MXPA99008086A - 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines;dopamine receptor subtype specific ligands - Google Patents

Abstract

Disclosed are compounds useful in treating psychotic disorders such as schizophrenia and other central nervous system diseases, where the compounds have general Formula (I), wherein:Ar represents an aryl or heteroaryl group;R1 and R2 independently represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(C1-C6)alkyl amino, cyano or trifluoromethyl;and R5 represents hydrogen or C1-C6 alkyl.

Description

l - (2 -NAFTIL) Y 1 - (2 -AZANAFTIL) -4- (1-Phenyl-ethyl) PIPERAZ INAS LI LI LIKE GENDERS OF THE SUB-TYPE OF DOPAMINE D4 RECEPTOR.

Field of Invention This invention relates to 1- (isoquininoin-1-yl) - - (1-phenylethyl) piperazine s and compositions and pharmaceutical preparations containing compound limes. This also refers to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other disorders of the central nervous system.

Background of the Invention The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to exert a blockade through dopamine receptors. However, neuroleptics are frequently responsible for undesirable external sputtering effects.

(? PS) and tardive dyssymesis, which is attributed to the blockage of D2 receptors in the brain's esthetic region.The sub-type of D4 receptor Ref: 031113 of dopamine was recently identified (Sokoloff, P. et al., Na t ure, 1990, 34 7, 146). Its unique location in the limbic areas of the brain and its differential recognition of several antipsychotics suggests that the D4 receptor may play a major role in the etiology of schizophrenia. Selective D4 antagonists are considered as effective antipsychotics free from neurological side effects exhibited by conventional neuroleptics.

European Patent Application EP 512755 A2 discloses piperazine derivatives which are called 5-HT aa antagonists.

Description of the invention This invention provides novel compounds of Formula I that interact with the dopamine receptor subtypes. A broad aspect of the invention is directed to the compounds of Formula I: wherein Ar represents an optionally substituted heteroaryl group or an optionally substituted aryl group; Ri and R 2 independently represent hydrogen, halogen, Ci-Ce alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) amino alkyl, cyano or tri-fluororne yl; and R5 represents hydrogen or Ci-Cg alkyl.

In this aspect, when Ar is phenyl, this is not an unsubstituted phenyl group. In other words, when Ar is phenyl, the phenyl is substituted with at least one non-hydrogen group.

In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I.

Since the D4 dopamine receptors are concentrated in the limbic system (Taubes, Sci in ce 265: 1034, 1994) that controls perception and emotion, the compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits that are a significant component of the negative symptoms (social withdrawal and insensitivity) of schizophrenia. In addition, disorders involving memory impairment or attention deficit disorders can be treated with the compounds of the invention. These compounds specifically interact with the dopamine D4 sub-type receptor.

The compounds of the invention demonstrate high affinity and selectivity by binding the D4 receptor subtype. The use of the compounds of this invention in methods of treating neuropsychological disorders is predicated on the ability of the compounds to selectively bind to a sub-type dopamine receptor, the D4 receptor. The compounds of the invention can therefore be used in the treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated disorders such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by the modulation of the D4 receptors.

Thus, in another aspect, the invention provides methods for the treatment and / or prevention of neuropsychological disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficiencies, motor disorders such as Parkinson's and movement disorders related to the use of neuroleptic agents. This also provides methods for the treatment of affective disorders such as Alzheimer's disorder and certain movement disorders such as Parkinsonism and dystonia.

The invention further provides methods for the treatment of the extra-racoidal side effects associated with the use of conventional neuroleptic agents. The compounds of the present invention are useful for the treatment of other disorders responsive to dopaminergic blocking such as substance abuse and compulsive obesity disorders.

Detailed description of the invention.

In addition to the compounds of Formula I, the invention provides compounds of Formula IA: IA wherein Ar represents aryl or heteroaryl, each of which is optionally substituted with R3 and / or R4, with the proviso that Ar is not unsubstituted phenyl Ri and R2 independently represent hydrogen, halogen, Ci-Cg alkyl, C-alkoxy C 4, C 1 -C 4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkyl amino, cyano or trifluoromethyl; and R 5 represents hydrogen or C 1 -C 6 alkyl- Preferred compounds of Formula 1 are those wherein R 3 and R 4 independently represent hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, trifluoromethyl, trifluoromethoxy or S 0 2 NH 2, with the proviso that none of R3 and R4 are hydrogen simultaneously; or R3 and R4 together represent an alkylene, alkyleneoxy, or alkylenedioxy chain which together with the atoms to which it is attached form a ring having 5-7 atoms.

In compound IA, R3 is preferably in the para position at the point of attachment of the aryl or heteroaryl group to the methylene group.

Thus, in the compounds of the invention, Ar is unsubstituted phenyl since a substituent on the phenyl group is required for the activity of the D4 receptor. That is, phenyl can contain at least one non-hydrogen substituent. Suitable non-hydrogen substrates are the non-hydrogen substrates R3 and R4 defined above.

Preferred Ar groups of Formulas I and IA are In addition to the compounds of Formula I above, the invention provides compounds of Formula I I: p wherein: Ri and R 2 independently represent hydrogen, halogen, Ci-Ce alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino, mono- or di (Ci-Cg) alkyl amino, cyano or trifluoromethyl; R3 and R4 independently represent hydrogen, halogen, hydroxy, C? -C6 alkyl, trifluoromethyl, trifluoromet oxy or S02NH2, with the proviso that neither R3 nor R4 are hydrogen simultaneously; and R = represents hydrogen or Ci-Cß- algayl In the preferred compounds of Formula II, at least one of R3 and R4 is Ci-Cβ alkoyl or halogen. In the most preferred compounds of Formula II, R5 is hydrogen, and R3 and R4 are independently hydrogen or C ± -C e alkyl. In still other more preferred compounds of Formula II, R5 is hydrogen, and R3 and R4 are hydrogen and halogen, respectively, or both are halogen.

In still other preferred compounds of Formula II, the femlo group (Ar) is substituted with methyl or is mono- or di substected with halogen, and R5 is hydrogen.

The most preferred compounds of Formula II are those wherein Ri and R2 are both hydrogen.

Particularly preferred compounds of Formula II are those where Ri and R2 are hydrogen and the phenyl group (Ar) is monosubstituted in the 4-position with methyl or chloro (4-methylphenyl or 4-chlorofernyl) or the phenyl group is disubstituted with fluorine in either position 3 and 4 (3,4-di fluorophenyl).

The invention also provides compounds of Formula III: III wherein: Ri and R2 independently represents hydrogen, halogen, C?-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cβ) alkyl amino, cyano or tri fluorometyl; R6 represents hydrogen, halogen, hydroxy, Ci-Cβ alkyl, trifluoromethyl, tri fluorome toxy or S02NH2; and Rs represents hydrogen or Ci-Cß alkyl.

In the preferred compounds of Formula III, Re is hydrogen, Ci-Cß alkyl, or halogen. In more preferred compounds of Formula IV, R5 is hydrogen, C? -C alkyl, or halogen. In still other preferred compounds of Formula III, Ri and R2 are halogen, C?-C6 aligyl, or hydroxy, R5 is hydrogen and R6 is hydrogen, C?-C6 aligyl, or halogen.

The most preferred compounds of Formula III are those wherein Ri and R2 are both hydrogen, and Rs and Re are hydrogen.

The invention also provides compounds of Formula IV IV wherein Ri and R2 independently represent hydrogen, halogen, C?-C6 alkoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkylamino, cyano or tri fluoromethyl; R6 represents hydrogen, halogen, hydroxy, C6-C6 alkyl, t-fluoromethoxy, trifluoromethoxy or S02NH2; and R5 represents hydrogen or C? -C6 alkyl.

In the preferred compounds of Formula IV, R6 is hydrogen, Ci-Cß alkyl or halogen. In more preferred compounds of Formula IV, R5 is hydrogen and R is hydrogen, Ci-C al alkoyl, or halogen. In still other preferred compounds of Formula IV, Ri and R2 are halogen, C? -C6 alkyl, or hydroxy, R5 is hydrogen and R6 is hydrogen, Ci-Ce alkyl, or halogen.

The most preferred compounds of Formula IV are those wherein Ri and R2 are both hydrogen, and Rs and R are hydrogen.

In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For example, where R 5 in Formula I is a methyl group, the resulting compound may be presented as (R) and (S) is e-isomers. In these situations, simple enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. The resolution of the racemates can be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral CLAP column.

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable salts. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basification of a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in an appropriate organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.

The salts include pharmaceutically acceptable non-toxic salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, phthalic t oluens, ul phonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic as, for example, acetic, HOOC- (CH2) n-C00H where n is 0-4, such as, for example, oxalic (n = 0), and the like. Those skilled in the art will be able to recognize a very wide variety of pharmaceutically acceptable non-toxic addition salts.

The present invention also encompasses the acylated pro-drugs of the compounds of Formula I. Those skilled in the art will be able to recognize various synthetic methodologies that can be employed to prepare pharmaceutically acceptable non-toxic addition salts and acylated prodrugs of the compounds encompassed by the Formula I.

By the terms alkyl (C? -C6) alkyl and lower alkyl, it means straight or branched chain alkyl groups having from 1-6 carbon atoms as well as cyclic alkenyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred Ci-Cg alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmethyl.

By the terms alkoxy (C? ~ C6) and lower alkoxy, it means straight or branched chain alkoxy groups having from 1-6 carbon atoms.

By hydroxy Ci-Cβ alkyl, it means a C?-C6 alkyl group bearing a terminal hydroxy portion.

By the term piperonyl as used herein, it means a group of the Formula: By halogen, halo, or halide, it means substituents of fluorine, chlorine, bromine, and iodine.

By aryl or "Ar" it means an aromatic carbocyclic group that has a simple ring (for example, phenyl), multiple rings (for example biphenyl), or multiple condensed rings in which at least one is aromatic, (for example, 1, 2, 3, 4 - 1-tetrahydrone phyl, naphthyl, anthryl, or phenanthyl) ), which is optionally mono-, di-, or trisubstituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, t-fluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

By "aryl" or "Ar" is meant also heteroaryl groups where heteroaryl is defined as a 5, 6, or 7-membered aromatic ring system having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.

Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridinnynyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which may be optionally substituted with, for example, halogen, lower alkoyl, lower alkoxy, alkylthio lower, tri fluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

As noted above, R3 and R can be connected together to form another ring with the atoms to which they are attached in the familiar aryl or heteroaryl group. Thus, R3 and R4 can represent a chain of alkylene, alkenylene, or alkyldioxy that together with the atoms to which it is linked form a ring having 5-7 atoms. For example, Ar can be an optionally substituted naphthyl group or a bicyclic oxygen-containing group of the formula wherein the oxygen-containing heterocyclic ring has a ring with a total of from 5 to 7 members, the heterocyclic ring being saturated or unsaturated, and optionally substituted. R6 is as previously defined by Formula III. " Preferred examples of oxygen containing bicyclic groups are: Representative examples of isoquinolinii piperazines according to the invention are shown in Table 1 below.

Table 1 The number in Table 1 that is below each structure is its compound number.

As noted above, the invention also relates to the use of the compounds of the general Formula I in the treatment of various neurophysiological disorders. "" "~~ The compounds of the general Formula I can be administered orally, topically, parenterally, by inhalation or by dispersion or rectally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular injections, back injections or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier is provided. One or more of the compounds of general Formula I may be presented in association with one or more pharmaceutically acceptable non-toxic carriers and / or diluents and / or adjuvants and if desired other active ingredients. Pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs The compositions intended 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 preservatives with object to provide pleasant and elegant pharmaceutically preparations. The tablets contain the active ingredient in a mixture with pharmaceutically acceptable non-toxic excipients 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-sodium phosphate.; granulating and disintegrating agents, for example, corn starch, or alginic acid; ligation agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncovered and these may be covered by known techniques to release disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, a temporary release material such as glycerin monostearate or glycerin diester can 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 wherein the active ingredient it is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example carboxymethyl cellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents which may be a naturally-manufactured phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols , for example hept adecae t ilenoxicetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene monoleate of sorbitol, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example polyethylene monoleate sorbitan. The 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 aboriginating 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 shown above, and flavoring agents may be added to provide pleasing preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water, provides the active ingredient in a mixture 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 oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof.

Suitable emulsifying agents can be naturally created gums, for example acacia gum or tragacanth gum, naturally created phosphatides, for example soy, lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of said partial esters with ethylene oxide, for example sorbitan polyoxyethylene monoleate. 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 or oleaginous injectable aqueous suspension. This suspension can be formulated according to the known art using those dispersants or wetting agents and suspending agents 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, certain oils, sterile, are conventionally employed as a solvent or suspension medium. For this purpose any given soft oil may be employed including synthetic mono- or diglycerides. 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 medicament. These compositions can be prepared by mixing the medicaments with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and can therefore melt in the rectum to release the medicament. Such materials are cocoa butter and polyethylene glycols.

The compounds of the general Formula I can be administered parenterally in a sterile medium. The medication, depending on the vehicle and the concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and regulating agents can be dissolved in the vehicle.

Dosage levels in the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dose form may vary depending on the host treated and the particular mode of administration. Unit dosage forms may generally contain between about 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 specific compound activity employed, age, body weight, general health, sex, diet, time of administration , route of administration, and range of excretion, combination of medications and the severity of the therapy experienced in the particular disorder.

Representative illustrations of the methods suitable for the preparation of compounds of the present invention are shown in Schemes I and II, those skilled in the art will be able to recognize that the starting materials may be varied and additional steps employed to produce the compounds encompassed by them. the present invention.

Scheme I where Ar, Ri and R2 are as previously defined by Formula I.

As described in Scheme I, a suitable substituted 1-chloroisoquinoline of Formula V is condensed with piperazine to provide a 1-isoquinoline-1-ylpiper zine of Formula VI. The compound of Formula VI is typically reductively alkylated with an arylaldehyde of Formula VII with a reducing agent such as, for example, sodium cyanoborohydride to produce 1- (1-isoquinolin-1-yl) -4- (1-phenylmethyl) ) desired piperazine of Formula I. In certain situations, the protection of reactive portions such as nitrogen and hydroxy group may be needed to allow a conversion to be performed is to adversely affect the reactive portion. Those skilled in the art will recognize the appropriate protection groups and methods to facilitate the removal of protecting groups. Protective groups can be added and removed using methods taught in the literature or similar methods.

Alternatively, the compounds of Formula I can be prepared in accordance with Scheme II Scheme II where Ar, Ri and R2 are as previously defined by Formula I.

As shown in Scheme II, an in- 1-isoquinol in-1-piperazine of Formula VI (prepared as shown above in Scheme I) can be alkylated using an alkyl ester compound of Formula VIII to provide the 1- (isoquinolin-1-yl) -4- (1-arylmethyl) piperazine of Formula 1. Again, when necessary, the reactive groups can be protected in accordance with the methods of the literature or modified literature methods.

The descriptions in this application of all articles and references, including patents, are incorporated herein for reference.

Those skilled in the art will recognize that the starting materials may vary and the additional steps employed to produce the compounds encompassed by the present invention.

The invention is further illustrated by the following examples that are not constructed as limiting the invention in scope or spirit of the methods and compounds described herein.

Ahem 1 1. 1- (i soquinolin-1-yl) piperazine A solution of 2-chloroisoquinoline (5 g) in mL of toluene is added dropwise to a piperazine reflux solution (20 g) in 150 mL of toluene. The solution is heated for an additional 48 hours. After cooling to 0 ° C for 0.5 hours, the solution was filtered. The filtrate was then extracted with 10% acetic acid. The aqueous extracts were washed with ether, basified and subsequently extracted with dichloromethane. The dichloromethane layer was finally washed with water, dried and concentrated. The material was placed under vacuum overnight to yield the title compound (6.8 g, mp 54-56 ° C). XH NMR (CDC13) 8.14 (d, J = 5.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.24 (d, j = 5.5 Hz, 1H), 3.39 (t, J = 5.0 Hz, 4H), 3.16 (t, J = 5.0 Hz, 4H) .

Cl orhydrate of 1- (isoquinolin-1-yl) -4- (1 [piperonyl] methyl) piperazine A solution of 1- (i soquinolin-1-yl) piperazine (215 mg, 1.0 mmol) and piperonal (160 mg) in methanol (10 mL) was prepared and adjusted to pH 4 using acetic acid. Sodium cyanoborohydride (500 mg ") was then added and the reaction mixture allowed to stand at room temperature overnight The solvent was evaporated and the oil residue was partitioned between dichloromethane and 5% aqueous ammonia. then subjected to preparative CCD (10: 2 hexane: ethyl acetate) which produced the free base of the title compound as a colorless oil (300 mg) .The hydrochloride salt was obtained - then from an ethyl acetate solution. ethyl after treatment with hydrochloric acid (mp 250-251 ° C). 1 H NMR (CDC13) 8.15 (d, J = 5.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), 6.91 (s, 1H) , 6.80 (m, 2H), 3.55 (s, 2H), 3.43 (s br, 4H), 2.71 (s br, 4H).

Example 2 Oxalat or 1- (isoquinolin-1-yl) -4- (1- [4-chlorophenyl] methyl) piperazine.

A solution of 1- (i soquinol in- 1-yl) piperazine (215 mg, 1.0 mmol) and 4-chlorobenzyl chloride or (180 mg) in acetonitrile (10 L) containing potassium carbonate (500 mg) it was stirred and heated at 60 ° C for 4 hours. After cooling, the reaction mixture was partitioned between ether and water. The organic layer was extracted with 1N HCl. The acid extract was then basified and extracted with chloroform. The resulting organic layer was dried and concentrated to provide the free base of the title compound as a white solid (300 mg, 88%).

The oxalate salt is prepared from isopropanol (mp 207-208 ° C). XH NMR (DMSO) 8.09 (d, J = 5.5 Hz, 1H), 8.06 (d, J = 8.5 Hz), 7.87 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.0 Hz, 1H) , 7.58 (t, J = 7.6 Hz, 1H), 7.46 (s br, 4H), 7.40 (d, J = 6.1 Hz, 1H), 3.93 (s br, 2H), 3.40 (s br, 4H), 2.95 (s br, 4H).

E j us 3 The following compounds were prepared essentially in accordance with the procedures shown above in Examples 1 and 2.

Oxalate of 1- (isoquinolin-1 -yl) -4- (1 - [3,4-fluorophenyl] methyl) piperazine (mp 212-213 ° C).

Oxalate of 1- (i soquinolin-1 -yl) -4 - (1 - [3,5-di fluoropheni 1] methyl) piperazine (p.f. 223-224 ° C). 1- (Isoquinolin-1-yl) -4 - (1 - [2-naphthyl] methyl] piperazine hydrochloride (mp 265-268 ° C).

Oxalate of 1 - (i s oquinolin-1 -yl) -4- (1 - [4-methylphenyl] methyl) piperazine (mp 192-194 ° C). 1- (isoquinolin-1-yl) -4- (1- [3-chlorophenyl] methyl) piperazine.

Example 4 The pharmaceutical utility of the compounds of this invention is indicated by the following analyzes for the affinity of the dopamine receptor. 1. Test for the Linking Activity of Receiver D2 and D4.

Pellets of COS cells containing recombinantly produced D2 or D4 receptors of African green monkeys were used for the analysis.

The sample was homogenized in 100 volumes (weight / volume) of Tris HCl buffer 0. 05 M at 4 ° C and pH 7.4. The sample was then centrifuged at 30,000 x g and resuspended and homogenized. The sample was centrifuged again as described above and the final tissue sample was frozen until used. The tissue was resuspended 1:20 (weight / volume) in 0.05 M Tris HCl buffer containing 100 mM NaCl Incubations were carried out at 48 ° C and containing 0.4 ml of the tissue sample, 0.5 nM 3H-YM 09151-2 and the compound of interest in a total incubation of 1.0 ml. A non-specific link was defined as the link was found in the presence of InM spiperone; without additional additions, the non-specific link is less than 20% of the total link. The characteristics of the binding for the representative examples of this invention for the receptor subtypes D2 and D4 are shown in Table 2 below for rat striatal homogenates. The binding characteristics of compounds of Formula I for the D4 receptor, expressed in nM, are generally in the range from about 0.5 nanomolar (nM) to about 25 nanomolar (nM). These compounds typically have binding constants for the D2 receptor from about 200 nM to more than 1000 nM. Thus, the compounds of the invention are generally at least 10 times more selective for the D4 receptor than for the D2 receptor. More preferably, these compounds are at least 20, and more preferably at least 25-50, times more selective for the D4 receptor than for the D2 receptor.

TABLE 2 Bonding characteristics of 1 - (i s oquinol in- 1-yl) -4- (1-phenylmethyl) piperazines for D2 receptors Y_D1 Compound Number 1 D4Ki (nM) D2K? (nM) 1 5 556 2 13 1003 4 19 ND 6 9 220 1 Numbers of compound related to the compounds shown in Table 1.

The invention and the manner and process for making and using these are now described in complete, clear, concise and exact terms so as to enable any person skilled in the art to which it is pertinent, to make and use it. It will be understood that the above described preferred embodiments of the present invention and the modifications can be made without departing from the spirit of the present invention as shown in the claims. For the point outside and distinct from the subject matter appreciated 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.

Having described the invention as above, the content of the following is claimed as property.

Claims (18)

Claims

1. A compound of the formula or pharmaceutically acceptable addition salts thereof, characterized in that: Ar represents, aryl or heteroaryl, each of which is optionally substituted with R3 and / or R4, with the proviso that Ar is not substituted phenyl; R1 and R2 independently represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono p di (Cl- C6) alkyl amino, cyano or trifluoromethyl; R3 and R4 are the same or different and represent hydrogen, halogen, hydroxy, C1-C6 alkyl, tri fluoromethyl, trifluoromethoxy or S02NH2, with the proviso that neither R3 nor R4 are hydrogen; or R3 and R4 together with the atoms to which they are attached represent a ring having 5-7 atoms; and R5 represents hydrogen or C1-C6 alkyl.

2. The compound according to claim 1, characterized in that Ar is phenyl monosubstituted with C 1 -C 6 alkyl or mono- or disubstituted with halogen.

3. The compound according to claim 2, characterized in that Ar is phenyl substituted with methyl or mono- or disubstituted with fluorine or chlorine.

4. The compound according to claim 1, characterized in that at least one of R3 and R4 is in a position for the point of attachment of Ar to methyl tilpiperazine.

5. The compound according to the rei indication 1, characterized in that R3 and R4 form an alkylene, alkenyl, alkyleneoxy, or alkylenedioxy group which together with the carbon atoms to which they are attached form a ring having 5-7 atoms.

A compound of the formula or pharmaceutically acceptable addition salts thereof, characterized in that R1 and R2 independently represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono p di (Cl- C6) alkyl amino, cyano or trifluoromethyl; R3 and R4 are the same or different and represent hydrogen, halogen, hydroxy, C1-C6 alkyl, tri-fluororhexyl, t-fluorometoxy or S02NH2, with the proviso that neither R3 nor R4 are hydrogen; or R3 and R4 together with the atoms to which they are attached represent a ring having 5-7 atoms; and R5 represents hydrogen or C1-C6 alkyl.

7. The compound according to claim 6, characterized in that R5 is hydrogen.

8. The compound according to claim 6, characterized in that Rl and R2 are hydrogen.

9. The compound according to claim 1, characterized in that Ar is

10 A compound of the formula or pharmaceutically acceptable addition salts thereof, characterized in that: Ri and R2 independently represent hydrogen, halogen, C6-C6 alkoxy, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkyl amino, cyano or trifluoromethyl; R6 represents hydrogen, halogen, hydroxy, C-Ce alkyl, trifluoromethyl, trifluoromet oxy or S02NH2; and R5 represents hydrogen or alkenyl? ~ C.

11. A compound of the formula or pharmaceutically acceptable addition salts thereof, characterized by: Ri and R2 independently represent hydrogen, halogen, Ci-Cß alkyl / C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino, mono- or di (Ci-Cβ) alkyl amino, cyano or trifluoromethyl;

R6 represents hydrogen, halogen, hydroxy, C? -C6 alkyl, trifluoromethyl, trifluoromethoxy or S02NH2; and Rs represents hydrogen or Ci-Cß alkyl. 12. The compound according to claim 1, characterized in that it is 1- (isoquinolin-1-yl) - A - (1- [4-chlorophenyl] methyl) piperazine.

13. The compound according to the rei indication 1, characterized in that it is 1- (isoquinolin-1-yl) -4- (1- [3,5-difluorophenyl] methyl) piperazine.

14. The compound according to claim 1, characterized in that it is 1- (isoquinolin-1-yl) -4- (1- [3, 4-difluorophenyl] methyl) piperazine.

15. The compound according to claim 1, characterized in that it is 1- (isoquinol in- 1 -yl) -4- (1- [2-naphthyl] methyl) piperazine.

16. The compound according to claim 1, characterized in that it is 1- (isoquinolin-1-yl) -4- (1 - [3-chlorophenyl] methyl) piperazine.

17. The compound according to claim 1, characterized in that it is 1- (isoquinolin-1-yl) -4- (1- [4-methyl phenyl] methyl) piperazine.

18. A compound according to claim 11, characterized in that it is 1 (isoquinine? \ In-1-i ".) - 4- (piperone il'met iI '.) Piperazine.