EP0981516A1 - Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d?3 receptors - Google Patents

Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d?3 receptors

Info

Publication number
EP0981516A1
EP0981516A1 EP98929278A EP98929278A EP0981516A1 EP 0981516 A1 EP0981516 A1 EP 0981516A1 EP 98929278 A EP98929278 A EP 98929278A EP 98929278 A EP98929278 A EP 98929278A EP 0981516 A1 EP0981516 A1 EP 0981516A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
4alkyl
tetrahydroisoquinoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98929278A
Other languages
German (de)
English (en)
French (fr)
Inventor
Clive Leslie SmithKline Beecham Pharma. BRANCH
Geoffrey SmithKline Beecham Pharma. STEMP
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0981516A1 publication Critical patent/EP0981516A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their 5 use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.
  • Rl, R ⁇ and R ⁇ are each inter alia hydrogen;
  • X is inter alia (CH2)mNR ⁇ CO;
  • m is 2-4; and
  • Ar ⁇ is an optionally substituted heterocyclic ring or an 15 optionally substituted phenyl ring.
  • the compounds are said to be useful as antiarrhythmic agents.
  • Rl represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Cj ⁇ alkyl, C1.4al.coxy, arylCj ⁇ alkoxy, Cj ⁇ alkylthio, C ⁇ _4alkoxyC ⁇ _4alkyl, C3_6cycloalkylC ⁇ _4alkoxy, C j ⁇ alkanoyl, C ⁇ alkoxycarbonyl,
  • Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system; and salts thereof.
  • alkyl group or moiety may be straight or branched.
  • Alkyl groups which may be employed include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-pentyl, and the like.
  • Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system and in which R ⁇ is other than pentafluoroethyl.
  • R! represents an arylC ⁇ alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylC ⁇ _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC ⁇ alkyl, arylcarboxamidoC ⁇ _4alkyl, aroyl, aroylC ⁇ alkyl, or arylC ⁇ _4alkanoyl group
  • the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring.
  • an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C1 _4alkyl, C]_4alkylamino, C ⁇ _ 4dialkylamino, Cj ⁇ alkylamido, C ⁇ alkanoyl, or R ⁇ R ⁇ NCO where each of R ⁇ and R ⁇ independently represents a hydrogen atom or C ⁇ _4alkyl group.
  • a halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
  • the substituents R may be the same or different.
  • An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for either of the groups Ar or Ar ⁇ may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N.
  • Examples of 5 and 6- membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.
  • bicyclic, for example bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[l,5- a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl, 1,2- dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1 ,2-dihydro-2-oxo-3 ⁇ - indoly
  • the group Ar may be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C1.4a.kyl,
  • Ar may be optionally substituted by one or more 5- or 6- membered heterocyclic rings, as defined above, optionally substituted by a C]_2 alkyl or R 7 R 8 N- group; wherein R 7 and R 8 are as defined above.
  • substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring.
  • salts of formula (I) should be physiologically acceptable.
  • suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p- toluenesulphonic, methanesulphonic or naphthalenesulphonic acid.
  • Other non- physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
  • R ⁇ represents a substituent selected from: a halogen atom, methyl, cyano, trifluoromethylsulfonyloxy, trifluoromethyl, pentafluoroethyl, or trifluoromethoxy group.
  • the group Ar is optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
  • substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
  • Certain of the substituted heteroaromatic ring systems included in compounds of formula (I) may exist in one or more tautomeric forms.
  • the present invention includes within its scope all such tautomeric forms, including mixtures.
  • Particular compounds according to the invention include:
  • the present invention also provides a process for preparing compounds of formula (I) and salts thereof which process comprises : (a) reacting a compound of formula (II):
  • R ⁇ a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH)2 or a metal function such as trialkylstannyl e.g. SnBu3, zinc halide or magnesium halide, and when q is 2 the other R ⁇ a is R!
  • W* is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W ⁇ is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;
  • Process (a) requires the presence of a reducing agent.
  • Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation.
  • the reaction may conveniently be effected in a solvent such as ethanol or dichloroethane.
  • Process (b) may be effected by methods well known in the art for formation of an amide bond.
  • Reaction of a compound of formula (VI) with Ar ⁇ Wl, according to process (c) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrafa ' s-triphenylphosphinepalladium (0).
  • a transition metal eg palladium catalyst
  • M represents a boronic acid function such as B(OH) 2
  • the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane.
  • M is trialkylstannyl
  • the reaction may be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl.
  • M is a zinc or magnesium halide
  • the reaction may be effected in an aprotic solvent such as tetrahydrofuran.
  • the substituent W is preferably a halogen atom such as bromine, or a sulphonyloxy group such as trifluoromethylsulphonyloxy; and W ⁇ is preferably a goup M, such as trialkylstannyl or B(OH)2-
  • the reagent serving to introduce the group Ar* is preferably a compound of formula Ar ⁇ -Hal, wherein Hal is a halogen atom.
  • the reaction may be effected in the presence of a base, such as potassium carbonate, in a solvent such as dimethylformamide.
  • Interconversion reactions according to process (e) may be effected using methods well known in the art.
  • Compounds of formula (II) may be prepared by methods known in the art.
  • a compound of formula (IV) may be prepared by alkylation of a compound (II) by standard methods.
  • a compound of formula (II) may be reacted with N-(4-bromobutylphthalimide) followed by removal of the phthalimide group to give a compound of formula (IV) where R ⁇ is hydrogen.
  • R ⁇ is hydrogen
  • Compounds where R ⁇ is alkyl may be prepared by subsequent reaction with the appropriate aldehyde using conditions analogous to process (a) above.
  • Compounds of formula (VI), and (VII) may be prepared by processes analogous to (a) or (b) described above.
  • Compounds Ar Wl an( j Ar ⁇ Hal are commercially available or may be prepared by standard methods.
  • Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D2 receptors.
  • antipsychotic agents neuropeptides
  • eps extrapyramidal side effects
  • Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors.
  • D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders.
  • Conditions which may be treated by dopamine D3 receptor agonists include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, memory disorders, sexual dysfunction and drug (eg.
  • the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
  • the invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia.
  • a preferred use for D3 antagonists according to the present invention is in the treatment of psychoses such as schizophrenia.
  • a preferred use for D3 agonists according to the present invention is in the treatment of dyskinetic disorders such as Parkinson's disease.
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
  • the compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base.
  • the physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg,e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors.
  • the inhibition constants (Kj) of test compounds for displacement of [ ⁇ 1] iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -
  • Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.
  • the membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
  • the functional activity of compounds at human D2 and human D3 receptors may be determined using a Cytosensor Microphysiometer (McConnell HM et al Science 1992 257 1906-1912)
  • McConnell HM et al Science 1992 257 1906-1912 a Cytosensor Microphysiometer
  • cells hD2_CHO or hD3_CHO were seeded into 12mm Transwell inserts (Costar) at 300000 cells/cup in foetal calf serum (FCS)-containing medium. The cells were incubated for 6h at 37°C in 5%CO2, before changing to FCS-free medium.
  • cups were loaded into the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers perfused with running medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min. Each pump cycle lasted 90s. The pump was on for the first 60s and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Agonists and antagonists were diluted in running medium. In experiments to determine agonist activity, cells were exposed (4.5 min for hD2, 7.5 min for hD3) to increasing concentrations of putative agonist at half hour intervals. Seven concentrations of agonist were used.
  • Peak acidification rate to each agonist concentration was determined and concentration-response curves fitted using Robofit [Tilford, N.S., Bowen, W.P. & Baxter, G.S. Br. J. Pharmacol. (1995) in press].
  • cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells), before exposure to the lowest concentration of putative antagonist. At the end of the next 30 min interval, cells were pulsed again with quinpirole (in the continued presence of the antagonist) before exposure to the next highest antagonist concentration. In all, five concentrations of antagonist were used in each experiment. Peak acidification rate to each agonist concentration was determined and concentration- inhibition curves fitted using Robofit.
  • compositions represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol. Tablet
  • Diluent e.g. Microcrystalline cellulose, lactose, starch
  • Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
  • Suspending agent e.g. Xanthan gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • Trifluoromethylsulfonic anhydride (33ml, 0.194 mmol) was added dropwise with stirring to an ice-cooled solution of 7-hydroxy-2-(4-phthalimidobutyl)- 1,2,3,4- tetrahydroisoquinoline (51.3g, 0.146 mmol) in anhydrous pyridine (150ml). After stirring at room temperature for 18h the reaction mixture was added to 10% aqueous Copper (II) sulfate (IL) and extracted into ethyl acetate (IL). The organic layer was separated, washed with 10% aqueous copper (II) sulfate (2x500ml), dried (Na j SO 4 ) and evaporated in vacuo. Chromatography on silica gel using 10-100% ethyl acetate- hexane gradient elution gave the title compound as a green oil (49.4g, 40%).

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP98929278A 1997-04-30 1998-04-27 Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d?3 receptors Withdrawn EP0981516A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9708694.6A GB9708694D0 (en) 1997-04-30 1997-04-30 Compounds
GB9708694 1997-04-30
PCT/EP1998/002581 WO1998049145A1 (en) 1997-04-30 1998-04-27 Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors

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EP0981516A1 true EP0981516A1 (en) 2000-03-01

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EP (1) EP0981516A1 (ja)
JP (1) JP2001522366A (ja)
CA (1) CA2288308A1 (ja)
GB (1) GB9708694D0 (ja)
WO (1) WO1998049145A1 (ja)

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GB9810876D0 (en) 1998-05-20 1998-07-22 Smithkline Beecham Plc Compounds
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GB201604020D0 (en) 2016-03-09 2016-04-20 Ctxt Pty Ltd Compounds
GB201604022D0 (en) 2016-03-09 2016-04-20 Ctxt Pty Ltd Compounds
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EP3744721A4 (en) 2018-01-26 2021-11-10 Shionogi & Co., Ltd CONDENSED CYCLIC COMPOUND WITH ANTAGONISM TO DOPAMINE D3 RECEPTOR

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US10870660B2 (en) 2016-07-28 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11345716B2 (en) 2016-07-28 2022-05-31 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11897899B2 (en) 2016-07-28 2024-02-13 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect

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CA2288308A1 (en) 1998-11-05
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WO1998049145A1 (en) 1998-11-05

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