MXPA97009451A - Derivatives of benzisoxazol and indazol as agents antipsicoti - Google Patents

Abstract

This invention relates to compounds of the formula (I), wherein X, Y, Z, m, n and p are as defined therein, pharmaceutical compositions containing these compounds and their use as anti-psychotic agents, particularly in the treatment of schizophrenia. Deposit derivatives of the compounds are useful to provide long-term effects of the compounds

Description

DERIVATIVES OF BENZISOXAZOL AND INDAZOL AS ANTI-PSYCHOTIC AGENTS DESCRIPTION OF THE INVENTION This invention relates to heteroarylpiperazines having anti-psychotic activity and to their use as anti-psychotic drugs. The therapeutic treatment of schizophrenic patients by the administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride and closely related chemical compounds, is widespread. Since the control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who certainly always relapses if the medication is discontinued. There is a continuing need in the art for anti-psychotic drugs for the treatment of psychosis. In addition, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many anti-psychotic drugs include so-called extrapyramidal symptoms, such as stiffness and tremor, continuous walking, and tardive dyskinesia, which causes facial gestures, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. In this way, there is also a need in the art for anti-psychotic drugs that produce few or less severe manifestations of these common side effects. In addition, due to the frequent long-term administration of neuroleptics and problems with the patient's complaint, there is a further need in the art for long-acting neuroleptics, which can be formulated as depot preparations of sustained release, without the effects previously mentioned laterals. The invention relates to a compound of the formula, wherein, X is -OH, -OC (= O) alkyl (C? -C18), -OC (= O) aryl (C6-C10), -OC (= O) -alkyl (C, -C? 2) ) -aryl (C6-C? o), -OC (= O) NH-alkyl (C? -C?), -OC (= O) alkyl (C? -C? 2) cycloalkyl (C3-C8) , -OC (= O) O alkyl (C? -c18), or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen, trifluoromethyl, (C? -C6) alkoxy, cyano or nitro; Z is O or NRT; RI is hydrogen, (C? -C6) alkyl, formyl, -C (= O) alkyl (C? -C?), Or -C (= O) O alkyl (C? -C?); m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts; pharmaceutical compositions containing these compounds and their use as anti-psychotic agents, particularly in the treatment of schizophrenia. The compounds of the invention are atypical anti-psychotic agents. This invention also provides methods, which are suitable for acylation with carboxylic acids (Ci-Ciß) or reactive functional derivatives thereof to form highly lipophilic esters, amides and carbamates, such compounds are also compounds of this invention. Said selected compounds possess a hydroxyl group bonded to an aromatic carbon atom capable of forming the highly lipophilic esters of the invention or a secondary nitrogen atom including the nitrogen in the 1-position of an indazole ring system capable of forming the amides highly lipophilic of the invention. The secondary nitrogen atom can alternatively be acylated with a (C? -C? 8) -carbonyl alkoxy chloride to form a highly lipophilic carbamate derivative of the invention. The invention also provides highly lipophilic compounds, which provide long-acting pharmaceutical effects when administered in the form of depot preparations. This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier thereof. In one embodiment of the invention, the pharmaceutical composition is an anti-psychotic composition comprising a compound of the invention in an amount sufficient to produce an anti-psychotic effect. In addition, this invention provides a method for the treatment of psychosis, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention. further, this invention provides a method of sustained release of a pharmaceutically effective amount of a lipophilic compound of the invention in the form of a depot preparation. Unless otherwise specified or indicated, the following definitions should be applied through the specification and appended claims. The term "alkyl" should represent a straight or branched alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, sec-butyl, and pentyl, hexyl, decyl, undecyl, dodecyl, etc., straight and branched chain with a chain length of up to 18 carbons. The term halo or halogen should represent fluorine, chlorine, bromine or iodine. The term (C3-C2) cycloalkyl should represent polycycloalkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, and the like. The term aryl (C6-C? 0) must represent aromatic carbocyclic rings such as benzene and naphthalene. Through the specification and appended claims, a given formula or name should encompass all stereo, optical, enantiomeric and tautomeric isomers, wherein said isomers exist. In a class of compounds of this invention is a compound of the formula, is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) NH-alkyl (C? C? 8), -OC (= O) O-alkyl (d-C18) ) or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen, trifluoromethyl, alkoxy (Ci-Cß), cyano or nitro; Z is O or NR; Ri is hydrogen, alkyl (C? -C6), formyl, -C (= O) alkyl (Ci- C? 8), or -C (= O) O alkyl (C? -C? 8); m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable salts. In a preferred embodiment of this class is a compound of the formula, ti NHChyrn-C- ^ X is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) NH-alkyl (dC? 8), -OC (= O) ) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl (C3-C12); And it is hydrogen, halogen; m is 1, 2, 3, or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. Most preferably, m is 3 and Y is 4-fluoro. Most preferably X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) hexyl, 6-OC (= O) nonyl, or 6-OC (= O) adamantyl; and their pharmaceutically acceptable salts. In another preferred embodiment of this class is a compound of the formula, wherein X is -OH, -OC (= O) (C1-C18) alkyl, -OC (= O) NH- (C1-Ci8) alkyl, -OC (= O) O-alkyl (dC? 8) or -OC (= O) -cycloalkyl (C3-C12); And it is hydrogen, halogen; R is hydrogen, (d-C6) alkyl, formyl, -C (= O) (C1-C8) alkyl, or -C (= O) alkyl (d-C18); m is 1, 2, 3 or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. Most preferably, m is 3 and Y is 4-fluoro. Most preferably X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) O-hexyl, 6-OC (= O) nonyl, or 6-OC (= O) adamantyl; and R, is hydrogen or -C (= O) nonyl; and their pharmaceutically acceptable acid addition salts. In another class of compounds of this invention is a compound of the formula, wherein X is -OH, -OC (= O) alkyl (d-C18), -OC (= O) NH-alkyl (Ci- C? 8), -OC (= O) O-alkyl (d-C18) ) or -OC (= O) -cycloalkyl Y is hydrogen, halogen, trifluoromethyl, (C? -C6) alkoxy, cyano or nitro; Z is O u NRÍ; Ry is hydrogen, formyl, alkyl (Ci-Ce), -C (= O) (C1-Ciß) alkyl, or -C (= O) O alkyl (C? -C?); m is 1, 2, 3, or 4; p is 1 or 2; and their pharmaceutically acceptable salts. In a preferred embodiment of this class is a compound of the formula, wherein X is -OH, -OC (= O) alkyl (d-C18), -OC (= O) NH-alkyl (Ci- C? 8), -OC (= O) O-alkyl (C? C18) or -OC (= O) -cycloalkyl (C3-C12); And it is hydrogen, halogen; m is 1, 2, 3 or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. Most preferably, m is 3 and Y is 4-fluoro. Most preferably, X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) O-hexyl, 6-OC (= O) nonyl, or 6-OC (= O) adamantyl; and their pharmaceutically acceptable acid addition salts. In another preferred embodiment of this class are the compounds of the formula, wherein X is -OH, -OC (= O) alkyl (C? -C?), -OC (= O) NH-alkyl (Ci- C18), -OC (= O) O-alkyl (C? -C18) or -OC (= O) -cycloalkyl (C3-C? 2); And it is hydrogen, halogen; Ri is hydrogen, alkyl (Ci-Cß), formyl, -C (= O) alkyl (d-C18), or -C (= O) O alkyl (C? -C? 8); m is 1, 2, 3, or 4; n is 1; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts. Most preferably, m is 3 and Y is 4-fluoro. Most preferably, X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) O-hexyl, 6-OC (= O) nonyl, or 6-OC (= O) adamantyl; Rt is hydrogen or -C (= O) nonyl; and their pharmaceutically acceptable acid addition salts. Non-limiting examples of the compounds of the invention include: 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1,2-benzisoxazole 3- [1- (4'-Fluoro be nzoil ) propyl-4- piperazinyl] - 5-hydroxy-1,2-benzisoxa-zol 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -4-hydroxy-1, 2-benzisoxazole 3- [1 - (4'-Fluorobenzoyl) propyl-4-piperazinyl] -7-hydroxy-1, 2-benzisoxazole 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1, 2-hydrochloride -benzisoxazole 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1,2-benzisoxazole 3- [1- (4'-Fluorobenzoyl) butyl-4-piperazinyl] - hydrochloride 6-hydroxy-1,2-benzisoxazole 3- [1- (4'-Fluorobenzoyl) ethyl-4-piperazinyl] -6-hydroxy-1, 2-benzisoxazole 3- [1- (4'-Fluorobenzoyl) methyl-4-piperazinyl] -6- hydroxy-1,2-benzisoxazol Ester 3- [4- [4- (4-f luorofenil ) -4- oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazol-6-yl butyl carbamic acid ester 3- [4- [4- (4-f luorof en il) -4-oxo -butyl] -piperazin-1-yl] -1,2-benzisoxazol-6-yl hexyl of carbamic acid Ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1- il] -1,2-benzisoxazol-6-yl dodecyl of carbamic acid Ester 3- [4- [4- (4-f luorof in yl) -4-oxo-butyl] -piperazin-1-yl] -1, 2-Benzisoxazol-6-yl octadecyl of carbamic acid Ester 3- [4- [4- (4-f luorof eni l) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6 -decanoic acid ester Ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of dodecanoic acid Ester 3- [ 4- [4- (4-f luorofenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of hexadecanoic acid Ester 3- [4- [4- (4 -fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of octa acid ecanoic Ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of adamantane-1-carboxylic acid Ester 3- [ 4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of cyclohexylhexanoic acid Ester 3- [4- [4- (4-fluorophenyl) ) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of cyclohexylcarboxylic acid ester ester 3- [4- [4- (4-fluorophenyl) -4-oxo- butyl] -piperazin-1-yl] -1,2-benzisoxazole-6-yl of carbonic acid Ester dodecyl ester of 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1 ester -yl] -1,2-benzisoxazole-6-yl of carbonic acid Octadecyl ester of 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1 ester, 2-Benzisoxazole-6-yl of carbonic acid 3- [1- (4'-Fluorobenzoyl) propyl-4-homopiperazinyl] -6-hydroxy-1,2-benzisoxazole Ester 3- [4- [4- (4-fluorophenyl) ) -4-oxo-butyl] -homopiperazin-1-yl] -1,2-benzisoxazol-6-yl butyl carbamic acid ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -homop iperazin-1-yl] -1,2-benzisoxazole-6-yl of decanoic acid ester hexyl ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -homopiperazin-1-yl] -1, 2-benzisoxazole-6-yl of carbonic acid 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1H-indazole 3- [1- (4'-Fluorohydrate benzoyl) pro-pil-4-piperazinyl] -6-hydroxy-1H-indazole Ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1H- Carbamic acid indazol-6-yl butyl Ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1-indazole-6-yl octadecanoic acid Octadecyl ester of 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1-indazole-6-yl ester of carbonic acid. The compounds of the invention can be synthesized using one or more of the following general procedures described below. Through the description of the synthetic procedures, the annotations X, Y, m, n, and p have the respective meanings given above, unless otherwise stated or indicated, R is alkyl (C? -C18), aryl ( C6-C? 0), alkylaryl (C? -C? 2), alkyl (C? -C? 2) -cycloalkyl (C3-C8) or cycloalkyl (C3-C? 2), and other annotations have the respective meanings defined in their first appearances. More particularly, as shown in the Scheme of Reaction A, benzoxazoles are prepared from the chlorine compound of Formula III, wherein X is alkoxy, reaction is made with the cyclic amine of formula IV to form the compound of Formula V, wherein X is alkoxy. The reaction is typically carried out neat in a sealed tube or under nitrogen at a temperature of from about 100 ° C to about 200 ° C, preferably from about 120 ° C to about 180 ° C, most preferably from about 1 30 ° C to 1 50 ° C for about 0.5 hours to about 100 hours, preferably from about 0.5 hours to about 8 hours, most preferably from 0.45 hours to about 6 hours. The compound of Formula V is then reacted with the haloalkylphenone compound of Formula VI to provide the compound of Formula Vi 1, wherein X is alkoxy. The reaction is carried out in a polar non-protic organic solvent such as, for example, acetonitrile, at a temperature from about 0 ° C to about 120 ° C, preferably from about 60 ° C to about 100 ° C, very preferably at about 80 ° C for 0.5 hours to about 24 hours, preferably about 1 hour to about 12 hours, most preferably about 4 hours to about 6 hours. The reaction is generally carried out in the presence of a base such as potassium or sodium carbonate and a catalyst such as sodium iodide. The indazoles will be prepared as shown in Reaction Scheme B, starting from the appropriate acetophenone of Formula IX, wherein X is alkoxy, which is oxidized to the corresponding carboxylic acid of Formula X, wherein X is alkoxy under known conditions such as in the presence of sodium hydroxide and bromine.

REACTION SCHEME A vp 48% HBr XIX X = OC (= O) NHR XXI X = OC (= O) R xxm X = OC (= O) OR The acid of Formula X, wherein X is alkoxy is then treated with sulfonyl chloride and p-toluene hydrazide under known conditions to form the hydrazide of Formula XI, which is further treated with sulfonyl chloride under known conditions to produce the chlorotoxylhydrazone of Formula XII, wherein X is alkoxy. The chlorosylhydrazone of Formula XI I, wherein X is alkoxy is reacted with the appropriate phenylpiperazinyl ketone of Formula XI II (prepared from the appropriate haloalkylphenone and piperazine under known conditions) to produce the hydrazone compound of Formula XIV, wherein X is alkoxy. The reaction is typically carried out in an organic solvent of from about 0 ° C to about 50 ° C, preferably from about 10 ° C to about 35 ° C, and preferably about room temperature. The compound of Formula XIV is then heated in a non-polar polar solvent such as dimethylformamide for about 1 hour to about 24 hours, preferably about 2 hours to about 12 hours, most preferably from 3 hours to about 6 hours, a temperature of about 35 ° C to 125 ° C, preferably about 50 ° C to about 100 ° C, most preferably about 90 ° C to produce the compound of Formula XV. The compound of Formula XV is heated in the presence of hydrochloric acid to form the compound of Formula XVI, wherein X is alkoxy. The compound of Formula XVI is alkylated under known conditions, such as with dimethyl sulfate in the presence of a base such as potassium carbonate in a non-protic organic solvent to form the compound of Formula XVII. The compounds of Formulas Vi 1 and XVI I, wherein X is alkoxy, can be treated with an acid such as, for example, 48% hydrobromic acid to produce the hydroxy compounds of Formulas VI I I and XVI I I. The reaction is typically performed at reflux for about 1 hour to about 12 hours, preferably from about 2 hours to about 4 hours.

REACTION SCHEME B XX X = OC (= O) NHR, Ri = alkyl XXD X = OC (= O) R, Re alkyl XXTV X = OC (= 0) OR, Ri = alkyl The compounds of Formulas VIII and XVI II are treated with the appropriate isocyanate, carbamoyl chloride or carbonyldimidazole and an amine to obtain the corresponding compounds of formulas XIX and XX, wherein R is alkyl (C? -C18) or arylalkyl (Ci-Cyano) - The reaction is carried out in an inert organic solvent such as, for example, ethyl acetate, for about 0.5 hour to about 24 hours, optionally in the presence of a catalyst such as, for example, copper (I) chloride. In addition, the hydroxy compounds of Formulas VI II and XVI II are treated with an alkyl, aryl or aralkylcarboxylic acid halide, such as, for example, adamantan-carbonyl chloride or decanoyl chloride, under basic conditions known in the art to produce the corresponding alkoxy, aryloxy or aralkyloxy compounds of Formulas XXI and XXI I. The compounds of Formulas VI I I and XVI I I are also reacted under basic conditions known in the art with the appropriate chloroformate to produce the carbonate compounds of Formulas XXI I I and XXIV. In the case of the indazoles, the nitrogen in position 1 of the indazole can also be substituted by means known in the art. The preparation of the starting materials is known in the art. For example, the preparation of the compounds of Formula I 1 is described in WO 9412495A 1. The compounds selected from the invention possess a hydroxyl group or amine attached to either an aliphatic or aromatic carbon capable of forming the highly lipophilic esters or amides of this invention. The hydroxy group can alternatively be acylated with an alkoxycarbonyl (C? -C18) to form the highly lipophilic carbonate derivative or with a carbamoyl halide (C? -C? 8) to form a highly lipophilic carbamate derivative. Representative examples of said alcohols and amines and their highly lipophilic derivatives are found in the Examples of this invention. It is known in the art that derivatives of long-acting drugs can be obtained through said transformation. European Patent Publication No. 26,070 describes the prolonged action of the haloperidol decanoate ester. International Publication No. WO 92/06089 describes sustained release sertindole amide derivatives. The compounds of the present invention are useful for the treatment of psychosis, by virtue of their ability to produce an anti-psychotic response in mammals. In particular, the compounds of the present invention are potent atypical anti-psychotic agents, ie, compounds that exhibit an affinity ratio of D2 / 5-HT2 greater than 1. The compounds of the invention also show a reduced potential for extra side effects. pyramidal (EPS) as evidenced by a large difference in ED5o for the Climber Mouse Test (CMA) and the Apomorphine-induced Esterotipia in Rat Testing (APO-S).

It is known that it is possible to predict the anti-psychotic efficacy and Ability of the potential lateral effect by observing the electrophysiological profile of a drug on dopamine neurons (DA) in the mesolimbic (A 10) and nigrostriatal (A9) regions, respectively, of the brain of rat. In this way, it has been shown that using extracellular single unit registration techniques, all the compounds that were effective both classical and atypical antipsychotics, could cause, after repeated administration, a activation of tonic depolarization of neurons A10 and DA . This result could support the hypothesis that the symptoms of schizophrenia are predominantly due to excessive DA activity in the mesolimbic area of the brain. However, it has also been shown that the classic anti-psychotic, those that are known to have Ability to E PS, such as haloperidol, could additionally cause an inactivation of depolarization of the DA neurons in the A9 area of the brain. Since this area of the brain has been linked to motor function, the inhibition of these neurons provided a reason for the EPS ability of typical anti-psychotics. The compounds of the invention show a significant reduction in the number of spontaneously active DA neurons in the A 10 area of the brain. However, similar to clozapine and other than the haloperid, the compounds of the invention do not cause a reduction in the number of DA neurons in the A9 area. This result strongly suggests that the compounds must be effective anti-psychotics with little propensity to cause EPS.

TREPATOR MOUSE ESSAY The anti-psychotic activity was determined in the test of climbing mice, through a method similar to those described by P. Protais, and others, Psychopharmacol., 50: 1 (1976) and B. Costall, Eur. J. Pharmacol ., 50:39 (1978). Male CK-1 mice (23-27 grams) were pooled under normal laboratory conditions. The mice were placed individually in wire mesh cages (10.16 cm x 25.4 cm) and left for an hour to adapt and explore the new environment. Then, apomorphine was injected subcutaneously at 1.5 mg / kg, a dose that caused the climbing action in all animals for 30 minutes. The compounds, which are to be tested for anti-psychotic activity, were injected intraperitoneally or given as oral doses at various intervals, for example, 30 minutes, 60 minutes, etc. before the attack with apomorphine at a dose of 10.60 mg / kg. To evaluate the climbing action, 3 readings were taken at 10, and 30 minutes after the administration of apomorphine according to the following scale: The mice climbing consistently before the apomorphine injection were discarded. With a fully developed climbing action by apomorphine, the animals hung on the walls of the cage, rather without movement, for long periods. In contrast, climbing actions due to mere motor stimulation usually only lasted a few seconds. Climbing action classifications were individually totaled (maximum classification: 6 per mouse over 3 readings) and the total classification of the control group (vehicle intraperitoneally, apomorphine subcutaneously), was set at 100%. The EDS0 values with 95% confidence limits, calculated by a linear regression analysis, of some of the compounds of the present invention as well as the normal anti-psychotic agents of reference, are presented in Table 1.

TABLE 1 INHIBITION OF STEREOTYPY BY APOMORFIN IN RATS Purpose: Classify the neuroleptic compounds, which act directly in the dopaminergic system, blocking the action of apomorphine in post-synaptic dopamine receptors (Anden et al., 1967; Ernst, 1967).

Method: Subjects are male Wistar rats (125-250 grams) stored under normal laboratory conditions. For a first classification, a group size of six was used. The drug was administered one hour before the labeling and the animals were placed in individual clear plastic cages (24 x 14 x 13 cm). The control group received the vehicle. Apomorphine was prepared at a concentration of 15 mg / 10 ml in an ascorbic acid supply solution at 0.003%, prepared with 30 mg of ascorbic acid in 100 ml of 1% saline to increase the stability of the apomorphine while in solution . Apomorphine was administered at a dose of 1.5 mg / kg, subcutaneously (s.c.) with a dose volume of 1 ml / kg 50 minutes after administration of the test compound or vehicle. Ten minutes later the stereotypic behavior was observed. Stereotypy occurred in a repetitive manner and was continuous for a period of 10 seconds in the presence of white noise. Stereotypic behavior was defined as an aspiration, licking or chewing behavior, which occurred in a repetitive manner and was continuous for a period of 10 seconds in the presence of white noise. The animal was considered protected if this behavior was interrupted. The percentage of effectiveness of a drug was determined through the number of protected animals in each group. A dose response was determined in the same way as a primary classification, except that a group size of 10 was used, and the animals were dosed in a random fashion. One group received the vehicle The values of EDS0 for the inhibition of stereotyping were calculated through the Litchfield and Wilcoxon analysis. It was verified that the compounds that avoid the behavioral response of stereotypy to apomorphine have post-synaptic dopamine receptor antagonist properties.

References: Anden, N.E., Rubenson, A., Fuxe, K. and Kokfelt, T. Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol. 19: 627-629, 1967. Ernst, A.M., Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats.

Psychopharmacology (Berl.) 10: 316-323, 1967. The ED50 values are set forth in Table 2.

TABLE 2 UNION TESTS OF D? / 5-HT, Binding of 3 H-Spiroperidol to Striatal Membranes (D2-Dopaminergic Site) in Rats Tests were performed according to the method of Leysen et al. [1978]. Striatal membranes were incubated with 3 H-spiroperidol (0.4 nM) and various concentrations of the test drug at 37 ° C for 10 minutes in 1 ml of 0.05 M Tris-HCl pH buffer, pH 7.7 containing 120 mM NaCl, mM KCl, 2 mM CaCl2, and 1 mM MgCl2. The non-specific binding was determined in the presence of 2μM (+) -butaclamol. The bound ligand was separated through rapid filtration through Whatman GF / B filters.

Binding of 3 H-Spiroperidol to Cerebral Cortical Membranes (5HT2 Site) in Rats Trials were conducted by a modification of the method of Peroutka and Snyder [1979]. Cortical membranes were incubated with 3 H-spiroperidol (1.5 nM) and various concentrations of the test drug at 37 ° C for 10 minutes in 1 ml of 0.05 M Tris-HCL pH buffer, pH 7.7 containing 120 mM NaCl, mM of KCl, 2 mM CaCl2 and 1 mM MgCl2. The non-specific binding was determined in the presence of 5 μM methysergide. Incubation was terminated by rapid filtration through Whatman GF / B filters. The results are established in Table 3.

TABLE 3 DOPAMINE NEURONE SAMPLING Dopamine Neuron Sampling. Male Wistar rats (280-360 grams) were used in this procedure. They stayed for at least 48 hours in a nursery with controlled climate, with food and water continuously available. Each rat was initially anesthetized with doral hydrate (400 mg / kg ip) and maintained with additional injections as needed throughout the experiment. The animal was mounted on a stereotaxic apparatus (Kopf, model 900). The skull was exposed, cleaned of the connective tissue and dried. The skull covering both the substantia nigra [A9: anterior (A) 3000-3400 micras, lateral (L) 1800-2400 micras from the lambda] and the ventral tegmental area (A10: A 3000-3400 micras, was removed). L 400-1000 microns from lambda) 47. Using the dura as a reference point, a micropipette driven by a hydraulic microdriver was introduced through opening in the skull at 6000-8500 vertical microns. The spontaneously activated dopamine neurons were counted within both the substantia nigra and the ventral tegmental areas, by lowering the electrode in 12 separate lanes (each lane separated from the other by 200 microns) in each region. The sequence of the lanes was kept constant, forming a block of tissue, which could be reproducibly located from animal to animal. The extracellular neuronal signals were sampled using an individual barrel micropipette approximately one miera at its tip, and filled with 2M NaCl saturated with 1% sky blue dye of pontamine. The in vitro impedance of this pipette (measured with Winston, Electronics Co., BL-1000 Micro Electrode Tester) was between 5 and 10 megaohms. Electric potentials were passed through a high-impedance preamplifier and the signal was sent to a window discriminator (WPl model 121), which converted the potentials above the previous noise levels to discrete pulses of fixed amplitude and duration. Only the cells whose electrophysiological characteristics coincided with those previously established for medium brain dopamine neurons were counted. In an anesthetized rat, a neuron was considered an inertgic dopam if it exhibits a positive-negative-positive three-phase peak profile with an amplitude of 0.4 to 1.5 microvolts and a duration of 2.5 milliseconds., activating in an irregular pattern of 3 to 9Hz with occasional burstings characterized by a progressive reduction of the peak amplitude and with an increase in the peak duration. At the end of each experiment, the location of the last registered lane path was marked by passing a cathode current of 25 microamperes through the register micropipette barrel for 15 minutes in order to deposit a dye stain. The rat was sacrificed; then the brain was removed, cut and frozen on a bed of dry ice. Frozen serial sections (width of 20 micras) were cut, mounted, and stained with cresil violet or examined using a microscope. Animals pretreated with the vehicle before neuronal sampling served as controls. Compounds were prepared as a percentage base. Each compound was suspended in distilled water and one drop of Tween 80, and kept constantly stirred during dosing. All compounds were delivered at a dose volume of 1 mg / kg via the intraperitoneal route. For the animals used in the chronic individual unit, the dopamine neuron sampling test, the compounds were administered once a day for 21 days, and the dopamine neuron sampling was done two hours after the last dose on day 21. The treatment groups were compared with vehicle groups with a one-way ANOVA with a Neuman-Keuls post hoc analysis for importance. The results are established in Table 4.

TABLE 4 The anti-psychotic response was achieved when the compounds of the present invention are administered to a subject requiring such treatment as an oral, parenteral or intravenous effective dose of 0.01 to 50 mg / kg of body weight per day. However, it should be understood that for any particular subject, the specific dose regimens must be adjusted according to the need of the individual and the professional judgment of the person administering or supervising the administration of the aforementioned compound. It should further be understood that the doses set forth herein are illustrative only and do not limit, to any degree, the scope or practice of the invention. Effective amounts of the compounds of the present invention can be administered to a subject, by any of several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously of sterile solutions. The compounds of the present invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility, and the like. The pharmaceutically acceptable acid addition salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, for example, acetic acid, propionic acid, and the like, salts of dibasic carboxylic acids, for example, maleic acid, fumaric acid, and the like; and salts of tribasic carboxylic acids, such as carboxy succinic acid, citric acid, and the like. Effective amounts of the compounds of the invention can be administered orally, for example, with an inert diluent or with an edible vehicle. They can also be enclosed in gelatin capsules or tablets to tablets. For therapeutic administration purposes, the compounds of the invention can be incorporated with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations must contain at least 0.5% of the effective compound of the invention, but may be varied depending on the particular form and may conveniently be between 4% to about 70% by weight of the unit. The amount of active compound in said composition is such that an adequate dose will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 0.1-300 milligrams of the active compound of the invention. The tablets, pills, troches and the like may also contain the following ingredients: a binder, such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient, such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch, and the like; a lubricant such as magnesium stearate or Sterores; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose; or saccharin, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavor. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid vehicle such as a fatty oil. Other dosage unit forms may contain various materials that modify the physical form of the dosage unit, for example, as coatings. In this way, the tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, colorants, and flavors. The materials used to prepare these various compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administrations, the active compound of the invention can be incorporated into the solution or suspension. These preparations should contain at least 0.1% of the active compound, but can be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that an adequate dose will be obtained. Preferred compositions and preparations according to the present invention are prepared so that the parenteral dosage unit contains between 0.5 to 100 milligrams of the active compound. The solutions or suspensions may also include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; pH regulators such as acetates, citrates, or phosphates, and agents for tonicity adjustment such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, dispensable syringes or multiple dose vials made of glass or plastic. The highly lipophilic esters, amides, carbonates and carbamates of the present invention are capable of sustained release in mammals over a period of several days from about one to four weeks, when formulated or administered as depot preparations, for example, when injected into a properly selected pharmaceutically acceptable oil. Preferred oils of vegetable origin such as sesame oil, cottonseed oil, corn oil, coconut oil, soybean oil, olive oil, or are synthetic esters of fatty acids and polyfunctional alcohols such as glycerol or propylene glycol . The deposit compositions of the present invention are prepared by dissolving or suspending a highly lipophilic ester, amide, carbonate or carbamate of the present invention in a pharmaceutically acceptable oil under sterile conditions. The oil is selected in order to obtain a release of the active ingredient for a desired period. The appropriate oil can be easily determined by consulting the prior art, or without undue experimentation by one skilled in the art. An appropriate dose of a compound according to this embodiment of the invention is from about 0.01 to 10 mg / kg of body weight per injection. Preferably, the depot formulations of this invention are administered as an oral dose preparations comprising from about 0.5 to 5.0 ml of a solution of 0. 1 to 20% w / w of a compound in the oil. It should be understood that the doses set forth herein are illustrative only and that they do not limit, to any degree, the scope or practice of the invention. Representative examples of the compounds of the invention and of intermediates used in their synthesis are set forth in Table 5. The examples are for illustrative purposes only and are not construed as limiting the invention. All temperatures are given in degrees Celsius (° C) unless otherwise indicated.

TABLE 5 EXAMPLES EXAMPLE 1 3-ri- (4'-Fluorobenzoyl) propyl-4-piperazinyl-6-methoxy-1,2-benzisoxazole to. 6-Methoxy-3- (1-piperazinyl) -1,2-benzisoxazole hemidrate A mixture of 3-chloro-6-methoxy-1,2-benzisoxazole (3.0 g) and piperazine (6.0 g) was heated to 140 °. C for 4 hours in a sealed tube and then cooled to room temperature. The contents of the tube were dissolved in MeOH and further diluted with EtOAc (1L). The precipitate was filtered and the filtrate was dried over MgSO 4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 30% MeOH / EtOAc provided a residue after evaporation (3.6 g, mp 79-80 ° C). ANALYSIS: Calculated for C? 2H? SN3O20.5H2O: 59.49% C 6.65% H 17.34% N Found: 59.25% C 6.28% h 17.30% N b. 3- [1- (4'-Fluorobenzoyl) propyl-4-piperazinyl] -6-methoxy-1,2-benzisoxazole To a stirred solution of 6-methoxy-3- (1-piperazinyl) -1,2-benzisoxazole ( 5.0 g, 21.4 mmol) in acetonitrile (25 ml) was added K2CO3 (3.6 g, 25.7 mmol), Kl (0.4 g, 2.1 mmol) and 4-chloro-4'-fluorobutyrophenone (5.2 g, 25.7 mmol) under N2. . The reaction was refluxed for 5 hours and allowed to cool to room temperature. The material was diluted with EtOAc, washed with water and brine, dried with MgSO 4, and concentrated in vacuo. The materials were flash chromatography (silica gel) eluting with 3: 2 EtOAc / heptane to provide the pure free base of the product. ANALYSIS: Calculated for C22H24N3O3F: 66.48% C 6.09% H 10.57% N It was found: 66.32% C 6.00% h 10.45% N EXAMPLE 2 3-ri- (4'-Fluorobenzoyl) propyl-4-piperazinyl-6-hydroxy-1, 2-benzisoxazole A solution of 3- [1- (4'-fluorobenzoyl) propyl-4-piperazinyl] -6-methoxy-1,2-benzisoxazole (3.5 g, 8.8 mmol) and 45% hydrobromic acid was heated at 120 ° C for 4 hours. The reaction was neutralized with a saturated Na 2 CO 3 solution, extracted with EtOAc, and the organic phase was dried (MgSO 4) and concentrated in vacuo. Flash chromatography (silica gel) eluting with 5% MeOH / CH 2 Cl 2, concentration of the desired fractions and recrystallization from EtOAc provided the product as an off-white solid (0.5 g, 15%, mp 181-182 ° C). ANALYSIS: Calculated for C2? H22N3? 3F: 65.78% C 5.78% H 10.96% N Found: 65.53% C 5.89% H 10.76% N EXAMPLE 3 3-Ri- (4'-Fluorobenzoyl) propyl-4-piperazin-p-6-hydroxy-1,2-benzisoxazole Bromhydrate A solution of ethereal hydrobromic acid was added to a solution of 3- [1- (4'-fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1,2-benzisoxazole (0.31g, 0.8 mmol) in 50% strength. CH3CN / EtOAc and cooled to 0 ° C for 1 hour. The precipitate was filtered under N2 and dried under vacuum to provide the hydrobromide salt as a white solid (0.3g, 81%, mp 260-261 ° C). ANALYSIS: Calculated for C21H22N3O3F HBr: 54.32% C 4.99% H 9.05% N It was found: 54.75% C 5.05% H 9.04% N EXAMPLE 4 Ester hexyl ester (3-r4-r4- (4-fluorophenol) -4-oxo-butyl-1-piperazin-1-yl-1,2-benzisoxazole-6-yl) of carbonic acid To a suspension of the compound of Example 3 (7.6 g, 16.4 mmol) in EtOAc (200 mL) was added NaHCO 3 (sat 100 mL) at room temperature. After stirring overnight, the solids were removed via filtration and the two-phase filtrate was transferred to a separatory funnel. The layers were separated and the organic phase was dried over Na2SO4. Filtration and concentration of the filtrate gave 2.9 g (47%) of the compound of Example 2. This free amine (0.50 g, 1.31 mmol) was suspended in anhydrous THF (25 mL), under nitrogen, and treated with hexyl chloroformate. (97%, 0.27 ml, 1.57 mmol). Then ground potassium carbonate (0.22 g, 1.57 mmol) was added and the reaction mixture was allowed to stir for 18 hours. The solids were removed by filtration and washed with DCM. The combined filtrates were concentrated to give the crude product, which was purified via flash chromatography (silica gel, ethyl acetate). The concentration of the desired fractions gave 0.51 g (76%) of the product as a light brown solid, m.p. 77-80 ° C. ANALYSIS: Calculated for C28H34FN3Os: 65.74% C 6.79% H 8.21% N It was found: 65.80% C 6.74% H 8.04% N EXAMPLE 5 Ester 3-T4-r4- (4-f luorofenyl) -4-oxo-buty I -piperazin -11-1.2- benzisoxazole-6-yl of adamantan-1-carboxylic acid The compound of Example 2 (0.50 g, 1.31 mmol) was suspended in acetonitrile (15 ml), under nitrogen, and treated with K2CO3 (0.20 g, 1.44 mmol). Then 1-adamantanecarbonyl chloride (0.30 g, 1.44 mmol) was added and the reaction mixture was allowed to stir for sixty hours. The solids were removed by filtration and washed with DCM. The combined filtrates were concentrated to give the crude product, which was purified via flash column chromatography (silica gel, ethyl acetate). The concentration of the desired fractions gave 0.52 g (73%) of the product as a white solid, m.p. 157-158 ° C. ANALYSIS: Calculated for C32H36F 3O4: 70.44% C 6.65% H 7.70% N Found: 70.29% C 6.62% H 7.54% N EXAMPLE 6 Ester 3-r4-r4- (4-fluorophenyl) -4-oxo-butyl-p-piperazin-il-1-, 2-benzisoxazole-6-yl of decanoic acid The compound of Example 2 (0.60 g, 1.57 mmol) was suspended in acetonitrile (15 ml), under nitrogen and treated with K2CO3 (0.24 g, 1.73 mmol). Then decanoyl chloride (0.36 ml, 1.73 mmol) was added and the reaction mixture was allowed to stir for 60 hours. The solids were removed via filtration and washed with DCM. The combined filtrates were concentrated to give 0.80 g (95%) of the desired product as a brown solid, m.p. 69-71 ° C.

ANALYSIS: Calculated for C3? H4oFN3O: 69.25% C 7.50% H 7.82% N Found: 69.28% C 7.71% H 7.76% N EXAMPLE 7 Ester 3-r4-f4- (4-f luorofenil i-4-oxo-buti I-pipe razin-i 11-1.2- benzisoxazol-6-yl butyl carbamic acid The compound of Example 2 (0.50 g, 1.31 mmol) was suspended in anhydrous THF, under nitrogen, and treated with butyl isocyanate (0.18 mL, 1.57 mmol). Then, ground potassium carbonate (0.22g, 1.57mmol) was added and the reaction mixture was allowed to stir for 18 hours. The solids were removed via filtration and washed with DCM. The combined filtrates were concentrated to give the crude product, which was purified via flash column chromatography (silica gel, ethyl acetate). The concentration of the desired fractions gave 0.40 g (63%) of the product as a light brown solid, m.p. 137-141 ° C. ANALYSIS: Calculated for C26H31 FN4O4: 64.72% C 6.48% H 1 1 .61% N Found: 64.29% C 6.83% H 1 1 .77% N EXAMPLE 8 3-M-Homopiperazinyl) -6-methoxy-1,2-benzisoxazole 3-Chloro-6-methoxy-1,2-benzisoxazole (5.0 g, 27.2 mmol) and homopiperazine (8.2 g, 81.6 mmol) were combined and mechanically stirred under N2 at 140 ° C for 45 minutes. The reaction mixture was cooled to room temperature, dissolved with EtOAc (500 ml), and the solution was washed with water, brine, dried over MgSO, and concentrated in vacuo. Flash column chromatography (silica gel, 20% MeOH / CH 2 Cl 2) provided the product (2.0 g, mp 74-74 ° C). ANALYSIS: Calculated for C? 3H17N3O2: 63.14% C 6.93% H 16.99% N It was found: 62.88% C 6.85% H 16.81% N EXAMPLE 9 1- (4-Fluorophenopyr-4-r4-f6-hydroxy-1-methyl-1H-indazol-3-ip-piperazin-1-yH-butan-1-one hydrochloride hydrate) to. 4- [4- [N- (p-toluenesulfonylhydrazono) -2-fluoro-4-methoxyphenyl-methyl] -piperazin-1-yl] -1- (4-fluorophenyl) butan-1-one To a stirred solution of alpha -chloro-2-fluoro-4-methoxy benzaldehyde, 1-p-toluenesulfonylhydrazone (4.6 g, 12.8 mmol) in chloroform (20 ml) was added a solution of 1- (4-fluorophenyl) -4-piperaz * n- 1-yl-butan-1-one (3.2 g, 12.8 mmol) in chloroform (20 ml) and allowed to stir at room temperature under nitrogen for 1 hour. The reaction was diluted with methylene chloride, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was flash chromatographed eluting with 3: 2 CH 2 Cl 2 / EtOAc to provide the product, 2.5 g, m.p. = 66-67 ° C. ANALYSIS: Calculated for C29H32N4O4F2S: 61.04% C 5.65% H 9.82% N Found: 60.74% C 5.53% H 9.69% N b. 1- (4-Fluorophenyl) -4- [4- [6-methoxy-1-toluene-4-sulfonyl) -1H-indazol-3-yl] -piperazin-1-yl] butan-1-one To one solution stirring of the compound of Example 9a (2.5 g, 4.4 mmol) in N, N-dimethylformamide (10 ml) was added K2CO3 (1.2 g, 8.8 mmol) under N2. The reaction was heated at 90 ° C for 3 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with brine (6 times), dried over Na2SO, and concentrated in vacuo. The residue was flash chromatographed eluting with 3: 2 CH 2 Cl 2 / EtOAc to provide the product, 2.3 g, m.p. 120-121 ° C. ANALYSIS: Calculated for C29H31N4O4FS: 63.26% C 5.67% H 10.17% N Found: 62.99% C 5.71% H 9.86% N c. 1- (4-Fluorophenyl) -4- [4- [6-methoxy) -1H-indazol-3-yl] -piperazin-1-yl-butan-1 -one A mixture of the compound of Example 9b (1 g, 1.8 mmol) and 30 ml of 12M hydrochloric acid was heated at 90 ° C for 1 hour under nitrogen. The reaction mixture was cooled, diluted with EtOAc and neutralized with Na2CO3 (sat.). The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and evaporated to provide 0.65 g of the desired product, m.p. = 157-162 ° C. d. 1- (4-Fluorophenyl) -4- [4- [6-methoxy) -1-methyl-1H-indazol-3-yl] -piperazin-1-yl-butan-1 -one To a mixture of the compound of Example 9c (0.45 g, 1.13 mmol) and potassium hydroxide (0.19 g, 3.4 mmol) in 40 ml of acetone, dimethylformamide (0.14 g, 0.11 ml, 1.13 mmol) was added and the mixture was refluxed for three hours . The reaction mixture was cooled, diluted with methylene chloride and washed with brine. The organic layer was dried over Na2SO and concentrated in vacuo. The residue was chromatographed by flash evaporation. Elution with 5% MeOH / CH 2 Cl 2 gave 0.4 g of the product, m.p. 103-104 ° C. and. Hydrochloride of 1- (4-Fluorophenyl) -4- [4- [6-hydroxy) -1-methyl-1 H -indazol-3-yl] -piperazin-1-yl-butan-1 -one A 48 % hydrobromic acid (20 ml) was added to the compound of Example 9d (0.40 g, 1.0 mmol) and the mixture was heated at 1 10 ° C under N2 for four (4) hours. The mixture was then cooled and diluted with EtOAc and neutralized with a saturated Na 2 CO 3 solution and extracted with additional EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo, the residue was chromatographed by flash (silica gel, 3% MeOH / CH2CI2 to produce a white solid, which was dissolved in EtOAc and acidified with Ethereal hydrochloric acid to provide the salt, 0.30 g, mp = 243-244 ° C. ANALYSIS: Calculated for C22 H2SN4O4F.H CI-H2O: 58.60% C 6.26% H 12.40% N Found: 58.60% C 6.06% H 12.36% N It should be understood that this specification and examples are set forth by way of illustration and not limitation and that various changes and modifications may be made without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims (1)

1. CLAIMS A compound of the formula: wherein, X is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) aryl (C? -C? 0), -OC (= O) -alkyl (C? -C? 2) -aryl (C6-C? 0), -OC (= O) NH-alkyl (C? -C?), -OC (= O) alkyl (C? -C? 2) cycloalkyl ( C3-C8), -OC (= O) O alkyl (d-c18), or -OC (= O) -cycloalkyl (C3-C? 2); Y is hydrogen, halogen, trifluoromethyl, alkoxy (Ci-Ce), cyano or nitro; Z is O or NR; Ri is hydrogen, alkyl (C? -C6), formyl, -C (= O) alkyl (C? -C? 8), or -C (= O) O alkyl (C? -C? 8); m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts. 2 - The compound according to claim 1, of the formula: X is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) NH-alkyl (C? C? 8), -OC (= O) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl (C3-C, 2); Y is hydrogen, halogen, trifluoromethyl, alkoxy (d-cß), cyano or nitro; m is 1, 2, 3, or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. 3. The compound according to claim 2 of the formula, X is -OH, -OC (= O) alkyl (C? -C?), -OC (= O) NH-alkyl (Ci-Ci), -OC (= O) O-alkyl (dC? 8) or -OC (= O) -cycloalkyl Y is hydrogen, halogen; m is 1, 2, 3, or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. 4. The compound according to claim 3, wherein m is 3 and Y is 4-fluoro. 5. The compound according to claim 4, wherein X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) hexyl, 6-OC (= O) nonyl, or 6- OC (= O) adamantyl; and their pharmaceutically acceptable salts. 6. The compound according to claim 5, which is 3- [1 - (4'-f luoro benzoyl) propyl-4-piperazinyl] -6-hydroxy-1,2-benzisoxazole. 7. The compound according to claim 5, which is 3- [1- (4'-fluorobenzoyl) propyl-4-piperazinyl] -6-hydroxy-1,2-benzisoxazole hydrobromide. 8. The compound according to claim 5, which is hexyl ester of 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-ester. -benzisoxazole-6-yl. 9 - The compound according to claim 5, which is 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1-yl] -1,2-benzisoxazole-6 ester - adamantane-1-carboxylic acid. 10 - The compound according to claim 5, which is ester 3- [4- [4- (4-fluorophenyl) -4-oxo-butyl] -piperazin-1 -yl] -1,2-benzisoxazole-6 -decanoic acid-alkyl. The compound according to claim 5, which is ester 3- [4- [4- (4-f luo rof eni l) -4-oxo-buti I] -piperazin-1-yl] - 1, 2-benzisoxazol-6-yl butyl carbamic acid. 12. The compound according to claim 1, which is a compound of the formula: wherein X is -OH, -OC (= O) alkyl (C? -C18), -OC (= O) NH-alkyl (dC? 8), -OC (= O) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen, trifluoromethyl, alkoxy (d-C6), cyano or nitro; m is 1, 2, 3 or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. 13. The compound according to claim 12 of the formula, wherein X is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) NH-alkyl (dC? 8), -OC (= O) O-alkyl ( C? -C?) Or -OC (= O) -cycloalkyl (C3-C12); And it is hydrogen, halogen; m is 1, 2, 3 or 4; and P is 1; and their pharmaceutically acceptable acid addition salts. 14 - The compound according to claim 13, wherein m is 3 and Y is 4-fluoro. The compound according to claim 14, wherein X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) hexyl, 6-OC (= O) nonyl, or 6-OC (= O) adamantyl; and their pharmaceutically acceptable salts. 16. The compound of claim 1 of the formula, wherein X is -OH, -OC (= O) alkyl (C? -C18), -OC (= O) NH-alkyl (C? C? 8), -OC (= O) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen trifluoromethyl, alkoxy (C6C6), cyano or nitro; Ry is hydrogen, alkyl (d-C6), formyl, -C (= O) alkyl (Ci- C? 8), or -C (= O) O alkyl (C? -C? 8); m is 1, 2, 3, or 4; p is 1 or 2; and their pharmaceutically acceptable acid addition salts. 17. The compound of claim 16 of the formula, wherein X is -OH, -OC (= O) alkyl (d-C18), -OC (= O) NH-alkyl (Ci- Cie), -OC (= O) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl Y is hydrogen, halogen; R1 is hydrogen, (d-C6) alkyl, formyl, -C (= O) (C1-C8) alkyl, or -C (= O) O alkyl (d-C8); m is 1, 2, 3, or 4; p is 1 or 2; and their pharmaceutically acceptable acid addition salts. 18. The compound according to claim 17, wherein m is 3 and Y is 4-fluoro. 19. The compound according to claim 18, wherein X is 6-hydroxy, 6-OC (= O) NHbutyl, 6-OC (= O) hexyl, 6-OC (= O) nonyl, or 6- OC (= O) adamantyl; and their pharmaceutically acceptable salts. The compound according to claim 19, which is 1- (4-f luorofenyl) -4- [4- (6-hydroxy) -1-methyl-1 H-ind azo l-3 -il] -pi pe razin-il] -butan-1-one. 21 - The compound of claim 1 of the formula, wherein X is -OH, -OC (= O) alkyl (dC? 8), -OC (= O) NH-alkyl (Ci- C18), -OC (= O) O-alkyl (C? -C? 8) or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen trifluoromethyl, alkoxy (Ci-Ce), cyano or nitro; Ri is hydrogen, alkyl (d-C6), formyl, -C (= O) alkyl (Ci- C? 8), or -C (= O) O alkyl (C? -C? 8); m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts. 22. The compound of claim 21 of the formula, where X is -OH, -OC (= O) alkyl (C? -C? 8), -OC (= O) NH-alkyl (Ci- C18), -OC (= O) O-alkyl (d-C18) ) or -OC (= O) -cycloalkyl (C3-C12); And it is hydrogen, halogen; R is hydrogen, (C? -C6) alkyl, formyl, -C (= O) alkyl (Ci- C? 8), or -C (= O) O alkyl (C? -C? 8); n is 1; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts. 23. The compound according to claim 21, wherein m is 3 and Y is 4-fluoro. 24. The compound according to claim 23, wherein X is 6-hydroxy, 6-OC (= O) N Hbutyl, 6-OC (= O) hexyl, 6-OC (= O) nonyl, or -OC (= O) adamantyl; and their pharmaceutically acceptable salts. 25. A pharmaceutical composition, which comprises the compound of claim 1 and a pharmaceutically acceptable carrier. 26. An anti-psychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an anti-psychotic effect and a pharmaceutically acceptable carrier. 27 - A method for treating psychosis, which comprises administering to a mammal an effective amount for treating psychosis of the compound of claim 1. 28 - A reservoir composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1, wherein the compound contains a hydroxy group or an amino group, which has been acylated. 29. - The composition according to claim 28, wherein the hydroxy or amino group is acylated with an alkanoyl group (C4-C? 8) or an alkoxycarbonyl group (C4-C? 8). 30 - The composition according to claim 28, which contains a pharmaceutically acceptable oil. 31. - The composition according to claim 30, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, and esters of fatty acids and polyfunctional alcohols. 32. A depot composition, which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of claim 1. 33.- A method for providing a long-acting anti-psychotic effect, which comprises injecting a mammal an amount of the composition of claim 32, sufficient to produce a long-lasting anti-psychotic effect. 34.- A method for providing a long-acting anti-psychotic effect, which comprises injecting to a mammal an amount of the composition of claim 28, sufficient to produce a long-acting anti-psychotic effect. 35.- The use of a compound according to any of claims 1-24 for the manufacture of a medicament for the treatment of psychosis. 36.- The use of a compound according to any of claims 1-24 for the manufacture of a medicament that provides a long-acting anti-psychotic effect. 37 - A process for preparing a compound of the formula, -OC (= O) -alkyl (C? -C12) -aryl (C6-C? O), -OC (= O) NH-alkyl (d-C18), -OC (= O) alkyl (C? -C12) cycloalkyl (C3-C8), -OC (= O) O alkyl (C? -C? 8), or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen, trifluoromethyl, alkoxy (Ci-Cß), cyano or nitro; m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts, which comprises reacting a compound of the formula: where X and n are as defined above, with a compound of the formula: herd- (Cr «rtrl- £ wherein halo is Br or Cl, and Y, m and p are as defined above, in a polar non-protic organic solvent in the presence of a base and a catalyst. 38 - A process for preparing a compound of the formula, wherein X is -OH, -OC (= O) alkyl (d-C? 8), -OC (= O) aryl (C6-C10), -OC (= O) -alkyl (C? -C? 2) -aryl (C6-C? 0), -OC (= O) NH-alkyl (C? -C18), -OC (= O) alkyl (C? -C? 2) cycloalkyl (C3-C8), -OC (= O) O alkyl (C? -c18), or -OC (= O) -cycloalkyl (C3-C12); Y is hydrogen, halogen, trifluoromethyl, alkoxy (d-C6), cyano or nitro; m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts, which comprises treating a compound of the formula: where Ts is tosylate and X, Y, m, n and p are as defined above, with concentrated HCl. 39.- A process for preparing a compound of the formula, rQrcw - > p wherein Y is H, halogen, trifluoromethyl, (C? -C6) alkoxy, cyano or nitro; m is 1, 2, 3 or 4; n is 1 or 2; and p is 1 or 2; and their pharmaceutically acceptable acid addition salts, which comprises heating a compound of the formula: wherein X is -OH, -OC (= O) alkyl (d-C? 8), -OC (= O) aryl (C6-C? o), -OC (= O) -alkyl (C? -C? 2) -aryl (C6-C10), -OC (= O) NH-alkyl (C? -C? 8), -OC (= O) alkyl (C? -C? 2) cycloalkyl (C3-C8), -OC (= O) O alkyl (d-C? 8), or -OC (= O) -cycloalkyl (C3-C? 2), and Y, m, n and p are as defined above, with 48% HBr.