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WO1999043670A1 - Derives de benzylpiperazinyl et piperidinyl ethanone, preparation, et utilisation comme antagonistes des recepteurs d4 de la dopamine - Google Patents

Derives de benzylpiperazinyl et piperidinyl ethanone, preparation, et utilisation comme antagonistes des recepteurs d4 de la dopamine Download PDF

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Publication number
WO1999043670A1
WO1999043670A1 PCT/US1999/004309 US9904309W WO9943670A1 WO 1999043670 A1 WO1999043670 A1 WO 1999043670A1 US 9904309 W US9904309 W US 9904309W WO 9943670 A1 WO9943670 A1 WO 9943670A1
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compound according
hydrogen
alkyl
formula
piperazinyl
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PCT/US1999/004309
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English (en)
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Renata X. Kover
Silva Terdjanian
Jennifer Tran
Andrew Thurkauf
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Neurogen Corporation
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Priority to JP2000533426A priority Critical patent/JP2002504549A/ja
Priority to EP99909657A priority patent/EP1068193A1/fr
Priority to KR1020007009454A priority patent/KR20010041341A/ko
Priority to HU0100926A priority patent/HUP0100926A3/hu
Priority to CA002321830A priority patent/CA2321830A1/fr
Priority to AU28814/99A priority patent/AU2881499A/en
Priority to IL13793099A priority patent/IL137930A0/xx
Priority to PL99342597A priority patent/PL342597A1/xx
Publication of WO1999043670A1 publication Critical patent/WO1999043670A1/fr
Priority to NO20004271A priority patent/NO20004271L/no

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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
    • C07D295/04—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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to substituted 2- (4- benzylpiperazin-1-yl) and 2 - (l-benzylpiperidin-4-yl) ethanones 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.
  • neuroleptics 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 extrapyra idal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D 2 receptors in the striatal region of the brain.
  • EPS extrapyra idal side effects
  • tardive dyskinesias which are attributed to blockade of D 2 receptors in the striatal region of the brain.
  • the dopamine D 4 receptor subtype has been identified (Nature, 347 : 146 (Sokoloff et al . , 1990)). Its unique localization in li bic brain areas and its differential recognition of various antipsychotics suggest that the D 4 receptor may play a major role in the etiology of schizophrenia.
  • Selective D 4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptic
  • the invention provides novel compounds which interact with dopamine receptor subtypes. Accordingly, in a broad aspect, the invention provides compounds of Formula I:
  • Y represents oxygen or sulfur;
  • Z is nitrogen or CH;
  • R-, R 2 and R 3 independently represent hydrogen, halogen, hydroxy, lower alkoxy, C.-C 6 alkyl, trifluoromethyl or trifluoromethoxy;
  • R 4 and R 4 ' independently represent hydrogen or C- ⁇ C g alkyl; or R 4 and R 4 ' together with the atom to which they are attached form a ring having from 3-7 members;
  • R 5 represents hydrogen, C j ,-C 6 alkyl, C-Cg alkoxy, or C ⁇ C g alkylthio;
  • R 6 is hydrogen or C.-C 6 alkyl; or R 5 and R 6 together represent C--C 5 alkylene, C 1 -C 4 alkyleneoxy,
  • R 7 , R 8 , R 9 , R 10 , and R.. independently represent hydrogen or C ⁇ C g alkyl .
  • 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.
  • the invention provides methods for treatment and/or prevention of neuropsychochological 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, and motion disorders related to the use of neuroleptic agents.
  • the compounds of the invention 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 .
  • the invention provides pharmaceutical compositions comprising compounds of Formula I .
  • the invention provides intermediates useful for preparing compounds of Formula I. DETAILED DESCRIPTION OF THE INVENTION
  • the invention encompasses substituted 2- (4-benzyl) -piperazinyl- and piperidinyl-1-ethanones of Formula I.
  • Preferred compounds of Formula I are those where R 2 and R 3 are not both hydrogen simultaneously.
  • Other preferred compounds of Formula I are those where R 7 , R 8 , R 9 , and R 10 are hydrogen.
  • R-. is preferably hydrogen, methyl or ethyl, most preferably hydrogen.
  • the invention encompasses compounds where R 5 and R 6 together represent C--C 5 alkylene, C.-C 4 alkyleneoxy, and C 1 - C 4 alkylenethio .
  • the oxygen or sulfur atoms are immediately adjacent the phenyl ring carrying the R 5 group.
  • R 5 and R 6 together with the atoms to which they are attached form a ring having from 5-9 members. Examples of such rings include the following:
  • R 4 and R 4 ' independently represent hydrogen or C.-Cg alkyl, or R 4 and R 4 ' together with the atom to
  • Representative resulting spiro ring systems include the following:
  • X represents oxygen, or sulfur, or CH; Y is oxygen or sulfur; Z is nitrogen or CH;
  • -7- n is zero or an integer of from 1-4;
  • R., R 2 and R 3 independently represent hydrogen, halogen, hydroxy, lower alkoxy, C--C 6 alkyl, trifluoromethyl or trifluoromethoxy;
  • R 4 and R 4 ' independently represent hydrogen or C.-C 6 alkyl; or R 4 and R 4 ' together with the atom to which they are attached form a ring having from 3-7 members;
  • R 7 , R 8 , R 9 , R 10 , and R X1 independently represent hydrogen or C ⁇ C g alkyl .
  • Preferred compounds of Formula II are those where R 2 and
  • R 3 are not simultaneously hydrogen.
  • R 4 and R 4 ' are independently hydrogen or C--C 4 alkyl.
  • n is 0 or 1, and more preferably 0.
  • a preferred group of compounds of Formula II are those where Y is oxygen, X is CH 2 and Z is CH. Such compounds are depicted by Formula Ila:
  • R 3 Ila wherein n, R l t R 2 , R 3 , R 4 , R 4 ' R 7 , R 8 , R 9 , R 10 , and R are as defined above for Formula II.
  • R__ is preferably hydrogen, methyl or ethyl.
  • R__ is preferably hydrogen, methyl or ethyl.
  • R_ is hydrogen or halogen
  • R 2 and R 3 are independently selected from hydrogen, C_-C_ alkyl, and halogen. More preferred such compounds of Formula Ila are those where R.. is hydrogen or methyl, R_ is hydrogen or halogen, and not both of R 2 and R 3 are hydrogen simultaneously. Particularly preferred compounds of Formula Ila are those where R__ is hydrogen or methyl, R 2 is hydrogen, R 3 is methyl, methoxy, chloro, or fluoro, R 4 and R 4 ' are independently hydrogen or lower alkyl, most preferably C--C 2 alkyl, and R_ is hydrogen or halogen.
  • Another preferred group of compounds of Formula II are those where Z is nitrogen and X is CH 2 . Such compounds are generally represented by Formula lib:
  • n, Y, R_ , R 2 , R 3 , R 4 , R 4 ' R 7 , R 8 , R 9 , R 10 , and R X1 are as defined above for Formula II.
  • R u is preferably hydrogen, methyl or ethyl.
  • Y is oxygen
  • R. is hydrogen or halogen
  • R 2 and R 3 are independently selected from hydrogen, C_-C 6 alkyl, and halogen.
  • More preferred compounds of Formula lib are those where R.. is hydrogen or methyl, Y is oxygen, R ⁇ is hydrogen or halogen, and not both of R 2 and R 3 are hydrogen simultaneously.
  • R X1 is hydrogen or methyl
  • Y is oxygen
  • R 2 is hydrogen
  • R 3 is methyl, methoxy, chloro, or fluoro
  • R 4 and R 4 ' are independently hydrogen or lower alkyl, most preferably C.-C-, alkyl
  • R- is hydrogen or halogen.
  • R 2 and R 3 are preferably not both hydrogen simultaneously.
  • a preferred group of compounds of Formula III, hereinafter Formula Ilia are those where Y is oxygen, Z is nitrogen, R_ is hydrogen or halogen, and R 2 and R 3 are independently selected from hydrogen, C--C 6 alkyl, and halogen. Still more preferred compounds of Formula Ilia are those where not both of R 2 and R 3 are hydrogen simultaneously.
  • R 2 is hydrogen, R 3 is methyl, chloro, or fluoro, and one or both of R 4 and R 4 ' are lower alkyl, most preferably C 1 -C 2 alkyl, and R. is hydrogen or halogen.
  • Particularly preferred compounds of Formula Ilia are those where R 2 is hydrogen and R 3 is a methyl, chloro, or fluoro group in the 4 position on the phenyl ring.
  • Other particularly preferred compounds of Formula Ilia are those where the phenyl substituted with R 2 and R 3 is 2 -alkoxy- 5-halophenyl . Representative of such particularly preferred compounds are those where the phenyl carrying R 2 and R 3 is 2- (C 1 -C 2 ) alkoxy-5-fluoro or 5-chlorophenyl .
  • Formula Illb Another preferred group of compounds of Formula III, hereinafter Formula Illb, are those where Y is oxygen, Z is CH, R ⁇ is hydrogen or halogen, and R 2 and R 3 are independently selected from hydrogen, C.-C 6 alkyl, and halogen. Still more
  • -11- preferred compounds of Formula I I lb are those where not both of R 2 and R 3 are hydrogen simultaneously.
  • Other preferred compounds of Formula 11lb are those where R 2 is hydrogen, R 3 is methyl, chloro, or fluoro, and one or both of R 4 and R 4 ' are lower alkyl, most preferably C--C- alkyl, and R_ is hydrogen or halogen.
  • Particularly preferred compounds of Formula Illb are those where R 2 is hydrogen and R 3 is a methyl, chloro, or fluoro group in the 4 position on the phenyl ring.
  • Other particularly preferred compounds of Formula 11 lb are those where the phenyl substituted with R 2 and R 3 is 2-alkoxy-5- halophenyl . Representative of such particularly preferred compounds are those where the phenyl carrying R 2 and R 3 is 2-
  • X, n, Y, Z, R-, R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , and R X1 are as defined above for Formula I, and is zero or an integer of from 1-4.
  • R 2 and R 3 are not both hydrogen simultaneously in the compounds of Formula IV.
  • Preferred compounds of Formula IV are those where X is CH 2 , n is 0, R 4 and R 4 ' form a five-membered carbocyclic ring with the atom to which they are attached (i.e., m is 2), and R 1X is hydrogen.
  • Z in Formula IV is CH
  • X is CH 2 , Y is oxygen, and n is 0. More preferred compounds are those where X is CH 2 , Y is oxygen, and n is 0, R_ is hydrogen or halogen, and R 2 and R 3 are independently selected from hydrogen, C--C 6 alkyl, and halogen. Still more preferred compounds of these formulae are those where X is CH 2 , Y is oxygen, and n is 0 and not both of R 2 and R 3 are hydrogen simultaneously.
  • Other preferred compounds of Formulae IVa and IVb are those where Z is CH, Y is oxygen, R 2 is hydrogen, and R 3 is methyl, fluoro or chloro.
  • Particularly preferred compounds of these formulae are those where X is CH 2 , Y is oxygen, and n is 0, R 2 is hydrogen and R 3 is a methyl, chloro or fluoro group in the 4 position on the phenyl ring.
  • Other particularly preferred compounds of these formulas are those where the phenyl substituted with R 2 and R 3 is 2-alkoxy-5-
  • Vll-a wherein X, n, Y, and R_ are as defined above for Formula I, m is zero or an integer of from 1-4, and L is a leaving group, such as, for example, halogen, methane sulfonyl, or toluenesulfonyl .
  • a preferred group of compounds of Formula VII -a are those where Y is oxygen, X is oxygen or, more preferably, methylene, m is 2, and R- is hydrogen or halogen.
  • L is a leaving group
  • a preferred group of compounds of Formula VII -b are those where Y is oxygen or, more preferably, methylene, and R. is
  • 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 of the present invention include, but are not limited to the compounds in Table I 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
  • 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-ACOOH 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-ACOOH 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 C--C 6 alkyl, i.e., 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 .
  • alkoxy or “lower alkoxy” in the present invention is meant C,-C 6 alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • the compounds of the invention are useful in the treatment of neuropsychological disorders; the pharmaceutical utility of compounds of this invention is indicated by the assays for dopamine receptor subtype affinity described below in the Examples.
  • the interaction of the substituted 2- (4- Phenylmethyl) -piperazino-1-ethanones of the invention with dopamine receptor subtypes results in the pharmacological activities 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
  • 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 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.
  • 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
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated
  • -20- 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 monostearate 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.
  • 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
  • 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,
  • 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.
  • 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.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • 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 monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • 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 .
  • a non-toxic parentally acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
  • 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. lmg to about 140mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5mg to about 7g per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials are useful in the treatment of the above-indicated conditions (about 0.5mg to about 7g per patient per day) .
  • Dosage unit forms will generally contain between from about lmg to about 500mg 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.
  • R,, R 2 , R 3 , R 4 , R 4 ' , R s , R 6 , and Y are as defined above for Formula I .
  • the piperazine derivatives VIII are generally commercially available but may also be prepared using methods described in the literature.
  • (XI) may be reduced with hydrogen gas in the presence of a catalyst, e.g., platinum, to provide piperidine aminoester derivative XII.
  • a catalyst e.g., platinum
  • Aminoester XII may be condensed with an appropriate benzylic alkylating agent containing a leaving
  • W may be a halogen or a sulfonate ester or the like, to provide an N-benzylpiperidine of general structure XIII.
  • the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
  • HBr salt of the title compound (Compound 19) is prepared from a methanolic solution (using 48% aqueous HBr) , and recrystallized from ethanol/acetone to yield a white solid, mp: 258-260°C.
  • Pellets of CHO cells containing human D 2 or D 4 receptors cloned from c-DNA are used for assays (Tallman, J. F. et . al . , J. Pharm . Exp . Ther. , 1997, 282, 1011).
  • the cloned membranes are homogenized in 100 volumes (wt/vol) of 0.05M Tris-HCl buffer at 4°C and pH 7.4 containing 120 mM NaCl , 1 mM EDTA and 5mM MgCl 2 .
  • the samples were centrifuged at 48,000 X g then resuspended and re-homogenized.
  • the final tissue sample is kept frozen until use.
  • the tissue is resuspended 1:20 (wt/vol) in 0.05M Tris-HCl buffer containing 120 mM NaCl prior to use.
  • the binding constants of compounds of Formula I for the D 4 receptor generally range from about 0.1 nanomolar (nM) to about 500 nanomolar (nM) .
  • Preferred compounds have binding constraints of from about 0.1 to 100 nM.
  • Preferred compounds typically have binding constants for the D 2 receptor at least about 10-15 times that of the D 4 binding constant.
  • the compounds of the invention are generally at least about 10 time more selective for the D 4 receptor than the D 2 receptor.
  • these compounds are
  • the compounds of Formula I are at least 100 times more selective for the D 4 receptor than the D 2 receptor.

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Abstract

L'invention concerne des composés représentés par la formule (I) ou certains de leurs sels d'addition pharmaceutiquement acceptables. Dans ladite formule, Y représente oxygène ou soufre: Z représente azote ou CH; R1, R2 et R3 représentent hydrogène, halogène, hydroxy, alcoxy, alkyle, trifluorométhyle ou trifluorométhoxy; R4 et R4' représentent hydrogène, alkyle ou forment un noyau avec l'atome auquel ils sont fixés; R5 représente hydrogène, alkyle, alcoxy ou alkylthio et R6 représente hydrogène ou alkyle; R5 et R6 peuvent aussi former un noyau avec les atomes auxquels ils sont fixés; R7, R8, R10 et R11 représentent hydrogène ou alkyle. Lesdits composés sont utiles pour le traitement et/ou la prévention de troubles neuropsychologiques, parmi lesquels la schizophrénie, la manie, la démence, la dépression, l'anxiété, les comportements compulsifs, les abus d'intoxicants, les troubles moteurs du type Parkinson et les troubles du mouvement associés à la consommation de neuroleptiques. L'invention concerne également des intermédiaires représentés par les formules (VII-a) et (VII-b), dans lesquelles X représente oxygène, soufre ou CH2, m représente 0 ou un entier de 1 à 4, et L représente un groupe partant.
PCT/US1999/004309 1998-02-26 1999-02-26 Derives de benzylpiperazinyl et piperidinyl ethanone, preparation, et utilisation comme antagonistes des recepteurs d4 de la dopamine WO1999043670A1 (fr)

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JP2000533426A JP2002504549A (ja) 1998-02-26 1999-02-26 ベンジルピペラジニル−およびベンジルピペリジニルエタノン誘導体、その調製、およびドーパミンｄ４受容体アンタゴニストとしてのその使用
EP99909657A EP1068193A1 (fr) 1998-02-26 1999-02-26 Derives de benzylpiperazinyl et piperidinyl ethanone, preparation, et utilisation comme antagonistes des recepteurs d 4? de la dopamine
KR1020007009454A KR20010041341A (ko) 1998-02-26 1999-02-26 벤질피페라지닐 및 벤질피페리디닐 에탄온 유도체, 이의제조 방법 및 도파민 ｄ４ 수용체 길항제로서의 이의 용도
HU0100926A HUP0100926A3 (en) 1998-02-26 1999-02-26 Benzylpiperazinyl- and benzylpiperidinyl ethanone derivatives, their preparation and their use as dopamine d4 receptor antagonists
CA002321830A CA2321830A1 (fr) 1998-02-26 1999-02-26 Derives de benzylpiperazinyl et piperidinyl ethanone, preparation, et utilisation comme antagonistes des recepteurs d4 de la dopamine
AU28814/99A AU2881499A (en) 1998-02-26 1999-02-26 Benzylpiperazinyl- and benzylpiperidinyl ethanone derivatives, their preparationand their use as dopamine d4 receptor antagonists
IL13793099A IL137930A0 (en) 1998-02-26 1999-02-26 Benzylpiperazinyl and benzylpiperidinyl ethanone derivatives, their preparation and their use as a dopamine d4 receptor antagonists
PL99342597A PL342597A1 (en) 1998-02-26 1999-02-26 Benzylopiperazinylic and benxylopiperidinylic derivatives of ethanone, method of obtaining them and their application as antagonists of dopamine d4 receptor
NO20004271A NO20004271L (no) 1998-02-26 2000-08-25 Benzylpiperazinyl- og benzylpiperidinyletanonderivater, deres fremstilling og deres anvendelse som dopamin D4- reseptorantagonister

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WO2000076967A1 (fr) * 1999-06-14 2000-12-21 Neurogen Corporation Benzylpiperazinyl-indolinylethanones
US6316470B1 (en) 1998-02-26 2001-11-13 Neurogen Corporation Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands
US6355644B1 (en) 1999-06-14 2002-03-12 Neurogen Corporation Benzylpiperazinyl-indolinylethanones
US6548502B2 (en) 2000-07-27 2003-04-15 Pfizer Inc Dopamine D4 ligands for the treatment of novelty-seeking disorders
US6673800B2 (en) 2000-12-04 2004-01-06 Korea Institute Of Science And Technology 4,5,-dihydroisoxazolylakylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
US6723724B2 (en) 2000-12-04 2004-04-20 Korea Institute Of Science And Technology Isoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors
US8268815B2 (en) 2004-06-04 2012-09-18 Abbott Gmbh & Co. Kg Pyrimidine compounds and use thereof
CN103966340A (zh) * 2014-05-26 2014-08-06 宁波大学 一种用于辅助诊断阿尔茨海默病的检测试剂盒及其应用
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10618895B2 (en) 2013-12-20 2020-04-14 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US11866428B2 (en) 2011-04-21 2024-01-09 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy

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CN1181065C (zh) * 2002-05-08 2004-12-22 上海医药工业研究院 芳烷甲酰烷基哌嗪衍生物及其作为脑神经保护剂的应用

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US6316470B1 (en) 1998-02-26 2001-11-13 Neurogen Corporation Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands
WO2000076967A1 (fr) * 1999-06-14 2000-12-21 Neurogen Corporation Benzylpiperazinyl-indolinylethanones
US6355644B1 (en) 1999-06-14 2002-03-12 Neurogen Corporation Benzylpiperazinyl-indolinylethanones
US6548502B2 (en) 2000-07-27 2003-04-15 Pfizer Inc Dopamine D4 ligands for the treatment of novelty-seeking disorders
US6673800B2 (en) 2000-12-04 2004-01-06 Korea Institute Of Science And Technology 4,5,-dihydroisoxazolylakylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
US6723724B2 (en) 2000-12-04 2004-04-20 Korea Institute Of Science And Technology Isoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
US8268815B2 (en) 2004-06-04 2012-09-18 Abbott Gmbh & Co. Kg Pyrimidine compounds and use thereof
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors
US11866428B2 (en) 2011-04-21 2024-01-09 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10618895B2 (en) 2013-12-20 2020-04-14 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US11225476B2 (en) 2013-12-20 2022-01-18 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US11643410B2 (en) 2013-12-20 2023-05-09 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US12202828B2 (en) 2013-12-20 2025-01-21 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
CN103966340A (zh) * 2014-05-26 2014-08-06 宁波大学 一种用于辅助诊断阿尔茨海默病的检测试剂盒及其应用

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IL137930A0 (en) 2001-10-31
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