JP2001512491A - 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) piperazine; a dopamine receptor subtype-specific ligand - Google Patents

Abstract

(57) Abstract: Disclosed are compounds useful in the treatment of psychiatric disorders such as schizophrenia and other central nervous system disorders, which compounds have the general formula (I) wherein Ar is an aryl Or a heteroaryl group; R ₁ and R ₂ are independently hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino, mono or di (C ₁ -C ₆₎ alkyl amino, cyano or trifluoromethyl; and R ₅ represents hydrogen or C ₁ -C ₆ alkyl.

Description

DETAILED DESCRIPTION OF THE INVENTION                      1- (isoquinolin-1-yl)                  -4- (1-phenylmethyl) piperazine;                 Dopamine receptor subtype-specific ligand                                Background of the Invention Field of the invention   The present invention relates to 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) pipe Razine and pharmaceutical compositions and preparations containing such compounds. Also the spirit It is particularly useful in the treatment or prevention of mental disorders such as schizophrenia and other central nervous system disorders. It also relates to the use of such compounds.Description of related technology   The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally Is believed to be exerted by the blockade of a receptor. However, nervous Blockers are often undesirable for extrapyramidal side effects (EPS) and tardive dyskinesia And D in the striatum region of the brain_TwoDue to receptor blockade Things. Recently, dopamine D_FourReceptor subtypes have been identified (Sok oloff, P .; Et al., Nature, 1990, 347, 146). Limbic system Its unique localization in the region and its discriminatory recognition of various antipsychotics_FourReceiving Suggests that condition can play a major role in the pathogenesis of schizophrenia. Selective D_Four Antagonists are traditional neuroleptic It is considered to be an effective antipsychotic without the neurological side effects of the drug. European Patent Application EP512755A2 discloses 5-HT_1aWhat is an antagonist Disclosed are piperazine derivatives.                                Summary of the Invention   The present invention provides novel compounds of Formula I that interact with dopamine receptor subtypes. Offer. A broad aspect of the present invention is directed to compounds of Formula I below.(here,   Ar is an optionally substituted heteroaryl group or an optionally substituted Represents a hydroxyl group;   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   as well as   R_FiveIs hydrogen or C₁-C₆Represents alkyl. )   In this aspect, when Ar is phenyl, Is not an unsubstituted phenyl group. In other words, when Ar is phenyl, that phenyl The phenyl is substituted with at least one non-hydrogen group.   In yet another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I .   Dopamine D_FourReceptors focus on the limbic system that controls cognition and emotion (Taub) es, Science265: 1034, 1994). Interacting compounds are useful in treating cognitive disorders. Such obstacles An important component of the negative symptoms of schizophrenia (social withdrawal and refractory) Includes certain cognitive deficits. In addition, disorders related to memory disorders and attention deficit disorders It can be treated with a compound of the present invention. These compounds are dopamine D_FourAcceptance Interacts specifically with body subtypes.   The compound of the present invention has D_FourHigh affinity and selection for binding to receptor subtypes Shows sex. The use of the compounds of the invention in a method of treating neuropsychological disorders Pamine receptor subtype, D_FourThe ability of these compounds to selectively bind to receptors Is predicted based on Therefore, the compounds of the present invention are schizophrenic, psychotic It can be used in the treatment of depression and mania. Other dopamine-mediated diseases, for example, Parkinsonism and tardive dyskinesia also_FourDirect or intermittent by receptor modulation Can be treated indirectly.   Thus, in another aspect, the invention relates to, for example, schizophrenia, mania, dementia, For depression, anxiety, obsessive-compulsive behavior, substance abuse, memory impairment, cognitive deficits, use of neuroleptics Associated Parkinson-like motor and motor disorders And / or a method for treating and / or preventing a neuropsychological disorder. Also affective disorders Such as Alzheimer's disease, and movement disorders such as Parkinson's disease and dystonia A.   The invention further provides for the treatment of extrapyramidal side effects associated with the use of conventional neuroleptics. Provide a way. The compounds of the present invention may also be used in other diseases responsive to dopamine blockade. For example, it is also useful in the treatment of substance abuse and paranoid obsessive-compulsive disorder.                             Detailed description of the invention   In addition to compounds of formula I, the invention provides compounds of formula IA: (here,   Ar represents aryl or heteroaryl, each of which is an unsubstituted aryl. R if not nil_ThreeAnd / or R_FourOptionally substituted with;   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   as well as   R_FiveIs hydrogen or C₁-C₆Represents alkyl. )   Preferred compounds of formula IA are_ThreeAnd R_FourAre independently hydrogen, halogen, hydroxy , C₁-C₆Alkyl, trifluoromethyl, trifluoromethoxy or SO_TwoN H_TwoWhere R_ThreeAnd R_FourAre not both hydrogen at the same time; or , R_ThreeAnd R_FourForm together with the atoms to which they are attached a ring having 5-7 ring atoms Alkylene, alkenylene, alkyleneoxy, or alkylenedioxy chains It is expressed together.   In formula IA, R_ThreeIs preferably its aryl or heteroaryl It is located para to the point of attachment of the group to the methylene group.   Thus, in the compounds of the invention, Ar is not unsubstituted phenyl, which is The substituent on the phenyl group is D_FourIt is necessary for activity at the receptor. sand That is, the phenyl must have at least one non-hydrogen substituent. Suitable non-hydrogen substituents are non-hydrogen R as defined above._ThreeAnd R_FourIs a substituent.   Preferred Ar groups of formulas I and IA are as follows:   In addition to the compounds of formula I above, the present invention provides compounds of formula II: (here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   R_ThreeAnd R_FourIs independently hydrogen, halogen, hydroxy, C₁-C₆Alkyl, Triff Fluoromethyl, trifluoromethoxy or SO_TwoNH_TwoWhere R_ThreeAnd R_Four Are not simultaneously hydrogen; and   R_FiveIs hydrogen or C₁-C₆Represents alkyl. )   In preferred compounds of formula II, at least one R_ThreeAnd R_FourIs C₁-C₆ Alkyl or hydrogen. In more preferred compounds of formula II,_FiveIs hydrogen And R_ThreeAnd R_FourIs independently hydrogen or C₁-C₆Alkyl You. In yet another more preferred compound of formula II, R_FiveIs hydrogen, or One R_ThreeAnd R_FourIs hydrogen and halogen, or both are halogen.   In yet another preferred compound of formula II, the phenyl group (Ar) is methyl Or mono- or di-substituted by halogen, and R_FiveIs hydrogen.   Most preferred compounds of formula II are₁And R_TwoAre both hydrogen .   Particularly preferred compounds of formula II are₁And R_TwoIs hydrogen and a phenyl group ( Ar) is mono-substituted at the 4-position with methyl or chloro; Phenyl or 4-chlorophenyl), or the phenyl group is in both the 3- and 4-positions (3,4-difluorophenyl) disubstituted with fluoro.   The present invention also provides compounds of Formula III: (here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl; R₆Is hydrogen, halogen, hydroxy, C₁-C₆Alkyl, trifluoromethyl, Trifluoromethoxy or SO_TwoNH_TwoRepresents; and   R_FiveIs hydrogen or C₁-C₆Represents alkyl. )   In preferred compounds of formula III, R₆Is hydrogen, C₁-C₆Alkyl or ha Rogen. In a more preferred compound of formula IV,_FiveIs hydrogen, and R₆Is hydrogen, C₁-C₆Alkyl or halogen. Yet another preferred formula I In the compound of II, R₁And R_TwoIs halogen, C₁-C₆Alkyl or hydrid Roxy and R_FiveIs hydrogen and R₆Is hydrogen, C₁-C₆Alkyl or halo Gen.   The most preferred compound of formula III is R₁And R_TwoAre both hydrogen and R_Five And R₆Is hydrogen.   The present invention also provides compounds of Formula IV: (here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Lequil Represents amino, cyano or trifluoromethyl;   R₆Is hydrogen, halogen, hydroxy, C₁-C₆Alkyl, trifluoromethyl , Trifluoromethoxy or SO_TwoNH_TwoRepresents; and   R_FiveIs hydrogen or C₁-C₆Represents alkyl. ) In preferred compounds of formula IV,₆Is hydrogen, C₁-C₆Alkyl or halogen It is. In more preferred compounds of formula IV, R_FiveIs hydrogen and R₆Is Hydrogen, C₁-C₆Alkyl or halogen. Yet another preferred formula IV In the compound, R₁And R_TwoIs halogen, C₁-C₆With alkyl or hydroxy Yes, R_FiveIs hydrogen and R₆Is hydrogen, C₁-C₆Alkyl or halogen You.   Most preferred compounds of formula IV are₁And R_TwoAre both hydrogen and R_Five And R₆Is hydrogen.   In certain circumstances, the compounds of formula I may contain one or more asymmetric carbon atoms. And thereby can exist in different stereoisomeric forms. These compounds For example, it can be in racemic or optically active form. For example, in Formula I R_FiveIs a methyl group, the resulting compound has (R) and (S) stereoisomers May exist. In these situations, a single enantiomer, namely the optical The most active forms can be obtained by asymmetric synthesis or resolution of racemic compounds. Race The resolution of the compound can be performed, for example, by a conventional method, for example, by crystallization in the presence of a separating agent. Or by chromatography, for example using a chiral HPLC column. be able to.   Representative compounds of the present invention encompassed by Formula I include the compounds of Table I and their pharmaceuticals. Including, but not limited to, commercially acceptable salts. Embodiment of the present invention When the compound is obtained as an acid addition salt, by basifying the solution of the acid salt, Free base can be obtained. Conversely, if the product is a free base, Pharmaceutically acceptable addition salts are commonly used to prepare acid addition salts from base compounds. Dissolve the free base in a suitable organic solvent and treat the solution with acid according to standard procedures. Can be generated by processing.   Non-toxic pharmaceutically acceptable salts include hydrochloric, phosphoric, hydrobromic, sulfuric, Finic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, Enic acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid such as acetic acid, where n is 0 HOOC- (CH which is -4_Two)_n-COOH, such as tartaric acid (n = 0) Includes acid salts. One of skill in the art will recognize a wide variety of non-toxic pharmaceutically acceptable additives. Will recognize salting.   The present invention also encompasses acylated prodrugs of the compounds of formula I. Skilled person Is a non-toxic pharmaceutically acceptable addition salt and acyl of a compound encompassed by Formula I Recognize the various synthetic methods that can be used to prepare the There will be.   (C₁-C₆) The terms alkyl and lower alkyl mean 1-6 Cyclic alkyl groups, in addition to straight-chain and branched-chain alkyl groups having three carbon atoms, e.g. For example, cyclopropyl, cyclobutyl, or cyclohexyl. like that Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl. Butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n- Pentyl. Preferred C₁-C₆Alkyl groups are methyl, ethyl, propyl, Tyl or cyclopropylmethyl.   (C₁-C₆) The terms alkoxy and lower alkoxy mean 1 -Straight and branched chain alkoxy groups having 6 carbon atoms.   Hydroxy C₁-C₆What alkyl means carries a terminal hydroxy moiety C₁-C₆It is an alkyl group.   What is meant by the term piperonyl as used herein is a group of the formula:   Halogen, halo or halide means fluorine, chlorine, bromine and iodine. It is a urine substituent.   Aryl or “Ar” means a single ring (eg, phenyl), multiple rings. Rings of numbers (eg, biphenyl), Or a plurality of fused rings wherein at least one is aromatic (eg, 1,2,3,4 -Tetrahydronaphthyl, naphthyl, anthryl, or fenanthryl) Which are, for example, halogen, lower alkyl, lower Lucoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl , Heteroaryl, and hydroxy optionally mono-, di-, or tri-substituted You.   Also, what is meant by aryl or "Ar" can be heteroaryl, Here, the heteroaryl is at least one member selected from the group consisting of nitrogen, oxygen and sulfur. Are also defined as 5, 6 or 7 membered aromatic ring systems having one heteroatom You. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl , Pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquino Linyl, thiazolyl, and thienyl, for example, halogen, lower Alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyl Optionally substituted with ruoxy, aryl, heteroaryl, and hydroxy Is also good.   As mentioned above, R_ThreeAnd R_FourAre linked together to form the parent aryl or Another ring can be formed on the loaryl group with the atoms to which they are attached. Therefore, R_ThreeAnd R_FourHas 5-7 atoms with the atoms to which they are attached Alkylene and alkenyl to form a ring Or an alkyleneoxy or alkylenedioxy chain. For example , Ar is an optionally substituted naphthyl or a bicyclic oxygen-containing group of the formula Wherein the heterocyclic oxygen-containing group has a total of 5 to 7 ring members. The heterocycle is saturated or unsaturated, and is optionally substituted ing. R₆Is as defined above for Formula III.   Preferred examples of the bicyclic oxygen-containing group are as follows.   Representative examples of isoquinolinyl piperazine according to the present invention are shown in Table 1 below.  The number under each structure in Table 1 is the number of the compound.   As mentioned above, the present invention provides a method for treating various neuropsychological disorders of the general formula I It also relates to the use of the compounds.   Compounds of general formula I can be administered orally, topically, parenterally, by inhalation or spray. Or from the rectum, the usual non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Can be administered in dosage unit formulations containing the drug. Parenteral as used here The term includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Addition Thus, a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier is provided. Provided. One or more compounds of general formula I may comprise one or more non-toxic pharmaceutically Acceptable carriers and / or diluents and / or auxiliaries and, if desired, other activities. May be present with the sexual component. Pharmaceutical compositions comprising compounds of general formula I are suitable for oral use Forms, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible Powder or granules, emulsion, hard or soft capsule, or syrup May be in the form of an elixir.   Compositions intended for oral use are known in the art for preparing pharmaceutical compositions. And can be prepared according to any method known in the art. Pharmaceutical formulation of one or more drugs selected from the group consisting of fragrances, flavors, colorings and preservatives It can be included to provide a sophisticated and palatable preparation. tablet Contains the active ingredient together with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. No. These excipients include, for example, inert diluents such as calcium carbonate, carbonate Sodium, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegration Agents, such as corn starch, or alginic acid; binders, such as starch, Latin or gum acacia, lubricants such as magnesium stearate, stear It can be phosphoric acid or talc. These tablets may be uncoated, or Slows disintegration and absorption in the gastrointestinal tract, thereby leading to longer lasting It may be coated with a known technique that provides a utility. For example, a time delay Quality, such as glyceryl monostearate or glyceryl distearate Can be   Formulations for oral use also include those in which the active ingredient is an inert solid diluent, such as calcium carbonate. Hard gelatin capsules mixed with calcium, calcium phosphate or kaolin As an active ingredient or a water or oil medium such as peanut oil, liquid paraffin Be presented as soft gelatin capsules mixed with olive oil or olive oil. Can also be.   Aqueous suspensions contain the active ingredients together with excipients suitable for the manufacture of aqueous suspensions. this Such excipients may be suspending agents, for example, sodium carboxymethylcellulose, methyl Cellulose, hydropropyl methylcellulose, sodium alginate, poly Vinylpyrrolidone, tragacanth gum and acacia gum; dispersed or moist The lubricant is a natural phosphatide such as lecithin, or an alkylene oxide and a fatty acid. Condensation products, such as polyoxyethylene stearate, or ethyleneoxy Condensation products of alcohols with long-chain aliphatic alcohols such as heptadecaethyleneoxy Tanol or moieties derived from ethylene oxide and fatty acids and hexitol Condensation products with esters, such as polyoxyethylene sorbitol monooleate Or moieties derived from ethylene oxide and fatty acids and hexitol anhydride Condensation products with esters, such as polyethylene sorbitan monooleate obtain. Aqueous suspensions may also contain one or more preservatives, such as p-hydroxy. Ethyl or n-propyl benzoate, one or more coloring agents, one or more scents And one or more sweeteners, such as sucrose or saccharin. Wear.   Oily suspensions may contain the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil Or by suspending in palm or mineral oil, for example liquid paraffin. Can be The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cellulose. Chill alcohol can be included. Sweeteners and fragrances such as those shown above Additives may be added to provide a palatable oral preparation. These compositions Can be preserved by adding an antioxidant such as ascorbic acid. Wear.   Dispersible powders and granules suitable for preparing an aqueous suspension by adding water Is an active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives I will provide a. Suitable dispersing or wetting agents and suspending agents are those already mentioned above. Therefore, it is exemplified. Additional excipients are present, for example, sweetening, flavoring and coloring agents. It may be.   The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. Oil phase is planted Natural oils, such as olive oil or peanut oil, or mineral oils, such as liquid paraffin Or a mixture thereof. Suitable emulsifiers are natural gums, e.g. red oak Agum or tragacanth, natural phosphatides such as soybean, lecithin And also esters derived from fatty acids and hexitols, anhydrides Or partial esters such as sorbitan monooleate and their partial esters. Condensation products of stel and ethylene oxide, such as polyoxyethylene monooleate It can be sorbitan formate. These emulsions also contain sweeteners and flavors. May be included.   Syrups and elixirs are sweeteners, for example glycerol, propylene glycol , Sorbitol or sucrose. Such a prescription Demulcents, preservatives and flavoring and coloring agents can also be included. These pharmaceutical compositions May be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension is Formulation according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Can be Sterile injectable preparations are non-toxic parenterally acceptable diluents. Sterile injectable solution or suspension in a diluent or solvent, for example, as a 1,3-pig Can be a solution in diol. Acceptable vehicles or solvents that can be used Among the media are water, Ringer's solution and isotonic sodium chloride solution. Addition Alternatively, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose Uses any mild non-volatile oil, including synthetic mono- or diglycerides. Can be In addition, the use of fatty acids such as oleic acid in preparing injectable solutions Is found in   The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. it can. These compositions are An object is solid at normal temperature but liquid at rectal temperature and therefore in the rectum Prepared by mixing with a suitable nonirritating excipient that will melt and release the drug Can be Such substances are cocoa butter and polyethylene glycol. is there.   The compounds of general formula I can be administered parenterally in a sterile medium. medicine Substance must be suspended or dissolved in the vehicle, depending on the vehicle and concentration used. Can be. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents are added to the vehicle. Can be dissolved.   About 0.1 mg to about 140 mg per kilogram of body weight per day Is useful in the treatment of the conditions indicated above (per day). About 0.5 mg to about 7 g per patient). Single dose form in combination with carrier substance The amount of active ingredient that can produce a drug depends on the host treated and the particular mode of administration. Change. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. including.   However, dose levels specific to a particular patient may vary depending on the particular compound used. Activity, age, weight, general health, gender, diet, time of administration, route of administration, and elimination Includes speed of delivery, drug combinations, and the severity of the particular disease being treated It will be appreciated that it depends on various factors.   Representative of methods suitable for preparing compounds of the invention An illustration is shown in Schemes I and II. Persons skilled in the art can modify and add starting materials It will be appreciated that the process can be used to produce compounds encompassed by the present invention. There will be.                                Scheme I (Where Ar, R₁And R_TwoIs as defined above for formula I. )   As shown in Scheme I, an appropriately substituted 1-chloroisoquinolyl of Formula V Is condensed with piperazine to give 1-isoquinolin-1-ylpiperazine of formula VI obtain. The compound of formula VI is typically treated with a reducing agent such as cyanoborohydride Reductive alkylation with an aryl aldehyde of formula VII using lium 1- (1-Isoquinolin-1-yl) -4- (1-phenylmethyl) pi of the formula I Get Perazine. In certain situations, such as reactive nitrogen and hydroxy groups The protection of a moiety can be used to achieve conversion without adversely affecting the reactive moiety. It is necessary for Those skilled in the art will facilitate the removal of appropriate protecting groups and those protecting groups. Will recognize the way. These protecting groups may be prepared by methods taught in the literature or by similar methods. Can be added and removed using methods.   Alternatively, compounds of Formula I can be prepared according to Scheme II.                               Scheme II (Where Ar, R₁And R_TwoIs as defined above for formula I. )   As shown in Scheme II, 1-isoquinolin-1-ylpipera of formula VI Gin (prepared as shown in Scheme I above) was prepared by treating an arylmethyl halide of formula VIII Alkylation with a compound of formula I to give the desired 1- (1-isoquinoline-1 of formula I -Yl) -4- (1-arylmethyl) piperazine can be obtained. here Again, if necessary, follow literature procedures with reactive groups modified or modified. Can be protected.   The disclosures of all articles and references, including patents, herein are incorporated by reference. Incorporated here.   One of skill in the art would be able to modify starting materials and use additional steps to incorporate compounds encompassed by the present invention. It can be appreciated that   The invention is further described by the following examples, which illustrate the invention in its scope or Is interpreted in the spirit to be limited to the specific procedures and compounds described therein. Should not be done.                                 Example 1 1 .1- (isoquinolin-1-yl) piperazine   A solution of 2-chloroisoquinoline (5 g) in 20 mL of toluene was added to toluene 15 Add dropwise to a refluxing solution of piperazine (20 g) in 0 mL. This solution Heat for an additional 48 hours. After cooling to 0 ° C. for 0.5 hour, the solution is filtered. Next, the filtrate is extracted with 10% acetic acid. Wash the aqueous extract with ether and add base After sensitization, it is extracted with dichloromethane. Finally, the dichloromethane layer is washed with water Wash, dry and concentrate. This material was placed under reduced pressure overnight to give the title compound. (6.8 g, mp 54-56 ° C).¹H NMR (CDCl_Three) 8.14 ( d, J = 5.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.7 4 (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).2. 1- (isoquinolin-1-yl) -4- (1- [piperonyl] methyl) pipe Razine hydrochloride   1- (isoquinolin-1-yl) piperazine (2 in methanol (10 mL) A solution of 15 mg, 1.0 mmol) and piperonal (160 mg) was prepared. Adjust to pH 4 with acetic acid. Next, sodium cyanoborohydride (500 mg) is added and the reaction mixture is stirred at room temperature overnight. Evaporate the solvent and leave Partition the oil between dichloromethane and 5% aqueous ammonia. Then, the organic layer Apply to preparative TLC (10: 2 hexane: ethyl acetate), thereby giving the title compound The combined free base is obtained as a colorless oil (300 mg). Then, ethyl acetate The hydrochloride is obtained from the solution after treatment with hydrochloric acid (mp 250-251 ° C.).¹ H NMR (CDCl_Three) 8.15 (d, J = 5.5 Hz, 1H), 8.06 ( d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.6 5 (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), 3.5 5 (s, 2H), 3.43 (sbr, 4H), 2.71 (sbr, 4H).                                 Example 2 1- (isoquinolin-1-yl) -4- (1- [4-chlorophenyl] methyl) Piperazine oxalate   1- (a) in acetonitrile (10 mL) containing potassium carbonate (500 mg) Soquinolin-1-yl) piperazine (215 mg, 1.0 mmol) and chloride 4 Stir the solution of -chlorobenzyl (180 mg) and heat at 60 ° C for 4 hours. cold After cooling, the reaction mixture is partitioned between ether and water. Extract the organic layer with 1N HCl Issued. Thereafter, the acidic extract is basified and extracted with chloroform. Arising The organic layer is dried and concentrated to give the free base of the title compound as a white solid (30 0 mg, 88%).   The oxalate is prepared from isopropanol (mp 207-208 ° C).¹ 1 H NMR (DMSO) 8.09 (d, J = 5.5 Hz, 1H), 8.06 ( d, J = 8.5 Hz, 1H), 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 (sbr, 2H), 3.40 (sbr, 4H), 2.95 (sbr , 4H).                                 Example 3   The following compounds were prepared essentially according to the procedure described in Examples 1 and 2 above. To be prepared.   1- (isoquinolin-1-yl) -4- (1- [3,4-difluorophenyl ] Methyl) piperazine oxalate (mp 212-213 ° C).   1- (isoquinolin-1-yl) -4- (1- [3,5-difluorophenyl Methyl) piperazine oxalate (mp 223-224 ° C).   1- (isoquinolin-1-yl) -4- (1- [2-naphthyl] methyl) pipe Razine hydrochloride (mp 265-268 ° C).   1- (isoquinolin-1-yl) -4- (1- [4-methylphenyl] methyl ) Piperazine oxalate (mp 192-194 ° C).   1- (isoquinolin-1-yl) -4- (1- [3-chlorophenyl] methyl ) Piperazine.                                 Example 4   The pharmaceutical usefulness of the compounds of the present invention is determined by the following dopamine receptor subtype affinity: Is shown by the test for 1. D_TwoAnd D_FourAssay for receptor binding activity   Recombinantly produced D from green monkeys_TwoOr D_FourCO containing receptor S cell pellets are used for these assays. Samples were collected in 100 volumes (w / vol) Homogenize in 0.05 M Tris HCl buffer at 4 ° C. and pH 7.4. Thereafter, the sample is centrifuged at 30,000 × g, resuspended and rehomogenized. You. The sample is centrifuged again as described above, and the final tissue sample is frozen until use. The tissue was placed in 0.05M Tris HCl buffer containing 100 mM NaCl for 1 hour. : Resuspend at 20 (wt / vol).   Incubate at 48 ° C., 0.4 ml tissue sample, 0.5 nM^Three H-YM09151-2 and the compound of interest are incubated in a total of 1.0 ml. Included in the application. Non-specific binding was found in the presence of 1 mM spiperone. Non-specific binding is less than 20% of the total binding without further addition. Is full. D_TwoAnd D_FourBinding Characteristics of Representative Examples of the Invention to Receptor Subtypes The characteristics are shown in Table 2 below for rat striatal homogenate. D_FourAgainst the receptor The binding characteristic of the compound of formula I in nM is generally about 0.5 nanomolar. Concentration (nM) to about 25 nanomolar (nM). These compounds Is typically D_TwoFor the receptor And has a binding constant of about 200 nM to over 1000 nM. Therefore, the book The compounds of the invention generally have D_FourD for receptor_TwoAt least about 10 more than the receptor There is double selectivity. More preferably, these compounds are D_FourD for receptor_TwoAcceptance At least 20-fold, more preferably at least 25-50-fold selective over the body You.                                   Table 21 for D ₄ and D ₂ receptors (isoquinolin-1-yl) -4- (1-phenyl Characteristics of the binding of methyl) piperazine Compound No. ¹ D ₄ Ki (nM) D ₂ Ki (nM)       1 556       2 13 1003       419 ND       6 9 220   ¹The compound numbers relate to the compounds shown in Table 1.   The invention and the manner and methods of making and using it will be described by those skilled in the art to which it pertains. Are described in clear, concise and accurate terms so that they can be manufactured and used . What has been described above describes preferred embodiments of the present invention and is set forth in the following claims. It is understood that changes can be made without departing from the spirit or scope of the invention as defined. Will be. Particularly point out and distinctly claim the subject matter related to this invention. Therefore, the following claims conclude this specification.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, M W, SD, SZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AL, AM , AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, E S, FI, GB, GE, GH, GM, GW, HU, ID , IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, M G, MK, MN, MW, MX, NO, NZ, PL, PT , RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, V N, YU, ZW

Claims (1)

[Claims] 1. A compound of the following formula: or a pharmaceutically acceptable addition salt thereof. (here,   Ar represents aryl or heteroaryl, each of which is an unsubstituted aryl. R if not nil_ThreeAnd / or R_FourOptionally substituted with;   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   R_ThreeAnd R_FourAre the same or different, and R_ThreeAnd R_FourThat both are hydrogen , Hydrogen, halogen, hydroxy, C₁-C₆Alkyl, Triff Fluoromethyl, trifluoromethoxy or SO_TwoNH_TwoRepresents; or   R_ThreeAnd R_FourRepresents a ring having 5-7 atoms with the atoms to which they are attached; as well as   R_FiveIs hydrogen or C₁-C₆Represents alkyl. ) 2. Ar is C₁-C₆Mono-substituted with alkyl, or halo The compound of claim 1, which is phenyl mono- or di-substituted with gen. 3. Ar is substituted with methyl, or at least one of fluoride or chloride 3. The compound according to claim 2, wherein the compound is phenyl. 4. R_ThreeAnd R_{Four of}At least one of the points at which Ar binds to methylpiperazine; 2. The compound of claim 1, wherein the compound is in the para position with respect to 5. R_ThreeAnd R_FourHas 5-7 atoms with the carbon atoms to which they are attached Alkylene, alkenylene, alkyleneoxy, or alkylene The compound according to claim 1, which forms a dioxy group. 6. A compound of the following formula: or a pharmaceutically acceptable addition salt thereof.(here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   R_ThreeAnd R_FourAre the same or different, and R_ThreeAnd R_Four Are not hydrogen, hydrogen, halogen, hydroxy, C₁ -C₆Alkyl, trifluoromethyl, trifluoromethoxy or SO_TwoNH_TwoTo Represent; or   R_ThreeAnd R_FourForm a ring having 5-7 atoms with the carbon atoms to which they are attached. And;   R_FiveIs hydrogen or C₁-C₆Represents alkyl. ) 7. R_FiveThe compound according to claim 6, wherein is hydrogen. 8. R₁And R_TwoThe compound according to claim 6, wherein is hydrogen. 9. Ar is The compound of claim 1, wherein 10. A compound of the following formula: or a pharmaceutically acceptable addition salt thereof. (here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hide Roxy, amino, mono or di (C₁-C₆) Alkylamino, cyano or tri Represents fluoromethyl;   R₆Is hydrogen, halogen, hydroxy, C₁-C₆Alkyl, trifluoromethyl , Trifluoromethoxy or SO_TwoNH_TwoRepresents; and   R_FiveIs hydrogen or C₁-C₆Represents alkyl. ) 11. A compound of the following formula: or a pharmaceutically acceptable addition salt thereof. (here,   R₁And R_TwoIs independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C_FourAlkoxy , C₁-C_FourAlkylthio, hydroxy, amino, mono or di (C₁-C₆A) Represents alkylamino, cyano or trifluoromethyl;   R₆Is hydrogen, halogen, hydroxy, C₁-C₆Alkyl, trifluoromethyl , Trifluoromethoxy or SO_TwoNH_TwoRepresents; and   R_FiveIs hydrogen or C₁-C₆Represents alkyl. ) 12. 1- (isoquinolin-1-yl) -4- (1- [4-chlorophenyl ] The compound according to claim 1, which is methyl) piperazine. 13. 1- (isoquinolin-1-yl) -4- (1- [3,5-difluoro The compound according to claim 1, which is [phenyl] methyl) piperazine. 14． 1- (isoquinolin-1-yl) -4- (1- [3,4-difluoro The compound according to claim 1, which is [phenyl] methyl) piperazine. 15. 1- (isoquinolin-1-yl) -4- (1- [2-naphthyl] methyl 2) The compound according to claim 1, which is piperazine. 16. 1- (isoquinolin-1-yl) -4- (1- [3-chlorophenyl ] The compound according to claim 1, which is methyl) piperazine. 17． 1- (isoquinolin-1-yl) -4- (1- [4-methylphenyl ] The compound according to claim 1, which is methyl) piperazine. 18. 1- (isoquinolin-1-yl) -4- (piperonylmethyl) pipera The compound of claim 1 which is a gin.