CN101072765A - 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 Download PDF

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Publication number
CN101072765A
CN101072765A CNA2005800420702A CN200580042070A CN101072765A CN 101072765 A CN101072765 A CN 101072765A CN A2005800420702 A CNA2005800420702 A CN A2005800420702A CN 200580042070 A CN200580042070 A CN 200580042070A CN 101072765 A CN101072765 A CN 101072765A
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compound
tautomer
disease
chain
steric isomer
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罗楼夫·范海斯
彼得·史密德
科尼里斯·G·克鲁希
马提纳斯·希·M·图普
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Abbott Products GmbH
Abbott Healthcare Products BV
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Solvay Pharmaceuticals GmbH
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    • 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
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    • 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
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Abstract

The invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action: serotonin reuptake inhibition and affinity for dopamine -D2 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. The compounds have the general formula ( 1 ) wherein the symbols have the meanings given in the specification.

Description

Simultaneously to Dopamine HCL-D 2The phenylpiperazine that acceptor and serotonin reuptake sites have avidity
The present invention relates to one group and have the dual function mode: serotonin reuptake inhibition and Dopamine HCL-D 2The neophyl bridged piperazine derivatives of the avidity of acceptor, and relate to the preparation method of these compounds.The invention still further relates to the application that compound disclosed herein is used to prepare the medicine that beneficial effect is provided.Beneficial effect discloses in this article or is conspicuous according to specification sheets and technology general knowledge to those skilled in the art.The invention still further relates to compound of the present invention and be used to prepare the application of the medicine of treatment or preventing disease or symptom.More particularly, the present invention relates to a kind of new application that is used for the treatment of disease or symptom, this disease or symptom disclose in this article or are conspicuous according to specification sheets and technology general knowledge for a person skilled in the art.In embodiments of the invention, specific compound disclosed herein is used for preparing to be used for the treatment of relating to Dopamine HCL-D 2Acceptor and serotonin reuptake sites or can be by operating the medicine of the disease that these targets treat.
Have as Dopamine HCL-D according to WO01/014330 is known 2The Phenylpiperazine derivatives of antagonist and serotonin reuptake inhibitor dual function.This combination can be used for treating schizophrenia and other mental disorder, thereby can treat more completely all disease symptomses (for example positive symptom and negative symptoms).
In patent specification GB1378080 (1974), openly has useful pharmacological activity, especially as pain killer, anti-inflammatory agent with to the 9 oxime derivate of the halogenophenyl piperazinyl-alkyl ketone of flesh spasmolytic.
The object of the present invention is to provide further and have as Dopamine HCL-D 2The compound of the dual function of antagonist and serotonin reuptake inhibitor.
The present invention relates to compound and tautomer, steric isomer and the N-oxide compound of general formula (1), and acceptable salt, hydrate and solvate on the pharmacology of the compound of this formula (1) and tautomer, steric isomer and N-oxide compound:
Figure A20058004207000071
Wherein:
M and n are 1,2,3,4,5,6,7 or 8 independently,
X is 0,1,2 or 3,
R 2Be halogen, branched-chain or straight-chain alkyl (C 1-6), phenyl, benzyl, side chain or straight chain alkoxyl group (C 1-6), trifluoromethyl or cyano group,
R 3And R 4Represent hydrogen, alkyl (C independently 1-6), phenyl, benzyl or ethanoyl,
Group Q is selected from structure fragment A-N
Figure A20058004207000072
Wherein:
Y is 1,2 or 3,
R 1Be halogen, branched-chain or straight-chain alkyl (C 1-6), phenyl, benzyl, side chain or straight chain alkoxyl group (C 1-6), trifluoromethyl or cyano group.
The prodrug of above-claimed cpd within the scope of the present invention.Prodrug is non-activity own but can changes into the therapeutical agent that one or more plant active metabolite.Prodrug is the biological reversible derivatization thing of drug molecule that is used to overcome some obstacle of parent drug molecular application.These obstacles include but not limited to solubleness, perviousness, stability, presystemic metabolism (presystemicmetabolism) and target restriction (Medicinal Chemistry:Principles andPractice, 1994, ISBN 0-85186-494-5, Ed.:F.D.King, p.215; J.Stella, " Prodrugs as therapeutics ", Expert Opin.Ther. Patents, 14 (3), 277-280,2004; People such as P.Ettmayer, " Lessonslearned from marketed and investigational prodrugs ", J.Med.Chem., 47,2393-2404,2004).Prodrug promptly be metabolized to the have formula compound of compound of (1) during to people's administration by any known approach, belongs to the present invention.Especially, this relates to the compound with uncle or secondary amino group or hydroxyl.These compounds can with organic acid reaction obtain the having formula compound of (1), wherein there is the additional group of removing easily after the administration, such as but not limited to amidine (amidine), enamine, Mannich base (Mannich base), hydroxyl-methylene derivatives, O-(acyloxy methene amido manthanoate) derivative, carbamate, ester, acid amides or enamine ketone (enaminone).
The N-oxide compound of above-claimed cpd within the scope of the invention.Tertiary amine may produce or not produce N-oxide compound meta-bolites.The degree that the N-oxidation takes place is that trace is extremely near Quantitative yield.The N-oxide compound may be than their tertiary amine active greater or lesser of correspondence.Though the N-oxide compound becomes the tertiary amine of their correspondence easily by the chemical process reduction, this takes place with different degree in human body.Some N-oxide compound changes into corresponding tertiary amine near reducing quantitatively, and this conversion in other cases only is the trace reaction or even does not exist fully.(M.H.Bickel：“The pharmacology and Biochemistry of N-oxides”， Pharmaco-logical Reviews， 21(4)，325-355，1969)。
Compound and tautomer, steric isomer and the N-oxide compound of preferred compound of the present invention for having formula (1), and acceptable salt, hydrate and solvate on the pharmacology of the compound of this formula (1) and tautomer, steric isomer and N-oxide compound, wherein m is 1 in formula (1), n is 2,3,4 or 5, x is 1, R 2Be 4-fluorine or 4-trifluoromethyl, R 3And R 4Represent hydrogen or methyl independently, group Q is selected from structure fragment A, D, F or N, and y is 1, and R 1Be side chain or straight chain alkoxyl group (C 1-3).
Found that compound according to the present invention shows dopamine D 2Acceptor and serotonin reuptake sites all have the height avidity.This compound shows as dopamine D 2The activity of receptor antagonist is because their antagonism apomorphine (apomorphine) inductive mouse climbing behaviors potentially.This compound also shows the activity as the serotonin reuptake inhibitor, because they strengthen the behavior of 5-HTP inductive mouse.This compound is to the treatment model of clinical relevant antipsychotic drug sensitivity (CAR (conditionedavoidance response) for example; Van der Heyden ﹠amp; Bradford, Behav.BrainRes., 1988,31:61-67) and to the treatment model of thymoleptic or anxiolytic sensitivity (for example the sounding that brings out of pressure suppresses (suppression of stress-inducedvocalization); People such as van der Poel, Psycho-pharmacology, 1989, have activity in 97:147-148).With clinical relevant dopamine D 2Receptor antagonist is opposite, and described compound induces the cataleptic proneness of rodent little, and therefore compares with existing antipsychotic drug and may induce the outer side reaction of less pyramidal tract.The inhibition activity of these compound inherent serotonin reuptakes may cause observed result of treatment in to the behavior model of thymoleptic or anxiolytic sensitivity.This compound can be used for the treatment of central nervous system disorders or the disease that is caused by dopaminergic or serotonergic system obstacle, for example attack (aggression), anxiety disorder (anxiety disorders), autism (autism), dizzy (vertigo), depressed, cognition or dysmnesia, Parkinson's disease (Parkinson ' sdisease), particularly schizophrenia (schizophrenia) and other mental disorder.
Synthetic overview
The synthetic of all bridged piperazine derivatives in this patent can carry out as described in the preparation of compound 3 as scheme 1.The raw material phenylpiperazine can be as EP 0 189 612:Hartog, people such as J, 1985: ' New pharmaceutical compositions having a psychtropicactivity '; Feenstra, R.W.; De Moes, J.P; Hofma, J.; Kling, H.; Kuipers, W; Long, S.K.; Tulp, M.T.M.; Van der Heyden, J.A.M and Kruse, C.G.; ' New 1-ary1-4-(biarylmethylene) piperazines aspotential atypical antipsychotics sharing dopamine D 2Receptorand serotonin 5HT 1AReceptor affinities.Bioorg.﹠amp; Med.Chem.Lett., 2001,11, the described acquisition of 2345-2349 and WO01/14330.Alkyl phenyl ketone derivatives 2 is available commercially.
Figure A20058004207000101
aReagent and condition: (i) DIPEA, KI, CH 3CN refluxes; (ii) H 2NO-CH 2CH 2NH 22HCl, DIPEA, EtOH refluxes
Factor well known by persons skilled in the art is depended in the selection of concrete synthetic method; the consistency of functional group and agents useful for same for example; use the possibility of protecting group, catalyzer, activation and coupling reagent, and the final constitutional features that exists in the final compound of preparation.
Can for example pass through compound of the present invention and suitable acid with well known to a person skilled in the art that standard method obtains pharmacy acceptable salt, for example mineral acid example hydrochloric acid or organic acid mix.
Pharmaceutical preparation
Can use auxiliary material such as liquid or solid solid support material compound of the present invention to be transformed into the form that is suitable for administration by conventional method.Pharmaceutical composition of the present invention can carry out intestines, mouth, parenteral (intramuscular or intravenously), rectum or zone (part) administration.They can be with solution, powder, tablet, capsule (comprising microcapsule), ointment (emulsifiable paste or gel) or suppository form administration.The suitable vehicle that is used for these preparations is pharmaceutically conventional liq or solid weighting agent and swelling agent, solvent, emulsifying agent, lubricant, seasonings, painted and/or buffer substance.The auxiliary material commonly used that can mention is magnesiumcarbonate, titanium dioxide, lactose, N.F,USP MANNITOL and other sugar, talcum, milk-protein, gelatin, starch, Mierocrystalline cellulose and its derivative, animal and plant oil as Oils,glyceridic,cod-liver, sunflower oil, peanut oil or sesame oil, polyoxyethylene glycol and solvent such as sterilized water and one or polyhydroxy-alcohol such as glycerine.
Compound of the present invention is generally as the pharmaceutical composition administration, and this pharmaceutical composition is owing to exist this compound, specific compound especially disclosed herein, thereby be important and new embodiment of the present invention.The type of operable pharmaceutical composition includes but not limited to other type that tablet, chewable tablet, capsule, solution, parenteral solution, suppository, suspension and disclosed herein or those skilled in the art obviously know according to specification sheets and technology general knowledge.In embodiments of the invention, provide a kind of drug packages or medicine box that comprises the container of one or more compositions of having filled one or more pharmaceutical compositions of the present invention.Relevant with these containers can be multiple written material, working instructions for example, perhaps by the mark of the government organs regulation of production, use or the sale of management medicine, this mark reflection is permitted producing, using or sell to be used for people or beastly administration by this mechanism.
Pharmacological method
To Dopamine HCL-D 2The external avidity of acceptor
Use I.Creese, R.Schneider and S.H.Snyder: " [ 3H]-Spiroperidollabels dopamine receptors in rat pituitary and brain ", Eur.J.Pharmacol., 46,377-381,1977 described receptor binding assays are measured compound to Dopamine HCL-D 2The avidity of acceptor.
External avidity to the serotonin reuptake sites
With people such as E.Habert: " Characterisation of [ 3H]-paroxetinebinding to rat cortical membranes ", Eur.J.Pharmacol., 118,107-114,1985 described receptor binding assays are measured the avidity of compound to the serotonin reuptake sites.
Dosage
As above-mentioned mensuration The compounds of this invention to Dopamine HCL-D 2The avidity of acceptor and serotonin reuptake sites.Can the estimation theory minimum effective dose according to binding affinity to the compound determination of the formula (1) determined.The K that is equaling to measure iUnder the compound concentrations of-value twice, 100% acceptor may occupy by combined thing.Suppose the ideal bioavailability, this concentration is changed into mg compound/kg patient, obtain theoretical minimum effective dose.Pharmacokinetics, pharmacodynamics and other consideration may change to higher or lower value with actual dosage.Suitable dosage is 0.001-1000mg/kg, preferred 0.1-100mg/kg weight in patients.
Treatment
Term used herein " treatment " refers to Mammals, any treatment of preferred people's symptom or disease, comprise: (1) preventing disease or symptom are having ill tendency but the ill experimenter of N is taken place on one's body, (2) suppress disease or symptom, promptly stop its development, (3) palliate a disease or symptom, promptly cause disease to disappear, perhaps (4) symptom of palliating a disease and causing promptly stops the symptom of disease.
The preparation of the compound with formula (1) is described in following examples now in more detail.
Embodiment
Embodiment 1: material and method
On Bruker Avance DRX600 instrument (600MHz), Varian UN400 instrument (400MHz) or Varian VXR200 instrument (200MHz), use DMSO-D 6Or CDCl 3As solvent, and with tetramethylsilane as interior mark, record 1H and 13C NMR spectrum.With ppm (δ scale) is unit, provides chemical shift from the tetramethylsilane downfield.Coupling constant (J) is unit representation with Hz.(0.040-0.063mm Merck) carries out flash chromatography and handles (Flash chromatography) with silica gel 60.(0.063-0.200mm Merck) carries out column chromatography and handles with silica gel 60.On B ü chi B-545 fusing point instrument, measure fusing point.On the Micromass QTOF-2 instrument that has the MassLynx application software that is used to obtain and reproduce data, write down mass spectrum.Finish quasi-molecular ion [M+H] +Exact mass measure.
Embodiment 2: synthetic particular compound
The synthetic of compound 3 is the two-step reaction that originates in 4-(2,3 dihydros-1,4 benzo dioxine-5-yl)-1-piperazine (3i).The piperazine (3i) of 15mmol is suspended in the 125ml acetonitrile, and adds 2 normal di-isopropyl ethyl-amine (DIPEA).Stir after 5 minutes under the room temperature, add 5-chloro-1-(4-trifluoromethyl-phenyl)-pentane-1-ketone of 1 equivalent (15mmol), add 1 normal sodium iodide then.This mixture was stirred 20 hours down in 80 ℃.Evaporation removes and desolvates, and residuum is dissolved in the 100ml methylene dichloride.
Wash organic layer with water, and use dried over mgso, then evaporation.With column chromatography purifying residuum, so obtain ketone-derivative 3ii of 6.4mmol, it is dissolved in 30ml methyl alcohol.Add 1 normal O-(2-amino-ethyl)-oxyamine two-HCl salt toward this solution, and this mixture was heated 12 hours down in 80 ℃.Behind the evaporating solvent, residuum is dissolved in methylene dichloride, and washes with water.Use the dried over mgso organic layer, and evaporating solvent obtains residuum, be purified with column chromatography.After being added to this pure substance, 3 normal HCl in ethanol obtain three HCl-salt of compound 3.
Mp.156-60 ℃; Overall yield 15%.
The synthetic of compound 7 is the two-step reaction that originates in 2-sec.-propyl oxygen base-phenylpiperazine (7i).7i is suspended in the 40ml acetonitrile with the 4.2mmol phenylpiperazine.Add 2 normal DIPEA, 1 normal 4-chloro-1-(4-trifluoromethyl-phenyl)-butane-1-ketone and 1 normal potassiumiodide.This mixture backflow is spent the night, and at second day evaporating solvent.With column chromatography purifying residuum, obtain pure ketone-compound 7ii of 2.5mmol, it is dissolved in 30ml ethanol (100%) once more.Add 1 normal O-(2-amino-ethyl) oxyamine two-HCl salt and 1 normal pyridine.This mixture was heated 4 hours down in 80 ℃.With column chromatography purifying residuum, so obtain the 2mmol orange oil behind the evaporating solvent.This oily mater is dissolved in ethanol, and adds 1 normal fumaric acid.Obtain the amorphous fumarate of compound 7 after the evaporation; Overall yield 50%
The synthetic of compound 8 is the two-step reaction that originates in 4-(2,3 dihydros-1,4 benzo dioxine-5-yl)-1-piperazine (3i).The phenylpiperazine (3i) of 3.5mmol is suspended in the 40ml acetonitrile.Add 2 normal DIPEA, 1 normal 6-chloro-1-(4-trifluoromethyl-phenyl)-hexane-1-ketone and 1 equivalent potassiumiodide.This mixture backflow is spent the night, and at second day evaporating solvent.With column chromatography purifying residuum, obtain pure ketone-compound 8ii of 1.7mmol, it is dissolved in 10ml ethanol (100%) once more.Add 1 normal O-(2-amino-ethyl) oxyamine, two HCl salt, and this mixture was heated 4 hours down in 80 ℃.With column chromatography purifying residuum, so obtain the 1.6mmol yellow oil behind the evaporating solvent.Oily mater is dissolved in ethanol, and adds 2 normal fumaric acid.Obtain the amorphous fumarate of compound 8 after the evaporation; Overall yield 45%.
Compound 9 synthesize the two-step reaction that originates in 4-(2,3 dihydros-1,4 benzo dioxine-5-yl)-1-piperazine.Compound 3ii (30mmol) is dissolved in the methyl alcohol of 20ml.Add 1 normal O-(N-methyl-2-amino-ethyl)-oxyamine two-HCl salt toward this solution, and this mixture was heated 5 hours down in 80 ℃.Behind the evaporating solvent, residuum is dissolved in methylene dichloride, and, uses the salt water washing then with the sodium hydrogen carbonate solution washing.Use the dried over mgso organic layer, and evaporating solvent obtains residuum, be purified by column chromatography.The ethanolic soln of 1 normal fumaric acid is added to the material of purifying, then obtains the fumarate of compound 9 after the evaporating solvent; Overall yield 15%.
The synthetic of compound 10 is the two-step reaction that originates in 4-(2,3 dihydros-1,4 benzo dioxine-5-yl)-1-piperazine (3i).3i is suspended in the 40ml acetonitrile with the 6mmol phenylpiperazine.Add 2 normal DIPEA, 1 normal 7-chloro-1-(4-trifluoromethyl-phenyl)-heptane-1-ketone and 1 equivalent potassiumiodide.This mixture backflow is spent the night, and at second day evaporating solvent.With column chromatography purifying residuum, obtain the pure ketone of 4.2mmol-compound 10ii, it is dissolved in the ethanol (100%) of 25ml once more.Add 1 normal O-(2-amino-ethyl) oxyamine two-HCl salt, and this mixture was heated 4 hours down in 80 ℃.With column chromatography purifying residuum, so obtain the 2mmol yellow oil behind the evaporating solvent.This oily mater is dissolved in ethanol, and adds 1.5 equivalent fumaric acid.Obtain the amorphous fumarate of compound 10 after the evaporation; Overall yield 35%.
The compound of table 1. general formula (1)
Figure A20058004207000141
Wherein Q can be one of structure fragment A-N
Figure A20058004207000151
Compound y R 1 Q x R 2 R 3 R 4 n m mp(℃)
3 - - A 1 4-CF 3 H H 3 1 156-160
4 1 2-OMe N 1 4-F H H 2 1 150-152
5 - - F 1 4-CF 3 H H 3 1 158
6 - - D 1 4-CF 3 H H 3 1 153-154
7 1 OCH(Me) 2 N 1 4-CF 3 H H 2 1 Amorphous
8 - - A 1 4-CF 3 H H 4 1 Amorphous
9 - - A 1 4-CF 3 Me H 3 1 Amorphous
10 - - A 1 4-CF 3 H H 5 1 Amorphous
11 1 2-OMe N 1 4-CF 3 H H 5 1 Amorphous
Synthetic as above-mentioned particular compound is intended to further illustration the present invention in more detail.Therefore they are not considered to limit the scope of the invention by any way.Other embodiment of the present invention is conspicuous for the those skilled in the art that considered explanation of the present invention disclosed herein and enforcement.Therefore this specification sheets and embodiment are intended to be regarded as merely and exemplify, and this true scope and design are represented by claim.
Embodiment 3: the preparation that is used for the compound 3 of zooscopy
For carrying out oral (p.o.) administration: the solid chemical compound 3 toward the desired amt in Glass tubing (0.5-5mg) adds some granulated glass spherees, and by vortex 2 minutes solid is pulverized.After the solution of the Poloxamer188 (Lutrol F68) of 1% methylcellulose gum and 2% (v/v) of adding 1ml in water, came suspended compound in 10 minutes by vortex.Regulate pH to 7 with the several NaOH aqueous solution (0.1N).Further be suspended in remainder particulate in the suspension with ultra sonic bath.
For carrying out intraperitoneal (i.p.) administration: add some granulated glass spherees toward the desired amt in glass (0.5-15mg) solid chemical compound 3, and solid is pulverized by vortex 2 minutes.Add after 1% methylcellulose gum and the solution of 5% N.F,USP MANNITOL of 1ml in water, came suspended compound in 10 minutes by vortex.At last with pH regulator to 7.
Embodiment 4: the pharmacology test result
In following table, shown the Dopamine HCL-D that obtains according to above-described scheme 2With serotonin reuptake acceptor avidity data.
The external avidity of table 2. The compounds of this invention
External avidity
Dopamine HCL-D 2 The 5-HT reuptake
Compound pK i pK i
3 8.3 8.2
4 8.6 7.3
5 8.2 8.3
6 6.6 8.3
7 8.1 7.0
8 8.3 8.0
9 8.4 7.5
10 8.4 8.5
11 8.3 8.3

Claims (10)

1. the compound of general formula (1) and tautomer thereof, steric isomer and N-oxide compound, and acceptable salt, hydrate and solvate on the pharmacology of the compound of this formula (1) and tautomer, steric isomer and N-oxide compound:
Figure A2005800420700002C1
Wherein:
M and n are 1,2,3,4,5,6,7 or 8 independently,
X is 0,1,2 or 3,
R 2Be halogen, branched-chain or straight-chain alkyl (C 1-6), phenyl, benzyl, side chain or straight chain alkoxyl group (C 1-6), trifluoromethyl or cyano group,
R 3And R 4Represent hydrogen, alkyl (C independently 1-6), phenyl, benzyl or ethanoyl,
Group Q is selected from structure fragment A-N
Figure A2005800420700002C2
Wherein:
Y is 1,2 or 3,
R 1Be halogen, branched-chain or straight-chain alkyl (C 1-6), phenyl, benzyl, side chain or straight chain alkoxyl group (C 1-6), trifluoromethyl or cyano group.
2. the compound of the desired general formula of claim 1 (1) and tautomer thereof, steric isomer and N-oxide compound, and acceptable salt, hydrate and solvate on the pharmacology of the compound of this formula (1) and tautomer, steric isomer and N-oxide compound, wherein m is 1, n is 2,3,4 or 5, x is 1, R 2Be 4-fluorine or 4-trifluoromethyl, R 3And R 4Represent hydrogen or methyl independently, group Q is selected from structure fragment A, D, F or N, and y is 1, R 1Be side chain or straight chain alkoxyl group (C 1-3).
3. be selected from desired compound of following claim 1 and tautomer thereof, steric isomer and N-oxide compound, and acceptable salt, hydrate and solvate on the pharmacology of the compound of this formula (1) and tautomer, steric isomer and N-oxide compound:
y R 1 Q x R 2 R 3 R 4 n m - - A 1 4-CF 3 H H 3 1 1 2-OMe N 1 4-F H H 2 1 - - F 1 4-CF 3 H H 3 1 - - D 1 4-CF 3 H H 3 1 1 OCH(Me) 2 N 1 4-CF 3 H H 2 1 - - A 1 4-CF 3 H H 4 1 - - A 1 4-CF 3 Me H 3 1 - - A 1 4-CF 3 H H 5 1 1 2-OMe N 1 4-CF 3 H H 5 1
Those symbols in the symbology formula (1) wherein:
Figure A2005800420700004C1
With structure fragment A, D, F or N:
Figure A2005800420700004C2
4. pharmaceutical composition comprises pharmaceutically acceptable carrier and/or at least a acceptable accessories and as the compound or its salt of one of at least a claim 1-3 of the pharmacological activity amount of activeconstituents.
5. the desired preparation of compositions method of claim 4 is characterized in that the compound or its salt of one of at least a claim 1-3 is made the form that is suitable for administration.
6. the desired compound or its salt arbitrarily of claim 1-3 is used as medicine.
7. the arbitrarily desired compound of claim 1-3 is used to prepare the application of the pharmaceutical composition of treatment CNS disease.
8. claim 7 desired application is characterized in that this disease is attack, anxiety disorder, autism, dizzy, depressed, cognition or dysmnesia, Parkinson's disease, schizophrenia and other mental disorder.
9. claim 7 desired application is characterized in that this disease is for depressed.
10. claim 7 desired application is characterized in that this disease is schizophrenia and other mental disorder.
CNA2005800420702A 2004-12-07 2005-12-06 Phenylpiperazines with a combination of affinity for dopamine -D2 receptors and serotonin reuptake sites Pending CN101072765A (en)

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