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WO1996016057A1 - Certains derives d'aminoethyl imidazole et pyrrole substitues en 1; nouveaux ligands specifiques d'un sous-type de recepteur dopaminergique - Google Patents

Certains derives d'aminoethyl imidazole et pyrrole substitues en 1; nouveaux ligands specifiques d'un sous-type de recepteur dopaminergique Download PDF

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Publication number
WO1996016057A1
WO1996016057A1 PCT/US1995/015369 US9515369W WO9616057A1 WO 1996016057 A1 WO1996016057 A1 WO 1996016057A1 US 9515369 W US9515369 W US 9515369W WO 9616057 A1 WO9616057 A1 WO 9616057A1
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Prior art keywords
straight
carbon atoms
branched chain
chain lower
lower alkyl
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PCT/US1995/015369
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English (en)
Inventor
Jun Yuan
Jan W. F. Wasley
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Neurogen Corporation
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Filing date
Publication date
Priority claimed from US08/344,498 external-priority patent/US5478934A/en
Application filed by Neurogen Corporation filed Critical Neurogen Corporation
Priority to AU42455/96A priority Critical patent/AU4245596A/en
Publication of WO1996016057A1 publication Critical patent/WO1996016057A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain 1 -substituted aminomethylimidazole and pyrrole derivatives which selectively bind to brain dopamine receptor subtypes.
  • This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Description of the Related Art
  • Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). These disorders have an age onset of adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalization. In the U.S. today, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
  • neuroleptics This classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain suggesting altered neuronal firing of the dopamine system. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmitter dopamine was involved in schizophrenia.
  • One of the major actions of antipsychotic medication is the blockade of dopamine receptors in the brain.
  • dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified upon these differences in the pharmacology of different chemical series. Butyrophenones, containing many potent antipsychotic drugs were quite weak at the dopamine receptor that activated adenylate cyclase (now known as the Dl dopamine receptor). In contrast, they labeled other dopamine receptors (called D2 receptors) in the subnanomolar range and a third type D3 in the nanomolar range. Two additional receptor subtypes have also been identified.
  • D5 which is somewhat similar to Dl receptor type and D4 which is closely related to D3 and D2 receptor types.
  • Phenothiazines possess nanomolar affinity for all three types of dopamine receptors.
  • Other drugs have been developed with great specificity for the Dl subtype receptor and for the D2 subtype receptor.
  • Recently a new group of drugs (such as sulpiride and clozapine) have been developed with a lesser incidence of extrapyramidal side effects than classical neuroleptics.
  • sulpiride and clozapine have been developed with a lesser incidence of extrapyramidal side effects than classical neuroleptics.
  • U.S. Patent 5,159,083 discloses 4-Aminoalkyl 2-phenylimidazoles.
  • U.S. Patent 4,829, 065 describes a series of l-(Diphenylmethyl)-4-[(5 methyl-2-p-tolylimidazol-4- yl)methyl]piperazines.
  • European Patent Application 87200296.9 discloses 2-Aryl-5(N- piperaziny methyl pyrroles.
  • This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • the invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.
  • compounds of this invention may be useful in treating the extrapyramidyl side effects associated with the use of conventional neuroleptic agents. Since particularly D3 and D4 receptor subtypes are concentrated in the limbic system (Taubes, Science, 1994, 265, 1034) which controls cognition and emotion, compounds which interact with these receptors also have utility 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.
  • A is arylalkyl, aryl or heteroaryl optionally substituted with up to 3 groups selected from the group consisting of halogen trifluoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms.
  • X is N or CRi where Ri may be hydrogen, halogen straight or branched chain lower alkyl having
  • R 2 is hydrogen, straight or branched chain, lower alkyl having 1-6 carbon atoms or phenyl substituted or unsubstituted
  • R3 is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, or R3 and R 4 together may represent -(CH2)n2 _ where n2 is 3 or 4: and R4 and R5 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, aryl straight or branched chain lower alkyl having 1-6 carbon atoms; or NR4R5 together represent 2-(l,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms on
  • NR4R5 represents
  • W is N or CH
  • R is hydrogen, arylalkyl, particularly benzyl, benzoyl, phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; and n is 1, 2, or 3 when W is CH. or n is 2 or 3 when W is N; or
  • NR 4 R5 represents
  • R7 is as defined above.
  • R2 and A. where A is phenyl may together form a tricyclic structure fused to the 5-membered nitrogen heterocycle to yield tetracyclic compounds of formula 0:
  • Y is oxygen, -OCH2-, sulfur, -SCH2-, or NR or -NRCH2- where R represents hydrogen or alkyl;
  • Figures 1A-1E show representative aminomethyl phenylimidazoles of the present invention.
  • novel compounds encompassed by the instant invention can be represented by general formulas I and II shown above.
  • Preferred compound of Formula I include those where A is phenyl, pyridyl, or naphthyl.
  • the present invention further encompasses compounds from Formula HI:
  • Z is hydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkyl having 1-
  • T is hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms;
  • X, R3, R4 and R5 are as defined above for Formula I.
  • Z and T may form an additional ring as indicated by Formula IV and V
  • the present invention also encompasses compounds or Formula VI
  • Z is hydrogen, halogen, trifluoromethyl, straight or branched chain lower alkyl having 1-6 carbon atom.; or straight or branched chain lower alkoxy having 1-6 carbon atoms: and
  • X, R3, R 4 and R5 are as defined above for Formula I.
  • the invention further provides compounds of Formula VII
  • W represents phenyl, pyrimidinvl. pyridyl. or phenylalkyl where the phenyl group is optionally mono- or disubstituted with halogen, alkyl, or alkoxy.
  • Preferred compounds of Formula VIII are those where Z and T arc hydrogen and W represents phenyl. pyrimidinyl, pyridyl, or benzyl.
  • V is nitrogen or CH; and W represents phenyl, pyrimidinyl, pyridyl, or phenylalkyl where the phenyl group is optionally mono- or disubstituted with halogen, alkyl, or alkoxy.
  • Preferred compounds of Formula DC are those where Z and T are hydrogen, V is CH; and W represents phenyl or benzyl.
  • Other preferred compounds of Formula IX are those where Z and T are hydrogen, V is nitrogen and W represents phenyl, pyrimidinyl, pyridyl. or benzyl.
  • the invention also provides compounds of Formula X
  • W represents phenyl or phenylalkyl where the phenyl group is optionally mono- or disubstituted with halogen, alkyl, or alkoxy.
  • Preferred compounds of Formula X are those where W is phenyl or benzyl.
  • Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic. sulfuric, sulfinic, formic, toluene sulfonic, hydroiodic, acetic and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • 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.
  • 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.,
  • alkyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms.
  • lower alkoxy and alkoxy is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms.
  • heteroaryl is meant 5, 6, or 7 membered aromatic ring systems having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur.
  • heteroaryl groups are pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl. and thienyl.
  • halogen fluorine, chlorine, bromine and iodine.
  • arylalkyl and aralkyl is meant the group -R-Ar where Ar is an aryl group and R is a straight or branched chain aliphatic group.
  • Arylalkyl groups may optionally be substituted with. e.g., halogen, lower alkyl. lower alkoxy, lower alkylthio. trifluoromethyl, lower acyloxy, and hydroxy.
  • Preferred arylalkyl groups in the above formulas where W is CH and R8 represents arylalkyl are phenylalkyl groups where the alkyl portion is lower alkyl.
  • a particularly preferred phenylalkyl group is benzyl where the phenyl ring may be substituted with up to three substituents independently selected from hydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms.
  • cycloalkyl cyclic hydrocarbons having from 3-8 carbon atoms. These cyclic hydrocarbon groups may be substituted with up to three substituents independently selected from hydrogen, halogen, trifluoromethyl, cyano, straight or branched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or SO2 9 where R9 is NH2 or NHCH3.
  • the pharmaceutical utility of compounds of this invention are indicated by the following assays for dopamine receptor subtype affinity.
  • Striatial tissue is dissected from adult male Sprague Dawley rats or BHK 293 cells are harvested containing reco binantly produced D2 or D3 receptors. The sample is homogenized in
  • Incubations are carried out at 48° C and contain 0.5 ml of tissue sample. 0.5 nM 3H- raclopride and the compound of interest in a total incubation of 1.0 ml.
  • Nonspecific binding is defined as that binding found in the presence of 10-4 M dopamine; without further additions, nonspecific binding is less than 20% of total binding.
  • the binding characteristics of examples of this patent are shown in Table 1 for Rat Scriatal Homogenates.
  • Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and the cells centrifuged and the pellets stored at -80° C noisy used in the binding assay.
  • the pellets were resuspended and the cells lysed at 4° C in 50 mM T ⁇ s pH 7 4 buffer containing 120 mM NaCl, 2 mM EDTA and 5 mM mMgC_2.
  • the homogenate is cent ⁇ fuged at 48000 x g for 10 minutes at 4° C.
  • the resulting pellet is resuspended in fresh buffer and centrifuged again. After resuspension of the pellet in fresh buffer at lOOul aliquot removed for the protein determination.
  • the remaining homogenate is centrifuged as above, the supernatant removed and the pellet stored at 4° C until needed at which time it is resuspended to a final concentration of 625 ug ml (250 ug per sample) with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use. Incubations were carried out for 60 minutes at 25° C in the presence of 0.1 nM [ 3 H] YM-09151-2. The incubation was terminated by rapid filtration through Whatman GF/C filters and rinsed with 2 x 4 ml washes of chilled 50 M Tris (pH 7.4) and 120 M NaCl.
  • Nonspecific binding was determined with 1 uM spiperone and radioactivity determined by counting in an L B beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant Ki could be calculated for each test compound.
  • the binding characteristics of some examples of this patent are shown in Table 2 for the dopamine D4 binding assay. In general, compounds of the accompanying examples were tested in the above assay, and all were found to possess a Ki value for the displacement of [ 3 H] YM-09151-2 from the human dopamine D4 receptor subtype of below 500 mM. Some specific data is indicated in Table 2.
  • Compounds 1. 3, and 6 are particularly preferred embodiments of the present invention because of their potency in binding to dopamine receptor subtypes.
  • 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, adjutants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal 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 adjutants 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 an for the manufacture of pharmaceutical compositions and such compositions may contain one or more 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 may be for example, ine ⁇ diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium sterate, 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 monosteratc or glyceryl dis
  • 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 posphate of 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, sodium alginate, polyvinylpyrrolidone. gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide.
  • 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.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • 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 phospatides. 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, 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 suspensions. This suspension may be formulated according to known an 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 of 1 ,3- butanediol.
  • the acceptable vehicles and solvents that may be employed are water.
  • 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. 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.
  • adjutants 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 singe dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between ca 1 mg to about 500 mg of an active ingredient. It will be understood, however, that 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 adminisu-ation. route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • n 0, 1 or 2;
  • Z is hydrogen, halogen, hydroxy, trifluoromethyl, straight or branched chain lower alkyl having 1- 6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
  • T is hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms; or Z and T may together form an carbocyclic or heterocyclic ring system; and R4 and R5 are as defined as above for Formula I.
  • Representative illustrations of the starting materials A have been described by Antonini et al.. Euro. J. Med. Chem., 1£: 285 (1984).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule générale (I) et leurs sels acceptables d'un point de vue pharmaceutique. Dans cette formule, A représente un arylalkyle, aryle ou hétéroaryle; X représente azote ou CH; R2, R3, R4 et R5 représentent des substituants organiques ou non organiques. Ces dérivés conviennent particulièrement au traitement des troubles du système nerveux central.
PCT/US1995/015369 1994-11-23 1995-11-22 Certains derives d'aminoethyl imidazole et pyrrole substitues en 1; nouveaux ligands specifiques d'un sous-type de recepteur dopaminergique WO1996016057A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42455/96A AU4245596A (en) 1994-11-23 1995-11-22 Certain 1-substituted aminomethyl imidazole and pyrrole derivatives; novel dopamine receptor subtype specific ligands

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US08/344,498 1994-11-23
US08/344,498 US5478934A (en) 1994-11-23 1994-11-23 Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands
US45973995A 1995-06-01 1995-06-01
US08/459,739 1995-06-01
US08/459,093 1995-06-02
US08/459,093 US5750700A (en) 1994-11-23 1995-06-02 Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands
US08/458,343 US5760234A (en) 1994-11-23 1995-06-02 Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036591A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase
WO1997036593A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de la farnesyle-proteine transferase
US5972942A (en) * 1997-03-27 1999-10-26 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO2000018763A3 (fr) * 1998-09-29 2000-05-25 Neurogen Corp 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles; ligands specifiques du sous-type du recepteur de dopamine
WO2000012500A3 (fr) * 1998-09-02 2000-07-27 Neurogen Corp 2-aryl-4-[4-heteroaryl]piperazin-1-yl methylimidazoles: ligands pour le sous-type de recepteur d4 de la dopamine
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
US6288230B1 (en) 1998-09-29 2001-09-11 Neurogen Corporation 2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles: dopamine receptor subtype specific ligands

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EP0241053A1 (fr) * 1986-02-27 1987-10-14 Duphar International Research B.V (N-Pipéridinyl)-méthyl-et(N-pipérazinyl)-méthylazoles substitués par un groupes aryle et ayant des propriétés antipsychotiques
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

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0241053A1 (fr) * 1986-02-27 1987-10-14 Duphar International Research B.V (N-Pipéridinyl)-méthyl-et(N-pipérazinyl)-méthylazoles substitués par un groupes aryle et ayant des propriétés antipsychotiques
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

Non-Patent Citations (1)

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Title
H.M.H. VAN TOL ET AL.: "Cloning of the gene for a human dopamin D4 receptor with high affinity for the antipsychotic clozapine", NATURE, vol. 350, 18 April 1991 (1991-04-18), LONDON GB, pages 610 - 614 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036591A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase
WO1997036593A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de la farnesyle-proteine transferase
US5972942A (en) * 1997-03-27 1999-10-26 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO2000012500A3 (fr) * 1998-09-02 2000-07-27 Neurogen Corp 2-aryl-4-[4-heteroaryl]piperazin-1-yl methylimidazoles: ligands pour le sous-type de recepteur d4 de la dopamine
WO2000018763A3 (fr) * 1998-09-29 2000-05-25 Neurogen Corp 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles; ligands specifiques du sous-type du recepteur de dopamine
US6288230B1 (en) 1998-09-29 2001-09-11 Neurogen Corporation 2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles: dopamine receptor subtype specific ligands
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
US6432958B1 (en) 1998-09-30 2002-08-13 Neurogen Corporation 2-piperazinoalkylaminobenzoazole derivatives: dopamine receptor subtype specific ligands

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