CN1167694C - 1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: dopamine receptor ligands - Google Patents
1-phenyl-4-(1-[2-aryl]cyclopropyl) methylpiperazines: dopamine receptor ligands Download PDFInfo
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- CN1167694C CN1167694C CNB008040923A CN00804092A CN1167694C CN 1167694 C CN1167694 C CN 1167694C CN B008040923 A CNB008040923 A CN B008040923A CN 00804092 A CN00804092 A CN 00804092A CN 1167694 C CN1167694 C CN 1167694C
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- additive salt
- useful additive
- hydrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed are compounds of formula (I) or pharmaceutically acceptable addition salts thereof wherein: R1, R2, R3, R4 and R5, R6, R7 and R8 represent organic and/or inorganic substituents as defined herein, which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.
Description
Background of invention
Invention field
The present invention relates to 1-phenyl-4-(1-[2-aryl] cyclopropyl) methyl piperazine derivate and comprise the pharmaceutical composition of this compound.The invention still further relates to this compound is treating or is preventing as the purposes in the mental disorderes such as schizophrenia and other central nervous system disease.
Description of Related Art
It is generally acknowledged that the conventional antipsychotic drug that is called Antipsychotic drug is brought into play its curative effect by the blocking-up Dopamine Receptors.But Antipsychotic drug usually is the reason that causes outer side effect (EPS) of undesirable pyramidal tract and slowness dyskinesia, and outer side effect of described pyramidal tract and slowness dyskinesia are owing to the blocking-up of the D2 acceptor in big brain striatum district.Determined recently dopamine d 4 receptor hypotype (Nature,
350: 610 (people such as Van Tol, 1991); Nature,
347: 146 (people such as Sokoloff, 1990)).It shows that in unique positioning action in brain zone, edge and to the difference identification effect of various antipsychotic drugs the D4 acceptor plays a major role in the schizoid cause of disease.Optionally the D4 antagonist is considered to effective antipsychotic drug, does not have the shown neurological side effects of coming out of conventional Antipsychotic drug.
Summary of the invention
The invention provides the compound of novel formula I, this compound and Dopamine HCL hypotype interact.Therefore, a first aspect of the present invention relates to the compound of formula I:
Wherein:
R
1And R
2Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
A is the alkylidene group with 1-3 carbon atom; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
6Alkyl.
Dopamine d 4 receptor concentrate on the cognitive and mood of control the limbic brain system (Science,
265: 1034 (Taubes, 1994)).Therefore, can be used for treating cognitive disorders with the compound of these acceptor interactions.This disease comprises cognitive the shortage, and this is the remarkable integral part of negative symptoms of schizophrenia (social activity is shunk back and anergy).Other disease comprises memory injury or attention-deficient.
Aspect the D4 receptor subtype combines, compound of the present invention shows the affinity and the selectivity of height.Therefore, these compounds can be used for treating various neuropsychopathies, as schizophrenia, depression and mania.Also can treat other disease directly or indirectly, as similar Parkinson's disease and slowness dyskinesia by regulating the D4 acceptor with the Dopamine HCL mediation.
Compound of the present invention can also be by regulating the D4 acceptor, be used for that treatment is depressed, the loss of memory or Alzheimer's (Alzheimer) disease, because they optionally are present in known controlling the emotion and the zone of cognitive function.
So another aspect of the present invention provides the method that treats and/or prevents, to treat and/or prevent neuropsychopathy or thymopathy, these diseases comprise, for example, and schizophrenia, mania, dementia, dysthymia disorders, anxiety, obsessional idea and behavior, (mentation) substance abuse, the loss of memory, the cognitive shortage, the motor disorder of similar Parkinson's disease, as Parkinson's disease and myodystonia, and with use the relevant motor disorder of psychosis.In addition, compound of the present invention can be used for treatment depression, the loss of memory or Alzheimer's disease.And compound of the present invention can be used to treat other disease that blocking-up responds to dopaminergic, as substance abuse and anancastic disease.Simultaneously, these compounds can be used to treat the outer side effect of the pyramidal tract relevant with the use of conventional Antipsychotic drug.
In addition, need only suitably mark, compound of the present invention can also be as the probe of location Dopamine Receptors.The location of acceptor can be carried out external, is for example undertaken by the radioautography art of organizing section; Also can carry out in vivo, for example be undertaken by positron emission computerized tomography (PET).
On the one hand, the invention provides the pharmaceutical composition that comprises formula I compound again.
In addition, the invention provides and be used for the intermediate of preparation I compound.
Simultaneously, the invention provides the method for preparation compound of the present invention.
Detailed Description Of The Invention
The present invention includes the compound of formula I recited above.
The compound of preferred formula I is those R wherein
5, R
6, R
7And R
8Be C
1-C
3Alkyl, the more preferably compound of hydrogen or methyl.The compound of preferred formula I is those R wherein
5, R
6, R
7And R
8Compound for hydrogen.In the compound of preferred formula I, R
5And R
8The hydrogen of position is transconfiguration each other.Preferred especially R
1, R
2, R
3And R
4Compound for the formula I of hydrogen, halogen or low alkyl group.
In the compound of other preferred formula I, work as R
1And R
3-R
8When being hydrogen, R
2Be not the tertiary butyl, more preferably it is not C
1-C
6Alkyl.
In addition, the present invention includes the compound of following formula II:
Wherein:
R
1And R
2Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
6Alkyl;
Condition is to work as R
1And R
3-R
8When being hydrogen, R
2It is not the tertiary butyl.
In the compound of preferred formula II, R
5And R
8Transconfiguration each other.In the compound of preferred formula II, R
5, R
6, R
7And R
8Be hydrogen or methyl.The compound of preferred formula II is those R
5, R
6, R
7And R
8Be the compound of hydrogen.In the compound of most preferred formula I, R
5And R
8The hydrogen of position is transconfiguration each other.Preferred especially R
1, R
2, R
3And R
4Compound for the formula I of hydrogen, halogen or low alkyl group.
In the compound of other preferred formula I, work as R
1And R
2One of when being hydrogen, another can be halogen, and is preferably placed at the contraposition of phenyl ring.In these preferred compounds, preferred R
3And R
4Be positioned at contraposition, one and be positioned at the ortho position, promptly be positioned at 4 and 2 with respect to the phenyl ring tie point, and be hydrogen, halogen or C
1-C
3Alkyl, condition are R
3And R
4One of be not hydrogen.
In addition, the present invention includes the compound of following formula III:
Wherein:
R
1And R
2Represent hydrogen, halogen, C independently
1-C
3Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
3Alkyl.
The compound of preferred formula III is those R wherein
1And R
2Be the compound of hydrogen, halogen, methyl or ethyl independently.In the compound of preferred formula III, R
1And R
2Be hydrogen.
In other preferred formula III compound, at least one R
1And R
2Be not hydrogen.In preferred formula III compound, R
1And R
2At least one is not a hydrogen, and promptly it is selected from halogen, C
1-C
3Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group, and R
3And R
4Be positioned at 2 and 4 of phenyl ring.In the compound of these preferred formula IIIs, R
5, R
6, R
7And R
8Be hydrogen or methyl.In addition, in the compound of these preferred formula IIIs, R
5And R
8Transconfiguration each other.
In addition, the present invention includes the compound of following formula IV:
Wherein:
R
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
3Alkyl.
The compound of preferred formula IV is those R wherein
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro or perfluoro (C
1-C
6) compound of alkoxyl group.The compound of preferred formula IV is those R wherein
5, R
6, R
7And R
8Compound for hydrogen or methyl.In the compound of preferred formula IV, R
5And R
8Transconfiguration each other.
Other preferred formula IV compound is those R wherein
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.Particularly preferred formula IV compound is those R
4Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3Alkoxyl group, and R
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.
The compound of other preferred formula IV is those R wherein
3Compound for hydrogen, chlorine or methyl.The compound of preferred formula IV is those R wherein
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.The compound of particularly preferred formula IV is those R wherein
3Be hydrogen, chlorine or methyl, and R
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.
In addition, the present invention includes the compound of following formula Va:
Wherein:
R
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
3Alkyl.
The compound of preferred formula Va is those R wherein
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro or perfluoro (C
1-C
6) compound of alkoxyl group.The compound of preferred formula Va is those R wherein
5, R
6, R
7And R
8Compound for hydrogen or methyl.In the compound of preferred formula Va, R
5And R
8Transconfiguration each other.
Other preferred formula Va compound is those R wherein
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.Particularly preferred formula Va compound is those R
4Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3Alkoxyl group, and R
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.
The compound of other preferred formula Va is those R wherein
3Compound for hydrogen, chlorine or methyl.Also having the compound of other preferred formula Va is those R wherein
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.The compound of particularly preferred formula Va is those R wherein
3Be hydrogen, chlorine or methyl, and R
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.
In the compound of other preferred formula Va, R
1And R
2One of can be halogen, and be preferably placed at the contraposition of phenyl ring, another is a hydrogen simultaneously.In these preferred compounds, preferred R
3And R
4Be positioned at contraposition, one is positioned at the ortho position, promptly is positioned at 4 and 2 with respect to the phenyl ring tie point, and is hydrogen, halogen or C
1-C
3Alkyl, condition are R
3And R
4At least one is not a hydrogen.
Particularly preferred compound of the present invention is those compounds with following steric configuration skeleton:
This compound is included among the formula Va.
In addition, the present invention includes the compound of following formula Vb:
Wherein:
R
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group;
R
3And R
4Identical or different and represent hydrogen, halogen, C
1-C
6Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro, perfluoro (C
1-C
6) alkyl or perfluoro (C
1-C
6) alkoxyl group; And
R
5, R
6, R
7And R
8Identical or different and represent hydrogen or C
1-C
3Alkyl.
The compound of preferred formula Vb is those R wherein
1And R
2Represent hydrogen, halogen, C independently
1-C
6Alkoxyl group, C
1-C
4Alkylthio, hydroxyl, amino, one or two (C
1-C
6) alkylamino, cyano group, nitro or perfluoro (C
1-C
6) compound of alkoxyl group.The compound of preferred formula Vb is those R wherein
5, R
6, R
7And R
8Compound for hydrogen or methyl.In the compound of preferred formula Vb, R
5And R
8Transconfiguration each other.
Other preferred formula Vb compound is those R wherein
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.Particularly preferred formula Vb compound is those R
4Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3Alkoxyl group, and R
3Be hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3The compound of alkoxyl group.
The compound of other preferred formula Vb is those R wherein
3Compound for hydrogen, chlorine or methyl.Also having the compound of other preferred formula Vb is those R wherein
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.The compound of particularly preferred formula Vb is those R wherein
3Be hydrogen, chlorine or methyl, and R
4Be hydrogen, bromine, chlorine, methyl, nitro or amino compound.
In the compound of other preferred formula Vb, R
1And R
2One of can be halogen, and be preferably placed at the contraposition of phenyl ring, another is a hydrogen simultaneously.In these preferred compounds, preferred R
3And R
4Be positioned at contraposition, one is positioned at the ortho position, promptly is positioned at 4 and 2 with respect to the phenyl ring tie point, and is hydrogen, halogen or C
1-C
3Alkyl, condition are at least one R
3And R
4Be not hydrogen.
In some cases, the compound of formula I can comprise one or more unsymmetrical carbons, so that this compound exists with different stereoisomer forms.For instance, these compounds can be racemic modification or optical activity form.In these cases, can split single enantiomorph, i.e. the optical activity form of obtaining by asymmetric synthesis or racemic modification.For example, the fractionation of racemic modification can be passed through ordinary method, as has the crystallization under the resolution reagent or finish with the chromatogram that chirality HPLC post carries out.
Be included in the representative compounds of the present invention among the formula I, include but not limited to compound and pharmaceutically useful additive salt thereof in the table 1.In addition, obtain, can obtain free alkali by the solution of this acid-salt that alkalizes so if compound of the present invention is a form with additive salt.Conversely, if product is a free alkali, so can be according to the ordinary method for preparing acid salt by basic cpd, by this free alkali is dissolved in suitable organic solvent, and obtain additive salt, particularly pharmaceutically useful additive salt with this solution of acid treatment.
Nontoxic pharmaceutical salts comprises hydrochloride, phosphoric acid salt, hydrobromate, vitriol,-sulfinate, formate, tosylate, mesylate, nitrate, benzoate, Citrate trianion, tartrate, maleate, hydriodate, alkanoate such as acetate, HOOC-(CH
2)
n-COOH (wherein n is 0-4) salt etc.Those skilled in the art can expect a lot of nontoxic pharmaceutically useful additive salt.
The present invention also comprises the acylations prodrug of formula I compound.Those skilled in the art can expect various synthetic methods, in order to prepare the acylations prodrug of nontoxic pharmaceutically useful additive salt and formula I compound.
Although compound exists with the form of multiple tautomer, the present invention is not subject to any specific tautomer.The present invention includes all tautomeric forms of compound.
In the present invention, " C
1-C
6Alkyl " or " low alkyl group " be meant straight or branched alkyl with 1-6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl and 3-methyl amyl.Preferred C
1-C
6Alkyl is a methyl, ethyl, propyl group, butyl, cyclopropyl and cyclopropyl methyl.
In the present invention, " C
1-C
6Alkoxyl group " or " lower alkoxy " be meant straight or branched alkoxyl group with 1-6 carbon atom, as methoxyl group, oxyethyl group; propoxy-, isopropoxy, n-butoxy; sec-butoxy, tert.-butoxy, pentyloxy; 2-pentyloxy; isopentyloxy, neopentyl oxygen, hexyloxy; 2-hexyloxy, 3-hexyloxy and 3-methyl pentyloxy.Herein, preferred alkoxyl group is C
1-C
4Alkoxyl group.
Perfluoro (C of the present invention
1-C
6) alkyl is preferably trifluoromethyl.Perfluoro (C of the present invention
1-C
6) alkoxyl group is preferably the trifluoro chain alkoxy.
In the present invention, term " halogen " is meant fluorine, chlorine, bromine and iodine.
Aryl is meant the aromaticity carbon ring group with a ring (as phenyl ring) or two rings (as xenyl).This group can be single replacement, two replacements or trisubstituted.Suitable substituting group comprises as halogen low alkyl group, lower alkoxy, lower alkylthio, trifluoromethyl, low-grade acyloxy, aryl, heteroaryl and hydroxyl.
In the present invention, heteroaryl (fragrant heterocycle) is meant the aromatic ring system of one or more 5-, 6-or 7-unit ring, wherein contains at least 1 maximum 4 heteroatoms that are selected from nitrogen, oxygen or sulphur.This heteroaryl comprises as thienyl, furyl, thiazolyl, imidazolyl, (different) oxazolyl, pyridyl, pyrimidyl, (different) quinolyl, naphthyridine base, benzimidazolyl-and benzoxazolyl.
Representational compound of the present invention is shown in Table 1.
Table 1
Compound with this skeleton is preferred.
The invention still further relates to the purposes of compound in treatment nervosa mental disorder of general formula I.The interaction of compound of the present invention and Dopamine HCL is shown among the embodiment.This interaction has caused the pharmacological activity of these compounds.
The compound of general formula I is the form oral administration of unit formulation according to dosage, topical, and parenteral administration, by sucking or spraying administration or pass through rectal administration, described preparation contains conventional nontoxic pharmaceutically useful carrier, adjuvant and vehicle.Term used herein " parenteral administration " comprises subcutaneous injection, vein, muscle, breastbone inner injection, or infusion techniques.In addition, the invention provides a kind of pharmaceutical preparation, said preparation comprises the compound and the pharmaceutically useful carrier of general formula I.The compound of one or more formulas I can exist together with one or more nontoxic pharmaceutically useful carriers and/or thinner and/or adjuvant and other activeconstituentss (if desired).The pharmaceutical composition that contains compound of Formula I can be to be suitable for oral form, for example, and tablet, lozenge (troches), lozenge (lozenge), water or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule or syrup or elixir.
Be used for oral composition, can prepare according to any known drug preparation of compositions method in this area, this composition can comprise one or more reagent that is selected from sweeting agent, seasonings, tinting material and sanitas, so that pharmaceutically very good to eat preparation to be provided.Tablet comprises activeconstituents, wherein is mixed with the nontoxic pharmaceutically useful vehicle that is suitable for preparing tablet.For instance, these vehicle can be inert diluents, as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent are as W-Gum or alginic acid; Tackiness agent is as starch, gelatinum or Sudan Gum-arabic; And lubricant, as Magnesium Stearate, stearic acid or talcum.Tablet is dressing not, also can be by known technology coatings, delaying, and provide a kind of secular slow releasing function thus in GI disintegration and absorption.For instance, can use such as time-delay materials such as Zerol or Stearic diglycerides.
Oral preparations also can be a hard gelatinum capsule, activeconstituents wherein and inert diluent such as lime carbonate, calcium phosphate or kaolin are mixed together, also can be soft gelatinum capsule, activeconstituents wherein and water or oily medium be mixed together as peanut oil, whiteruss or sweet oil.
Water suspension comprises the activeconstituents that is mixed with vehicle, and this vehicle is suitable for preparing water suspension.This vehicle is a suspension agent, for example, and Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, Polyvinylpyrolidone (PVP), gum tragacanth and Sudan Gum-arabic; Dispersion and wetting agent can be naturally occurring phosphatide, as Yelkin TTS, or the condensation product of alkylene oxide and lipid acid, as polyoxyethylene stearic acid ester, or the condensation product of ethylene oxide and long chain aliphatic alcohol, as heptadecaethylene oxycetanol, perhaps ethylene oxide and condensation product from the partial ester of lipid acid and hexitol, as octadecanoic acid ester of polyethylene glycol, perhaps ethylene oxide and condensation product from the partial ester of lipid acid and hexitan are as the polyethylene dehydrated sorbitol mono-fatty acid ester.Water suspension can also comprise one or more sanitass, as ethyl p-hydroxybenzoate or n-propyl, and one or more tinting materials, one or more seasoningss, and one or more sweeting agents are as sucrose or starch.
The oily suspensoid can be by being suspended in activeconstituents vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois, perhaps is suspended in mineral oil such as the whiteruss and prepares.The oily suspensoid can comprise viscosifying agent, as beeswax, paraffinum durum or hexadecanol.Sweeting agent is as above-mentioned those seasoningss, can adds seasonings, so that good to eat oral preparations to be provided.These compositions can pass through to add oxidation inhibitor, and are anticorrosion as adding xitix.
Be suitable for being mixed with dispersion agent or wetting agent, suspension agent and or the activeconstituents of one or more sanitass by adding dispersible powder and the particle that water prepares water suspension, providing.The suitable dispersion agent or the example of wetting agent and suspension agent be already mentioned above those.Also can add additional excipients, as sweeting agent, seasonings and tinting material.
Pharmaceutical composition of the present invention also can be oil-in-water emulsion.Oil phase can be a vegetables oil, as sweet oil or peanut oil, and perhaps mineral oil, as whiteruss, perhaps these oily mixtures.Examples of suitable emulsifiers can be a natural gum, as Sudan Gum-arabic or gum tragacanth, natural phospholipid (as soybean), Yelkin TTS, with be derived from ester lipid acid and hexitol, hexitan or partial ester, as dehydrated sorbitol mono-fatty acid ester and as described in the condensation product of partial ester and ethylene oxide, as the polyoxyethylene sorbitan monoleate.Described emulsifying agent can also comprise sweeting agent and seasonings.
Syrup and elixir can prepare with sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose.This preparation can also comprise negative catalyst, sanitas and seasonings and tinting material.This pharmaceutical composition can be the water quality of sterile injectable or the form of oily suspensoid.This suspensoid can be according to known technology, prepares with those suitable dispersions above-mentioned or wetting agent and suspension agent.The preparation of sterile injectable can also be nontoxic intestines and stomach external administration acceptable diluent or aseptic parenteral solution or the suspensoid in the solvent, as the solution in 1,3 butylene glycol.Operablely accept vehicle and solvent is water, Ringer solution and isoosmotic sodium chloride solution.In addition, aseptic, nonvolatile oil commonly used is as solvent or suspension medium.For this reason, any non-stimulated expressed oil be can use, synthetic direactive glyceride or two glyceryl ester comprised.In addition, find that lipid acid such as oleic acid can be used in this injectable formulation.
The compound of general formula I can also be by the suppository form administration that is used for rectum.These compositions can prepare by this medicine is mixed with suitable non-toxic excipients, and this non-toxic excipients is solid and be liquid and therefore fusing and discharge medicine in rectum under rectal temperature at normal temperatures.This material is theobroma oil and polyoxyethylene glycol.
The compound of general formula I can be with the form of sterile media without the stomach administration.According to employed vehicle and concentration, this medicine can suspend or be dissolved in the vehicle.Preferably adjuvant such as local anesthetic, sanitas and buffer reagent can be dissolved in the vehicle.
0.1 milligram of every kg body weight every day is to about 140 milligrams doctor's advice dosage level, can be used to treat above-mentioned various diseases (about 0.5 milligram to every patient of about 7 grams every day).Can mix activeconstituents consumption with carrier substance, will change according to the host that will treat and concrete administering mode with preparation single dose form.Dosage unit form comprise usually about 1 milligram to about 500 milligrams activeconstituents.
But, be to be understood that, given dose level to any concrete patient will change according to many factors, and these factors comprise activity, patient age, body weight, general health situation, sex, diet, administration time, route of administration, drainage rate, the drug regimen of employed particular compound and the severity of the disease specific that stands to treat.
Provided the representational synthetic method of The compounds of this invention among the diagram I.One skilled in the art will recognize that and to change raw material and use other step to prepare compound of the present invention.
Diagram I
R wherein
1, R
2, R
3, R
4And R
5, R
6, R
7And R
8Suc as formula defined the same among the I.
As implied above, 2-aryl cyclopropane-carboxylic acid
VIIBe by styracin
VIPreparation, method is to make styracin and the methylene iodide (R that suitably replaces
6R
7CI
2) contact with the zinc metal sheet of cover cement copper.It is well-known that the variable of this method (Simmons-Smith reaction) (is seen Organic Reaction, Vol.20, pages 1-131,1982) in the literature.Make carboxylic acid then
VIIWith the 1-phenylpiperazine of suitable replacement (
VIII) condensation in the presence of coupling agent, obtain the cyclopropyl carboxylic acid amides
IXSuitable coupling agent comprises phosphinylidyne diimidazole (CDI), dicyclohexyl phosphinylidyne diimine (DCC), phosphofluoric acid benzotriazole-1-base oxygen base three (dimethylamino) Phosphonium (BOP) etc.Thereafter, formula Ia compound can pass through with suitable reductive agent such as aluminium alkane (AlH
3), borine (BH
3) or lithium aluminium hydride reduction IX and preparing.The compound of formula I can be begun to prepare similarly by piperazine VIII.Like this, piperazine VIII can be with suitable alkylated, then makes itself and sour VII coupling.Described coupling can be carried out with the derivative of sour VII, carries out as the reduction form (being alcohol or aldehyde) with this acid.
General structure
VI,
VIIWith
VIIICompound both can be purchased, also can prepare by method as known in the art.If can not buy, then can prepare general structure by the method that is similar to described in the document from commercial
VI,
VIIWith
VIIICompound.One skilled in the art will recognize that and to change raw material and use other step to prepare compound of the present invention.
Instead-enantiomer of 2-phenyl cyclopropane-carboxylic acid can use Overberger (Macromolecules, 4,718 (1971)) method to prepare.
One skilled in the art will recognize that to change raw material and use other step to prepare compound of the present invention, shown in following embodiment.Under the certain situation, need protection that some has the functional group of reactive behavior, to realize some above-mentioned conversion.In general, the condition that needs this blocking group and connect and remove this group is conspicuous to the technician in organic synthesis field.
Disclosed in this application all papers and reference comprise patent, all draw the reference of making this paper.
The present invention will further be set forth by the following examples, can not think that described embodiment is limited to wherein described concrete grammar with scope of the present invention and design.
Embodiment 1
Instead-2-(4-chlorophenyl) cyclopropane-carboxylic acid
Stir zinc powder (6.54 grams, 0.1 mole) and the mixture of cuprous chloride (1 restrains 0.01 mole) in methylene dichloride (30 milliliters), and under nitrogen atmosphere reflux 30 minutes.After the question response mixture is cooled to room temperature, in this mixture, add methylene iodide (13.4 grams, 0.05 mole), then this mixture was refluxed 1 hour again.Be cooled to after 0 ℃, add anti--4-chloro-cinnamic acid (9.1 gram).Reactant was warmed to room temperature in 2 hours, refluxed then 3 days.Under 0 ℃, by adding 30 milliliters of ether and 30 milliliters of 10% ice-cooled sulphuric acid solns finish this reaction.Organic layer MgSO
4Dry and concentrated, to obtain required white solid product.
1H NMR(CDCl
3)7.25(d，J＝7Hz，2H)，7.05(d，J＝7Hz，2H)，2.58(m，1H)，1.85(m，1H)，1.65(m，1H)，1.37(m，1H)。
Embodiment 2
1-(4-chlorophenyl)-4-(anti--the 2-[4-chlorophenyl] cyclopropyl) carbonyl piperazine
To instead-(80 milligrams of 2-(4-chlorophenyl) cyclopropane-carboxylic acids, 0.4 mmole) in the solution of 3 milliliters of dry methylene chloride, add diisopropyl ethyl amine (0.15 milliliter), 1-(4-chlorophenyl) piperazine (110 milligrams) and phosphofluoric acid benzotriazole-1-base oxygen base three (dimethylamino) Phosphonium (BOP, 0.2 gram).Resulting mixture stirring is spent the night, wash this solution to wherein adding 10 milliliters of methylene dichloride and water (2 * 10 milliliters).Organic layer MgSO
4Dry and concentrated.Gains are that eluent carries out purifying by flash chromatography with the 30%EtOAc/ hexane, obtain the acid amides of required yellow oily.
1H NMR(CDCl
3)7.2(m，4H)，7.03(d，J＝7Hz，2H)，6.83(d，J＝7Hz，2H)，3.8(m，4H)，3.18(m，4H)，2.50(m，1H)，1.95(m，1H)，1.62(m，1H)，1.25(m，1H)。
Embodiment 3
1-(4-chlorophenyl)-4-(anti--the 2-[4-chlorophenyl] cyclopropyl) methylpiperazine
In tetrahydrofuran (THF) (3 milliliters) solution of 1-(4-chlorophenyl)-4-([anti--the 2-phenyl] cyclopropyl) carbonyl piperazine (70 milligrams), add the tetrahydrofuran solution (1M, 0.6 milliliter) of aluminium alkane.Resulting mixture was at room temperature stirred 2 hours, concentrate, with the ethyl acetate dilution, and with NaOH solution and the water washing of 1N.The organic layer MgSO that obtains
4Dry and concentrated.Gains are that eluent carries out purifying by radial development chromatography with 2% ethanol/methylene, obtain the solid product (compound 3) of 30 milligrams of whites.
1H NMR(CDCl
3)：7.2(m，4H)，6.97(d，J＝7Hz，2H)，6.82(d，J＝7Hz，2H)，3.18(M，4H)，2.70(m，4H)，2.63(dd，J＝7，5Hz，1H)，2.4(m，1H)，1.65(m，1H)，1.22(m，1H)，0.9(m，2H)。Fumarate (compound 3A) prepares in methyl alcohol and crystallizes out from ethyl acetate.m.p.111-113℃。
Embodiment 4
Basically according to the method for preparing following compounds.
(a) 1-(2-aminomethyl phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 6)
(b) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 7)
(c) (S, S) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 4, m.p.224-225 ℃)
(d) (R, R) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 5, m.p.205-206 ℃)
(e) 1-(2-methyl-4-nitrophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (m.p.197-198 ℃) (compound 8)
(f) 1-(2-methyl-4-aminophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (m.p.284-285 ℃) (compound 9)
(g) 1-(2-methyl-4-bromo phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (m.p.182-183 ℃) (compound 10)
(h) 1-(4-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (m.p.229-231 ℃) (compound 11)
(i) 1-(2,4-dichloro-phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 2, m.p.206-207 ℃)
(j) 1-(2-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine hydrobromate (compound 1, m.p.201-203 ℃)
Embodiment 5
By following avidity test, be briefly described the drug effect of The compounds of this invention to dopamine receptor subtype.
The mensuration of D2 and D4 receptor-binding activity
Test with the human D2 that contains the reorganization generation and the COS cell mass of D4 acceptor.Sample homogenizes in the Tris HCl damping fluid of 100 volumes (w/vol) 0.05M under 4 ℃ and pH7.4.Then, with sample centrifugation under 30000 * g, and resuspending homogeneous again.Afterwards, sample is by carrying out centrifugation as mentioned above, and freezing standby with final tissue sample.With described tissue by 1: 20 (wt/vol) resuspending in the Tris of the 0.05M that contains 100mM NaCl HCl damping fluid.
Cultivation is carried out under 48 ℃, and contains 0.4 milliliter of tissue sample, 0.5nM
3H-YM09151-2 and relevant compound, whole nutrient solution are 1.0 milliliters.The definition of non-specific binding is the combination of finding during for 1mM at Spiropitan; Further do not adding fashionablely, this non-specific binding is lower than whole bonded 20%.The embodiment of this patent is shown in table 2 to the binding characteristic of D2 and D4 receptor subtype.
Table 2
| The compound sequence number | D4 Ki(nM) | D2 Ki(nM) |
| 1 | 8 | 7 |
| 2 | 8 | 90 |
| 3 | 8 | 523 |
| 4 | 2 | 75 |
| 5 | 10 | 51 |
Formula I compound is that 0.1 nmole (nM) is to about 50 nmoles (nM) to the scope of the binding constant (representing with nM usually) of D4 acceptor.Preferably, the binding constant of this compound constrains in about 0.1 to 10nM.These compounds to the binding constant of D2 preferably at least about 50nM, although can use the lower compound of D2 binding constant.Like this, compound of the present invention is to the D2 acceptor optionally 5 times to the selectivity of D4 acceptor at least.Preferred these compounds are to D2 optionally 10 times to the selectivity of D4 at least, and more preferably 15-50 doubly.
Embodiment 6
The preparation of the radiolabeled probe compound of the present invention
Synthetic by what use the precursor comprise a kind of radio isotope atom at least to carry out, compound of the present invention is become radiolabeled probe.Such product is the compound that comprises a kind of radioactive atom at least of the present invention.It is (preferred that described radio isotope is preferably selected from carbon
14C), hydrogen is (preferred
3H), sulphur is (preferred
35S) or iodine (preferred
125I) at least a in.This radiolabeled probe is synthetic by radio isotope supplier usually, and described radio isotope supplier is by the probe compound of the special synthesizing radioactive mark of order.There is Amersham Corporation in such supplier, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc.Andover, MA; SRIInternational, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St.Louis, MO and Moravek Biochemicals Inc., Brea, CA.
Tritium-labeled probe compound equally can be by the platinum catalytic exchange in the tritiate acetate, the acid catalysis exchange in the tritiate trifluoroacetic acid or heterocatalysis exchange and the preparation of carrying out with tritium gas easily.This radiolabeled preparation also can use compound of the present invention to customize as base material by the cited any supplier of preamble.In addition, the tritium gas reduction of tritium-halogen exchange that some precursor can carry out with tritium gas, unsaturated link(age) is perhaps suitably reduced with boron tritiate sodium.
Embodiment 7
The receptor autoradiography gamma radiography
Receptor autoradiography gamma radiography (topography) is with radio-labeled compound of the present invention (press described in the embodiment 6 method preparation), save John Wiley ﹠amp at Current Protocols inPharmacology (1998) 8.1.1 to 8.1.9 by Kohar; Sons, New York and Kuhar et al. be at Annu.Rev.Neurosci., and 1986, method described in the vol.9, pages 27-59 is carried out external.
So far, the mode of the present invention and preparation and use The compounds of this invention and method with complete, clear, clearly and accurately term is described, so that any technician in affiliated field can both prepare and use compound of the present invention.What should be appreciated that the preamble description is the preferred embodiments of the invention, and under the situation of design of being set forth in not breaking away from claims of the present invention and scope, can make various modifications to the present invention.In order to point out particularly and propose the claimed theme of the present invention clearly that this specification sheets is summarized as following claims.
Claims (23)
1. the compound of following formula or its pharmaceutically useful additive salt:
Wherein:
R
1And R
2Be selected from hydrogen and halogen independently of one another;
R
5And R
8Be hydrogen; And
R
3And R
4Be selected from hydrogen, C independently of one another
1-6Alkyl, halogen, nitro and amino.
2. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1
5And R
8Trans each other.
3. according to compound or its pharmaceutically useful additive salt of claim 1, wherein said halogen is a chlorine or bromine.
4. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1
3And R
4Be methyl independently of one another.
5. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 2
1And R
2Be hydrogen.
6. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 1
1And R
2In at least one is not a hydrogen.
7. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 5
3And R
4On 2 and 4 of phenyl ring.
8. according to each compound or its pharmaceutically useful additive salt, wherein R among the claim 2-4
1And R
2Be hydrogen or halogen independently of one another, condition is R
1And R
2In at least one be not hydrogen.
9. according to compound or its pharmaceutically useful additive salt of claim 1, be the compound or its salt of following formula:
R
1And R
2Be selected from hydrogen and halogen independently of one another; And
R
3And R
4Be selected from hydrogen, C independently of one another
1-6Alkyl, halogen, nitro and amino.
10. according to compound or its pharmaceutically useful additive salt, the wherein R of claim 9
3And R
4With respect to the site that links to each other with piperazine ring on 2 and 4 of phenyl ring.
11. compound or its pharmaceutically useful additive salt, wherein R according to claim 10
2On 4 of phenyl ring.
12. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is (S, S) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
13. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is (R, R) 1-(2, the 4-3,5-dimethylphenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
14. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-nitrophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
15. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-aminophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
16. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-methyl-4-bromo phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
17. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(4-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
18. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2,4-dichloro-phenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
19. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(2-chlorophenyl)-4-(anti--the 2-phenycyclopropyl) methylpiperazine.
20. according to compound or its pharmaceutically useful additive salt of claim 1, this compound is 1-(4-chlorophenyl)-4-(anti--2-[4-chlorophenyl] cyclopropyl) methylpiperazine.
21. the compound of claim 1 or its pharmaceutically useful additive salt are used for the treatment of purposes in the medicine of central nervous system disease in preparation, described central nervous system disease be selected from schizophrenia, mania, dementia, dysthymia disorders, anxiety, obsessional idea and behavior, substance abuse, similar Parkinson's disease motor disorder and with use the relevant motor disorder of psychosis.
22. according to the purposes of claim 21, wherein said central nervous system disease is a schizophrenia.
23. a pharmaceutical composition comprises compound or its pharmaceutically useful additive salt and the pharmaceutical carrier of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22764699A | 1999-01-08 | 1999-01-08 | |
| US09/227,646 | 1999-01-08 |
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| Publication Number | Publication Date |
|---|---|
| CN1341111A CN1341111A (en) | 2002-03-20 |
| CN1167694C true CN1167694C (en) | 2004-09-22 |
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|---|---|---|---|
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| Country | Link |
|---|---|
| EP (1) | EP1140879A1 (en) |
| JP (1) | JP2002534421A (en) |
| CN (1) | CN1167694C (en) |
| AU (1) | AU771199B2 (en) |
| CA (1) | CA2359989A1 (en) |
| HK (1) | HK1043360A1 (en) |
| NZ (1) | NZ512772A (en) |
| WO (1) | WO2000040572A1 (en) |
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| IL157363A0 (en) * | 2001-02-16 | 2004-02-19 | Aventis Pharma Inc | Novel heterocyclic urea derivatives and their use as dopamine d3 receptor ligands |
| IL157412A0 (en) * | 2001-02-16 | 2004-03-28 | Aventis Pharmaceuticals Inc Av | Novel heterocyclic amide derivatives and their use as dopamine d3 receptor ligands |
| JP4691669B2 (en) * | 2007-08-22 | 2011-06-01 | アストラゼネカ・アクチエボラーグ | Cyclopropylamide derivative |
| TW201039825A (en) * | 2009-02-20 | 2010-11-16 | Astrazeneca Ab | Cyclopropyl amide derivatives 983 |
| TWI520945B (en) | 2010-02-18 | 2016-02-11 | 阿斯特捷利康公司 | New crystalline form of a cyclopropyl benzamide derivative |
| US10882834B2 (en) | 2013-09-20 | 2021-01-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compounds for treating prostate cancer |
| US10980806B2 (en) | 2016-03-24 | 2021-04-20 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer |
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| DE3501488C1 (en) * | 1985-01-18 | 1986-07-17 | Messerschmitt-Bölkow-Blohm GmbH, 8012 Ottobrunn | Wheel set for rail vehicles |
| EP0793653A1 (en) * | 1994-11-23 | 1997-09-10 | Neurogen Corporation | Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands |
| US6048876A (en) * | 1995-01-23 | 2000-04-11 | Suntory Limited | Medicament for the alleviation or treatment of symptom derived from ischemic disease and compound useful therefor |
| US5859246A (en) * | 1997-01-30 | 1999-01-12 | Neurogen Corporation | 1-phenyl-4-benzylpiperazines: dopamine receptor subtype specific ligands |
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2000
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- 2000-01-06 EP EP00905545A patent/EP1140879A1/en not_active Withdrawn
- 2000-01-06 WO PCT/US2000/000275 patent/WO2000040572A1/en not_active Application Discontinuation
- 2000-01-06 AU AU27203/00A patent/AU771199B2/en not_active Ceased
- 2000-01-06 CN CNB008040923A patent/CN1167694C/en not_active Expired - Fee Related
- 2000-01-06 JP JP2000592280A patent/JP2002534421A/en active Pending
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|---|---|
| AU771199B2 (en) | 2004-03-18 |
| CA2359989A1 (en) | 2000-07-13 |
| NZ512772A (en) | 2003-11-28 |
| AU2720300A (en) | 2000-07-24 |
| EP1140879A1 (en) | 2001-10-10 |
| JP2002534421A (en) | 2002-10-15 |
| HK1043360A1 (en) | 2002-09-13 |
| WO2000040572A1 (en) | 2000-07-13 |
| CN1341111A (en) | 2002-03-20 |
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