[go: up one dir, main page]

WO1999000386A1 - Ligands du recepteur d4 de la dopamine - Google Patents

Ligands du recepteur d4 de la dopamine Download PDF

Info

Publication number
WO1999000386A1
WO1999000386A1 PCT/CA1998/000615 CA9800615W WO9900386A1 WO 1999000386 A1 WO1999000386 A1 WO 1999000386A1 CA 9800615 W CA9800615 W CA 9800615W WO 9900386 A1 WO9900386 A1 WO 9900386A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolo
piperazin
methyl
pyridine
halo
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.)
Ceased
Application number
PCT/CA1998/000615
Other languages
English (en)
Inventor
Alfred Pollak
Robert Dunn-Dufault
David Roe
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.)
Resolution Pharmaceuticals Inc
Original Assignee
Resolution Pharmaceuticals Inc
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
Priority claimed from US08/905,546 external-priority patent/US5976497A/en
Application filed by Resolution Pharmaceuticals Inc filed Critical Resolution Pharmaceuticals Inc
Priority to AU80967/98A priority Critical patent/AU8096798A/en
Publication of WO1999000386A1 publication Critical patent/WO1999000386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to compounds that bind to the dopamine D4 receptor, and to their use for therapeutic and diagnostic purposes.
  • Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
  • D4 dopamine receptor classified as D4 in the etiology of schizophrenia. It has been suggested that compounds capable of interfering with the function of this receptor, which is present in schizophrenics at levels that are six times normal, would be useful in the treatment of this disease (Seeman et al, Nature, 1993, 365:441). Some dopamine receptor ligands currently sold as pharmaceuticals exhibit the desired affinity and antagonism for the D4 receptor, yet interact non-selectively with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia. It would be desirable to provide compounds that exhibit not only a high degree of affinity for the D4 receptor, but also a relatively low degree of affinity for the D2 receptor. In this specification, this desired combination of receptor binding properties is referred to as D4 selectivity.
  • Products currently marketed to treat indications in which the D4 receptor function is implicated include the dibenzodiazepine, clozapine, and the dibenzoxazepine, isoloxapine. Analysis of their dopamine receptor binding properties has shown that the preference for binding to the D4 receptor relative to the D2 receptor is about 10 fold, for both products. Similarly, both bind to the D4 receptor with about the same affinity (Ki value approximately 20 nM).
  • this non-selective binding at the D4 receptor prevents the generation of an accurate image of the localization and prevalence specifically of the D4 type of dopamine receptor. It would therefore be desirable to provide compounds that, in their radiolabeled state, bind at the D4 receptor with affinity and selectivity appropriate for diagnostic imaging purposes.
  • diagnostic imaging techniques as single photon emission tomography (SPECT) and positron emission tomography (PET)
  • SPECT single photon emission tomography
  • PET positron emission tomography
  • Z is selected from N and C(R 5 );
  • R 1 is selected from H and an acid labile protecting group;
  • R 2 , R 3 , R 4 and R 5 are independently selected from H, hydroxy, loweralkyl, loweralkyl optionally substituted with one or more groups selected from halo, hydroxy and loweralkoxy; loweralkyl-S-, halo, radioisotopic halo, loweralkoxy, trifluoromethylsulfonyi, cycloalkyl, aryl and tri(loweralkyl)tin; with the proviso that when Z is C(R 5 ) then at least one of R 2 , R 3 , R 4 and R 5 are selected from radioisotopic halo and tri(loweralkyl)tin; and salts, solvates or hydrates thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) wherein Z is N, R 1 is as defined hereinabove, and R 2 , R 3 and R 4 are independently selected from H, hydroxy, loweralkyl, loweralkyl optionally substituted with one or more groups selected from halo, hydroxy and loweralkoxy; loweralkyl-S-, halo, loweralkoxy, trifluoromethylsulfonyi, cycloalkyl and aryl, in an amount effective to antagonize D4 receptor stimulation.
  • R 1 is as defined hereinabove
  • R 2 , R 3 and R 4 are independently selected from H, hydroxy, loweralkyl, loweralkyl optionally substituted with one or more groups selected from halo, hydroxy and loweralkoxy; loweralkyl-S-, halo, loweralkoxy, trifluoromethylsulfonyi, cycloalkyl and aryl, in an amount effective to antagonize
  • the invention provides the use of compounds of
  • a radiopharmaceutical composition comprising a pharmaceutically acceptable carrier such as physiological buffered saline and a compound of Formula (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is a radioisotopic halo.
  • a method for imaging D4 receptors in vivo comprising the step of administering systemically to a patient an effective amount of a radiopharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is a radioisotopic halo, allowing the radiopharmaceutical to localize within the brain, and then taking an image of the brain of the patient so treated.
  • a radiopharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) wherein at least one of R 2 , R 3 , R 4 and R 5 is a radioisotopic halo
  • loweralkyl as used herein means straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radicals containing three to six carbon atoms and includes methyl, n-butyl, 1-methylethyl and the like.
  • alkoxycarbonyl' as used herein means straight and branched chain alkyl carbonates containing from two to six carbon atoms and includes methoxycarbonyl, ethoxycarbonyl, f-butoxycarbonyl and the like.
  • 'halo' as used herein means a halogen radical selected from bromo, chloro, iodo or fluoro. Radioisotopic halo include 123 l, 124 l, 125 l, 131 l, 18 F, and 76 Br.
  • 'cycloalkyl' as used herein means saturated or unsaturated non- aromatic cyclic hydrocarbon containing from 3 to 6 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • acid labile protecting group as used herein means a protecting group that affords protection to the functional group to which it is attached from undesired side reactions yet is cleavable from the molecule under acidic conditions. In this particular case the protecting group serves to stabilize the trialkyltin molecule to enable it to be isolated.
  • Suitable acid labile protecting groups are disclosed in, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2 nd Edition, 1991 , John Wiley & Sons Inc., New York, and include groups such as f-butoxycarbonyl.
  • Compounds of the present invention are those of Formula (I) in which R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • a preferred group of compounds of this invention are represented by Formula (I) wherein Z is N, R 1 is selected from H, alkoxycarbonyl and alkoxyalkyl, and R 2 , R 3 and R 4 are independently selected from H, halo, radioisotopic halo, loweralkyl, loweralkoxy, hydroxy, phenyl, trifluoromethylsulfonyi, tributyltin and trimethyltin.
  • a more preferred group of compounds of this invention is represented by Formula (I) wherein Z is N, R 1 is selected from H, .-butoxycarbonyl and methoxymethyl, and R 2 , R 3 and R 4 are independently selected from H, I, Cl, Br, F, 123 l, 124 l, 125 l, 131 l, 18 F, 76 Br, phenyl, tributyltin, trimethyltin and methoxy.
  • a most preferred group of compounds of this invention are represented by Formula (I) wherein Z is N, R is selected from H and -butoxycarbonyl, and R 2 , R 3 and R 4 are independently selected from H, I, Cl, 123 l, phenyl, trimethyltin and methoxy.
  • R 1 is selected from H, alkoxycarbonyl and alkoxyalkyl
  • R 2 , R 3 , R 4 and R 5 are independently selected from H, halo, radioisotopic halo, loweralkoxy, tributyltin and trimethyltin with the proviso that at least one of R 2 , R 3 , R 4 and R 5 are selected from radioisotopic halo, tributyltin and trimethyltin.
  • a more preferred group of compounds of this invention is represented by Formula (I) wherein Z is C(R 5 ), R 1 is selected from H, f-butoxycarbonyl and methoxymethyl, and R 2 , R 3 , R 4 and R 5 are independently selected from H, 123 l, 12 l, 125 l, 131 l, 18 F, methoxy, tributyltin, trimethyltin and methoxy with the proviso that at least one of R 2 , R 3 , R 4 and R 5 are selected from 123 l, 124 l, 125 l, 131 l, 18 F, tributyltin and trimethyltin.
  • a most preferred group of compounds of this invention are represented by Formula (I) wherein Z is C(R 5 ), R 1 is selected from H and f-butoxycarbonyl, and R 2 , R 3 , R 4 and R 5 are independently selected from H, 123 l, methoxy and trimethyltin with the proviso that at least one of R 2 , R 3 , R 4 and R 5 are selected from 123 l and trimethyltin.
  • Acid addition salts of the compound of Formula (I) are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
  • Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • solvates and hydrates of the invention are also included within the scope of the invention.
  • the conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an appropriate solvent, such as ether.
  • the free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
  • base e.g. sodium carbonate or potassium hydroxide
  • Radioactive isotopes for example 123 l, 124 l, 125 l, 18 F for use as radiopharmaceuticals are typically prepared by either nucleophilic displacement of a suitable leaving group (for example trifluoromethylsulfonate) using for example potassium 18 F fluoride by methods known to one skilled in the art, or by an electrophilic substitution of a suitable group (for example trialkyltin) using for example sodium 123 l iodide in the presence of a suitable oxidant (for example chloramine-T), or related methods known to one skilled in the art (Hasrat, A. and Van Lier, J. Synthesis, 1996, 425).
  • a suitable leaving group for example trifluoromethylsulfonate
  • potassium 18 F fluoride for example potassium 18 F fluoride
  • electrophilic substitution of a suitable group for example trialkyltin
  • sodium 123 l iodide for example sodium 123 l iodide
  • a suitable oxidant for
  • R 5 is a radioisotopic iodide
  • R 5 can be prepared by reacting a compound of Formula (I) wherein one or more of R 2 , R 3 , R 4 and R 5 is tri(loweralkyl)tin and R 1 is H or an acid labile protecting group, with radioisotopic iodide source, for example a solution of radioisotopic sodium iodide (e.g. as a solution in 1N NaOH), in the presence of an acid and an oxidizing agent in an alcoholic solvent.
  • radioisotopic iodide source for example a solution of radioisotopic sodium iodide (e.g. as a solution in 1N NaOH), in the presence of an acid and an oxidizing agent in an alcoholic solvent.
  • Preferred conditions are Chloramine T and hydrochloric acid in ethanol.
  • compounds of Formula (I) wherein R 1 is H and one or more of R 2 , R 3 , R 4 and R 5 is a radioisotopic iodide are prepared by reacting a compound of Formula (I) wherein one or more of R 2 , R 3 , R 4 and R 5 is tri(loweralkyl)tin and R 1 is alkoxycarbonyl, with a radioisotopic iodide source as described above, followed by removal of the alkoxycarbonyl protecting group under acidic conditions in the same reaction vessel.
  • the preferred acid is hydrochloric acid.
  • R 3 , R 4 and R 5 are as described hereinabove, an appropriately substituted piperazine is coupled with 1 H-pyrrolo[2,3-b]pyridine in the presence of formaldehyde in an aqueous buffer solution, for example aqueous sodium acetate in acetic acid.
  • the 1 H-pyrrolo[2,3-b]pyridine is commercially available and the piperazines are either commercially available or can be prepared by methods known to one skilled in the art.
  • 1-(pyridin-2-yl)piperazine is coupled with 1H-pyrrolo[2,3-b]pyridine in the presence of formaldehyde in a buffer made up of sodium acetate and acetic acid.
  • the substituted piperazines are prepared by reaction of an appropriately substituted pyridine with piperazine in the presence of a base in an inert solvent such as acetonitrile, at temperatures between 0 and 100°C, preferably at reflux.
  • Suitable bases include piperazine itself, sodium or potassium carbonate.
  • an appropriately substituted piperazine is coupled with 1 H-pyrrolo-[2,3-b]-pyridine in the presence of formaldehyde in an aqueous buffer solution, for example aqueous sodium acetate in acetic acid.
  • an aqueous buffer solution for example aqueous sodium acetate in acetic acid.
  • 1H-pyrrolo-[2,3-b]-pyridine is commercially available and the piperazines are either commercially available or can be prepared by methods known to one skilled in the art.
  • 1-[6-iodopyridazin-3-yl)piperazine is coupled with 1 H-pyrrolo-[2,3-b]-pyridine in the presence of formaldehyde in a buffer made up of sodium acetate and acetic acid.
  • the 1-[6-iodopyridazin-3-yl)piperazine can be prepared from 3,6- diiodopyridazine by reaction with piperazine in a suitable solvent, for example acetonitrile, at reflux.
  • the 3,6-diiodopyridazine is prepared as described in the literature (P. Coad et al. Journal of Organic Chemistry, 1963, 28, 218)
  • Compounds of Formula (I) wherein R 1 is alkoxycarbonyl and one or more of R 2 , R 3 , R 4 and R 5 are tri(loweralkyl)tin can also be prepared by reacting compounds of Formula (I) wherein R 1 is alkoxycarbonyl and one or more of R 2 , R 3 , R 4 and R 5 is iodo with hexa(loweralkyl)ditin reagents under standard palladium catalyzed cross- coupling conditions, for example, in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium (0) in an inert solvent, for example, toluene at temperatures ranging from 50-120°C preferably at about 110°C.
  • the compounds are selected from:
  • the compounds are selected from:
  • R 2 , R 3 , R 4 and R 5 are radioisotopic iodide
  • any physiologically and radiologically tolerable vehicle appropriate for administering the compound systemically. Included among such vehicles are phosphate buffered saline solutions, buffered for example to pH 7.4.
  • the compounds of the present invention can be administered in a standard pharmaceutical composition.
  • the present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a Formula (I) compound or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to antagonize D4 receptor stimulation.
  • the compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, or as solid forms such as tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers 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 hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically 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 lyophilized 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 after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • Suitable unit doses i.e. therapeutically effective amounts; can be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will of course vary depending on the desired clinical endpoint.
  • each dosage unit for oral administration may contain from 1 to about 500 mgs, and will be administered in a frequency appropriate for initial and maintenance treatments.
  • the present compounds will be administered to patients by intravenous injection or infusion at doses suitable (e.g. between 1 and 10 mCi) to generate an image of the compound as localized within the brain, using for example a gamma camera.
  • doses suitable e.g. between 1 and 10 mCi
  • the compounds will be administered and allowed to localize within the brain for 30 minutes to 48 hours prior to generating an image of the brain of the patient so treated.
  • the method of the present invention can usefully be applied diagnose to patients suspected of suffering from schizophrenia.
  • diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
  • Example 4 Preparation of 1-f-butoxycarbonyl-3-[4-(6-trimethylstannylpyridazin-3- yl)-piperazin-1-yl]methyl-1 H-pyrrolo[2,3-b]pyridine
  • a mixture of 1-f-butoxycarbonyl-3-[4-(6-iodopyridazin-3-yl)-piperazin-1- yl]methyl-1 H-pyrrolo[2,3-b]pyridine 52 mg, 0.1 mmol
  • hexamethylditin (30 OL, 47 mg, 0.145 mmol)
  • tetrakis triphenylphosphine palladium (0) 23 mg, 0.02 mmol
  • reaction mixture was cooled to room temperature and dissolved in 2 mL of distilled water.
  • aqueous solution was extracted 3 times with 3 mL of dichloromethane.
  • the combined extracts were dried with anhydrous Na 2 S0 4 and evaporated in vacuo.
  • a tan cloured product was obtained (130 mg, 61% yield) and used without further purification.
  • 125 l-3-[4-(5-iodopyridin-2-yl)-piperazin-1-yl]methylpyrrolo[2,3-b]pyridine can be prepared.
  • Example 22 3-[4-(6-bromopyridin-2-yl)-piperazin-1 -yl]methyl-1 H-pyrrolo[2,3- bjpyridine
  • piperazine 725 mg, 8.43 mmol
  • 2,6-dibromopyridine (1 g, 4.22 mmol)
  • acetonitrile 20 mL
  • K 2 C0 3 2.91 g, 21.1 mmol
  • D2 and D4 receptor-binding affinities of the compounds prepared in Examples 1 , 2 and 3 were evaluated as described in Grandy et al., 1989, Proc. Natl. Acad. Sci, 86:9762-9766 and Van Tol et al, 1992, Nature, 358:149-152 (the disclosures of which are hereby incorporated by reference) for their ability to reduce binding of 3 H- spiperone as compared to the reference compound clozapine.
  • the potency of the test compound to reduce 3 H-spiperone binding is directly correlated to its binding affinity for the receptor.
  • test compounds were assayed at a range of concentrations and the % inhibition of 3 H-spiperone binding at each test concentration was measured. Specific binding in the absence of test compound is the difference of total binding minus nonspecific binding and similarly specific binding (in the presence of test compound) is the difference of displacement binding minus non-specific binding.
  • An inhibition response curve was used to determine the IC 50 of the test compound 3-[4-(5-iodopyridin-3-yl)- piperazin-1-yl]methyl-1 H-pyrrolo[2,3-b]pyridine. Ki was calculated by the Cheng and Prustoff transformation:
  • Ki IC 50 / (1 + [L]/K D ) where [L] is the concentration of 3 H-spiperone used in the assay and K D is the dissociation constant of 3 H-spiperone determined independently under the same binding conditions.
  • the D2 and D4 receptor-binding affinities of the compounds of the invention can be evaluated as described in WO95/17400 (the disclosure of which is hereby incorporated by reference) for their ability to reduce binding of 3H- spiperone as compared to the reference compound clozapine.
  • the potency of the test compound to reduce 3H-spiperone binding is directly correlated to its binding affinity for the receptor.
  • the D4 receptor is utilised in the form of membrane preparations obtained from HEK 298 cells stably transfected with human D4 receptor (D4.2 subtype).
  • D2 receptor is utilised in the form of membrane preparations obtained from GH4C1 (rat pituitary) cells stably transfected with the human D2 receptor (short isoform).
  • the total spiperone binding assay is started by the addition of 500 mL (50 mg protein) membrane homogenate to a solution of 900 mL incubation buffer and 100 mL (0.25 nM final cone.) 3H-spiperone.
  • the binding reaction is stopped and the samples are filtered under vacuum and the filters are then washed 3 times with 5 mL ice cold 50 mmol Tris buffer (pH 7.4). Individual filter disks are put in scintillation vials (Biovials, Beckman). Ready Protein Plus liquid scintillant (5 mL, Beckman) is added and the vials counted by liquid scintillation spectrophotometry (Beckman LSC 6500) after equilibrating for three hours at room temperature to determine total binding (BT).
  • Non-specific binding for D4 is assayed by incubating membrane homogenate, 3H-spiperone and fresh dopamine. Filtrate is counted using the same procedure as in the total binding assay described above to give the nonspecific binding value (NSB).
  • NBS nonspecific binding value
  • Non-specific binding for D2 is similarly assessed, with the exception that (-)-sulpiride is used in place of dopamine.
  • test compounds are assayed at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3 H-spiperone binding.
  • Specific binding in the absence of test compound (B 0 ) is the difference of total binding (B ⁇ ) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) is the difference of displacement binding (B D ) minus non-specific binding (NSB).
  • IC 50 is determined from an inhibition response curve, logit-log plot of %B/B 0 vs concentration of test compound, and Ki can be calculated from this using the Cheng and Prustoff transformation as described above.
  • Compound A 3-[4-(4-iodophenyl)-piperazin-1-yl]methyl-1 H-pyrrolo[2,3-b]pyridine;
  • Compound B 3-[4-(5-iodopyridin-2-yl)-piperazin-1-yl]methyl-1 H- pyrrolo[2,3-b]pyridine;
  • Compound C 3-[4-(6-iodopyridazin-3-yl)-piperazin-1-yl]methyl-1 H-pyrrolo[2,3- bjpyridine;
  • Compound D 3-[4-(6-methylpyridazin-3-yl)piperazin-1-yl]methyl-1 H-pyrrolo[2,3- bjpyridine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés sélectifs du récepteur D4 de la dopamine de formule (I) dans laquelle Z est choisi parmi N et C(R5); R1 est choisi parmi H et un groupe protecteur labile d'acide; R?2, R3, R4 et R5¿ sont indépendamment choisis parmi H, hydroxy, alkyle inférieur, alkyle inférieur éventuellement substitué par un ou plusieurs groupes choisis parmi halo, hydroxy et alcoxy inférieur; alkyle inférieur -S-, halo, halo radioisotopique, alcoxy inférieur, trifluorométhylsulfonyle, cycloalkyle, aryle et tri(alkyle inférieur)étain; à condition que lorsque Z est C(R5), au moins l'un parmi R?2, R3, R4 et R5¿ soit choisi parmi halo radioisotopique et tri(alkyle inférieur)étain, et sels et solvates ou hydrates desdites substances. La présente invention concerne également l'utilisation de ces composés en tant que substances pharmaceutiques pour traiter des pathologies pour lesquelles un antagoniste de récepteur D4 de la dopamine est indiqué. Ces composés radiomarqués sont utiles en particulier pour produire des images permettant de localiser le récepteur D4 dans le cerveau humain, et peuvent donc contribuer à la pose du diagnostic de schizophrénie et d'autres états pathologiques dans lesquels le récepteur D4 est impliqué.
PCT/CA1998/000615 1997-06-27 1998-06-26 Ligands du recepteur d4 de la dopamine Ceased WO1999000386A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU80967/98A AU8096798A (en) 1997-06-27 1998-06-26 Dopamine d4 receptor ligands

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US88455197A 1997-06-27 1997-06-27
US08/884,551 1997-06-27
US08/905,546 US5976497A (en) 1997-08-04 1997-08-04 Dopamine D4 receptor ligands
US08/905,546 1997-08-04

Publications (1)

Publication Number Publication Date
WO1999000386A1 true WO1999000386A1 (fr) 1999-01-07

Family

ID=27128729

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1998/000615 Ceased WO1999000386A1 (fr) 1997-06-27 1998-06-26 Ligands du recepteur d4 de la dopamine

Country Status (2)

Country Link
AU (1) AU8096798A (fr)
WO (1) WO1999000386A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011653A3 (fr) * 2003-07-30 2005-04-14 Xenon Pharmaceuticals Inc Derives de pyridazine et utilisation de ceux-ci en tant qu'agents therapeutiques
US6890919B2 (en) 2001-06-26 2005-05-10 Shitij Kapur Atypical antipsychotic agents having low affinity for the D2 receptor
WO2006086447A3 (fr) * 2005-02-09 2007-04-05 Xenon Pharmaceuticals Inc Derives de pyridazine et leur utilisation en tant qu'agents therapeutiques
US7335658B2 (en) 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7592343B2 (en) 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US7759348B2 (en) 2003-07-30 2010-07-20 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7767677B2 (en) * 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2017049321A1 (fr) 2015-09-17 2017-03-23 Miller Marvin J Composés hétérocycliques contenant de la benzylamine et compositions utiles contre une infection mycobactérienne
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994020497A1 (fr) * 1993-03-01 1994-09-15 Merck Sharp & Dohme Limited Derives de pyrrolo-pyridine
US5622950A (en) * 1993-03-01 1997-04-22 Merck, Sharp & Dohme Ltd. Pyrrolo-pyridine derivatives
WO1997046558A1 (fr) * 1996-05-31 1997-12-11 Resolution Pharmaceuticals Inc. Derives de pyrrolo[2,3-b]pyridine utiles en tant que ligands radiomarques du recepteur d4

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994020497A1 (fr) * 1993-03-01 1994-09-15 Merck Sharp & Dohme Limited Derives de pyrrolo-pyridine
US5432177A (en) * 1993-03-01 1995-07-11 Merck Sharpe & Dohme Ltd. Pyrrolo-pyridine derivatives
US5622950A (en) * 1993-03-01 1997-04-22 Merck, Sharp & Dohme Ltd. Pyrrolo-pyridine derivatives
WO1997046558A1 (fr) * 1996-05-31 1997-12-11 Resolution Pharmaceuticals Inc. Derives de pyrrolo[2,3-b]pyridine utiles en tant que ligands radiomarques du recepteur d4
US5725838A (en) * 1996-05-31 1998-03-10 Resolution Pharmaceuticals, Inc. Radiolabeled D4 receptor ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. PATEL ET AL.: "Identification and pharmacological characterization of [125 I]L750,667, a novel radioligand for the dopamine D4 receptor", MOLECULAR PARMACOLOGY, vol. 50, no. 6, 1996, New York, pages 1658 - 1664, XP002037689 *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6890919B2 (en) 2001-06-26 2005-05-10 Shitij Kapur Atypical antipsychotic agents having low affinity for the D2 receptor
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US7759348B2 (en) 2003-07-30 2010-07-20 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
JP2007500715A (ja) * 2003-07-30 2007-01-18 ゼノン・ファーマシューティカルズ・インコーポレイテッド ピリダジン誘導体および治療剤としての用途
US8148378B2 (en) 2003-07-30 2012-04-03 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as inhibitors of stearoyl-CoA desaturase-1 activity in a mammal
US7335658B2 (en) 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2005011653A3 (fr) * 2003-07-30 2005-04-14 Xenon Pharmaceuticals Inc Derives de pyridazine et utilisation de ceux-ci en tant qu'agents therapeutiques
AU2004261249B2 (en) * 2003-07-30 2008-09-04 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7514436B2 (en) 2003-07-30 2009-04-07 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
EP2316826A1 (fr) * 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Dérivés de pyridazine et utilisation de ceux-ci en tant qu'agents thérapeutiques
US7754711B2 (en) 2003-07-30 2010-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7592343B2 (en) 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US7767677B2 (en) * 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
WO2006086447A3 (fr) * 2005-02-09 2007-04-05 Xenon Pharmaceuticals Inc Derives de pyridazine et leur utilisation en tant qu'agents therapeutiques
JP2008530098A (ja) * 2005-02-09 2008-08-07 ゼノン・ファーマシューティカルズ・インコーポレイテッド ピリダジン誘導体および治療剤としてのその使用
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US12076322B2 (en) 2011-02-07 2024-09-03 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
WO2017049321A1 (fr) 2015-09-17 2017-03-23 Miller Marvin J Composés hétérocycliques contenant de la benzylamine et compositions utiles contre une infection mycobactérienne

Also Published As

Publication number Publication date
AU8096798A (en) 1999-01-19

Similar Documents

Publication Publication Date Title
WO1999000386A1 (fr) Ligands du recepteur d4 de la dopamine
KR102659859B1 (ko) 알파4β7 인테그린의 억제를 위한 화합물
CN112969700B (zh) 作为α4β7整合素抑制剂的咪唑并吡啶衍生物
RU2638116C2 (ru) Пиразоло[3,4-с]пиридины и способы их применения
KR102630416B1 (ko) 알파4베타7 인테그린 억제제로서의 퀴놀린 유도체
US7060699B2 (en) Aryl and heteroaryl diazabicycloalkanes, their preparation and use
TW201127385A (en) N-containing heteroaryl derivatives as JAK3 kinase inhibitors
MX2015004151A (es) Inhibidores del factor de diferenciacion de crecimiento-8 (gdf-8).
EP2251339A2 (fr) Composés
EP3653618A1 (fr) Nouveaux dérivés de dihydroquinoline-2-one
US20120302596A1 (en) Azaindoles having serotonin receptor affinity
EP4161927B9 (fr) Composés spiro en tant qu'antagonistes du récepteur de la mélanocortine 4 et leurs utilisations
EP1177196A1 (fr) Diazabicycloalcanes heteroaryles, leur preparation et leur utilisation
KR20210137134A (ko) 페롭토시스-관련 장애의 치료를 위한 헤테로방향족 및 헤테로바이시클릭 방향족 유도체
WO2023114472A1 (fr) Composés hétérocycliques en tant qu'agonistes polarisés 5ht2a
US20010049441A1 (en) Azaindoles having serotonin receptor affnity
KR20100113155A (ko) 이중 약물작용발생단 - ｐｄｅ４-무스카린성 길항제
TW200529860A (en) Nicotinic acetylcholine receptor ligands
US5976497A (en) Dopamine D4 receptor ligands
AU2020407600A1 (en) Compounds and probes for imaging huntingtin protein
EP4444708B1 (fr) Antagonistes du récepteur 4 de la mélanocortine et leurs utilisations
OA21024A (en) Spiro compounds as melanocortin 4 receptor antagonists and uses thereof.
TWI673268B (zh) 作為ｆｇｆｒ４抑制劑之稠環雙環吡啶基衍生物
US20120309792A1 (en) Tetrazole derivatives as nicotinic acetylcholine receptor modulators
HK40060547A (en) Compounds for inhibition of alpha4beta7 integrin

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1999505171

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA