MXPA01000990A

MXPA01000990A - Treatment of anxiety disorders

Info

Publication number: MXPA01000990A
Application number: MXPA/A/2001/000990A
Authority: MX
Inventors: Lee Alan Phebus; Tammy Joy Sajdyk
Original assignee: Eli Lilly And Company*
Priority date: 1998-07-27
Filing date: 2001-01-26
Publication date: 2001-11-21

Abstract

The present invention provides a method for the treatment or prevention of anxiety disorders which comprises administering to a mammal in need of such treatment a serotonin 5-HT1F receptor antagonist.

Description

MEDICATIONS FOR THE TREATMENT OF ANXIETY DISORDERS Field of the Invention Alterations of anxiety represent the most prevalent type of psychiatric disorders in the United States. Anxiety disorders include panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, specific phobia, social phobia, and generalized anxiety disorders. All are characterized by restlessness, a sense of terrible appearance and affliction for no apparent reason. These alterations, if left untreated, reduce the quality of life and productivity of patients who suffer from them. In the United States alone, more than 23 million people suffer from anxiety disorders. The cost to society of these alterations is staggering, estimated in 1990 at $ 46.6 billion in the United States alone in direct and indirect costs.

BACKGROUND OF THE INVENTION The methods currently available for the treatment of anxiety disorders include behavioral therapy, REF. DO NOT. 1261S6 cognitive therapy, and relaxation techniques. These methods typically take a considerable amount of time to achieve their desired effect. To increase the rate or rate of recovery, these methods can be used in combination with a number of medications. Currently, the medications used include benzodiazepines, beta-blockers, buspirones, monoamine oxidase inhibitors, serotonin reuptake inhibitors, and tricyclic antidepressants, all of which have responsibilities associated with their use. Benzodiazepines potentially cause habituation and may cause somnolence; Beta-blockers can not be used if the patient has certain pre-existing medical conditions such as asthma. congestive heart failure, diabetes, vascular diseases, hyperthyroidism, or angina; buspirone has a long induction period before its beneficial effects are realized; patients who take oxidase inhibitors under strict dietary restrictions and there is potential for drug interactions, low blood pressure, moderate weight gain, reduced sexual response, and insomnia; inhibitors of serotonin reuptake can cause nausea, and delayed ejaculation; and tricyclic antidepressants can cause dry mouth, constipation, blurred vision, difficulty in urination, dizziness, low blood pressure and moderate weight gain. New methods are needed for the treatment of anxiety disorders, which avoid or diminish the responsibilities of current therapies. Serotonin (5-HT) has diverse physiological activity mediated by at least four classes of receptors, the most heterogeneous of which appears to be 5-HT ?. A human gene which expresses a fifth subtype 5-TH ?, called 5-HT? F, was isolated by Kao et al. (Pro. Na ti. Acad.Sci. USA, 90_, 408-412 (1993)) . This 5-HT1F receptor has a pharmacological profile distinct from any serotonergic receptor already described. While 5-HT? F receptor agonists are known to be used for the treatment and prevention of migraine pain (Audia, et al., U.S. Patent No. 5,698,571), the utility of 5-HT? F receptor antagonists. for the treatment of anxiety disorders is unknown to date. - * _tfaa¿3Si_ £ __-: V. Description of the Invention The present invention provides a method for the treatment or prevention of anxiety disorders, which comprises the administration to a mammal in need of such treatment, of an effective amount of a 5-HT? F antagonist of the serotonin The present invention also provides a method for the prevention of anxiety disorders, which comprises administration to a mammal susceptible to such disturbances., of an effective amount of a 5-HT? F antagonist of sero tonine. The present invention provides a method for the treatment or prevention of anxiety disorders, which relapses into a new mechanism of action. This method comprises treating a mammal that suffers from or is susceptible to alterations of anxiety, with a compound which is an antagonist to the 5-HT? F receptor. This mechanism is operative in mammals and the preferred mammal is a human. A further embodiment of this invention comprises the administration of a composition which exhibits 5-HTiF antagonist activity. The The composition can be composed of one or more agents, which, individually or together, are antagonists of the 5-HT? F receptor. An especially preferred embodiment of this invention comprises the administration of a compound or composition, which is a selective antagonist to the 5-HT? F receptor relative to other serotonin receptors. While a compound or composition having some selectivity for the 5-HT.sub.r receptor relative to other serotonin receptors is preferred, a compound or composition having at least about 10 times selectivity for the 5-HT receptor is more preferred. HT? F relative to other serotonin receptors. It is more preferred that the compound or composition has at least about 100 times selectivity for the 5-HT? F receptor. The term "5-HT? F antagonist," as used in the description of this invention, is taken to mean a complete antagonist to the 5-HT? F receptor, a partial antagonist to the 5-HTF receptor, or an inverse agonist to the 5-HT? F receptor. The term "complete antagonist" as used in this invention is taken to mean a compound or composition with affinity for the 5-HT? F receptor, which also exhibits an intrinsic activity of about 15% or less of the maximum effect of serotonin to the 5-HT_F receptor. The use of a complete antagonist is a preferred embodiment of the present invention. The term "partial antagonist", as used in this invention, is taken to mean a compound or composition with affinity for the 5-HT] _F receptor, which also exhibits a greater intrinsic activity of approximately 15% of the maximum effect of serotonin to the 5-HT? F receptor and still exert an anxiolytic effect at an acceptable two Ls. The use of a partial antagonist is another preferred embodiment of the present invention. Compounds which exhibit negative intrinsic activity, known to those skilled in the art as inverse agonists, are also employed for the method of the present invention. Inverse agonists of the 5-HTXF receptor bind to the 5-HT? F receptor, block the effects of agonists to the 5-HTXF receptor, and decrease the constitutive activity of the 5-HT? F receptor. The present invention provides a method for the treatment or prevention of disorders of - * ^ - ^ - t * fefe ^ - anxiety comprising administration to a mammal in need of such treatment of a 5-HT1F receptor antagonist. The principle of this invention is demonstrated by the use of the 5-HT? F antagonists of Formula I: wherein: R and R 'are independently hydrogen or hydroxy; AR 1 is phenyl, naphthyl, quinolinyl, isoquinolinyl, indanyl, 1, 2, 3, 4-1 and rahydronaphthyl, indolyl, N- (C 1 -C alkyl) indole, benzothiazolyl, benzothienyl, benzofuryl, 2, 3-dihydrobenzo t ienyl, 2,3-dihydrobenzofuryl, julolidinyl or dibenzofuryl, each optionally substituted with one or de-substituents independently selected from the group consisting of C-C6 alkyl, Ci-Cg acyl, benzoyl, C?-Cd alkoxy, phenoxy, alkylthio C_ -EC. trifluoromethyl, tri fluoromethoxy, or halo; AR2 is pir idin-3-yl, quinol in-3-yl, -a_ ^ fcaftl_trf ._____. ^ isoquinolin-4-yl or quinoxalin-2-yl; and pharmaceutically acceptable acid addition salts thereof. The general chemical terms used e: the above formulas have their usual meanings. For example, the term "alkyl" includes such groups as methyl, ethyl, n-propyl. isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, and the like. The term "alkoxy" includes methoxy, ethoxy, isopropoxy, butoxy, tert-butoxy, hexyloxy, and the like. The term "alkylthio" includes methylthio, ethylthio, isopropylthio, butylthio, tere-butylthio, hexylthio and the like. The term "acyl" includes formula, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl and the like. The term "halo" includes fluoro, chloro, bromo and iodo. The compounds of Formula I wherein R is hydroxy, possess an asymmetric carbon labeled with an asterisk in the following formula: As such, each of the compounds of the Formula exists not only as the racemate, but as individual R and S enantiomers as well: Compounds of Formula I include the individual R and S enantiomers, and mixtures thereof, including the racemates. Stations that the compounds of Formula I are amines, are basic in nature and consequently react with any number of organic and inorganic acids to form pharmaceutically acceptable acid addition salts. Since many of the three amines of the compounds of this invention are low melting amorphous oils or solids, it is It is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration. The acids commonly used to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, _ _. - ~. _- &; ,,. phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulonic acid, carbonic acid, 5-succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are also sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chlorine, bromine, iodine, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, mannolate, succinate, suberate, sebacate, fumarate, maleate, butm- 1, 4-dioate , hexin-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinium trobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylepropionate, phenylbutyl, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. The compounds of Formula I are prepared by standard synthetic organic methodology as illustrates in Synthetic Scheme I, where AR1, AP2 and R1 are as previously defined Synthetic Scheme I The compounds of the invention wherein R is hydrogen are prepared by reacting a substituted piperidine of Formula II with a 3-chloropropyl ether AR1 of Formula III under standard alkylation conditions. The requisite piperidine and the chloropropyl ether are combined in a mutual solvent, typically acetonitrile, with an appropriate base, typically sodium or potassium carbonate. ..t? .. ^ -. »... f > -5 »-Aaa _.?, The reaction is carried out at a temperature from about room temperature to about reflux until complete. At reflux temperature, the reactions are typically completed from about 12 to about 48 hours. The compounds of the invention are then isolated by standard extractive uptake and purified by chromatography or crystallization as appropriate. The pharmaceutically acceptable salts are then prepared if necessary or desired, under standard conditions. The compounds of Formula I wherein R is hydroxy, are prepared by reacting a substituted piperidine of Formula II with a glycidyl ether AR1 of Formula IV under standard nucleophilic displacement conditions. The requisite piperidine and the glycidyl ether are combined in a mutual solvent, typically methanol, and the mixture is heated to about reflux until the reaction is complete. At reflux temperatures, the reactions are typically completed from 12 to 48 hours. The compounds of the invention are then isolated by standard extractive uptake and purified by chromatography or crystallization as appropriate. The pharmaceutically acceptable salts are then prepared if necessary, under standard conditions. The 3-chloropropyl ethers AR1 of Formula III are prepared by O-alkylation of an appropriate AR1 alcohol with l-bromo-3-chloropropanoate as illustrated in Synthetic Scheme II, wherein AR1 is as previously described.

Synthetic Scheme II An appropriate alcohol is deprotonated with a suitable base, typically sodium hydride, in a suitable solvent, typically dimethylformamide, from about 0 ° C to about room temperature. The resulting anion is then reacted with 1-bromo-3-chloropropane at about room temperature for about 1 hour to about 2 days. The desired chloropropyl ether is isolated by normal extractive lifting. The compound can . '•! A ^ - IM ** - - * _I ^ *. . ^ _¿: be used as isolated for subsequent reactions, or purified by chromatography if necessary or desired. The 3-glycidyl ethers AR1 of Formula IV are prepared by the reaction of an appropriate AR1 alcohol with a glycidyl-3-nitrobenzenesulfonate as illustrated in Synthetic Scheme III, where AR1 is as previously defined.

Synthetic Scheme III The requisite anion is prepared as described above and then reacted with an appropriate glycidyl-3-nor trobenzene sulfonate at room temperature from about 1 to about 24 hours. The desired glycidyl ether is isolated by normal extractive lifting. The compound can be used as isolated for subsequent reactions, or purified by chromatography or crystallization if necessary or desired. The compounds of Formula II wherein R 'is hydroxy, are prepared by the process illustrated in Synthetic Scheme IV, where halide is chlorine, bromine or iodine and AR2 is as previously defined.

Synthetic Scheme IV AR2-halide An appropriate R "halide is reacted: with an alkyl lithium, typically n-butyllithium or sec-butyllithium, at about -100 to about -78 ° C from about 1 to about 4 hours in a suitable solvent, such as diethyl ether or tetrahydrofuran to AR2-LL formed in this manner, 1-tert-butoxycarbonyl-4-piperdone is added and the reaction is stirred from about 4 to about 24 hours at room temperature. The resulting alcohol is isolated by extractive extraction can be isolated for subsequent reactions or purified by chromatography if necessary. The alcohol is N-deprotected by reaction with trifluoroacetic acid in a suitable solvent, typically dichloromethane, at room temperature from about 4 to about 24 hours. The excess acid is neutralized with an appropriate base, typically sodium or potassium hydroxide, and the desired product isolated by normal extractive lifting. The 4-hydroxypiperidine can be used as is or purified by chromatography if necessary or desired. The compounds of formula II wherein R 'is hydrogen are prepared as illustrated in Synthetic Scheme V, wherein the halide and AR1 are as previously defined.

E squem S schema V AR -haluro 1. Alauillitio Trifluoroacetic acid XZ The halide AR is reacted with an alkyl lithium, typically n-butyllithium or sec-butyllithium, at about -78 ° C from 1 to about 4 hours in a suitable solvent, such as diethyl ether or tetrahydrofuran. To the AR2-LL formed in this manner, triisopropylborate is added and the reaction is stirred for about 4 to about 24 hours at room temperature. The resulting alcohol that is isolated by extractive uptake can be isolated by subsequent reactions or purified by chromatography or crystallization if necessary. The resulting boronic acid and l-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1, 2,5,6-tetrahydropyridine are reacted together with [1,1-bis (di phenylphosphino) -1-ferrocene] palladium II chloride in tetrahydrofuran containing lithium chloride, aqueous sodium carbonate methanol. The reaction is carried out at about reflux for about 1 to about 12 hours. The desired tetrahydropyridine is isolated by standard extractive uptake and can be used as an isolate for subsequent reactions or purified by chromatography if necessary or desired. The substituted 4-tetrahydropyridine is then hydrogenated in the presence of a precious metal catalyst, typically palladium on carbon, in a suitable solvent, typically lower alkanol such as methanol or ethanol. Hydrogenation can be performed at approximately L ; j & atmosphere at a temperature of about ambient to reflux. Additional charges of hydrogen may be required to completely reduce the double bond. The piperidine product is isolated by purification of the reaction mixture and concentration under reduced pressure. The N-tert-butyloxycarbonyl protecting group is removed by the trifluoroacetic acid treatment as previously described to provide the 4-substi tuted piperidines of Formula II. Where AR2 is quinoxalin-2-yl, the halide AR2 is directly coupled with 1-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1, 2, 5, 5,6-tetrahydropyridine in the presence of hexamethyl iodides, ta and tetrakis (triphenylphosphine)] palladium in 1,4-dioxane containing lithium chloride. The reaction is carried out at reflux for approximately 18 hours. The tetrahydropyridine is isolated and converted to a compound of Formula II by the procedures previously described. . _Ife £ «» Preparation I 1-tere-butoxy carbonyl-4-piperidone A solution of 9.0 gm (61.5 mMol) 4-piperidone hydrochloride monohydrate in dioxane / water at 0 ° C was treated sequentially with aqueous sodium carbonate and 14.4 gm (68 mMol) of 2,2-dimethylpropanoic anhydride (anhydride) BOC). The resulting suspension was stirred vigorously at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with ethyl acetate. This mixture was treated with 1.5 M aqueous sodium hydrogen sulfate until the pH was approximately 2. The layers were separated and the remaining organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to give 9.8 gm (80%) of the title compound as a tan solid. 20 EA: Calculated for: C? 0H? 7NO3: Theory: C, 60.28; H, 8.60; N, 7.03. Found: C, 60.12; H, 8.54; N, 7.11. MS (m / e): 199 (M +) < Y. < tf & .. and ííix * Z? l »« -S, .-, / * - - -. j ^^^ _, _ áS__a * ._ ft-- ... Afe .- »» .-. > The glycidylaryl ethers required for the synthesis of the compounds of the present invention are prepared from the appropriate alcohol by the method described in detail in Preparation II.

Preparation II (2S) -glycidyl indol-4-yl ether A suspension of 0.53 gm (13.3 mMol), sodium hydride (60% dispersion in mineral oil) in 25 mL of dimethylformamide was cooled to 0 ° C under a nitrogen atmosphere. To this suspension was added 1.62 gm (12.2 mMol) of 4-hydroxy-indole for 30 minutes and the reaction mixture was allowed to stir at room temperature for 2 hours. To the reaction mixture was then added dropwise, a solution of 3.0 gm (11.5 mMol) of (2S) - (+) - glycidyl-3-nor trobenzenesulfonate (Aldrich Chemical Co., Milwaukee, Wl, USA) in 10 mL of dimethylformamide and the resulting mixture was stirred at room temperature for an additional 1.5 hours. The reaction mixture was then diluted with 100 mL of water and extracted well with ethyl acetate. The acetate phases of: The ethyl acetate was combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on flash silica gel, eluting with dichloromethane. The fractions containing the product were combined and concentrated under reduced pressure to provide 1.34 gm (62%) of the title compound as a yellow solid.

Preparation III (2 S) -glycidyl 1-methylindol-4-yl ether A suspension of 0.111 gm (0.28 mMol) of sodium hydride (60% dispersion in mineral oil) in dimethylformamide was cooled to 0 ° C under a nitrogen atmosphere. To this suspension was added 0.50 gm (2.6 mMol) of (2S) -glycidyl indol-4-yl ether and the reaction mixture was stirred at room temperature for 20 minutes. To the reaction mixture was then added, in the form of drops, 0.17 mL (2.8 mMol) of iodomethane and the mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with water and extracted well with - _S _- »& lllfi_i_ »s¿ fifca. > . ethyl acetate. The ethyl acetate phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on flash silica gel, eluting with 20% ethyl acetate. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.376 gm (70%) of the title compound as a white waxy solid. The 3-chloropropylaryl esters required for the synthesis of the compounds of Formula I were prepared from the appropriate alcohol by the method described in detail in Preparation III.

Preparation IV 3-Chloropropyl indole-4-yl ether A suspension of 1.6 gm (39.7 mMol) of sodium hydride (60% dispersion in mineral oil) in 80 mL of dimethylformamide was cooled to 0 ° C under a nitrogen atmosphere. This -c_fw "_- * - < * * A- -. _fe ^ fe ^ t __________. ^.-_____ suspension was added 5.0 gm (37.6 mMol) of 4-hydroxy-indole in portions for 30 minutes. The reaction was stirred at room temperature for 1.5 hours, after this addition was complete.To the resulting mixture was then added dropwise a solution of 5.91 gm (37.6 mMol) of 1-bromo-3-chloropropane in dimethylformamide and the mixture The reaction mixture was stirred for 18 hours at room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate.The ethyl acetate phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure, the residue was subjected to chromatography on flash silica gel, eluting with 10% ethyl acetate in hexanes.The fractions containing the product were combined and concentrated under reduced pressure. to provide 4.6 2 gm (591) of the title compound.

The 4-aryl-4-hydroxypiperidines required for the synthesis of the compounds of Formula I were prepared from the appropriate aryl halide and N-protected-4-piperidone by the method described in detail in Preparation IV.

AA, Preparation V 4- (isoquinolin-4-yl) -4-hydroxypiperidine A solution of 6.46 gm (31.1 mMol) of 4-bromoisoquinoline in 80 mL of tetrahydrofuran was cooled to -100 ° C under a nitrogen atmosphere. To this solution was added dropwise 28.7 mL (37.3 mMol) of sec-butyllithium (1.3 M in hexanes) and the reaction mixture was allowed to stir for 1.5 hours. To the reaction mixture was then added dropwise a solution of l-tert-butoxycarbonyl-4-piperidone in 120 mL of tetrahydrofuran in the form of drops. The reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 9: 1 dichloromethane: methanol. The fractions containing the product were combined and concentrated under reduced pressure to provide 3.95 (39%) of 1-tert-butoxycarbonyl-4- (isoquin-olin-4-yl) -4-hydroxypiperidine as a yellow solid. A mixture of 2.0 gm (6.1 mMol) of 1-tert-butoxycarbonyl-4- (isoquinolin-4-yl) -4-5 hydroxypiperidine, and 4 mL of trifluoroacetic acid in 20 mL of dichloromethane was stirred at room temperature for 20 minutes. hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash silica gel, eluting with dichloromethane containing from 10% to 40% methanol and traces of ammonium hydroxide. The fractions containing the product were combined and concentrated under reduced pressure to give 0.793 gm (57%) of the title compound as a slightly yellow solid. MS (m / e): 228 (M +) Calculated for C? 4H? 6N20-0.25 H20: Theory: C, 72.94; H, 7.10; N, 12.15. Found: C, 72.97; H, 7.09; N, 12.26. < ! & > & - > »Ts? ^ É? ~ &Ns? Z,. '»< _- _-, - ", 3í £ & ¿ÍISi¡? Ii« i¿¡? Is?, ~ V «t« "** ¡. - = áSfeíí- / »» Preparation VI 4- (quinolin-3-yl) -4-hydroxypiperidine Starting with 7.46 gm (35.9 mMol) 3-bromoquinoline, 7.25 gm (62%) N-tert-butoxycarbonyl-4- (quinolin-3-yl) -4-hydroxypiperidine, it was recovered as a light yellow solid by the procedure described in detail in Preparation IV. Starting with 1.5 gm (4.6 mMol) N-tert-butoxy-carbonyl-4- (quinolin-3-yl) -4-hydroxypiperidine, 0.645 gm (62%) of the title compound was recovered as a lightly tanned solid, by procedure described in detail in Preparation IV. MS (m / e): 228 (M +) Calculated for C? 4H15N20- 0.25 H20: Theory: C, 72.23; H, 7.14; N, 12.03. Found: C, 72.41; H, 7.12; N, 12.89.

Preparation VII l-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-, 2, 5, 5, 6-tetrahydropyridine A solution of 1.2 mL (8.2 mMol) of ^ A_Lwto ^ _ ^ í ^, »_ ^^^^^^^^^^^ __ ___i. -diisopropylamine in 15 mL of tetrahydrofuran was cooled to -78 ° C. To this solution, 5 mL (7.9 mMol) of n-butyl-1-thio (1.6 M in hexanes) was added dropwise and the reaction mixture was stirred for 1.5 h at -78 ° C and then allowed to warm room temperature. The resulting solution was cooled again to -78 ° C and then a solution of 1.56 gm (7.8 mMol) of N-tert-butoxycarbonyl-4-piperidone in tetrahydrofuran was added in the form of drops. After about 30 minutes, a solution of 3.0 gm (8.4 mMol) N-phenyltrifluoromethanesulfonimide in tetrahydrofuran was added as drops. The reaction mixture was allowed to warm gradually to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and placed on a neutral alumina pad. The alumina column was eluted with hexanes: ethyl acetate 9: 1. The fractions containing the product were combined and concentrated under reduced pressure to provide 2.24 gm (86%) of the title compound as an oil. . _? > sj »> . "^", M ^ gJBfe «a Preparation VIII 4- (Isoquinolin-4-yl) piperidine oxalate A solution of 2.0 gm (9.6 mMol) 4-bromoisoquinoline in 30 mL of tetrahydrofuran was cooled to -100 ° C. solution was added in the form of droplets 6.3 Ml (10.1 mMol) of n-butyllithium (1.6 M in hexanes) in the form of drops, and the resulting solution was stirred for 30 minutes, then this solution was added in the form of drops a solution of 4.4 mL (19.2 mMol) of triisopropylborate and the reaction mixture was then stirred for 18 hours at room temperature, then the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride. The aqueous phase was extracted well with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure, the residue being sonicated in a mixture of hexane: ethyl acetate. The resulting suspension was filtered for to give 0.57 gm (34%) of isoquinolin-4-ylboronic acid as a light orange solid. A mixture of 2.5 gm (14.5 mMol) of β-soquinolin-4-ylboronic acid, 3.43 gm (10.3 mMol) of 1-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-, 2, 5, 5,6-tetrahydropyridine, 1.3 gm ( 30.9 mMol) in lithium chloride, 0.04 gm (0.05 mMol) [1, 1 '-bis (diphenylphosphino) -1-ferrocene] palladium II chloride, and 2 mL of aqueous sodium carbonate in approximately 20 mL of tetrahydrofuran containing a few drops of methanol, was stirred at reflux for about 4 hours. The reaction was cooled to room temperature and then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash silica gel, eluting with 3: 2 hexane: ethyl acetate. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.216 gm (57%) of 1-tert-butoxycarbonyl-4- (isoquinolin-4-yl) -1,2,5,6-tetrahydro-pyridine as a slightly yellow oil. A mixture of 0.91 gm (2.9 mMol) of 1-tert-butoxycarbonyl-4- (isoquinolin-4-yl) -1,2,5,6-tetrahydropyridine and 0.1 gm of palladium on 5% carbon in 40 mL of methanol , was stirred at room temperature for 3 days under a nitrogen atmosphere.

The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on flash silica gel, eluting with 1: 1 ethyl acetate: hexanes. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.57 gm (63%) of 1-tert-butoxycarbonyl-4- (isoquinolin-4-yl) -piperidine as a clear oil. A mixture of 0.57 gm (1.8 mMol) of 1-tert-butoxycarbonyl-4- (isoquinolin-4-yl) piperidine and 6 mL of trifluoroacetic acid in 6 mL of dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash silica gel, eluting with dichloromethane containing from 10% to 40% methanol and traces of ammonium hydroxide. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.242 gm (63%) of 4- (so soqumolin-4-yl) piperidine as a tan solid. A portion of this material was converted to the oxalate salt to provide the title compound. MS (m / e): 212 (M +). Cal crated for C? 6H1 8N204 - 0. 25 H20: Theory: C, 62. 63; H, 6.08; N, 9.13. Found: C, 62.22; H, 5.99; N, 9. 04 Preparation IX 4- (quinolin-3-yl) piperidine Beginning with 3-bromoquinoline, the title compound was recovered as a clear oil by the procedure described in detail in Preparation VII. MS (m / e): 212 (M +) Preparation X 4- (pyridin-3-yl) piperidine Beginning with 3-bromopyridine, the title compound was recovered as a slightly tanned waxy solid, by the procedure described in detail in Preparation VII. A small amount of this material was converted to the salt of iiá ^ - a¡_8ii__e < ar. oxalate. MS (m / e): 162 (M +) Calculated for C? 2H16N2O.-0.75 H20: Theory: C, 54.23; H, 6.07; N, 10.53. Found: C, 54.30; H, 5.96; N, 10.14.

Preparation XI 4- (quinoxalin-2-yl) piperidine A mixture of 1.4 gm (8.5 mMol) 2-chloroquinoxaline, 2.82 gm (8.5 mMol) 1-tert-butoxycarbonyl 1-4 -tri fluoromethanesulfonyloxy-1, 2.5, 6-tetrahydropyridine, 2.8 gm (8.5 mMol, hexamethyl ildies, 1.08 gm (25.5 mMol), lithium chloride, and 0.491 gm (0.43 mMol [tetrakis (tri phenylphosphine)] palladium in dioxane, was stirred under reflux for 18 hours. The reaction mixture was cooled to room temperature and then poured into a mixture of saturated aqueous potassium fluoride and ethyl acetate.After stirring for two hours, the phases were separated.The organic phase was washed with saturated sodium chloride The residue was dried over magnesium sulfate and concentrated under reduced pressure, the residue was chromatographed on flash silica gel, eluting with a gradient.

^ ¿, Z ^ t &M • á.fc '.-... »< - ^ £ ^^^^ a | e ^^^ £ from 100: 0 to 25: 3 hexanes: ethyl acetate. The fractions containing the product were combined and concentrated under reduced pressure to provide 1.43 gm (54%) of 1-tert-butoxy-carbonyl-4- (quinoxalin-2-yl) -1, 2, 5, 6- tet rahidropiridma as a slightly yellow oil. A mixture of 0.55 gm (1.8 mMol) 1-tert-butoxycarbon-yl-4- (quinoxalin-2-yl) -1, 2, 5, 6-tetrahydropyridine and 0.1 gm palladium on 5% carbon in 10 mL of methanol , was stirred at room temperature for 45 minutes under a hydrogen atmosphere. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to provide 0.47 gm (84%) of 1- tert -butoxycarboni 1-4- (quinoxalin-2-yl) piper idine as a yellow oil. A mixture of 0.47 gm (1.5 mMol) of 1-tert-butoxycarbonyl-4- (quinoxalin-2-y1) pipepdine and 5 mj of trichloroacetic acid in 5 mL of dichloromethane were stirred at room temperature for 18 hours . The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is ^ £ ^^^^^^ a ^^^^^^^^^^^^ ____ 111 ____ ^^ _______ ^^^^^^^ 3 ^^^^^^ ^^^^^^^^^^^^^^^^^ chromatography on flash silica gel, eluting with dichloromethane containing from 01% to 40% methanol and ammonium hydroxide residues. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.133 gm (42%) of the title compound as a foam.

EXAMPLE 1 1- (3-phenoxyprop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine oxalate A mixture of 0.112 gm was heated to reflux (0.7 mMol) 3-chloropropyl ether phenyl, 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, and 0. 136 gm (1.5 mMol) potassium carbonate in 5 mL of acetonitrile for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase was bier extracted. with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is ? ^ _ a ^ l_ »^ ^^ - ^^ - '2 ^^^^^ J- ^^^' * * & *. & * - chromatographed on flash silica gel, elution with 25: 2 dichloromethane: methanol. The fractions containing the product were combined and concentrated under reduced pressure to provide 0.142 gm (60%) of 1- (3-phenoxyprop-1-yl) -4-hydroxy-4- (quinolin-3-y1) piperidine as a slightly yellow viscous oil. The oil was converted to the oxalate salt to provide the title compound. p.f. = 76 ° C MS (m / e): 362 (M +) The compounds of Examples 2-12 were prepared by the procedure described in detail in Example 1.

EXAMPLE 2 1- (3- (2-tert-butyl phenoxy) prop-1-yl) -4-hydroxy-4- (quinol in-3-yl) piperidine Starting with 0.298 gm (1.3 mMol) 3-chloropropyl ether 2-tert-butylphenyl and 0.300 gm (1.3 mMol) 4-hydroxy-4- (quinol in-3-y1) piperidine, 0.212 gm (39%) of the compound of the title became like a waxy, white solid. MS (m / e): 418 (M +) Calcium for C27H3. N202: Theory: C, 77. 4 8; H, 19, N, 6.69. Found: C, 77.64; H, 8.40; N, 6.91 EXAMPLE 3 1- (3- (3, 4-dimethylphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) iperidine Starting with 0.218 gm (1.1 mMol) 3-chloropropyl ether 3, 4-dimet i 1 phenyl and 0.250 gm (1.1 mMol) 4-hydroxy-4- (quinol in-3-y1) piperidine, 0.114 gm (27%) of the title compound were converted as a white solid. MS (m / e): 391 (M + l) Calculated for C25H30N2O2-0.25 H20: Theory: C, 76.01; H, 7.85; N, 7.15. Found: C, 75.96; H, 7.57; N, 7.07.

EXAMPLE 4 1- (3- (2,4-dimethylphenoxy) prop-1-yl) -4-hydroxy-4- (quinol-3-yl) piperidine Starting with 0.235 gm (1.2 mMol) 3-chloropropyl ether 2,4-dimethylphenyl and 0.270 gm (1.2 mMol) 4-hydroxy-4- (quinolin-3-y1) piperidine, 0.209 (45%) of the title compound They became like a white solid. MS (m / e): 390 (M +) Calculated for C25H30N2O2-0.25 H20: Theory: C, 76.01; H, 7.85; N, 7.15. Found: C, 76.08; H, 7.56; N, 7.07.

EXAMPLE 5 1- (3- (2,4-Dichlorophenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine oxalate Starting with 0.314 gm (1.3 mMol) 3-chloropropyl ether 2,4-dichlorophenyl and 0.300 gm (1.3 mMol) 4-hydroxy? -4- (quinol in 3-i 1) piperidine, 0.277 gm (49%) 1- (3- (2,4-dichlorophenoxy) prop-1-yl) -4-hydroxy-4- (quinolm-3-yl) piperidine were converted as a white, waxy solid. A portion was converted to the oxalate salt. p.f. = 118 ° C MS (m / e): 430 (M +) Calculated for C23H2.fr2? 2Cl2-C2H204: Theory: C, 57.59; H, 5.02; N, 5.37. Found: C, 57.83; H, 5.07; N, 5.49.

EXAMPLE 6 1- (3- (2,6-dimethoxyphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine oxalate Starting with 0.303 gm (1.3 mMol) 3-chloropropyl ether 2,4-dichlorophenyl and 0.300 gm (1.3 mMol) 4-hydroxy-4- (quinol in 3-i 1) piperidine, 0.318 gm (57%) of 1 - (3- (2,6-dimethoxyphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine were converted as a white foam. A portion was converted to the oxalate salt. p.f. = 102 ° C MS (m / e): 422 (M +) EXAMPLE 7 1- (3- (indol-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinol in 3-yl) piperidine Starting with 0.253 gm (1.2 mMol) 3-chloropropyl ether ndol-4-yl and 0.275 gm (1.2 mMol) 4- ~ I * ié &bJL _-. ^, - .- > < • -. - * ri »M_ Mft_IM_ahA»; Mw?. «*» -. < ^ »~». - • "» - * - i »-?,.« A & ys. hydroxy-4- (quinolin-3-yl) piperidine, 0.253 gm (52?) of the title compound were converted as a white solid. MS (m / e): 401 (M +) Ca l crated for C25H27N302: T eor: C, 74. 79; H, 6 7 8; N, 10.47. Found: C, 74.66; H, 6.87; N, 10.43.

EXAMPLE 8 10 1- (3- (indo 1-4-yloxy) prop-1-yl) -4-hydroxy-4- (isoquinolin-4-yl) piperidine Starting with 0.184 gm (0.88 mMol) 3-chloropropyl ether ? ndol-4-? lo and 0.200 gm (0.88 mMol) 4- hydroxy-4- (isoquinolin-4-yl) piperidine, 0.169 gm (48%) of the title compound were converted as a light yellow solid. MS (m / e): 401 (Mt) Calculated for C25H27N302: Theory: C, 74.79; H, 6.78; N, 10.47. Found: C, 74.51; H, 6.76; N, 10.43. twenty EXAMPLE 9 1- (3- (indol-5-yloxy) prop-1-yl) -4-hydroxy-4- (quino lin • 3-yl) piperidine 25 Starting with 0.275 gm (1.3 mMol) 3-chloropropyl indol-5-yl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.238 gm (45%) of the title compound they became like a whitish solid. MS (m / e): 401 (M +) Calculated for C25H27N302: Theory: C, 74.79; H, 6.78; N, 10.47. Found: C, 74.77; H, 6.73; N, 10.36.

EXAMPLE 10 1- (3- (2, 2-dimet i 1-2, 3-dihydroxybenzofur-7-yloxy) prop-1-yl) -4-hydroxy-4- (qu? Nolm-3-yl) p? perina Starting with 0.316 gm (1.3 mMOl) ether? 3-chloropropyl 2,2-dimet-l-2,3-dihydrobenzofur-7-yl and 0.300 gm (1.3 mMol) 4-hydroxy-4- (qumolm-3-yl) piperidma, 0.262 gm (46%) of the title compound were converted as a white solid. MS (m / e): 432 (M +) Calculated for C27H32N_0_: Theory: C, 74.97; H, 7.46; N, 6.48. Found: C, 75.25; H, 7.73; N, 6.68.

EXAMPLE 11 1- (3- (Indol-4-yloxy) prop-1-yl) -4- (isoquinolin-4-yl) piperidine oxalate Starting with 0.109 gm (0.5 mMol) ether of ' 3-chloropropyl indol-4-yl and 0.110 gm (0.5 mMol) 4- (isoquinolin-4-yl) piperidine, 0.112 gm (56%) of l- (3- (indol- 4 -i loxi) prop-l- il) -4- (isoquinolin-4-yl) piperidine were converted as a whitish solid. A portion was converted to the oxalate salt. p.f. = 99 ° C MS (m / e): 385 (Mt) Calculated for C25H27N3o-C2H2? 4-0.75 H20: Theory: C, 66.32; H, 6.24; N, 8.59. Found: C, 66.54; H, 6.23; N, 8.88.

EXAMPLE 12 1- (3- (Indole-4-yloxy) prop-1-yl) -4- (quinolin-3-yl) piperidine Starting with 0.175 gm (0.83 mMol) ether of 3-chloropropyl indol-4-yl and 0.177 gm (0.83 mMol) 4- (quinolin-3-yl) piperidine, 0.217 gm (68%) of the title compound were converted as an off-white solid. MS (m / e): 385 (M +) Calcium for C25H27N3o: Theory: C, 77. 8 9; H, 7 0 6; N, 10.90. Found: C, 77.66; H, 7.07; N, 10.68.

EXAMPLE 13 1- ((2R, S) -hydroxy-3-phenoxyprop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine A mixture of 0.18 mL (1.3 mMol) ether of (2R, S) -glycidyl phenyl and 0.300 gm (1.3 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine in 10 mL of methanol was heated to reflux. 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash silica gel, eluting with 25: 1 dichloromethane methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.209 gm (42%) of the title compound as a waxy, tan solid. MS (m / e): 378 (M +) 5 Calculated for C23H26N203: Theory: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.53; H, 6.78; N, 7.33.

The compounds of Examples 14-60 were prepared by the procedure described in detail 10 in Example 13.

EXAMPLE 14 1- ((2S) -hydroxy-3- (4-methylphenoxy) prop-1-yl) -4- 15 hydroxy-4- (quin lin-3-yl) piperidine Starting with 0.108 gm (0.7 mMol) ether of (S) -glycidyl 4-methephenol and 0.150 gm (0.7 mMol) 4- h? Drox? -4- (quinol in-3-yl) piperidine, 0.175 gm (68 %) 0 of the title compound were converted as a white solid. MS (m / e): 392 (M +) Calculated for C 24 H 28 N 2 O 3-O. 5 H 20: Theory: C, 71.80; H, 7.28; N, 6.98. Found: C, 72.01; H, 6.99; N, 5 7.03.

EXAMPLE 15 1- ((2S) -hydroxy-3- (4-ethylphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.117 gm (0.7 mMol) ether of (S) -glycidyl 4-ethylphenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.100 gm (37%) of the title compound were converted as a waxy solid ur. This material was converted to the oxalate salt. p.f. = 76 ° C MS (m / e): 406 (M +) Ca l crated for C25H3oN203-C2H20. : Theory: C, 65. 3 1; H, 6. fifty; N, 5.64. Found: C, 65.23; H, 6.46; N, 5.56.

EXAMPLE 16 1- ((2S) -hydroxy-3- (4-isopropyl phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.126 gm (0.7 mMol) ether of (S) -glycidyl 4- isopropyl phenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinol in 3-i 1) piperidine, 0.121 gm (44%) of the composed of the title they became like a * i? ~ * & klk &i? íz > ~, _y .. «- * & solid slightly yellow. This material was converted to the oxalate salt. MS (m / e): 421 (M + 1) Calculated for C 25 H 3 o N 2? 3-C 2 H 204-0.5 H 20: Theory: C, 64.72; H, 6.79; N, 5.39. Found: C, 64.61; H, 6.75; N, 5.39.

EXAMPLE 17 1- ((2S) -hydroxy-3- (4-tert-butyl phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.136 gm (0.7 mMol) ether (S) -glycidyl 4-tert-butyl phenyl and 0.150 gm (0.7 mMol) 4- hydroxy-4- (quinolm-3- 11) piperidine, 0.115 gm (40%) of the compound of the title became a white foam. MS (m / e): 434 (M +) Calculated for C H34N1OJ-0.5 H20: Theory: C, 73.11; H, 7.95; N, 6.32. Found: C, 72.92; H, 7.53; N, 6.48.

EXAMPLE 18 1- ((2S) -hydroxy-3- (4-chlorophenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.121 gm (0.7 mMol) of (S) -glycidyl 4-chlorophenyl ether and 0.150 gm (0.7 mMol) 4- hydroxy-4- (quinolin-3-yl) piperidine, 0.156 gm (58%) of the title compound They became like whitish foam. Calculated for C23H25N203C1: Theory: C, 66.90; H, 6.10; N, 6.78. Found: C, 66.73; H, 6.00; N, 6.94. This foam was converted to the oxalate salt. p.f. = 81 ° C MS (m / e): 413 (Mt) Calcium for C23H25 2O3C I - C2H2O4: T eor: C, 59. 70; H, 5.41; N, 5.57. Found: C, 59.58; H, 5.70; N, 5.58.

EXAMPLE 19 1- ((2S) -h? Droxi-3- (4-iodophenoxy) prop-l-? L) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.181 gm (0.7 mMol) ether of (S) -glycidyl 4-iodo-phenyl and 0.150 gm (0.7 mMol) 4- hydroxy-4- (quinolin-3?) Piperidine, 0.201 gm (61%) of the compound of the title became a white solid. This solid was converted to the oxalate salt. MS (m / e): 504 (M +) Calculated for C23H25N2? 3l-C2H2? 4: Theory: C, 50.52; H, 4.58; N, 4.72. Found: C, 50.40; H, 4.70; N, 4.42.

EXAMPLE 20 1- ((2S) -hydroxy-3- (4-tp-fluoromethyl-1-phenoxy) prop-1-yl) 4-hydroxy-4- (q mol-3-yl) piperidine Starting with 0.143 gm (0.7 mMol) of (S) -glycidyl 4-trifluoromethylphenyl ether and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.200 gm (68%) of the title compound They became like a white solid. MS (m / e): 446 (M +) Calculated for C 24 H 25 N 2 O 3 F 3 -O .25 H 20: Theory: C, 63.92; H, 5.70; N, 6.21. Found: C, 63.85; H, 5.58; N, 6.22.

EXAMPLE 21 1- ((2S) -hydroxy-3- (2-methoxy phenoxy) prop-1-yl) -4-hydroxy-4- (quin lin-3-yl) piperidine Starting with 0.118 gm (0.7 mMol) ether of (S) -glycidyl 2-methoxy phenyl and 0.150 gm (0.7 mMol) 4-h? Drox? -4- (quinolin-3-yl) piperidine, 0.145 gm (54%) of the title compound were converted as a white foam . Calculated for C24H28N2? 4-0.75 H20: Theory: C, 68.31; H, 7.05; N, 6.64. Found: C, 68.61; H, 6.83; Nr 6. 56. [a] D25 (methanol) = + 11.719 ° This foam was converted to the oxalate salt. p.f. = 182-185 ° C MS (m / e): 408 (M +) Calculated for C2.H2flN2? _- C: H2? 4: Theory: C, 62.64; H; 6. 07; N, 5.62. Found: C, 62.51; H, 6.13; N, 5.46. [a] D25 (methanol; -8,741) * .v ¿¡"< s_fr- 5, - a. • aa ii &ampflfiB-faith * -: ^ .- »- ~ _. - > * - EXAMPLE 22 1- ((2S) -hydroxy-3- (3-methox-phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidma Starting with 0.118 gm (0.7 mMol) ether of (S) -glycidyl 3-methox? phenyl and 0.150 gm (0.7 mMol) 4- h? drox? -4- (quinolin-3-yl) piperidine, 0.179 gm (67%? of the title compound were converted as a white foam, calculated for C24H28N2? 4-0.25 H20: Theory: C, 69.80: H, 6.96; N, 6.78, Found: C, 69.57; H, 6.74; N ,, 6.92. [A] D25 (methanol) = + 25.254 ° This foam was converted to the salt of oxalate mp = 79 ° C MS (m / e): 408 (M +) Calculated for C 24 H 28 N 2 4 4-C 2 H 2 4 4-2 H 20: Theory: C, 58.42; H, 6.41; N, 5.24 Found: C, 58.45; H, 5.67; N, 5.27. [A] D25 (methanol) = -15.444 ° EXAMPLE 23 1- ((2S) -hydroxy-3- (4-methoxy-phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.118 gm (0.7 mMol) ether of (S) -glycidyl 4-methoxyphenyl and 0.150 gm (0.7 mMol) 4-h? Drox? -4- (quinolin-3-yl) piperidine, 0.168 gm (63%) of the title compound were converted as a white waxy solid . Calculated for C24H28N204: Theory: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.58; H, 7.04; N, 7.01. [a] D25 (methanol) = + 12.635 ° This foam was converted to the oxalate salt. p.f. = 63 ° C MS (m / e): 408 (M +) Catalyzed by C 24 H 28 N 2? 4 -C 2 H 2 O 4 - 0. 75 H20: T eo rí a: C, 60. 99; H, 6.20; N, 5.47. Found: C, 60.89; H, 6. 3. 4; N, 5.47. [to. [methanol) = -7,843 ° EXAMPLE 24 1- ((2S) -hydroxy-3- (4-tri fluorometoxyphenoxy) prop-1-yl) -4-hydroxy-4- (quinol? N-3-yl) piperidine Starting at 0.154 gm (0.7 mMol) ether; (S) -glycidyl 4-trifluoromethoxyphenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.207 gn (68%) of the title compound were converted as a white foam. This foam was converted to the oxalate salt. MS (m / e): 462 (M +) Calculated for C 24 H 28 N 2? 4 F 3: Theory: C, 56.52; H, 4.93; N, 5.07. Found: C, 56.46; H, 4.77; N, 4.86.

EXAMPLE 25 1- ((2S) -hydrox? -3- (4-phenoxyphenoxy) prop-1-yl) -4-hydroxy-4- (quin lin-3-yl) piperidine Starting with 0.169 gm (0.7 mMol) ether of (S) -glycidyl 4-phenoxy phenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.117 gm (38%) of the compound of title became a slightly yellow foam. This foam was converted to the oxalate salt. p.f. = 63 ° C MS (m / e): 470 (M +) Calculated for C2.H3.N2? 4-C2H2? 4: Theory: C, 66.42; H, 5.75; N, 5.00. Found: C, 66.23; H, 5.88; N, 5.07 EXAMPLE 26 1- ((2S) -hydroxy-3- (2-methylthiophenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.300 gm (1.5 mMol) ether of (S) -glycidyl 2-methylthiophenyl and 0.349 gm (1.5 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.333 gm (51%) of the title compound were converted as a white solid. Calculated for C2.H28 2O3S: Theory: C, 67.90; H, 6.65; N, 6.60. Found: C, 68.08; H, 6.70; N, 6.63. [a] D25 (methanol) = -3,984 ° This foam was converted to the oxalate salt. p.f. = 186-189 ° C MS (m / e): 424 (M +) Calculated for C 24 H 28 N 2 O 3 S-C 2 H 2 O 4: Theory: C, 60.69; H, . 88; N, 5.44. Found: C, 60.69; H, 5.74; N, . 43. ta] _5 methanol) = -30.361 EXAMPLE 27 1- ((2S) -hydroxy-3- (4-methylthiophenoxi) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.169 gm (0.7 mMol) of (S) -glycidyl 4-methylthiophenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.104 gm (22%) of the title compound They became like a white solid. This solid was converted to the oxalate salt. MS (m / e): 424 (M +) Calculated for C2.H28N2? 3S-C2H2? 4: Theory: C, 60.69; H, 5.88; N, 5.44. Found: C, 60.95; H, 6.07; N, 5.53.

EXAMPLE 28 2S) -hydroxy-3- (2,3-dimethylphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.117 gm (0.7 mMol) ether; (S) -glycidyl 2, 3-dimethylphenyl and 0.150 gm (0.7 mMol; 4-hydroxy-4- (quinolm-3-yl) piperidine, 0.152 gm (57% i of the title compound were converted as an off-white solid.

Calculated for C25H30 2O3: Theory: C, 73.86; H, 7.44; N, 6.89. Found: C, 77.59; H, 7.26; N, 6.90. [a] D25 (methanol) = + 5.714 ° This solid was converted to the salt of; oxalate. p.f. = 72 ° C MS (m / e): 406 (M +) Calculated for C25H3o 2? 3-C2H204: Theory: C, 65.31; H, 6.50; N, 5.64. Found: C, 65.13; H, 6.58; N, 5.63. [a] D25 (methanol) = -21.016 ° EXAMPLE 29 1- ((2S) -hydroxy-3- (3,4-dimethyl phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.117 gm (0.7 mMol) of (S) -glycidyl 3,4-dimethylphenyl ether and 0.150 gm (0.7 mMol, 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.163 gm (61%) of the compound The title was converted to a whitish solid, calculated for C25H3.N2O3: Theory: C, 73.86; H, 7.44, N, 6.89, Found: C, 73.64; H, 7.53; N, 6.82. [a] D25 (methanol) = + 10.0381 ° This solid became the salt of; oxalate. p.f. = 117 ° C MS (m / e): 406 (M +) [a] D25 (methanol) = -5,455 ° EXAMPLE 30 1- ((2S) -hydroxy-3- (2,4-dimethyl-phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.180 gm (1.0 mMol) ether of (S) -glycidyl 2,4-dimethylphenyl and 0.231 gm (1.0 mMol) 4-hydroxy-4- (quinol in-3-y1) piperidine, 0.318 gm (77%) of the title compound were converted as a slightly pink solid. Calculated for C25H30 2O3: Theory: C, 73.86; H, 7.44; N, 6.89. Found: C, 73.70; H, 7.28; N, 6.61. [to; 25 [methanol] = + 7.38 ° This solid was converted to the oxalate salt. p.f. = 102 ° C MS (m / e): 406 (M +) [a] D 25 (methanol 5,747 al? tt _______________ _ EXAMPLE 31 1- ((2S) -hydroxy-3- (2,4-dichloro phenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.144 gm (0.7 mMol) ether of (S) -glycidyl 2,4-dichlorophenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.176 gm (60%) of the title compound were converted as a whitish solid ur. Calculated for C23H24N2? 3Cl2: Theory: C, 61.75; H, 5.41; N, 6.26. Found: C, 61.50; H, 5.60; N, 6.13. [a] D25 (methanol) = + 8.913 ° This solid was converted to the oxalate salt. p.f. = 86 ° C MS (m / e): 447 (M +) [a] D25 (methanol) = -3.521 ° EXAMPLE 32 1- ((2S) -hydroxy-3- (2-methoxy-4-methyl phenoxy) prop-1-yl) 4-hydroxy- (quinolin-3-yl) piperidine Starting with 0.091 gm (0.7 mMol) ether; v ^^^^^^^^^^^^ (S) -glycidyl 2-methoxy-4-methylphenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-y1) piperidine, 0.142 gm (59%) of the title compound became a whitish foam. Calculated for C25H30N2O4-0.50 H20: Theory: C, 69.58; H, 7.24; N, 6.49. Found: C, 69.45; H, 7.24; N, 6.43. This foam was converted to the salt of: oxalate. p.f. = 81 ° C MS (m / e): 422 (Mt) EXAMPLE 33 1- ((2S) -hydroxy-3- (2-methyl-4-methylthiophenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.138 gm (0.7 mMol) ether; (S) -glycidyl 2-methyl-4-methylthiophenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.184 gm (64%) of the title compound were converted as a slightly foam yellow. Calculated for C25H30N2O3S: Theory: C, 68.46; H, 6.90; N, 6.39. Found: C, 68.19; H, 6.67; N, 6.33. This foam was converted to the oxalate salt.

MS (m / e): 438 (M +) Calculated for C25H3oN2? 3S-C2H204: Theory: C, 61.35; H, 6. 10; N, 5.30. Found: C, 61.55; H, 6.14; N, . 1! EXAMPLE 34 1- ((2S) -hydroxy-3- (3-methyl-4-acetylphenoxy) prop-1-yl) -4-hydroxy-4- (qu? Nolin-3-yl) piperidine Starting with 0.135 gm (0.7 mMol) of (S) -glycidyl 3-methyl-4-acetyl-phenyl ether and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.147 gm (52%) of the title compound were converted to a whitish foam. This foam was converted to the oxalate salt. MS (m / e): 435 (M + 1) Calculated for C 26 H 3 o N 204-C 2 H 2 4 4-0.5 H20: Theory: C, 63.03; H, 6.23; N, 5.25. Found: C, 62.87; H, 6. 02; N, 5.31.

EXAMPLE 35 1- ((2S) -hydroxy-3- (2-methyl-4-acetylphenoxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.135 gm (0.7 mMol) ether of: (S) -glycidyl 2-methyl-4-acetylphenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.134 gn (49%) of the title compound became a whitish foam. Calculated for C26H3oN204: Theory: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.71; H, 6.86; N, 6.42. This foam was converted to the oxalate salt. p.f. = 90 ° C MS (m / e): 435 (M + l) EXAMPLE 36 1- ((2S) -hydroxy-3- (2-benzoyl-4-methyl-phenoxy) prop-1-yl) -4-hydroxy-4- (qumolin-3-yl) piperidine Starting with 0.176 gm (0.7 mMol) ether of (S) -glycidyl 2-benzoyl-4-methylphenyl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinol in-3-yl) piperidine, 0.199 gm (61%) of the title compound were converted as • ^ H__r- _. ..__ «_» _ - .--, - .. a whitish foam. Calculated for C3? H32N204: Theory: C, 74.98; H, 6.49; N, 5.64. Found: C, 74.82; H, 6.26; N, 5.58. This foam was converted to the oxalate salt. p.f. = 97 ° C MS (m / e): 497 (M + l) Calculated for C 31 H 32 2 O -C 2 H 2 O: Theory: C, 67.57; H, 5.84; N, 4.78. Found: C, 67.76; H, 6.00; N, 10 4.85.

EXAMPLE 37 1- ((2S) -hydroxy-3- (naphth-2-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.132 gm (0.7 mMol) ether; (S) -glycidyl naphth-2-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.139 gm (49%; 20 of the title compound were converted as a solid white MS (m / e): 428 (M +) [a] D2 (methanol) = -5.814 ° Calculated for C2 H28N2? 3-0.25 H20: Theory: C, 74.89: 25 H, 6.63; N, 6.47. : C, 74.71; H, 6.67; N ,, __ ^ .____ «. _. _ ^ _ 4_ ». t «^^. flrtft * - -, < • .- "". _ ^ ... ^^ ___ É_ > ¿___ ^ a __ ^ _: __ "A ..-_ .... _._ ^. ^ _____ ^. 6. 37 EXAMPLE 38 5 l - ((2S) -hydroxy-3- (6-methoxynaphth-2-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.151 gm (0.7 mMol) ether; (S) -glycidyl 6-methoxynaphth-2-yl and 0.150 gm (0.7 10 mMol) 4-hydroxy-4- (quinol in-3-yl) piperidine, 0.172 gm (57%) of the title compound were converted as a white foam. This foam was converted to oxalate sa.L. MS (m / e): 458 (M +) 15 Calculated for C28H3o 2? 4-C2H204: Theory: C, 65.68; H, 5.88; N, 5.11. Found: C, 65.43; H, 6.10; N, 5.06.

EXAMPLE 39 1- ((2S) -hydroxy-3- (indol-4-yloxy) prop-1-yl) -4-hydroxy-4- (quin lin-3-yl) piperidine Starting with 0.228 gm (1.2 mMol) ether of 25 (S) -glycidyl indol-4-yl and 0.275 gm (1.2 mMol) 4- hydroxy-4- (quinolin-3-yl) piperidine, 0.283 gm (56%) of the title compound were converted as white solid ur. Calculated for C25H27N303: Theory: C, 71.92; H, 6.52; N, 10.06. Found: C, 71.76; H, 6.66; N, 9.99. [a] D25 (methanol) = + 13.841 ° This solid was converted to the oxalate salt. p.f. = 117-120 ° C MS (m / e): 417 (M +) [a] D25 (methanol) = -7.018 ° EXAMPLE 40 1- ((2S) -hydroxy-3- (indo1-5-i loxi) prop-l-i 1) -4-hydrox? -4- (qumolin-3-yl) piperidine Starting with 0.129 gm (0.7 mMol) ether of (S) -glycidyl indole-5α and 0.156 gm (0.7 mMol) 4-hydroxy-4- (quinolm-3-yl) piperidine, 0.134 gm (47%) of the title compound were converted as white solid ur. Calculated for C25H27N303: Theory: C, 71.92; H, 6.52; N, 10.06. Found: C, 71.63; H, 6.71; N, 9.85. [a] D25 (methanol) = + 7.505 ° This solid was converted to the oxalate salt. p.f. = 122 ° C MS (m / e): 417 (M +) Calculated for C25H27N303-C2H2? : Theory: C, 63.90; H, 5.76; N, 8.28. Found: C, 63.87; H, 5.76; N, 8.17. [a] D25 (methanol) = -6.479 ° EXAMPLE 41 1- ((2R) -hydroxy-3- (indol-5-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.335 gm (1.8 mMol) ether of: (R) -glycidyl indol-5-yl and 0.404 gm (1.8 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.397 gm (54%) of the title compound were converted as a white solid. Calculated for C25H27N3O3-1.25 H20: Theory: C, 68.23; H, 6.18; N, 9.54. Found: C, 68.51; H, 6.28; N, 9.44. [α] D 25 (methanol) = -12,635 ° This solid was converted to the salt of: oxalate. p.f. = 99 ° C MS (m / e): 417 (M +) Calculated for C25H27N3? 3-C2H2? : Theory: C, 63.90; H, . 76; N, 8.28. Found: C, 64.40; H, 5.82; N, 8. 36. [a] D25 (methanol) = + 8.547 ° EXAMPLE 42 1- ((2S) -hydroxy-3- (l-methylindol-4-yloxy) prop-1-yl) -4-h? Drox? -4- (quinolin-3-yl) piperidine Starting with 0.134 gm (0.7 mMol) ether of (S) -glycidyl l-met? Lmdol-4-yl and 0.150 gm (0.7 mMol) 4-h? Drox? -4- (qumolin-3-yl) piperidine, 0.217 gm (76%) of the title compound became a whitish foam. Calculated for C26H29N3O3-O .25 H20: Theory: C, 71.62; H, 6.82; N, 9.64. Found: C, 71.76; H, 6.82; N, 9.72. [a] D25 (methanol) = + 22.414 ° This foam was converted to the oxalate salt. p.f. = 86 ° C MS (m / e): 431 (M +) a¡w > 3k-? Calculated for C26H29N303-C2H204: Theory: C, 64.48; H, 5.99; N, 8.06. Found: C, 64.21; H, 5.89; N, 7.95. [a] D25 (methanol) = -5,367 ° EXAMPLE 43 1- ((2S) -hydroxy-3- (2-methylindol-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperine Starting with 0.134 gm (0.7 mMol) ether of (S) -glycidyl 2-methylindol-4-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinol in 3-i 1) piperidine, 0.198 gm (68%) of the title compound were converted to a whitish foam. Calculated for C26H2.N3O3-O .25 H20: Theory: C, 71.62; H, 6.82; N, 9.64. Found: C, 71.35; H, 6.60; N, 9.36. [a] D25 (methanol) = + 3766 ° This foam was converted to the oxalalte salt. p.f. = 117 ° C MS (m / e): 431 (M +) Calculated for C26H29 3? 3-C2H2? 4: Theory: C, 64.48; H, 5.99; N, 8.06. Found: C, 64.33; H, 5.95; N, 8. 06 [a] 25 methanol) = -9.96 ' EXAMPLE 44 1- ((2S) -hydroxy-3- (benzofur-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.094 gm (0.5 mMol) ether of: (S) -glycidyl benzofur-4-yl and 0.113 gm (0.5 mMol) 4-hydroxy-4- (quinol? N-3-yl) piperidm, 0.088 gm ( 43%) of the title compound were converted as a whitish foam. This foam was converted to the oxalate salt. MS (m / e): 419 (M + 1) Calculated for C 25 H 26 N 2 O 4 -C 2 H 2 O 4: Theory: C, 63.77; H, 5.55; N, 5.51. Found: C, 63.79; H, 5.66; N, 5.54.

EXAMPLE 45 1- ((2S) -hydroxy-3- (benzothien-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.090 gm (0.4 mMol) ether of: (S) -glycidyl benzothien-4-yl and 0.100 gm (0.4 mMol 4-hydroxy-4- (quinol-3-yl) piperidine, 0.139 gm (73% i of the title compound became a whitish foam. foam was converted to the oxalate salt MS (m / e): 434 (M +) Calculated for C25H26N2? 3S-C2H2? 4: Theory: C, 61.82; H, 5.38; N, 5.34 Found: C, 61.86; , 5.21; N, 5.04.

EXAMPLE 46 1- ((2S) -hydroxy-3- (2-methyl-l-benzothiazol-5-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.145 gm (0.7 mMol) ether of (S) -glycidyl 2-methybenzothiazol-5-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine ,. 0.181 gm (61%) of the title compound were converted to a whitish foam. Calculated for C25H27N3O3S: Theory: C, 71.62; H, 6.82: N, 9.64. Found: C, 71.76; H, 6.82; N, 9.72. [a] D25 (methanol) = + 22.414 ° This foam was converted to the oxalate salt. p.f. = 86 ° C MS (m / e): 431 (M +) Calculated for C26H2.N3? 3-C2H2? 4: Theory: C, 64.48; H, 5.99; N, 8.06. Found: C, 64.21; H, 5.89; N, 7.95. [a] D25 (methanol) = -5,367 ° EXAMPLE 47 10 1- ((2S) -hydroxy-3- (indane-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.150 gm (0.8 mMol) ether of (S) -glycidyl indol-4-yl and 0.180 gm (0.8 mMol) 4- 15 hydroxy-4- (quinolin-3-yl) piperidine, 0.202 gm (61%) of the compound of the title became a white foam. Calculated for C26H30N2O3.-0.25 H20: Theory: C, 73.82; H, 7.15; N, 6.62. Found: C, 73.66; H, 7.11; N, 20 6.92. [a] D25 (methanol) = + 9.158 ° This foam was converted to the oxalate salt. p.f. = 85 ° C 25 MS (m / e): 418 (M +) [a] 2 b methanol) = -5,254 EXAMPLE 48 1- ((2S) -hydroxy-3- (indan-5-yloxy) prop-1-) 1) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.125 gm (0.7 mMol) ether; (S) -glycidyl mdol-5-? Lo and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.160 gm (58% i of the title compound were converted as a solid white, calculated for C26H30 2O3-0.50 H20: Theory: C, 73.04; H, 7.31; N, 6.55. Found: C, 72.68; H, 7.13; N, 6.74. [α] D 25 (methanol) = -205.31 ° This solid was converted to the oxalate salt. p.f. = 66 ° C MS (m / e): 418 (M +) [a] D25 (methanol) = -3,472 ° »* -Jr_8_ c. ^ * - ^,. ^ ^ fe ^ j ^^ EXAMPLE 49 1- ((2S) -hydroxy-3- (7-methylindan-4-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.134 gm (0.7 mMol) ether of (S) -glycidyl 7-methylindan-4-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.165 gm (58%) of the title compound were converted to a lightly tanned foam. 10 Calculated for C27H32N203: Theory: C, 74.97; H, 7.46; N, 6.48. Found: C, 74.81; H, 7.43; N, 6.18. [a] D25 (methanol) = + 3.61 ° This foam was converted to the oxalate salt. 15 p.f. = 94 ° C MS (m / e): 432 (M +) Calculated for C26H2QN3O3-C2H2O4-O .25 H20: Theory: C, 66.08; H, 6.60; N, 5.31. Found: C, 65.87; H, 6.02; N, 5.46. 20 [a] D25 (methanol) = -9.058 ° _k &. "« - * • ^ ~? 2i & & amp; _ =. . _. *. & Aw £ &&$ & ^^^^^^ ^ ^ - EXAMPLE 50 1- ((2S) -hydroxy-3- (1,2,3,4-tetrahydronaphth-6-yloxy) prop-1-yl) -4-hydroxy-4 - (quinolin-3-yl) piperidine Starting with 0.134 gm (0.7 mMol) of (S) -glycidyl 1,2,3-tetrahydronaphth-6-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.109 gm (38%) of the title compound were converted as a white foam. This foam was converted to the oxalate salt. MS (m / e): 433 (M + l) Calculated for C2 H32 2? 3-C2H2? 4: Theory: C, 66.65; H, 6.56; N, 5.36. Found: C, 66.51; H, 6.49; N, 5.64.

EXAMPLE 51 1- ((2S) -h? Droxi-3- (quinolin-6-yloxy) prop-1-yl) -4-h? Droxi-4- (quinolm-3-yl) piperidine Starting at 0.132 gm ( 0.7 mMol) (S) -glycidyl quinolin-6-yl ether and 0.150 gm (0.7 mMol) 4- hydroxy-4- (quinolin-3-yl) piperidine, 0.182 gm (65%) of the title compound were converted as a white solid.

Calculated for C? TH? TNSO.-I .5 H20: Theory: C, 6 $ .40; H, 6.62; N, 9.20. Found: C, 68.68; H, 6.17; N, 9.22. a] 25 Imethanol) = -24.39 ° This solid converted to the oxalate salt. p.f. = 91 ° C MS (m / e): 430 (M + l) Calculated for C26H27N3? 3-C2H2? 4-H2? : Theory: C, 62.56; 10 H, 5.81; N, 7.82. Found: C, 62.66; H, 5.81; N, 7.58. [a] D (methanol) = -5,367 EXAMPLE 52 1- ((2S) -hydroxy-3- (quinolin-7-yloxy) prop-1-yl) -4-hydroxy-4- (qumolin-3-yl) piperidine Starting with 0.132 gm (0.7 mMol) ether of 20 (S) -glycidyl quinolin-7-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.199 gm (71%) of the title compound became a whitish foam. This foam was converted to the oxalate salt. 25 MS (m / e): 430 (M + l) vñ-? - '-i -,' - ~ > ^^ aa¡ ^ B__ £ ___ ..... ..,. < _. _________ '^ a. * ^. ^^ ...

Calculated for C2eH27N3? 3-C6H204-H20: Theory: C, 62.56; H, 5.81; N, 7.82. Found: C, 62.76; H, 5.75; N, 7.53.

EXAMPLE 53 1- ((2S) -hydroxy-3- (julolidin-7-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.134 gm (0.5 mMol) ether of (S) -glycidyl j ulol? Din-7-yl and 0.125 gm (0.5 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.159 gm (61%) of the title compound were converted as a lightly tanned foam. Calculated for C2qH35N3O3-0.5 H20: Theory: C, 72.85; H, 7. 48; N, 8.79. Found: C, 72.50; H, 7.15; N, 8. 52. [a] D25 (methanol) = + 7.59 ° This foam was converted to the oxalate salt. p.f. = 84 ° C MS (m / e): 473 (M +) [a] D25 (methanol) = -9,728 ° * ^^ * ¡^ ----____! i ^ b ___________ ta____ EXAMPLE 54 1- ((2S) -hydroxy-3- (dibenzofur-3-yloxy) prop-1-yl) -4-hydroxy-4- (quinolin-3-yl) piperidine Starting with 0.202 gm (0.8 mMol) ether of: (S) -glycidyl dibenzofur-3-yl and 0.192 gm (0.8 mMol) 4-hydroxy-4- (quinolin-3-yl) piperidine, 0.133 gm (34%; compound of the title was converted to a whitish foam, calculated for C2.H28N2O4-O.5H20: Theory: C, 72.94; H, 6.12; N, 5.87. Found: C, 73.01 H, 6.01; N, 5.87. was converted to the oxalate salt pf = 92 ° C MS (m / e): 468 (M +) Calculated for C2qH28N2? 4-C2H2? 4-0.75 H20: Theory: C, 65.08; H, 5.55; N, 4.90 Found: C, 65.15; H, 5.59; N, 4.90.

EXAMPLE 55 1- ((2S) -hydroxy-3- (carbazol-2-yloxy) prop-1-yl) -4-hydroxy-4- (quin lin-3-yl) piperidine Starting with 0.157 gm (0.7 mMol) ether of (S) -glycidyl carbazol-2-yl and 0.150 gm (0.7 mMol) 4-hydroxy-4- (quin-3-yl) piperidine, 0.034 gm (11% I of the title compound were converted as a lightly tan solid. MS (m / e): 467 (M +) EXAMPLE 56 1- ((2S) -hydroxy-3- (indol-4-yloxy) prop-1-yl) -4-hydroxy-4- (isoquin-4-yl) piperidine Starting with 0.166 gm (0.88 mMol) ether of (S) -glycidyl indol-6α and 0.200 gm (0.88 mMol) 4-hydroxy-4- (isoquin-4-yl) piperidine, 0.125 gm (34%) of the title compound were converted as a slightly yellow solid. . Calculated for C25H27N3O3-0.25 H20: Theory: C, 71.15; H, 6.45; N, 9.96. Found: C, 70.84; H, 6.55; N, 9. 43. [a] D25 (metha = -7.233 ° This solid converted to the oxalate salt. p.f. = 123 ° C MS (m / e): 417 (M +) Calculated for C25H27N303-C2H204-H20: Theory: C, 61.70; H, 5.56; N, 7.99. Found: C. 61.87; H, 5.55; N, 7.63. [a] D25 (metha = -18.382 ° EXAMPLE 57 1- ((2S) -h? Drox? -3- (indol-4-yloxy) prop-1-yl) -4- (p? R? Dm-3-? L) p? Per? Dine Beginning with 0.152 gm (0.8 mMol) ether of (S) -glycidyl mdol-4-yl and 0.130 gm (0.8 mMol) 4- (p? R? Dm-3-yl) piperidm, 0.147 gm (52%) of The compound of the title became a whitish solid. 15 Calculated for C2? H: 5N3O2-0.5 H20: Theory: C, 69.98; H, 6.99; N, 11.66. Found: C, 70.18; H, 6.89; N, 11.44. [a] D25 (metha = + 12.195 ° This solid converted salt from oxalate. p.f. = 77 ° C MS (m / e): 351 (M +) a] 25 metha-5,988 c- * ag_2__ ^^ EXAMPLE 58 1- ((2S) -hydroxy-3- (indol-4-yloxy) prop-1-yl) -4- (quiin-3-yl) piperidine Starting with 0.133 gm (0.7 mMol) of (S) -glycidyl indol-4-yl ether and 0.149 gm (0.7 mMol) 4- (quin-3-yl) piperidine, 0.133 gm (40%) of the title compound was They turned like a whitish solid. 10 Calculated for C25H27N3O2-0.25 H20: Theory: C, 73.96; H, 6.83; N, 10.35. Found: C, 73.72; H, 6.58; N, 10.16. [α] D 25 (metha = + 3,876 ° This solid converted to the oxalate salt. p.f. = 124 ° C MS (m / e): 401 (M +) [a] D25 (metha = -7.207 ° 20 EXAMPLE 59 1- ((2S) -hydroxy-3- (indol-4-yloxy) prop-1-yl) -4- 25 (isoquin-4-yl) piperidine ___ ~ ___ ^ _ __-_-. -I-. | ^ F _ ^ -_ .... », - - - < -. , .-,. ^ A, ___-._. ^ __-.._ ^ a __? ___.-. ^ _.____ ^ Starting with O.Ü * 83 gm (0.4 mMol) ether of; (S) -glycidyl indol-4-yl and 0.093 gm (0.4 mMol) of 4-- (isoquin-4-yl) piperidine, 0.072 gm (41%) decomposed from the title recovered as a whitish solid. This solid was converted to the salt of; oxalate. p.f = 118 ° C MS (m / e): 401 (M +) Calculated for C25H27N3? 2-C2H204-H20: Theory: C, 63.64; H, 5.74; N, 8.25. Found: C, 63.77; H, 5.62; N, 8.25. [α] D 25 (metha = -15.2381 °.

EXAMPLE 60 1- ((2S) -hydroxy-3- (indol-4-yloxy) prop-1-yl) -4- (quinoxalin-2-yl) piperidine Starting with 0.108 gm (0.6 mMol) of (S) -glycidyl indol-4-yl ether and 0.122 gm (0.6 mMol) of 4- (quinoxalin-2-yl) piperidine, 0.137 gm (60%) of the title compound was They obtained as a lightly tanned foam. This foam was converted to the oxalate salt. S (m / e): 402 (M +) a Calculated for C2.H26N4O2-C2H2O4: Theory: C, 63.40; H, 5.73; N, 11.38 Found: C, 63.30; H, 5.85; N, 11.15.

The compounds and compositions employed for the method of the present invention could have affinity for and be antagonists of the]: 5-HTIF receptor. The ability of the compounds employed by the method of this invention to bind to the subtype of the 5-HT ?F receptor is measured essentially as described in N. Adha, et al.,. Preceeding of the National Academy of Sciences (USA); 90, 408-412 (1993).

Preparation of the membrane: Membranes were prepared from transfected Ltk cells, which were grown at 100% confluence. The cells were washed twice with phosphate buffered saline, scraped from the culture boxes in 5 mL of ice cold phosphate buffered saline, and centrifuged at 200 x g for 5 minutes at 4 ° C. The pellets were suspended in 2.5 mL of ice-cooled Tris buffer (20 mM Tris HCl, pH = 7.4 at 23 ° C, 5 Mm EDTA) and homogenized with a ---- ftswilhm ,,,,,. . ..- ".? _ "° ^ itA ^ J * i- - ^ > -. • .3 _____ .. aS ¿_..... ...... A *.,., ...,.,. _ Grinder of Wheaton tissue, subsequently lysate, centrifuged at 200 xg for 5 minutes at 4 ° C to large pellet fragments, which were: discharged, the supernatant was collected and centrifuged) at 40,000 xg for 20 minutes at 4 ° C. The pellet resulting from this centrifugation was washed once in ice-washed Tris-washed buffer and resuspended in a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH = 7.4 at 23 ° C. The membrane was kept on ice and was used within two hours for the radioligand binding assays.The protein concentrations were determined by the Bradford method (Anal. Bi och em., 72, 248-254 (1976)) .

Link to Radioligand: The linkage [3H-5-HT] was made using slight modifications of the 5-HT? D assay conditions reported by Herrick-Davis and Titeler (J. Neuroche., 50, 1624-1631 (1988)) with the omission of masked ligands. Studies of radioligand binding were achieved at 37 ° C in a total volume of 250 mL of the buffer (50 mM Tris, 10 mM MgCl2, 0.2 mM EDTA, 10 mM pargyline, 0.1% ascorbate, pH = 7.4 at 37 ° C ) in 96 microtiter plate wells. Saturation studies were conducted using iE] -5-HT 12 different concentrations ranging from 0.5 nM to 100 nM. The displacement studies were performed using 4.5-5.5 mM [3H] -5-HT. The binding profile of the drugs in the competition experiments was covered using 10-12 concentrations of the compound. The incubation times were 30 minutes for both saturation and displacement studies based on the initial investigations, which determined the conditions of the equilibrium bond. The non-specific binding was defined in the presence of 10 mM of 5-HT. The link was initiated by the addition of 50 mL of the membrane homogenates (10-20 μg). The reaction was terminated by rapid filtration through presumed filters (0.5% polyethyleneimine) using a Brandel 48R Cell Harvester (Gaithersburg, MD). Subsequently, the filters were washed for 5 seconds with cooled chill absorber (50 mM Tris HCl, pH = 7.4 at 4 ° C), dried and placed in flasks containing 2.5 mL of Readi-Safe (Beckman, Fullerton, CA) and the radioactivity was measured using a LS 5000TA Beckman liquid scintillation counter. The counting efficiency averaged [3H] -5-HT between 45-50%. The data of the link '? they were analyzed by computer-assisted non-linear regression analyzes (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). The IC5o values were converted to KL values using the Cheng-Prusof equation (Biochem Pharmacol., 22, 3099-3108 (1973).) All the experiments were performed in triplicate.The representative compounds of Formula I were tested in this assay and were found to have affinity to the 5-HT_F receptor As reported by RL Weinshank et al., WO93 / 14201, the 5-HT_F receptor is functionally coupled to a G protein, as measured by the ability of the drugs of serotonin and serotonergic by inhibiting cAMP production stimulated by forskolin in NIH3T3 cells transfected with the 5-HTiF receptor.Agonist activation of G protein-coupled receptors also results in the release of GDP from the α-subunit of the protein G and the subsequent binding of GTP.The binding of the [35S] GTP? S stable analogue is an indicator of this receptor activation.The activation of the 5-HT? F receptor in vitro, as measured by the link [35S] GTP? S, it carried out essentially as described by Wainscott, et al., European Journal of Pharmacolgy ,. 352, 117-124 (1998).

Preparation of the Membrane Mouse LM (tk-) cells were stably transfected with the human 5-HTiF receptor, and were grown in a suspension harvested by centrifugation, resuspended in 50 mM Tris-HCl, pH 7.4, in aliquots of 2 x 108 cells and frozen at -70 ° C until the day of the assay. On the day of the assay, the aliquot of cells was primed, resuspended in 35 mL of Tris-HCl, pH 7.4, and centrifuged at 39,800 x g for 10 minutes at 4 ° C. The resulting pellet was resuspended in 50 mM TrisHCl, pH 7.4, incubated for 10 minutes at 37 ° C and centrifuged at 39,800 x g for 10 minutes at 4 ° C. The pellet was resuspended and centrifuged once again, with the final pellet being resuspended in 4 mM of MgCl2, 160 mM of NaCl, 0.267 mM of EGTA, 67 M of Tris-HCl, pH 7.4, such that a aliquot of 200 mL contained contains approximately 15-25 mg of protein 25 ? «? Í,, __ j_a _» _____ J ___.-. ". ....... . . , -. fa "« -) -? f- | t ^ ifi ^ ¡B__ Links of [35S] GTP? S The assay was modified from the published conditions (Sim et al., Proc. Na ti. Acad.

Sci. USA, 92, 7242-7246 (1995); Thomas et al. L. , J. Rec. Yes gnal Transduct. Res. , 15, 199-211 (1995). Two versions of the trial, one using vacuum filtration (Wainscott et al., Eur J. Pharmacol., 352, 117-124 (1998)) and one using a scintillation proximity assay, have been developed for the determination of potency and intrinsic activity (efficacy) of the 5-HT_F ligands.

Linkage of [35S] GTP? S using vacuum filtration Incubations were performed in a total volume of 800 μl. Test compounds in water (Glacial acetic acid and / or dimethyl sulfoxide [DMSO] may have been used to aid in the solubilization of some compounds), 200 μl was added to 400 μl of Tris-HCl, pH 7.4, which contains MgCl2, NaCl, EGTA, GDP and [35S] GTP? S. Membrane homogenate (200 μl) was added and the tubes were incubated for 30 minutes at 37 ° C. The final concentrations of MgCl2, NaCl, EGTA, GDP, [35S] GTP? S and Tris were 3 mM, 120 mM, 0.2 mM, 10 μM, 0.1 nM and 50 feA; ...... ^ ..., ^. ^ .. ^ ¡mmmM, respectively. For the experiments examining the inhibition of the binding of [35S] GTP? S stimulated by 5-HT, the final concentration of 5-HT was 1 μM, Using a Bradel cell harvester (model MB-48R, Brandel, Gaithersburg, * MD ), the incubations are; They ended up by vacuum filtering through; Whatman GF / B filters, which have been moistened with water or 20 mM Na4 207 and pre-chilled with 4 ml ice water 50 mM Tris-HCl, pH 7.4. The filters were then rapidly washed with 4 ml of ice water, 50 mM Tris-HCl, pH 7.4. The amount of [35S] GTP? S captured in the filters was determined by liquid scintillation spectrometry.

Linkage of [35S] GTP? S using a scintillation proximity assay Incubations were performed in a total volume of 200 μl in 96-well assay plates. He [35S] GTP? S and guanosine-5'-diphosphate in a test buffer (MgCl2, NaCl, EGTA, in Tris-HCl, pH 7.4) 50 μl, were added to 50 μl of test compounds dissolved in water (Glacial acetic acid and / or dimethyl sulfoxide [DMSO] may have been used to help in the solubilization of some compounds Then the perillas of; Wheat Germ Aglitinin (WGA) (Amersham Life: Sciences, Inc., Arlington Heights, IL) for the scintillation proximity assay (SPA), in assay buffer (20, 25 or 50 μl). The homogenate of the membrane (80, 75 or 50 μl) was then added and the plates were covered with a sealing cap (Wallac, Inc., Gaithersburg, MD), and allowed to incubate at room temperature for 2 hours. The final concentrations of MgCl2, NaCl, EGTA, GDP, [35S] GTP? S and Tris, were 3 mM, 12 mM, 0.2 M, 10 μM, 0.25 nM and 50 mM, respectively. For experiments that examine the inhibition of the binding of; [j5S] GTP? S stimulated by 5-HT, the final concentration of 5-HT was 1 μM. The plates were then centrifuged at approximately 200 x g for 10 minutes at room temperature. The amount of [35 S] GTP? S bound to the membrane, i.e., in close proximity to the WGA SPA pellets, was then determined using a Trilux Wallac MicroBeta Scintillation Counter "(Wallac, Inc.).

Data Analysis The non-linear regression analysis is; performed in the concentration response curves (generating EC5_ and Emax values for the stimulation of the binding of [35S] GTP? S or the generation of EC5o and Emax values for the inhibition of the [35S] GTP? S binding stimulated by HT), using a four-parameter logistic equation described by DeLean et al., (De Lean et al., Mol Ph. Col. Col., 21, 5-16 (1982)). The equation was modified in such a way that the tilt was a positive number for the stimulation of L bond of [35S] GTP? S. The efficacy values (Emax) r were determined by the non-linear regression analysis, for the selected compounds were expressed as the percent of the [35S] GTP? 3 binding relative to 10 μM of 5-HT, which was run as a standard with each concentration response curve. The efficacy values for run compounds as single point determinations may also have been calculated relative to 10 μM of the [35S] GTP? S link stimulated by 5-HT, which was run as a standard in each of these test plates. For the inhibition of [35 S] GTPγS binding stimulated by 5-HT, the IC 50 values were converted to K values using the equation ¿¿¿& * »* - = ^ - -4a« ^. _. * £ & amp; *, Cheng-Prusoff (Cheng &Prusoff, Bi och, Ph.P. col., 22, 3099-3108 (1973)). In addition, the minimum for the inhibition of the [35 S] GTPγS binding stimulated by 5-HT also represents a determination of the efficacy value (Ema?) For the compounds tested, calculated as the percentage of [35 S] GTPα binding. relative to 10 μM of 5-HT alone as the standard run with each of these curves. The utility of the 5-HT_F antagonists of: serotonin for the treatment of anxiety disorders was demonstrated by the 'social interaction' essay described by TJ Sajdyk and A. Shekhar in The Journal of Phological Weapons and Ecperimen t al Th erapeu ti cs, 238, 969-977 (1997), a completely validated test of anxiety (SE, File, Journal of Neurosci en Meth ods, 2, 219-238 (1989)). The procedure for this trial is summarized below.

Animals All experiments were performed on male Wister rats (they would make laboratories, 275-300 gm). The rats were housed individually in a controlled temperature room (72 ° F) in a 12 hour cycle day Night. The rats were given food and water ad libitum.

Test Compound Approximately 40 mg of the test compound were weighed into a 20 Ml glass flask. To this solid was added 80 μL of lactic acid (85%). The mixture was sonicated for 2 minutes and then 4 mL of distilled water was added in 1 Ml increments. The sonication of this mixture was continued until all the solids had dissolved. After sonication, the pH of the mixture was increased by the addition of dilute aqueous sodium hydroxide until the mixture reached a pH of about 5.5.

Protocols Each rat was weighed and the test compound was administered by intraperitoneal injection at 20 mg / kg body weight. The animals were then placed back in their cages for 1 hour before the protocol related to the behavior was initiated. Each animal was first tested for its baseline activity "Üfi the test, and then tested two days later with the compound.

Experimental anxiety was measured by a social interaction test. The device was a solid wooden box (36 inches long x 3 (5 inches wide x 12 inches high) with an open roof, a video camera was fixed above the social interaction box and all the tests were recorded. During the test session, the rat which received the test compound was placed in the social interaction box with another male Wistar rat, which has been housed individually and is not familiar to the rat which received it. Test compound The rat which received the test compound was observed for 5 minutes The other rat recorded the amount of time the rat interacted with the consumption of the test compound received (ie, grooming). , sample of contempt, climbing) All these tests were performed under illuminated conditions An increase in the interaction time represents a decrease in anxiety. in eL Interaction time represents an increase in anxiety.

Statistical analysis The social interaction data were analyzed as the total interaction time e: seconds and the pure records were compared between the baseline and the treatment. Statistical analyzes were conducted by the use of a student's t mating test. Statistical significance was accepted at p < 0.01. The 5-HT_F antagonist of serotonin of Example 37 was tested in this assay and found by significantly increase the time of social interaction as compared to the baseline at a dose of 20 mg / kg. The suitability of a compound or composition for use in the method of the present invention is therefore determined as follows: 1. Demonstration of affinity for the 5-HT? F receptor and 2. Once the affinity for the 5-HT? F receptor, the determination of the complete antagonist, partial antagonist or reverse agonist activity.

Anxiety disorders are a heterogeneous class of ailments. The most common types of anxiety disorders are described in the following paragraphs.

Panic Disorder Panic disorder is characterized by the sudden onset of intense apprehension, intrepid behavior or terror. A panic disorder attack is not triggered and may take a discrete period of time. During these attacks, it is not common for the victim to experience shortness of breath, palpitations, chest pain or discomfort, suffocation or suffocation, and fear of losing control.

Generalized Anxiety Disorders Generalized anxiety disorders are characterized by at least 6 months of excessive and persistent anxiety and torment. Are associated . »» Jh. tt «M» t) '< .. > ^,. _____ " .. *. • .- • 'L_s ^. ^ - aiife¿_a ___ fc. * ^. L- > a.J? .--. »- ^ .- .. - *.-... -. . - »fi -? ^». «_ With symptoms of physical anxiety such as muscle pain, fatigue, difficulty sleeping, exudation, sleepiness and nausea.

Specific phobia Specific phobia is a persistent, intense and irrational fear associated with a particular object or situation that leads to the evasion of such an object or situation.

Social phobia Social phobia is a persistent medium of one or more situations in which the person is exposed to possible trials by others and the fears that the person he or she may sometimes have or act in a way that would be humiliating . Social phobias can include extreme shyness.

Obsessive-compulsive disorder Obsessive-compulsive disorder is characterized by obsessions which cause anxiety and compulsions which serve to neutralize anxiety. The common obsessions they include fear of dirt, germs or contamination or fears of harming oneself; The common compulsions are excessive cleaning, checks, double counting, and accumulation.

Post-traumatic stress disorder Post-traumatic stress disorder is characterized by the experimentation of an extremely traumatic event accompanied by increased incitement symptoms and evasion of the stimulus associated with the trauma. Individuals become so concerned with experience that they are not available to lead a normal life The conditions described above, as well as other anxiety disorders contemplated by the method of the present invention, are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th. Version, published by the American Psychiatric Association (DMS). In such cases, the DMS code numbers are provided below for the convenience of the reader.

Disorder due to panic without Agoraphobia DSM 300.01 Disorder due to panic with Agorabobia DSM 300.21 Agoraphobia without disorder history Panic DSM 300.22 Specific phobia DSM 300.29 Social phobia DSM 300.23 5 Obsessive-compulsive disorder DSM 300.3 Disorder due to post-traumatic stress DSM 309.81 Acute stress disorder DSM 308.3 Generalized anxiety disorder DSM 300.02 Disorder of anxiety due 10 to a medical condition DSM 300.02 Disorder of anxiety induced by a substance DSM 293.84 Alcohol DSM 291.89 Amphetamine (or similar to an amphetamine substance) DSM 292.89 Caffeine DSM 292.89 Canabis DSM 292.89 Cocaine DSM 292.89 Halucinogens DSM 292.89 20 Inhalants DSM 292.89 Phencyclidine (or substance similar to phencyclidine) DSM 292.89 Sedatives, hypnotics or anxiolytics DSM 292.89 25 Other substances [unknown] DSM 292.89 lf - »-,. ... ... -rAs A¿ ^ & ---- "-" - '"wa____. ... _ _. ......", _> _, _ ____> .. to ____. A Other unspecified other disorders ^ DSM 300.00 Separation anxiety disorder DSM 309.21 5 Disorder due to sexual aversion DSM 302.79 Any of these disorders, if presented alone or in a combination in a mammalian individual, can be treated or prevented by the method of the present invention. While it is possible to administer the compound used in the methods of this invention directly without any formulation, the compounds will usually be administered in the form of: pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous ,. intravenous, intramuscular and intranasal. Many of the compounds employed in the methods of this invention are effective both injectable and in oral compositions. Such compositions are prepared in a manner well known in the art.

Pharmaceutical and comprises at least one compound ^ ¿* * ¿Hm? M, *. ... .. __ »«. --- T ^ - active. See, for example, REMINGTON 'S PHARMACEUTICAL SCIENCES, (16 ed., 1980). In making the compositions employed in the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier, which may be in the form of a capsule, pouch, paper or other container . When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, dragees, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft gelatin capsules, hard capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing the formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, this Ordinarily it will be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size will normally be adjusted by milling, to provide a substantially uniform distribution in the formulation, for example, about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated in this manner to provide more rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art. The compositions are formulated * "- - - - -« _a _ »« ^ a- ^ _ »_ ^^^^^, - t_í, JJ _., A ^ _tL * _¿ = -fe preferably in a unit dosage form, each dosage contains about 0.05 to about 100 g, more usually about 1.0 to about 30 mg, of the active ingredient The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutical excipient. The active compounds are generally effective over a broad dosage range. For example, the dosage per day usually falls within the range of about 0.01 to about 30 mg / kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg / kg / day, in a single or divided dose, is preferred especially. However, it will be understood that the amount of the compound currently administered may be determined by a physician, in view of the relevant circumstances, which include the condition to be treated, the route selected from. administration, the current compound or compounds » administered, the age, weight, and individual response of the patient, and the severity of the patient's symptoms, and therefore the ranges of previous dosages are not intended to limit the scope of the invention in any way. In some examples, dosing levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even larger dosages may be employed without causing any harmful side effects, provided that such broad doses are first divided into Smaller doses for administration during the day.

Formulation Example 1 The hard gelatine capsules containing the following ingredients are prepared: Ingredient mg / capsule quantity) Compound of Example 37 30. 0 Starch 305. .0 5 Magnesium stearate 5 .0 The above ingredients are mixed and filled into hard gelatin capsules in amounts of 340 mg. 10 Formulation Example 2 A tablet formula is prepared using the following 15 ingredients: Ingredient Quantity (mg / t intact) 20 Compound of Example 37 25.0 Microcrystalline Cellulose 200.0 Colloidal Silicon Dioxide 10.0 Stearic Acid 5.0 The components are mixed and compressed to form tablets, each 240 mg in weight. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusions of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, U.S. Patent 5,023,252, published June 11, 1991, incorporated herein by reference. Such patches can be constructed for continuous, pulsatile, or demand release of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the use of a drug delivery catheter in the ventricular system of the host by a bypass or bypass of the blood bank of the brain. Such an implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in the U.S. Patent ? ^ MA ^. ^ ._-__ .., __, .. ». ^^ .._., ..__ 3 _ ^. A, ^. __., ___ ,. »*. " * _. ^ ..... LL »_ ^^ .. ^ _. ,011,472, published April 30, 1991, which is incorporated herein by reference. Indirect techniques, which are generally preferred, involve the formulation of the compositions to provide drug latency by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. The latency is generally carried through blockers of the hydroxy, carbonyl, sulfate, and primary amine groups present in the drug to provide more lipid-soluble drugs available for transportation through the blood-brain barrier. Alternatively, the release of hydrophilic drugs can be increased by the intra-arterial infusion of hypertonic solutions, which can temporarily open the blood barrier of the brain. The type of formulation used for the administration of compounds used in the methods of the present invention can be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound or compounds, and the patient's status. 25 "** MMl < l" Ji ^ f i .. < * »-__-, * ... > ~~ -. -. * »¿, X ^? *** A .a ^ ..-.,. . _ ^ .. ^ ... «ZZ & _." ..

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description 5 of the invention. Having described the invention as above, the content of the following is claimed as property. fifteen twenty

Claims

CLAIMS 1. The use of a 5-HTiF antagonist of serotonin for the preparation of a medicament for the treatment or prevention of anxiety disorders in a mammal. 2. The use of a complete 5-HT1F receptor antagonist of serotonin for the preparation of a medicament for the treatment or prevention of anxiety disorders in a mammal. 3. The use of a partial antagonist of the 5-HTiF serotonin receptor for the preparation of a medicament for the treatment or prevention of anxiety disorders in a mammal. 4. The use according to any of claims 1-3 wherein the 5-HT1F receptor antagonist of serotonin is selective for the 5-HT? F receptor of serotonin relative to other serotonin receptors. 5. The use according to any of claims 1-3 wherein the anxiety disorders are selected from the group consisting of panic disorder, disorders generalized anxiety, specific phobia, social phobia, obsessive-compulsive disorder, and post-traumatic stress disorder.

1. 6. The use according to any of claims 1-3 wherein the mammal is a human. & __? __. _k ** "» * á ______? _____--- _________ i-