JP2002519350A - 6- (4-arylalkylpiperazin-1-yl) benzodioxane and 6- (4-arylalkylpiperazin-1-yl) chroman derivatives: dopamine receptor subtype specific ligands - Google Patents

Abstract

  (57) [Summary] Compounds of general formula (I) or pharmaceutically acceptable acid addition salts thereof are disclosed;₁, R₂, R₃, R₄And R₅May be the same or different and include hydrogen, halogen, C₁~ C₆Alkyl, C₁~ C₆An alkoxy, C₁~ C₄Alkylthio, hydroxy, amino, mono- or di (C ₁~ C₆) Alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; and X is oxygen, a bond, C₁~ C₂Or alkylene or methyleneoxy. The compounds include, but are not limited to, schizophrenia, mania, dementia, depression, anxiety, obsessive-compulsive behavior, substance abuse, Parkinson-like movement disorders, and emotional disorders associated with the use of neuroleptics. And the like for the treatment and / or prevention of neuropsychological disorders. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to 6- (4-arylalkylpiperazin-1-yl) benzodioxane and 6- (4-arylalkylpiperazin-1-yl) chromans, and It relates to pharmaceutical compositions containing such compounds. It also relates to the use of such compounds for the treatment or prevention of psychiatric disorders such as schizophrenia and other central nervous system disorders.

2. Description of Related Art It is generally believed that the therapeutic effect of conventional antipsychotics, known as neuroleptics, is exerted by inhibiting dopamine receptors. However, neuroleptics, often there is a cause of undesirable extrapyramidal side effects (EPS) and tardive dyskinesia, it is due to the inhibition of D ₂ receptors in the linear region of the brain are doing. Dopamine D ₄ receptor subtype has recently been identified (Na
Nature, 350 : 610 (Van Tol et al., 1991);
re, 347 : 146 (Sokoloff et al., 1990)). Different awareness of localization and various antipsychotics Dokutoku in brain region of their limbic system, D ₄ receptor, indicates that plays a primary role in schizophrenia etiology. Selective D ₄ antagonists without side effects on appearing nerve by conventional neuroleptic agents, are considered to be effective antipsychotics.

SUMMARY OF THE INVENTION [0003] The present invention provides novel compounds of general formula I that interact with dopamine subtypes. That is, a broad embodiment of the present invention relates to compounds of general formula I below, or pharmaceutically acceptable acid addition salts thereof:

Embedded image(Where A is C₁~ C₂C optionally substituted with alkyl₁~ C ₄ R.₁, R₂, R₃, R₄And R₅Is independently hydrogen, halogen, C₁~ C₆No
Luquil, C₁~ C₆An alkoxy, C₁~ C₆Alkylthio, hydroxy, a
Mino, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, par
R represents fluoroalkyl or perfluoroalkoxy; and R₆, R₇, R₈And R₉Is independently hydrogen or C₁~ C₆Is an alkyl
And X is oxygen, a bond, C₁~ C₂Or alkylene or methyleneoxy. ) Dopamine D₄Receptors focus on the limbic system, controlling cognition and emotions
Yes (Science,Volume 265: 1034 pages (Taubes, 1994)
). Therefore, compounds that interact with these receptors are useful for treating cognitive disorders.
It is for. Such diseases include schizophrenia rejection symptoms (withdrawal from society).
And cognitive deficits, which are important factors of the coordination and asynchrony. Other diseases
Examples include those containing memory impairment or attention deficit disorder.

The compounds of the present invention, the binding to the D ₄ receptor subtypes, exhibit high affinity and selectivity. Therefore, these compounds are useful in the treatment of various neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Disease Parkinsonism and tardive other dopamine, such as movement disorders mediated may also be directly or indirectly treated by modulation of D ₄ receptor.

The compounds of the present invention also, since D ₄ receptor selectively in a region known to control emotion and cognitive functions, by adjusting the D ₄ receptor, depression, memory impairment or It is also useful for treating Alzheimer's disease.

[0006] Accordingly, in another aspect, the invention relates to schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, such as Parkinson's syndrome and dystonia And methods for treatment and / or prevention of neuropsychological or emotional disorders, including Parkinson-like movement disorders, and movement disorders associated with the use of neuroleptic agents. In addition, the compounds of the invention are useful for treating depression, memory impairment or Alzheimer's disease. In addition, the compounds of the present invention are useful in treating other diseases that respond to inhibition of dopamine action, such as drug abuse and obsessive-compulsive disease. These compounds are also useful for treating extrapyramidal side effects associated with the use of conventional neuroleptic drugs.

In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of general formula I.

In another aspect, the invention provides intermediates useful for preparing compounds of general formula I.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the present invention relates to 6- (4-arylalkylpiperazin-1-yl) benzodioxane of general formula I and 6- (4-arylalkylpiperazine) -1-yl) chroman derivatives. Preferred compounds of general formula I are those wherein X is oxygen or methylene. Still other preferred compounds of general formula I are those wherein R ₁ , R ₂ and R ₅ are hydrogen and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl, or , C ₁ -C ₆ alkoxy. Other preferred compounds of general formula I are those wherein R ₆ , R ₇ , R ₈ and R ₉ are independently hydrogen, methyl or ethyl.

Other preferred compounds of general formula I are those wherein A is methylene or ethylene, each of which is independently optionally substituted with a C ₁ -C ₂ group.
More preferably, A is methylene.

[0011] Preferred compounds of the present invention include compounds of general formula IA:

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, C _1-
C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino, mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro, trifluoromethyl or tri It represents trifluoromethoxy; and, X is oxygen, binding, methyleneoxy, or _is an alkylene of C 1 -C _2. Preferred compounds of the general formula IA are those wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. It is a compound represented.

Other preferred compounds of general formula IA are those wherein R ₁ , R ₂ and R ₅ are hydrogen.

More preferred compounds of the general formula IA are those wherein R ₁ , R ₂ and R ₅ are hydrogen and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl, Or
A compound representing a C ₁ -C ₄ alkoxy, wherein both R ₃ and R ₄ are not hydrogen.

Particularly preferred compounds of general formula IA are those wherein R ₃ and R ₄ independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy,
A compound wherein both R ₃ and R ₄ are not hydrogen.

Other particularly preferred compounds of general formula IA are those wherein X is a bond or methyleneoxy and R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, methyl,
A compound representing ethyl, methoxy or ethoxy.

The present invention further includes compounds of general formula II:

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are defined as above for general formula I.) Preferred compounds of general formula II are R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently:
Hydrogen, _halogen, alkyl of C 1 -C _6, or _a compound of an alkoxy of C 1 -C _6.

Other preferred compounds of general formula II are those in which R ₁ , R ₂ and R ₅ are hydrogen.

More preferred compounds of general formula II are those wherein R ₁ , R ₂ and R ₅ are hydrogen, and
A compound wherein R ₃ and R ₄ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₄ alkoxy, but wherein both R ₃ and R ₄ are not hydrogen. .

Particularly preferred compounds of the general formula II are₃And R₄Is independently hydrogen, fluoro
, Chloro, bromo, methyl, ethyl, methoxy or ethoxy, but R ₃ And R₄Are compounds that are not both hydrogen.

The present invention further includes compounds of general formula III:

Embedded image Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are defined as above for general formula I. Preferred compounds of general formula III are R ₁ , R ₂ , R ₃ , A compound in which R ₄ and R ₅ independently represent hydrogen, halogen, C _{1 to} C ₆ alkyl, or C _{1 to} C ₆ alkoxy.

Other preferred compounds of general formula III are those in which R ₁ , R ₂ and R ₅ are hydrogen.

More preferred compounds of general formula III are those wherein R ₁ , R ₂ and R ₅ are hydrogen and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl, Or
A compound representing a C ₁ -C ₄ alkoxy, wherein both R ₃ and R ₄ are not hydrogen.

Particularly preferred compounds of general formula III are those wherein R ₃ and R ₄ independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy,
A compound wherein both R ₃ and R ₄ are not hydrogen.

The present invention also provides intermediates useful for preparing compounds of general formula I. These intermediates have the general formulas IV-A, IV-B, IV-C, IV-D, IV-E and IV-F.

[0025]

Embedded image

Embedded image In each of the general formulas IV-AF, R ₆ , R ₇ , R ₈ and R ₉ independently represent hydrogen or C ₁ -C ₆ alkyl. Particularly preferred compounds of the general formulas IV-AF are those in which R ₆ , R ₇ , R ₈ and R ₉ are all hydrogen.

In certain situations, the compounds of general 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, in racemic or optically active form. In these situations, the single enantiomer, ie the optically active form, may be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of the racemate can be accomplished by conventional methods, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column.

Representative compounds of the present invention that are encompassed by the general formula I include, but are not limited to, the compounds of Table 1 and their pharmaceutically acceptable acid addition salts. . In addition, if the compound of the present invention is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt, especially a pharmaceutically acceptable addition salt, dissolves the free base in a suitable organic solvent to prepare an acid addition salt from the basic compound. By treating the solution with an acid according to conventional techniques for preparing

Non-toxic pharmaceutical salts include hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic , hydroiodic acid, _{acetic, HOOC- (CH 2) n-} COO
And alkanolic acid salts such as H (where n is 0 to 4). One of skill in the art will generally appreciate a variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses acylated prodrugs of the compounds of general formula I. One skilled in the art will appreciate the various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by general formula I. Will do.

Where a compound exists in various tautomeric forms, the invention is not limited to any one of the particular tautomers. The present invention includes all tautomeric forms of the compounds.

In the present invention, “C₁~ C₆Alkyl or lower alkyl is a carbon atom
Means a linear or branched alkyl group having 1 to 6
Chill, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl
, Pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-he
Xyl, 3-hexyl, 3-methylpentyl and the like. Preferred C ₁ ~ C₆Alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl
, And cyclopropylmethyl.

In the present invention, “C ₁ -C ₆ alkoxy” or “lower alkoxy” means a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy , Isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

In the present invention, the term “halogen” means fluorine, bromine, chlorine and iodine.

Representative 1- (4-arylalkylpiperazin-1-yl) benzodioxane and 6- (4-arylalkylpiperazin-1-yl) chromans of the present invention are shown in Table 1.

[0035]

Embedded image The present invention also relates to the use of the compounds of general formula I for the treatment of neuropsychological disorders. The interaction of dopamine receptors with the compounds of the present invention is shown in the examples. This interaction results in the pharmacological activity of these compounds.

The compounds of the general formula I can be prepared from conventional non-toxic pharmaceutically acceptable carriers.
Can be administered orally, topically, parenterally, by inhalation or spray, or rectally, in dosage unit formulations containing a liposome, an adjuvant, and a vehicle. The term parenteral as used herein refers to subcutaneous injection, intravenous, intramuscular,
Examples include intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may comprise one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and, if desired, other It may be present with the active ingredient. Pharmaceutical compositions containing a compound of general formula I may be in a form suitable for oral use, such as tablets, troches, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or , Syrup or elixir.

[0037] Compositions intended for oral use may be prepared according to any of the known techniques for the manufacture of pharmaceutical compositions, such compositions providing pharmaceutically elegant and palatable preparations. For this purpose, they may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;
Granulating and powdering agents such as, for example, corn starch or alginic acid; binders such as, for example, starch, gelatin or acacia, for example, lubricating agents such as magnesium stearate, stearic acid or talc. Tablet
It may be uncoated or it may be coated by known techniques to delay gastrointestinal degradation and absorption and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may 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, wherein the active ingredient is water-soluble. Alternatively, they may be presented as soft gelatin capsules, mixed with an oily medium such as 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 sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersants or wetting agents, which are A naturally occurring phosphatide such as lecithin, or a condensation product of a fatty acid and an alkylene oxide, such as, for example, polyoxyethylene stearate; or Condensation products or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or, for example, polyethylene sorbitan monooleate Bet such as the condensation products of partial esters derived ethylene oxide anhydrides of fatty acids and hexitol. 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 sucrose or saccharin, etc. May also contain one or more sweeteners.

Oily suspensions may be formulated by dispersing the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules, suitable for preparation of an aqueous suspension by the addition of water, are dispersed in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Provide the active ingredient. Suitable dispersing or wetting agents and suspending agents are exemplified by the substances already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
The oil phase may be, for example, a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as, for example, acacia gum or tragacanth gum,
Soybeans, naturally occurring phosphatides such as lecithin, and esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitols and anhydrides, and ethylene oxide such as polyoxyethylene sorbitan monooleate and the like. It can be a condensation product with a partial ester. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may 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 may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may 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. And so on. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed 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 general formula I may 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 that is solid at room temperature but liquid at rectal temperature, and thus melts rectally to release the drug Will do. Such materials are cocoa butter and polyethylene glycol.

The compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle.

A dosage on the order of about 0.1 mg / kg to about 140 mg / kg of body weight per day
Useful for treating the conditions indicated above (from about 0.5 mg per patient per day).
About 7 g). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of the active ingredient.

However, the specific dosage for a particular patient will depend on the activity, age, weight, general health, sex, food and drink, dosing time, dosing route, excretion rate, drug of the particular compound used. It will be appreciated that this will depend on a variety of factors, such as the combination of and the severity of the particular disease for which treatment is being performed.

A representative synthesis of 6- (4-arylalkylpiperazin-1-yl) benzodioxanes and 6- (4-arylalkylpiperazin-1-yl) chromans of the present invention is shown in Scheme I. One skilled in the art will recognize that the starting materials can be varied and additional steps can be used to prepare compounds encompassed by the present invention.

[0049]

Embedded image In Scheme I, A, R ₁ -R ₉ and X are as defined above for Formula I, and Z is a leaving group.

Thus, for example, 5-piperazinyl-2,3-dihydrobenzo [b] furan (IV, X is a bond), 1- (1,4-benzodioxan-6-yl) piperazine (IV , X = oxygen), 1- (chroman-6-yl) piperazine (IV, X = −
CH ₂ —) or 7-piperazinyl-2H, 3H, 4H, 5H-benzo [f]
Oxepin (IV, X is —CH ₂ CH ₂ —) is reacted with an appropriately substituted alkylating agent (V), for example, a benzylic alkylating agent in the presence of a suitable base to give a compound of the general formula Compound I may be provided.

The leaving group (Z) on the alkylating agent V can be a halide, sulfonic ester, and the like. If they are not commercially available, compounds of general structure V can be prepared by procedures analogous to those described in the literature. Compounds of general structure V are known or can be prepared by methods known in the art. One of skill in the art can vary the starting materials and to make the compounds encompassed by the present invention,
It will be appreciated that additional steps may be used. The base used may be an inorganic base such as potassium carbonate, sodium hydroxide or the like, or may be an organic base such as triethylamine or pyridine.

The disclosures of all articles and references mentioned herein, including patents, are hereby incorporated by reference.

The preparation of the compounds of the present invention is further illustrated by the following examples, which should not be construed as limiting the concept or spirit of the invention to the particular procedures and compounds described therein. Absent.

Example 1 1- (1,4-benzodioxan-6-yl) piperazine 1,4-benzodioxan-6-amine (2.
00g, 13.2 mmol), bis- (2-chloroethyl) amine hydrochloride (3.
54 g, 19.8 mmol) and potassium carbonate (1.83 g, 13.2 mmol)
) Is heated and refluxed for 24 hours. The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic phase was separated, dried over _Mg 2 SO _4, filtered and concentrated. Purification by flash column chromatography (8% methanol / methylene chloride on silica) gives 0.88 of the desired 1- (1,4-benzodioxan-6-yl) piperazine as a white solid.
g (30%) are obtained (melting point 138 ° C., TLC R _f 0.37 with 10% methanol / methylene chloride).

Example 2 1- (Chroman-6-yl) piperazine 4-Chromanone (2.00 g, 13.50 mmol in 20 ml of acetic acid
) Is added to a suspension consisting of zinc dust (20 g) in acetic acid (40 ml). The mixture is heated at 100 ° C. for 16 hours. After cooling to room temperature, the excess zinc is filtered off and the solvent is evaporated. The residue was stirred in water (20 ml),
It was made basic with NaOH pellets and extracted with ethyl acetate (20 ml). The organic phase was dried over _Mg 2 SO _4, filtered and concentrated. Purification by flash column chromatography (10% ethyl acetate-hexane)
1.63 g (91%) of 4-chromane as a yellow oil are obtained. TLC R _f 0
. 50 (10% ethyl acetate: hexane).

[0056] 2. 1. First Embodiment 4-chroman (1.63 g, 12.16 m) obtained in
The mol), at 15 to 20 ° C., treated with 70% _HNO 3 (6ml).
The mixture is stirred for 1 hour at room temperature. The solution is cooled to 0 ° C. with ice water, extracted with ethyl acetate and concentrated. The crude material was then added to ethanol (50
ml), treated with Raney nickel (1 g) and hydrogenated for 3 hours at room temperature. The resulting mixture was filtered, concentrated and purified by flash column chromatography (20% ethyl acetate-hexane) to give a yellow oil, 6-
0.48 g (26%) of the aminochroman is obtained. TLC R _f 0.28 (3
5% ethyl acetate: hexane).

[0057] 3. 1. Use Example 2 in 10 ml of chlorobenzene. 6-aminochroman (0.300 g, 2.013 mmol), bis- (2-chloroethyl) amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.
(278 g, 2.013 mmol) is heated under reflux for 24 hours.
The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic phase was separated, dried over _Mg 2 SO _4, filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) gave 0.157 g of 1- (chroman-6-yl) piperazine as a white solid (3
6%). TLC _Rf 0.35 (eluted with 10% methanol-methylene chloride).

Example 3

Embedded image 1- (1,4-benzodioxan-6-yl) -4- (4-fluorobenzyl)
Of piperazine oxalate CH ₃ CN (5ml), was prepared as described in Example 1 1- (1
, 4-benzodioxan-6-yl) piperazine (0.146 g, 0.663 m
ol) is treated with potassium carbonate (0.458 g, 3.32 mmol) and 4-fluorobenzyl chloride (0.144 g, 0.995 mmol).
The mixture is heated under reflux for 4 hours. The resulting mixture is then cooled to room temperature and washed successively with saturated aqueous NH ₄ Cl (20 ml) and saturated aqueous NaCl (20 ml). The organic portion was dried over _Mg 2 SO _4, filtered and concentrated. Purification by flash column chromatography (30% ethyl acetate-hexane) gave 0.074 g (34) of 1- (1,4-benzodioxan-6-yl) -4- (4-fluorobenzyl) piperazine as a white solid. %) (TLC _Rf 0.35; 30% ethyl acetate: hexane). A solution consisting of this material in 1 ml of ethanol was treated with oxalic acid (0.020 g, 0.225 mmol
) And concentrated to give 1- (1- (1,4-benzodioxane-6).
-Yl) -4- (4-fluorobenzyl) piperazine oxalate (compound 1) 0.0
79 g (88%) are obtained. Melting point 177-179 [deg.] C.

(Example 4)

Embedded image 1- (chroman-6-yl) -4- (4-methylbenzyl) of piperazine oxalate CH ₃ CN (5 ml), prepared as described in Example 2 was 1- (chroman-6-yl ) A solution consisting of piperazine (0.157 g, 0.723 mol) is treated with potassium carbonate (0.500 g, 3.615 mmol) and 4-methylbenzyl chloride (0.102 g, 0.723 mmol). The mixture was heated under reflux for 4 hours, cooled to room _temperature, diluted with CH ₂ Cl ₂ (20ml). The mixture is washed successively with saturated aqueous NH ₄ Cl (20 ml) and saturated aqueous sodium chloride (20 ml). The organic phase is dried over MgSO ₄ and concentrated. Purification by flash column chromatography (30% ethyl acetate-hexane) provided 40 mg (17%) of the desired 1- (chroman-6-yl) -4- (4-methylbenzyl) piperazine as a white solid. Can be T
LC _Rf 0.35 (30% ethyl acetate: hexane). A solution consisting of this substance in 1 ml of ethanol is treated with oxalic acid (11 mg) and concentrated,
1- (chroman-6-yl) -4- (4-methylbenzyl) piperazine oxalate (
51 mg of compound 4) are obtained. Melting point 199 [deg.] C.

Example 5 The following compound is prepared essentially according to the procedure described in Examples 3 and 4 above: (a) 1- (1,4-benzodioxan-6-yl) -4- (4-chlorobenzyl) piperazine oxalate (compound 3, melting point: 213 to 215 ° C.) (b) 1- (1,4-benzodioxan-6-yl) -4- (4-methylbenzyl) piperazine oxalate (compound 5, melting point 200-201 ° C) (c) 1- (1,4-benzodioxan-6-yl) -4- (4-methoxybenzyl) piperazine oxalate (compound 6, melting point 193-195 ° C) (d) 1- (1,4-benzodioxan-6-yl) -4- (3-chlorobenzyl) piperazine oxalate (compound 7, melting point: 213 to 215 ° C.) (e) 1- (1,4-benzodioxane-6) -Yl) -4- (3 -Methoxybenzyl) piperazine oxalate (compound 2, melting point: 213 to 215 ° C) (f) 1- (1,4-benzodioxan-6-yl) -4- (2-chlorobenzyl) piperazine oxalate (compound 8, (Mp 175 ° C) (g) 1- (1,4-benzodioxan-6-yl) -4- (2-methoxybenzyl) piperazine oxalate (compound 9, melting point 143 ° C) (h) 1- (1,4 -Benzodioxan-6-yl) -4-benzylpiperazine hydrochloride (compound 10, melting point 143-145 ° C) (i) 1- (chroman-6-yl) -4- (4-chlorobenzyl) piperazine oxalate ( Compound 11) (Example 6) Assay of D ₂ , D ₃ and D ₄ receptor binding activity The pharmaceutical utility of the compounds of the present invention was assessed against the dopamine receptor subtype affinity described below. Shown by Say.

COS containing D ₂ , D ₃ and D ₄ receptors obtained recombinantly from humans
The cell pellet is used for the assay. The sample was prepared at pH 4 ° C. at pH 7.4.
Homogenize in 100 volumes (w / vol) of 05M Tris HCl buffer. The sample is then centrifuged at 30,000 × g, resuspended and homogenized again. The sample is then centrifuged as described above, and the final tissue sample is frozen until use. Tissues were treated with 0 mM containing 100 mM NaCl.
. Resuspend 1:20 (wt / vol) in 05M Tris HCl buffer.

Incubation is performed at 48 ° C., and 0.4 ml of a tissue sample, 0.5 nM of ³ H-YM09151-2 and a compound of interest are contained in 1.0 ml of the whole incubation solution. Non-specific binding is defined as the binding found in the presence of 1 mM spiperone; without further addition, non-specific binding is less than 20% of the total binding. The binding properties of representative compounds of the invention to the D ₂ , D ₃ and D ₄ receptor subtypes are shown in Table 2 against murine striatum homogenates.
Shown in

[0063]

[Table 1] The above data is representative of _Ki values for compounds of the present invention; all compounds of the present invention are active in the above assays. Binding constant of the compound of general formula I for the D ₄ receptor (expressed in nM) is generally from about 0.5 nanomolar (nM)
In the range of from about 100 nanomolar (nM). Binding constant for D ₂ receptors for these compounds is at least about 1000nM the typical. Accordingly, the compounds of the present invention generally against D ₄ receptor than D ₂ receptors, at least about 10-fold selective. Preferably, these compounds are at least 20-fold, more preferably at least 25-50 fold, are selective for _{D 4} receptors than _{D 2} receptors. Most preferably, these compounds are at least 100-fold, selective for the D ₄ receptor than D ₂ receptors. Similarly, compounds of the present invention, with respect to D ₄ receptor than D ₃ receptor, the at least about 10 fold selective is common.

The present invention and the methods and processes for making and using it, are completely, clearly, concisely and accurately described so that those skilled in the art can make and use the same. Described here in terms. It is understood that the foregoing describes preferred embodiments of the invention and that modifications can be made to the invention without departing from the spirit or concept of the invention as set forth in the appended claims. Should. In order to particularly point out and distinctly claim the subject matter regarded as the invention, the following claims conclude this specification.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/22 A61P 25/22 25/24 25/24 25/28 25/28 25/30 25/30 43 / 00 111 43/00 111 C07D 307/79 C07D 307/79 313/08 313/08 319/18 319/18 321/10 321/10 405/04 405/04 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, A M, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR , HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72 Inventor Turkauf, Andrew United States 06811 Connecticut, Danbury Fox Denlord 16 F-term (reference) 4C022 KA10 4C037 PA01 4C062 FF12 JJ13 4C063 AA01 BB02 CC76 CC79 CC80 DD34 EE01 4C086 AA02 ZA12 ZA12 ZA12 ZA12 ZA94 ZC 39 ZC42

Claims (36)

[Claims] 1. A compound of the following general formula: or a pharmaceutically acceptable acid thereof.
Addition salt:(Where A is C₁~ C₂C optionally substituted with alkyl₁~ C ₄ An alkylene; R₁, R₂, R₃, R₄And R₅May be the same or different and represent hydrogen
, Halogen, C₁~ C₆Alkyl, C₁~ C₆An alkoxy, C₁~ C₄No
Alkylthio, hydroxy, amino, mono- or di (C₁~ C₆) Alkyria
Mino, cyano, nitro, trifluoromethyl or trifluoromethoxy
I; and R₆, R₇, R₈And R₉May be the same or different and are hydrogen, or
, C₁~ C₆X is oxygen, a bond, C₁~ C₂Or alkylene or methyleneoxy. ) 2. The compound according to claim 1, wherein A is methylene. 3. The method of claim ₁ , wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy. 2
A compound as described. 4. The compound according to claim 3, wherein R ₁ , R ₂ and R ₅ are hydrogen. 5. R ₁ , R ₂ and R ₅ are hydrogen, and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl or C ₁ -C _4. The compound of claim 3, wherein R ₃ and R ₄ are not hydrogen. 6. The method of claim _3, wherein R ₃ and R ₄ independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, but both R ₃ and R ₄ are not hydrogen. 5. The compound according to 5. 7. The compound according to claim 2, wherein X is oxygen. 8. The method of claim ₁ , wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy. 7
A compound as described. 9. The compound according to claim 8, wherein R ₁ , R ₂ and R ₅ are hydrogen. 10. R ₁ , R ₂ and R ₅ are hydrogen, and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C _4. 9. A compound according to claim 8, wherein R < ₃ > and R < ₄ > are not hydrogen. 11. The method of claim _3, wherein R ₃ and R ₄ independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, but both R ₃ and R ₄ are not hydrogen. 10. The compound according to 10. 12. The compound according to claim 2, wherein X is methylene. 13. The method of claim ₁ , wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy. 12. The compound according to 12. 14. The compound according to claim 13, wherein R ₁ , R ₂ and R ₅ are hydrogen. 15. R ₁ , R ₂ and R ₅ are hydrogen and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl or C ₁ -C _4. 14. The compound of claim 13, wherein R ₃ and R ₄ are not hydrogen. 16. The method of claim _3, wherein R ₃ and R ₄ independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, but both R ₃ and R ₄ are not hydrogen. 15. The compound according to 15. 17. The compound according to claim 2, wherein X is a bond. 18. The compound according to claim 2, wherein X is ethylene. 19. R ₁ , R ₂ and R ₅ are hydrogen; and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl. Or a C ₁ -C ₄ alkoxy, wherein both R ₃ and R ₄ are not hydrogen.
7. The compound according to 7. 20. X is ethylene; R ₁ , R ₂ and R ₅ are hydrogen; and R ₃ and R ₄ are independently hydrogen, halogen, C ₁ -C ₆ alkyl. Or a C ₁ -C ₄ alkoxy, wherein both R ₃ and R ₄ are not hydrogen.
8. The compound according to 8. 21. 1- (1,4-benzodioxan-6-yl) -4- (4
3. The compound according to claim 2, which is -fluorobenzyl) piperazine. 22. 1- (1,4-benzodioxan-6-yl) -4- (4
The compound according to claim 2, which is -chlorobenzyl) piperazine. 23. 1- (1,4-benzodioxan-6-yl) -4- (4
3. The compound according to claim 2, which is -methylbenzyl) piperazine. 24. 1- (1,4-benzodioxan-6-yl) -4- (4
3. The compound according to claim 2, which is -methoxybenzyl) piperazine. 25. 1- (1,4-benzodioxan-6-yl) -4- (3
The compound according to claim 2, which is -chlorobenzyl) piperazine. 26. 1- (1,4-benzodioxan-6-yl) -4- (3
The compound according to claim 2, which is -methoxybenzyl) piperazine. 27. 1- (1,4-benzodioxan-6-yl) -4- (2
The compound according to claim 2, which is -chlorobenzyl) piperazine. 28. 1- (1,4-benzodioxan-6-yl) -4- (2
3. The compound according to claim 2, which is -methoxybenzyl) piperazine. 29. The compound according to claim 2, which is 1- (1,4-benzodioxan-6-yl) -4-benzylpiperazine hydrochloride. 30. The compound according to claim 2, which is 1- (chroman-6-yl) -4- (4-methylbenzyl) piperazine. 31. The compound according to claim 2, which is 1- (chroman-6-yl) -4- (4-chlorobenzyl) piperazine. 32. A compound having the following general formula: (Wherein, R ₆ , R ₇ , R ₈ and R ₉ may be the same or different and are hydrogen or C ₁ -C ₆ alkyl). 33. A compound represented by the following general formula: (Wherein, R ₆ , R ₇ , R ₈ and R ₉ may be the same or different and are hydrogen or C ₁ -C ₆ alkyl.) 34. A compound having the following general formula: (Wherein, R ₆ , R ₇ , R ₈ and R ₉ may be the same or different and are hydrogen or C ₁ -C ₆ alkyl). 35. A compound having the following general formula: (Wherein, R ₆ , R ₇ , R ₈ and R ₉ may be the same or different and are hydrogen or C ₁ -C ₆ alkyl). 36. A compound represented by the following general formula: (Wherein, R ₆ , R ₇ , R ₈ and R ₉ may be the same or different and are hydrogen or C ₁ -C ₆ alkyl).