JP2002525373A - 2-piperazinoalkylaminobenzoazole derivatives: dopamine receptor subtype special ligand - Google Patents

Abstract

(57) Abstract: Compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A is a (un) substituted alkylene; R ₁ and R ₂ are the same or different And hydrogen, halogen, alkyl, alkoxy, alkylthio, hydroxy, (un) substituted amino, cyano, nitro, sulfonamide, trifluoromethyl or trifluoromethoxy; R ₃ , R ₄ , R ₅ , R ₆ and R ₈ is independently hydrogen or alkyl; X is sulfur, oxygen or NR ₇ where R ₈ is defined herein; m is 0, 1 or 2 Ar is an aryl or heteroaryl group as further defined herein. The compounds are useful in psychopsychology, including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, forced behavior, substance abuse, Parkinson-like dyskinesia, and dyskinesia involving the use of neuroleptics. Useful for the treatment and / or prevention of dysfunction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] FIELD OF THE INVENTION The present invention is 2-piperazino alkylamino benzoazole derivative, and to pharmaceutical compositions containing such compounds. The present invention also relates to the use of such compounds in the treatment and prevention of psychiatric disorders such as schizophrenia and other central nervous system disorders.

2. Description of the Related Art The therapeutic effect of common antipsychotics known as neuroleptics is generally believed to be exerted by blocking dopamine receptors. But often,
Neuroleptics are responsible for undesirable extrapyramidal side effects (EPS) and extrapyramidal endings defect disease syndrome caused by blockade of D ₂ receptors in striatal regions of the brain. Dopamine _{D 4} receptor subtype has recently been identified (Nature, 350
: 610 (Van Tol et al., 1991); Nature, 347: 146 (S
okoloff et al., 1990)). The identification recognition for their unique localization and antipsychotic agent in the limbic area of the brain shows that D ₄ receptor plays a major role in the pathogenesis of schizophrenia. Selective D ₄ antagonist is considered to neurological side effects exhibited by typical neuroleptic drugs are not effective antipsychotics.

[0003] US Patent No. 5,632,898 discloses N-benzothiazol-2-yl-2-yl.
(4-phenylpiperazinyl) acetamide is disclosed.

[0004] US Pat. No. 5,229,398 discloses aminomethylpiperazine derivatives.

SUMMARY OF THE INVENTION The present invention provides novel compounds of Formula I that interact with dopamine subtypes. Accordingly, a main embodiment of the present invention is a compound of formula I:

Embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₁And R₂Are the same or different and are hydrogen, halogen, C₁~ C₆ Alkyl, C₁~ C₆Alkoxy, C₁~ C₆Alkylthio, hydroxy, ami
No, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, C₁~ C ₆ Alkylsulfonyl, sulfonamide or C₁~ C₆Alkyl sulfonami
De, perfluoro (C₁~ C₆) Alkyl or perfluoro (C₁~ C₆A)
Stands for Rukoxy, R₃, R₄, R₅And R₆Are the same or different and hydrogen or C₁ ~ C₆X represents sulfur, oxygen or NR₇(Where R₇Is hydrogen or C₁~ C₆Al
Kill)) and R₈Is hydrogen or C₁~ C₆M is 0, or an integer selected from 1 and 2, and Ar is each optionally C₁~ C₆Alkyl, C₁~ C₆Alkoxy, ha
Rogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Methoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyls
Monocyclic or independently substituted with up to five groups selected from rufonamide
Bicyclic aryl or heteroaryl).

[0006] Dopamine D ₄ receptors are concentrated in the limbic system, which controls cognition and emotion (Science, 265: 1034 (Taubes, 1994)). Thus, compounds that interact with these receptors are useful for treating cognitive disorders. These disorders include cognitive deficits that are important components of the negative symptoms of schizophrenia (withdrawal and unresponsiveness). Other disorders include those with memory impairment or attention deficit disorder.

The compounds of the present invention show a high affinity and binding selectivity to D ₄ receptor subtypes. Accordingly, these compounds are useful for treating a variety of psychopsychological disorders such as, for example, schizophrenia, psychotic manic depression. The rotor type the D ₄ receptor, other dopamine-mediated diseases such as Parkinsonism and extrapyramidal endings defect syndrome can also be treated directly or indirectly.

The compounds of the present invention can also be used to selectively present in Shiraru region by controlling the emotion and cognitive functions, depression due to rotor type of D ₄ receptor, for the treatment of memory disorders or Alzheimer's disease, Is also useful.

[0009] Thus, in another aspect, the present invention relates to, for example, schizophrenia, mania, dementia, depression, anxiety, forced behavior, substance abuse, memory impairment, cognitive impairment, Parkinson-like dyskinesia (eg, Parkinson's Disease and dystonia), and methods for treating and / or preventing psychopsychological or emotional disorders, including movement disorders involving the use of neuroleptics. Further, the compounds of the present invention may be used for depression, memory impairment,
Or it is useful for treating Alzheimer's disease. In addition, the compounds of the invention are useful for treating other disorders responsive to dopaminergic blockade, such as substance abuse and obsessive-compulsive disorder. These compounds are also useful for treating extrapyramidal side effects associated with the use of conventional neuroleptics.

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

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

[0012] DETAILED As the foregoing description of the present invention, the present invention relates to compounds of formula I. Preferred compounds of formula I include those wherein R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or methyl, and R ₈ is hydrogen. In more preferred compounds of I,
m is 0 or 1, and A is unsubstituted _C 1 -C _4, more preferably unsubstituted _C 2, _{C 3} or _{C 4} alkylene. In a preferred compound of formula I, when X is S, R ₁ and R ₂ are both hydrogen, all of R _{2 to} R ₆ are hydrogen, and m is 0, Ar is unsubstituted phenyl Absent.

Preferred Ar groups in Formula I are those having up to three non-hydrogen substituents selected from the groups described above. More preferred Ar groups in Formula I are those having two or fewer substituents. Particularly preferred compounds of formula I include those wherein Ar is

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. .

In other particularly preferred compounds of I, R ₉ and R ₁₀ are independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, chloro or fluoro, or trifluoromethyl. . In still other highly preferred compounds of formula I, Ar is

Embedded image (Wherein each _{R 9} and _{R 10,} on condition that one of _{R 9} and _{R 10} are hydrogen, hydrogen, _4-C 1 ~C ₃ alkyl, _2-C 1 ~C ₃ alkoxy, 4- Halogen, or independently selected from 3-trifluoromethyl). Even more preferred are compounds wherein R ₉ and R ₁₀ are independently selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro, or fluoro.

In another group of preferred compounds of the formula I, R ₁ and R ₂ are hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulphonyl, alkylsulphonamide Or sulfonamide independently. A highly preferred group of such compounds is that at least one of R ₁ and R ₂ is hydrogen;
And those where the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. Particularly preferred compounds of this group include those wherein R ₁ is hydrogen and R ₂ is at the 4- or 6-position on the nitrogen-containing ring structure.

In yet another group of preferred compounds of formula I, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. A preferred group of compounds are those having the above naphthyl, wherein X is NH.

A preferred group of compounds of the present invention is represented by Formula II:

Embedded image Wherein A is C ₂ -C ₆ alkylene optionally substituted with one or two C ₁ -C ₆ alkyl groups, wherein R ₁ and R ₂ are as defined above for formula I R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or C ₁ -C ₃ alkyl, preferably methyl; R ₈ is hydrogen or C ₁ -C ₂ alkyl; , 0, 1 or 2 and Ar is as defined above with respect to formula I).

In further preferred compounds of II, m is 0 or 1, and A is unsubstituted C ₁ -C ₄ , more preferably unsubstituted C ₂ , C ₃ or C ₄ alkylene.

Particularly preferred compounds of formula II include:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. . In such highly preferred compounds, when Ar is phenyl, R ₁ -R ₆ are hydrogen, m is 0, and A is ethylene,
Not necessarily both R ₉ and R ₁₀ are hydrogen. Other highly preferred formulas I
Compounds of I have the formula:

Embedded image Wherein each R ₉ and R ₁₀ are independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl) pyridyl and pyrimidinyl groups. You.

In other particularly preferred compounds of II, Ar is phenyl and R₁~
R₆Is hydrogen, A is ethylene and m is 0, R₉and
R₁₀, Provided that both are not hydrogen₉And R₁₀Is hydrogen, C ₁ ~ C₃Alkyl, C₁~ C₃Alkoxy, chloro or fluoro, or
Independently selected from trifluoromethyl. Still other highly preferred formulas I
In the compound of I, Ar is

Embedded image (Wherein each of R ₉ and R ₁₀ is hydrogen, 4-C ₁ -C ₃ alkyl, 2-C ₁ -C ₃ alkoxy, 4-6, provided that only one of R ₉ and R ₁₀ is hydrogen.
-Independently selected from halogen, or 3-trifluoromethyl).
When R _{1 to} R ₆ are hydrogen, A is ethylene, m is 0, and Ar is phenyl, provided that both R ₉ and R ₁₀ are not necessarily hydrogen.
Even more preferred are compounds wherein R ₉ and R ₁₀ are independently selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro, or fluoro.

In another group of preferred compounds of formula II, R ₁ and R ₂ are hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulfonyl, alkylsulfonamide Or sulfonamide independently. Highly preferred groups of such compounds include those in which at least one of R ₁ and R ₂ is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. Particularly preferred compounds of this group include those wherein R ₁ is hydrogen and R ₂ is at the 4- or 6-position on the nitrogen-containing ring structure.

In yet another group of preferred compounds of formula II, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. A preferred group of compounds are those having the above naphthyl wherein X is NH.

Another preferred group of compounds of the invention are compounds of formula III:

Embedded image Wherein A is C ₂ -C ₆ alkylene optionally substituted with one or two C ₁ -C ₆ alkyl groups, wherein R ₁ and R ₂ are as defined above for formula I R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or C ₁ -C ₃ alkyl, preferably methyl; R ₈ is hydrogen or C ₁ -C ₂ alkyl; , 0, 1 or 2 wherein Ar is as defined above for formula I).

In further preferred compounds of III, m is 0 or 1, and A is unsubstituted C ₁ -C ₄ , more preferably unsubstituted C ₂ , C ₃ or C ₄ alkylene.

Particularly preferred compounds of formula III include those wherein Ar is

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. .

In other particularly preferred compounds of III, R ₉ and R ₁₀ are hydrogen,
C ₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, chloro or fluoro, or is independently selected from trifluoromethyl.

In a highly preferred compound of formula III, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ are independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl) pyridyl and pyrimidinyl groups. You.

In still other highly preferred compounds of formula III, Ar is

Embedded image(Wherein each R₉And R₁₀Is R₉And R₁₀That one of the two is hydrogen
Hydrogen, 4-C₁~ C₃Alkyl, 2-C₁~ C₃Alkoxy, 4-ha
Or 3-trifluoromethyl). R₉And R ₁₀ Is hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro, or
Compounds independently selected from fluoro are even more preferred.

In another group of preferred compounds of formula III, R ₁ and R ₂ are hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulfonyl, sulfonamide, Or independently represents an alkylsulfonamide. Highly preferred groups of such compounds include those in which at least one of R ₁ and R ₂ is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. Particularly preferred compounds of this group include those wherein R ₁ is hydrogen and R ₂ is at the 4- or 6-position on the nitrogen-containing ring structure.

In yet another group of preferred compounds of formula III, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. A preferred group of compounds are those having the above naphthyl, wherein X is NH.

Yet another preferred group of compounds of the invention is represented by Formula IV:

Embedded image Wherein A is C ₂ -C ₆ alkylene optionally substituted with one or two C ₁ -C ₆ alkyl groups, wherein R ₁ and R ₂ are as defined above for formula I R ₃ , R ₄ , R ₅ and R ₆ independently represent hydrogen or C ₁ -C ₃ alkyl, preferably methyl; R ₇ is hydrogen or C ₁ -C ₃ alkyl; R ₈ Is hydrogen or C ₁ -C ₂ alkyl, m is an integer selected from 0, 1 or 2, and Ar is as defined above with respect to formula I).

In further preferred compounds of III, m is 0 or 1, and A is unsubstituted C ₁ -C ₄ , more preferably unsubstituted C ₂ , C ₃ , or C ₄ alkylene.

Particularly preferred compounds of formula III include those wherein Ar is

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. .

In other particularly preferred compounds of III, R ₉ and R ₁₀ are hydrogen,
C ₁ -C _{3 alkyl,} C 1 -C ₃ alkoxy, chloro or fluoro, or is independently selected from trifluoromethyl. In still other highly preferred compounds of formula III, Ar is

Embedded image(Wherein each R₉And R₁₀Is R₉And R₁₀That one of them is not hydrogen
Conditions include hydrogen, 4-C₁~ C₃Alkyl, 2-C₁~ C₃Alkoxy, 4-
Halogen, or independently selected from 3-trifluoromethyl). R ₉ And R₁₀Is hydrogen, methyl, methoxy, ethoxy, isopropoxy,
Compounds independently selected from b or fluoro are even more preferred.

In another group of preferred compounds of formula III, R ₁ and R ₂ are hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulfonyl, sulfonamide, Or independently represents an alkylsulfonamide. Highly preferred groups of such compounds include those in which at least one of R ₁ and R ₂ is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. Particularly preferred compounds of this group include those wherein R ₁ is hydrogen and R ₂ is a non-hydrogen group as defined immediately above, at the 4- or 6-position on the nitrogen-containing ring structure.

In yet another group of preferred compounds of the formula III, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. A preferred group of compounds are those having the above naphthyl, wherein X is NH.

The present invention also provides intermediates useful for preparing compounds of formula I. These intermediates have the formula VIII.

[0038]

Embedded image In Formula VIII, R ₃ , R ₄ , R ₅ , R ₆ , A, m, and Ar are as defined above for Formula I.

In preferred VIII compounds, m is 0 or 1, and A is unsubstituted C ₁ -C ₄ , more preferably unsubstituted C ₂ , C ₃ or C ₄ alkylene.

Particularly preferred compounds of formula VIII include:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. .

In other particularly preferred compounds of VIII, R ₉ and R ₁₀ are independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, chloro or fluoro, or trifluoromethyl . In still other highly preferred compounds of formula VIII, Ar is

Embedded image(Wherein each R₉And R₁₀Is hydrogen, 4-C₁~ C₃Alkyl, 2-C₁~ C ₃ Independently selected from alkoxy, 4-halogen, or 3-trifluoromethyl
Is). R₉And R₁₀Is hydrogen, methyl, methoxy, ethoxy, i
Compounds independently selected from sopropoxy, chloro, or fluoro are furthermore
Is still more preferred.

In yet another group of preferred compounds of formula VIII, Ar is of the formula:

Embedded image Wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl.

In certain circumstances, the compounds of formula I contain one or more asymmetric carbon atoms, and the compounds can exist in different stereoisomeric forms. These compounds are
For example, it may be a racemic form or an optically active form. In these circumstances, single enantiomers, ie, optically active forms, can be obtained by asymmetric synthesis or separation of the racemates. Separation of the racemates can be accomplished by conventional methods, for example, crystallization in the presence of a separating agent, or chromatography, for example, using a chiral HPLC column.

Representative compounds of the present invention encompassed by Formula I include, but are not limited to, the compounds in Table 1 and their pharmaceutically acceptable acid addition salts. Further, when the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, then dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. , Addition salts, especially pharmaceutically acceptable addition salts.

Non-toxic pharmaceutical salts include hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, succinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, iodide hydrochloric acid, and acetic, HOOC- _{(CH 2) (wherein,} n is 0 to 4) n -COOH and salts, such as alkanoic acids, such as. One skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses acylated prodrugs of the compounds of formula I. One skilled in the art will appreciate that Formula I
It will be appreciated that there are a variety of synthetic techniques that can be utilized to produce the non-toxic pharmaceutically acceptable addition salts and acylated prodrugs that are encompassed by.

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

In the present invention, “C ₁ -C ₆ alkyl” or “lower alkyl” is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, 2-pentyl, Isopentyl, neopentyl, hexyl, 2-
A straight or branched chain alkyl group having 1 to 6 carbon atoms such as hexyl, 3-hexyl and 3-methylpentyl is meant. Preferred _C 1 -C ₆ alkyl groups include methyl, ethyl, propyl, butyl, cyclopropyl, and cyclopropylmethyl.

In the present invention, “C ₁ -C ₆ alkoxy” or “lower alkoxy” is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, s-
Linear or branched alkoxy groups having 1 to 6 carbon atoms such as butoxy, t-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy; means. Preferred alkoxy groups in the present invention are C ₁ -C ₄ alkoxy groups.

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

When the substituent is a di (C ₁ -C ₆ ) alkylamino group, the two alkyl groups are the same or different. Representative di (C ₁ -C ₆ ) alkylamino groups include dimethylamino, methylpropylamino, diisopropylamino, and ethylpentylamino.

Aryl means an aromatic carbocyclic group having one ring (eg, phenyl) or two rings (eg, biphenyl). These groups can be unsubstituted or
C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ alkylthio, hydroxy, amino, mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro, trifluoromethyl, tri Substituted with up to 5 groups selected from fluoromethoxy, C ₁ -C ₆ alkylsulfonyl, alkylsulfonamide, and sulfonamide.

In the present invention, heteroaryl (aromatic heterocycle) is a 5-aryl containing at least 1 to 4 and preferably 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur. Means one or more aromatic ring structures of a 5-, 6-, or 7-membered, preferably 5- or 6-membered ring. A heteroaryl Ar group is attached to the parent alkylpiperazine moiety via a carbon atom in the heteroaryl group, preferably a carbon atom adjacent to a heteroatom such as nitrogen. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (iso) oxazolyl,
Pyridyl, pyrimidinyl, (iso) quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.

“C ₁ -C ₆ alkylsulfonyl” has the formula:

Embedded image Means the group

The terms “C ₁ -C ₆ alkylsulfonamide” and “alkylsulfonamide” have the formula:

Embedded image Wherein R _a and R _b independently represent C ₁ -C ₆ alkyl. Preferred C ₁ -C ₆ alkylsulfonamides are methylsulfonamide,
Dimethylsulfonamide and diethylsulfonamide.

The term “sulfonamide” has the formula:

Embedded image Means the group

As used herein, the rules for counting substituents on a nitrogen-containing ring structure are as follows:

Embedded image Table 1 shows representative compounds of the present invention.

[0058]

[Table 1] The invention also relates to the use of the compounds of general formula I in the treatment of psychopsychological disorders. The interaction of the compounds of the invention with the dopamine receptor is shown in the examples. This interaction results in the pharmacological activity of these compounds.

Compounds of general formula I in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients may be administered orally, topically, parenterally, by inhalation or spray, or Can be applied rectally. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Further, 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
One or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and, if desired, other active ingredients can be present. Pharmaceutical compositions containing a compound of general formula I may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or It can be syrup or elixir.

Compositions for oral use can be prepared by any of the methods known in the art for the preparation of pharmaceutical compositions, and such compositions are pharmaceutically elegant and delicious products Can provide one or more agents selected from the group consisting of sweetening, flavoring, coloring and preservative agents. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These adjuvants include, for example, calcium carbonate,
Inert diluents such as sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia;
A lubricant such as magnesium stearate, stearic acid or talc may be used. The tablets may be uncoated or they may be coated by known techniques to provide a sustained action over a longer period of time by delaying disintegration and absorption in the gastrointestinal tract. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.

Formulations for oral use may be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or the active ingredient may be in a water or oil medium. , For example, peanut oil,
It may be provided as a soft gelatin capsule mixed with liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in a mixture with adjuvants suitable for the manufacture of aqueous suspensions. Such adjuvants are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia.
Dispersing or wetting agents include natural phosphatides, such as lecithin; or condensation products of fatty acids and alkylene oxides, such as polyoxyethylene stearate; or condensation products of long-chain fatty alcohols with ethylene oxide, such as heptadecaethyleneoxycetanol Or a condensation product of a partial ester derived from a fatty acid such as polyoxyethylene sorbitol monooleate and hexitol with ethylene oxide; or a condensation product of a partial ester derived from a fatty acid and hexitol anhydride and ethylene oxide, for example, polyethylene It may be sorbitan monooleate. Aqueous suspensions may contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more fragrances, and one or more preservatives such as sucrose or saccharin. Sweetening agents may be included.

Oily suspensions may be formulated by suspending 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.

[0064] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional adjuvants may be present, for example, sweetening, flavoring and coloring agents.

[0065] The pharmaceutical compositions of the invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof.
Suitable emulsifiers are natural gums, for example gum arabic or tragacanth; natural phosphatides, for example soy, lecithin; and esters or partial esters derived from fatty acids and hexitols, anhydrides, for example, sorbitan monooleate; It would be the condensation product of an ester and ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsifier may contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives 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 can be a sterile injectable solution or suspension in a non-toxic parent compound-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and physiological saline. 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 the general formula I can also be applied in the form of suppositories for rectal application of the drug. These compositions are solid at ambient temperature, but liquid at rectal temperature, and can be prepared by mixing the drug with a suitable nonirritating excipient that dissolves in the rectum and releases the drug. it can. Such materials include cocoa butter and polyethylene glycols.

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

[0069] Dosage levels on the order of about 0.1 mg / kg to about 140 mg / kg body weight per day are useful in treating the above indicated conditions (about 0 to about 0 per patient per day).
. 5 mg to about 7 g). The amount of active ingredient that can be combined with the carrier to produce a single dosage form will vary depending upon the host treated, and in particular, its application. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

However, the particular dosage level for a particular patient, any, depends on the activity, age, weight, general health, gender, daily food, application time, application route, and elimination of the particular compound used. It will be appreciated that various factors will vary depending on the rate, combination of drugs, and the severity of the particular disease being treated.

A representative synthesis of the compounds of the invention is shown in Scheme I. Those skilled in the art will appreciate that starting materials can be varied and additional steps can be used to produce compounds encompassed by the present invention.

[0072]

Embedded image

Embedded image Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , X, m and Ar are of the formula I
Is as defined above for L ₁ , L ₂ and L ₃ represent a leaving group described below.

As shown in Scheme I, an N-alkylphthalimide VI substituted with a suitable leaving group L reacts with an appropriately substituted piperazine VII in the presence of a base to give N
-(Piperazinylalkyl) phthalimide VIII can be obtained. VI
The above leaving group L may be a halogen, a trialkylamino group, a sulfonate ester or the like. Any suitable base can be used, and representative bases include inorganic bases such as sodium hydroxide, potassium carbonate and the like, and organic bases such as triethylamine, pyridine and the like.

The phthalimide VIII can be treated with hydrazine or the like to give the amine IX. Amine IX is then substituted with an appropriately substituted formula X having a leaving group L2 at position _2.
To give compounds of formula I. Leaving group L ₂ of the alkylating agent is a halide, it may be a sulfonic acid ester or the like. Conversion of a compound of I where R ₈ is H to a compound of I where R ₈ is alkyl can be accomplished by treating I with a suitable alkyl halide, R ₈ L ₃ .

If they are not commercially available, compounds of the general structures VI, VII and X can be prepared by procedures analogous to those described in the literature.
Compounds of general structure VI, VII and X are all known or can be prepared by methods known in the art. Those skilled in the art will appreciate that starting materials can be varied and additional steps can be used to produce compounds encompassed by the present invention. The base used may be an inorganic base such as potassium carbonate or sodium hydroxide, or an organic base such as triethylamine or pyridine.

Alternatively, a compound of formula X (where L ₂ is NH ₂ ) is reacted sequentially with chloroacetyl chloride and a compound of general structure VII in the presence of a base, followed by reduction to give a compound of formula X Compounds of I (A is ethylene) can be obtained.

Example 1 1- (5-Fluoropyrimidin-2-yl) -4- (4-aminobutyl) piperazine 4-Bromo-N in dimethylformamide (100 mL) containing potassium carbonate (8.2 g) A solution of -butylphthalimide (8.37 g) and 1- (5-fluoropyrimidin-2-yl) piperazine (5.4 g) is stirred at 80 ° C for 12 hours. After cooling, the mixture is poured into water and extracted with ether. Dry the ether phase with sodium sulfate, filter and concentrate to obtain the intermediate as a yellow solid. The resulting phthalamide is then taken up in hydrazine monohydride (100 mL) and refluxed under nitrogen overnight. After cooling, the mixture is poured into a 30% solution of potassium carbonate (500 mL), extracted with methylene chloride, dried and concentrated to give an orange semi-solid (4.66 g). This material is dissolved in a mixture of 10% methanol / isopropanol (50 mL) and treated with fumaric acid (4.25 g, 2 equiv.) To reduce the solvent volume to 20 mL. The resulting yellow crystals are collected by filtration (
6.5 g).

Example 2 1- (5-fluoropyrimidin-2-yl) -4- (2- [6-benzothiazol-2-ylamino] butyl) piperazine difumarate

Embedded image 2- in acetonitrile (10 mL) containing potassium carbonate (300 mg)
Chlorobenzothiazole (920 mg) and 1- (5-fluoropyrimidine-
A solution of 2-yl) -4- (4-aminobutyl) piperazine (254 mg) is refluxed under nitrogen for 10 hours. After cooling, the mixture is concentrated and the residue obtained is partitioned between ethyl acetate and water. Separate the organic phase and extract with 10% citric acid. The acidic aqueous phase is basified with a 10N NaOH solution and extracted with chloroform. The chloroform phase is then dried over sodium sulfate, filtered and concentrated to give a white solid (
0.31 g) to give the title compound. [Also known as benzothiazol-2-yl {4- [4- (5-fluoropyrimidin-2-yl) piperazinyl] butyl}
Amine]. This material is dissolved in 10% methanol / isopropanol and treated with fumaric acid (190 mg). The amount of solvent is partially reduced and the resulting crystals are isolated by filtration (347 mg, mp 168-170 ° C).

Example 3 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-ylamino] ethyl) piperazine difumarate

Embedded image While vigorously stirring a solution of 6-fluoro-2-aminobenzothiazole (5 g) and triethylamine (5 mL) in chloroform (100 mL), a solution of chloroacetyl chloride (5 mL) in chloroform (10 mL) is added dropwise. . The reaction mixture is stirred overnight, filtered and concentrated. The residue is triturated with isopropanol to give an off-white solid (3.82 g).

A part (150 mg, 0.61 mmol) of this solid was acetonitrile (10 m
L), and 1- (2-methoxyphenyl) piperazine (11
8 mg) and potassium carbonate (150 mg) are added. Reflux the mixture overnight. After cooling, the solvent is removed and the residue obtained is partitioned between ethyl acetate and water. The organic phase is dried and evaporated to give a yellow oil, which is purified by preparative thin-layer chromatography, eluting with 9% methanol / chloroform.

After chromatography, the isolated product is dissolved in tetrahydrofuran (5 mL) and the resulting solution is mixed with a 1 M solution of allane in tetrahydrofuran. After 2 hours, the reaction mixture is treated with 20 mL of a 15% sodium hydroxide solution, stirred and extracted with chloroform. Dry and concentrate the organic layer. The residue obtained is 1
Purify by preparative TLC eluting with 0% methanol / chloroform. The resulting oil is dissolved in isopropanol (5 mL) and the solution is treated dropwise with a saturated solution of fumaric acid in methanol until the pH is 3. After 2 hours, difumaric acid 1
-(2-methoxyphenyl) -4- (2- [6-fluorobenzothiazole-2
-Ylamino] ethyl) piperazine crystals (180 mg, mp 169-170 ° C).
) Is recovered as an off-white solid. Compound 2, base, H ¹ NMR (CDCl ₃ ) 7.45 (m, 1H), 7.25 (m, 1H), 6.8-7.05 (m, 5H)
), 6.18 (bs, 1H), 3.85 (s, 3H), 3.55 (m, 2H),
3.0-3.1 (b, 4H), 2.7 (b, 6H).

Example 4 The following compounds are prepared essentially following the procedures of Examples 1-3 described above.

(A) 1- (Pyrimidin-2-yl) -4- (2- [benzothiazole-2-
[Ill] aminoethyl) piperazine difumarate (compound 7, melting point 161-163)
° C).

(B) 1- (pyrimidin-2-yl) -4- (4- [benzothiazol-2-
Yl] aminobutyl) piperazine difumarate (compound 8).

(C) 1- (5-fluoropyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate (compound 9, melting point 1)
74-175 ° C).

(D) 1- (5-Methylpyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate (mp 167-170)
C); [alias: benzothiazol-2-yl {2- [4- (5-methylpyrimidin-2-yl) piperazinyl] ethyl} amine] (compound 10).

(E) 1-phenyl-4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate (melting point: 131 to 132 ° C.); [alias: benzothiazol-2-yl [2 -(4-phenylpiperazinyl) ethyl] amine (compound 1
1).

(F) 1- (pyridin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate (mp 159-160 ° C.); [benzothiazole-2 -Yl [2- (4- (2-pyridyl) piperazinyl) ethyl]
Amine] (Compound 12).

(G) 1- (4-chlorophenyl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine dihydrochloride (mp 230-232 ° C.); [benzothiazol-2-yl} 2 -[4- (4-Chlorophenyl) piperazinyl] ethyldiamine] (compound 13).

(H) 1- (4-Fluorophenyl) -4- (2- [benzothiazole-2-
Yl] aminoethyl) piperazine dihydrochloride (mp 229-231 ° C); [benzothiazol-2-yl {2- [4- (4-fluorophenyl) piperazinyl] ethyl} amine] (compound 14).

(I) 1- (2-methoxyphenyl) -4- (2- [benzothiazole-2-
[Benzoyl] aminoethyl) piperazine difumarate (melting point 101-103 ° C); [benzothiazol-2-yl {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} amine] (compound 15).

(J) 1- (2-methoxyphenyl) -4- (3- [benzothiazole-2-
[Yl] aminopropyl) piperazine hydrobromide (mp 195-197 ° C);
Benzothiazol-2-yl {3- [4- (2-methoxyphenyl) piperazinyl] propyl} amine] (compound 16).

(K) 1- (2-methoxyphenyl) -4- (2- [4-methoxybenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 17, melting point 1
71-173 ° C).

(L) 1- (2-methoxyphenyl) -4- (2- [4-methylbenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 18, melting point 22
6-227 ° C).

(M) 1- (2-methoxyphenyl) -4- (2- [4-chlorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromic acid (Compound 19, melting point 19)
[(4-chlorobenzothiazol-2-yl) {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} amine].

(N) 1- (2-methoxyphenyl) -4- (2- [6-ethoxybenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 20, melting point 2
27-228 ° C).

(O) 1- (2-methoxyphenyl) -4- (2- [6-methylsulfonylbenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 21
[2-({2- [4- (2-methoxyphenyl) piperazinyl] ethyl} amino) -6- (methylsulfonyl) benzothiazole].
.

(P) 1- (Pyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine difumarate (Compound 22, melting point 179-180 ° C.) [(6-fluorobenzothiazol-2-yl) [2- (
4-pyrimidin-2-ylpiperazinyl) ethyl] amine] (q) 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine difumarate (compound 23, melting point 169-170 ° C).

(R) 1-benzyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine difumarate (compound 24, melting point 228-229 ° C.)
).

(S) 1- (4-chlorobenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 25, mp 2
38-240 ° C).

(T) 1- (2-ethoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 26, melting point 235-237 ° C.) .

(U) 1- (5-Fluoropyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 27, mp 279) ２８281 ° C.).

(V) 1- (5-Methylpyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 28, mp 240 ２５０250 ° C.).

(W) 1- (pyridin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 29, melting point 2
59-260 ° C).

(X) 1- (3-trifluoromethylphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 30, melting point 259-261) ° C).

(Y) 1-phenyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 31, melting point 268-270 ° C.)
).

(Z) 1- (4-Fluorophenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 32, melting point 270-271 ° C.) .

(Aa) 1- (2-Isopropoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 3
3, melting point: 216 to 217 ° C); [alias: (6-fluorobenzothiazole-2-
Yl) [2- (4-{[2- (methylethoxy) phenyl] methyl} piperazinyl) ethyl] amine].

(Bb) 1- (2-methoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 34).

(Cc) 1- (2-isopropoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide;
Fluorobenzothiazol-2-yl) [2- (4-{[2- (methylethoxy) phenyl] methyl} piperazinyl) ethyl] amine] (compound 35).

(Dd) 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzoxazol-2-yl] aminoethyl) piperazine hydrochloride; [alias: (6-fluorobenzoxazol-2-yl) ) {2- [4- (2-Methoxyphenyl) piperazinyl] ethyl} amine] (compound 36).

(Ee) 1- (pyrimidin-2-yl) -4- (2- [benzoxazole 2
-Yl] aminoethyl) piperazine hydrochloride (compound 37, mp 197-202 ° C)
[Alias: benzoxazol-2-yl [2- (4-pyrimidin-2-ylpiperazinyl) ethyl] amine].

(Ff) 1- (pyridin-2-yl) -4- (2- [benzoxazole2-
Yl] aminoethyl) piperazine hydrochloride (melting point 255-265 ° C); [alias: benzoxazol-2-yl [2- (4- (2-pyridyl) piperazinyl) ethyl] amine] (compound 3).

(Gg) 1- (2-methoxyphenyl) -4- (2- [benzimidazole-
2-yl] aminoethyl) piperazine hydrobromide (compound 38, melting point 215-
216 [deg.] C); [benzimidazol-2-yl {2- [4- (2-methoxyphenyl) piperazinyl] ethyl} amine].

(Hh) 1-phenyl-4- (2- [benzimidazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 39, mp 241-247 ° C).

(Ii) 1- (pyridin-2-yl) -4- (2- [benzimidazole-2
-Yl] aminoethyl) piperazine hydrobromide (compound 42, mp 290-2
91 ° C).

(Jj) 1- (pyridin-2-yl) -4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide; (1-ethylbenzimidazole-2) -Yl) [2- (4- (2-pyridyl) piperazinyl) ethyl] amine] (compound 41).

(Kk) 1- (pyridin-2-yl) -4- (2- [1-isopropylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 42
).

(11) 1- (2-methoxyphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 43, mp 273-274 ° C.) .

(Mm) 1- (2-Isopropoxylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 44, mp 285 ° C., Disassembly).

(Nn) 1- (3-trifluoromethylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (Compound 1, melting point 283 ° C. Decomposition); [alias: (1-methylbenzimidazole-2-
Yl) (2- {4- [3- (trifluoromethyl) phenyl] piperazinyl} ethyl) amine].

(Oo) 1- (2-methoxyphenyl) -4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (compound 45, melting point 109-110 ° C.) .

(Pp) 1-phenyl-4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide (compound 46, melting point 270 ° C, decomposition).

(Qq) 1-phenyl-4- (2- [1-isopropylbenzimidazole-
2-yl] aminoethyl) piperazine hydrobromide (Compound 47).

(Rr) Benzothiazol-2-yl [2- (4- (2-naphthyl) piperazinyl) ethyl] amine (Compound 4).

Example 5 The following salts were prepared essentially according to the procedures of Examples 1 to 6 described above and, if necessary, with reference to literature methods for preparing pharmaceutically acceptable salts. did.

1- (5-Fluoropyrimidin-2-yl) -4- (2- [6-benzothiazol-2-ylamino] butyl) piperazine (Compound 48).

1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-ylamino] ethyl) piperazine (Compound 49).

(A) 1- (Pyrimidin-2-yl) -4- (2- [benzothiazole-2-
Yl] aminoethyl) piperazine (compound 50).

(B) 1- (pyrimidin-2-yl) -4- (4- [benzothiazol-2-
Yl] aminobutyl) piperazine (compound 51).

(C) 1- (5-Fluoropyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine (Compound 52).

(D) 1- (5-Methylpyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine (Compound 53).

(E) 1-phenyl-4- (2- [benzothiazol-2-yl] aminoethyl) piperazine (Compound 54).

(F) 1- (Pyridin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine (Compound 55).

(G) 1- (4-Chlorophenyl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine (Compound 56).

(H) 1- (4-Fluorophenyl) -4- (2- [benzothiazole-2-
Yl] aminoethyl) piperazine (compound 57).

(I) 1- (2-methoxyphenyl) -4- (2- [benzothiazole-2-
Yl] aminoethyl) piperazine (compound 58).

(J) 1- (2-methoxyphenyl) -4- (3- [benzothiazole-2-
Yl] aminopropyl) piperazine (compound 59).

(K) 1- (2-methoxyphenyl) -4- (2- [4-methoxybenzothiazol-2-yl] aminoethyl) piperazine (Compound 60).

(L) 1- (2-methoxyphenyl) -4- (2- [4-methylbenzothiazol-2-yl] aminoethyl) piperazine (Compound 61).

(M) 1- (2-methoxyphenyl) -4- (2- [4-chlorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 62).

(N) 1- (2-methoxyphenyl) -4- (2- [6-ethoxybenzothiazol-2-yl] aminoethyl) piperazine (Compound 63).

(O) 1- (2-methoxyphenyl) -4- (2- [6-methylsulfonylbenzothiazol-2-yl] aminoethyl) piperazine (Compound 64).

(P) 1- (Pyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 65).

(Q) 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 66).

(R) 1-benzyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 67).

(S) 1- (4-Chlorobenzyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 68).

(T) 1- (2-ethoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 69).

(U) 1- (5-Fluoropyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 70).

(V) 1- (5-Methylpyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 71).

(W) 1- (pyridin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 72).

(X) 1- (3-trifluoromethylphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 73).

(Y) 1-phenyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 74).

(Z) 1- (4-Fluorophenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 75).

(Aa) 1- (2-Isopropoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 76).

(Bb) 1- (2-methoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 77).

(Cc) 1- (2-Isopropoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine (Compound 78).

(Dd) 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzoxazol-2-yl] aminoethyl) piperazine (Compound 79).

(Ee) 1- (pyrimidin-2-yl) -4- (2- [benzoxazole 2
-Yl] aminoethyl) piperazine (Compound 80).

(Ff) 1- (pyridin-2-yl) -4- (2- [benzoxazole2-
Yl] aminoethyl) piperazine (compound 81).

(Gg) 1- (2-methoxyphenyl) -4- (2- [benzimidazole-
2-yl] aminoethyl) piperazine (Compound 82).

(Hh) 1-phenyl-4- (2- [benzimidazol-2-yl] aminoethyl) piperazine (Compound 83).

(Ii) 1- (pyridin-2-yl) -4- (2- [benzimidazole-2
-Yl] aminoethyl) piperazine (compound 84).

(Jj) 1- (pyridin-2-yl) -4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 85).

(Kk) 1- (pyridin-2-yl) -4- (2- [1-isopropylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 86).

(11) 1- (2-Methoxyphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 87).

(Mm) 1- (2-Isopropoxylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 88).

(Nn) 1- (3-trifluoromethylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 89).

(Oo) 1- (2-methoxyphenyl) -4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 90).

(Pp) 1-phenyl-4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine (Compound 91).

(Qq) 1-phenyl-4- (2- [1-isopropylbenzimidazole-
2-yl] aminoethyl) piperazine (compound 92).

Example 6 Analysis of D ₂ , D ₃ and D ₄ Receptor Binding Activity A pellet of Kos cells containing human recombinant D ₂ or D ₄ receptor is used for the analysis. 0.05 M Tris HCl buffer, pH 7.4 at 4 ° C., 100 volumes (w
/ Vol), homogenize the sample. Then, the sample was 30,000 x
Centrifuge at g, resuspend and homogenize again. After that, the sample was
Centrifuge again at 00 × g and freeze the final tissue sample until use. Samples were prepared in 0.05 M Tris HCl buffer containing 100 mM NaCl in a 1:
Resuspend at 20 (wt / vol).

Incubations were performed at 48 ° C. and 0.4 mL of tissue sample, 0.5 nM ³ H-YM 091511-2 (nemonapride, cis-5-chloro-2-methoxy-4 in 1.0 mL of total incubation). -(Methylamino) -N- (2-
Methyl-2- (phenylmethyl) -3-pyrrolidinyl) benzamide) and the compounds of interest. Non-specific binding is defined as binding seen in the presence of 1 mM spiperone, and without further addition, non-specific binding is less than 20% of total binding. The binding properties of the samples of the present invention for D ₂ and D ₄ receptor subtype relates rat striatal homogenates are shown in Table 2.

[0174]

[Table 2] coupling constants for _{D 4} receptor of the compounds of the formula I represented by nM units, generally ranging from about 0.1 nanomolar (nM) of about 75 nanomolar (nM). Preferably, such compounds have a binding constant of about 0.1 to 20 nM. These compounds typically have binding constants for D ₂ receptor of at least about 100 nM. Accordingly, the compounds of the present invention are generally D ₄ selective about 10 times or more for the receptor than for D ₂ receptors. Preferably, these compounds are at least 20 times the _{D 4} receptor than for _{D 2} receptors, more preferably at least 25-50 fold selective. Most preferably, the compound of Formula I is at least 500 fold selective for D ₄ receptors than for D ₂ receptors.

The present invention, and the present methods and processes for making and using it, are now fully, clearly, concisely, and accurately described so that any person skilled in the art could make and use it. Explained in words. It is to be understood that the foregoing describes preferred embodiments of the invention, and that modifications can be made to the invention without departing from the spirit and scope of the invention, which is set forth in the following claims. Will be understood. For the purpose of illustrating and clearly claiming the subject matter regarded as the invention, reference is made to the following claims.

──────────────────────────────────────────────────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 C07D 263/58 C07D 263/58 277/82 277/82 401/12 401/12 413/12 413/12 417/12 417/12 (81) Designated country 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, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AE, AL, AM, AT, AU AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, 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, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference ) 4C033 AE13 AE17 AE20 4C056 CA25 4C063 AA01 AA03 BB09 CC34 CC52 CC62 DD12 DD26 DD29 DD34 EE01 4C086 AA01 AA02 AA03 BC50 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZA02 ZA05 ZA12 ZA15 ZA18 ZC

Claims (30)

[Claims] 1. The formula: embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₁And R₂Are the same or different and are hydrogen, halogen, C₁~ C₆ Alkyl, C₁~ C₆Alkoxy, C₁~ C₆Alkylthio, hydroxy, ami
No, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, C₁~ C ₆ Alkylsulfonyl, sulfonamide, perfluoro C₁~ C₆Alkyl
Is perfluoro C₁~ C₆Represents alkoxy, R₃, R₄, R₅And R₆Are the same or different and hydrogen or C₁ ~ C₆Represents alkyl, and X is sulfur, oxygen or NR₇(Where R₇Is hydrogen or C₁~ C₆Al
Kill)) and R₈Is hydrogen or C₁~ C₆M is 0, 1 or 2; and Ar is each optionally C₁~ C₆Alkyl, C₁~ C₆Alkoxy,
Halogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C ₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Lomethoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyl
Monocyclic or independently substituted with up to 5 groups selected from sulfonamides
Represents a bicyclic aryl or heteroaryl) or a pharmaceutical thereof.
And acceptable salts. 2. The compound according to claim 1, wherein A is unsubstituted C ₁ -C ₄ alkylene. 3. The compound according to claim 1, wherein A is C ₂ , C ₃ or C ₄ alkylene. 4. Ar is: embedded image 4. The method of claim 3, wherein each R ₉ and R ₁₀ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl. A compound as described. 5. R₉And R₁₀Is hydrogen, C₁~ C₃Alkyl, C₁~ C ₃ Independent from alkoxy, chloro or fluoro, or trifluoromethyl
The compound according to claim 4, which is selected from the group consisting of: 6. Ar is represented by the formula: (Wherein each _{R 9} and _{R 10,} on condition that one of _{R 9} and _{R 10} are hydrogen, hydrogen, _4-C 1 ~C ₃ alkyl, _2-C 1 ~C ₃ alkoxy, 4- Selected from halogen or 3-trifluoromethyl). 7. R ₉ and R ₁₀ are hydrogen, methyl, methoxy, ethoxy,
7. The compound according to claim 6, wherein the compound is independently selected from isopropoxy, chloro, or fluoro. 8. R ₁ and R ₂ independently represent hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulfonyl, sulfonamide, or alkylsulfonamide A compound according to claim 3. 9. The compound according to claim 8, wherein at least one of R ₁ and R ₂ is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy, or methylsulfonyl. 10. The compound according to claim 9, wherein R ₁ is hydrogen and R ₂ is at the 4- or 6-position on the nitrogen-containing ring structure. 11. The formula: embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₁And R₂Are the same or different and are hydrogen, halogen, C₁~ C₆ Alkyl, C₁~ C₄Alkoxy, C₁~ C₆Alkylthio, hydroxy, ami
No, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, C₁~ C ₆ Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoro
Represents romethoxy, R₃, R₄, R₅And R₆Are the same or different, and hydrogen or methyl
And R₈Is hydrogen or C₁~ C₆M is 0, 1 or 2; and Ar is each optionally C₁~ C₆Alkyl, C₁~ C₆Alkoxy,
Halogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C ₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Lomethoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyl
Monocyclic or independently substituted with up to 5 groups selected from sulfonamides
Represents a bicyclic aryl or heteroaryl).
Compound. 12. The compound of claim 11, wherein when R ₁ -R ₆ are hydrogen, A is ethylene, R ₈ is hydrogen, and m is 0, Ar is not unsubstituted phenyl. . 13. Ar is represented by the formula: (Wherein each _{R 9} and _{R 10} are _hydrogen, C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy, halogen or trifluoromethyl independently selected from,) of claim 3 wherein Compound. 14. The compound according to claim 13, wherein X is NH. 15. The formula: embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₁And R₂Are the same or different and are hydrogen, halogen, C₁~ C₆ Alkyl, C₁~ C₄Alkoxy, C₁~ C₆Alkylthio, hydroxy, ami
No, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, C₁~ C ₆ Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoro
Represents romethoxy, R₃, R₄, R₅And R₆Are the same or different, and hydrogen or methyl
And R₈Is hydrogen or C₁~ C₆M is 0, 1 or 2; and Ar is each optionally C₁~ C₆Alkyl, C₁~ C₆Alkoxy,
Halogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C ₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Lomethoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyl
Monocyclic or independently substituted with up to 5 groups selected from sulfonamides
Represents a bicyclic aryl or heteroaryl).
Compound. 16. The formula: embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₁And R₂Are the same or different and are hydrogen, halogen, C₁~ C₆ Alkyl, C₁~ C₄Alkoxy, C₁~ C₆Alkylthio, hydroxy, ami
No, mono- or di (C₁~ C₆) Alkylamino, cyano, nitro, C₁~ C ₆ Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoro
Represents romethoxy, R₃, R₄, R₅And R₆Are the same or different, and hydrogen or methyl
R₇Is hydrogen or C₁~ C₆Alkyl and R₈Is hydrogen or C₁~ C₆M is 0, 1 or 2; and Ar is each optionally C₁~ C₆Alkyl, C₁~ C₆Alkoxy,
Halogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C ₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Lomethoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyl
Monocyclic or independently substituted with up to 5 groups selected from sulfonamides
Represents a bicyclic aryl or heteroaryl).
Compound. 17. 1- (pyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine, 1- (pyrimidin-2-yl) -4- (4- [benzo] Thiazol-2-yl]
Aminobutyl) piperazine, 1- (5-fluoropyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine, 1- (5-fluoropyrimidin-2-yl) -4 -(4- [benzothiazol-2-yl] aminobutyl) piperazine, 1- (5-methylpyrimidin-2-yl) -4- (2- [benzothiazol-
2-yl] aminoethyl) piperazine, 1-phenyl-4- (2- [benzothiazol-2-yl] aminoethyl) piperazine, or 1- (pyridin-2-yl) -4- (2- [benzothiazole -2-yl] aminoethyl) piperazine. 18. 18- (4-chlorophenyl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine, 1- (4-fluorophenyl) -4- (2- [benzothiazole-2] -Ill]
Aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [benzothiazol-2-yl]
Aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (3- [benzothiazol-2-yl]
Aminopropyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [4-methoxybenzothiazol-2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [ 4-methylbenzothiazole-
2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [4-chlorobenzothiazole-
2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [6-ethoxybenzothiazol-2-yl] aminoethyl) piperazine, or 1- (2-methoxyphenyl) -4 The compound according to claim 1, which is-(2- [6-methylsulfonylbenzothiazol-2-yl] aminoethyl) piperazine. 19. 19- (Pyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [6-Fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1-benzyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (4-chlorobenzyl-4) -(2- [6-Fluorobenzothiazole-2
-Yl] aminoethyl) piperazine, 1- (2-ethoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (5-fluoropyrimidin-2-yl) -4- (2- [6-Fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (5-methylpyrimidin-2-yl) -4- (2- [6-fluorobenzothiazol-2-yl) ] Aminoethyl) piperazine, or 1- (pyridin-2-yl) -4- (2- [6-fluorobenzothiazole-
2-yl] aminoethyl) piperazine. 20. 1- (3-trifluoromethylphenyl) -4- (2- [
6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1-phenyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (4-fluorophenyl) -4 -(2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine, 1- (2-isopropoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine 1- (2-methoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine; 1- (2-isopropoxybenzyl) -4- (2- [6-fluoro Benzothiazol-2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [6-fluorobenz Xazol-2-yl] aminoethyl) piperazine, 1- (pyridin-2-yl) -4- (2- [benzoxazol-2-yl] aminoethyl) piperazine, or 1- (pyrimidin-2-yl) -4- (2- [benzoxazol-2-yl]
The compound according to claim 1, which is (aminoethyl) piperazine. 21. 1- (2-methoxyphenyl) -4- (2- [benzimidazol-2-yl] aminoethyl) piperazine, 1-phenyl-4- (2- [benzimidazol-2-yl] amino ethyl)
Piperazine, 1- (pyridin-2-yl) -4- (2- [benzimidazol-2-yl]
Aminoethyl) piperazine, 1- (pyridin-2-yl) -4- (2- [1-ethylbenzimidazole-
2-yl] aminoethyl) piperazine, 1- (pyridin-2-yl) -4- (2- [1-isopropylbenzimidazol-2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4 -(2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine, 1- (2-isopropoxylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) Piperazine, 1- (3-trifluoromethylphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2- [1 -Ethylbenzimidazol-2-yl] aminoethyl) piperazine, 1-phenyl-4- (2- [1-ethylbenzimidazol-2-yl) Aminoethyl) piperazine or 1-phenyl-4- (2- [1-isopropyl-benzimidazol-2-yl] aminoethyl) compound of claim 1 which is piperazine. 22. The formula: embedded image(Where A is one or two C₁~ C₆C optionally substituted with an alkyl group₁~ C₆ Alkylene; R₃, R₄, R₅And R₆Are the same or different and hydrogen or C₁ ~ C₆Represents alkyl, and m is 0, 1 or 2; and Ar is each optionally₁~ C₆Alkyl, C₁~ C₆Alkoxy,
Halogen, C₁~ C₆Alkylthio, hydroxy, amino, mono- or di (C ₁ ~ C₆) Alkylamino, cyano, nitro, trifluoromethyl, trifluoro
Lomethoxy, C₁~ C₆Alkylsulfonyl, sulfonamide, or alkyl
Monocyclic or independently substituted with up to 5 groups selected from sulfonamides
Represents a bicyclic aryl or heteroaryl). 23. A method of treating and / or preventing a psychopsychological disorder, comprising administering to a host in need of such treatment an effective amount of a compound of claim 1. 24. A psychiatric disorder comprising schizophrenia, mania, dementia, depression,
Anxiety, coercive behavior, memory impairment, cognitive impairment, substance abuse, Parkinson-like dyskinesia,
24. The method of claim 23, wherein the method is selected from dyskinesia associated with the use of neuroleptics. 25. Use of a compound according to claim 1 for the manufacture of a medicament for use in treating a psychopsychological disorder. 26. 1- (5-fluoropyrimidin-2-yl) -4- (2-
[6-benzothiazol-2-ylamino] butyl) piperazine difumarate, 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-ylamino] ethyl) piperazine difumarate 1- (pyrimidin-2-yl) -4- (2- [benzothiazol-2-yl]
Aminoethyl) piperazine difumarate, 1- (pyrimidin-2-yl) -4- (4- [benzothiazol-2-yl]
Aminobutyl) piperazine difumarate, 1- (5-fluoropyrimidin-2-yl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate, 1- (5-methyl Pyrimidin-2-yl) -4- (2- [benzothiazole-
2-yl] aminoethyl) piperazine difumarate, 1-phenyl-4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate, 1- (pyridin-2-yl) -4 -(2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate, 1- (4-chlorophenyl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine dihydrochloride, or 1- (4-fluorophenyl) -4- (2- [benzothiazol-2-yl]
The salt according to claim 1, which is (aminoethyl) piperazine dihydrochloride. 27. 1- (2-methoxyphenyl) -4- (2- [benzothiazol-2-yl] aminoethyl) piperazine difumarate, 1- (2-methoxyphenyl) -4- (3- [Benzothiazol-2-yl]
Aminopropyl) piperazine hydrobromide, 1- (2-methoxyphenyl) -4- (2- [4-methoxybenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (2- Methoxyphenyl) -4- (2- [4-methylbenzothiazole-
2-yl] aminoethyl) piperazine hydrobromide, 1- (2-methoxyphenyl) -4- (2- [4-chlorobenzothiazole-
2-yl] aminoethyl) piperazine hydrobromide, 1- (2-methoxyphenyl) -4- (2- [6-ethoxybenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1 -(2-methoxyphenyl) -4- (2- [6-methylsulfonylbenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (pyrimidin-2-yl) -4- (2- [6-Fluorobenzothiazol-2-yl] aminoethyl) piperazine difumarate, 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazinedi Fumarate, 1-benzyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine difumarate, or 1- (4-chloro Njiru) -4- (2- [6-fluoro-benzothiazole -
2-yl] aminoethyl) piperazine hydrobromide. 28. 1- (2-ethoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (5-fluoropyrimidine-2- Yl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (5-methylpyrimidin-2-yl) -4- (2- [6- Fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (pyridin-2-yl) -4- (2- [6-fluorobenzothiazol-
2-yl] aminoethyl) piperazine hydrobromide, 1- (3-trifluoromethylphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide 1-phenyl-4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide; 1- (4-fluorophenyl) -4- (2- [6-fluorobenzo Thiazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (2-isopropoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide Salt, 1- (2-methoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-yl] aminoethyl) piperazine hydrobromide, or 1- (2 Isopropoxyphenyl) -4- (2-salt according to claim 1 [6-fluoro-benzothiazol-2-yl] aminoethyl) piperazine hydrobromide. 29. 1- (2-methoxyphenyl) -4- (2- [6-fluorobenzoxazol-2-yl] aminoethyl) piperazine hydrochloride, 1- (pyrimidin-2-yl) -4- (2 -[Benzoxazol-2-yl]
Aminoethyl) piperazine hydrochloride, 1- (pyridin-2-yl) -4- (2- [benzoxazol-2-yl] aminoethyl) piperazine hydrochloride, 1- (2-methoxyphenyl) -4- (2- [Benzimidazol-2-yl] aminoethyl) piperazine hydrobromide, 1-phenyl-4- (2- [benzimidazol-2-yl] aminoethyl)
Piperazine hydrobromide, 1- (pyridin-2-yl) -4- (2- [benzimidazol-2-yl]
Aminoethyl) piperazine hydrobromide, 1- (pyridin-2-yl) -4- (2- [1-ethylbenzimidazole-
2-yl] aminoethyl) piperazine hydrobromide, 1- (pyridin-2-yl) -4- (2- [1-isopropylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (2-methoxyphenyl) -4- (2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide or 1- (2-isopropoxylphenyl) -4- ( The salt according to claim 1, which is 2- [1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide. 30. 1- (3-trifluoromethylphenyl) -4- (2- [
1-methylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide, 1- (2-methoxyphenyl) -4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine odor 1-phenyl-4- (2- [1-ethylbenzimidazol-2-yl] aminoethyl) piperazine hydrobromide, 1-phenyl-4- (2- [1-isopropylbenzimidazole) -2-yl] aminoethyl) piperazine hydrobromide.