EP1828161A2 - Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites - Google Patents

Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites

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Publication number
EP1828161A2
EP1828161A2 EP05819231A EP05819231A EP1828161A2 EP 1828161 A2 EP1828161 A2 EP 1828161A2 EP 05819231 A EP05819231 A EP 05819231A EP 05819231 A EP05819231 A EP 05819231A EP 1828161 A2 EP1828161 A2 EP 1828161A2
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Prior art keywords
compounds
compound
oxides
tautomers
stereoisomers
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EP05819231A
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German (de)
English (en)
French (fr)
Inventor
Roelof Solvay Pharmaceuticals B.V. VAN HES
Pieter Solvay Pharmaceuticals B.V. SMID
Cornelis G. Solvay Pharmaceuticals B.V. KRUSE
Martinus Th.M. Solvay Pharmaceuticals B.V. TULP
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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Priority to EP05819231A priority Critical patent/EP1828161A2/en
Publication of EP1828161A2 publication Critical patent/EP1828161A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • 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
    • C07D295/125—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 attached to the same carbon chain, which is not 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
    • C07D295/125—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/02—Seven-membered rings
    • C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action: serotonin reuptake inhibition and affinity for dopamine-D 2 receptors and to methods for the preparation of these compounds.
  • the invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect.
  • a beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. Mor e particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of disorders in which dopamine-D 2 receptors and serotonin reuptake sites are involved, or that can be treated via manipulation of those targets.
  • Phenylpiperazine derivatives with a dual action as dopamine -D 2 antagonists and serotonin reuptake inhibitors are known from WO 01/014330. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms).
  • the goal of the present invention was to provide further compounds with a dual action as dopamine-D 2 antagonists and serotonin reuptake inhibitors.
  • the invention relates to compounds of the general formula ( 1):
  • m and n independently are either 1, 2, 3, 4, 5, 6, 7 or 8, x is 0, 1 , 2 or 3
  • R 2 is halogen, branched or unbranched alkyl(d -6 ), phenyl, benzyl, branched or unbranched alkoxy(Ci- 6 ), trifluoromethyl or cyano
  • R 3 and R 4 independently represent hydrogen, alkyl (Ci- 6 ), phenyl, benzyl or acetyl group Q is chosen from structural fragments A-N
  • - y is 1 , 2 or 3 - Ri is halogen, branched or unbranched alkyl(C i- 6 ), phenyl, benzyl, branched or unbranched alkoxy(Ci -6 ), trifluoromethyl or cyano,
  • Prodrugs of the compounds mentioned above are in the scope of the present invention.
  • Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites.
  • Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p.
  • Pro-drugs i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups.
  • Such compounds can be reacted with organic acids to yield compounds having formula (1) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hyd roxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hyd roxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • N-oxides of the compounds mentioned above are in the scope of the present invention.
  • Tertiary amines may or may not give rise to N -oxide metabolites. The extend to what N -oxidation takes place varies from trace amounts to a near quantitative conversion.
  • N-oxides may be more active than their corresponding tertiary amines or less active. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases the conversion is a mere trace reaction or even completely absent. (M. H. Bickel: "The pharmacology and Biochemistry of N-oxides", Pharmaco-logical Reviews, 21.(4), 325 - 355, 1969).
  • Preferred compounds of the invention are compounds having formula (I) wherein m is 1 , n is 2, 3, 4 or 5, x is 1 , R2 is 4-fluoro or 4-trifluoromethyl, R 3 and R4 independently represent hydrogen or methyl, group Q is chosen from structural fragments A, D, F or N, y is 1 , and Ri is branched or unbranched alkoxy(Ci -3 ), and tautomers, stereoisomers a nd N -oxides thereof, as well as pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (1) and its tautomers, stereoisomers and N-oxides.
  • the compounds according to the invention show high affinity fo r both the dopamine D 2 receptor and the serotonin reuptake site.
  • the compounds show activity as antagonists at dopamine D 2 receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice.
  • the compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5 -HTP induced behaviour in mice.
  • the compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61 -67) and antidepressants or anxiolytics (e.g.
  • the compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, and in particular schizophrenia and other psychotic disorders.
  • alkylphenone derivatives 2 are commercially available.
  • salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hy drochloric acid, or with an organic acid.
  • a suitable acid for instance an inorganic acid such as hy drochloric acid, or with an organic acid.
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid carrier material.
  • the pharmaceutical compositions of the invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel) or suppositories.
  • Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
  • Compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly specific compounds disclosed herein.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention.
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • Affinity of the compounds for dopamine -D 2 receptor s was determined using the receptor binding assay described by I. Creese, R. Schneider and S. H. Snyder: "[ 3 H]- Spiroperidol labels dopamine receptors in rat pituitary and brain", Eur.J. Pharmacol., 46, 377 - 381, 1977.
  • Affinity of the compounds for serotonin reuptake sites was determined using the receptor binding assay described by E. Habert et a/.,: "Characterisation of [ 3 H]- paroxetine binding to rat cortical membranes", Eur.J. Pharmacol., 118, 107 - 114, 1985.
  • the affinity of the compounds of the invention for dopamine-D 2 receptors and serotonine reuptake sites was determined as described above. From the binding affinity measured for a given compound of formula (1), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured Kj-value, 100% of the receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value.
  • the dosage expediently administered is 0.001 - 1000 mg/kg, preferably 0.1 -100 mg/kg of patient's bodyweight.
  • treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relievi ng the disease or condition, i.e., causing regression of the condition, or (4) relieving the conditions caused by the disease, i.e., stopping the symptoms of the disease.
  • the synthesis of compound 3 is a 2 -step reaction starting from 4 -(2,3 dihydro- 1,4 benzodioxin-5-yl)-1 -piperazine (3i). 15 mmol of piperazine (3i) was suspended in 125 ml of acetonitril and 2 equivalents of diisopropylethyl -amine (DIPEA) was added. After 5 minutes stirring at room temperature, 1 equivalent (15 mmol) of 5 - chloro-1-(4-trifluoromethyl-phenyl)-pentane-1-one was added, followed by 1 equivalent of sodium iodide. This mixture was stirred at 8O 0 C for 20 hours. The solvent was removed by evaporation and the residue dissolved in 100 ml of dichloromethane.
  • DIPEA diisopropylethyl -amine
  • the tri HCI -salt of compound 3 was obtained after adding 3 equivalents of HCI in Ethanol to the purified substance. mp.156-60°C; overall yield 15%.
  • the synthesis of compound 7 is a 2 -step reaction starting from 2-isopropyloxy- phenylpiperazine (7i). 4.2 mmol of phenyl piperazine 7i was suspended in 40 ml acetonitril. Added were 2 eq. of DIPEA, 1 eq. of 4-chloro-1-(4-trifluoromethyl-phenyl)- butane-1-one and 1 eq. potassium iodide. This mixture was refluxed overnight and the solvent evaporated the next day.
  • compound 8 is a 2 -step reaction starting from 4 -(2,3 dihydro- 1,4 benzodioxin-5-yl)-1 -piperazine (3i). 3.5 mmol of phenyl piperazine (3i) was suspended in 40 ml acetonitril. Added were 2 eq. of DIPEA, 1 eq. of 6-chloro-1-(4- trifluoromethyl-phenyl)-hexane-1-one and 1 eq. potassium iodide. This mixture was refluxed overnight and the solvent evaporated the next day.
  • the fumaric -salt of the compound 9 was obtained after adding an ethanolic solution of 1 equivalents of fumaric acid to the purified substance followed by evaporation of the solvent; overall yield 15%.
  • the synthesis of compound 10 is a 2 -step reaction starting from 4 -(2,3 dihydro- 1,4 benzodioxin-5-yl)-1 -piperazine (3i). 6 mmol of phenyl piperazine 3i was suspended in 40 ml acetonitril. Added were 2 eq. of DIPEA, 1 eq. of 7-chloro-1-(4- trifluoromethyl-phenyl)-heptane-1-one and 1 eq. potassium iodide.
  • Q can be one of the structural fragments A-N

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP05819231A 2004-12-07 2005-12-06 Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites Withdrawn EP1828161A2 (en)

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EP05819231A EP1828161A2 (en) 2004-12-07 2005-12-06 Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites

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US63344904P 2004-12-07 2004-12-07
EP04106350 2004-12-07
PCT/EP2005/056500 WO2006061372A2 (en) 2004-12-07 2005-12-06 Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites
EP05819231A EP1828161A2 (en) 2004-12-07 2005-12-06 Phenylpiperazines with a combination of affinity for dopamine -d2 receptors and serotonin reuptake sites

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EP1828161A2 true EP1828161A2 (en) 2007-09-05

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JP (1) JP2008523026A (es)
KR (1) KR20070091646A (es)
CN (1) CN101072765A (es)
AR (1) AR052258A1 (es)
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US8106056B2 (en) 2006-06-16 2012-01-31 Solvay Pharmaceuticals B.V. Combination preparations comprising bifeprunox and a dopamine agonist
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RU2007125636A (ru) 2009-01-20
AR052258A1 (es) 2007-03-07
WO2006061372A2 (en) 2006-06-15
WO2006061372A3 (en) 2006-11-23
KR20070091646A (ko) 2007-09-11
JP2008523026A (ja) 2008-07-03
ZA200704151B (en) 2008-08-27
TW200633987A (en) 2006-10-01
CN101072765A (zh) 2007-11-14
MX2007006756A (es) 2007-11-09
SA05260389B1 (ar) 2009-06-09
AU2005313386A1 (en) 2006-06-15

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