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WO2001032660A1 - Composes ayant une activite d'antagoniste de recepteur de 5-ht¿6? - Google Patents

Composes ayant une activite d'antagoniste de recepteur de 5-ht¿6? Download PDF

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Publication number
WO2001032660A1
WO2001032660A1 PCT/IB2000/001595 IB0001595W WO0132660A1 WO 2001032660 A1 WO2001032660 A1 WO 2001032660A1 IB 0001595 W IB0001595 W IB 0001595W WO 0132660 A1 WO0132660 A1 WO 0132660A1
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WIPO (PCT)
Prior art keywords
indole
bicyclopiperazinyl
compound according
compounds
compound
Prior art date
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Ceased
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PCT/IB2000/001595
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English (en)
Inventor
Tao Xin
Methvin Isaac
Abdelmalik Slassi
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NPS Allelix Corp Canada
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NPS Allelix Corp Canada
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Priority to US10/111,404 priority Critical patent/US6897215B1/en
Priority to AU15422/01A priority patent/AU1542201A/en
Publication of WO2001032660A1 publication Critical patent/WO2001032660A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to indole compounds having affinity for the serotonin 5-HTg receptor, to pharmaceutical compositions containing them and to their medical use, particularly in the treatment of CNS conditions.
  • the human 5-hydroxytryptamine-6 (5-HT 6 ) receptor one of the most recently cloned serotonergic receptors, is a 440-amino acid polypeptide with seven transmembrane spanning domains typical of the G-protein-coupled receptors. It is one of the 14 receptors that mediate the effects of the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin)(Hoyer et al, Neuropharmacology, 1997,36:419). Within the transmembrane region, the human 5-HT 6 receptor shows about 3CM-0% homology to other human 5-HT receptors and is found to be positively coupled to adenylyl cyclase.
  • 5-HT 6 receptor mRNA The prominent localization of 5-HT 6 receptor mRNA in the nucleus accumbens, striatum, olfactory tubercle, substantia nigra, and hippocampus of the brain (Ward et al, Neuroscience, 1995, 64:1105) together with its high affinity for several therapeutically important antipsychotics and antidepressants, suggest a possible role for this receptor in the treatment of schizophrenia and depression.
  • the prototypic atypical antipsychotic agent clozapine exhibits greater affinity for the 5-HT 6 receptor than for any other receptor subtype (Monsma et al, J. Pharmacol. Exp. Ther., 1994, 268:1403).
  • 5-HT 6 receptor has a distinct pharmacological profile, in vivo investigation of receptor function has been hindered by the lack of selective agonists and antagonists.
  • novel compounds typically in the form of 6-bicyclopiperazinyl-l-arylsulfonylindole and 6-bicyclopiperidinyl-l- arylsulfonylindole derivatives, of the Formula I, or a salt, solvate, or prodrug thereof:
  • R3 is H, or -C(O)-R4
  • R4 is H or a labile prodrug group n is 1, 2, 3 or 4; m and o are, independently, 0, 1, 2, 3 or 4 with the proviso that m + o is 1, 2, 3, or 4; and Ar is an aryl or heteroaryl group optionally substituted with 1-3 substituents.
  • compositions comprising a therapeutically effective amount of a compound of Formula I, or a salt, solvate, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a method useful for the treatment of a medical condition for which a 5-HT 6 receptor antagonist is indicated, comprising the step of administering to a subject afflicted with said condition, a pharmaceutical composition comprising a compound of Formula I.
  • aryl refers to a carbocyclic aromatic group selected from phenyl and naphthyl.
  • heteroaryl refers to an aryl group containing from 1 to 3 heteroatoms selected from O, N and S, and includes pyridyl, thienyl, quinolinyl, pyrimidyl, furyl, thiazolyl, oxazolyl, imidazolyl and the like.
  • aryl and heteroaryl groups are optionally substituted by 1, 2 or 3 independently selected substituents which include halo, nitro, trifluoromethyl, trifluoromethoxy, 1,2-alkylenediox ⁇ . alkoxycarbonyl and
  • C ⁇ - 4 alkyl means straight and branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
  • C alkylthio and Q. 4 alkylcarbonyl refer to groups in which there is a thio group or a carbonyl group bridging the group to the node at which that substituent is substituted.
  • the term " as used herein means straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • C ⁇ -4alkyloxycarbonyl refers to C ⁇ _ 4 alkoxy group in which there is a carbonyl group bridging the substituent to the node at which the substitution occurs.
  • 1,2-alkylenedioxy as used herein means "-0-(CH 2 ) n -0-". wherein n is 1 or 2, attached to adjacent nodes of an aryl or heteroaryl ring.
  • halo means halogen and includes fluoro. chloro, bromo and the like.
  • leaving group refers to a chemical group that is displaced in a chemical reaction, and the choice of leaving will depend on the nature of the reaction and the intended displacement. For instance, in scheme I shown herein, a leaving group suitable under those reaction conditions is halo and typically bromo.
  • labile prodrug group refers to a chemical moiety that is cleavable under conditions encountered following administration to the subject receiving the compound. Such compounds will convert in vivo to form the corresponding carboxyl moiety or in some instances, to form the hydroxyl moiety.
  • Such conversion can be effected, for instance, by endogenous enzymes including esterases, and the labile prodrug group therefore can be any group that is cleaved by those endogenous enzymes, including for instance alkyl groups and alkylamide groups.
  • the group Rl is H.
  • m, n and o are selected to form a bicyclic ring system of the type 5,5-, 5,6-, 5,7-, 5,8-, 6,5-, 6,6-, 6,7-, 6,8-, 7,5-, 7,6-, 7,7-, 7,8-, 8,5-, 8,6-, 8,7, and 8,8.
  • n is 1 or 2
  • m and o are 0, 1 or 2.
  • m and o are each 1.
  • m, n and o are selected to form a ring system which is 5,6-, 6,5- or 6,6-.
  • X is N and n is 1 or 2, and m and o are each 1 , thereby to form either a 6,5-bicyclopiperazine ring or a 6,6-bicyclopiperazine ring, respectively.
  • n is 1.
  • the compounds of Formula I are those in which Ar is an aryl group selected desirably from phenyl and naphthyl, including 1- naphthyl and 2-naphthyl that are either unsubsituted or substituted by one or two substituents.
  • Specific substituents include particularly including methyl and halo, particularly including chloro and fluoro.
  • Ar is 2-, 3- or 4-substituted phenyl, or
  • compounds of the present invention are those in which Ar is selected from 1 -naphthyl, 2-naphthyl, phenyl, 4-methyl-phenyl, and 2,4-dihalo-phenyl, including 2,4-difluoro-phenyl.
  • Ar is a naphthyl group, and particularly 1 -naphthyl.
  • n and o are each 1 and Ar is 1-napthyl.
  • the compounds of Formula 1 include:
  • the compounds include:
  • the compounds of the present invention are useful in the form of pharmaceutically acceptable salts, and as solvates and prodrugs.
  • pharmaceutically acceptable salt means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
  • a "pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic. sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • a "pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • Solvate means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol and the like.
  • the present compounds include any of their stereoisomeric forms, and racemates.
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • the present compounds are useful also in their "prodrugs" form.
  • prodrugs will be functional derivatives of the compounds of Formula I which are readily convertible in vivo into the required compound of Formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
  • the compounds of the present invention can be prepared by processes analogous to those established in the art.
  • the 6- bicyclopiperazinyl-1-arylsulfonylindoles, in which X is N and n, m, o, Rl, Y and Ar are as defined above, can be prepared by the reaction illustrated below as Scheme I:
  • N-silylation of 6-bromoindole or indazole 1 with triisopropylsilyl chloride yields 2, which is subjected to the conditions of metal-catalyzed aryl amination (Nishayama, M. et al;Tetrahedron Lett. 1998, 39, 617-620) to give 3. Subsequent desilylation of 3 affords 4, which is then sulfonylated to give 5.
  • the indole or indazole 1 is coupled to bicyclopiperidone (King et. al, J Med. Chem., 31, 9, 1988, 1708-1712 and J. Chem. Soc. Perkin TransX, 1986, 447-454) to give the carbinol 6.
  • Compound 6 is then treated with trifluoroacetic acid to effect the elimination to alkenes 7a and 7b.
  • Both intermediate 6 and 7a are subjected to aryl sulfonylation to give 8 and 9, respectively.
  • Palladium catalyzed hydrogenation of 7a and/or 7b gives two diastereoisomers 10 and 11, which are easily separated by column chromatography.
  • compound 1 is made by the following procedure.
  • the substituted phenone 15 is treated with hydrazine and acid to yeild the intermediate hydrazone, 16, which cyclizes to give the substituted indazole 1.
  • the present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT 6 receptor antagonist is indicated, such as in the treatment of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances. Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances.
  • Parkinsonism amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • schizophrenia means schizophrenia, schizophreniform, disorder, schizoaffective disorder and psychotic disorder wherein the term “psychotic” refers to delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington, D.C.
  • the present invention provides a method for treating medical conditions for which a 5-HT 6 receptor antagonist is indicated, which comprises the step of administering to the patient a therapeutically effective amount of a compound of Formula I, and a pharmaceutically acceptable carrier therefor.
  • 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 treat the target indication.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
  • the compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump 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 earner routinely used for prepanng sohd formulations
  • suitable pharmaceutical earner routinely used for prepanng sohd formulations
  • examples of such earners 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 earners and then filled into hard gelatin capsule, alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical earner, 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 stenle aqueous earner or parenterally acceptable oil, for example polyethylene glycol, polyvmyl pyrrohdone, lecithin, arachis oil or sesame oil Alternatively, the solution can be lyophi zed and then reconstituted with a suitable solvent just pnor to administration
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically compose a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented m single or multidose quantities m stenle form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metenng valve which is intended for disposal after use Where the dosage form compnses an aerosol dispenser, it will contain a propellant that 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 subhngual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a earner such as sugar, acacia, tragacanth, or gelatin and glycenne.
  • Compositions for rectal administration are conveniently m the form of suppositones 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 dosages i.e. therapeutically effective amounts
  • therapeutically effective amount means an amount of the compound which is effective in treating, e.g., reducing the severity or duration of, the named disorder or condition or of any symptom thereof, and includes particularly an amount effective to antagonize the 5HT 6 receptor.
  • Such amounts are revealed as an amount which when administered to a subject over the course of an appropriate treatment regimen results in reduction of the level or magnitude of an effect normally elicited by triggering of the endogenous 5-HT 6 receptor.
  • Each dosage unit for oral administration may contain, for instance, from 0.01 to 500 mg/kg (and for parenteral administration may contain from 0.1 to 50 mg) of a compound of Formula I, or a pharmaceutically acceptable salt thereof calculated as the free base, and will be administered in a frequency appropriate for initial and maintenance treatments.
  • the present compounds can be stored in packaged form for reconstitution and use.
  • the present compounds can be used to distinguish 5-HT 6 receptors from other receptor subtypes, for example glutamate or opioid receptors, within a population of receptors, and in particular to distinguish between the 5-HT 6 and other 5-HT receptor subtypes.
  • the latter can be achieved by incubating preparations of the 5-HT 6 receptor and one of the other 5-HT receptor subtypes (for example 5-HT 2A and 5- HT ) with a 5-HT 6 -selective compound of the invention and then incubating the resulting preparation with a radiolabeled serotonin receptor ligand, for example [ 3 H]-serotonin.
  • the 5- HT 6 receptors are then distinguished by determining the difference in membrane-bound activity, with the 5-HT 6 receptor exhibiting lesser radioactivity, i.e., lesser [ 3 H] -serotonin binding, than the other 5-HT receptor subtype.
  • the compound is provided in labeled form, such as radiolabeled form, e. g. labeled by incorporation within its structure ⁇ or 14 C or by conjugation to 125 I.
  • labeled form such as radiolabeled form, e. g. labeled by incorporation within its structure ⁇ or 14 C or by conjugation to 125 I.
  • the compounds in labeled form can be used to identify 5-HT 6 receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabeled compound of the invention. 5-HT 6 receptor ligands are thus revealed as those that are not significantly displaced by the radiolabeled compound of the present invention.
  • 5-HT 6 receptor ligand candidates may be identified by first incubating a radiolabeled form of a compound of the invention then incubating the resulting preparation in the presence of the candidate ligand. A more potent 5-HT6 receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
  • the compound 6-bromo-l-triisopropylindazole may be prepared from 6- bromo-indazole by the conditions described above.
  • indazole compounds are made from the appropriate n- protected indazole from example 1.
  • the corresponding indazole compounds are prepared from the corresponding bicyclopiperazinyl-lH-indazoles from example 3, treated with an arylsulphonylchloride as described in example 4.
  • indazole compounds are prepared using 6-bromoindazole in conversion A) and following the synthetic procedures described above for indole.
  • the assay protocol entails the incubation of membranes, prepared from HEK293 cells expressing the human 5-HT 6 subtype of receptor, with 3 H-LSD and using clozapine, a typical 5-HT 6 receptor antagonist, as a standard (for cloning and characterization of the human 5-HT 6 receptor see Kohen, et al. J. Neurochemistry, 66, 1996: 47-56). Specific concentrations of the test compounds were incubated with the radioligand ( H-LSD) and the receptor affinity (K, in nM) was determined. Particularly, increasing levels of the test compound were incubated with the radioligand and the membrane homogenates prepared from the recombinant cells.
  • the affinity of the test compound for the 5-HT 6 receptor was determined by computer-assisted analysis of the data and determining the amount of the compound necessary to inhibit 50% of the binding of the radioligand to the receptor.
  • the antagonist property of the compounds at the human 5-HT 6 receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HT 6 receptor will lead to an increase in adenyl cyclase activity. A compound that is an agonist will show an increase in cAMP production and a compound that is an antagonist will block the agonist effect.
  • Human 5-HT 6 receptors were cloned and stably expressed in HEK293 cells. These cells were plated in 6 well plates in DMEM/F12 media with 10% fetal calf serum (FCS) and 500ug/mL G418 and incubated at 37°C in a CO 2 incubator. The cells were allowed to grow to about 70%) confluence before initiation of the experiment. On the day of the experiment, the culture media was removed, and the cells were washed once with serum free medium (SFM). Two mL of SFM+IBMX media was added and incubated at 37°C for 10 min.
  • FCS fetal calf serum
  • the media were removed and fresh SFM+IBMX media containing various compounds, and luM serotonin (as antagonist) were added to the appropriate wells and incubated for 30 min. Following incubation, the media were removed and the cells were washed once with 1 mL of PBS (phosphate buffered saline). Each well was treated with 1 mL cold 95% ethanol and 5 mM EDTA (2:1) at 4°C for 1 hour. The cells were then scraped and transferred into PBS (phosphate buffered saline).
  • PBS phosphate buffered saline
  • cAMP content was determined by EIA (enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (Amersham RPN 225). The procedure used is as described for the kit. Briefly, cAMP is determined by the competition between unlabeled cAMP and a fixed quantity of peroxidase-labelled cAMP for the binding sites on anti-cAMP antibody. The antibody is immobilized onto polystyrene microtitre wells precoated with a second antibody.
  • the reaction is started by adding 50uL peroxidase-labeled cAMP to the sample (lOOuL) preincubated with the antiserum (lOOuL) for 2 hours at 4°C. Following 1 hour incubation at 4°C, the unbound ligand is separated by a simple washing procedure. Then an enzyme substrate, tetramethylbenzidine (TMB), is added and incubated at room temperature for 60 min. The reaction is stopped by the addition of lOOuL 1.0 M sulphuric acid and the resultant color read by a microtitre plate spectrophotometer at 450 nM within 30 minutes.
  • TMB tetramethylbenzidine

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Abstract

L'invention concerne des composés utiles en tant qu'antagonistes de récepteurs du 5-HT6 pour plusieurs troubles du SNC, tels que la schizophrénie, la dépression, l'hyperactivité avec déficit de l'attention et les troubles de la cognition et de la mémoire. Ces composés correspondent à la formule (I): dans laquelle R1 représente H ou C1-4alkyle ; ...X représente -CH, -C-O-R3, =C, ou -N ; ...Y représente -CH-R2, =C-R2, =N ou -NR2, R2 représente H ou C1-4alkyle ; R3 représente H, ou -C(O)-R4, R4 représente H ou un groupe de promédicaments labiles, n est égal à 1, 2, 3 ou 4; m et o sont égaux, de manière indépendante, à 0, 1, 2, 3 ou 4, à condition que m + o soit égal à 1, 2, 3, ou 4; et Ar représente un groupe aryle ou hétéroaryle éventuellement substitué par 1 à 3 substituants.
PCT/IB2000/001595 1999-11-05 2000-11-04 Composes ayant une activite d'antagoniste de recepteur de 5-ht¿6? Ceased WO2001032660A1 (fr)

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US10/111,404 US6897215B1 (en) 1999-11-05 2000-11-04 Compounds having 5-HT6 receptor antagonist activity
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098857A1 (fr) * 2001-06-07 2002-12-12 F. Hoffmann-La Roche Ag Nouveaux derives de l'indole a affinite pour le recepteur 5-ht6
WO2003053433A1 (fr) * 2001-12-20 2003-07-03 Wyeth Derives d'indolylalkylamine en tant que ligands de 5-hydroxytryptamine-6
WO2003068220A1 (fr) * 2002-02-12 2003-08-21 Akzo Nobel N.V. Derives d'indole et d'indoline 1-arylsulfonyl-3-substitues utiles dans le traitement de troubles du systeme nerveux central
WO2004000828A1 (fr) * 2002-06-20 2003-12-31 Biovitrum Ab Composes utiles pour le traitement de l'obesite, du diabete de type ii et des troubles du systeme nerveux central
US6790848B2 (en) 2001-06-15 2004-09-14 Syntex (U.S.A.) Llc 4-piperazinylindole derivatives with 5-HT6 receptor affinity
JP2005536551A (ja) * 2002-06-20 2005-12-02 ビオヴィトルム・アクチボラゲット 肥満症、ｉｉ型糖尿病およびｃｎｓ障害の治療に有用な新規化合物
JP2006515341A (ja) * 2003-03-03 2006-05-25 エフ．ホフマン−ラ　ロシュ　アーゲー ５−ｈｔ６調節物質として使用するための２，５−および２，６−置換テトラヒドロイソキノリン
US7144883B2 (en) 2001-06-11 2006-12-05 Biovitrum Ab Bicyclic sulfonamide compounds
WO2007021575A3 (fr) * 2005-08-15 2007-04-05 Astrazeneca Ab Piperazines acetyleniques servant d'antagonistes a des recepteurs de glutamate metabotropiques
US7381728B2 (en) 2004-07-28 2008-06-03 Glaxo Group Limited Piperazine derivatives useful for the treatment of gastrointestinal disorders
US7452888B2 (en) 2002-03-27 2008-11-18 Glaxo Group Limited Quinoline derivatives and their use as 5-ht6 ligands
WO2008101247A3 (fr) * 2007-02-16 2008-11-27 Memory Pharm Corp Composes substitues en 6 presentant une affinite avec le recepteur 5-ht6
WO2010021797A1 (fr) * 2008-08-22 2010-02-25 Memory Pharmaceuticals Corporation Composés hétérocycliques condensés ayant une affinité pour le récepteur 5-ht<sb>6</sb>
US7696229B2 (en) 2006-02-17 2010-04-13 Memory Pharmaceuticals Corporation Compounds having 5-HT6 receptor affinity
US7960374B2 (en) 2006-10-30 2011-06-14 Proximagen Limited Tricyclic compounds, compositions, and methods useful in the treatment or prophylaxis of 5-HT6 receptor-related disorders
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US9808455B2 (en) 2007-12-12 2017-11-07 Axovant Sciences Gmbh Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
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US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US10059691B2 (en) 2008-04-02 2018-08-28 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
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US6787535B2 (en) 2001-06-07 2004-09-07 Syntex (U.S.A.) Llc Indole derivatives with 5HT6 receptor affinity
RU2294932C2 (ru) * 2001-06-07 2007-03-10 Ф.Хоффманн-Ля Рош Аг Новые производные индола со сродством к рецептору 5-ht6
WO2002098857A1 (fr) * 2001-06-07 2002-12-12 F. Hoffmann-La Roche Ag Nouveaux derives de l'indole a affinite pour le recepteur 5-ht6
US7144883B2 (en) 2001-06-11 2006-12-05 Biovitrum Ab Bicyclic sulfonamide compounds
US7572787B2 (en) 2001-06-11 2009-08-11 Biovitrum Ab Substituted naphthalene sulfonamides
US6790848B2 (en) 2001-06-15 2004-09-14 Syntex (U.S.A.) Llc 4-piperazinylindole derivatives with 5-HT6 receptor affinity
AU2002357270B2 (en) * 2001-12-20 2007-06-14 Wyeth Indolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
US6770642B2 (en) 2001-12-20 2004-08-03 Wyeth Indolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
US7022701B2 (en) 2001-12-20 2006-04-04 Wyeth Indolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
WO2003053433A1 (fr) * 2001-12-20 2003-07-03 Wyeth Derives d'indolylalkylamine en tant que ligands de 5-hydroxytryptamine-6
RU2309157C2 (ru) * 2001-12-20 2007-10-27 Уайт Производные индолилалкиламина в качестве лигандов 5-гидрокситриптамина-6
CN1309385C (zh) * 2001-12-20 2007-04-11 惠氏公司 作为5－羟色胺－6配体的吲哚基烷基胺衍生物
US7838518B2 (en) 2002-02-12 2010-11-23 N.V. Organon 1-arylsulfonyl-3-substituted indole and indoline derivatives useful in the treatment of central nervous system disorders
WO2003068220A1 (fr) * 2002-02-12 2003-08-21 Akzo Nobel N.V. Derives d'indole et d'indoline 1-arylsulfonyl-3-substitues utiles dans le traitement de troubles du systeme nerveux central
US7601837B2 (en) 2002-03-27 2009-10-13 Glaxo Group Limited Quinoline derivatives and their use as 5-HT6 ligands
US7799774B2 (en) 2002-03-27 2010-09-21 Glaxo Group Limited Quinoline derivatives and their use as 5-HT6 ligands
US8236947B2 (en) 2002-03-27 2012-08-07 Glaxo Group Limited Quinoline derivatives and their use as 5-HT6 ligands
US7977337B2 (en) 2002-03-27 2011-07-12 Glaxo Group Limited Quinoline derivatives and their use as 5-HT6 ligands
US7452888B2 (en) 2002-03-27 2008-11-18 Glaxo Group Limited Quinoline derivatives and their use as 5-ht6 ligands
US7943639B2 (en) 2002-06-20 2011-05-17 Proximagen Limited Compounds
JP4754821B2 (ja) * 2002-06-20 2011-08-24 プロキシマゲン・リミテッド 肥満症、ｉｉ型糖尿病およびｃｎｓ障害の治療に有用な新規化合物
JP2005536551A (ja) * 2002-06-20 2005-12-02 ビオヴィトルム・アクチボラゲット 肥満症、ｉｉ型糖尿病およびｃｎｓ障害の治療に有用な新規化合物
SG156524A1 (en) * 2002-06-20 2009-11-26 Biovitrum Ab Publ New compounds useful for the treatment of obesity, type ii diabetes and cns disorders
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WO2004000828A1 (fr) * 2002-06-20 2003-12-31 Biovitrum Ab Composes utiles pour le traitement de l'obesite, du diabete de type ii et des troubles du systeme nerveux central
EA008835B1 (ru) * 2002-06-20 2007-08-31 Биовитрум Аб Замещенные сульфоны и сульфонамиды и фармацевтические композиции на их основе, применимые для лечения ожирения, сахарного диабета ii типа и расстройств центральной нервной системы
JP2006515341A (ja) * 2003-03-03 2006-05-25 エフ．ホフマン−ラ　ロシュ　アーゲー ５−ｈｔ６調節物質として使用するための２，５−および２，６−置換テトラヒドロイソキノリン
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US7381728B2 (en) 2004-07-28 2008-06-03 Glaxo Group Limited Piperazine derivatives useful for the treatment of gastrointestinal disorders
WO2007021575A3 (fr) * 2005-08-15 2007-04-05 Astrazeneca Ab Piperazines acetyleniques servant d'antagonistes a des recepteurs de glutamate metabotropiques
US7696229B2 (en) 2006-02-17 2010-04-13 Memory Pharmaceuticals Corporation Compounds having 5-HT6 receptor affinity
US7960374B2 (en) 2006-10-30 2011-06-14 Proximagen Limited Tricyclic compounds, compositions, and methods useful in the treatment or prophylaxis of 5-HT6 receptor-related disorders
JP2010519226A (ja) * 2007-02-16 2010-06-03 メモリー・ファーマシューティカルズ・コーポレイション ５−ｈｔ６受容体親和性を有する６’位置換インドール及びインダゾール誘導体
WO2008101247A3 (fr) * 2007-02-16 2008-11-27 Memory Pharm Corp Composes substitues en 6 presentant une affinite avec le recepteur 5-ht6
US9808455B2 (en) 2007-12-12 2017-11-07 Axovant Sciences Gmbh Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
US10059691B2 (en) 2008-04-02 2018-08-28 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US10787437B2 (en) 2008-04-02 2020-09-29 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
WO2010021797A1 (fr) * 2008-08-22 2010-02-25 Memory Pharmaceuticals Corporation Composés hétérocycliques condensés ayant une affinité pour le récepteur 5-ht<sb>6</sb>
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
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