WO2000040572A1 - 1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: ligands de recepteurs de la dopamine - Google Patents

1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: ligands de recepteurs de la dopamine Download PDF

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WO2000040572A1
WO2000040572A1 PCT/US2000/000275 US0000275W WO0040572A1 WO 2000040572 A1 WO2000040572 A1 WO 2000040572A1 US 0000275 W US0000275 W US 0000275W WO 0040572 A1 WO0040572 A1 WO 0040572A1
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compound according
alkyl
alkoxy
hydrogen
perfluoro
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PCT/US2000/000275
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English (en)
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Xiaoyan Zhang
Jennifer Tran
He Zhao
Andrew Thurkauf
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Neurogen Corporation
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Priority to AU27203/00A priority Critical patent/AU771199B2/en
Priority to CA002359989A priority patent/CA2359989A1/fr
Priority to EP00905545A priority patent/EP1140879A1/fr
Priority to NZ512772A priority patent/NZ512772A/en
Priority to JP2000592280A priority patent/JP2002534421A/ja
Publication of WO2000040572A1 publication Critical patent/WO2000040572A1/fr
Priority to HK02102665.8A priority patent/HK1043360A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • 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 treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases.
  • the therapeutic effect of conventional antipsychotics known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors.
  • neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain.
  • EPS extrapyramidal side effects
  • 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
  • This invention provides novel compounds of Formula I which interact with dopamine subtypes. Accordingly, a first aspect of the invention is directed to a compound of Formula I :
  • R 1 and R 2 are the same or different and represent hydrogen, halogen, alkyl, C _ C 6 alkoxy, C -C 6 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro alkyl or perfluoro alkoxy;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, alkyl, C -C 6 alkoxy, c 1 ⁇ c 6 alkylthio, hydroxy, amino, mono- or di (C 1 -C 6 ) alkylamino, cyano, nitro, perfluoro (C 1 -C 6 ) alkyl or perfluoro alkoxy;
  • A is an alkylene group of 1-3 carbon atoms; and
  • R5 , RQ , R7, and R ⁇ are the same or different and represent hydrogen or C 1 -C 6 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 disorders include those involving memory impairment or attention deficit disorders.
  • Compounds of the present invention demonstrate high affinity and selectivity in binding to the D 4 receptor subtype. These compounds 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 D 4 receptors.
  • Compounds of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's disease by modulation of D 4 receptors since they exist selectively in areas known to control emotion and cognitive functions.
  • the invention provides methods for treatment and/or prevention of neuropsychological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits,
  • Parkinson-like motor disorders e.g., Parkinsonism and dystonia
  • motion disorders related to the use of neuroleptic agents are useful in treatment of depression, memory- impairment or Alzheimer's disease.
  • the compounds 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 are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents .
  • compounds 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) .
  • PET positron emission tomography
  • the invention provides pharmaceutical compositions comprising compounds of Formula I .
  • the invention provides intermediates useful in the preparation of compounds of Formula I .
  • the invention also provides methods for preparing the compounds of the invention.
  • the invention encompasses the compounds of Formula I described above.
  • Preferred compounds of Formula I are those where R 5 , R 6 , R 7 , and R 8 are C- ⁇ C j alkyl, and more preferably, hydrogen or methyl . Even more preferred compounds of Formula I are those where R 5 , R 6 , R 7 and R 8 are hydrogen. In the more preferred compounds of Formula I the hydrogens at positions R 5 and R 8 are in a trans configuration to one another. Particularly preferred compounds of Formula I have R., R 2 , R 3 and R 4 as hydrogen, halogen or lower alkyl.
  • R 2 is not tert-butyl, or more preferably not -Cg alkyl .
  • the invention encompasses compounds of
  • Ri and R 2 are the same or different and represent hydrogen, halogen, alkyl, Ci-C ⁇ alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro (C 1 -C 6 ) alkyl or perfluoro alkoxy;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro alkyl or perfluoro alkoxy; and
  • R5 Re R7 and Re are the same or different and represent hydrogen or C 1 -C 3 alkyl; provided that R 2 is not t -butyl when R 1 and R 3 -R 8 are all hydrogen .
  • R 5 and R a are trans to each other.
  • R 5 , R 6 , R 7 , and R 8 are hydrogen or methyl.
  • More preferred compounds of Formula II are those where R s , R 6 , R 7 and R 8 are hydrogen.
  • the hydrogens at positions R 5 and R 8 are in a trans configuration to one another.
  • Particularly preferred compounds of Formula I have R 1# R 2 , R 3 and R 4 as hydrogen, halogen or lower alkyl.
  • one of R ⁇ and R 2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen.
  • R 3 and R 4 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 C 1 -C 3 alkyl, provided that at least one of R 3 and R 4 is not hydrogen .
  • R- L and R 2 independently represent hydrogen, halogen, C ⁇ alkyl, C3 . -C 4 alkoxy, C1-C 4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro ( C 1 -
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro (C 1 -C 6 ) alkyl or perfluoro (C 1 -C 6 ) alkoxy; and R5 , R , R7, and Rs are the same or different and represent hydrogen or C 1 -C 3 alkyl.
  • Preferred compounds of Formula III are those where R. and R 2 are independently hydrogen, halogen, methyl, or ethyl. In more preferred compounds of Formula III, R ⁇ and R 2 are both hydrogen .
  • At least one of R 1 and R 2 is not hydrogen.
  • at least one of R 1 and R 2 is not hydrogen, i.e., it is selected from halogen, C ⁇ C j alkyl, C1-C4 alkoxy, C1 . -C4 alkylthio, hydroxy, amino, mono- or di (C 1 -C 6 ) alkylamino, cyano, nitro, perfluoro (C x -C 6 ) alkyl and perfluoro alkoxy, and R 3 and R 4 are in the 2 and 4 positions on the phenyl group.
  • R 5 , R 6 , R 7 , and R 8 are hydrogen or methyl. Further, in these more preferred compounds of Formula III, R 5 and R 8 are trans to each other.
  • R x and R 2 independently represent hydrogen, halogen, C ⁇ C g alkyl, C 1 -C 6 alkoxy, C ⁇ alkylthio, hydroxy, amino, mono- or di (C- L -Cg) alkylamino, cyano, nitro, perfluoro (C ⁇ C g ) alkyl or perfluoro (C- L -Cg) alkoxy;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro alkoxy; and
  • R5, R ⁇ , R7, and Rs are the same or different and represent hydrogen or C- L -C J alkyl.
  • Preferred compounds of Formula IV are those where R x and R 2 independently represent hydrogen, halogen, alkoxy, C x -C 4 alkylthio, hydroxy, amino, mono- or di (C 1 -C 6 ) alkylamino, cyano, nitro or perfluoro alkoxy . More preferred compounds of Formula IV are those where R 5 , R 6 , R 7 , and R 8 are hydrogen or methyl. In the preferred compounds of Formula IV, R 5 and R 8 are trans to each other.
  • R 3 is hydrogen, halogen, C ⁇ -C ⁇ 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 ⁇ ⁇ -C j alkoxy and R 3 is hydrogen, halogen, C 1 -C 3 alkyl, or C x -C 3 alkoxy.
  • R 3 represents hydrogen, chloro, or methyl.
  • Still other preferred compounds of Formula IV are those where R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • Particularly preferred compounds of Formula IV are those wherein R 3 represents hydrogen, chloro, or methyl, and R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • R- L and R 2 independently represent hydrogen, halogen, alkyl, C1-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C x -C 6 ) alkylamino, cyano, nitro, perfluoro (C x - C 6 ) alkyl or perfluoro alkoxy;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, C 1 -C 6 alkyl, C1-C4 alkoxy, C1-C 4 alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, perfluoro alkyl or perfluoro (C x -C 6 ) alkoxy;
  • R5 , R ⁇ , R7 , and R ⁇ are the same or different and represent hydrogen or C 1 -C 3 alkyl.
  • Preferred compounds of Formula Va are those where R ⁇ and R 2 independently represent hydrogen, halogen, alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro or perfluoro (C 1 -C 6 ) alkoxy. More preferred compounds of Formula Va are those where R 5 , R 6 , R 7 , and R 8 are hydrogen or methyl. In the preferred compounds of Formula Va, R 5 and R 8 are trans to each other.
  • R 3 is hydrogen, halogen, C 1 -C 3 alkyl, or C ⁇ C., 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.
  • R 3 represents hydrogen, chloro, or methyl.
  • Still other preferred compounds of Formula Va are those where R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • Particularly preferred compounds of Formula Va are those wherein R 3 represents hydrogen, chloro, or methyl, and R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • one of R 1 and R 2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen.
  • R 3 and R 4 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 C ⁇ C;, alkyl, provided that at least one of R 3 and R 4 is not hydrogen.
  • Particularly preferred compounds of the invention are those having a skeleton with the following stereochemical configuration :
  • Such compounds are encompassed within Formula Va .
  • R 1 and R 2 independently represent hydrogen, halogen, C 1 -C 6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, hydroxy, amino, mono- or di (C x -C 6 ) alkylamino, cyano, nitro, perfluoro (C x - C 6 ) alkyl or perfluoro alkoxy;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, C ⁇ C g alkyl, C1 .
  • R5 , R ⁇ , R7 , and Rs are the same or different and represent hydrogen or C 1 -C 3 alkyl.
  • Preferred compounds of Formula Vb are those where R x and R 2 independently represent hydrogen, halogen, alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro or perfluoro alkoxy . More preferred compounds of Formula Vb are those where R 5 , R 6 , R 7 , and R 8 are hydrogen or methyl. In these preferred compounds of Formula Vb, R 5 and R 8 are tsrans to each other.
  • R 3 is hydrogen, halogen, C ⁇ C;, alkyl, or C- ⁇ C j alkoxy.
  • Particularly preferred compounds of Formula Vb are those where R 4 is hydrogen, halogen, C ⁇ C ; , alkyl, or C 1 -C J alkoxy and R 3 is hydrogen, halogen, C ⁇ -C 3 alkyl, or C x -C 3 alkoxy.
  • R 3 represents hydrogen, chloro, or methyl.
  • Still other preferred compounds of Formula Vb are those where R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • Particularly preferred compounds of Formula Vb are those wherein R 3 represents hydrogen, chloro, or methyl, and R 4 represents hydrogen, bromo chloro, methyl, nitro, or amino.
  • one of R- L and R 2 may be halogen, preferably in the para position on the phenyl ring, while the other is hydrogen.
  • R 3 and R 4 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 C ⁇ ⁇ -C j alkyl, provided that at least one of R 3 and R 4 is not hydrogen.
  • 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.
  • 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 of the present invention include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • 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, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) 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.
  • the present invention
  • 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- methylpentyl .
  • Preferred C -C ⁇ alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl .
  • 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, 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 C 1 -C 4 alkoxy groups.
  • Preferred perfluoro (C 1 -C 6 ) alkyl groups of the invention are trifluoromethyl groups.
  • Preferred perfluoro (C ⁇ C g ) alkoxy groups of the invention are trifluoroalkoxy groups.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • aryl an aromatic carbocyclic group having one 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.
  • 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.
  • heteroaryl groups include, for example, thienyl, furanyl , thiazolyl, imidazolyl, (is) oxazolyl , pyridyl , pyrimidinyl, (iso) quinolinyl , naphthyridinyl , benzimidazolyl , and benzoxazolyl .
  • the invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders.
  • the interaction of compounds of the invention with dopamine receptors is shown in the examples. This interaction results in the pharmacological activity of these compounds.
  • the compounds of general formula I 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 vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable 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.
  • compositions containing compounds of general 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 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 and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium 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.
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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.
  • 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 monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • 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 preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 , 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • 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 of general formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be 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 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.
  • 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.
  • Ri , R2 , R3 , R4 , R 5 , R 6 , R 7 , and R 8 are as defined above for Formula I .
  • a 2 -arylcyclopropanecarboxylic acid VII is prepared from a cinnamic acid VI through exposure to an appropriately substituted methylene iodide (R 6 R 7 CI 2 ) 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
  • compounds of Formula la may be prepared by reduction of IX with an appropriate reducing agent such as alane (AlH 3 ) , borane (BH 3 ) or lithium aluminum hydride.
  • an appropriate reducing agent such as alane (AlH 3 ) , borane (BH 3 ) or lithium aluminum hydride.
  • Compounds of Formula I can likewise be prepared starting with piperazine VIII.
  • 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 example, 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.
  • the enantiomers of trans-2-phenylcyclopropane carboxylic acid can be prepared using the method of Overberger (Macromolecules, 4, 718 (1971)).
  • Example 1 trans 2- (4-chlorophenyl) cyclopropanecarboxylic 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.
  • Example 4 The following compounds are prepared essentially according to the procedures set forth above.
  • Example 5 The pharmaceutical utility of compounds of this invention is indicated by the following assays for dopamine receptor subtype affinity.
  • 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 30,000 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 HC1 buffer containing 100 mM NaCl.
  • Incubations are carried out at 48 °C and contain 0.4 ml of tissue sample, 0.5 nM 3 H-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 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.
  • the binding constants of compounds of Formula I for the D 4 receptor generally range from about 0.1 nanomolar (nM) to about 50 nanomolar (nM) .
  • such compounds have binding constraints of from about 0.1 to 10 nM.
  • These compounds preferably have binding constants for the D 2 receptor of at least about 50 nM although compounds having lower D 2 binding constants may be used, although somewhat less preferably.
  • the compounds of the invention are generally at least about 5 time more selective for the D 4 receptor than the D 2 receptor.
  • these compounds are at least 10, and more preferably at least 15-50, times more selective for the D 4 receptor than the D 2 receptor.
  • the compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • the product is a compound of the invention that is comprised of at least 1 radioactive atom.
  • the radioisotope is preferably selected from of at least one of carbon (preferably
  • radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • 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.
  • 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,.
  • 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 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 invention, the following claims conclude this specification.

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Abstract

La présente invention concerne des composés représentés par la formule (I) ou des sels d'addition acceptables du point de vue pharmaceutique desdits composés. Dans ladite formule, R1, R2, R3, R4, R5, R6, R7 et R8 représentent des substituants organiques et/ou inorganiques définis dans la description. Lesdits composés sont utiles dans le traitement et/ou la prévention de troubles neuropsychologiques, dont, entre autres, la schizophrénie, la manie, la démence, la dépression, l'anxiété, les comportements compulsifs, l'abus de substances toxiques, les troubles moteurs apparentés à la maladie de Parkinson et les troubles du mouvement liés à l'utilisation d'agents neuroleptiques.
PCT/US2000/000275 1999-01-08 2000-01-06 1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: ligands de recepteurs de la dopamine WO2000040572A1 (fr)

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AU27203/00A AU771199B2 (en) 1999-01-08 2000-01-06 1-phenyl-4-(1-(2-aryl)cyclopropyl) methylpiperazines: dopamine receptor ligands
CA002359989A CA2359989A1 (fr) 1999-01-08 2000-01-06 1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: ligands de recepteurs de la dopamine
EP00905545A EP1140879A1 (fr) 1999-01-08 2000-01-06 1-phenyl-4-(1- 2-aryl]cyclopropyl) methylpiperazines: ligands de recepteurs de la dopamine
NZ512772A NZ512772A (en) 1999-01-08 2000-01-06 1-Phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines useful as dopamine receptor ligands
JP2000592280A JP2002534421A (ja) 1999-01-08 2000-01-06 １−フェニル−４−（１−［２−アリール］シクロプロピル）メチルピペラジン：ドーパミン受容体リガンド
HK02102665.8A HK1043360A1 (zh) 1999-01-08 2002-04-09 1-苯基-4-(1-[2-芳基]環丙基)甲基哌嗉：多巴胺受體配體

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JP2004518744A (ja) * 2001-02-16 2004-06-24 アベンティス・ファーマスーティカルズ・インコーポレイテツド 新規複素環式尿素誘導体およびドーパミンｄ３受容体リガンドとしてのそれらの使用
JP2004518745A (ja) * 2001-02-16 2004-06-24 アベンティス・ファーマスーティカルズ・インコーポレイテツド 新規な複素環式アミド誘導体およびドーパミンｄ３受容体リガンドとしてのその使用
WO2009024823A3 (fr) * 2007-08-22 2009-04-16 Astrazeneca Ab Dérivés de cyclopropyl amide 978
US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
US9012452B2 (en) 2010-02-18 2015-04-21 Astrazeneca Ab Processes for making cyclopropyl amide derivatives and intermediates associated therewith
US20190022093A1 (en) * 2016-03-24 2019-01-24 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer
US10882834B2 (en) 2013-09-20 2021-01-05 University of Pittsburgh—of the Commonwealth System of Higher Education Compounds for treating prostate cancer

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WO1996016040A1 (fr) * 1994-11-23 1996-05-30 Neurogen Corporation Certains derives 4-aminomethyl 2-substitues de l'imidazole et derives 2-aminomethyl 4-substitues de l'imidazole, nouvelles categories de ligands specifiques du sous-type du recepteur de la dopamine
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
WO1998033784A1 (fr) * 1997-01-30 1998-08-06 Neurogen Corporation Ligands de 1-phenyle-4-benzylpiperazines specifiques pour le sous-type du recepteur de dopamine (d4)

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EP0188887A1 (fr) * 1985-01-17 1986-07-30 Imperial Chemical Industries Plc Composés aminés tertiaires
WO1996016040A1 (fr) * 1994-11-23 1996-05-30 Neurogen Corporation Certains derives 4-aminomethyl 2-substitues de l'imidazole et derives 2-aminomethyl 4-substitues de l'imidazole, nouvelles categories de ligands specifiques du sous-type du recepteur de la dopamine
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
WO1998033784A1 (fr) * 1997-01-30 1998-08-06 Neurogen Corporation Ligands de 1-phenyle-4-benzylpiperazines specifiques pour le sous-type du recepteur de dopamine (d4)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004518744A (ja) * 2001-02-16 2004-06-24 アベンティス・ファーマスーティカルズ・インコーポレイテツド 新規複素環式尿素誘導体およびドーパミンｄ３受容体リガンドとしてのそれらの使用
JP2004518745A (ja) * 2001-02-16 2004-06-24 アベンティス・ファーマスーティカルズ・インコーポレイテツド 新規な複素環式アミド誘導体およびドーパミンｄ３受容体リガンドとしてのその使用
EA016687B8 (ru) * 2007-08-22 2012-07-30 Астразенека Аб Производные циклопропиламида
EP2805937A1 (fr) * 2007-08-22 2014-11-26 AstraZeneca AB Dérivés de cyclopropyl amide
EP2253615A1 (fr) * 2007-08-22 2010-11-24 AstraZeneca AB Derives de cyclopropyl amide
US8063215B2 (en) 2007-08-22 2011-11-22 Astrazeneca Ab Cyclopropyl amide derivatives
AU2008290329B2 (en) * 2007-08-22 2011-12-22 Astrazeneca Ab Cyclopropyl amide derivatives
EA016687B1 (ru) * 2007-08-22 2012-06-29 Астразенека Аб Производные циклопропиламида
WO2009024823A3 (fr) * 2007-08-22 2009-04-16 Astrazeneca Ab Dérivés de cyclopropyl amide 978
KR20100080768A (ko) * 2007-08-22 2010-07-12 아스트라제네카 아베 시클로프로필 아미드 유도체
KR101588466B1 (ko) 2007-08-22 2016-01-25 아스트라제네카 아베 시클로프로필 아미드 유도체
US9029381B2 (en) 2007-08-22 2015-05-12 Astrazeneca Ab Cyclopropyl amide derivatives
US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
US9012452B2 (en) 2010-02-18 2015-04-21 Astrazeneca Ab Processes for making cyclopropyl amide derivatives and intermediates associated therewith
US10882834B2 (en) 2013-09-20 2021-01-05 University of Pittsburgh—of the Commonwealth System of Higher Education Compounds for treating prostate cancer
US20190022093A1 (en) * 2016-03-24 2019-01-24 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer
US10980806B2 (en) * 2016-03-24 2021-04-20 University of Pittsburgh—of the Commonwealth System of Higher Education Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer
US11766433B2 (en) 2016-03-24 2023-09-26 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer

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