MXPA99007112A - 1-phenyl-4-benzylpiperazines:dopamine receptor subtype specific ligands (d4) - Google Patents

Abstract

Disclosed are compounds of formula (I) or the pharmaceutically acceptable addition salts thereof wherein:R1 is halogen or C1-C4 alkyl;and R2 and R3 are the same or different and represent hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, alkylthio, hydroxy, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, or R2 and R3 together represent a 4 carbon alkenylene moiety that together with the phenyl ring to which they are attached form a naphthyl moiety, which compounds are dopamine D4(ant)agonists and useful in the treatment of neuropsychological diseases such as schizophrenia, psychotic depression and mania.

Description

l-PHENYL-4-BENZYLPIPERAZINES: IGANDS (D4) SPECIFIC OF THE DOPAMINE RECEIVER SUBTYPE BACKGROUND OF THE INVENTION Field of the Invention This invention relates to certain 1-phenyl-4-benzylpiperazines and to pharmaceutical compositions containing them. This also refers to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other diseases of the central nervous system. The use of the compounds of this invention for the treatment of these disorders is indicated by the ability of the compounds to selectively bind to the subtypes of dopamine receptors.

Description of Related Art The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through the blockade of dopamine receptors. However, REF .: 31005 Neuroleptics are frequently responsible for undesirable extrapyral collateral effects (EPS) and tardive dyskinesias, which are attributed to the blockade of D2 receptors in the region of the striatum of the brain. The D4 receptor subtype of dopa 'ina has recently been identified (Van Tol, H. H. et al., Na t ure, 1991, 350, 610). Its unique location in the limbic areas of the brain and its differential recognition of various antipsychotics suggests that the D4 receptor plays a role in the etiology of schizophrenia. Selective D4 antagonists are effective antipsychotics free from the neurological side effects shown by conventional neuroleptics. Since the dopamine D4 receptors are concentrated in the limbic system which controls cognition and emotion, the compounds that interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social isolation and lack of responsiveness) of schizophrenia. Other disorders that involve memory impairment or attention deficit disorders can also be treated with compounds that specifically interact with the D4 receptor subtype of dopamine. Japanese Patent JP 47017306 describes m-trifluoromet ilphenyl-benzyl-piperazines as tranquilizers and analgesic agents. Nucí Med. Biol. 20 (6), 777-94, 1993, describes the radiolabelled 1- ([4- { Fluoro-18F.}. PhenylJmeti 1) -4- (3- [trifluoromethyl] phenylpiperazine), as a Image training agent. J. Med. Chem. 37, 1060-1062, 1994, and International Application No. WO 9304684 describe 4-arylpiperazines and 4-arylpiperidines. J. Med. Chem. 11, 1144-1150, 1968, describes certain 1-phenyl-4-benzylpiperazines as antihypertensive agents.

BRIEF DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I which interact with the subtypes of the dopamine receptor. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: or the pharmaceutically acceptable addition salts thereof wherein: Ri is halogen or alkyl of 1 to 4 carbon atoms; And R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, amino, mono (alkylamino) 1 to 4 carbon atoms), di (alkylamino of 1 to 4 carbon atoms), or R2 and R3 together represent an alkenylene portion of 4 carbon atoms which together with the phenyl ring to which they are attached form a portion of naphthyl . The compounds of the present invention demonstrate high affinity and selectivity in the binding to the D4 receptor subtype of dopamine. Consequently, these are useful in the treatment of schizophrenia, psychotic depression and mania. Other diseases Dopamine-mediated such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D receptors. The compounds of the invention are also useful in the treatment of extrapyramidal side effects associated with the use of conventional neuroleptic agents as well as in the treatment of other disorders that respond to dopaminergic blockade such as substance abuse and obsessive-compulsive disorder. . further, the compounds of this invention are useful in the treatment of depression, memory impairment or Alzheimer's disease, by modulation of the D4 receptors that selectively exist in the limbic areas known to control emotion functions and cognitive functions. The interaction of l-phenyl-4-benzylpiperazines with the subtypes of the dopamine receptor is also shown. This interaction results in the pharmacological activities of these compounds. The invention further provides pharmaceutical compositions comprising the compounds of Formula I. This also refers to the use of such compounds and compositions in the treatment and / or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, dystonia, compulsive behavior, substance abuse, memory impairment, deficits cognitive disorders, motor disorders similar to Parkinsonism and movement disorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the invention encompasses the substituted 1-phenyl-4-benzylpiperazines of the formula I. Preferred compounds of the formula I are those wherein R 2 and R 3 can not be 2-isopropoxy and hydrogen, respectively, when Ri is bromine The invention also provides the compounds of the formula IA: IA or the pharmaceutically acceptable acid salts thereof wherein: Ri is halogen or alkyl of 1 to 4 carbon atoms, and R 2 is hydrogen; or Ri and Ra together represent alkylene of 3 to 5 carbon atoms containing one or two oxygen atoms, which together with the phenyl group form a five- or six-membered ring containing one or two oxygen atoms; R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, nitro, amino, monoalkylamino or dialkylamino, or R2 and R3 together represent alkylene of 3 to 5 carbon atoms or alkenylene containing one or two oxygen atoms which together with the phenyl form a ring of five or six members substituted with one or two oxygen atoms, with the proviso that R2 and R3 they can not be 2- isopropoxyl and hydrogen respectively when Ri is bromine.

The invention also encompasses the compounds of formula II: p wherein Rx is fluorine, chlorine, bromine, or iodine; and R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, amino, monoalkylamino or dialkylamino. In the preferred embodiments of formula II, R2 and R3 can not be 2-isopropoxy and hydrogen, respectively, when Ri is bromine. The most preferred compounds of the formula II are those where Ri is chloro, R2 and R3 can not be 2-isopropoxy and hydrogen, respectively, when Ri is bromo; R2 is halogen, more preferably chloro, or methyl or methoxy; and R3 is hydrogen or methyl.

The invention also encompasses the compounds of formula III: m wherein Ra is alkyl of 1 to 4 carbon atoms; and R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, amino, monoalkylamino or dialkylamino. In the preferred embodiments of formula III, R 4 is methyl; R2 is halogen, more preferably chloride, or methyl or methoxy; and R3 is hydrogen or methyl. Particularly preferred compounds of formulas II and III are those wherein the phenyl group substituted with R2 and / or R3 is selected from the group consisting of: The invention also encompasses the compounds of formula VI: VT wherein Ri is alkyl of 1 to 4 carbon atoms or halogen. Preferred compounds of formula VI are those where Ri is methyl, Cl or F.

The invention also encompasses a method for the treatment or prevention of neuropsychological disorders such as, for example, schizophrenia and other diseases of the central nervous system, which comprises administering to a patient in need of such treatment, a compound of the invention. Representative compounds of the present invention, which are encompassed by formula I, include, but are not limited to, the compounds of Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric acids, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluensulonic, methanesulphonic, nitric, benzoic, citric, tartaric, maleic, iohydric, alkanoic such as acetic, HOOC- (CH2) n where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic addition salts. The present invention also encompasses acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare the pharmaceutically acceptable, non-toxic addition salts and the acylated prodrugs of the compounds encompassed by Formula I. By the terms alkyl of 1 to 4 carbon atoms and lower alkyl is meant the straight and branched chain alkyl groups having from 1 to 4 carbon atoms, as well as the cyclic alkyl groups such as, for example, cyclopropyl and cyclobutyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Preferred alkyl groups of 1 to 4 carbon atoms are methyl and ethyl. By the terms "alkoxy" and "lower alkoxy" 1 to 4 carbon atoms are understood to be the straight and branched chain alkoxy groups having 1 to 4 carbon atoms. By the term alkylthio is meant the lower alkyl groups linked to the parent system, for example, a phenyl group, by a sulfur atom. By halogen, halo, or halide is meant the substituents of fluorine, chlorine, bromine and iodine. Where R2 and R3 together represent alkylene of 3 to 5 carbon atoms or alkenylene of 3 to 5 carbon atoms containing one or two oxygen atoms, which together with the phenyl form a five- or six-membered ring substituted with one or two oxygen atoms, the resulting groups include the following: £ 0 J O Representative examples according to the invention are shown in Table 1 below.

Table 1 Compu is o 2 Compound 3 Compues to 4 The pharmaceutical utility of the compounds of this invention is indicated by the following assays for the affinity of the dopamine receptor subtype.

Test for the Receptor Link Activity D2 and D4 Buttons or concentrates of COS cells containing the D2 or D4 receptors recombinantly produced from humans are used for the assays. The sample is homogenized in 100 volumes (weight / volume) of buffer Tris HCl 0.05 M at 4 ° C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. "The sample is then centrifuged as described above and the final tissue sample is frozen until use.The tissue is resuspended 1:20 (weight / volume) in 0.05 M Tris HCl buffer containing 100 mM sodium chloride. Incubations are carried out at 48 ° C and contain 0.4 ml of tissue sample, 0.5 nM 3H-YM 09151-2 and the compound of interest in a total 1.0 ml incubation mixture.The nonspecific binding is defined as that link found in the presence of 1 nM spiperone, without additional aggregates, the non-specific binding is less than 20% of the total binding.The representative binding characteristics for the compounds of the invention for the subtypes of receptors D2 and D4 are shown in Table 2 for the cloned human dopamine receptors Typically, the compounds of the invention have similar link profiles.

Table 2 Compound Number D4 Ki (nM) D2 Ki (nM) 1 5 > 1000 2 16 > 600 3 5 > 1000 4 15 > 300 The numbers of compounds refer to the compounds described later in the examples. The compounds described in Japanese Patent JP 47017306 and in Nuci. Med. Biol. 20 (6), 777-94, 1993 were prepared and tested using the above assay. These compounds did not selectively bind to the dopamine subtypes. The compound described in J. Med. Chem. 11, 1144-1150, 1968, as Compound 97, for example, a 4-methoxy derivative, was prepared and found not to bind selectively to the subtypes of dopamine. The compounds of formula I can be administered orally, topically, parenterally, by inhalation or spray or rectally, in unit dose formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Further,The pharmaceutical formulation comprising a compound of the general formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula I may be present in association with one or more pharmaceutically acceptable, non-toxic carriers and / or diluents and / or adjuvants, and if desired, other active ingredients. The pharmaceutical compositions containing the compounds of the general formula I can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard gelatin capsules or soft, or syrups or elixirs. Compositions designed for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and agents preservatives in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in mixture with excipients pharmaceutically acceptable, non-toxic, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a prolonged period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may also be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents can be a phosphatide of natural origin, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic chain alcohols long, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylenesorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides , for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, and flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant agent such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable agent, for example olive oil, or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example, acacia gum or tragacanth gum, phosphatides of natural origin, for example soy, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example monooleate of sorbitan, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any fixed oil mixture, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the general formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the general formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and the concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. The dose levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-mentioned conditions (approximately 0.5 mg to approximately 7 g per patient per day). The amount of the active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. The dosage unit forms will generally contain between approximately 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the route of administration, and the rate of excretion, the combination of the drug and the severity of the particular disease subject to therapy. A representative illustration of the methods suitable for the preparation of the compounds of the present invention, is shown in Schemes I. Those skilled in the art will recognize that the starting materials may be varied and the additional steps employed to produce compounds encompassed by the present invention. For example, in certain situations, protection of reactive portions such as amino groups will be required.

Preparation of 1-phenyl-4-benzylpiperazines In the above Scheme, Ri, R2 and R3 are as defined above in formula I. As shown, a 4-substituted benzyl alkylating agent of the general structure IV, having a leaving group X, is reacted with a 1-phenylpiperazine of the general structure V in the presence of a suitable base to provide a compound of the Formula I as the desired product. The leaving group X can be a halogen, a sulfonic acid ester or the like. The reaction is typically carried out in a solvent such as acetonitrile with heating, for example to reflux.

Where these are not commercially available, the compounds of the general structures IV and V can be prepared using known procedures or procedures analogous to those described in the literature. Those of skill in the art will recognize that the starting materials may be varied and additional steps may be employed to produce the compounds encompassed by the present invention. The descriptions in this application of all articles and references, including patents, are incorporated by reference herein. The invention is further illustrated by the following examples, which do not have to be considered as limiting the invention in scope or spirit, to the specific procedures and the compounds described therein.

Example 1 4-chlorophenyl) -4- (4-chlorobenzyl) piperazine dihydrochloride (Compound 1) A mixture of 1- (4-chlorophenyl) piperazine (1.61 g, 0.01 mol), 4-chlorobenzyl chloride (2.10 g, 0.01 mol) and potassium carbonate (2 g) in 40 ml of acetonitrile is heated at reflux for 6 hours under nitrogen atmosphere. After cooling, the reaction mixture is poured into 50 ml of water and 50 ml of ether. The aqueous layer is discarded and the organic layer is extracted with 1 N hydrochloric acid aqueous solution. The acid extract is neutralized with 6 N ammonium hydroxide solution and extracted with ether. The organic layer is dried over sodium sulfate and concentrated to provide the crude free base of the desired symmetrically substituted piperazine. This material is dissolved in hot isopropanol (10 ml) and treated with a solution of 1 N HCl in ether until acidic to pH paper. After cooling, the crystals of the dihydrochloride salt (2.2 g, 56%) are collected. The following compounds are prepared essentially according to the procedure described above in Example 1. (a) 1- (3-chlorophenyl-4- (4-chlorobenzyl) piperazine dibromhydrate (mp 238-240 ° C) (b) dioxalate 1- (2-chlorophenyl) -4- (4-chlorobenzyl) piperazine (mp 203-204 ° C) (c) 1- (3,4-dichlorophenyl) -4- (4-chlorobenzyl) iperazine (mp 82- 83 ° C) (d) 1- (4-methylphenyl) -4- (4-chlorobenzyl) piperazine dioxalate (mp 204-206 ° C) (e) 1- (3-methylphenyl) -4- (4-chlorobenzyl) dioxalate ) piperazine (mp 233-235 ° C) (f) 1- (2-methylphenyl) -4- (4-chlorobenzyl) piperazine dioxalate (mp 205-206 ° C) (g) 1- (3, dihydrochloride 4-dimethylphenyl) -4- (4-chlorobenzyl) piperazine (mp 225-228 ° C, Compound 2) (h) dioxalate of 1- (4-methoxyphenyl) -4- (4-chlorobenzyl) piperazine (mp 211-212 ° C, Compound 3) (i) dioxalate of 1- (3-methoxyphenyl) -4- (4-chlorobenzyl) piperazine (mp 205-207 ° C) (j) dioxalate of 1- (2-methoxyphenyl) -4- (4) - chlorobenzyl) piperazine (mp 217-220 ° C) (k) 1- (4-ethoxy phenyl) -4- (4-chlorobenzyl) piperazine dihydrochloride (mp 235-237 ° C) (1) dibromhydrate from 1 - (2-Ethoxyphenyl) -4- (4-chlorobenzyl) piperazine (mp 215-217 ° C) (m) 1-phenyl-4- (4-chlorobenzyl) piperazine dioxalate (mp 228-231 ° C) (m) n) 1- (4-chlorophenyl) -4- (4-fluorobenzyl) piperazine dibromohydrate (o) 1- (4-chlorophenyl) -4- (4-methylbenzyl) piperazine dibromhydrate (Compound 4) (p) 1- (3-chlorophenyl) -4- (4-methylbenzyl) piperazine dioxalate (mp) 199-200 ° C) (q) dioxalate of 1- (4-chlorophenyl) -4- (4-methylbenzyl) piperazine (mp 219-221 ° C) (r) dibromhydrate 1- (3, 4-dichlorophenyl) -4- (4- methyl Ibenzyl) piperazine (s) 1- (4-methylphenyl) -4- (4-methylbenzyl) piperazine dioxalate (mp 203-204 ° C) (t) dioxalate 1- (2-methylphenyl) -4- (4-methylbenzyl) piperazine (mp 180-182 ° C) (u) 1- (4-methoxy phenyl) -4- (4-methylbenzyl) piperazine dibromhydrate (v) ) 1- (2-methoxy phenyl) -4- (4-methylbenzyl) iperazine dibromohydrate (mp 234-235 ° C) receptor binding in the previous assays (nm): D4: 900; D3: 6300; D2: 4166 (DC) ato p.f. 143 ° C link to the receptor in the D4 assay described above: 50 nm link to the receptor in the D4 assay described above: 554 nm link to the receptor in the D4 assay described above: D4: 47; D2: 447 nm link to the receptor in the D4 assay described above: D4: 37; D2: 1730 link to the receptor in the D4 assay described above: D4: 6; D2: 10, 000 The invention and the way and process to elaborate and use it, are now described in terms so clear, complete, concise and accurate as to make it possible for any person skilled in the technique to which it belongs, to elaborate and use it. It will be understood that the foregoing describes the preferred embodiments of the present invention, and that modifications may be made therein without departing from the spirit and scope of the present invention, as described in the claims. To particularly point out and distinctly claim the matter of interest considered as an invention, the following claims conclude this specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (55)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of the formula: or the pharmaceutically acceptable salts thereof, characterized in that: Ri is halogen or alkyl of 1 to 4 carbon atoms, and R2 is hydrogen; or Ri and R2 together represent alkylene of 3 to 5 carbon atoms containing one or two oxygen atoms which together with the phenyl group form a five- or six-membered ring containing one or two oxygen atoms; o Ri and Ra jointly represe: ínta - o * R2 and R3 are the same or different and represent hydrogen, halogen alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, nitro, amino, monoalkylamino or dialkylamino, or R2 and R3 together they represent alkylene of 3 to 5 carbon atoms or alkenylene containing one or two oxygen atoms, which together with the phenyl form a five- or six-membered ring substituted with one or two oxygen atoms, with the proviso that and R3 can not be 2- isopropoxy and hydrogen respectively when Ri is bromine.

2. A compound according to claim 1, characterized in that Ri is methyl.

A compound of the formula or the pharmaceutically acceptable salts thereof, characterized in that Rx is fluorine, chlorine, bromine or iodine; and R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, amino, monoalkylamino or dialkylamino.

4. A compound according to claim 3, characterized in that R2 and R3 can not be 2-isopropoxy and hydrogen, respectively, when Ri is bromine.

5. A compound according to claim 3, characterized in that Rx is chlorine; R2 and R3 can not be 2-isopropoxy and hydrogen, respectively, when Ri is bromo; R2 is chloride, methyl or methoxy; and R3 is hydrogen or methyl.

6. A compound according to claim 5, characterized in that the phenyl group substituted with R2 and R3 are selected from the group consisting of:

7. A compound of the formula: or the pharmaceutically acceptable salts thereof, characterized in that: Ra is alkyl of 1 to 4 carbon atoms; and R2 and R3 are the same or different and represent hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio, hydroxyl, amino, monoalkylamino or dialkylamino.

8. A compound according to claim 7, characterized in that Rx is methyl.

9. A compound according to claim 7, characterized in that R2 is chloride, fluoride, methyl or methoxy; and R3 is hydrogen or methyl.

10. A compound according to claim 8, characterized in that the phenyl group substituted with R2 and R3 is selected from the group consisting of:

11. A compound of the formula or the pharmaceutically acceptable salts thereof, characterized in that: Ri is alkyl of 1 to 4 carbon atoms or halogen.

12. A compound according to claim 11, characterized in that Ri is chlorine.

13. A compound according to claim 1, characterized in that it is l- (3-chlorophenyl) -4- (4-chlorobenzyl) piperazine.

14. A compound according to claim 1, characterized in that it is l- (2-chlorophenyl) -4- (4-chlorobenzyl) piperazine.

15. A compound according to claim 1, characterized in that it is l- (3,4-dichlorophenyl) -4- (4-chlorobenzyl) piperazine.

16. A compound according to claim 1, characterized in that it is l- (4-methylphenyl) -4- (4-chlorobenzyl) piperazine.

17. A compound according to claim 1, characterized in that it is l- (3-methylphenyl) -4- (4-chlorobenzyl) piperazine.

18. A compound according to claim 1, characterized in that it is l- (2-methylphenyl) -4- (4-chlorobenzyl) piperazine.

19. A compound according to claim 1, characterized in that it is 1- (3,4-dimethylphenyl) -4- (4-chlorobenzyl) piperazine dibromhydrate.

20. A compound according to claim 1, characterized in that it is 1- (4-methoxyphenyl) -4- (4-chlorobenzyl) piperazine dibromhydrate.

21. A compound according to claim 1, characterized in that it is l- (3-methoxyphenyl) -4- (4-chlorobenzyl) piperazine.

22. A compound according to claim 1, characterized in that it is l- (2-methoxyphenyl) -4- (4-chlorobenzyl) piperazin.

23. A compound according to claim 1, characterized in that it is l- (4-ethoxyphenyl) -4- (4-chlorobenzyl) piperazine.

24. A compound according to claim 1, characterized in that it is l-. { 2-ethoxyphenyl) -4- (4-chlorobenzyl) piperazine.

25. A compound according to claim 1, characterized in that it is l-phenyl-4- (4-chlorobenzyl) piperazin.

26. A compound according to claim 1, characterized in that it is l- (4-chlorophenyl) -4- (4-fluorobenzyl) piperazine.

27. A compound according to claim 1, characterized in that it is l- (4-chlorophenyl) -4- (4-methylbenzyl) piperazine.

28. A compound according to claim 1, characterized in that it is l- (3-chlorophenyl) -4- (4-methyIbenei 1) piperazine.

29. A compound according to claim 1, characterized in that it is l- (3,4-dichloro-phenyl) -4- (4-methylbenzyl) iperazine.

30. A compound according to claim 1, characterized in that it is l- (4-methyl-phenyl) -4- (4-meth i-Bebenei-1) piperazine.

31. A compound according to claim 1, characterized in that it is l- (2-methylphenyl) -4- (-methylbenzyl) piperazine.

32. A compound according to claim 1, characterized in that it is l- (4-methoxy phenyl) -4- (4-methylbenzyl) piperazine.

33. A compound according to claim 1, characterized in that it is l- (2-methoxy phenyl) -4- (4-methylbenzyl) piperazine.

34. A method for the treatment or prevention of neuropsychological disorders, characterized in that it comprises administering to a patient in need of such treatment, a compound selected from the group consisting of (a) 3-chloro-phenyl) -4- (4-chlorobenzyl) piperazine. (b) 1- 2 -chlorophenyl) -4- (4-chlorobenzyl) piperazine. (c) 1- 3, 4-dichlorophenyl) -4- (4-chlorobenzyl) piperazine (d) 1- 4-methylphenyl) -4- (4-chlorobenzyl) piperazine. (e) 1- 3 -methyl phenyl) -4- (4-chlorobenzyl) piperazine. (f) 1- 2-methylphenyl) -4- (4-chlorobenzyl) piperazine. (g) 1- 3, 4 -dimethylphenyl) -4- (4-chlorobenzyl) piperazine (h) 1-4-methoxy phenyl) -4- (4-chlorobenzyl) piperazine. (i) 1- 3 -methoxy phenyl) -4- (4-chlorobenzyl) piperazine. (j) 1- 2 -methoxy phenyl) -4- (4-chlorobenzyl) piperazine. (k) 1-4-ethoxyphenyl) -4- (4-chlorobenzyl) piperazine. (1) 1- 2-ethoxy phenyl) -4- (4-chlorobenzyl) piperazine. (m) 1-phenyl-4- (4-chlorobenzyl) piperazine (n) 1-4-chloro-phenyl) -4- (4-fluorobenzyl) piperazine. (o) 1-4-chloro-phenyl) -4- (4-methylbenzyl) piperazine. (P) 1- 3-chloro-phenyl) -4- (4-methylbenzyl) piperazine. (q) 1-4-chloro-phenyl) -4- (4-methylbenzyl) piperazine. (r) 1- 3, 4-dichlorophenyl) -4- (4-methylbenzyl) iperazine. (s) 1-4-methylphenyl) -4- (4-methylbenzyl) piperazine. (t) 1- 2-methylphenyl) -4- (4-methylbenzyl) piperazine. (u) 1- (4-methoxy phenyl) -4- (4-methylbenzyl) piperazine. () 1- (2-methoxy phenyl) -4- (4-methylbenzyl) piperazine. (w) 1- (4-chlorophenyl) -4- (4-chlorobenzyl) piperazine dihydrochloride; and (x) 1- (2-isopropoxy phenyl) -4- (4-bromobenzyl) -piperazine.

35. A compound according to claim 1, characterized in that it is l-Naphthyl-4- (4-chlorobenzyl) piperazine.

36. A compound of the formula or the pharmaceutically acceptable salts thereof, characterized in that: Ri is chloro, fluoro, or methyl; Y It is selected from the group consisting of:

37. A compound according to claim 36, characterized in that Ri is Cl.

38. A compound according to claim 36, characterized in that Ri is F.

39. A compound according to claim 36, characterized in that Ri is methyl.

40. A compound according to claim 37, characterized in that it is 4-chlorophenyl or 4-methoxyphenyl

41. A compound according to claim 38, characterized in that it is 4-methylphenyl, 4-chlorophenyl, or 4-methoxyphenyl.

42. A compound according to claim 39, characterized in that it is 4-ethoxyphenyl, 4-methylphenyl, or 4-chlorophenyl

43. A compound according to claim 1, characterized in that it is

44. A compound according to claim 1, characterized in that it is

45. A compound according to claim 1, characterized in that it is

46. A compound according to claim 1, characterized in that it is

47. A compound according to claim 1, characterized in that it is

48. A compound according to claim 1, characterized in that it is

49. A compound according to claim 1, characterized in that it is

50. A compound according to claim 1, characterized in that it is

51. A compound according to claim 1, characterized in that it is

52. A compound according to claim 1, characterized in that it is

53. A compound according to claim 1, characterized in that it is

54. A compound according to claim 1, characterized in that it is

55. A compound according to claim 1, characterized in that it is