EP1824480A1 - Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung - Google Patents

Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung

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Publication number
EP1824480A1
EP1824480A1 EP05816324A EP05816324A EP1824480A1 EP 1824480 A1 EP1824480 A1 EP 1824480A1 EP 05816324 A EP05816324 A EP 05816324A EP 05816324 A EP05816324 A EP 05816324A EP 1824480 A1 EP1824480 A1 EP 1824480A1
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Prior art keywords
scheme
mmol
added
compounds
mixture
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French (fr)
Inventor
Roelof W. Solvay Pharmaceuticals B.V. FEENSTRA
Axel Solvay Pharmaceuticals B.V. STOIT
Jan-Willem Solvay Pharmaceuticals B.V. TERPSTRA
Maria L. Solvay Pharmaceuticals B.V. PRAS-RAVES
Andrew C. Solvay Pharmaceuticals B.V. MCCREARY
Bernard J. Solvay Pharmaceuticals B.V. VAN VLIET
Mayke B. Solvay Pharmaceuticals B.V. HESSELINK
Cornelis G. Solvay Pharmaceuticals B.V. KRUSE
G. Solvay Pharmceuticals B.V. VAN SCHARRENBURG
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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Priority to EP05816324A priority Critical patent/EP1824480A1/de
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    • 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
    • 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
    • A61P25/02—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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action: serotonin reuptake inhibition and partial agonism on dopamine - D 2 receptors.
  • 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. More 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.
  • the goal of the present invention was to provide further compounds with a dual action as partial dopamine-D 2 antagonists and serotonin reuptake inhibitors.
  • the invention relates to a group of novel compounds of the formula (1):
  • Ri is H, (Ci-C 6 )alkyl, CF 3 , CH 2 CF 3 , OH or O-(Ci-C 6 )alkyl
  • R 2 is H, (Ci-C 6 )alkyl, halogen or cyano
  • R 3 is H or (Ci-C 6 )alkyl
  • T is a saturated or unsaturated carbon chain of 2 -7 atoms, wherein one carbon atom may be replaced with a nitrogen atom, optionally substituted with an (Ci-C 3 )alkyl, CF 3 or CH 2 CF 3 group, an oxygen atom or a sulphur atom, which chain is optionally substituted with one or more substituents selected from the group consisting of (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, halogen, cyano, trifluoromethyl, OCF 3 , SCF 3 , OCHF 2 and nitro,
  • Ar is selected from the groups:
  • Ar group is optionally further substituted with one or more substituents selected from the group consisting of (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, halogen, cyano, trifluoromethyl, OCF 3 , SCF 3 , OCHF 2 and nitro,
  • the dot represents the attachement point of group T'.
  • the abbreviation 'alkyl(C 1. 3 )' means 'methyl, ethyl, n -propyl or isopropyl'.
  • 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, Ed.: F. D. King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; 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.
  • 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) w herein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl -methylene derivative, an O-(acyloxy-methylene 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, £(4), 325 - 355, 1969).
  • the compounds according to the invention show high affinity for both the dopamine D 2 receptor and the serotonin reuptake site.
  • the compounds show activity at dopamine D 2 receptors with varying degree of agonism. All of the compounds show activity as inhibitors of serotonin reuptake, as they potentiate 5 - HTP induced behaviour in mice (B. L. Jacobs., 'An animal behaviour model for studying central serotonergic synapses', Life ScL 1976, 19(6), 777-785).
  • the use of partial dopamine -D 2 receptor agonists offers a dynamic medication that self-adjusts on a moment-to-moment basis to the endogenous state of the patient.
  • full dopamine-D 2 receptor agonists like bromocriptine (hallucinations, nausea, vomiting, dyskinesia, orthostatic hypotension, somnolescence) or full dopamine-D 2 receptor antagonists like haloperidol (emotional blunting, dysphoria, tardive dyskinesia).
  • Partial dopamine-D 2 receptor agonists not only show a flexible modulation and a favourable side-effect profile, they also have a pronounced anxiolytic profile in relevant animal models (Drugs of the Future 2001, 26(2): 128 -132).
  • Partial dopamine-D 2 receptor agonists are compounds that - when tested in a concentration response range - achieve activation in the functional cAMP cell based assay (as described below). Partial dopamine-D 2 receptor agonists will act as an agonist in cases when the endogenous synaptic tone of dopamine is low, or in the the presence of a full dopamine-D 2 receptor antagonist, and will act as an antagonist in cases when the endogenous synaptic tone of dopamine is high, or in the presence of a full dopamine D 2 receptor agonist. Like full agonists, partial dopamine -D 2 receptor agonists in general are active in sensitized systems.
  • a pharmaceutical preparation combining partial dopamine -D 2 receptor agonistic activity having low intrinsic functional activity with serotonin reuptake inhibitory activity is recommended.
  • a pharmaceutical preparation combining partial dopamine -D 2 receptor agonistic activity with high intrinsic functional activity and serotonin reuptake activity according to the invention has considerable advantages.
  • disorders characterized by dynamic fluctuations in dopamine neurotransmission like bipolar depression and addiction will profit in particular from the flexible adjustment of the dopamine system by the partial dopamine -D 2 receptor agonists in the pharmaceutical preparation.
  • Combining this "dopaminergic neurotransmission stabilizing" activity with serotonin reuptake inhibito ry activity will enhance antidepressive and anxiolytic efficacy.
  • the compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in the dopaminergic and 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.
  • 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 hydrochloric acid, or with an organic acid.
  • a suitable acid for instance an inorganic acid such as hydrochloric 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 sp ecific 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. Inhibition of forskolin-induced [ 3 H]-CAMP accumulation
  • the in vitro functional activity at dopamine-D 2 receptors, including the intrinsic activity ( ⁇ ) of the compounds of the invention was measured by their ability to inhibit forskolin-induced [ 3 H]-CAMP accumulation.
  • fibroblast cell line CHO -K1 cells Human dopamine D 2,L receptors were cloned in fibroblast cell line CHO -K1 cells and obtained from Dr. Grandy, Vollum Institute, Portland, Oregon, USA. CHO cells were grown in a Dulbecco's modified Eagle's medium (DMEM) culture medium, supplemented with 10% heat-inactivated fetal calf serum, 2 mM glutamine, 1 mM pyruvate, 5000 units/ml penicillin, 5000 ⁇ g/ml streptomycin and 200 ⁇ g/ml G-418 at 37 0 C in 93% air/7% CO 2 . For incubation with test compounds, confluent cultures grown in 24 wells plates were used. Each condition or substance was routinely tested in quadruplicate.
  • DMEM Dulbecco's modified Eagle's medium
  • the mean was taken as an estimate for drug -induced, receptor-mediated effects at specified second messenger accumulation, expressed as percentage of control values (forskolin -stimulated cAMP accumulation, subtracted by basal activity).
  • mean values were plotted against drug concentration (in molar) and a sigmoid curve (four - parameter logistic curve) was constructed.
  • the maximal forskolin -induced stimulated conversion is taken as maximum value and the maximal inhibition (usually at drug concentrations 10 "6 M or 10 "5 M) as minimum and these values were fixed during the fitting process.
  • concentrations of the compound causing 50% of the maximally obtained inhibition of forskolin -induced cAMP accumulation (EC 50 ), are averaged over several experiments and presented as mean pEC 5 o ⁇ SEM.
  • Antagonist potency is assessed by co -incubating cells with a fixed agonist concentration and specified antagonist concentrations. Curve fitting procedures are identical to those used for estimating EC 50 values.
  • IC 50 values i.e. the concentration that is able to achieve 50% of maximal antagonism that can be achieved by this compound.
  • IC 50 values are corrected using a Cheng-Prussoff equation, correcting it for agonist concentration and EC 50 values that is obtained in the same experiment.
  • K b IC50 / (1+ [agonist]/ECso, agonist).
  • the corresponding pA 2 value is -log (K b ).
  • Concentration -response curve fitting allows estimation of pECso values and of maximal achievable effect (intrinsic activity or efficacy ( ⁇ ).
  • 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 K r 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, assumi ng 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
  • 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) relieving 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.
  • Peakshapes in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double quartet), T (triplet), 'df (double triplet), 'd' (doublet), 'dd' (double doublet), 's' (singlet), 'bs' (broad singlet) and 'm' (multiplet). Flash chromatography was performed using silica gel 60 (0.040 -0.063 mm, Merck). Column chromatography was performed using silica gel 60 (0.063 -0.200 mm, Merck). Mass spectra were recorded on a Micromass QTOF -2 instrument with MassLynx application software for acquisition and reconstruction of the data. Exact mass measurement was done of the quasimolecular ion [M+H] + . Melting points were recorded on a B ⁇ chi B-545 melting point apparatus. Yields refer to isolated pure products.
  • step i To a suspension of 0.6 g (2.35 mmol) of the piperazine hydrochloride I-H.HCI in 100 ml of acetonitril were added 0.77 g (2.35 mmol) of the iodide, 0.71 g (4.7 mmol) of NaI and 1.39 ml (8 mmol) of DIPEA. The mixture was refluxed for 20 hours and concentrated in vacuo. The residue was taken up in CH 2 CI 2 and the resulting mixture washed with water. The organic layer was dried on Na 2 SO 4 . The drying agent was removed by filtration and the solvent by concentration in vacuo.
  • a solution of oxalyl chloride (0.45 ml, 5.2 mmol) in 15 ml DCM is placed in a three - necked round bottom flask equipped with a thermometer and two pressure - equalizing dropping funnels respectively containing dimethyl sulfoxide (0.74 ml, 10.4 mmol) in 3 ml DCM, and the 3-(6-chloro-indazo-1-yl)-propanol Q56-OH (1.0 g, 4.7 mmmol) in 5 ml DCM under an N 2 atmosphere.
  • the dimethyl sulfoxide is added to the stirred oxalyl chloride solution at -5O 0 C to -6O 0 C.
  • the reaction mixture is stirred for 2 minutes and the alcohol is added within 5 minutes ; stirring is continued for an additional 15 minutes.
  • Triethylamine (3.3 ml, 23.73 mmol) is added and the reaction mixture is stirred for 15 minutes and the n allowed to warm to room temperature. Water is added and the aqueous layer is re -extracted with additional DCM. The organic layer is washed with 0.3 N HCI, water, 5% NaHCO 3 , saturated NaCI solution and dried with Na 2 SO 4 . The filtered solution is evaporated yielding the corresponding aldehyde.
  • the crude product containing the aldehyde (from step i) is added to a stirred solution of 3-methyl-7-piperazin-1-yl-3H-benzooxazole-2-one.2HCI (V.2HCI) (0.57 g, 2.44 mmol) and tri-ethyl amine (0.76 ml, 5.38 mmol) in 100 ml DCE.
  • the reaction mixture is stirred for 1 hour and NaBH(OAc) 3 (0.83 g, 3.91 mmol) is added.
  • the mixture is stirred for an additional 8 hours. Water was added and the resulting fraction extracted with DCM (3 times). The combined organic layers were evaporated.
  • Table 1 examples of compounds of the invention.
  • step ii This step was done analogously to step ii in scheme IV. Boc -piperazine was used in this Buchwald reaction. Yield after chromatographic purification: 44% of a brown oil.
  • step iv This step was done analogously to the procedure described in the previous step ii (scheme VII). In this case benzylamine was used in the Buchwald reaction. Yield after chromatographic purification: 73% of a brown oil.
  • step v in scheme IV This step (ring closure with CDI) was done analogously to step v in scheme IV.
  • the crude product after work up was chromatographed (flash column, SiO 2 , eluent
  • step vi This methylation step was done analogously to the procedure described in step ii (scheme Vl). Yield: 98% of a brown foam of 97% purity.
  • a stirred solution of the silylated alcohol (3.35 g, 10 mmol) in 20 ml of dry THF was cooled to -70 0 C.
  • 2.5M n-BuLi 4.8 ml, 12 mmol was slowly added dropwise at such a rate that the temperature was kept below -65 0 C.
  • the solution was allowed to warm to -20 0 C and stirring was continued for 1 hour during which the color of the solution changed from light to dark yellow.
  • the 5-bromobenzthiophene was prepared according to: Leclerc, V.; Beaurain, N.; Pharm. Pharmacol. Commun., 6(2000)61 -66.
  • step H This step was carried out analogous to step ii from Scheme 51.
  • step iv This step was carried out analogous to step iii from scheme 10 -12.
  • This step was carried out analogous to step v from scheme 10 -12.
  • This step was carried out analogous to step iv from s cheme 1 -6.
  • the drying agent was removed by filtration and the solvent by evaporation under reduced pressure.
  • the residue was chromatographed (SiO 2 ) using CH 2 CI 2 /petroleum ether 3/2 -> CH 2 CI 2 as eluent to give 15.6 g (92%) of the 5- cyanobenzthiophene.
  • step v To a stirring solution of the 5-cyanobenzthiophene (15.6 g, 60.2 mmol) in 250 ml 96% EtOH at 15 0 C was added sodium borohydride (22.8 g, 602 mmol) in one time. The reaction mixture was stirred at room temperature for 48 h. H 2 O was added and the aqueous layer was extracted with Et 2 O (3x). The combined organic layers were washed with brine (1x). The Et 2 O fraction was dried (MgSO 4 ). The drying agent was removed by filtration and the solvent by evaporation under reduced pressure. The residue was chromatographed (SiO 2 ) with Et 2 O/CH 2 CI 2 1/9 as eluent to give 9.2 g (66%) of the alcohol Q12-OH.
  • step vi Was prepared according to the procedure described in Scheme 1 -6, step iii.
  • Q10-OH and Q11 -OH were prepared similarly using steps i, ii, iii and v respectively.
  • step i To a stirring solution of 3-nitro-p-tolunitrile (16.58 g, 102.3 mmol) in 55 ml DMF was added DMF-dimethylacetale (15.24 g, 128.1 mmol). The reaction mixture turned dark red and was stirred at 110 0 C for 3 h. The solvent was removed under reduced pressure and taken up in a mixture of 300 ml EtOH and 300 ml acetic acid. The reaction mixture was heated to 60 0 C and iron powder (33 g, 594 mmol) was added in portions. The reaction mixture was refluxed for 2 hours and filtered over a pad of Hyflo. Et 2 O was added to the filtrate and the acidic layer was extracted with Et 2O (1x).
  • the 6-cyano-indole derivative Q20-OH was prepared according to the procedure described above.
  • the indole, 6-Fluoroindole and 6-Chloroindole were commercially available and were further converted to the indole derivatives Q13-18-OH according to the procedures given above.
  • step Hi A mixture of the aniline (from step ii) (8.42 g, 42.5 mm ol) in 25 ml formic acid (96%) was refluxed for 2.5 hours after which it was allowed to cool to room temperature. H 2 O was added and after cooling, to the reaction mixture 50 ml of 50% NaOH was added. After stirring for 2 hours the aqueous layer was extracted with CH 2 CI 2 . The CH 2 CI 2 fraction was dried (by a Water Repelling Filter) and concentrated in vacuo under reduced pressure. The residue was chromatographed (SiO 2 ) with CH 2 CI 2 /Me0H 9:1 as the eluent to give 8.1 g (92%) of the benzimidazole.
  • step H To a stirring solution of 2-chloro-4-cyanonitrobenzene from step i (2.48 g, 13.6 mmol) in 12 ml DMF was cooled in ice. 4 -aminobutanol (5.50 ml, 59.3 mmol) was added and the reaction mixture was slowly allowed to warm to room temperature after which stirring was continued at room temperature for 72 h. H 2 O was added and the aqueous layer was extracted with CH 2 CI 2 (2x) The combined organic layers were washed with H 2 O (3x), dried (by a Water Repelling Filter) and evaporated under reduced pressure. The residue was chromatographed with Et 2 O/petroleum ether 4:1 as eluent to give 2.6 g (49%) of the amino -alkylated product.
  • the naphtylpropylalcohol was prepared according to: Searles, J.Amer.Chem.Soc, 73 (1951 ) 124.
  • step H A 100 ml threeneck roundbottom flask under a nitrogen atmosphere was charged with 2-allyl-7-chloro-napthalene (1.8Og, 8.9 mmol) and 12 ml of dry THF. The mixture was cooled in an ice-bath and borane-THF (3.05 mmol, 3.05 ml 1.0 M borane in THF) was added dropwise in about 20 minutes After the addition the mixture was allowed to warm to room temperature and stirred for 20 hours.
  • the fluorobromonaphtalene was prepared according to: Adcock.W. et al., AustJ.Chem., 23 (1970)1921 -1937.
  • a mixture of KOH pellets (140 g, 2.5 mol) and 10 ml H 2 O in a nickel crucible was heated to 250 0 C with a Bunsen burner while being stirred with a stainless steel stirrer. The flame is removed and 7-amino-2-naphtalenesulfonic acid sodium salt (0.245 mol, 60.0 g) was added to the clear liquid in 3 portions. The clear liquid changes into a thick black slurry which is again strongly heated with a Bunsen burner. At about 28O 0 C gas evolved and the temperature of the mixture quickly rises to 310-320 0 C. This temperature was maintained for 8 minutes after which the mixture was allowed to cool to about 200 0 C.
  • the dry -ice bath was replaced by a normal ice-bath and the mixture was stirred at O 0 C for 20 minutes after which it was heated to 55 - 6O 0 C on an oilbath (evolution of nitrogen was observed). After 1.5 hours nitrogen evolution ceased and the mixture was allowed to cool to room temperature and poured into a large beaker filled with ice. The mixture was transferred to a separatory funnel and extracted 3 times with DCM. The organic layers where pooled together, washed with brine and dried (Na 2 SO 4 ).
  • Q32 was synthesized as Q32-I, Q33-36, Q38-39 and Q41 -42 derivatives were prepared similarly to the above described procedures (as bromides).
  • This step can be performed similar to step iii in scheme 1 -6, and yielded Q44-OH.
  • the starting acid and reagents were commercially available.
  • the Cl -C4-MgBr was prepared according to: CR. Hebd, Seances Acad. Ser. C, 268 (1969)1152-1154.
  • AICI 3 (27.8 g, 208 mmol) was suspended in 200 ml 1 ,2 -dichloroethane. The mixture was cooled under a nitrogen atmosphere to 0 -5 0 C and a solution of the acid chloride (27.75 g, 148.8 mmol) in 140 ml 1 ,2 -dichloroethane was added dropwise in 1 h. The cooling bath was removed and after stirring for 30 min., stirring was continued for 2 hours at 70 0 C. After cooling to room temperature the reaction mixture was poured into a mixture of ice and 330 ml concentrated HCI (36 -38%).
  • the starting materials were commercially available.
  • step Hi To 20 ml toluene under a nitrogen atmosphere was added the urethane derivative (from step ii) (0.45 g, 2 mmol), 3 -bromopropanol (0.18 ml, 2.1 mmol), Bu 3 P (0.40 g, 2 mmol) and ADDP (0.5 g, 2 mmol). After the addition of ADDP the solution turned clear. The reaction mixture was heated at 85 0 C for 20 hours and cooled to room temperature. 2N NaOH and EtOAc were add ed and the aqueous layer was extracted with EtOAc (2x).
  • 6-chloro-indazole (7,5 g, 49,15 mmol) was added at room temperature.
  • the mixture was stirred for 1 hour before cooling with an ice bath and (3 -bromo- propoxy)-tert-butyl-dimethyl-silane (11.4 ml, 49.15 mmol) was added dropwise. After stirring for an additional 15 minutes the mixture was allowed to reach room temperature, stirring was continued for another 8 hours.
  • step ii tetrabutyl ammonium chloride in THF can be used instead of the combination KF.2H 2 O/ benzyl tri -ethyl ammonium chloride.
  • step i A solution of Red -Al (4.47 ml of a 3.4 M solution in toluene) in 25 ml of dry diethyl ether was cooled in an ice-bath under nitrogen to which a solution of Q63-OH (1.90 g, 9.5 mmol) in 40 ml of diethylther (dry) was added dropwise. After the addition was complete, the resulting mixture is stirred for 10 min at 0 0 C after which it was allowed to reach room temperature and stirred for an additional 2.5 hours. The reaction mixture was again cooled in a ice -bath and quenched by the careful addition of 50 ml of 3.6 M H 2 SO 4 .
  • Dopamine-D 2 and serotonin reuptake receptor affinity data obtained according to the protocols given above are shown in the table below.

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EP05816324A 2004-12-08 2005-12-06 Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung Withdrawn EP1824480A1 (de)

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EP05816324A EP1824480A1 (de) 2004-12-08 2005-12-06 Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung

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EP05850037A Expired - Lifetime EP1827427B1 (de) 2004-12-08 2005-12-06 Aryloxyethylaminderivate mit einer kombination aus partiellem dopamin-d2-rezeptoragonismus und serotonin-wiederaufnahmehemmung
EP05816322A Expired - Lifetime EP1824479B1 (de) 2004-12-08 2005-12-06 Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung
EP05816324A Withdrawn EP1824480A1 (de) 2004-12-08 2005-12-06 Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung

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EP05850037A Expired - Lifetime EP1827427B1 (de) 2004-12-08 2005-12-06 Aryloxyethylaminderivate mit einer kombination aus partiellem dopamin-d2-rezeptoragonismus und serotonin-wiederaufnahmehemmung
EP05816322A Expired - Lifetime EP1824479B1 (de) 2004-12-08 2005-12-06 Phenylpiperazin-derivate mit einer kombination aus teilweisem dopamin-d2-rezeptor-agonismus und serotonin-wiederaufnahmehemmung

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US20090088576A1 (en) * 2006-01-30 2009-04-02 Peter Herold Process for the Stereoselective Preparation of Alcohols From Alpha, Beta-Insaturated Compounds
US8063062B2 (en) 2006-12-20 2011-11-22 Solvay Pharmaceuticals B.V. Compounds with a combination of cannabinoid-CB1 antagonism and acetylcholinesterase inhibition
AU2008204456A1 (en) * 2007-01-10 2008-07-17 Solvay Pharmaceuticals B.V. Compounds with a combination of cannabinoid-CB1 antagonism and serotonin reuptake inhibition
US8138174B2 (en) 2007-01-10 2012-03-20 Solvay Pharmaceuticals B.V. Compounds with a combination of cannabinoid CB1 antagonism and serotonin reuptake inhibition
AU2008240729B2 (en) * 2007-04-23 2012-08-23 Janssen Pharmaceutica N.V. Thia(dia)zoles as fast dissociating dopamine 2 receptor antagonists
WO2008128994A1 (en) * 2007-04-23 2008-10-30 Janssen Pharmaceutica N.V. Pyridine derivatives as fast dissociating dopamine 2 receptor antagonists
KR20100016620A (ko) * 2007-04-23 2010-02-12 얀센 파마슈티카 엔.브이. 속해리성 도파민 2 수용체 길항제로서의 4-알콕시피리다진 유도체
CN103360342B (zh) * 2012-04-09 2015-12-16 江苏恩华药业股份有限公司 3-氰基苯胺烷基芳基哌嗪衍生物及在制备药物中的应用
CN103570698B (zh) * 2012-08-01 2016-08-03 江苏恩华药业股份有限公司 用于制备维拉佐酮的化合物及其中间体和应用
ITMI20130392A1 (it) * 2013-03-15 2014-09-16 Dipharma Francis Srl Sintesi di un inibitore della ricaptazione della serotonina
EP3010586A1 (de) 2013-06-21 2016-04-27 Lupin Limited Substituierte heterocyclische verbindungen als crac-modulatoren
US9790231B2 (en) 2013-06-24 2017-10-17 Lupin Limited Chromane and chromene derivatives and their use as CRAC modulators
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof

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EP0900792B1 (de) * 1997-09-02 2003-10-29 Duphar International Research B.V Piperidin- und Piperazin Derivate als 5-HT1-Rezeptor-Agonisten
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HRP20000847A2 (en) * 1998-06-19 2001-12-31 Lundbeck & Co As H 4,5,6 i 7 - INDOLE AND INDOLINE DERIVATIVES, THEIR PREPARATION AND USE
AR022303A1 (es) * 1999-01-22 2002-09-04 Lundbeck & Co As H Derivados de piperidina, tetrahidropiridina y piperazina, su preparacion y utilizacion
AU772189B2 (en) * 1999-08-23 2004-04-08 Solvay Pharmaceuticals B.V. New phenylpiperazines
KR20050085472A (ko) * 2002-12-10 2005-08-29 메르크 파텐트 게엠베하 인돌 유도체 및 ５-ｈｔ 리간드로서의 이의 용도

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