climbing in mammals. Antipsychotic activity is determined in the climbing mice assay by a method simiiar to those described by P. Protais et al., Psychopharmacoi., 5(3, 1 (1976) and B. Costall, Eur. J. Pharmacol., 5(3, 39 (1978). The subject CK-1 maie mice (23-27 grams) are group-housed under standard laboratory conditions. The mice are individually placed in wire mesh stick cages ($" x 4" x I0") and are allowed one hour for adaptation and exploration of the new environment. Then apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 3(3 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneaiiy 3(3 minutes prior to the apomorphine chalienge at a screening dose of 18 mg/kg. For evaluation of climbing, 3 readings are taken at 1(3, 20 and 3(3 minutes after apomorphine administration according to the following scale: Climbing Behavior Score Mice with: 4 paws on bottom (no 'climbing) 0 2 paws on the wall (rearing) 1 4 paws on the wall (full climb) 2 Mice consistently climbing before the injection of apormorphine will be discarded. With full-developed apomorphine climbing, the animals are hanging onto the cage wails, rather motionless, over longer periods of time. By contrast, ciimbs due to mere motor stimulation usually only last a few seconds. The climbing scores are individually totaied (maximal score: 6 per mouse over 3 readings) and the total score of the control qroup (vehicie intraperitoneally - apomorphine subcutaneously) is set to 100%. ED5(3 values with 95t confidence limits are calculated by a Linear Regression Analysis. Antipsychotic activity expressed as the ED50 value of representative 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4phenylpiperidines as weil as two standard 'antipsychotics are presented in Table II. TABLE ii Antipsychotic Activity Compound ED50 (mg/kg) 4-(4-chlorophenyl)-1-[3-(6fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydorxypiperidine 0.51 1-[3-(6-fluoro-1,2-benzisoxazol- 3-yl)propyl]-4-hydroxy-4-phenylpiperidine 9.6 1-[3-(6-fluoro-1,2-benzisoxazol3-yl)propyl]-4-hydroxy-4-(4-tolyl)piperidine 0.56 1-[3-(6-fluoro-1,2-benzisoxazol- 3-yl)propyl]-4-hydroxy-4-(4-tri fluoromethylphenyi)piperidine 3.1 1-[3-(6-fluoro-1,2-benzisoxazol3-yi)propyl]-4-(3-chlorophenyl)4-hydroxypiperidine hydrochloride 1-[3-(6-fluoro-1,2-benzisoxazol3-yi)propyi]-4-(4-fluorophenyi)4-hydroxypiperidine 0.8 1-[3-(6-fluoro-1,2-benzisoxazol3-yl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride 0.25 1-[3-(6-fluoro-1,2-benzisoxazol3-yl)propyl]-4-hydroxy-4-(2-methylphenyl)piperidine hydrochloride 8.3 haloperidol (standard) 0.11 sulpiride (s-tandard) 4.5 Antipsychotic activity is achieved when the present 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 phenyipiperidines are administered to a subject requiring such treatment as an effective orai, parenteral or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. A particularly preferred effective amount is about 25 mg/kg of body weight per day. It is,to be understood, however, that for any particular subject, specific dosage regimens should be adjusted to the individuai need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. ft is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the sccpe or practice of the invention. Effective amounts of the compounds of the invention may be administered to a subject by any one of various methods, for example, orally as in capsule or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like. Preferred pharmaceuticaiiy acceptable addition salts include salts of mineral acids, for example, hydrochioric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid and the like, salts of'dibasic carboxylic acids such as, for example, maicic acid, fumaric acid, oxalic acid and the like, and salts or tribasic carboxylic acids such as, for example, carboxysuccinic acid, citric acid and the like. The active compounds of the present invention may be administered orally, for example, with an inert diluent or with ||an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic l adminiswration the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, susponsions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 75% of the weight of the unit. The amount of present compound in such composition is such that a suitable dosage wiii be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 mgs of active compound. The tablets, pills, capsules, troches and the like may aiso contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or iactose, a disintegrating agent such as aiginic acid, Primogei, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as coiloidal silicon dioxide; amd a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added. When the dosage unit form. is a capsule, it may contain, in addition to materials lof the above type, a iiquid carrier such as a fatty oil, Other dosage unit forms may contain other various materiais which modify the physicai form of the dosage unit, for example, as coatings. Thus tablets or pilis may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweeteing 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 purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of the aforesaid compound, but may be varied between 0.5 and about 5(3% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage wiii be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenterai dosage unit contains between (3.5 to 100 mgs of the active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saiine solution, fixed oiis, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacteriai agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity suc as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syrinyes or Multiple de viais made of glass or plastic. The following Examples are for illustrative purposes only and are not to be construed as limiting the invention. EXAMPLE 1 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenylpiperidine to 50 ml of dry dimethylformamide was added, 6.0 g of 4-hydroxy4-phenylpiperidine, 8.0 g of 3-(3-chloropropoyl)-6-fluoro-1,2benzisoxazole, 13.0 g of sodium bicarbonate, and a few crystals of potassium iodide. After stirring at 80 C for one hr, the mixture was cooled, filtered, and the filtrate evaporated to an oil. The oil was stirred with 100 ml water for five mins, and then extracted with ether/ethyl acetate. The organic layer was washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvents were evaporated. Trituration with ether gave 3.0 g (25%) of product, mp 133 - 137 C. Recrystallization twich from ethyl ether gave the analytical sample, mp 138 - 139 C. ANALYSIS: Calculated for C21 H23FN2O2: 71.16%C 6.54%H 7.91%N Found: 71.34%C 6.51%H 7.66%N EXAMPLE 2 4-(3-Chlorophenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl] 4-hydroxypiperidine hydrochloride To a suspension of 1.2 g of magnesium shavings and a few drops of dibromoethane in 3(3 ml of ether was added a solution of 8.7 g of 3-bromochlorobenzene in 2(3 mi of ether at such a rate so as to maintain reflux. After the addition was complete, the mixture was diluted with 3(3 ml of tetrahydrofuran and then a solution 6.3 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4 piperidone in 3(3 mi of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 4(3(3 mi of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated to an oii. The oil was converted to 8*5 g (88%) of product, mp 170 - l720C, by treatment with ethereal hydrogen chioride. An analyticai sample was obtained by recrystallization from ethyl acetate/methanol and had, mp 1880 - 189 I II ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ ANALYSIS: Calculated for C21H22ClFN2O2.HCl: 59.30%C 5.45%H Found: 59.52%C 5.56%H EXAMPLE 3 4-(4-Chlorphenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]4-hydroxypiperidine To 30 ml of dry dimethylformamide was added 3.0 g of 4-(4-chlorphenyl)-4-hydroxypiperidine , 2.99 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 8.(3 g of sodium bicarbonate, and a crystal of potassium iodide. After stirring at 90 C for one hr, the mixture was evaporated to an oil. The oil was stirred with 100 ml of water for five mins, and then extracted with ether. The ether solution was washed with water (2x), saturated sodium chloride solution and dried over anhydrous 'magnesium sulfate. After filtering, the solvent was evaporated. Recrystallizetion cf the residue from ethyl ether gave 3.6 g of product, mp l420-l450C. The analytical sample was obtained by recrystallization from ethyl ether and had mp 148-150 C. ANALYSIS: Calculated for C21H22CiFN202: 64.86%C 5.70%H 7.21%N Found: 64.75%C 5.64%H 7.15%N EXAMPLE 4 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-fluorophenyl)4-hydroxypiperidine To a suspension of 1.1 g of magnesium shavings and a few drops of dibromoethane in 3(3 ml of ether was added a solution of 7.9 g of p-bromofluorobenzene in 2(3 ml of ether at a rate to maintain reflux of the mixture. After the addition was complete, the mixture was slowly d-iluted with 3(3 mi of tetrahydrofuran and then a solution of 5 g of 1-(3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4piperidone in 3(3 ml of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 4(3(3 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from hexanes/ether to give 3.6 g (54%) of product, mp 100 -101 C. ANALYSIS: aicuiated for C21H22F2N2 2 67.72%C 5.95%H Found: 67.88%C 5.67%H EXAMPLE 5 1- (3- (6-Fluoro-l ,2-benzisoxazol-3-yl) propyli -4-hydroxy-4- (2-methylphenyl)piperidine hydrochloride To a suspension of (3.9 g of magnesium shavings and a few drops of dibromoethane in 3(3 mi of ether was added a solution of 6.2 g of 2-bromotoluene in 3(3 ml of ether. After the addition was complete, the mixture was stirred under reflux for one hr, cooled, and a solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazoi3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was added. After one hr, the mixture was diluted with ether, poured into 400 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to 6.4 g (828) of product by treatment with ethereal hydrogen chloride. Recrystallization from ethyl acetate/methanci gave the analytical sample, mp 191 -192 C (dec). ANALYSIS: Calculated for C22H25FN2O2.HCl: 65.26%C 6.47%H Found: 65.14%C 6.62%H EXAMPLE 6 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-tolylpiperidine To 5(3 mi of diethyl ether was added a solution of i5 mi of p-toiyimagnesium bromide (1.96'M in ether). The resultant solution was cooled to 0 C with an ice-bath and a solution of 5.3 g of 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidine in 50 mi of ether was added over a period of thirty mins, with stirring. The mixture was stirred at ambient temperature for two hrs, poured into 500 mi of ice-coid ammonium chloride solution, stirred for five mins and extracted with ether/ethyl acetate. The organic layer was washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvents were evaporated. Crystaiiization of the residue from ethyl ether gave 2.6 g (36%) of product, mp 96 -99 C. Recrystallizetion from ethyl ether gave the analytical sample, mp 98 -100 C. ANALYSIS: Calculated for C22H25FN2O2: 71.71%C 6.84%H 7.61%N Found: 71.81%C 6.85%H 7.56%N EXAMPLE 7 (4-methoxyphenyl)piperidine hydrochloride A solution of 6.3 g of 1-[3-(6-fluoro, 2-benzisoxazol-3- yj)propyl]-4-piperidone in 35 mi of tetrahydrofuran was slowly added to a solution of 49 ml of p-anisylmagnesium bromide (1.4 M in tetrahydrofuran). After the addition was complete, the reaction mixture was stirred at ambient temperature for one hr, diluted with ether, poured into 4(3(3 of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to 8.5 g t89O) of product, mp 100 -105 C, by treatment with ethereai hydrogen chloride. An analytical sample was obtained by recrystallization from ethyl acetate/methanol and had mp 181 -182 C (dec) ANALYSIS: Calculated for C22H25FN2O3.HCl: 62.77%C 6.23%H Found: 63.04%C 6.35%H EXAMPLE 8 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 (3-trifluoromethylphenyl)piperidine hydrochloride To a suspension of 1.1 g of magnesium shavings and a few drops of dibromoethane in 30 ml of ether was added a solution of 9.8 g of 3-bromobenzotrifluoride in 3(3 ml of ether at a rate to maintain reflux of the mixture. After the magnesium was consumed, a solution of 6 g of 1-[3-(6-Fluoro-1, 2-benzisoxazol-3-yl)propyl]-4-piperidone in 500 ni of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 4(3(3 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts ere washed with water (2x) , saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrateds Treatment of the residue with ethereai hydrogen chloride gave a sait. Recrystallization from ethyl acetate/methanol gave 4 g (55%) of product, mp 214 -215 C ANALYSIS: Calculated for C22H22F4N2O2.HCl: 57.58%C 5.05%H Found: 57.48%C 5.04%H EXAMPLE 9 1-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 (4-trifiuoromethylchenyì)piperidine To a suspension of 1.2 g of magnesium shavings and a few drops of dibromoethane in 3(3 ml of ether was added a solution of 10.3 g of 4-bromobenzotrifluoride, in 2(3 ml of ether at such a rate so as to maintain refiux of the mixture. After the addition was complete, the mixture was diluted with 35 ml of tetrahydrofuran, and a solution of 6.3 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 4(3(3 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride soiution and dried over anhydrous magnesium sulfate, filtered and concentrated. Trituration with hexane/ether gave 7 y (73%) of product, mp 150 -152 C. Recrystallization from ether gave the analytical sample, mp 152 -153 C. ANALYSIS: Calculated for C22H22F4N2O2: 62.55%C 5.25%H 6.63%N Found: 62.38%C 5.19%H 6.84%N EXAMPLE 10 4-(4-Chloro-3-trifluoromethylphenyl)-1-[3-(6-fluoro-1,2benzisoxazol-3-yl)propyl)-4-hydroxypiperidine hydrochloride To a suspension of 0.9 g of magnesium shavings and a few drops of dibromoethane in 3(3 ml of ether was added a solution of 9.4 g of 5-bromo-2-chlorobenzotrifluoride in 30 ml of ether at a rate to maintain reflux. After the magnesium was consumed a solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 mi of tetrahydrofuran was added. After thirty mins the reaction mixture was poured into 4(3(3 ml of saturated ammonium chloride solution and extracted with ethyl acetate/ether. The organic extracts were washed with water (2x) , saturated sodium chlorIde solution and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil, which was purified by column chromatography (silic gel, tetrahydrofuran). The desired fractions were combined and concentrated to an oil, which was converted to a salt by treatment with ethereai hydrogen chloride. Recrystallization from ethyl acetate/methanol gave 3 g (34%) of product, mp 203 -204 C. I ANALYSIS: Calculated for C22H21C1F4N2O2.HCl: 53.56%C 4.50%H Found: 53.53%C 4.35%H EXAMPLE 11 4-(4-Bromphenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl] 4-hydroxypiperidine To 25 ml of ethyl ether was added 1,0 g of magnenesium turnings, 0.5 ml of 1,2-dibromoethane and a few drops of a solution of 9.4 g of 1,4-dibrombenzene in 5(3 ml of ethyl ether. The reaction was initiated with heat and maintained by the addition of the solution of l,4-dibromobenzene. The resultant solution was stirred at ambient temperature for fifteen-mins and then a solution of 7.0 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3 ylpropyl]-4-piperidone in 5(3 ml of tetrahydrofuran was added with vigorous stirring. After the addition was complete, the mixture was stirred at ambient temperature for thirty mins and then poured into an ice cold solution of ammonium chloride. After dilution with 2(3(3 mi of ethyl ether, the organic layer was collected, washed with water (2X), saturated sodium chloride solution and then dried over anyhydrous magnesium sulfate. After filtering, the solvents were evaporated to an oil, which was |triturated with petroleum ether. The resultant precipitate was collected and dried to give 4.4 g (41%) of product, mp 138-145 C. Recrystallization four times from ethyl ether gave the analytical sample, mp 150-151 C. ANALYSIS: Calculated for C21H22BrFN2O2: 58.20%C 5.12%H 6.47%N Found: 58.66%C 5.20%H 6.44%N EXAMPLE 12 t-Chloro-4-fluoro-2-hydroxybuyrophenone To 350 ml (2.8 mols) cold boron trifluoride etherate is added 100 g (0.89 mole) of 3-fluorophenol and 252 g (200 ml 1.78 mole) of 4-chlorobutyryl chloride. The resulting solution is stirred for twenty hours at 1300C. The mixture is cooled and poured into one liter of mixed ice and water. After stirring for ten minutes, the water mixture is extracted three times with 200 ml of ether each time. The ether extracts are combined and washed three times with water. The ether extract is dried by washing with a saturated solution of sodium chloride in water and is then dried over anhydrous magnesium sulfate. The magnesium sulfate is filtered from the dry ether a solution and the ether is evaporated. The resultant oil is vacuum distilled and a fraction is collected at 110 - 150 C (1.0 mm, pot at 170 - 2500C) weighing 115 g (50 % of the theoretical yield). This material is recrystallized from a mixed solvent solution (hexane/ether at 8 : 1 ratio) to obtain white crystals of > -chloro-4-fluoro-2-hydroxybuty- rophenone, melting at 68 - 700C. EXAMPLE 13 E-&gamma;-chloro-4-fluoro-2-hydroxybutyrophenone oxime To 25 ml of pyridine is added 11.2 g (0.052 mole) of &gamma;-chloro-4-fluoro-2-hydroxybutyrophenone of Example 12 and 4.14 g (0.06 mole) of hydroxylamine hydrochloride. This mixture is stirred overnight (20 hours) at ambient temperature. It is then poured into 100 ml of dilute hydrochloric aicd, stirred for five minutes, and is extracted with ether. The ether solution is washed two times with water before it is dried by washing with a saturated solution or sodium chloride in water followed by final drying over anhydrous magnesium sulfate. The magnesium sulfate is filtered from the ether solution, and the ether is evaporated. The white solid obtained is recrystallized from a mixed hexane and ether solvent to obtain 11.5 g (95 % of the theoretical yield) of white crystals melting at 68 - 700C. A sample of this material is again recrystallized from hexane/ether to yield white crystals of E-&gamma;-chloro-4-fluoro-2-hydroxybutyrophe- none oxime, melting at 74 - 60C. Analysis: Calculated for C10H11C1FN02: 51.84 %C 4.79 gH 6.05 %N Found: 52.20 %C 4.77 sH 6.00 %N EXAMPLE 14 -E-ç-chloro-4-fluoro-2-hydroxybtuyrophenone-0-acetyl oxime To 5.5 ml (0.06 mole) of acetic anhydride is added 10.0 g (0.043 mole) of E-&gamma;-chloro-4-fluoro-2-hydroxybutyro- phenone oxime. This mixture is heated at 600C for one and one-half hours. The resulting mixture is cooled to room temperature and is dissolved in 100 ml of ether. The ether solution is washed twice with a sodium bicarbonate solution in water. It is then washed twice with water. The ether solution remaining is dried by washing with a saturated solution of sodium chloride in water before finally drying it over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration after drying is complete and the ether is evaporated from the dry ether solution to give a solid which is recrystallized from a mixed hexane/ether solvent to obtain 9.0 g (76 % of the theoretical yield) of E-&gamma;-chloro-4-fluoro-2-hydroxybutyro- phenone-0-a^efly'^-ime possessing a melting point ^ QA 870C. A sample of this material is recrystallized from a mixed hexane/ether solvent. The crystals of E-&gamma;-chloro-4- fluoro-2-hydroxy-butyrophenone-0-acetyloxime which are obtained melt at 86 - 880C. Analysis: Calculated for C12H13C1FN03: 52.66 %C 4.79 %H 5.12 %N Found: 52.56 sC 4.81 %H 5.05 %N EXAMPLE 15 3-[&gamma;-chloropropyl]-6-fluoro-1,2-benzisoxazole The cyclization of the acetylated oxime of Example 3 is effected by adding 6.5 g (0.024 mole) of E-g-chloro-4- fluoro2-hydroxy-butyrophenone-O-acetyl oxime to 20 ml of dry dimethylformamide (DMF) and 4.14 g (0.03 mole) of potassium carbonate. This mixture is stirred for five hours at room -temperature. It is poured into 500 ml of water, stirred for five minutes, and is then extracted with a mixed solvent of ether/ethyl acetate. The extracted organic layer is washed two times with water and once with a saturated solution of sodium chloride in water. The organic layer is finally dried over anhydrous magnesium sulfate. After drying, the magnesium sulfate is removed by filtration and the solution is evaporated to remove ether and ethyl acetate. The product is an oil. This oil is distilled to yield 4.0 g (80 % of the theoretical yield) of an oil of 3-(&gamma;-chloropropyl)-6-fluoro-1,2-benzisoxazole boiling at 1300C/0.5 mm. Analysis: Calculated for C10i9ClFN0: 56.22 %C 4.25 fiH 6.56 %N Found: . 56.21 fiC 4.25 %H 6.52 %N

Claims: Patent claims: 1. A compound of the formula EMI34.1 wherein X is hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl; Y is hydrogen or trifluoromethyl with the proviso that Y is hydrogen when X is hydrogen, loweralkyl, loweralkoxy or trifluoromethyl and Y is hydrogen, trifluoromethyl when X is hydrogen; the optical antipodes thereof, or pharmaceutically acceptable acid addition salt thereof. 2. A compound according to Claim i wherein X is halogen and Y is hydrogen. 3. A compound according to Claim 2 wherein the halogen is bound to the 4-position of the benzene ring. 4. The compound according to Claim l which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-phenyl pipridne, 5 The compound according to Claim 2 which is 4-(3-chlorphenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl] 4-hyd roxypiper id ine. 6. 6. The compound according to Claim 3 which is 4-(4-chlorophenyl)-1-[3-(6-fluoro-1,2-benzisolxazol-3-yl)propyl)4-hydroxypiperidine. 7. The compound according to Claim 3 which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(4-fluorophenyl) 4-hydroxypiperidine. 8. The compound accoridng to Claim l which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 (2-methyiphenyl) piperidine. 9. The compound according to Claim 1 which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 (4-tolyl)piperidine. 18, The compound according to Claim 1 which is l-(3-(6-fluoro-l,2-benzisoxazol-3-yl)propyl)-4-hydroxy-4-(4- methoxyphenyi)piperidine. 11. The compound according to Claim 1 which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4-(3-tri fluoromethylphenyl)piperidine. 12t The compound according to Claim 1 which is 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-hydroxy-4 (4-trifluoromethylphenyl)piperidine. 13. The compound according to Claim 1 which is 4-(4-chioro-3-trifluoromethyiphenyi)-l-{3-(6-fluoro-l,2" 'I benzisoxazol-3-yl)propyl]-4-hydroxypiperidine. 14. The compound according to Claim 3 which is 4-(4-bromphenyl)-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl] 4-hydroxypiperidine. 15. A pharmaceutical composition which comprises as active ingredient a compound of the formula 1 or a pharmaceutically acceptable acid addition salt thereof in admixture of or conjunction with a pharaceutically acceptable carrier and/or stabilizer. 16. A compound of the formula 1 as claimed in claim 1 for use as medicament. 17. A process for preparing a compound of the formu- la 1 as claimed in claim 1 which comprises a) condensing a compound of the formula 2 EMI36.1 wherein X is hydrogen, loweralkyl, loweralkoxyS halogen or trifluoromethyl, and Y is hydrogen or trifluoromethyl with the proviso that Y is hydrogen when X is as defined above, and Y is hydrogen, trifluoromethyl when X is halogen, with a compound of the formula 4 EMI36.2 or b) condensing a compound of the formula 5 EMI36.3 with a compound of the formula 6 EMI37.1 wherein X and Y are as defined above. 18. The compound 3-( 'd--chloropropyl)6-fluoro-l ,2- benzisoxazole. 19. A process for preparing 3-(g-chloropropyl)-6- fluoro-1,2-benzisoxazole which comprises cyclizing an oxime derivative having the formula of EMI37.2 where R is a substituent selected from the group consisting of EMI37.3 where alkyl is a straight or branched chain hydrocarbon substituent of 1 to 6 carbon atoms, and EMI37.4 20. The process as defined in claim 19 wherein said cyclization is carried out in the presence of an alkaline reagent. Patent claims for Austria: 1. A process for preparing a compound of the formula 1 EMI38.1 which comprises a) condensing a compound of the formula 2 EMI38.2 wherein X is hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl, and Y is hydrogen or trifluoromethyi with the proviso that Y is hydrogen when- X is as defined above, and Y is hydrogen, trifluoromethyl when X is halogen, with a compound of the formula 4 EMI38.3 or b) condensing a compound of the formula 5 EMI38.4 with a compound of the formula 6 EMI39.1 herein X and Y are as defined above. 2. A process for preparing 3-(&gamma;-chloropropyl)-6- fluoro-1,2-benzisoxazole which comprises cyclizing an oxime derivative having the formula of EMI39.2 where R is a substituent selected from the group consisting of EMI39.3 where alkyl is a straight or branched chain hydrocarbon substituent of 1 to 6 carbon atoms, and EMI39.4 3. The process as defined in claim 2 wherein said cyclization is carried out in the presence of an alkaline reagent.

Inventors: DAVIS, LARRY, EFFLAND, RICHARD CHARLES, KLEIN, JOSEPH THOMAS
Applicants: HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1982
Main classification: C07D413
IPC codes: C07C45, C07C49, C07D261