WO2000018763A2 - 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles; ligands specifiques du sous-type du recepteur de dopamine - Google Patents

2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles; ligands specifiques du sous-type du recepteur de dopamine Download PDF

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Publication number
WO2000018763A2
WO2000018763A2 PCT/US1999/022699 US9922699W WO0018763A2 WO 2000018763 A2 WO2000018763 A2 WO 2000018763A2 US 9922699 W US9922699 W US 9922699W WO 0018763 A2 WO0018763 A2 WO 0018763A2
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dihydrobenzofuran
imidazole
methyl
compound according
piperazin
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PCT/US1999/022699
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English (en)
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WO2000018763A3 (fr
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Xi Chen
Xiao-Shu He
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Neurogen Corporation
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Publication of WO2000018763A3 publication Critical patent/WO2000018763A3/fr

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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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • This invention relates to 2- (2 , 3-dihydrobenzofuran-5- yl) -4-aminomethylimidazoles and to pharmaceutical compositions 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.
  • 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 the brain.
  • EPS extrapyramidal side effects
  • tardive dyskinesias which are attributed to blockade of D2 receptors in the striatal region of the brain.
  • Selective D 4 antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
  • n 1, 2, or 3;
  • Ri represents hydrogen, halogen, Ci-C ⁇ alkyl, C ⁇ -C 6 alkoxy, alkylthio, hydroxy, amino, mono- or di (C ⁇ C e ) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
  • R 2 represents halogen or Cx-Cg alkyl
  • A is alkylene of 1 to 4 carbon atoms
  • X is either a carbon atom, CH, or nitrogen; and R 3 represents either an (un) substituted aryl or a heteroaryl group; and R 4 is hydrogen or alkyl.
  • disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia.
  • Other disorders include those involving memory impairment or attention deficit disorders.
  • Compounds of the present invention demonstrate high affinity and selectivity in binding to the D 4 receptor subtype. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, 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 D 4 receptors.
  • Compounds of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's disease by modulation of D 4 receptors since they exist selectively in areas known to control emotion and cognitive functions .
  • the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents.
  • the compounds of the invention are useful in treatment of depression, memory- impairment or Alzheimer's disease.
  • the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents .
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • the invention provides intermediates useful in the preparation of compounds of Formula I .
  • DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the invention encompasses aminomethylimidazole derivatives of Formula I.
  • Preferred compounds of Formula I are those where n is 1 and are represented by Formula IA.
  • R l t R 2 , R 4 , and R N are as defined above for Formula I.
  • Suitable R 3 groups include aryl and heteroaryl groups optionally substituted with up to three groups independently selected from halogen, Ci-Cg alkyl, Cx-C ⁇ alkoxy, hydroxy, phenyl, amino, mono- or di alkylamino, and perfluoroalkyl , such as trifluoromethyl .
  • Other substituents include lower, i.e. Ci-Cg, alkylthio, acyloxy, aryl, and heteroaryl . These latter aryl and heteroaryl substituents may also be substituted in a fashion similar to the parent aryl or heteroaryl group.
  • Representative aryl groups are aromatic carbocyclic groups 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) .
  • Representative heteroaryl groups include groups having one or more aromatic ring systems of 5, 6, or 7 members, preferably 5 or 6 members, containing at least one and up to four hetero atoms, preferably one or two hetero atoms, selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups include, for example, thienyl, furanyl , thiazolyl, imidazolyl, (is) oxazolyl, pyridyl, pyrimidinyl , (iso) quinolinyl, naphthyridinyl , benzimidazolyl, and benzoxazolyl .
  • the hetero aryl R 3 groups are bound to the parent piperazine, piperidine or tetrahydropyridine group via a carbon atom in the hetero aryl group, preferably a carbon atom immediately adjacent a hetero atom such as nitrogen in the hetero aryl group.
  • Preferred compounds of Formula IA are those where X is nitrogen and R 3 is pyrimidinyl, phenyl, pyridyl, naphthyl , benzyl, 4 , 5-benzopyrimidin-2-yl , or isoquinolinyl , preferably 1-isoquinolinyl , each of which R 3 groups is optionally unsubstituted or substituted with up to three groups selected from halogen, Cx-Cg alkyl, C ⁇ -C alkoxy, hydroxy, phenyl, amino, mono- or di alkylamino, or trifluoromethy1.
  • R 3 is pyrimidinyl, phenyl, pyridyl, naphthyl, benzyl, benzopyrimidin-yl , or isoquinolinyl, preferably 1- isoquinolinyl , each of which R 3 group is optionally unsubstituted or substituted with up to three groups selected from halogen, Cx-Cg alkyl, Ci-C 4 alkoxy, hydroxy, phenyl, amino, mono- or di alkylamino, or trifluoromethyl .
  • More preferred compounds of Formula IA are those where A is methylene, R 3 is phenyl, 2 -pyridyl, pyrimidin-2-yl, 1- or 2 -naphthyl, quinolinyl, preferably 2-quinolinyl, isoquinolinyl, preferably 1-isoquinolinyl , 4,5- benzopyrimidin-2-yl or benzoisothiazol-3-yl , each of which is optionally substituted with up to three groups selected from halogen, Cx-Cg alkyl, C -C 4 alkoxy, alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, phenyl, nitro, trifluoromethyl or trifluoromethoxy.
  • R l t R 2 , and R 3 are as defined above for Formula I.
  • Preferred compounds of Formula II include those where R 3 is phenyl, pyridyl, more preferably 2 -pyridyl, pyrimidin-2- yl, 1 or 2 naphthyl, quinolinyl, isoquinolinyl, preferably 1-isoquinolinyl, benzopyrimidinyl or benzoisothiazol-3-yl , each of which is optionally substituted with up to three groups selected from halogen, C ⁇ -C 6 alkyl, C ⁇ -C alkoxy, C ⁇ C g alkylthio, hydroxy, amino, mono- or di alkylamino, cyano, nitro, phenyl, trifluoromethyl or trifluoromethoxy.
  • More preferred compounds of Formula II include those where R 3 is a pyrimidinyl group optionally substituted with up to three groups selected from alkyl, trifluoromethyl, halogen, or phenyl.
  • R 3 is phenyl optionally substituted with up to three groups selected independently from alkoxy, C 1 -C 6 alkyl, halogen, trifluoromethyl , and phenyl.
  • Particularly preferred compounds of Formula II where R 3 is phenyl include those where the phenyl group is mono- or disubstituted independently with alkoxy, alkyl, chloro, fluoro, and trifluoromethyl .
  • the invention also encompasses compounds of Formula III.
  • A is alkylene of 1 to 2 carbon atoms; and R 3 is as defined above for Formula I .
  • Preferred compounds of Formula III include those where is
  • R 3 is as defined above for Formula I .
  • Such compounds are hereinafter referred to as compounds of Formula III-A.
  • Preferred compounds of III-A include those where R 4 is hydrogen, R 3 is phenyl, benzyl, 2-pyridyl, or pyrimidin-2-yl .
  • Particularly preferred compounds of Formula III -A are those where R 4 is hydrogen, R 3 is phenyl or benzyl optionally substituted with one to three groups independently selected from halogen, hydroxy, alkyl, C 1 -C 6 alkoxy, amino, or mono- or di alkylamino.
  • Such compounds are hereinafter referred to as compounds of Formula III-B. More preferred compounds of III-B include those where R 4 is hydrogen, R 3 is phenyl, benzyl, 2-pyridyl, or 2 -pyrimidinyl . Particularly preferred compounds of Formula III-B are those where R 3 is phenyl or benzyl optionally substituted with one to three groups independently selected from halogen, hydroxy,- alkyl, alkoxy, amino, or mono- or di alkylamino.
  • the invention also provides intermediates useful in preparing compounds of Formula I . These intermediates have Formulae IV-A, IV-B, and IV-C.
  • A, n, R x and R 2 are as defined above for Formula I.
  • R 4 is as defined above for Formula I, and R 5 is hydroxy or halogen.
  • Preferred compounds of Formulae IV-A-C are those where n is 1.
  • Preferred halogens at R 5 in IV-C are chloro and fluoro.
  • Particularly preferred compounds of Formulae IV-A-C are those where R x , and R 4 are both hydrogen.
  • the 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.
  • 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 1 and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • 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 .
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,
  • 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 .
  • the invention is not limited to any one of the specific tautomers .
  • the invention includes all tautomeric forms of a compound.
  • C ⁇ -C 6 alkyl or “lower alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl , hexyl, 2-hexyl, 3- hexyl , and 3-methylpentyl .
  • Preferred C ⁇ . -C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl .
  • C -C 6 alkoxy or “lower alkoxy” in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert- butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2 -hexoxy, 3 -hexoxy, and 3-methylpentoxy.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • a substituent is a di alkylamino group
  • the two alkyl groups are the same or different.
  • Representative di alkylamino groups include dimethylamino, methylpropylamino, diisopropylamino, and ethylpentylamino.
  • Preferred aryl and heteroaryl groups are phenyl , pyridyl, pyrimidin-2-yl, 1 or 2 naphthyl, quinolinyl, isoquinolinyl, benzopyrimidinyl and benzoisothiazol-3-yl .
  • Each of these groups may be substituted with up to three substituents which are the same or different and are selected from halogen, C ⁇ -C 6 alkyl, C ⁇ -C 4 alkoxy, C ⁇ -C alkylthio, hydroxy, amino, mono- or di (C j _-C 6 ) alkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
  • the invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders.
  • the interaction of compounds of the invention with dopamine receptors is shown in the examples. This interaction results in the pharmacological activity of these compounds .
  • 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.
  • 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 such as sucrose or saccharin.
  • 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 .
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, sorbitol, sorbitol, gly
  • 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 .
  • a non-toxic parentally acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
  • acceptable 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 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 .
  • R 1# R 2 , R 3 and X are as defined above for Formula I.
  • a 2 , 3-dihydrobenzofuran-5-carboxylic acid of Formula V may be converted into corresponding 2,3- dihydrobenzofuran-5-nitrile of Formula IV-A via standard methods.
  • Nitrile IV-A can be converted into benzamidine Formula IV-B by, for example, treatment with lithium hexamethyldisilazane in diethyl ether or, alternatively, by dissolution in a saturated solution of hydrogen chloride in methanol followed by treatment of the intermediate iminoether with ammonia.
  • NH 4 OH is heated at reflux for about 90 minutes cooled and filtered (2.2 g, 51 %) .
  • the filtrate is used as is.
  • the filtrate may be recrystallized using, e.g., ethyl acetate.
  • Example 3 The following compounds are prepared essentially according to the procedures set forth above in Example 1.
  • Pellets of COS cells containing recombinantly produced D2 or D4 receptors from African Green monkey are used for
  • 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 then centrifuged again at 30,000 x g 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 .
  • 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.
  • the binding characteristics of representative compounds of the invention for the D2 and D4 receptor subtypes are shown in Table 2 for
  • the binding constants of compounds of Formula I for the D 4 receptor generally range from about 0.1 nanomolar (nM) to about 75 nanomolar (nM) . These compounds typically have binding constants for the D 2 receptor of at least about 100 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. 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.

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Abstract

L'invention concerne des composés représentés par la formule (I) ou leurs sels d'apport acide acceptables sur le plan pharmaceutique, dans laquelle: n est un entier; R1 représente un groupe organique ou inorganique; R2 représente halogène ou alkyle C1-C6; RN représente un alkylène portant une pipérazine, pipéridine ou tétrahydropyridine substituées; R4 représente hydrogène ou alkyle C1-C6. Ces composés sont utiles pour le traitement et/ou la prévention de maladies neuropsychologiques, y compris, mais non exclusivement, la schizophrénie, la manie, la démence, la dépression, l'anxiété, les comportements compulsifs, l'abus de drogues, les troubles moteurs de type Parkinson et les troubles moteurs associés à l'utilisation d'agents neuroleptiques.
PCT/US1999/022699 1998-09-29 1999-09-29 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles; ligands specifiques du sous-type du recepteur de dopamine WO2000018763A2 (fr)

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Cited By (1)

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WO2002050070A2 (fr) * 2000-12-21 2002-06-27 Warner-Lambert Company Llc Derives de piperidine en tant qu'antagonistes vis-a-vis de n-methyl-d-aspartate (nmda), avec selectivite en termes de sous-type

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WO1992012134A2 (fr) * 1990-12-28 1992-07-23 Neurogen Corporation Certains derives de phenylimidazole aminomethyle; nouvelle classe de ligands a specificite de sous-type de recepteur de dopamine
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WO1996016040A1 (fr) * 1994-11-23 1996-05-30 Neurogen Corporation Certains derives 4-aminomethyl 2-substitues de l'imidazole et derives 2-aminomethyl 4-substitues de l'imidazole, nouvelles categories de ligands specifiques du sous-type du recepteur de la dopamine
WO1997043279A1 (fr) * 1996-05-10 1997-11-20 Janssen Pharmaceutica N.V. Derives de la 2,4-diaminopyrimidine utilises comme antagonistes du recepteur d4 de la dopamine

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DE2061515A1 (de) * 1969-12-15 1971-06-24 Merck & Co Ine, Rahway, N J (V St A) 2,5 disubstituierte Imidazole und Ver fahren zur Herstellung derselben
WO1992012134A2 (fr) * 1990-12-28 1992-07-23 Neurogen Corporation Certains derives de phenylimidazole aminomethyle; nouvelle classe de ligands a specificite de sous-type de recepteur de dopamine
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