JP2002534421A - 1-phenyl-4- (1- [2-aryl] cyclopropyl) methylpiperazine: dopamine receptor ligand - Google Patents

Abstract

(57) [Summary] (I) Disclosed are compounds of formula I wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , R ₆ , R ₇ and R ₈ are defined herein. Or pharmaceutically acceptable addition salts thereof, and the compounds include, but are not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse , Parkinson-like dyskinesia, and neuropsychological disorders, including dyskinesias associated with the use of neurostabilizers.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to 1-phenyl-4- (1- [2-aryl] cyclopropyl) methylpiperazine derivatives and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychological disorders such as schizophrenia and other central nervous system diseases.

2. Description of the Related Art The therapeutic effect of conventional antipsychotics, known as neurostabilizers, is generally thought to be exerted through dopamine receptor blockade. But neuroleptics often cause undesirable extrapyramidal side effects (EPS) and tardive dyskinesia, and it is attributed to the blockade of D ₂ receptors in striatal regions of the brain. Dopamine _{D 4} receptors subtypes has been confirmed recently (Nature, 350: 610 (V
and Tol et al., 1991); Nature, 347: 146 (Sokolof).
f et al., 1990)). Its sole position measurement and distinguished recognition of its various antipsychotic in brain edge region, D ₄ receptor, indicating that play an important role in schizophrenia etiology. Selective D ₄ antagonist is considered conventional nerve without neurological side effects as indicated by a stable drug effective antipsychotics.

SUMMARY OF THE INVENTION [0003] The present invention provides novel compounds of formula I that interact with a dopamine variant. Accordingly, a first aspect of the present invention provides a compound of the formula:

Embedded image I wherein R ₁ and R ₂ are the same or different and are 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, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
Represents alkoxy; R ₃ and R ₄ are the same or different and are hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, hydroxy, amino , Mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
And A represents an alkylene group of 1-3 carbon atoms; and R ₅ , R ₆ , R ₇ , and R ₈ are the same or different and represent hydrogen or C ₍ Representing _1- C ₆ alkyl).

[0004] The dopamine D ₄ receptor is a limbic system that controls cognition and emotion (Science
265: 1034 (Taubes, 1994)). Therefore,
Compounds that interact with these receptors are useful for treating cognitive disorders. Such disorders include cognitive deficits that are important components of the negative symptoms of schizophrenia (social abandonment and nonresponsiveness). Other disorders include those involved in memory impairment or attention deficit disorder.

The compounds of the present invention represents a high affinity and selectivity in combining the D ₄ receptor subtypes. Thus, these compounds are useful in treating a variety of neuropsychological disorders such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-dependent diseases such as Parkinson's disease and tardive dyskinesia also by adjusting the D ₄ receptor, directly or indirectly treatable.

The compounds of the present invention, because they selectively exerted in an area known to control emotion and cognitive functions, by adjusting the D ₄ receptor, depression, in the treatment of memory disorders or Alzheimer's disease Useful.

[0007] Thus, in another aspect, the invention relates to, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like movement disorders, such as Parkinson's disease and ataxia Methods for treating and / or preventing neuropsychological or emotional disorders, including disorders, and movement disorders associated with the use of neural stabilizers. In addition, the compounds of the invention are useful for treating depression, memory impairment or Alzheimer's disease. In addition, the compounds of the invention are useful in treating other disorders that respond to dopaminergic blockade, such as, for example, drug abuse and obsessive-compulsive disorder. These compounds are also useful for treating extrapyramidal side effects associated with the use of conventional neuroleptics.

In addition, when appropriately labeled, the compounds of the invention are useful as probes for localization of dopamine receptors. Receptor localization was performed in vitro
For example, via autoradiography of tissue sections, or in vivo, via positron emission tomography (PET).

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

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

The present invention also provides a method for preparing a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of Formula I described above.

A preferred compound of formula I is R₅, R₆, R₇, And R₈But C₁−
C₃Alkyl, and more preferably hydrogen or methyl. formula
Even more preferred compounds represented by I are R₅, R₆, R₇, And R₈ Is hydrogen. In more preferred compounds of the formula I,
R₅And R₈Are in trans configuration to each other. In particular of the formula I
Preferred compounds are those wherein R is hydrogen, halogen, or lower alkyl.₁, R₂, R ₃ , And R₄Having.

In other preferred compounds of formula I, when R ₁ and R ₃ -R ₈ are all hydrogen, R ₂ is not tert-butyl, or more preferably C _1-
Not a C ₆ alkyl.

Further, the present invention provides a compound of formula II:

Embedded image II wherein R ₁ and R ₂ are the same or different and are 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, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
Represents alkoxy; R ₃ and R ₄ are the same or different and are hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino , Mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
Represents alkoxy; and R ₅ , R ₆ , R ₇ , and R ₈ are the same or different and represent hydrogen or C ₁ -C ₃ alkyl; provided that R ₁ and R ₃ -R _{When 8} are all hydrogen, R ₂ is not t-butyl).

In preferred compounds of formula II, R ₅ and R ₆ are trans to each other. In an even more preferred compound of formula II, R ₅ , R ₆ , R ₇ , and R ₈ are hydrogen or methyl. Further preferred compounds of formula II are
R ₅ , R ₆ , R ₇ , and R ₈ are those wherein they are hydrogen. In the most preferred compounds of formula I, hydrogen in position R ₅ and R ₈ are in trans configuration to each other. Particularly preferred compounds of formula I have a hydrogen, halogen or _R 1 as lower _alkyl, R 2, _{R 3,,} and _{R 4.}

In another preferred compound of formula I, _one of R ₁ and R ₂ can be halogen, preferably in the para position on the phenyl ring, while the other is
Hydrogen. In these preferred compounds, R ₃ and R ₄ are preferably in the para position and in the ortho position, ie, one of the 4 and 2 positions with respect to the point of attachment to the phenyl ring, and hydrogen, halogen or C ₁ -C ₃ alkyl, provided that at least one of R ₃ and R ₄ is not hydrogen.

Further, the present invention provides a compound of formula III:

Embedded image III where R₁And R₂Is independently hydrogen, halogen, C₁-C₃Alkyl, C₁-C ₄ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Which represents alkyl).

Preferred compounds of formula III are those in which R ₁ and R ₂ are independently hydrogen, halogen, methyl or ethyl. In further preferred compounds of formula III, R ₁ and R ₂ are both hydrogen.

In other preferred compounds of formula III, at least one of R ₁ and R ₂ is not hydrogen. In further preferred compounds of formula III, at least one of R ₁ and R ₂ is not hydrogen, ie, it is halogen, C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino, mono - or di _(C 1 -C ₆₎ alkylaminocarbonyl, is cyano, nitro, a perfluoro _(C 1 -C ₆₎ alkyl and perfluoro _(C 1 -C ₆₎ alkoxy, and _{R 3} And R ₄ are at positions 2 and 4 on the phenyl group. In these more preferred compounds of formula III, R ₅ , R ₆ , R ₇ and R ₈ are hydrogen or methyl. Further, in these more preferred compounds of formula III, R ₅ and R ₈ are trans to each other.

Further, the present invention provides a compound of formula IV:

Embedded image IV (where R₁And R₂Is independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C ₆ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Which represents alkyl).

Preferred compounds of the formula IV are those wherein R ₁ and R ₂ are independently hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino, mono- or di (C ₁ -C ₆₎ alkylamino, cyano, and represents a nitro or perfluoro _(C 1 -C ₆₎ alkoxy. Further preferred compounds of formula IV are those wherein R ₅ , R ₆ , R ₇ , and R ₈ are hydrogen or methyl. In preferred compounds of formula IV, R ₅ and R ₈ are trans to each other.

Other more preferred compounds of formula IV are R₃Is hydrogen, halogen, C ₁ -C₃Alkyl, or C₁-C₃Which is an alkoxy. Table in Formula IV
Particularly preferred compounds are₄Is hydrogen, halogen, C₁-C₃Alkyl,
Or C₁-C₃Alkoxy and R₃Is hydrogen, halogen, C₁-C ₃ Alkyl, or C₁-C₃Which is an alkoxy.

Other preferred compounds of formula IV are those wherein R ₃ represents hydrogen, chloro or methyl. Still other preferred compounds of formula IV are those wherein R ₄ is
Represents hydrogen, bromo, chloro, methyl, nitro, or amino. Formula I
Particularly preferred compounds represented by V are those wherein R ₃ represents hydrogen, chloro or methyl and R ₄ represents hydrogen, bromo, chloro, methyl, nitro or amino.

Further, the present invention provides a compound of formula V:

Embedded image Va (where R₁And R₂Is independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C ₆ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Which represents alkyl).

Preferred compounds of formula Va are those wherein R ₁ and R ₂ are independently hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino,
Mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro or perfluoro (C ₁ -C ₆ ) alkoxy. Further preferred compounds of formula Va are those wherein R ₅ , R ₆ , R ₇ , and R ₈ are hydrogen or methyl. In preferred compounds of formula Va, R ₅ and R ₈ are trans to each other.

Other more preferred compounds of formula Va are those wherein R ₃ is hydrogen, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy. Particularly preferred compounds of formula Va are those wherein R ₄ is hydrogen, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy, and R ₃ is hydrogen, halogen, C ₁ -C _3. Alkyl or C ₁ -C ₃ alkoxy.

Other preferred compounds of formula Va are those wherein R ₃ represents hydrogen, chloro or methyl. Still other preferred compounds of formula Va are those wherein R ₄ represents hydrogen, bromo, chloro, methyl, nitro or amino. Particularly preferred compounds of the formula Va are those in which R ₃ represents hydrogen, chloro or methyl and R ₄ represents hydrogen, bromo, chloro, methyl, nitro or amino.

In still other preferred compounds of Formula Va, R₁And R₂Of
One can be halogen, preferably while in the para position on the phenyl ring,
The other is hydrogen. In these preferred compounds, R₃And R₄Is preferred
Is in the para position and is attached to one of the ortho positions, i.e., the phenyl group.
Positions 4 and 2) with respect to the point of attachment, and hydrogen, halogen or C₁-C ₃ Alkyl, provided that R₃And R₄At least one of which is hydrogen
is not.

Particularly preferred compounds of the present invention have the following stereochemical configuration:

Embedded image Having a skeleton represented by Such compounds are included within Formula Va.

Further, the present invention provides a compound of formula Vb:

Embedded image Vb (where R₁And R₂Is independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C ₆ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Which represents alkyl).

Preferred compounds of formula Vb are those wherein R ₁ and R ₂ are independently hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino,
Mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro or perfluoro (C ₁ -C ₆ ) alkoxy. Further preferred compounds of formula Vb are those wherein R ₅ , R ₆ , R ₇ and R ₈ are hydrogen or methyl. In these preferred compounds of formula Vb, R ₅ and R ₈ are trans to each other.

Another more preferred compound of formula Vb is R₃Is hydrogen, halogen, C₁ -C₃Alkyl, C₁-C₃Which is an alkoxy. The characteristic represented by the formula Vb
A preferred compound for R is₄Is hydrogen, halogen, C₁-C₃Alkyl, or C ₁ -C₃Alkoxy and R₃Is hydrogen, halogen, C₁-C₃Archi
Or C₁-C₃Which is an alkoxy.

Other preferred compounds of formula Vb are those wherein R ₃ represents hydrogen, chloro or methyl. Still other preferred compounds of the formula Vb are those wherein R ₄ represents hydrogen, bromo, chloro, methyl, nitro or amino. Particularly preferred compounds of the formula Vb are those wherein R ₃ represents hydrogen, chloro or methyl and R ₄ represents hydrogen, bromo, chloro, methyl, nitro or amino.

In still other preferred compounds of formula Vb, _one of R ₁ and R ₂ may be halogen, preferably in the para position on the phenyl ring,
The other is hydrogen. In these preferred compounds, R ₃ and R ₄ are preferably in the para position and in one of the ortho positions, ie 4 and 2) with respect to the point of attachment to the phenyl group, and hydrogen, halogen Or C ₁ -C ₃ alkyl, provided that at least one of R ₃ and R ₄ is not hydrogen.

In certain circumstances, the compounds of formula I contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds are, for example, in racemic or optically active form. In these situations, the single enantiomer, ie, the optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Racemic resolution can be achieved by conventional methods, eg, by crystallization in the presence of a resolving agent, or by 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 of 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. In contrast, when the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, dissolve the free base in a suitable organic solvent and provide a conventional method for preparing acid addition salts from basic compounds. The solution can be obtained by treating the solution with an acid.

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

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

Where the compounds exist 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, by “C ₁ -C ₆ alkyl” or “lower alkyl”, for example,
Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, te
A straight or branched chain alkyl group having 1-6 carbon atoms, such as rt-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl is meant. You. Preferred C ₁ -C ₆ alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.

In the present invention, by “C ₁ -C ₆ alkoxy” or “lower alkoxy”, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec
-Butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-
A straight or branched chain alkoxy group having 1-6 carbon atoms such as methylpentoxy is meant. Preferred alkoxy groups here are C ₁ -C ₄ alkoxy groups.

A preferred perfluoro (C ₁ -C ₆ ) alkyl group of the present invention is a trifluoromethyl group. Preferred perfluoro (C ₁ -C ₆ ) alkoxy groups of the present invention are
It is a trifluoroalkoxy group.

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

By aryl is meant an aromatic carbocyclic group having one ring (eg, phenyl) or two rings (eg, biphenyl). Such groups are mono-
, Di-, or tri-substitution. Suitable substituents include, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower alkoxy, aryl, heteroaryl, and hydroxy.

In the present invention, depending on the heteroaryl (aromatic heterocyclic ring), at least one selected from nitrogen, oxygen or sulfur, and 5- or 6-containing at least 4 heteroatoms.
Or one or more aromatic ring systems of 7-membered ring. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (iso) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl,
Naphthyridinyl, benzimidazolyl and benzoxazolyl.

Representative compounds of the present invention are shown in Table 1.

[0048]

Embedded image Compounds having this skeleton are preferred.

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

The compounds of general formula I are conventionally administered orally, topically, parenterally, by inhalation or spray, or rectally, in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Can be administered. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Further provided is 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 active ingredients. It can exist in combination. Pharmaceutical compositions comprising a compound of general formula I include, for example, tablets, lozenges, confectionery tablets,
It may be in a form suitable for oral use as an aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir.

Compositions intended for oral use can be manufactured by any of the methods known in the art for the manufacture of pharmaceutical compositions, and the compositions are pharmaceutically excellent and palatable products In order to provide a sweetener, a flavoring agent, a coloring agent, and a preservative. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, calcium carbonate, sodium carbonate, lactose,
Inert diluents such as calcium phosphate or sodium phosphate; corn starch,
Or granules and disintegrants such as alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glycerol monostearate or glycerol distearate may be employed.

Formulations for oral use may be prepared as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or the active ingredient may be water or, for example, peanut oil, liquid paraffin or olive oil. And soft gelatin capsules to be mixed with oily media such as

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents are naturally occurring, such as lecithin Phosphatide, or the condensation product of an alkylene oxide such as polyoxyethylene stearate and a fatty acid, or the condensation product of ethylene oxide such as heptadecaethyleneoxycetanol and a long-chain aliphatic alcohol, or polyoxyethylene sorbitol monooleate Condensation product of ethylene oxide such as ethylene oxide and a partial ester derived from fatty acid and hexitol, or ethylene oxide such as polyethylene sorbitan monooleate, fatty acid and anhydrous hex It may be condensation products of partial esters derived from tall. Aqueous suspensions may contain, for example, one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and sucrose or One or more sweeteners, such as saccharin, may also 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 product. 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 provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. . Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of an aqueous emulsion in oil. The oil layer may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as, for example, liquid paraffin or a mixture thereof. Suitable emulsifiers include, for example, naturally occurring gums such as gum acacia or tragacanth, naturally occurring phosphatides such as soybean, lecithin,
And esters or partial esters derived from fatty acids and hexitols,
It may be an anhydride such as sorbitan monooleate, or a condensation product of the above partial ester such as polyoxyethylene sorbitan monostearate with ethylene oxide. Emulsifiers also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations also contain demulcents, preservatives and flavors and colorings. 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 for dispersing or wetting agents and suspending agents which have been mentioned above.
The sterile injectable product 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile solid oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland solid 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 are solid at normal temperatures, but liquid at rectal temperature, and therefore, by mixing the drug with a suitable nonirritating excipient that melts in the rectum and releases the drug. Can be manufactured. 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 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.

[0060] Dosage concentrations on the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in treating the conditions indicated above (about 0,0 per day per patient).
. 5 mg to about 7 g). The amount of active ingredient that can produce a single dosage form, depending on the carrier material, will vary with the host treated, and in particular, the mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

However, the particular dosage concentration for any particular patient will depend on the activity, age, weight, general health, sex, diet, number of doses, route of administration, of the particular compound used.
And it depends on a variety of factors, including the rate of elimination, drug combination, and the severity of the particular disease being treated.

The synthesis of each of the compounds of the invention is depicted in Scheme I. One skilled in the art will recognize that the starting materials may be varied and that the additional steps used to produce the compounds are included in the present invention.

[0063]

Embedded image Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are as defined above for Formula I.

As shown, 2-arylcyclopropanecarboxylic acids VII are prepared from cinnamic acid VI through exposure to a suitable substituted methylene iodide (R ₆ R ₇ CI ₂ ) and a zinc-copper bond. A variant of this procedure (Simons-Smith reaction) is well known in the literature (Organic Reactions, Vol. 20, 1-).
131, 1982). The carboxylic acid VII is then condensed with an appropriately substituted 1-phenylpiperazine (VIII) in the presence of a coupling agent to produce cyclopropylcarboxamide IX. Suitable coupling agents include carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC
), Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and the like. Thereafter, the compound of formula Ia, the IX, Alan _(AlH 3), may be prepared by reduction with borane (BH ₃₎ or suitable reducing agent such as lithium aluminum hydride. Similarly, compounds of formula I can be prepared starting with piperazine VIII. Thus, piperazine VIII can be alkylated with a suitable alkylating agent that addresses the sequential coupling with acid VII. Coupling can be, for example, an acid in reduced form,
That is, it can be performed using a derivative of acid VII such as an alcohol or an aldehyde.

The compounds represented by general structures VI, VII, and VIII are either commercially available, known, or capable of being prepared by methods known in the art. is there. If they are not commercially available, the compounds represented by general structures VI, VII, and VIII can be prepared by means analogous to those described in the literature. One skilled in the art will recognize that the starting materials may be varied and that additional steps will be used to produce the compounds included in the present invention.

The enantiomer of trans-2-phenylcyclopropanecarboxylic acid was obtained by the method of Overberger (Macromolecules).
4, 718 (1971)).

Those skilled in the art will recognize that the starting materials can be varied and additional steps are used to produce the compounds encompassed by the present invention, as shown by the following examples. In certain cases, protection of certain reactive functional groups may need to achieve some of the above transformations. In general, the need for such protecting groups, as well as the conditions required to remove such groups, will be apparent to those skilled in the art of protecting groups for organic synthesis.

The disclosure in this application of all articles and materials, including patents, is incorporated herein by reference.

The present invention is further illustrated by the following examples, which should not be construed as limiting the invention to the scope and concept of the particular means described therein.

Example 1 (trans-2- (4-chlorophenyl) chloropropanecarboxylic acid) Zinc powder (6.54 g, 0.1 mol) in methylene chloride (30 mL) and copper chloride (
(1 g, 0.01 mol) is stirred and heated to reflux under a nitrogen atmosphere for 30 minutes. After the mixture was cooled to room temperature, methylene iodide (13.
4 g, 0.05 mol) is added to the mixture and it is then
Reflux for hours. After cooling to 0 ° C., trans-4-chlorocinnamic acid (9.1 g)
) Is added. The reaction is warmed to room temperature for 2 hours and then refluxed for 3 days. The reaction was combined with 30 ml of diethyl ether and 30 ml of ice-cold 10%
Quench to 0 ° C. by adding H ₂ SO ₄ solution. The mixture is filtered and washed with ether. The organic layer is dried over MgSO ₄ and concentrated to give the desired product as a white solid. ¹ H NMR (CDCl ₃ ) 7.25 (d, J = 7H
z, 2H), 7.05 (d, J = 7 Hz, 2H), 2.58 (m, 1H), 1.
85 (m, 1H), 1.65 (m, 1H), 1.37 (m, 1H).

Example 2 (1- (4-Chlorophenyl) -4- (trans-2- [4-chlorophenyl] cyclopropyl) carbonylpiperazine) trans 2- (4-Chlorophenyl) in 3 mL of dry methylene chloride To a solution of chloropropanecarboxylic acid (80 mg, 0.4 mmol) was added diisopropylethylamine (0.15 ml), 1- (4-chlorophenyl) piperazine (110 ml).
g) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP, 0.2 g) are added. The resulting mixture was stirred overnight, 10 mL of methylene chloride was added, and the solution was added with water (
2 × 10 mL). The organic layer is dried over MgSO ₄ and concentrated. The resulting material is purified by flash chromatography eluting with 30% EtOAc / hexane to give the desired amide as a yellow oil (70
mg, 39%). ¹ H NMR (CDCl ₃ ) 7.2 (m, 4H), 7.03 (
d, J = 7 Hz, 2H), 6.83 (d, J = 7 Hz, 2H), 3.8 (m, 4
H), 3.18 (m, 4H), 2.50 (m, 1H), 1.95 (m, 1H),
1.62 (m, 1H), 1.25 (m, 1H).

Example 3 (1- (4-Chlorophenyl) -4- (trans-2- [4-chlorophenyl] cyclopropyl) methylpiperazine) 1- (4-Chlorophenyl) -4 in tetrahydrofuran (3 mL) To a solution of-([trans-2-phenyl] cyclopropyl) carbonylpiperazine (70 mg) is added a solution of allane in tetrahydrofuran (1 M, 0.6 mL). The reaction was stirred at room temperature for 2 hours, concentrated, diluted with ethyl acetate and 1N
Wash with NaOH solution and water. The resulting organic layer is dried over MgSO ₄
Then concentrate. Purification by radial chromatography, eluting with 2% methanol / methylene chloride, gives 30 mg of the product as a white solid (compound 3). ¹ H NMR (CDCl ₃ ) 7.2 (m, 4H), 6.97 (d, J = 7 Hz)
, 2H), 6.82 (d, J = 7 Hz, 2H), 3.18 (M, 4H), 2.7
0 (m, 4H), 2.63 (dd, J = 7.5 Hz, 1H), 2.4 (m, 1H)
), 1.65 (m, 1H), 1.22 (m, 1H), 0.9 (m, 2H). The fumarate salt (Compound 3A) is prepared in methanol and crystallized from ethyl acetate. 111-113 ° C.

Example 4 The following compounds are prepared essentially by the means defined above.

(A) 1- (2-methylphenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (Compound 6).

(B) 1- (2,4-dimethylphenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (Compound 7).

(C) (S, S) 1- (2,4-dimethylphenyl) -4- (trans-2-
Phenylcyclopropyl) methylpiperazine hydrobromide (compound 4, melting point 22
4-225 ° C).

(D) (R, R) 1- (2,4-dimethylphenyl) -4- (trans-2-
Phenylcyclopropyl) methylpiperazine hydrobromide (compound 5, melting point 20)
5-206 ° C).

(E) 1- (2-methyl-4-nitrophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (mp 197-198 ° C.)
(Compound 8).

(F) 1- (2-methyl-4-aminophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (mp 284-285 ° C.)
(Compound 9).

(G) 1- (2-methyl-4-bromophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (mp 182-183 ° C.)
(Compound 10).

(H) 1- (4-chlorophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (mp 229-231 ° C.) (compound 11
).

(I) 1- (2,4-dichlorophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (Compound 2, melting point 206-207)
° C).

(J) 1- (2-chlorophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine hydrobromide (Compound 1, melting point 201-203 ° C.).

Example 5 Therapeutic utility of the compounds of the invention is demonstrated by the following assay for dopamine receptor specific affinity.

Measurement of D ₂ and D ₄ Receptor Binding Activity A pellet of COS cells containing D ₂ and D ₄ receptors recombinantly produced from humans is used for the assay. Samples were taken at 4 ° C and pH 7.4 for 1
Homogenize with 00 volumes (w / vol) of 0.05 M Tris HCl buffer. Thereafter, the sample is centrifuged at 30,000 × g and resuspended and rehomogenized. Thereafter, the sample is centrifuged as described and the final tissue sample is frozen until use. Tissues are resuspended 1:20 (wt / vol) in 0.05M Tris HCl buffer containing 100 mM NaCl.

Incubation at 48 ° C. and 0.4 ml of tissue sample,
5 nM ³ H-YM09151-2 and the compound of interest are contained in a total incubation of 1.0 ml. Non-specific binding is defined as the binding seen in the presence of 1 mM spiperone; without further addition, non-specific binding is 20% of the total binding
%. Binding properties of an embodiment of the patient for D ₂ and D ₄ receptors subtypes is shown in Table 2.

[0087]

[Table 1] represented by nM, binding constants of the compounds of the formula I for D ₄ receptor,
Generally, it will range from about 0.1 nanomonols (nM) to about 50 nanomoles (nM). Preferably, such compounds exhibit a binding limit from about 0.1 to about 10 nM. Lower, preferably is a compound that shows a degree less D ₂ binding constants can be used, these compounds preferably exhibit a binding constant connexion to D ₂ receptor of at least about 50 nM. Accordingly, the compounds of the present invention, generally there are at least 5 times more selective for D ₄ receptors than D ₂ receptors. Preferably, these compounds have at least 10 and more preferably at least 15-50 times more selective for D ₄ receptors than D ₂ receptors.

Example 6 (Preparation of Radiolabeled Probe Compound of the Present Invention) The compound of the present invention is radiolabeled by synthesizing them using a precursor containing at least one atom that is a radioisotope. Manufactured as a probe. Thus, the product is a compound of the invention containing at least one radioactive atom. The radioisotope preferably has at least one carbon (preferably, ¹⁴ C), hydrogen (preferably, ³ H), sulfur (preferably, ³⁵ S).
Or iodine (preferably ¹²⁵ I). Such radiolabeled probes are routinely synthesized by the radioisotope supplier specified in the custom synthesis of the radiolabeled probe compound. As such a supplier,
Amersham Corporation, Arlington Heights, Illinois
am Corporation); Cambridge Isotope Laboratories, Andover, Mass.
Laboratories, Inc. ), Menlo Park, California,
SRI International (SRI Internationala
l); Wizard Laboratories, West Sacramento, CA (
Wizard Laboratories); Chemsin, Lexena, Kansas.
Labs (ChemSyn Laboratories); American Radio-Labeled Chemicals, Inc., St. Louis, Mo.
Radiolabeled Chemicals, Inc. ); And Moravek Biochemicals, Inc., Blair, California.
Chemicals Inc. ).

Tritium-labeled probe compounds are also routinely prepared with a catalyst via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or exchange with a heterogeneous catalyst for tritium gas. You. Such preparations are also routinely made as custom radiolabels by any of the suppliers listed in the preceding paragraph using the compounds of the invention as substrates. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or, where appropriate, reduction with sodium borotritiate.

Example 7 Receptor Autoradiography Receptor autoradiography (receptor mapping) was performed using Kuhar's “Cu
rent Protocols in Pharmacology (1998
) John Wiley & Sons, New York, and by Kuhar et al., "Annu. Rev. Neurosci, 1986, Voi.
. 9, pages 27-59 "(see Example 6).
Prepared in vitro).

The present invention and the means and methods for making and using it are well-defined, concise and accurate in order for those skilled in the art to which it pertains to make and use the same. Described here in terms. It should be understood that the foregoing describes preferred embodiments of the invention, and that modifications may be made therein without departing from the spirit or scope of the invention as defined in the claims.
In order to particularly point out and distinctly claim the subject matter with respect to the present 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 25/24 A61P 25/24 25/28 25/28 25/30 25/30 C07D 295/04 C07D 295 / 04 A 295/06 295/06 A (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, MA, 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 Tolan, Jennifer United States 06437 Guildford, Connecticut Barrier Hill Drive 56 (72) Inventor Zhao, He United States 06405 Branford Stoneridge Lane, Connecticut 4 (72) Inventor Tarkauf, Andrew United States 06811 Connecticut Tsu door Danbury Fox Den load 16 F-term (reference) 4C086 AA01 AA03 BC50 NA14 ZA12 ZA15 ZA18

Claims (39)

[Claims] 1. The formula: embedded image Wherein R ₁ and R ₂ are the same or different and are 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, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
Represents alkoxy; R ₃ and R ₄ are the same or different and are hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino , Mono- or di (C ₁ -C ₆ ) alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ )
Represents alkoxy; and R ₅ , R ₆ , R ₇ , and R ₈ are the same or different and represent hydrogen or C ₁ -C ₃ alkyl; provided that R ₁ and R ₃ -R _{When 8} are all hydrogen, R ₂ is not t-butyl) or a pharmaceutically acceptable addition salt thereof. 2. The compound according to claim 1, wherein R ₅ , R ₆ , R ₇ , and R ₈ are hydrogen or methyl. 3. The compound according to claim 2, wherein R ₅ and R ₈ are trans to each other. 4. The formula: embedded image(Where R₁And R₂Is independently hydrogen, halogen, C₁-C₃Alkyl, C₁-C ₄ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Or a pharmaceutically acceptable addition salt thereof. 5. The compound according to claim 4, wherein R ₁ and R ₂ are both hydrogen. 6. The compound according to claim 5, wherein R ₁ and R ₂ are independently hydrogen, halogen, methyl or ethyl. 7. The method of claim 6, wherein at least one of R ₁ and R ₂ is not hydrogen.
The compound according to the above. 8. The compound according to claim 4, wherein R ₃ and R ₄ are at positions 2 and 4 on the phenyl group. 9. The compound according to claim 8, wherein R ₅ , R ₆ , R ₇ and R ₈ are hydrogen or methyl. 10. The compound according to claim 9, wherein R ₅ and R ₈ are trans to each other. 11. The formula: embedded image(Where R₁And R₂Is independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C ₆ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Or a pharmaceutically acceptable salt thereof. 12. R ₁ and R ₂ are independently hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxy, amino, mono- or di (
C ₁ -C ₆₎ alkylamino, cyano, nitro or perfluoro _(C 1 -C ₆₎ A compound according to claim 11 alkoxy. 13. The method of claim 12, wherein R ₁ and R ₂ are independently hydrogen or C ₁ -C ₆ alkyl, provided that at least one of R ₁ and R ₂ is not hydrogen.
The compound according to the above. 14. The compound according to claim 13, wherein R ₅ , R ₆ , R ₇ , and R ₈ are hydrogen or methyl. 15. The compound according to claim 14, wherein R ₅ and R ₈ are trans to each other. 16. R₃Is hydrogen, halogen, C₁-C₃Alkyl, or C ₁ -C₃16. The compound according to claim 15, which is an alkoxy. 17. R₄Is hydrogen, halogen, C₁-C₃Alkyl, or C ₁ -C₃17. The compound according to claim 16, which is an alkoxy. 18. The compound according to claim 11, wherein R ₃ represents hydrogen, chloro, or methyl. 19. The compound according to claim 11, wherein R ₄ represents hydrogen, bromo, chloro, methyl, nitro, or amino. 20. The formula: embedded image(Where R₁And R₂Is independently hydrogen, halogen, C₁-C₆Alkyl, C₁-C ₆ Alkoxy, C₁-C₄Alkylthio, hydroxy, amino, mono- or di-
(C₁-C₆) Alkylamino, cyano, nitro, perfluoro (C₁-C₆)
Alkyl or perfluoro (C₁-C₆R) represents alkoxy;₃And R₄Are the same or different and are hydrogen, halogen
N, C₁-C₆Alkyl, C₁-C₄Alkoxy, C₁-C₄Alkylthio, ar
Droxy, amino, mono- or di (C₁-C₆) Alkylamino, cyano, d
Toro, perfluoro (C₁-C₆) Alkyl or perfluoro (C₁-C₆)
Represents alkoxy; and R₅, R₆, R₇, And R₈Are the same or different, and
Hydrogen or C₁-C₃Or a pharmaceutically acceptable addition salt thereof. 21. The point at which R ₃ and R ₄ are attached to the piperazine ring is at positions 2 and 4 on the phenyl ring, and at least one of R ₁ and R ₂ is R _3-
Not C ₁ -C ₆ alkyl at the 4-position on the phenyl ring when R ₈ is hydrogen A compound according to claim 20. 22. The method of claim 21, wherein R ₂ is at the 4-position on the phenyl ring and represents halogen, alkoxy, hydroxy, amino, mono- or di (C ₁ -C ₆ ) alkylamino, or nitro. Compound. 23. The method of claim 23, wherein R ₂ is in the para position or a phenyl ring and represents C ₁ -C ₄ alkylthio, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ ) alkoxy. Item 22. The compound according to item 21, 24. The compound according to claim 1, which is 1- (2-methylphenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 25. 1- (2,4-dimethylphenyl) -4- (trans-2
The compound according to claim 1, which is -phenylcyclopropyl) methylpiperazine. 26. The compound according to claim 1, which is (S, S) 1- (2,4-dimethylphenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 27. The compound according to claim 1, which is (R, R) 1- (2,4-dimethylphenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 28. The compound of claim 1, which is 1- (2-methyl-4-nitrophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 29. The compound according to claim 1, which is 1- (2-methyl-4-aminophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 30. The compound according to claim 1, which is 1- (2-methyl-4-bromophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 31. The compound according to claim 1, which is 1- (4-chlorophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 32. 1- (2,4-dichlorophenyl) -4- (trans-2
The compound according to claim 1, which is -phenylcyclopropyl) methylpiperazine. 33. The compound according to claim 1, which is 1- (2-chlorophenyl) -4- (trans-2-phenylcyclopropyl) methylpiperazine. 34. 1- (4 Chlorophenyl) -4- (trans-2- [4
-Chlorophenyl] cyclopropyl) methylpiperazine. 35. A method for treating a CNS (central nervous system) disorder comprising administering to a patient in need of such treatment a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 36. The method of claim 35, wherein the CNS disorder is schizophrenia. 37. The method of claim 35, wherein the CNS disorder is mania, dementia, depression, anxiety, obsessive-compulsive disorder, substance abuse, Parkinson-like dyskinesia, or a movement disorder associated with the use of neurostabilizers. . 38. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier thereof. 39. The compound according to claim 1, wherein the compound comprises at least one radioactive atom.
A method for localizing a dopamine receptor in a tissue sample, comprising contacting the compound according to 1 with a biological tissue sample.