CN1167694C - 1-Phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazine: dopamine receptor ligand - Google Patents

Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable addition salts thereof wherein: R1, R2, R3, R4 and R5, R6, R7 and R8 represent organic and/or inorganic substituents as defined herein, which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

Description

1-Phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazine: dopamine receptor ligand

Background of the invention

field of invention

The present invention relates to 1-phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazine derivatives and pharmaceutical compositions comprising such compounds. The invention also relates to the use of such compounds in the treatment or prevention of psychiatric disorders such as schizophrenia and other central nervous system disorders.

Related technical description

Conventional antipsychotic drugs, called neuroleptics, are thought to exert their effects by blocking dopamine receptors. However, neuroleptics are often responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to the Blockade of D2 receptors. A subtype of the dopamine D4 receptor was recently identified (Nature, 350 :610 (Van Tol et al., 1991); Nature, 347 :146 (Sokoloff et al., 1990)). Its unique localization in limbic brain regions and its differential recognition of various antipsychotics suggest that D4 receptors play a major role in the etiology of schizophrenia. Selective D4 antagonists are considered potent antipsychotics without the neurological side effects exhibited by conventional neuroleptics.

Summary of the invention

The present invention provides novel compounds of formula I that interact with dopamine subtypes. Accordingly, a first aspect of the present invention relates to compounds of formula I:

in:

R ₁ and R ₂ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )alkoxy;

A is an alkylene group having 1-3 carbon atoms; and

R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent hydrogen or C ₁ -C ₆ alkyl.

Dopamine D4 receptors are concentrated in the limbic system that controls cognition and emotion (Science, 265 : 1034 (Taubes, 1994)). Compounds capable of interacting with these receptors are therefore useful in the treatment of cognitive disorders. The disorder includes cognitive deficits that are a prominent component of the negative symptoms of schizophrenia (social withdrawal and unresponsiveness). Other disorders include memory impairment or lack of concentration.

The compounds of the present invention exhibit high affinity and selectivity in binding to the D4 receptor subtype. These compounds are therefore useful in the treatment of various neuropsychiatric disorders such as schizophrenia, depression and mania. It can also directly or indirectly treat other dopamine-mediated diseases, such as similar Parkinson's disease and tardive motor dysfunction, by regulating D4 receptors.

The compounds of the present invention may also be used to treat depression, memory loss or Alzheimer's disease by modulating D4 receptors, since they are selectively present in areas known to control mood and cognitive function.

Thus, another aspect of the present invention is to provide methods of treatment and/or prophylaxis for the treatment and/or prevention of neuropsychiatric or affective disorders including, for example, schizophrenia, mania, dementia, depression , anxiety, obsessions and behaviors, (psychotropic) substance abuse, memory loss, cognitive deficits, parkinsonian-like movement disorders such as parkinsonism and dystonia, and movements associated with the use of neuroleptics out of order. Additionally, the compounds of the invention are useful in the treatment of depression, memory loss or Alzheimer's disease. Furthermore, the compounds of the present invention may be used to treat other disorders responsive to dopaminergic blockade, such as substance abuse and obsessive-compulsive disorders. Also, these compounds can be used to treat extrapyramidal side effects associated with the use of conventional neuroleptic drugs.

In addition, the compounds of the present invention can also be used as probes for localizing dopamine receptors, provided they are properly labeled. Localization of receptors can be performed in vitro, for example by autoradiography of tissue sections, or in vivo, for example by positron emission tomography (PET).

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

Furthermore, the present invention provides intermediates useful in the preparation of compounds of formula I.

Also, the present invention provides methods for preparing the compounds of the present invention.

Detailed description of the invention

The present invention includes compounds of formula I as described above.

Preferred compounds of formula I are those wherein R ₅ , R ₆ , R ₇ and R ₈ are C ₁ -C ₃ alkyl, more preferably hydrogen or methyl. More preferred compounds of formula I are those wherein _R5 , _R6 , _R7 and _R8 are hydrogen. In more preferred compounds of formula I, the hydrogens at _R5 and _R8 are in trans configuration to each other. Particular preference is given to compounds of formula I in which R ₁ , R ₂ , R ₃ and R ₄ are hydrogen, halogen or lower alkyl.

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

Additionally, the present invention includes compounds of the following formula II:

in:

R ₁ and R ₂ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )alkoxy; and

R ₅ , R ₆ , R ₇ and R ₈ are the same or different and represent hydrogen or C ₁ -C ₆ alkyl;

with the proviso that when _R1 and _R3 - _R8 are all hydrogen, _R2 is not tert-butyl.

In preferred compounds of formula II, _R5 and _R8 are in the trans configuration of each other. In more preferred compounds of formula II, R ₅ , R ₆ , R ₇ and R ₈ are all hydrogen or methyl. More preferred compounds of formula II are those wherein _R5 , _R6 , _R7 and _R8 are all hydrogen. In the most preferred compound of formula I, the hydrogens at the _R5 and _R8 positions are in trans configuration to each other. Particular preference is given to compounds of formula I in which R ₁ , R ₂ , R ₃ and R ₄ are hydrogen, halogen or lower alkyl.

In other preferred compounds of formula I, when one of _R1 and _R2 is hydrogen, the other may be halogen and is preferably located in the para position of the phenyl ring. In these preferred compounds, preferably _R3 and _R4 are located in the para position, one is located in the ortho position, that is, located in the 4 and 2 positions relative to the attachment point of the benzene ring, and are hydrogen, halogen or C ₁ -C ₃ alkyl, with the proviso that one of _R3 and _R4 is not hydrogen.

Additionally, the present invention includes compounds of formula III below:

in:

R ₁ and R ₂ independently represent hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ ) Alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ ) alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )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.

Preferred compounds of formula III are those wherein _R1 and _R2 are independently hydrogen, halogen, methyl or ethyl. In more preferred compounds of formula III, _both R1 and _R2 are hydrogen.

In other preferred compounds of formula III at least one of _R1 and _R2 is other than hydrogen. In more preferred compounds of formula III, at least one of R _{and R} is not hydrogen, i.e. it is selected from 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 )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )alkane Oxygen, and R ₃ and R ₄ are located at the 2 and 4 positions of the benzene ring. In these preferred compounds of formula III, _R5 , _R6 , _R7 and _R8 are hydrogen or methyl. Furthermore, in these preferred compounds of formula III, _R5 and _R8 are in the trans configuration of each other.

Additionally, the present invention includes compounds of the following formula IV:

in:

R ₁ and R ₂ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ ) Alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ ) alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )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.

Preferred compounds of formula IV are those wherein R _{and R} independently represent hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, mono or di(C ₁ -C ₆ )alkylamino, cyano, nitro or perfluoro(C ₁ -C ₆ )alkoxy compounds. More preferred compounds of formula IV are those wherein _R5 , _R6 , _R7 and _R8 are hydrogen or methyl. In preferred compounds of formula IV, _R5 and _R8 are in the trans configuration of each other.

Other more preferred compounds of formula IV are those wherein R ₃ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. Particularly preferred compounds of formula IV are those where 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 compounds.

Other preferred compounds of formula IV are those wherein _R3 is hydrogen, chloro or methyl. More preferred compounds of formula IV are those wherein _R4 is hydrogen, bromo, chloro, methyl, nitro or amino. Particularly preferred compounds of formula IV are those wherein _R3 is hydrogen, chloro or methyl, and _R4 is hydrogen, bromo, chloro, methyl, nitro or amino.

Additionally, the present invention includes compounds of the following formula Va:

in:

R ₁ and R ₂ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ ) Alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ ) alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )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.

Preferred compounds of formula Va are those wherein R _{and R} independently represent hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, mono- or di(C ₁ -C ₆ )alkylamino, cyano, nitro or perfluoro(C ₁ -C ₆ )alkoxy compounds. More preferred compounds of formula Va are those wherein _R5 , _R6 , _R7 and _R8 are hydrogen or methyl. In preferred compounds of formula Va, _R5 and _R8 are in the trans configuration of each other.

Other more preferred compounds of formula Va are those wherein _R3 is hydrogen, halogen, _C1 - _C3 alkyl or _C1 - _C3 alkoxy. Particularly preferred compounds of formula Va are those where 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 compounds.

Other preferred compounds of formula Va are those wherein _R3 is hydrogen, chloro or methyl. Still other preferred compounds of formula Va are those wherein _R4 is hydrogen, bromo, chloro, methyl, nitro or amino. Particularly preferred compounds of formula Va are those wherein _R3 is hydrogen, chloro or methyl, and _R4 is hydrogen, bromo, chloro, methyl, nitro or amino.

In other preferred compounds of formula Va, one of _R1 and _R2 may be halogen, preferably in the para position of the benzene ring, while the other is hydrogen. In these preferred compounds, it is preferred that _R3 and _R4 are in the para position, one is in the ortho position, i.e. in the 4 and 2 positions relative to the attachment point of the benzene ring, and both are hydrogen, halogen or _C1 - _C3 alkane group, with the proviso that at least one of _R3 and _R4 is not hydrogen.

Particularly preferred compounds of the present invention are those having the following stereoconfiguration skeletons:

Such compounds are included in formula Va.

Additionally, the present invention includes compounds of the following formula Vb:

in:

R ₁ and R ₂ independently represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ ) Alkylamino, cyano, nitro, perfluoro (C ₁ -C ₆ ) alkyl or perfluoro (C ₁ -C ₆ ) alkoxy;

R ₃ and R ₄ are the same or different and represent hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, one or two (C ₁ -C ₆ )alkylamino, cyano, nitro, perfluoro(C ₁ -C ₆ )alkyl or perfluoro(C ₁ -C ₆ )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.

Preferred compounds of formula Vb are those wherein R _{and R} independently represent hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, amino, mono or di(C ₁ -C ₆ )alkylamino, cyano, nitro or perfluoro(C ₁ -C ₆ )alkoxy compounds. More preferred compounds of formula Vb are those wherein _R5 , _R6 , _R7 and _R8 are hydrogen or methyl. In preferred compounds of formula Vb, _R5 and _R8 are in the trans configuration of each other.

Other more preferred compounds of formula Vb are those wherein R ₃ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. Particularly preferred compounds of formula Vb are those where 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 compounds.

Other preferred compounds of formula Vb are those wherein _R3 is hydrogen, chloro or methyl. Still other preferred compounds of formula Vb are those wherein _R4 is hydrogen, bromo, chloro, methyl, nitro or amino. Particularly preferred compounds of formula Vb are those wherein _R3 is hydrogen, chloro or methyl, and _R4 is hydrogen, bromo, chloro, methyl, nitro or amino.

In other preferred compounds of formula Vb, one of _R1 and _R2 may be halogen, preferably in the para position of the benzene ring, while the other is hydrogen. In these preferred compounds, it is preferred that _R3 and _R4 are in the para position, one is in the ortho position, i.e. in the 4 and 2 positions relative to the attachment point of the benzene ring, and both are hydrogen, halogen or _C1 - _C3 alkane group, with the proviso that at least one of _R3 and _R4 is not hydrogen.

In some cases, compounds of formula I may contain one or more asymmetric carbon atoms, so that the compounds exist in different stereoisomeric forms. For example, these compounds may be in racemic or optically active form. In these cases, the single enantiomers, ie optically active forms, can be obtained by asymmetric synthesis or racemic resolution. For example, resolution of racemates can be accomplished by conventional methods such as crystallization in the presence of resolving reagents or chromatography with chiral HPLC columns.

Representative compounds of the invention included in Formula I include, but are not limited to, the compounds in Table 1 and pharmaceutically acceptable addition salts thereof. Alternatively, if a compound of the present invention is obtained in the form of an addition salt, the free base can be obtained by basifying a solution of the acidic salt. Conversely, if the product is a free base, the addition salt, in particular Pharmaceutically acceptable addition salts.

Non-toxic pharmaceutically acceptable salts include hydrochloride, phosphate, hydrobromide, sulfate, sulfinate, formate, tosylate, methanesulfonate, nitrate, benzoate, lemon salt, tartrate, maleate, hydroiodide, alkanoate such as acetate, HOOC-(CH ₂ ) _n -COOH (wherein n is 0-4) salt, etc. Many non-toxic pharmaceutically acceptable addition salts will occur to those skilled in the art.

The present invention also includes acylated prodrugs of the compounds of formula I. Various synthetic methods will occur to those skilled in the art for the preparation of non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of compounds of formula I.

Although the compounds exist in various tautomeric forms, the present invention is not limited to any one particular tautomer. The present invention includes all tautomeric forms of the compounds.

In the present invention, "C ₁ -C ₆ alkyl" or "lower alkyl" refers to straight chain or branched chain alkyl with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl base, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. Preferred C ₁ -C ₆ alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.

In the present invention, "C ₁ -C ₆ alkoxy" or "lower alkoxy" refers to a straight or branched alkoxy group with 1-6 carbon atoms, such as methoxy, ethoxy, Propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2- Hexyloxy, 3-hexyloxy and 3-methylpentyloxy. Preferred alkoxy groups herein are C ₁ -C ₄ alkoxy groups.

The perfluoro(C ₁ -C ₆ )alkyl of the present invention is preferably trifluoromethyl. The perfluoro(C ₁ -C ₆ )alkoxy groups according to the invention are preferably trifluoroalkoxy groups.

In the present invention, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

Aryl refers to an aromatic carbocyclic group having one ring (such as benzene ring) or two rings (such as biphenyl). Such groups may be monosubstituted, disubstituted or trisubstituted. Suitable substituents include, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy.

In the present invention, heteroaryl (heteroaromatic ring) refers to an aromatic ring system of one or more 5-, 6- or 7-membered rings containing at least 1 and at most 4 atoms selected from nitrogen, oxygen or sulfur heteroatoms. Such heteroaryl groups include, for example, thienyl, furyl, thiazolyl, imidazolyl, (iso)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolyl, 1,5-naphthyridine, benzene imidazolyl and benzoxazolyl.

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

Table 1

Compounds having such a skeleton are preferred.

The present invention also relates to the use of compounds of general formula I in the treatment of neuropsychiatric diseases. The interaction of the compounds of the invention with dopamine is shown in the Examples. This interaction is responsible for the pharmacological activity of these compounds.

The compound of general formula I can be administered orally, topically, parenterally, by inhalation or spray or rectally in the form of dosage unit preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. As used herein, the term "parenteral administration" includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. In addition, the present invention provides a pharmaceutical preparation, which comprises the compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of formula I can be present together with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and other active ingredients (if necessary). Pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral administration, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, Hard or soft capsules, or syrup or elixir.

Compositions for oral administration can be prepared according to any known pharmaceutical composition preparation method in the art, and this composition can contain one or more selected from sweeteners, flavoring agents, coloring agents and preservatives reagents to provide pharmaceutically extremely palatable formulations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch , gelatin, or gum arabic; and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated according to known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long-term sustained release. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Oral formulations may also be hard gelatin capsules in which the active ingredient is mixed with an inert diluent such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as Mix together peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia; dispersing and wetting agents Can be a naturally occurring phospholipid, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long-chain fatty alcohol, such as heptadecene Oxycetyl alcohol, or condensation products of ethylene oxide with partial esters from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters from fatty acids and hexitol anhydrides, Such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners. Flavoring agents such as sucrose or starch.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents are flavoring agents such as those mentioned above, which may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of antioxidants, 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 or one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be added.

The pharmaceutical composition of the present invention may also be an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture of these oils. Suitable emulsifiers may be natural gums such as acacia or tragacanth, natural phospholipids (such as soy), lecithin, and esters or partial esters of anhydrohexitols derived from fatty acids and hexitols, such as sorbitan Monooleate and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsifier may also contain sweeteners and flavoring agents.

Syrups and elixirs may be prepared with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such 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, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-toxic excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycols.

Compounds of general formula I may be administered parenterally in sterile media. Depending on the vehicle and concentration used, the drug can be suspended or dissolved in the vehicle. Preferably, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle.

Prescribed dosage levels of 0.1 mg to about 140 mg per kilogram of body weight per day can be used to treat each of the above conditions (about 0.5 mg to about 7 grams per patient per day). The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 milligram to about 500 milligrams of an active ingredient.

It is to be understood, however, that the specific dosage level for any particular patient will vary depending on many factors, including the activity of the particular compound being used, the patient's age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and severity of the specific disease being treated.

A representative synthesis of compounds of the invention is given in Scheme I. Those skilled in the art will recognize that starting materials may be altered and additional steps used to prepare compounds of the invention.

Diagram I

wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , R ₆ , R ₇ and R ₈ are as defined in formula I.

As shown above, 2-arylcyclopropanecarboxylic acids VII were prepared from cinnamic acid VI by contacting cinnamic acid with appropriately substituted diiodomethane (R ₆ R ₇ CI ₂ ) and a copper-coated zinc plate . The variants of this method (Simmons-Smith reaction) are well known in the literature (see Organic Reaction, Vol. 20, pages 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 afford the cyclopropylcarboxamide IX . Suitable coupling agents include carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) wait. Compounds of formula Ia can thereafter be prepared by reduction of IX with a suitable reducing agent such as alane ( _AlH3 ), borane ( _BH3 ) or lithium aluminum hydride. Compounds of formula I can be prepared analogously starting from piperazines VIII. Thus, piperazine VIII can be alkylated with a suitable alkylating reagent followed by coupling with acid VII. Said coupling may be performed with a derivative of acid VII, such as with the reduced form of the acid (ie alcohol or aldehyde).

Compounds of general structural formulas VI , VII and VIII are either commercially available or can be prepared by methods known in the art. If not commercially available, compounds of general structural formulas VI , VII and VIII can be prepared analogously to those described in the literature. Those skilled in the art will recognize that starting materials may be altered and additional steps used to prepare compounds of the invention.

The enantiomers of trans-2-phenylcyclopropanecarboxylic acid can be prepared by the method of Overberger (Macromolecules, 4, 718 (1971)).

Those skilled in the art will appreciate that starting materials may be altered and additional steps used to prepare compounds of the invention, as exemplified in the following Examples. In some cases, it is necessary to protect certain reactive functional groups to achieve some of the above transformations. In general, the need for such protecting groups and the conditions for attaching and removing such groups will be apparent to those skilled in the art of organic synthesis.

All papers and references, including patents, published in this application are hereby incorporated by reference.

The present invention will be further illustrated by the following examples, which are not to be construed as limiting the scope and concept of the invention to the specific methods described therein.

Example 1

trans-2-(4-Chlorophenyl)cyclopropanecarboxylic acid

A mixture of zinc powder (6.54 g, 0.1 mol) and cuprous chloride (1 g, 0.01 mol) in dichloromethane (30 mL) was stirred and heated to reflux under nitrogen for 30 minutes. After the reaction mixture was cooled to room temperature, diiodomethane (13.4 g, 0.05 mol) was added to the mixture, and then the mixture was refluxed for another 1 hour. After cooling to 0°C, trans-4-chlorocinnamic acid (9.1 g) was added. The reaction was warmed to room temperature over 2 hours, then refluxed for 3 days. The reaction was quenched by adding 30 ml of diethyl ether and 30 ml of ice-cold 10% sulfuric acid solution at 0°C. The organic layer was dried over _MgSO4 and concentrated to give the desired product as a white solid. ¹ H NMR (CDCl ₃ ) 7.25(d, J=7Hz, 2H), 7.05(d, J=7Hz, 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

To a solution of trans-2-(4-chlorophenyl)cyclopropanecarboxylic acid (80 mg, 0.4 mmol) in 3 mL of dry dichloromethane was added diisopropylethylamine (0.15 mL), 1 -(4-Chlorophenyl)piperazine (110 mg) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.2 g). The resulting mixture was stirred overnight, 10 mL of dichloromethane was added and the solution was washed with water (2 x 10 mL). The organic layer was dried over _MgSO4 and concentrated. The resultant was purified by flash chromatography eluting with 30% EtOAc/hexanes to afford the desired amide as a yellow oil. ¹ H NMR (CDCl ₃ ) 7.2 (m, 4H), 7.03 (d, J=7Hz, 2H), 6.83 (d, J=7Hz, 2H), 3.8 (m, 4H), 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

To a solution of 1-(4-chlorophenyl)-4-([trans-2-phenyl]cyclopropyl)carbonylpiperazine (70 mg) in THF (3 mL) was added a solution of alane in THF ( 1M, 0.6 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, diluted with ethyl acetate, and washed with 1N NaOH solution and water. The resulting organic layer was dried over _MgSO4 and concentrated. The resultant was purified by radial development chromatography with 2% methanol/dichloromethane as eluent to obtain 30 mg of a white solid product (compound 3). ¹ H NMR (CDCl ₃ ): 7.2 (m, 4H), 6.97 (d, J=7Hz, 2H), 6.82 (d, J=7Hz, 2H), 3.18 (M, 4H), 2.70 (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) was prepared in methanol and crystallized from ethyl acetate. mp111-113°C.

Example 4

The following compounds were prepared essentially according to the methods described 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, m.p.224- 225℃)

(d) (R, R) 1-(2,4-dimethylphenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (compound 5, m.p.205- 206°C)

(e) 1-(2-methyl-4-nitrophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (m.p.197-198°C) (compound 8 )

(f) 1-(2-methyl-4-aminophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (m.p.284-285°C) (compound 9)

(g) 1-(2-methyl-4-bromophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (m.p.182-183°C) (Compound 10 )

(h) 1-(4-chlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (m.p.229-231°C) (compound 11)

(i) 1-(2,4-dichlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (compound 2, m.p.206-207°C)

(j) 1-(2-chlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine hydrobromide (compound 1, m.p.201-203°C)

Example 5

The pharmacological effects of the compounds of the present invention are briefly illustrated by the following affinity tests for dopamine receptor subtypes.

Determination of D2 and D4 receptor binding activity

Experiments were performed with COS cell pellets containing recombinantly produced human D2 and D4 receptors. Samples were homogenized in 100 volumes (w/vol) of 0.05M Tris HCl buffer at 4°C and pH 7.4. Then, the samples were centrifuged at 30000 x g, resuspended and homogenized. Afterwards, the samples were centrifuged as described above, and the final tissue samples were frozen until use. The tissue was resuspended 1:20 (wt/vol) in 0.05M Tris HCl buffer containing 100 mM NaCl.

Incubation was carried out at 48°C and contained 0.4 ml of tissue samples, 0.5 nM of ³ H-YM09151-2 and related compounds, and 1.0 ml of total culture. Non-specific binding was defined as that found at 1 mM spirocyclone; this non-specific binding was less than 20% of total binding without further addition. The binding properties of the examples of this patent to the D2 and D4 receptor subtypes are shown in Table 2.

Table 2 Compound No. D4 Ki(nM) D2 Ki(nM) 1 8 7 2 8 90 3 8 523 4 2 75 5 10 51

The binding constants (usually expressed in nM) of the compounds of Formula I for the D4 receptor range from 0.1 nanomolar (nM) to about 50 nanomolar (nM). Preferably, the binding constant of such compounds is constrained to about 0.1 to 10 nM. These compounds preferably have a binding constant for D2 of at least about 50 nM, although compounds with lower D2 binding constants can be used. Thus, the compounds of the invention are at least 5-fold more selective for the D4 receptor than for the D2 receptor. Preferably, these compounds are at least 10-fold, more preferably 15-50-fold selective for D4 over D2.

Example 6

Preparation of radiolabeled probe compound of the present invention

The compounds of the invention are prepared as radiolabeled probes by synthesis using precursors comprising at least one radioisotope atom. Such products are compounds of the invention comprising at least one radioactive atom. The radioactive isotope is preferably at least one selected from carbon (preferably ¹⁴ C), hydrogen (preferably ³ H), sulfur (preferably ³⁵ S) or iodine (preferably ¹²⁵ I). Such radiolabeled probes are typically synthesized by radioisotope suppliers who specialize in the synthesis of radiolabeled probe compounds to order. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; ., St. Louis, MO and Moravek Biochemicals Inc., Brea, CA.

Tritiated probe compounds can also be conveniently prepared by platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneously catalyzed exchange with tritium gas. The preparation of such radiolabels can also be custom made by any of the suppliers listed above using the compounds of the invention as substrates. Additionally, certain precursors can be tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or, where appropriate, reduction with sodium borotritide.

Example 7

receptor autoradiography

Receptor autoradiography (receptor images) was performed using radiolabeled compounds of the invention (prepared as described in Example 6) according to Kohar in Current Protocols in Pharmacology (1998) pp. 8.1.1 to 8.1 .9, performed in vitro by the method described by John Wiley & Sons, New York, and Kuhar et al. in Annu.Rev.Neurosci., 1986, vol.9, pages 27-59.

Heretofore, the invention and the manner and methods of making and using the compounds of the invention have been described in full, clear, unambiguous and precise terms to enable any person skilled in the art to make and use the compounds of the invention. It should be understood that the foregoing describes preferred embodiments of the invention and that various modifications may be made to the invention without departing from the spirit and scope of the invention as set forth in the claims. To particularly point out and distinctly set forth the subject matter claimed in the invention, the specification is concluded in the following claims.

Claims (23)

1. the compound of following formula or its pharmaceutically useful additive salt:

Wherein:

R ₁And R ₂Be selected from hydrogen and halogen independently of one another;

R ₅And R ₈Be hydrogen; And

R ₃And R ₄Be selected from hydrogen, C independently of one another _1-6Alkyl, halogen, nitro and amino.

2. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1 ₅And R ₈Trans each other.

3. according to compound or its pharmaceutically useful additive salt of claim 1, wherein said halogen is a chlorine or bromine.

4. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1 ₃And R ₄Be methyl independently of one another.

5. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 2 ₁And R ₂Be hydrogen.

6. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1 ₁And R ₂In at least one is not a hydrogen.

7. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 5 ₃And R ₄On 2 and 4 of phenyl ring.

8. according to each compound or its pharmaceutically useful additive salt, wherein R among the claim 2-4 ₁And R ₂Be hydrogen or halogen independently of one another, condition is R ₁And R ₂In at least one be not hydrogen.

9. according to compound or its pharmaceutically useful additive salt of claim 1, be the compound or its salt of following formula:

R ₁And R ₂Be selected from hydrogen and halogen independently of one another; And

R ₃And R ₄Be selected from hydrogen, C independently of one another _1-6Alkyl, halogen, nitro and amino.

10. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 9 ₃And R ₄With respect to the site that links to each other with piperazine ring on 2 and 4 of phenyl ring.

11. compound or its pharmaceutically useful additive salt, wherein R according to claim 10 ₂On 4 of phenyl ring.

12. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is (S, S) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

13. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is (R, R) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

14. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-nitrophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

15. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-aminophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

16. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-bromo phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

17. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(4-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

18. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2,4-dichloro-phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

19. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.

20. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(4-chlorophenyl)-4-(anti--2-[4-chlorophenyl] cyclopropyl) methylpiperazine.

21. the compound of claim 1 or its pharmaceutically useful additive salt are used for the treatment of purposes in the medicine of central nervous system disease in preparation, described central nervous system disease be selected from schizophrenia, mania, dementia, dysthymia disorders, anxiety, obsessional idea and behavior, substance abuse, similar Parkinson's disease motor disorder and with use the relevant motor disorder of psychosis.

22. according to the purposes of claim 21, wherein said central nervous system disease is a schizophrenia.

23. a pharmaceutical composition comprises compound or its pharmaceutically useful additive salt and the pharmaceutical carrier of claim 1.