WO1998039301A1 - 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands - Google Patents
1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands Download PDFInfo
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- WO1998039301A1 WO1998039301A1 PCT/US1998/004051 US9804051W WO9839301A1 WO 1998039301 A1 WO1998039301 A1 WO 1998039301A1 US 9804051 W US9804051 W US 9804051W WO 9839301 A1 WO9839301 A1 WO 9839301A1
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- alkyl
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- compound according
- halogen
- isoquinolin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
Definitions
- This invention relates to l-(isoquinolin-l-yl)-4-(l-phenylmethyl)piperazines and pharmaceutical compositions and preparations containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases. Description of the Related Art
- neuroleptics The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors.
- neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of EPS.
- EPS extrapyramidal side effects
- tardive dyskinesias which are attributed to blockade of D2 receptors in the striatal region of EPS
- the dopamine D4 receptor subtype has recently been identified (Sokoloff, P. et al.,
- European Patent Application EP 512755 A2 discloses piperazine derivatives said to be 5-HTj a antagonists.
- Ar represents an optionally substituted heteroaryl group or an optionally substituted aryl group
- Ri and R 2 independently represent hydrogen, halogen, C]-C 6 alkyl, C 1 -C 4 alkoxy, C,-C 4 alkylthio, hydroxy, amino, mono- or di(C,-C 6 )alkyl amino, cyano or trifluoromethyl
- R 5 represents hydrogen or Cj-C 6 alkyl
- Ar when Ar is phenyl, it is not an unsubstituted phenyl group. In other words, where Ar is phenyl, the phenyl is substituted with at least one non-hydrogen group.
- the invention provides pharmaceutical compositions comprising compounds of Formula I.
- dopamine D 4 receptors are concentrated in the limbic system (Taubes, Science 265: 1034, 1994) which controls cognition and emotion
- compounds which interact with these receptors are useful in the treatment of cognitive disorders.
- Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia.
- disorders involving memory impairment or attention deficit disorders can be treated with the compounds of this invention. These compounds interact specifically with the dopamine D 4 receptor subtype.
- the compounds of the invention demonstrate high affinity and selectivity in binding to the D4 receptor subtype.
- the use of the compounds of this invention in methods of treating are possible.
- neuropsychological disorders is predicated on the ability of the compounds to bind selectively to a dopamine receptor subtype, the D 4 receptor.
- the compounds of the invention can therefore be used in the treatment of schizophrenia, psychotic depression and mania.
- Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 receptors.
- the invention provides methods for treating and/or preventing neuropsychological disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. It also provides methods of treating affective disorders such as Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia.
- the invention further provides methods for treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
- the compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
- Ar represents aryl or heteroaryl, each of which is optionally substituted with R 3 and/or R 4 , provided that Ar is not unsubstituted phenyl;
- Rj and R independently represent hydrogen, halogen, C ⁇ -C 6 alkyl, C]-C 4 alkoxy, C,-C 4 alkylthio, hydroxy, amino, mono- or di(C,-C 6 )alkyl amino, cyano or trifluoromethyl; and
- R 5 represents hydrogen or C ⁇ -C 6 alkyl.
- Preferred compounds of Formula IA are those where R 3 and R 4 independently
- R 3 and R 4 together represent an alkylene, alkenylene, alkyleneoxy, or alkylenedioxy chain that together with the atoms to which they are attached form a ring having 5-7 ring atoms.
- R 3 is preferably in a position para to the point of attachment of the aryl or heteroaryl group to the methylene group.
- Ar is not unsubstituted phenyl since a substituent on the phenyl group is required for activity at the D 4 receptor.
- phenyl must contain at least one non-hydrogen substituent.
- Suitable non-hydrogen substituents are the non-hydrogen R 3 and R 4 substituents defined above.
- Preferred Ar groups of Formulas I and IA are
- Ri and R 2 independently represent hydrogen, halogen, C ⁇ -C 6 alkyl, C 1 -C 4 alkoxy, C,-C 4 alkylthio, hydroxy, amino, mono- or di(C,-C 6 )alkyl amino, cyano or trifluoromethyl;
- R 3 and R 4 independently represent hydrogen, halogen, hydroxy, C]-C 6 alkyl, trifluoromethyl, trifluoromethoxy or SO 2 NH , with the proviso provided that not both R 3 and R 4 are hydrogen simultaneously; and
- R 5 represents hydrogen or C ⁇ -C 6 alkyl.
- R 3 and R 4 are C,-C 6 alkyl or halogen.
- R 5 is hydrogen
- R 3 and R 4 are independently hydrogen or C,-C 6 alkyl.
- R 5 is hydrogen
- R 3 and R 4 are hydrogen and halogen, respectively, or are both halogen.
- the phenyl group (Ar) is substituted with methyl or mono- or disubstituted with halogen, and R 5 is hydrogen.
- the most preferred compounds of Formula II are those where R, and R, are both hydrogen.
- Particularly preferred compounds of Formula II are those where R, and R 2 are hydrogen and the phenyl group (Ar) is monosubstituted in the 4 position with methyl or chloro (4-methylphenyl or 4-chlorophenyl) or the phenyl group is disubstituted with fluoro in both the 3 and 4-positions (3,4-difluorophenyl).
- the invention also provides compounds of Formula III:
- R] and R 2 independently represent hydrogen, halogen, C ⁇ -C 6 alkyl, -C 4 alkoxy, C,-C 4 alkylthio, hydroxy, amino, mono- or di(C,-C 6 )alkyl amino, cyano or trifluoromethyl;
- R 6 represents hydrogen, halogen, hydroxy, C]-C 6 alkyl, trifluoromethyl, trifluoromethoxy or
- R 5 represents hydrogen or C ⁇ -C 6 alkyl.
- R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- R 5 is hydrogen and R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- R, and R are halogen, C)-C 6 alkyl, or hydroxy, R 5 is hydrogen and R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- the most preferred compounds of Formula III are those where R, and R, are both hydrogen, and R s and R 6 are hydrogen.
- the invention also provides compounds of Formula IV:
- Ri and R 2 independently represent hydrogen, halogen, C ⁇ -C 6 alkyl, C 1 -C 4 alkoxy, C,-C 4 alkylthio, hydroxy, amino, mono- or di(C,-C 6 )alkyl amino, cyano or trifluoromethyl;
- R 6 represents hydrogen, halogen, hydroxy, C 1 - 5 alkyl, trifluoromethyl, trifluoromethoxy or SO 2 NH 2 ; and
- R 5 represents hydrogen or C ⁇ -C 6 alkyl.
- R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- R 5 is hydrogen and R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- R, and R 2 are halogen, C ⁇ -C 6 alkyl, or hydroxy, R 5 is hydrogen and R 6 is hydrogen, C,-C 6 alkyl, or halogen.
- the most preferred compounds of Formula IV are those where R, and R 2 are both hydrogen, and R 5 and R 6 are hydrogen.
- compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
- These compounds can be, for example, racemates or optically active forms.
- R 5 in Formula I is a methyl group
- the resulting compound can be present as (R) and (S) stereoisomers.
- the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
- Representative compounds of the present invention include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
- the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
- acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
- (C r C 6 )a ⁇ kyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms as well as cyclic alkyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred C,-C 6 alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmefhyl.
- (C,-C 6 )alkoxy and lower alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.
- hydroxy C,-C 6 alkyl is meant a C,-C 6 alkyl group carrying a terminal hydroxy moiety.
- piperonyl as used herein is meant a group of the Formula:
- halogen, halo, or halide fluorine, chlorine, bromine and iodine substituents.
- aryl or “Ar” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
- aryl or “Ar” is also meant heteroaryl groups where heteroaryl is defined as 5, 6, or
- heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
- R 3 and R 4 may be connected together to form another ring with the atoms to which they are attached on the parent aryl or heteroaryl group.
- R 3 and R 4 may represent an alkylene, alkenylene, alkyleneoxy, or alkylenedioxy chain that together with the atoms to which they are attached form a ring having 5-7 atoms.
- Ar may be an optionally substituted naphthyl group or a bicyclic oxygen-containing group of the formula
- heterocyclic oxygen containing ring has a total of from 5 to 7 ring members, the heterocyclic ring being saturated or unsaturated, and optionally substituted.
- R 6 is as defined above for Formula III.
- bicyclic oxygen-containing groups are:
- each structure is its compound number.
- the invention also pertains to the use of compounds of general Formula I in the treatment of various neuropsychological disorders.
- the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
- One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
- compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl p- hydroxybenzoate
- coloring agents for example ethyl, or n-propyl p- hydroxybenzoate
- flavoring agents for example ethyl, or n-propyl p- hydroxybenzoate
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- Compounds of general Formula I may be administered parenterally in a sterile medium.
- the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
- adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
- Dosage levels on the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
- a suitably substituted 1-chloroisoquinoline of Formula V is condensed with piperazine to provide a 1-isoquinolin-l-ylpiperazine of Formula VI.
- the compound of Formula VI is typically reductively alkylated with an arylaldehyde of Formula VII with a reducing agent such as, for example, sodium cyanoborohydride to yield the desired l-(l-isoquinolin-l-yl)-4-(l-phenylmethyl)piperazine of Formula I.
- a reducing agent such as, for example, sodium cyanoborohydride
- the oxalate salt is prepared from isopropanol (m.p.207-208 °C).
- Example 4 The pharmaceutical utility of compounds of this invention is indicated by the following assays for dopamine receptor subtype affinity. 1. Assay For D2 And D4 Receptor Binding Activity
- African Green monkey are used for the assays.
- the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer at 4°C and pH 7.4.
- the sample is then centrifuged at 30,000 x g and resuspended and rehomogenized.
- the sample is again centrifuged as described above and the final tissue sample is frozen until use.
- the tissue is resuspended 1 :20 (wt/vol) in 0.05 M Tris HC1 buffer containing 100 mM NaCl.
- Incubations are carried out at 48°C and contain 0.4 ml of tissue sample, 0.5 nM ⁇ H-
- Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20%> of total binding.
- Binding characteristics for representative examples of this invention for the D2 and D4 receptor subtypes are shown in Table 2 below for rat striatal homogenates.
- the binding characteristics of compounds of Formula I for the D 4 receptor, expressed in nM generally range from about 0.5 nanomolar (nM) to about 25 nanomolar (nM). These compounds typically have binding constants for the D 2 receptor of from about 200 nM to more than 1000 nM.
- the compounds of the invention are generally at least about 10 time more selective for the D 4 receptor than the D 2 receptor. More preferably, these compounds are at least 20, and more preferably at least 25- 50, times more selective for the D 4 receptor than the D 2 receptor.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98908854A EP0970054A1 (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
JP53866498A JP2001512491A (en) | 1997-03-04 | 1998-03-03 | 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) piperazine; a dopamine receptor subtype-specific ligand |
CA002283256A CA2283256A1 (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
HU0001391A HUP0001391A3 (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl) piperazines, dopamine receptor subtype specific ligands |
IL13142798A IL131427A0 (en) | 1997-03-04 | 1998-03-03 | 1-(Isoquinolin-1-yl)-4- (1-phenylmethyl) piperazines dopamine receptor subtype specific ligands |
AU66785/98A AU6678598A (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
NZ337183A NZ337183A (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands useful for the treatment of psychotic disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US81072997A | 1997-03-04 | 1997-03-04 | |
US08/810,729 | 1997-03-04 |
Publications (1)
Publication Number | Publication Date |
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WO1998039301A1 true WO1998039301A1 (en) | 1998-09-11 |
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ID=25204554
Family Applications (1)
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PCT/US1998/004051 WO1998039301A1 (en) | 1997-03-04 | 1998-03-03 | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
Country Status (9)
Country | Link |
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EP (1) | EP0970054A1 (en) |
JP (1) | JP2001512491A (en) |
KR (1) | KR20000075918A (en) |
AU (1) | AU6678598A (en) |
CA (1) | CA2283256A1 (en) |
HU (1) | HUP0001391A3 (en) |
IL (1) | IL131427A0 (en) |
NZ (1) | NZ337183A (en) |
WO (1) | WO1998039301A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999021850A1 (en) * | 1997-10-24 | 1999-05-06 | Neurogen Corporation | 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines being dopamine d4 receptor subtype ligands |
US6008352A (en) * | 1997-04-03 | 1999-12-28 | Neurogen Corporation | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl) piperazines; dopamine receptor subtype specific ligands |
US6331629B1 (en) | 1997-10-24 | 2001-12-18 | Neurogen Corporation | Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
WO2008115593A1 (en) * | 2007-03-21 | 2008-09-25 | The University Of Montana | 1-[(2'-substituted)-piperazin-1'-yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4596792B2 (en) * | 2004-02-24 | 2010-12-15 | あすか製薬株式会社 | Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0167045A1 (en) * | 1984-06-22 | 1986-01-08 | Beiersdorf Aktiengesellschaft | Benzo[c][1,8]naphthyridines, process for their preparation and their use, and compositions containing these compounds |
JPS63227570A (en) * | 1987-03-13 | 1988-09-21 | Ss Pharmaceut Co Ltd | Isoquinoline derivative |
EP0512755A2 (en) * | 1991-05-02 | 1992-11-11 | JOHN WYETH & BROTHER LIMITED | Piperazine derivatives |
-
1998
- 1998-03-03 NZ NZ337183A patent/NZ337183A/en unknown
- 1998-03-03 JP JP53866498A patent/JP2001512491A/en active Pending
- 1998-03-03 CA CA002283256A patent/CA2283256A1/en not_active Abandoned
- 1998-03-03 EP EP98908854A patent/EP0970054A1/en not_active Withdrawn
- 1998-03-03 KR KR1019997007998A patent/KR20000075918A/en not_active Application Discontinuation
- 1998-03-03 WO PCT/US1998/004051 patent/WO1998039301A1/en not_active Application Discontinuation
- 1998-03-03 AU AU66785/98A patent/AU6678598A/en not_active Abandoned
- 1998-03-03 HU HU0001391A patent/HUP0001391A3/en unknown
- 1998-03-03 IL IL13142798A patent/IL131427A0/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0167045A1 (en) * | 1984-06-22 | 1986-01-08 | Beiersdorf Aktiengesellschaft | Benzo[c][1,8]naphthyridines, process for their preparation and their use, and compositions containing these compounds |
JPS63227570A (en) * | 1987-03-13 | 1988-09-21 | Ss Pharmaceut Co Ltd | Isoquinoline derivative |
EP0512755A2 (en) * | 1991-05-02 | 1992-11-11 | JOHN WYETH & BROTHER LIMITED | Piperazine derivatives |
Non-Patent Citations (2)
Title |
---|
G. TAUBES, SCIENCE, vol. 265, 19 August 1994 (1994-08-19), pages 1034 - 5, XP000652295 * |
P. SOKOLOFF ET AL., NATURE, vol. 347, 13 September 1990 (1990-09-13), pages 146 - 51, XP000652293 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6008352A (en) * | 1997-04-03 | 1999-12-28 | Neurogen Corporation | 1-(isoquinolin-1-yl)-4-(1-phenylmethyl) piperazines; dopamine receptor subtype specific ligands |
WO1999021850A1 (en) * | 1997-10-24 | 1999-05-06 | Neurogen Corporation | 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines being dopamine d4 receptor subtype ligands |
US6331629B1 (en) | 1997-10-24 | 2001-12-18 | Neurogen Corporation | Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands |
US6384224B2 (en) | 1997-10-24 | 2002-05-07 | Neurogen Corporation | Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl) piperazines; dopamine receptor subtype specific ligands |
WO2008115593A1 (en) * | 2007-03-21 | 2008-09-25 | The University Of Montana | 1-[(2'-substituted)-piperazin-1'-yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents |
US7887784B2 (en) | 2007-03-21 | 2011-02-15 | University Of Montana | 1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents |
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HUP0001391A3 (en) | 2001-12-28 |
IL131427A0 (en) | 2001-01-28 |
JP2001512491A (en) | 2001-08-21 |
KR20000075918A (en) | 2000-12-26 |
EP0970054A1 (en) | 2000-01-12 |
HUP0001391A2 (en) | 2000-10-28 |
CA2283256A1 (en) | 1998-09-11 |
NZ337183A (en) | 2001-05-25 |
AU6678598A (en) | 1998-09-22 |
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