EP0991642A1 - 2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d4 - Google Patents

2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d4

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Publication number
EP0991642A1
EP0991642A1 EP98933291A EP98933291A EP0991642A1 EP 0991642 A1 EP0991642 A1 EP 0991642A1 EP 98933291 A EP98933291 A EP 98933291A EP 98933291 A EP98933291 A EP 98933291A EP 0991642 A1 EP0991642 A1 EP 0991642A1
Authority
EP
European Patent Office
Prior art keywords
compound according
piperazinyl
propyl
amine
hydrobromide
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Withdrawn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
EP98933291A
Other languages
German (de)
English (en)
Inventor
Xiao-Shu He
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.)
Neurogen Corp
Original Assignee
Neurogen Corp
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 Neurogen Corp filed Critical Neurogen Corp
Publication of EP0991642A1 publication Critical patent/EP0991642A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/38—Nitrogen 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
    • 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
    • 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

Definitions

  • This invention relates to aminoquinoline derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to 2- quinolyl(azacycloalkylalkyl)amines and pharmaceutical compositions and preparations containing such compounds. It also relates to the use of such compounds in the treatment or prevention of neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
  • 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. See Nature 350:
  • This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.
  • a broad aspect of the invention is directed to compounds of Formula I:
  • Ri, R 2 , and R 3 independently represent hydrogen, halogen, C]-C 6 alkyl, Cj-C alkoxy, Cj-C alkylthio, hydroxy, amino, mono(C,-C 6 ) alkylamino, di(C ⁇ -C 6 ) alkylamino, cyano,
  • R is hydrogen or C ⁇ -C 6 alkyl
  • Q represents a substituted azacycloalkylalkyl group of the formula:
  • W is nitrogen, CH or COH
  • A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms; and T is an aryl or heteroaryl moiety optionally substituted with up to two groups selected from hydrogen, halogen, C ⁇ -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino,
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • 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 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.
  • Ri, R 2 , R 3 , R4 and R 5 are the same or different and represent hydrogen, halogen, C]-C 6 alkyl,
  • Re is hydrogen or C ⁇ -C 6 alkyl;
  • W is nitrogen, COH, or CH;
  • Y and Z independently represent nitrogen or CH;
  • A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
  • the dashed segment represents either a single bond resulting in a 3,4 dihydroquinoline; or a double bond resulting in a quinoline.
  • W preferably represents nitrogen or COH.
  • T groups in Formula I are 6-membered carbocyclic aromatic ring systems having zero, one or two nitrogen atoms.
  • Particularly preferred “T” groups are phenyl, 2- pyridinyl, and 2-pyrimidinyl.
  • the particularly preferred “T” groups are optionally mono- or disubstituted with halogen, Ci-C ⁇ alkyl, -C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, amino,
  • Preferred compounds of Formula IA are those where Rg is hydrogen, methyl or
  • the invention also provides compounds of Formula II:
  • Ri, R 2 , R 3 , R4 and R 5 are the same or different and represent hydrogen, halogen, C ⁇ -C 6 alkyl,
  • R 6 is hydrogen or C ⁇ -C 6 alkyl
  • W is nitrogen, COH, or CH; Y and Z independently represent nitrogen or CH; and A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or ⁇ more alkyl groups having from one to four carbon atoms.
  • Preferred compounds of Formula II are those where R is hydrogen, methyl or ethyl. Particularly preferred compounds of Formula II are those where
  • Ri, R 2 , R 3 , R4 and R 5 are the same or different and represent hydrogen, halogen, C ⁇ -C 6 alkyl,
  • R 6 is hydrogen or -C ⁇ alkyl
  • W is nitrogen, COH, or CH;
  • Y and Z independently represent nitrogen or CH;
  • A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
  • Rg is hydrogen, methyl or ethyl.
  • 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 6 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.
  • Formula I 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,-C 6 )alkyl 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.
  • 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 r C 6 alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmethyl.
  • (C,-C 6 )alkoxy and lower alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.
  • hydroxy C r C 6 alkyl is meant a C,-C 6 alkyl group carrying a terminal hydroxy moiety.
  • halogen halo, or halide is meant fluorine, chlorine, bromine and iodine substituents.
  • the binding characteristics of compounds of Formula I for the D 4 receptor generally range from about 0.5 nanomolar (nM) to about 50 nanomolar (nM). These compounds typically have binding constants for the D 2 receptor of from at least about 100 nM to more than 3000 nM.
  • the compounds of the invention are generally at least about 3, preferably at least about 5, and most preferably at least about 10 time more selective for the
  • 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.
  • 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 monosterate 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.
  • 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, hydropropyl methylcellulose, 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.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or
  • 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.
  • 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • Pharmaceutical 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 and 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, sorbitor 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.
  • 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 of 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.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • Ri-R ⁇ , W, Y and Z are as defined above for Formula I.
  • a quinoline of general structure IV possessing an appropriate leaving group (X) at the 2 position, e.g., a halogen or S-methyl group, may be reacted with a primary or secondary amine of general structure V in the presence of a base to afford a compound of Formula I as the desired product.
  • the reaction may be carried out at elevated temperature with or without a solvent. Further, the reaction mixture may also contain an acid scavenger such as diisopropylamine or an inorganic salt such as ammonium chloride.
  • the compounds of general structure IV may be prepared by literature procedures or procedures analogous to those described in the literature.
  • Compounds of general structure V are either known or capable of being prepared by the methods known in the art. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention.
  • compounds of the invention may be prepared according to the reactions shown in Scheme II.
  • compounds may be prepared from readily available substituted or unsubstituted 4-haloquinoline compounds by allowing them to react with a Wittig reagent, such as an alkyl triphenylphosphonate generated from an alkyltriphenylphosphonium halideM plus a base, such as n-butyllithium in an organic solvent, such as tetrahydrofuran.
  • a Wittig reagent such as an alkyl triphenylphosphonate generated from an alkyltriphenylphosphonium halideM plus a base, such as n-butyllithium in an organic solvent, such as tetrahydrofuran.
  • the resulting 4-alkylquinoline can be converted to a 4-alkyl-2-haloquinoline by treatment with an oxidizing agent, such as m-chloroperbenzoic acid (MCPBA) in an appropriate solvent, such as chloroform, to give the corresponding 4-alkylquinoline N-oxide, followed by reaction with a halogenating agent, such as phosphorus oxychloride to give a 4-alkyl-2-haloquinoline of Formula IVa.
  • MCPBA m-chloroperbenzoic acid
  • a halogenating agent such as phosphorus oxychloride
  • R t -R 6 are as defined above, Rj is alkyl of 1 to 4 carbon atoms, and X is halogen.
  • Example 6 The following compounds are prepared essentially according to the procedures set forth above in Examples 3 and 4.
  • Example 7 The pharmaceutical utility of compounds of this invention is indicated by the assays for dopamine receptor subtype affinity described below.
  • African Green monkey were used for the assays.
  • the sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCI 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 then centrifuged as described and the final tissue sample is frozen until use.
  • the tissue is resuspended 1 :20 (wt/vol) in 0.05 M Tris HCI buffer containing 100 mM NaCl.
  • Incubations are carried out at 48°C and contain 0.4 ml of tissue sample, 0.5 nM -1H-
  • 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 of various compounds of the invention for D2 and D4 receptor subtypes are shown in Table 1 fof

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Abstract

L'invention concerne un composé de formule (IA) ou des sels d'addition d'acide pharmaceutiquement acceptables de ceux-ci. Dans ladite formule (I), R1, R2, R3, R4 et R5 sont identiques ou différents et représentent hydrogène, halogène, alkyle C1-C6, alcoxy C1-C4, alkylthio C1-C4, hydroxy, amino, monoalkylamino(C1-C6), dialkylamino(C1-C6), cyano, nitro, trifluorométhyle ou trifluorométhoxy; R6 représente hydrogène ou alkyle C1-C6; W représente azote, COH, ou CH; Y et Z représentent séparément azote ou CH; et A représente un groupe alkylène à 2 à 5 atomes de carbone éventuellement substitués par un ou plusieurs groupes alkyle à un à quatre atomes de carbone. Les composés de l'invention présentent une grande affinité et sélectivité dans la liaison au sous-type du récepteur de D4.
EP98933291A 1997-06-13 1998-06-11 2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d4 Withdrawn EP0991642A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US87486497A 1997-06-13 1997-06-13
US874864 1997-06-13
PCT/US1998/014235 WO1998056786A1 (fr) 1997-06-13 1998-06-11 2-aminoalkylaminoquinoleines utilisees comme ligands de la dopamine d¿4?

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EP0991642A1 true EP0991642A1 (fr) 2000-04-12

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EP (1) EP0991642A1 (fr)
JP (1) JP2002504125A (fr)
AU (1) AU8296998A (fr)
CA (1) CA2293480A1 (fr)
WO (1) WO1998056786A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6281216B1 (en) * 1998-02-09 2001-08-28 Duphar International Research B.V. 2-aminoquinoline derivatives having d4-agonistic activity
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
CA2345944A1 (fr) * 1998-09-30 2000-04-06 Neurogen Corporation Derives de 2-piperazino -alkyl- aminobenzoazole: ligands specifiques du sous-type du recepteur de la dopamine
FR2877005A1 (fr) 2004-10-22 2006-04-28 Bioprojet Soc Civ Ile Nouveaux derives d'arylpiperazine

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US5681956A (en) * 1990-12-28 1997-10-28 Neurogen Corporation 4-aryl substituted piperazinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
IL101722A (en) * 1991-05-02 1996-05-14 Wyeth John & Brother Ltd History of piperazine, their preparation and pharmaceutical preparations containing them
EP0687255A1 (fr) * 1993-03-05 1995-12-20 MERCK SHARP & DOHME LTD. Derives de la quinolone comme ligands des recepteurs d4 de la dopamine
AU5982696A (en) * 1995-06-05 1996-12-24 Neurogen Corporation 1-(n'-(arylalkylaminoalkyl)) aminoisoindoles as dopamine rec eptor ligands

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Title
See references of WO9856786A1 *

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WO1998056786A1 (fr) 1998-12-17

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