NZ512772A

NZ512772A - 1-Phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines useful as dopamine receptor ligands

Info

Publication number: NZ512772A
Application number: NZ512772A
Authority: NZ
Inventors: Jennifer Tran; He Zhao; Andrew Thurkauf; Xiaoyan Zhang
Original assignee: Neurogen Corp
Priority date: 1999-01-08
Filing date: 2000-01-06
Publication date: 2003-11-28
Also published as: HK1043360A1; WO2000040572A1; AU2720300A; CN1341111A; JP2002534421A; EP1140879A1; AU771199B2; CA2359989A1; CN1167694C

Abstract

A piperazine derivative or pharmaceutically acceptable addition salts thereof has the formula (I) wherein: R1, R2, R3 and R4 are independently hydrogen, halogen, alkyl, alkoxy, alkylthio, hydroxy, amino, mono or di alkylamino, cyano, nitro, perfluoroalkyl or perfluoroalkoxy and R5, R6, R7, and R8 are independently hydrogen or alkyl; provided that neither R1 or R2 is t-butyl and at least one of R3 and R4 are halogen. The compounds are useful for treating schizophrenia, mania, dementia, depression, anxiety, obsessive-compulsive disorder, substance abuse, Parkinson-like motor disorder or a motion disorder related to the use of a neuroleptic agent.

Description

New Zealand Paient Spedficaiion for Paient Number 512772 512772 l-Phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazines: Dopamine Receptor Ligands BACKGROUND OF THE INVENTION Field of the Invention This invention relates to l-phenyl-4-(1-[2- aryl]cyclopropyl)methylpiperazine derivatives and to pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the manufacture of medicaments for treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases.

Description of the Related Art The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyrimidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain. The dopamine D4 receptor subtype has recently been identified (Nature, 350: 610 (Van Tol et al., 1991); Nature, 347: 146 (Sokoloff et al., 1990)). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics indicates that the D4 receptor plays a major role in the etiology of schizophrenia. Selective D4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.

SUMMARY OF THE INVENTION In a first aspect the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a compound of the formula: INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 jun 2003 dirnpi\/l=n r 0 r2 or (b) a pharmaceutically acceptable addition salt thereof Ri and R2 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(C1-C6)alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro(C1-C6)alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(C1-C6)alkylamino, cyano, nitro, perfluoro(C1-C6)alkyl or perfluoro(C1-C6)alkoxy; and R5, R6, R7, and Re are the same or different and represent hydrogen or C1-C3 alkyl.

Also provided is a compound of the formula: or pharmaceutically acceptable addition salts thereof wherein: Ri and R2 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, Ci-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(C1-C6)alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (Ci-Cg) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, wherein: INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 j'jm 2003 512772 hydroxy, amino, mono- or di (C1-C6)alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (C1-C6) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl; provided that neither of Ri and R2 is t-butyl and at least one of R3 and R4 is halogen.

Further provided is a compound of the formula: or pharmaceutically acceptable addition salts thereof wherein: Ri is hydrogen, halogen, C1-C6 alkyl, Ci~C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C1-C6) alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (C1-C6) alkoxy; R2 represents C1-C4 alkylthio, perfluoro (Ci-C6) alkyl, or perfluoro (C1-C6) alkoxy; R3 and R4 are hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro(C1-C6)alkyl or perfluoro(Ci-C6) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl.

Dopamine D4 receptors are concentrated in the limbic system (Science, 265: 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other 3 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 jun 2003 512772 disorders include those involving memory impairment or attention deficit disorders.

Compounds and compositions of the present invention demonstrate high affinity and selectivity in binding to the D4 receptor sybtype. These compounds and compositions are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 receptors.

Compounds and compositions of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's disease by modulation of D4 receptors since they exist selectively in areas known to control emotion and cognitive functions.

Described but not claimed are methods of treatment and/or prevention of neuropsychological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavour, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents. In addition, the compounds and compositions of the invention are useful for treatment of depression, memory-impairment or Alzheimer's disease. Further, the compounds and compositions of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds and compositions are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. (followed by page 4a) INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 jun 2003 512772 Additionally, when appropriately labeled, compounds and compositions of this invention are useful as probes for the localization of dopamine receptors. Localization of receptors may be performed in vitro, e.g., via autoradiography of tissue sections, or in vivo, e.g., via positron emission tomography (PET).

In another aspect, the invention provides use of a compound for formula: or (b) a pharmaceutically acceptable addition salt thereof wherein: Ri and R2 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, Ci-C6 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (C1-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, Ci~C4 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di(Ci-Ce)alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-Ce) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a CNS disorder selected from schizophrenia, mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of a neuroleptic agent. r2 4a INTELLECTUAL PROPERTY OFFICE OF N.Z. (followed by page 4b) 1 2 jjm 2003 RECEIVED 512772 The invention also provides use of (a) a compound of the formula: or (b) a pharmaceutically acceptable addition salt thereof Ri and R2 independently represent hydrogen, halogen, C1-C3 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C1-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (C1-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (Ci-Ce) alkoxy; and Rs, Re, R7, and Rg are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

Further provided is use of a compound of the formula: or (b) a pharmaceutically acceptable salt thereof wherein: Ri and Ro independently represent hydrogen, halogen, C1-C6 alkyl, Ci-Ce alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or r2 wherein: r4 r2 4b (followed by page 4c ) INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 jun 2gq3 rfdfiv/Pn di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-Ce) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce)alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (Ci-C6) alkoxy; and R5, R6, R-7, and Re are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

Yet further provided is use of (a) a compound of the or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, C1-C6 alkyl, Ci-Ce alkoxy, Ci~Cj alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, Ci-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkylamino, cyano, nitro, perfluoro (C1-C6) alkyl or perfluoro (Ci-C6) alkoxy; and R5, Re, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

Also provided is use of (a) a compound of the formula: formula: r2 4c (followed by page 4d ) INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 jun 2003 RECEIVED 512772 C ■o r2 or (b) a pharmaceutically acceptable addition salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, C1-C3 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (C1-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-Ce)alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-C6) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorder or a motion disorder related to the use of a neuroleptic agent.

Further provided is use of (a) a compound of the formula: or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or r2 4d (followed by page 4e ) INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 jun 2003 512772 di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-Ce) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci~C6 alkyl, C1-C4 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce) alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-Ce) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for use in the treatment of schizophrenia.

Yet further provided is use of (a) a compound of the or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, C1-C6 alkyl, Ci-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C1-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-Ce) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, Ci-C4 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (C1-C6) alkoxy; and R5, Re, R7/ and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorder or a motion disorder related to the use of a neuroleptic agent. formula: r2 4e (followed by page 5 ) INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 j'jn 2003 nprpiucn 512772 DETAILED DESCRIPTION OF THE INVENTION Rs i wherein: Ri and R2 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, Ci-C6 alkoxy, C1-C6 alkylthio, hydroxy, amino, mono- or di(Ci-Ce)alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-Ce) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, Ci-C6 alkoxy, C1-C6 alkylthio, hydroxy, amino, mono- or di (Ci-Ce)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-Ce) alkoxy; A is an alkylene group of 1-3 carbon atoms; and R5, R6, R7, and R8 are the same or different and represent hydrogen or Ci-C6 alkyl.

Preferred compounds of Formula I are those where R5, R6, R7, and R8 are C1-C3 alkyl, and more preferably, hydrogen or methyl. Even more preferred compounds of Formula I are those where R5, R6, R7, and R8 are hydrogen. In the more preferred compounds of Formula I the hydrogens at positions R5 and R8 are in a trans configuration to one another. Particularly, preferred compounds of Formula I have Ri, R2, R3 and R4 as hydrogen, halogen or lower alkyl.

In other preferred compounds of I, when Ri and R3-R8 are all hydrogen, R2 is not tert-butyl, or more preferably not C1-C6 alkyl.

Also described are compounds of Formula II: (followed by page 5a) INIELLECTUAL PROPhRTY OFFICE OF N.Z. 12 2003 RECEIVED 512772 _ rs a r. r^n r2 II wherein: Ri and R2 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-Ce) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C1-C6)alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (C1-C6) alkoxy; and R5, R6, R7, and Rs are the same or different and represent hydrogen or C1-C3 alkyl. - 5a -(followed by page 6) 'NTEllECTUAi PROPERTY office OF n.z. 12 2003 ppp.pi\/Fn provided that R2 is not t-butyl when R2 and hydrogen. 512 772 d R3-R8 are afr In preferred compounds of Formula II, r5 and r8 are trans to each other. In yet more preferred compounds of Formula II, rs, r6, r,, and r8 are hydrogen or methyl. More preferred compounds of Formula II are those where rs, r6, r, and r8 are hydrogen. In the most preferred compounds of Formula I the hydrogens at positions rs and r8 are in a trans configuration to one another. Particularly preferred coupounds of Formula I have rlf r2, r3 and r„ as hydrogen, halogen or lower alkyl.

In other preferred compounds of Formula I, one of Rj and r2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen. In these preferred compounds r3 and r4 are preferably in the para and one of the ortho, i.e., the 4 and 2) positions with respect to the point of attachment to the phenyl ring and are hydrogen, halogen or ci-cj alkyl, provided that at least one of r3 and r4 is not hydrogen.

Also described Formula III: but not claimed are compounds- of III wherein Ra and R2 independently represent hydrogen, halogen, Cj-Cj alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Cj-Cg) alkylamino, cyano, nitro, perfluoro (Ci- Cg) alkyl or perfluoro (Ci-Cg) alkoxy ; in1ellectual PROPERTY office-* of n.z. 1 2 jun 2003 512772 R3 and R4 are the same or different and represent hydrogen, halogen, Cj-Cg alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro (Cj-Cg) alkyl or perfluoro (C^Cg) alkoxy; and R5, R6, R7, and Rs are the same or different and represent hydrogen or Cj-Cj alkyl.

Preferred compounds of Formula III are those where Rx and R2 are independently hydrogen, halogen, methyl, or ethyl. In more preferred compounds of Formula III, Rx and R2 are both hydrogen.

In other preferred compounds of Formula III, at least one of Ri and R2 is not hydrogen. In more preferred compounds of Formula III, at least one of Rx and R2 is not hydrogen, i.e., it is selected from halogen, Ci-C3 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cs) alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl and perfluoro (C^Cg) alkoxy, and R3 and R4 are in the 2 and 4 positions on the phenyl group. In these more preferred compounds of Formula III, Rs, Rs, R7, and R8. are hydrogen or methyl. Further, in these more preferred compounds of Formula III, R5 and R„ are trans to each other.

IV Ri and R2 independently represent hydrogen, halogen, Ci-Cg alkyl, Ci-Cg alkoxy, Cj-C, alkylthio, hydroxy, amino, mono- In another embodiment are compounds of Formula IV: r2 INILLLECFUAL PF.GFLRTY GFr OF N.Z. 12 jun 2g33 rfp.fi\/Fn 512772 or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro!Cj-Cg" alTyl or perfluoro (Cj-Cg) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-Cg alkyl, C1-C4 alkoxy, C1-C4 alkylthio, 5 hydroxy, amino, mono- or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (Ci-C6) alkoxy; and R5, Rg, R7, and Rs are the same or different and represent hydrogen or Ci-C3 alkyl.

Preferred compounds of Formula IV are those where Rj and R2 independently represent hydrogen, halogen, Cj-Cg alkoxy, C2-C4 alkylthio, hydroxy, amino, mono- or di (Cj-Cg) alkylamino, cyano, nitro or perfluoro (Ci-Cg) alkoxy. More preferred compounds of Formula IV are those where Rs, R6, R7, and R„ are hydrogen or 15 methyl. In the preferred compounds of Formula IV, R5 and R8 are trans to each other.

Other more preferred compounds of Formula IV are those where R3 is hydrogen, halogen, Ci~C3 alkyl, or Cj-Cj alkoxy. Particularly preferred compounds of Formula IV are those where 20 R4 is hydrogen, halogen, Ci~C3 alkyl, or Ci-C3 alkoxy and R3 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy.

Other preferred compounds of Formula IV are those where R3 represents hydrogen, chloro, or methyl. Still other preferred compounds of Formula IV are those where R4 represents hydrogen, 25 bromo chloro, methyl, nitro, or amino. Particularly preferred compounds of Formula IV are those wherein R3 represents hydrogen, chloro, or methyl, and R4 represents hydrogen, bromo chloro, methyl, nitro, or amino.

In a further embodiment are compounds of Formula V: INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 9 'V I L RECEIVED 512772 compounds of Formula Va are those where R4 represents hydrogen, bromo chloro, methyl, nitro, or amino. Particularly preferred compounds of Formula Va are those wherein R3 represents hydrogen, chloro, or methyl, and R4 represents hydrogen, bromo 5 chloro, methyl, nitro, or amino.

In still other preferred compounds of Formula Va, one of and R2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen. In these preferred compounds R3 and R4 are preferably in the para and 10 one of the ortho, i.e., the 4 and 2) positions with respect to the point of attachment to the phenyl ring and are hydrogen, halogen or C^-Cj alkyl, provided that at least one of R3 and R4 is not hydrogen. those having a skeleton with the following stereochemical configuration: Particularly preferred compounds of the invention are Such compounds are encompassed within Formula Va.

Also described are compounds of Formula Vb: r2 Vb wherein IfvjTpi i Fr.TUAL PROPERTY OFFICE OF N.Z. 1 2 jun 2003 received WO 00/40572 PCT/US00/00275 Rj and R2 independently represent hydrogen, halogen, C^-Cg alkyl, C1-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (Cj-Cg) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Cj-Cg alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (Cj-Cg) alkoxy; and R5, Rg, R7, and Rg are the same or different and represent hydrogen or Ci~C3 alkyl.

Preferred compounds of Formula Vb are those where R2 and Rz independently represent hydrogen, halogen, Ci-Cg alkoxy, C!-C4 alkylthio, hydroxy, amino, mono- or di(Cj-Cg)alkylamino, cyano, nitro or perfluoro (Ci-C6) alkoxy. More preferred compounds of Formula Vb are those where Rs, R6, R7, and RB are hydrogen or methyl. In these preferred compounds of Formula Vb, Rs and R8 are tsrans to each other.

Other more preferred compounds of Formula Vb are those where R3 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy. Particularly preferred compounds of Formula Vb are those where R4 is hydrogen, halogen, Ci-C3 alkyl, o-r Cj-Cj alkoxy and R3 is hydrogen, halogen, Ci-C3 alkyl, or Ci-Cj alkoxy.

Other preferred compounds of Formula Vb are those where R3 represents hydrogen, chloro, or methyl. Still other preferred compounds of Formula Vb are those where R4 represents hydrogen, bromo chloro, methyl, nitro, or amino. Particularly preferred compounds of Formula Vb are those wherein R3 represents hydrogen, chloro, or methyl, and R4 represents hydrogen, bromo chloro, methyl, nitro, or amino.

In still other preferred compounds of Formula Vb, one of Rj and R2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen. In these preferred compounds R3 and R„ are preferably in the para and 512772 one of the ortho, i.e., the 4 and 2) positions with respect to the point of attachment to the phenyl ring and are hydrogen, halogen or C^-Cj alkyl, provided that at least one of R3 and R4 is not hydrogen.

In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

Representative compounds, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable acid addition salts. In addition, if the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, me thane sulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. ~12~ INTELLECTUAL PROPERTY OFFICE \ OF N.Z. 1 2 jj;! 2g03 RECEIVED 512772 Also described are the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable 5 addition salts and acylated prodrugs of the compounds encompassed by Formula I.

Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound. 10 By "Ci-Cg alkyl" or "lower alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-15 methylpentyl. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.

By »Ci-C6 alkoxy" or "lower alkoxy" in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, 20 propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Preferred alkoxy groups herein are Cj-C^ alkoxy groups.

Preferred perfluoro (Ci-C6) alkyl groups of the invention 25 are trifluoromethyl groups. Preferred perfluoro(Cx-C6) alkoxy groups of the invention are trifluoroalkoxy groups.

By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine.

By aryl is meant an aromatic carbocyclic group having one 30 ring (e.g., phenyl), or two rings (e.g., biphenyl) . Such groups may be mono-, di-, or trisubstituted. Suitable substituents include, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.

INTELLECTUAL PROPERTY OFFICE [ OF N.Z. 12 jun 2003 RECEIVED By heteroaryl (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.

Representative compounds of the invention are shown in Table 1.

Table 1 CH3 CI Compound 3 Compound 4 (-) ISOMER Compound 5 (+) ISOMER Compounds having this skeleton are preferred. 512772 Also described is use of compounds of general Formula I in the treatment of neuropsychological disorders. The interaction of these compounds with dopamine receptors is shown in the examples. This interaction results in the pharmacological 5 activity of these compounds.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and 10 vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Also described is a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable 15 carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general 20 formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared 25 according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant 30 and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium IN1ELLECTUAL PROPERTY OFFICE** OF N.Z. 1 ? I'!' I L JvJi \ 0f!f RECEIVED WO 00/40572 PCT/US00/00275 phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example 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 glyceryl monosterate or glyceryl distearate may be employed.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more WO 00/40572 PCT/US00/00275 coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients 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 palatable oral preparations. 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.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a 512772 preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those 5 suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among 10 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 15 diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds and compositions of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared 20 by mixing the drug with a suitable non-irritating 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 materials are- cocoa butter and polyethylene glycols.

Compounds and compositions of the invention 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 local anesthetics, preservatives and buffering agents can be 30 dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) . The amount of active intellectual property office OF N.Z. 1 2 JUN 2003 PCT/USOO/00275 ingredient that may be combined with the carrier materials 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 between from about 1 mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

A representative synthesis of the compounds of the invention is presented in Scheme I. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.

Scheme 1 ?5 O R2 VI OH Zn, CuCl2 CUupm agent 1 HN. J VI11 F reduction R2 WO 00/40572 PCT/USOO/00275 wherein Ri, R2, R3, R4, R5, R6/ R7f and R8 are as defined above for Formula I.

As shown, a 2-arylcyclopropanecarboxylic acid VII is prepared from a cinnamic acid VI through exposure to an appropriately substituted methylene iodide (R6R7CI2) and zinc-copper couple. Variations of this procedure (the Simmons-Smith reaction) are well known in the literature (see Organic Reactions, Vol. 20, pages 1-131, 1982). Carboxylic acid VII is then condensed with an appropriately substituted 1-phenylpiperazine (VIII) in the presence of a coupling agent to provide a cyclopropylcarboxamide IX. Suitable coupling agents include carbonyl diimidazole (CDI), dicyclohexylcarbodiimide (DCC), benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or the like. Thereafter, compounds of Formula la may be prepared by reduction of IX with an appropriate reducing agent such as alane (AlH3) , borane (BH3) or lithium aluminum hydride. Coitpounds of Formula I can likewise be prepared starting with piperazine VIII. Thus, piperazine VIII can be alkylated with a suitable alkylating agent that allows for subsequent coupling with acid VII. Coupling may be carried out with a derivative of acid VII such as, for exaitple; a reduced form of the acid, i.e., an alcohol or aldehyde.

The compounds of general structure VI, VII. and VIII are either commercially available, known, or capable of being prepared by the methods known in the art. Where they are not commercially available, the compounds of general structure VI, VII and VIII may be prepared by procedures analogous to those described in literature. Those having skill in the art will recognize that the starting material may be varied and additional steps employed to produce compounds encompassed by the present invention.

WO 00/40572 PCT/US00/00275 The enantiomers of trans-2-phenylcyclopropane carboxylic acid can be prepared using the method of Overberger (Macromolecules, 4, 718 (1971)).

Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present inventions, as demonstrated by the following examples. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups.

The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.

Example 1 trans 2-(4-chlorophenvl)cvclopropanecarbokvlic acid.

A mixture of zinc dust (6.54 g, 0.1 mole) and cuprous chloride (1 g, 0.01 mole) in" methylene chloride (30 mL) is stirred and heated to reflux under a nitrogen atmosphere for 30 min. After the mixture is cooled to room temperature, methylene iodide (13.4 g, 0.05 mole) is added to the mixture which is then refluxed for an additional hour. After cooling to 0 °C, trans-4-chlorocinnamic acid (9.1 g) is added. The reaction is allowed to warm to room temperature over 2 hours and then refluxed for 3 days. The reaction is quenched at 0 °C by the addition of 30 ml of diethyl ether and 3 0 ml of ice cold 10% H2S04 solution. The mixture is filtered washed with ether. The organic layer is dried over MgS04 and concentrated to WO 00/40572 PCT/US00/00275 provide the desired product as a white solid. *H NMR (CDC13) 7.25 (d, J = 7 Hz, 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-chlorophenvl1cvclopropvl)carbonvlpiperazine To a solution of trans 2-(4- chlorophenyl) cyclopropanecarboxyxlic acid (80 mg, 0.4 mmol) in 3 mL of dry methylene chloride is added diisopropylethylamine (0.15 ml), 1-(4-chlorophenyl)piperazine (110 mg) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.2 g). The resulting mixture is stirred overnight, 10 mL of methylene chloride is added and the solution washed with water (2 X 10 mL) . The organic layer is dried over MgS04 and concentrated. The resulting material is purified by flash chromatography eluting with 30% EtOAc/hexane to provide the desired amide as a yellow oil (70 mg, 39%) *H NMR (CDClj) 7.2 (m, 4H) , 7.03 (d, J = 7Hz, 2H) , 6.83 (d, J = 7 Hz, 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-chlorophenvllcvclopropvl)methvlpjperazine To a solution of 1-(4-chlorophenyl)-4-([trans-2-phenyl]cyclopropyl)carbonylpiperazine (70 mg) in tetrahydrofuran (3 mL) is added a solution of alane (1 M, 0.6 mL) in tetrahydrofuran. The reaction is stirred at room temperature for 2 hr, concentrated, diluted with ethyl acetate and washed with IN NaOH solution and water. The resulting organic layer is dried over MgS04 and concentrated. Purification by radial chromatography eluting with 2% WO 00/40572 PCT/US00/00275 methanol/methylene chloride provides 30 mg of the product as a white solid (Compound 3). 1H NMR (CDC13) 7.2 (m, 4H) , 6.97 (d, J = 7Hz, 2H) , 6.82 (d, J = 7 Hz, 2H) , 3.18 (M, 4H) , 2.70 (m, 4H), 2.63 (dd, J = 7, 5 Hz,lH), 2.4 (m, 1H), 1.65 (m, 1H) , 5 1.22 (m, 1H) , 0.9 (m, 2H) . The fumarate salt (Compound 3A) is prepared in methanol and crystallized from ethyl acetate. m.p. 111-113 °C.

Example 4 The following compounds are prepared essentially according to the procedures set forth above. (a) 1-(2-methylphenyl)-4-(trans-2- phenylcyclopropyl)methylpiperazine hydrobromide (Compound 6). (b) l-(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 °C). (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).

WO 00/40572 PCT/US0O/OO275 (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 pharmaceutical utility of compounds of this invention is indicated by the following assays for dopamine receptor subtype affinity.

Determination of D2 And Receptor Binding Activity Pellets of COS cells containing recombinantly produced D2 or D4 receptors from human are used for the assays. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer at 4° C and pH 7.4. The sample is then centrifuged at 3 0,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48°C and contain 0.4 ml of tissue sample, 0.5 nM 3H-YM 09151-2 and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is WO 00/40572 PCT/US00/00275 less than 20% of total binding. The binding characteristics of examples of this patent for the D2 and D4 receptor subtypes are shown in Table 2.

TABLE 2 Compound Number D4 Ki (nM) D2 Ki (nM) 18 7 2 8 90 3 8 523 4 2 75 10 51 The binding constants of compounds of Formula I for the D4 receptor, expressed in nM, generally range from about 0.1 10 nanomolar (nM) to about 50 nanomolar (nM). Preferably, such compounds have binding constraints of from about 0.1 to 10 nM. These compounds preferably have binding constants for the D2 receptor of at least about 50 nM although compounds having lower Da binding constants may be used, although somewhat less 15 preferably. Thus, the compounds of the invention are generally at least about 5 time more selective for the D4 receptor than the D2 receptor. Preferably, these compounds are at least 10, and more preferably at least 15-50, times more selective for the D4 receptor than the D2 receptor.

Example 6 Preparation of radiolabeled probe compounds of the invention The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using 25 precursors comprising at least one atom that is a radioisotope. Thus, the product is a compound of the invention that is comprised of at least 1 radioactive atom. The radioisotope is WO 00/40572 PCT/USOO/00275 preferably selected from of at least one of carbon (preferably 14C) , hydrogen (preferably 3H) , sulfur (preferably 35S) , or iodine (preferably 1Z5I) . Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. 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; American Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea, CA.

Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.

Example 7 Receptor autoradiography Receptor autoradiography (receptor mapping) is carried out in vitro using radiolabeled compounds of the invention (prepared as described in Example 6) as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York and by Kuhar et al. in Annu. Rev. Neurosci, 1986, vol. 9, pages 27-59,.

WO 00/40572 PCT/US00/00275 The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood 5 that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as 10 invention, the following claims conclude this specification.

Claims

WHAT WE CLAIM IS:

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a compound of the formula: or (b) a pharmaceutically acceptable addition salt thereof wherein: Ri and R2 are the same or different and represent hydrogen, halogen, Ci-^ alkyl, Ci-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Cj-Cg)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, Ca-C4 alkylthio, hydroxy, amino, mono- or di(C!-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci—C6) alkoxy; and R5, Rg, R7, and R? are the same or different and represent hydrogen or C1-C3 alkyl.

2. A pharmaceutical composition according to claim 1, wherein R5, R6, R-7, and R8 are hydrogen or methyl.

3. A pharmaceutical composition according to claim 2, wherein R5 and Rs are trans to each other.

4. A pharmaceutical composition according to claim 1, where the compound has the formula: r2 28 intellectual property office OF N.Z. 12 jjm 2003 RECEIVED wherein: R: and R- independently represent hydrogen, halogen, C!-C3 alkyl, C1-C4 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Ce)alkylamino, cyano, nitro, perfluoro(Ci~Ct)alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci~C6 alkyl, Cj-Cj alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Cx-Ct)alkylamino, cyano, nitro, perfluoro (Ci~C6) alkyl or perfluoro (Ci~C6) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or Ci-C3 alkyl.

5. A pharmaceutical composition according to claim 4 wherein R; and R: are both hydrogen.

6. A pharmaceutical composition according to claim 4 wherein R: and R^ are independently hydrogen, halogen, methyl, or ethyl.

7. A pharmaceutical composition according to claim 4 wherein at least one of Ri and R- is not hydrogen.

8. A pharmaceutical composition according to claim 4 wherein R3 and R4 are in the 2 and 4 positions on the phenyl group.

9. A pharmaceutical composition according to claim 8, wherein Rr,, R6, R7, and R8 are hydrogen or methyl. - 29 - intellectual property ofpicf of n.z - 9 SEP 2003

RECEIVED 51277

11. A pharmaceutical composition according to claim 1, where the compound has the formula: Rx and R2 independently represent hydrogen, halogen, Ci-C6 alkyl, Ci-Cb alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci~C6 alkyl, Ci-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; and Rr, Rri, R-7, and Rs are the same or different and represent hydrogen or Ci-C3 alkyl.

12. A pharmaceutical composition according to claim 11, wherein Ri and R: independently represent hydrogen, halogen, Ci-C6 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci~ C6)alkylamino, cyano, nitro or perfluoro(Ci-Ce) alkoxy.

13. A pharmaceutical composition according to claim 11, wherein Ri and R; are independently hydrogen or Ci-Cg alkyl, provided that at least one of Ri and R; is not hydrogen.

14. A pharmaceutical composition according to claim 13, wherein R5, Rg, R7, and R8 are hydrogen or methyl.

15. A pharmaceutical composition according to claim 14, wherein R5 and Rfi are trans to each other. r2 wherein: 30 INTELLECTUAL PROPERTY OFFICE f, of n.z. 12 jun 2g03 RECEIVED 512 772

16. A pharmaceutical composition according to claim 15, wherein R3 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy.

17. A pharmaceutical composition according to claim 16, wherein R4 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy.

18. A pharmaceutical composition according to claim 11 wherein R3 represents hydrogen, chloro, or methyl.

19. A pharmaceutical composition according to claim 1, wherein R4 represents hydrogen, bromo chloro, methyl, nitro, or amino.

20. A pharmaceutical composition according to claim 1, where the compound has the formula: or pharmaceutically acceptable addition salts thereof wherein: Ri and R; independently represent hydrogen, halogen, C!-C6 alkyl, Ci-Ce alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (C!-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-Cg alkyl, Ci-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci~C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Cx-Ce) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C].-C3 alkyl. r2 31 intellectual property office OF N.Z. 1 2 2003 512772

21. A pharmaceutical composition according to claim 20, wherein R3 and R4 are in the 2 and 4 positions on the phenyl ring with respect to the point of attachment to the piperazine ring.

22. A pharmaceutical composition according to claim 21, wherein R- is in the 4 positions on the phenyl ring and represents halogen, alkoxy, hydroxy, amino, mono or di(Ci-C6)alkylamino, or nitro.

23. A pharmaceutical composition according to claim 21, wherein R2 is in the para position of the phenyl ring and represents Ci~ C4 alkylthio, perfluoro (Ci-C6) alkyl, or perfluoro (Ci-C6) alkoxy.

24. A pharmaceutical composition according to claim 1, where the compound is 1-(2-methylphenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

25. A pharmaceutical composition according to claim 1, where the compound is 1-(2,4-dimethylphenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

26. A pharmaceutical composition according to claim 1, where the compound is (S,S) 1-(2,4-dimethylphenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

27. A pharmaceutical composition according to claim 1, where the compound is (R,R) 1-(2,4-dimethylphenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

28. A pharmaceutical composition according to claim 1, where the compound is 1-(2-methyl-4-nitrophenyl)-4-(trans-2- phenylcyclopropyl)methylpiperazine. INTELLECTUAL PROPERTY OFFICE j OF N.Z. 12 jjn 2003 RECEIVED 512772

29. A pharmaceutical composition according to claim 1, where the compound is 1-(2-methyl-4-aminophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

30. A pharmaceutical composition according to claim 1, where the compound is 1-(2-methyl-4-bromophenyl)-4-(trans-2- phenylcyclopropyl)methylpiperazine.

31. A pharmaceutical composition according to claim 1, where the compound is 1-(4-chlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

32. A pharmaceutical composition according to claim 1, where the compound is 1-(2, 4-dichlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

33. A pharmaceutical composition according to claim 1, where the compound is 1-(2-chlorophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

34. A pharmaceutical composition according to claim 1, where the compound is l-(4 chlorophenyl)-4-(trans-2-[4- chlorophenyl]cycloproply)methylpiperazine.

35. Use of a compound for formula: or (b) a pharmaceutically acceptable addition salt thereof wherein: Rx and R; are the same or different and represent hydrogen, halogen, Ci-Cg alkyl, Ci-C^ alkoxy, Ci-C4 alkylthio, hydroxy r2 33 INTELLECTUAL PROPERTY OFriCE OF N.Z. 1 2 jum 2003 r f n f i \/ f n 51277 amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C;l-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (C!-C6) alkyl or perfluoro (Ci~C6) alkoxy; and R5, R6, R7, and Rs are the same or different and represent hydrogen or C1-C3 alkyl or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a CNS disorder selected from schizophrenia, mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of a neuroleptic agent.

36. A compound of the formula: or pharmaceutically acceptable addition salts thereof wherein: Ri and R: are the same or different and represent hydrogen, halogen, Ci-Cg alkyl, Ci~C6 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-Cg alkyl, C1-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-Cg) alkoxy; and Rs, Rg, R7, and R8 are the same or different and represent hydrogen or Ci-Cj alkyl; provided that neither of Rx and Rj is t-butyl and at least one of Rj and R4 is halogen. r2 34 INTELLECTUAL PROPERTY OFriC OF N.Z. 1 2 mi 2g03 ocrciUFD 512772

37. A compound according to claim 36, wherein R5/ R6, R7, and Rs are hydrogen or methyl.

38. A compound according to claim 37, wherein R5 and Rs are trans to each other.

39. A compound of the formula: or pharmaceutically acceptable addition salts thereof wherein: Ri is hydrogen, halogen, C^-Cg alkyl, Ci-C6 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di(Ci~C6)alkylamino, cyano, nitro, perfluoro (Ci~C5) alkyl or perfluoro (C^-Ck) alkoxy; R2 represents Ci-C4 alkylthio, perfluoro (C^-Ce) alkyl, or perfluoro (Ci-C6) alkoxy; R3 and R4 are hydrogen, halogen, Ci-C6 alkyl, Ci~C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-Cs) alkyl or perfluoro (Ci— C6) alkoxy; and R5, R6, R7, and Rs are the same or different and represent hydrogen or C!-C3 alkyl.

40. A compound according to claim 36, which is 1-(2-methyl-4-nitrophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

41. A compound according to claim 36, which is 1-(2-methyl-4-aminophenyl)-4-(trans-2-phenylcyclopropyl)methylpiperazine.

42. Use of (a) a compound of the formula: 35 intellectual propertTof? OF N.Z. 19 !! 'M *"000 1 £ I nr a 512772 R6 R % O * ^ ^ J r2 or (b) a pharmaceutically acceptable addition salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, C1-C3 alkyl, Ca-C4 alkoxy, Ci-C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C!-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, cyano, nitro, perfluoro (Ci-Cg) alkyl or perfluoro (Cx-Cg) alkoxy; and Rs, R6, R7, and R3 are the same or different and represent hydrogen or C!-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

43. A use according to claim 42 wherein Ri and R2 are both hydrogen.

44. A use according to claim 42 wherein Ri and R2 are independently hydrogen, halogen, methyl, or ethyl, wherein at least one of Ri and R2 is not hydrogen.

45. A use according to claim 44, wherein R5, R6, R7, and R8 are hydrogen or methyl.

46. A use according to claim 45, wherein R5 and Rs are trans to each other.

47. Use of a compound of the formula: - 36 - r4 r2 or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, Ci~C6 alkyl, Ci-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C!-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro(Ci-Cfi)alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; and R5, Rg, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

43. A use according to claim 47, wherein R: and RL are independently hydrogen or Ci-Ce alkyl, provided that at least one of Ri and R- is not hydrogen.

49. A use according to claim 48, wherein R5, R6, R7, and Re are hydrogen or methyl.

50. A use according to claim 49, wherein R5 and R8 are trans to each other.

51. A use according to claim 47 wherein: R-j represents hydrogen, chloro, or methyl; and R4 represents hydrogen, bromo chloro, methyl, nitro, or amino.

52. Use of (a) a compound of the formula: 37 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 jjm 2003 □ cncu/cn 51 2772 re r- k r? * *'//.. .>» n ^ / Ri ''//// N\^ i r2 or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R2 independently represent hydrogen, halogen, Ci-C6 alkyl, Ci-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro(Ci-C6)alkyl or perfluoro(Ci—C6)alkoxy; and R5, Rg, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of schizophrenia.

53. Use of (a) a compound of the formula: or (b) a pharmaceutically acceptable addition salt thereof wherein: Ri and R; independently represent hydrogen, halogen, C1-C3 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Cj-Cg)alkylamino, cyano, nitro, perfluoro(Ci-Cg)alkyl or perfluoro (Cn -C,5) alkoxy; r2 38 R3 and R4 are the same or different and represent hydrogen, halogen, Ci-Ce alkyl, C1-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di (Ci-C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; and rr, re, r7, and re are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorder or a motion disorder related to the use of a neuroleptic agent.

54. A use according to claim 53 wherein Rj and R; are both hydrogen.

55. A use according to claim 53 wherein R2 and Rj are independently hydrogen, halogen, methyl, or ethyl, wherein at least one of R: and R; is not hydrogen.

56. A use according to claim 55, wherein R5, R6, R7, and R8 are hydrogen or methyl.

57. A use according to claim 56, wherein R5 and R8 are trans to each other.

58. Use of (a) a compound of the formula: or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R: independently represent hydrogen, halogen, Ci-Cg alkyl, Ci-Cg alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or r2 39 INTELLECTUAL PROPERTY OFFICE OF N.Z - 9 SEP 2003 di (Ci—C6) alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, Ci-C4 alkoxy, Ci~C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-C6) alkyl or perfluoro (Ci-C6) alkoxy; and R5, R6, R7, and Ra are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for use in the treatment of schizophrenia.

59. A use according to claim 58, wherein Ri and R2 are independently hydrogen or Ci-C6 alkyl, provided that at least one of Ri and R2 is not hydrogen.

60. A use according to claim 59, wherein R5, R6, R7, and R8 are hydrogen or methyl.

61. A use according to claim 60, wherein R5 and Rg are trans to each other.

62. A use according to claim 58 wherein R3 represents hydrogen, chloro, or methyl; and R4 represents hydrogen, bromo chloro, methyl, nitro, or amino.

63. Use of (a) a compound of the formula: or (b) a pharmaceutically acceptable salt thereof wherein: Ri and R: independently represent hydrogen, halogen, C!-C6 alkyl, Cx-Ct, alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or r2 40 512772 di(Ci-C6)alkylamino, cyano, nitro, perfluoro(Ci-C6)alkyl or perfluoro (Ci~C6) alkoxy; R3 and R4 are the same or different and represent hydrogen, halogen, Ci-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di(Ci-C6)alkylamino, cyano, nitro, perfluoro (Ci-Ce) alkyl or perfluoro (Ci-C6) alkoxy; and R5, R6, R7, and R8 are the same or different and represent hydrogen or C1-C3 alkyl in the manufacture of a medicament for the treatment of mania, dementia, depression, anxiety, obsessive compulsive disorder, substance abuse, Parkinson-like motor disorder or a motion disorder related to the use of a neuroleptic agent.

64. A pharmaceutical composition as defined in claim 1 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

65. A use in the manufacture of a medicament as claimed in claim 35 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

66. A compound as defined in claim 36 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

67. A compound as defined in claim 39 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

68. A use as defined in claim 42 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. - 41 - INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 jun 2003 51277

69. A use as defined in claim 47 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

70. A use as claimed in claim 52 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

71. A use as defined in claim 53 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

72. A use as defined in claim 58 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

73. A use as defined in claim 63 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 jun 2003 RECEIVED