WO2002085892A1 - Heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands - Google Patents

Heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands Download PDF

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WO2002085892A1
WO2002085892A1 PCT/US2002/012415 US0212415W WO02085892A1 WO 2002085892 A1 WO2002085892 A1 WO 2002085892A1 US 0212415 W US0212415 W US 0212415W WO 02085892 A1 WO02085892 A1 WO 02085892A1
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optionally substituted
formula
compound
alkyl
aryl
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PCT/US2002/012415
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French (fr)
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Ping Zhou
Boyd Lynn Harrison
Yanfang Li
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Wyeth
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Priority to MXPA03009476A priority Critical patent/MXPA03009476A/en
Priority to EA200301142A priority patent/EA200301142A1/en
Priority to EP02764248A priority patent/EP1385842A1/en
Priority to JP2002583419A priority patent/JP4323810B2/en
Priority to KR10-2003-7013585A priority patent/KR20030088508A/en
Priority to CA002444095A priority patent/CA2444095A1/en
Priority to BR0209056-2A priority patent/BR0209056A/en
Priority to IL15844502A priority patent/IL158445A0/en
Priority to HU0303958A priority patent/HUP0303958A2/en
Publication of WO2002085892A1 publication Critical patent/WO2002085892A1/en
Priority to NO20034648A priority patent/NO20034648L/en

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D401/14—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 three or more hetero rings
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands, to processes for preparing them, to methods of using them and to pharmaceutical compositions containing them.
  • 5-HT neurotransmitter 5- hydroxytryptamine
  • serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others.
  • the effects of serotonin are regulated by the various 5-HT receptor subtypes.
  • Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A) , the 5-HT2 family (e.g. 5-HT2A) , 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes .
  • 5-HT6 receptor subtype The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor RNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CAl, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT ⁇ receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues.
  • 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia and bulimia) , panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines) , schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
  • CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia and bulimia) , panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines) , schizophrenia, or the like; or in the treatment of certain gastrointestinal
  • the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
  • the present invention provides compounds of formula
  • W is S0 2 , CO, CONH, CSNH or (CH 2 ) X ;
  • X is 0, SO n or NR U ;
  • Y is CR 12 or N;
  • Z is CR 13 or N with the proviso that when Y is N then Z must be CR 13 ;
  • m and x are each independently 0 or an integer of 1, 2 or 3 ;
  • R x is halogen, CN, 0R 14 , C0 2 R 15 , C0NR 1S R 17 , CNR 18 NR 19 R 20 , S0 2 NR 21 R 22 , SO p R 23 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
  • R 2 is H, CNR 24 NR 25 R 26 or a C ⁇ -C ⁇ lkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
  • R 3/ R ⁇ , R 5 , R 6 , R 7 , R 8 , R 9 , R 2S and R 29 are each independently H or an optionally substituted C- C 6 alkyl group;
  • R 10 is an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2;
  • R l ⁇ is H or a C 1 -C 6 alkyl / C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 3 C 6 cycloalkyl or cycloheteroalkyl group each optionally substituted;
  • R 12 and R 13 are each independently H, halogen or a C,- C 6 alkyl, aryl, heteroaryl or C,-C 6 alkoxy group each optionally substituted;
  • R u is H, COR 27 or a C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, aryl or heteroaryl group each optionally substituted;
  • R 15 and R 27 are each independently H or a C ⁇ C g alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
  • R 16 , R 17 , R 18 , R 19 , R 20 , R 2i , R 2S and R 26 are each independently H or an optionally substituted C j - C 6 alkyl group;
  • R 21 and R 22 are each independently H or a C j -C 8 alkyl, aryl or heteroaryl group each optionally substituted; and R 23 is an optionally substituted C 1 -C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
  • the present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor. DETAILED DESCRIPTION OF THE INVENTION
  • the 5-hydroxytryptamine-6 (5-HT ⁇ ) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT ⁇ receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
  • heterocyclyloxy-, -thioxy- or -a inobenzazole derivatives of formula I demonstrate 5-HT6 affinity.
  • said benzazole derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor.
  • CNS central nervous system
  • the present invention provides heterocyclyloxy-, -thioxy- or -aminobenzazole derivatives of formula I
  • X is 0, SO or NR..
  • Y is CR 12 or N
  • Z is CR 13 or N with the proviso that when Y is N then
  • Z must be CR 13 ; m and x are each independently 0 or an integer of 1,
  • R x is halogen, CN, 0R M , C0 2 R 15 , CONR 16 R 17 , CNR 18 NR 19 R 20 , S0 2 NR 21 R 22 , SO p R 23 or a C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
  • R 2 is H, CNR 24 NR 25 R 26 or a C ⁇ -C 8 alkyl, C 2 -C 6 alkenyl , C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
  • R 3 , R 4 , R s , R 6 , R 7 , R 8 , R 9 , R 28 and R 29 are each independently H or an optionally substituted C.- C 6 alkyl group ;
  • R 10 is an optionally substituted C x -C 6 alkyl, aryl or heteroaryl group;
  • n and p are each independently 0 or an integer of 1 or 2 ;
  • R X1 is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 cycloalkyl, cyclo
  • R 14 is H, COR 27 or a C.,-C 6 alkyl , C 2 -C 6 alkenyl , C 2 -
  • R 15 and R 27 are each independently H or a C 1 -C 6 alkyl , C 2 -C 6 alkenyl , C 2 -C 6 alkynyl , C 3 -C 6 cycloalkyl , cycloheteroalkyl , aryl or heteroaryl group each optionally substituted;
  • R 16 , R 17 / R ⁇ s r R 19 , R 20 , R 24 / R 2S and R 26 are each independently H or ah optionally substituted C x - C 6 alkyl group;
  • R 21 and R 22 are each independently H or a C 1 -C 5 alkyl, aryl or heteroaryl group each optionally substituted;
  • R 23 is an optionally substituted C j -C j alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
  • halogen designates Br, Cl, I or F
  • cycloheteroalkyl designates a C 5 -C 7 cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond.
  • exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein X x is
  • NR, 0 or S and R is H or an optional substituent as defined hereinbelow.
  • heteroaryl designates a 5- to 10-membered aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, 0 or S.
  • heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, iso uinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like.
  • haloalkyl designates a C n H 2n+1 group having from one to 2n+l halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OC n H 2n+1 group having from one to 2n+l halogen atoms which may be the same or different.
  • substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkyla ino, formyl, alkoxycarbonyl , carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl (e.g.
  • heteroaryl and cycloheteroalkyl) or cycloalkyl groups preferably halogen atoms or lower alkyl groups.
  • 0-3 substituents may be present .
  • any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12 , preferably up to 6, more preferably up to 4 carbon atoms.
  • Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
  • a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
  • Stereoisomers of the invention may exist as one or more stereoisomers .
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric iso ers.
  • one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other steroisomer (s) or when separated from the other stereoisomer (s) .
  • the skilled artisan knows how to separate, enrich, or selectively prepare said stereoisomers.
  • the present invention comprises compounds of Formula I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form.
  • Preferred compounds of the invention are those compounds of formula I wherein W is S0 2 or CO. Also preferred are those compounds of formula I wherein X is
  • Another group of preferred compounds of the invention are those compounds of formula I wherein Y is CR 12 .
  • Further preferred compounds of the invention are those compounds of formula I wherein R 10 is an aryl or heteroaryl group each optionally substituted.
  • Q is an optionally substituted 3-pyrrolidinyl group.
  • Z may be for example N.
  • R 10 are aryl e.g. phenyl or naphthyl, or heteroaryl e.g. ,pyrazolyl (such as pyrazol-4-yl) thienyl (such as thien-2-yl) or guinolyl (such as guinolin-8-yl) ; said aryl and heteroaryl groups being unsubstituted or optionally substituted by one or more (e.g., 1 to 3) substituents the same or different as described herein.
  • aryl and heteroaryl groups being unsubstituted or optionally substituted by one or more (e.g., 1 to 3) substituents the same or different as described herein.
  • substituents include halo, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl of 1-6 carbon atoms, halo (C ⁇ C g ) alkyl, (C ⁇ -C 8 ) alkoxy, halo (C j -C alkoxy, amino, (C,-C 6 )alkylamino, di- (C 1 -C 6 alkyl)amino, formyl, (C 1 -
  • More preferred compounds of the invention are those compounds of formula I wherein W is S0 2 ; X is 0; and R 10 is an aryl or heteroaryl group each optionally substituted.
  • Another group of more preferred compounds of the invention are those compounds of formula I wherein W is
  • This invention also provides a process for the preparation of a compound of formula I which comprises one of the following:
  • R 10 -W- where R 10 is as defined above and W is S0 2 , CO, CONH, CSNH or (CH 2 ) x ; said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, to give a corresponding compound of formula (I) ; or b) removing a protecting group from a compound of formula (C) :
  • compounds of formula I wherein W is S0 2 ; X is 0; Y is CR 12 ; Z is CR 13 ; Q is an optionally substituted 3- pyrrolidinyl group; and R 2 is H (la) may be prepared by reacting an hydroxyindole of formula II with a protected 3-hydroxypyrrolidine of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the pyrrolidinyloxyindole of formula IV. Sulfonylation followed by deprotection gives the desired compound of formula la. The reaction is shown in flow diagram I wherein P is a protecting group.
  • Commonly used protecting groups include t-butyl- carboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.
  • Compounds of formula I wherein W is S0 2 ; X is 0; Y is CH; Z is N; and Q is optionally substituted 3- pyrrolidinyl group (lb) may be prepared by reacting a nitromethylphenol of formula VI with a protected 3- hydroxypyrrolidine of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the corresponding pyrrolidinyloxybenzene of formula VII, reducing the nitro group, for example via catalytic hydrogenation, to give the amine of formula VIII, reacting the formula VIII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the pyrrolidinyl-oxyindazole of formula IX.
  • Compounds of formula I wherein W is S0 2 ; X is NR lx ; Y is CH; Z is N; and Q is an optionally substituted 3- pyrrolidinyl group (Id) may be prepared by reacting the nitromethylphenol compound of formula VI with trifluoromethanesulfonic anhydride in the presence of a base to give the compound of formula XIV, coupling the formula XIV compound with a protected 3-aminopyrrolidine compound of formula XV in the presence of a palladium catalyst to give the pyrrolidinylaminobenzene of formula XVI, reducing the nitro group to give the amine of formula XVII and reacting the formula XVII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the pyrrolidinylaminoindazole of formula XVIII.
  • Corresponding compounds of formula I wherein Q is an optionally substituted 3- or 4-piperidinyl group may be prepared by utilizing the reaction sequences described hereinabove and illustrated in flow diagrams I, II, III and IV and by employing the appropriate protected piperidinylhydroxy, piperidinone or piperidinylamine, respectively, in place of the corresponding pyrrolidinyl starting materials of formulas III, XII or XV.
  • Compounds of formula I wherein W is CO may be prepared by reacting the benzazole precursor, for example a compound of formula IV, IX, XIII or XVIII, with the appropriate isocyanate, carbonyl halide or carbamoyl halide in the presence of a base.
  • compounds of formula I wherein W is (CH 2 ) X and x is an integer of 1, 2 or 3 may be prepared by reacting the appropriately substituted alkylhalide with a compound of formula IV, IX, XIII or XVIII in the presence of a base.
  • the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders, for example, Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, migraine, sleep disorders, feeding disorders (such as anorexia or bulimia) , schizophrenia, memory loss, disorders associated with withdrawl from drug abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome.
  • the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove.
  • the compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof .
  • Providing as used herein with respect to providing a compound or substance covered by the invention, means either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.
  • the therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition (s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like.
  • effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
  • the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients .
  • the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove .
  • Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials.
  • the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I.
  • the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound.
  • Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention.
  • Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof.
  • Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo- regulators, or the like.
  • liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil) .
  • the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
  • compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously.
  • Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
  • the resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane 2/8 to give the protected pyrrolidinyloxy intermediate as an off-white foam, 0.50 g, mp 48-50°C, identified by NMR and mass spectral analyses .
  • HT6 receptor is evaluated in the following manner.
  • Cultured Hela cells expressing human cloned 5-HT6 receptors are harvested and centrifuged at low speed (1,000 x g) for 10.0 min to remove the culture media.
  • the harvested cells are suspended in half volume of fresh physiological phosphate buffered saline solution and recentrifuged at the same speed. This operation is repeated.
  • the collected cells are then homogenized in ten volumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA.
  • the homogenate is centrifuged at 40,000 x g for 30.0 min and the precipitate is collected.
  • the obtained pellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifuged at the same speed.
  • the final pellet is suspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 ⁇ l volumes.
  • Bovine Serum Albumin is used as the standard in the protein determination according to the method described in Lowry et al . , J. Biol . Chem. , 193:265 (1951) .
  • the volume of the suspended cell membranes is adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension.
  • the prepared membrane suspension is adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension.
  • Binding experiments are performed in a 96 well microtiter plate format, in a total volume of 200 ⁇ l. To each well is added the following mixture: 80.0 ⁇ l of incubation buffer made in 50 mM Tris.HCl buffer (pH 7.4) containing 10.0 mM MgCl 2 and 0.5 mM EDTA and 20 ⁇ l of [ 3 H] -LSD (S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM.
  • the dissociation constant, K D of the [ 3 H]LSD at the human serotonin 5-HT6 receptor is 2.9 nM, as determined by saturation binding with increasing concentrations of [ 3 H]LSD.
  • the reaction is initiated by the final addition of 100.0 ⁇ l of tissue suspension. Nonspecific binding is measured in the presence of 10.0 ⁇ M methiothepin.
  • the test compounds are added in 20.0 ⁇ l volume.
  • the reaction is allowed to proceed in the dark for 120 min at room temperature, at which time, the bound ligand-receptor complex is filtered off on a 96 well unifilter with a Packard Filtermate () 196 Harvester.
  • the bound complex caught on the filter disk is allowed to air dry and the radioactivity is measured in a Packard
  • TopCount ® equipped with six photomultiplier detectors, after the addition of 40.0 ⁇ l Microscint (5)-20 scintillant to each shallow well.
  • the unifilter plate is heat-sealed and counted a PackardTopCount with a tritium efficiency of 31.0%.
  • Specific binding to the 5-HT6 receptor is defined as the total radioactivity bound less the amount bound in the presence of lO.O ⁇ M unlabeled methiothepin. Binding in the presence of varying concentrations of test compound is expressed as a percentage of specific binding in the absence of test compound. The results are plotted as log % bound versus log concentration of test compound.
  • Nonlinear regression analysis of data points with a computer assisted program Prism ® yielded both the IC 50 and the K ⁇ values of test compounds with 95% confidence limits.
  • a linear regression line of data points is plotted, from which the IC 50 value is determined and the K. value is determined based upon the following equation: where L is the concentration of the radioactive ligand used and K D is the dissociation constant of the ligand for the receptor, both expressed in nM.
  • Ki values are determined and compared to those values obtained by representative compounds known to demonstrate binding to the 5-HT6 receptor.
  • the data are shown in Table III, below.
  • the compounds of the present invention have a high degree of affinity for the 5-HT6 receptor.

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Abstract

The present invention provides a compound of formula (I) and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.

Description

HETEROCYCLYLOXY- , -THIOXY- AND -AMINOBENZAZO E DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS
This invention relates to heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands, to processes for preparing them, to methods of using them and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5- hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A) , the 5-HT2 family (e.g. 5-HT2A) , 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes .
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor RNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CAl, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HTβ receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia and bulimia) , panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines) , schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor. It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow. SUMMARY OF THE INVENTION
The present invention provides compounds of formula
Figure imgf000004_0001
(D
wherein
W is S02, CO, CONH, CSNH or (CH2)X; X is 0, SOn or NRU; Y is CR12 or N; Z is CR13 or N with the proviso that when Y is N then Z must be CR13; m and x are each independently 0 or an integer of 1, 2 or 3 ;
Figure imgf000004_0002
Rx is halogen, CN, 0R14, C02R15, C0NR1SR17, CNR18NR19R20 , S02NR21R22, SOpR23 or a C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; R2 is H, CNR24NR25R26 or a C^-C^lkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R3/ RΛ, R5, R6, R7, R8, R9, R2S and R29 are each independently H or an optionally substituted C- C6alkyl group; R10 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2; Rlλ is H or a C1-C6alkyl/ C2-C6alkenyl, C2-C6alkynyl , C3 C6cycloalkyl or cycloheteroalkyl group each optionally substituted; R12 and R13 are each independently H, halogen or a C,- C6alkyl, aryl, heteroaryl or C,-C6alkoxy group each optionally substituted;
Ru is H, COR27 or a C^^alkyl, C2-C6alkenyl, C2- C6alkynyl, aryl or heteroaryl group each optionally substituted; R15 and R27 are each independently H or a C^Cgalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R16, R17, R18, R19, R20, R2i, R2S and R26 are each independently H or an optionally substituted Cj- C6alkyl group;
R21 and R22 are each independently H or a Cj-C8alkyl, aryl or heteroaryl group each optionally substituted; and R23 is an optionally substituted C1-C6alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor. DETAILED DESCRIPTION OF THE INVENTION
The 5-hydroxytryptamine-6 (5-HTβ) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HTβ receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that heterocyclyloxy-, -thioxy- or -a inobenzazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said benzazole derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides heterocyclyloxy-, -thioxy- or -aminobenzazole derivatives of formula I
Figure imgf000006_0001
(D wherein W is S02, CO, CONH, CSNH or (CH2)X;
X is 0, SO or NR..;
Y is CR12 or N;
Z is CR13 or N with the proviso that when Y is N then
Z must be CR13; m and x are each independently 0 or an integer of 1,
2 or 3;
Figure imgf000007_0001
Rx is halogen, CN, 0RM, C02R15, CONR16R17, CNR18NR19R20 , S02NR21R22, SOpR23 or a Cα-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
R2 is H, CNR24NR25R26 or a C^-C8alkyl, C2-C6alkenyl , C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R3, R4, Rs, R6, R7, R8, R9, R28 and R29 are each independently H or an optionally substituted C.- C6alkyl group ; R10 is an optionally substituted Cx-C6alkyl, aryl or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2 ; RX1 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R12 and R13 are each independently H, halogen or a Cx-
C6alkyl, aryl, heteroaryl or C^C^lko y group each optionally substituted; R14 is H, COR27 or a C.,-C6alkyl , C2-C6alkenyl , C2-
C6alkynyl , aryl or heteroaryl group each optionally substituted; R15 and R27 are each independently H or a C1-C6alkyl , C2-C6alkenyl , C2-C6alkynyl , C3-C6cycloalkyl , cycloheteroalkyl , aryl or heteroaryl group each optionally substituted;
R16 , R17 / Rιs r R19 , R20 , R24 / R2S and R26 are each independently H or ah optionally substituted Cx- C6alkyl group;
R21 and R22 are each independently H or a C1-C5alkyl, aryl or heteroaryl group each optionally substituted; and
R23 is an optionally substituted Cj-Cjalkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term cycloheteroalkyl designates a C5-C7cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein Xx is
NR, 0 or S and R is H or an optional substituent as defined hereinbelow.
Figure imgf000008_0001
Similarly, as used in the specification and claims, the term heteroaryl designates a 5- to 10-membered aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, 0 or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, iso uinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. The term haloalkyl as used herein designates a CnH2n+1 group having from one to 2n+l halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OCnH2n+1 group having from one to 2n+l halogen atoms which may be the same or different.
In the specification and claims, when the terms C^C^lkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkyla ino, formyl, alkoxycarbonyl , carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl (e.g. heteroaryl and cycloheteroalkyl) or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, 0-3 substituents may be present . When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12 , preferably up to 6, more preferably up to 4 carbon atoms. Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Compounds of the invention may exist as one or more stereoisomers . The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric iso ers. One skilled in the art will appreciate that one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other steroisomer (s) or when separated from the other stereoisomer (s) . Additionally, the skilled artisan knows how to separate, enrich, or selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds of Formula I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form.
Preferred compounds of the invention are those compounds of formula I wherein W is S02 or CO. Also preferred are those compounds of formula I wherein X is
0. Another group of preferred compounds of the invention are those compounds of formula I wherein Y is CR12. Further preferred compounds of the invention are those compounds of formula I wherein R10 is an aryl or heteroaryl group each optionally substituted. Preferably Q is an optionally substituted 3-pyrrolidinyl group. Z may be for example N.
Examples of R10 are aryl e.g. phenyl or naphthyl, or heteroaryl e.g. ,pyrazolyl (such as pyrazol-4-yl) thienyl (such as thien-2-yl) or guinolyl (such as guinolin-8-yl) ; said aryl and heteroaryl groups being unsubstituted or optionally substituted by one or more (e.g., 1 to 3) substituents the same or different as described herein.
Such substituents include halo, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl of 1-6 carbon atoms, halo (C^Cg) alkyl, (C^-C8) alkoxy, halo (Cj-C alkoxy, amino, (C,-C6)alkylamino, di- (C1-C6alkyl)amino, formyl, (C1-
C6alkoxy) carbonyl, carboxyl, (C.,-C6) alkanoyl, (Cx-
C6)alkylthio, (C^C alkylsuphinyl, (Cj-C8) alkyl-sulphonyl, carbamoyl, (C.,-C6) alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl and cycloheteroalkyl or (C3-
C8) cycloalkyl groups .
More preferred compounds of the invention are those compounds of formula I wherein W is S02; X is 0; and R10 is an aryl or heteroaryl group each optionally substituted.
Another group of more preferred compounds of the invention are those compounds of formula I wherein W is
S02; X is 0; Y is CR12; and Q is a 3-pyrrolidinyl group. Among the preferred compounds of the invention are: 1- (phenylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indole;
4- (3-pyrrolidinyloxy) 1- { thien-2-ylsulfonyl) -lH-indole;
4-{ [4- (3-pyrrolidinyloxy) -lH-indol-1-yl] sulfonyl}aniline;
1- (1-naphthylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indole;
1- [ (5-chloro-l, 3-dimethyl-lH-pyrazol-4-yl) sulfonyl] -4- (3- pyrrolidinyloxy) -lH-indole;
1- (phenylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indazole;
1- (1-naphthylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indazole;
1- [ (2-chlorophenyl) sulfonyl] -4- (3-pyrrolidinyloxy) -1H- indazole; 1- [ (2-fluorophenyl) sulfonyl] -4- (3-pyrrolidinyloxy) -1H- indazole;
1- [3, 4-dimethoxyphenyl) sulfonyl] -4- (3-pyrrolidinyloxy) - lH-indazole;
1- [ (5-chlorothien-2-yl) sulfonyl] -4- (3-pyrrolidinyloxy) - lH-indazole; N- (2-chloro-4-{ [4- (3-pyrrolidinyloxy) -lH-indazol-1- yl] sulfonyl}phenyl) acetamide; N- (4-{ [4- (3-pyrrolidinyloxy) -lH-indazol- ly} (sulfonyl]phenyl) acetamide; 8-{ [4- (3-pyrrolidinyloxy) -lH-indazol-1- yl] sulfonyl}guinoline; 1- (1-naphthylsulfonyl) -4- (piperidin-4-yloxy) -lH-indazole; 1- (1-naphthylsulfonyl) -4- (piperidin-3-yloxy) -lH-indazole; 1- [ (5-chlorothien-2-yl) sulfonyl] -4- (piperidin-4-yloxy) - lH-indazole;
1- [ (5-chlorothien-2-yl) sulfonyl] -4- (piperidin-3-yloxy) - lH-indazole; 1- (phenylsulfonyl) -4- (piperidin-3-yloxy) -lH-indole; 4-{ [4- (piperidin-3-yloxy) -lH-indol-1-yl] sulfonyl}aniline; 1- (1-naphthylsulfonyl) -4- (piperidin-3-yloxy) -lH-indole; 1- (phenylsulfonyl) -4- (piperidin-4-yloxy) -lH-indole; 4-{ [4- (piperidin-4-yloxy) -lH-indol-1-yl] sulfonyl}aniline; 1- (1-naphthylsulfonyl) -4- (piperidin-4-yloxy) -lH-indole; 1- (phenylsulfonyl) -5- (pyrrolidin-3-yloxy) -lH-indole; 1- (phenylsulfonyl) -6- (pyrrolidin-3-yloxy) -lH-indole;
1- (phenylsulfonyl) -6- (pyrrolidin-3-yloxy) -lH-indazole; 1- (phenylsulfonyl) -5- (pyrrolidin-3-yloxy) -lH-indazole; or the stereoisomers thereof or pharmaceutically acceptable salts thereof . This invention also provides a process for the preparation of a compound of formula I which comprises one of the following:
a) reacting a compound of formula (B)
Figure imgf000012_0001
(B) wherein , Q, X, Y, Z and R1 are as defined herein, with an appropriate sulphonylating, acylating, carbamoylating, thiocarbamoylating, arylating or alkylating agent containing the group:
R10-W- where R10 is as defined above and W is S02, CO, CONH, CSNH or (CH2)x ; said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, to give a corresponding compound of formula (I) ; or b) removing a protecting group from a compound of formula (C) :
Figure imgf000013_0001
(C)
wherein m, W, X, Y, Z , Rx and R10 are as defined herein and
Figure imgf000013_0002
where P is a protecting group to give a corresponding compound of formula (I) wherein R2 is H; or c) alkylating a compound of formula (I) as defined herein wherein R2 is hydrogen with an alkylating agent of formula R2-L wherein L is a leaving group, such as halogen, and R2 is as defined herein excepting hydrogen to give a corresponding compound of formula (I) ; or d) converting a compound of formula (I) having a reactive substituent group to a different compound of formula I; or e) converting a basic compound of formula (I) to an acid addition salt or vice versa. Compounds of the invention may be conveniently prepared using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I wherein W is S02; X is 0; Y is CR12; Z is CR13; Q is an optionally substituted 3- pyrrolidinyl group; and R2 is H (la) may be prepared by reacting an hydroxyindole of formula II with a protected 3-hydroxypyrrolidine of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the pyrrolidinyloxyindole of formula IV. Sulfonylation followed by deprotection gives the desired compound of formula la. The reaction is shown in flow diagram I wherein P is a protecting group.
Flow Diagram I
Figure imgf000015_0001
a) base b) R10SO2Cl
Figure imgf000015_0002
da) (V)
Commonly used protecting groups include t-butyl- carboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.
Compounds of formula I wherein W is S02; X is 0; Y is CH; Z is N; and Q is optionally substituted 3- pyrrolidinyl group (lb) may be prepared by reacting a nitromethylphenol of formula VI with a protected 3- hydroxypyrrolidine of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the corresponding pyrrolidinyloxybenzene of formula VII, reducing the nitro group, for example via catalytic hydrogenation, to give the amine of formula VIII, reacting the formula VIII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the pyrrolidinyl-oxyindazole of formula IX. Sulfonylation and deprotection of said formula IX compound gives the desired compound of formula lb. Subsequent reaction of the formula lb compound with a suitable alkylating reagent such as an alkyl or aryl halide, R2-Hal, gives those compounds of formula lb' wherein R2 is other than H. The reaction sequence is shown in flow diagram II wherein P is a protecting group and Hal is Cl, Br or I .
Flow Diagram II
Figure imgf000017_0001
[H]
Figure imgf000017_0002
la) base lb) R10SO2Cl
2) deprotection
Figure imgf000017_0003
(lb) (lb1) Similarly, compounds of formula I wherein X is S and W is S02 may be prepared by employing the appropriate indolylthiol or thiophenol and utilizing the reactions shown in flow diagrams I and II, respectively. Oxidation of the thus-formed heterocyclylthiobenzazole derivatives of formula I gives those compounds of formula I wherein X is S0n and n is 1 or 2.
Compounds of formula I wherein W is S02; X is NH; Y is CR12; Z is CR13; Q is an optionally substituted 3- pyrrolidinyl group; and R2 and R5 are H(Ic) may be prepared by hydrogenating a nitroindole of formula X to give the corresponding aminoindole of formula XI and reacting the formula XI aminoindole with a protected 3- pyrrolidinone of formula XII to give the protected pyrrolidinyla inoindole of formula XIII. Subsequent sulfonylation and deprotection afford the desired compound of formula Ic . The reaction sequence is shown in flow diagram III.
Flow Diagram III
Figure imgf000019_0001
(X) (XI)
Figure imgf000019_0002
Compounds of formula I wherein W is S02; X is NRlx; Y is CH; Z is N; and Q is an optionally substituted 3- pyrrolidinyl group (Id) may be prepared by reacting the nitromethylphenol compound of formula VI with trifluoromethanesulfonic anhydride in the presence of a base to give the compound of formula XIV, coupling the formula XIV compound with a protected 3-aminopyrrolidine compound of formula XV in the presence of a palladium catalyst to give the pyrrolidinylaminobenzene of formula XVI, reducing the nitro group to give the amine of formula XVII and reacting the formula XVII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the pyrrolidinylaminoindazole of formula XVIII. Subsequent sulfonylation and deprotection as described hereinabove give the desired compound of formula Id. The reaction sequence is shown in flow diagram IV wherein Tf designates a trifluoromethane- sulfonyl group.
Flow Diagram IV
Figure imgf000020_0001
(VI) (XIV)
Figure imgf000020_0002
(XVII) (XVI)
Figure imgf000020_0003
(XVIII) (Id) Corresponding compounds of formula I wherein Q is an optionally substituted 3- or 4-piperidinyl group may be prepared by utilizing the reaction sequences described hereinabove and illustrated in flow diagrams I, II, III and IV and by employing the appropriate protected piperidinylhydroxy, piperidinone or piperidinylamine, respectively, in place of the corresponding pyrrolidinyl starting materials of formulas III, XII or XV. Compounds of formula I wherein W is CO may be prepared by reacting the benzazole precursor, for example a compound of formula IV, IX, XIII or XVIII, with the appropriate isocyanate, carbonyl halide or carbamoyl halide in the presence of a base. Similarly, compounds of formula I wherein W is (CH2)X and x is an integer of 1, 2 or 3 may be prepared by reacting the appropriately substituted alkylhalide with a compound of formula IV, IX, XIII or XVIII in the presence of a base. Compounds of formula I wherein W is (CH2)X and x is 0 may be prepared via a palladium-catalyzed N-arylation such as that described by D. W. Old et al . , Organic Letters, 2000 (2), pp 1403-1406. Using these and other conventional methods, compounds of formula I may be prepared from readily available starting materials. Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders, for example, Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, migraine, sleep disorders, feeding disorders (such as anorexia or bulimia) , schizophrenia, memory loss, disorders associated with withdrawl from drug abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof .
"Providing" as used herein with respect to providing a compound or substance covered by the invention, means either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition (s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients . Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove .
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo- regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil) . For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way. Unless otherwise stated, all parts are parts by weight. The terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively. The terms THF and EtOAc designate tetrahydrofuran and ethyl acetate, respectively.
EXAMPLE 1
Preparation o£ t-Butyl 3-Hydro v-l-pyrrolidine- carboxylate
Figure imgf000025_0001
A stirred solution of 3-pyrrolidinol (5.0 g 57 mol) and potassium carbonate (8.23 g, 60 mmol) in a mixture of THF/H20 is treated with a solution of di-fc-butyl dicarbonate (12.5 g, 57 mmol) in THF over a 15 minute period at room temperature, stirred for 20 h at room temperature and diluted with EtOAc . The organic phase is separated, washed with H20, dried over Na2S04 and concentrated in vacuo . The resultant residue is dissolved in EtOAc/hexane and filtered through a thin layer of silica gel. The silica gel layer is washed with EtOAc. The combined filtrates are concentrated in vacuo to give the title product as a white solid, 8.5 g, mp 52- 54°C, identified by NMR and mass spectral analyses.
EXAMPLE 2
Preparation of t-Butyl 3- (lH-Indol-4-yloxy) -1- pyrrolidinecarboxylate
Figure imgf000025_0002
A solution of 4-hydroxyindole (2 . 66 g, 20. 0 mmol ) , t-butyl 3-hydroxy-l-pyrrolidinecarboxylate ( 7 .5 g, 40 . 0 mmol) and triphenylphosphine (φ3P) (10.5 g 40.0 mmol) in THF is treated with diethyl azodicarboxylate (DEAC) (6.3 ml, 40.0 mmol) under nitrogen at room temperature, stirred for 2 h at room temperature and concentrated in vacuo . The resultant residue is stirred under ether, cooled and filtered. The filtercake is washed with cold ether. The filtrates are combined and concentrated in vacuo . The residue is purified by flash chromatography (silica gel, EtOAc/hexane: 2/80) to give the title compound as a white solid, 3.98 g, mp 164-165°C, identified by NMR and mass spectral analyses.
EXAMPLE 3
Preparation of 1- (Phenylsulfonyl) -4- (3-pyrrolidinyloacy) - lH-indole Hydrochloride
Figure imgf000026_0001
A stirred solution of t-butyl 3- (lH-indol-4-yloxy) - 1-pyrrolidinecarboxylate (0.605 g 2.0 mmol) in THF is treated with sodium hydride (0.12 g, 60% in mineral oil, 3.0 mmol) under nitrogen at room temperature. After 30 minutes, benzenesulfonyl chloride (0.38 ml, 3.0 mmol) is added and the reaction mixture is stirred at room temperature for 48 h, quenched with ice-water and diluted with EtOAc. The organic phase is separated, washed sequentially with H20 and brine, dried over MgS04 and concentrated in vacuo . The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane 2/8 to give the protected pyrrolidinyloxy intermediate as an off-white foam, 0.50 g, mp 48-50°C, identified by NMR and mass spectral analyses .
A solution of thus-obtained t-butyl 3-{ [1- (phenylsulfonyl) -lH-indol-4-yl] oxy}-l- pyrrolidmecarboxylate (0.41 g, 0.93 mmol) in methanol and HC1 (5.0 ml, 1M in ether) is heated at 60°C under nitrogen for 2 h and concentrated in vacuo . The residue is treated with ethyl acetate and filtered. The filtercake is dried under vacuum to give the title product as an off white solid, 0.301 g, mp 200-201°C, identified by NMR and mass spectral analyses.
EXAMPLES 4-9
Preparation of 1- (Aryl sul fonyl) -4- O-pyrro idinyloa y) -1H- indole Hydrochloride
Figure imgf000027_0001
Using essentially the same procedures described hereinabove for Examples 2 and 3 and employing the appropriate protected pyrrolidinol or piperidinol (Q and arylsulfonyl chloride, the compounds shown in Table I are obtained and identified by NMR and mass spectral analyses. Table I
Figure imgf000028_0001
Ex. p No . RIO °C M+H
3 -pyrrol idinyl thiophene-2-yl 158-160 342
3 -pyrrol idinyl 4-aminophenyl 140 (dec) 359
3-pyrrolidinyl 1-naphthyl 179 (dec) 393
3-pyrrolidinyl 5-chloro-l, 3- 100 (dec) 395 dimethyl-lH-pyrazol- 4-yl 4-piperidinyl 4-aminophenyl 117-119 372
3-piperidinyl 4-aminophenyl 160 (dec) 372
EXAMPLE 10
Preparation of t-Butyl 3- (2-Methyl-3-nitrophenoxy) - pyrrolidin-l-carboxylate 0
Figure imgf000028_0002
A stirred solution of 3-nitro-2-methylphenol (7.6 g, 49.7 mmol), t-butyl 3-hydroxypyrrolidin-l-carboxylate (9.3 g, 49.7 mmol) and triphenylphosphine (13.0 g, 49.7 mmol) in THF is treated with diethyl azodicarboxylate (8.7 g, 49.7 mmol), stirred at room temperature for 3 h and concentrated in vacuo . The resultant residue is mixed with ethyl acetate and filtered. The filtrate is concentrated in vacuo to give a residue, which is purified by chromatography (Si02, 25% EtOAc in hexanes) to afford the title compound as an off-white solid, 11.7 g (73%) identified by NMR and mass spectral analyses.
EXAMPLE 11
Preparation of t-Butyl 3- (3-Amino-2-methylphenoxy) - pyrrolidin-1-σarboκylate
Figure imgf000029_0001
A mixture of t-butyl 3- (2-methyl-3- nitrophenoxy) pyrrolidin-l-carboxylate ( 11 . 0 g, 34 . 2 mmol ) and 10% Pd/C ( 0 . 55 g) in ethanol is hydrogenated (45 psi) at room temperature overnight . After filtering off the catalyst , the filtrate is concentrated to afford the title compound as an off-white solid, 9 . 98 g, mp 137°C , identified by NMR and mass spectral analyses . EXAMPLE 12
Preparation of t-Butyl 3-(lH-Indazol-4-ylo v)pyrrolidin- 1-carboxylate
Figure imgf000030_0001
A solution of t-butyl 3- (3-amino-2- methylphenoxy) pyrrolidin-1-carboxylate (4.6 g, 15.4 mmol), potassium acetate (1.81 g, 18.5 mmol) and acetic anhydride (5.02 g, 49.2 mmol) in benzene is treated dropwise with isoamylnitrite (4.13 ml, 30.8 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The combined filtrates are concentrated to give a yellow oil residue. The residue is purified by chromatography (Si02, 25% EtOAc in hexanes) . The resultant oil is dissolved in ethanol, treated with 40% aqueous NaOH, heated at reflux temperature for 45 min, cooled with an ice-water bath, neutralized to pH 9 with concentrated HCl and concentrated in vacuo . The resulting aqueous mixture is extracted with EtOAc. The combined extracts are washed with water and brine, dried over MgSO^ and concentrated in vacuo to give the title compound as a tan solid, 2.6 g, mp 196-198°C, identified by NMR and mass spectral analyses . EXAMPLE 13
Preparation of t-Butyl 3-{ [ (1-Phenylsulfonyl) -lH-indazol- 4-yl] oxyl} -pyrrolidin-1-carboxylate
Figure imgf000031_0001
A solution of t-butyl 3- (lH-indazol-4- yloxy)pyrrolidin-l-carboxylate (0.303 g, 1.00 mmol) in dimethyl formamide is treated with sodium hydride (80 mg, 2.0 mmol, 60% in mineral oil) at room temperature under nitrogen, stirred for 10 min, treated with benzenesul onyl chloride (0.21 g, 1.20 mmol), stirred for 18 h, quenched with H20 and diluted with ether. The organic phase is washed with H20 and brine, dried over MgS04 and concentrated in vacuo . The residue is purified by chromatography (Si02, 20% EtOAc in hexanes) to afford the title compound as a white solid, 0.42 g, mp 134-135°C, identified by NMR and mass spectral analyses.
EXAMPLE 14
Preparation of 1- (Phenylsulfonyl) -4- (pyrrolidin-3-yloxy) lH-indazole, trifluoroacetic acid salt
Figure imgf000032_0001
A mixture of t-butyl 3-{ [ (1-phenylsulfonyl) -1H- indazol-4-yl] oxy}-pyrrolidin-l-carboxylate (354 mg, 0.80 mmol) and trifluoroacetic acid (3 mL) is prepared at 0°C, stirred at room temperature for 90 min. and concentrated in vacuo . The residue is triturated with ether to afford the title compound as a white solid, 260 mg, mp 168-169°C, identified by NMR and mass spectral analyses.
EXAMPLES 15-22
Preparation of 1- (Arylsulfonyl) -4- (3-pyrrolidinyloxy) -1H- indazole trifluoroacetic acid salt
Figure imgf000032_0002
Using essentially the same procedures described hereinabove for Examples 8-12, and employing the appropriate arylsulfonyl chloride, the compounds shown in Table II are obtained and identified by NMR and mass spectral analyses .
Table II
Figure imgf000033_0001
Ex. mp No. °C
15 1-naphthyl 200- -201
16 2-chlorophenyl 161- -163
17 2-fluorophenyl 162- -163
18 3,4-dimethoxyphenyl 64-70
19 5-chlorothiophene-2-yl 102-103
20 4-acetamido-3-chlorophenyl 68-72
21 4-acetamidophenyl 110-112
22 8-quinolinyl 79 EXAMPLE 23
Comparative Evaluation of 5-HT6 Binding Affinity of Test
Compounds
The affinity of test compounds for the serotonin 5-
HT6 receptor is evaluated in the following manner.
Cultured Hela cells expressing human cloned 5-HT6 receptors are harvested and centrifuged at low speed (1,000 x g) for 10.0 min to remove the culture media. The harvested cells are suspended in half volume of fresh physiological phosphate buffered saline solution and recentrifuged at the same speed. This operation is repeated. The collected cells are then homogenized in ten volumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at 40,000 x g for 30.0 min and the precipitate is collected. The obtained pellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifuged at the same speed. The final pellet is suspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 μl volumes. Bovine Serum Albumin is used as the standard in the protein determination according to the method described in Lowry et al . , J. Biol . Chem. , 193:265 (1951) . The volume of the suspended cell membranes is adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension. The prepared membrane suspension
(10 times concentrated) is aliquoted in 1.0 ml volumes and stored at -70° C until used in subsequent binding experiments.
Binding experiments are performed in a 96 well microtiter plate format, in a total volume of 200 μl. To each well is added the following mixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH 7.4) containing 10.0 mM MgCl2 and 0.5 mM EDTA and 20 μl of [3H] -LSD (S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. The dissociation constant, KD of the [3H]LSD at the human serotonin 5-HT6 receptor is 2.9 nM, as determined by saturation binding with increasing concentrations of [3H]LSD. The reaction is initiated by the final addition of 100.0 μl of tissue suspension. Nonspecific binding is measured in the presence of 10.0 μM methiothepin. The test compounds are added in 20.0 μl volume. The reaction is allowed to proceed in the dark for 120 min at room temperature, at which time, the bound ligand-receptor complex is filtered off on a 96 well unifilter with a Packard Filtermate () 196 Harvester. The bound complex caught on the filter disk is allowed to air dry and the radioactivity is measured in a Packard
TopCount® equipped with six photomultiplier detectors, after the addition of 40.0μl Microscint (5)-20 scintillant to each shallow well. The unifilter plate is heat-sealed and counted a PackardTopCount with a tritium efficiency of 31.0%.
Specific binding to the 5-HT6 receptor is defined as the total radioactivity bound less the amount bound in the presence of lO.OμM unlabeled methiothepin. Binding in the presence of varying concentrations of test compound is expressed as a percentage of specific binding in the absence of test compound. The results are plotted as log % bound versus log concentration of test compound. Nonlinear regression analysis of data points with a computer assisted program Prism® yielded both the IC50 and the K± values of test compounds with 95% confidence limits. A linear regression line of data points is plotted, from which the IC50 value is determined and the K. value is determined based upon the following equation:
Figure imgf000035_0001
where L is the concentration of the radioactive ligand used and KD is the dissociation constant of the ligand for the receptor, both expressed in nM.
Using this assay, the following Ki values are determined and compared to those values obtained by representative compounds known to demonstrate binding to the 5-HT6 receptor. The data are shown in Table III, below.
Table III
Test Compound 5-HT6 Binding Ki
(Ex. No.) (nM)
3 8.0
4 25.0
5 5.0
6 13.0
7 --
8 3.0
9 11.0
14 19.0
15 3.0
16 19.0
17 25.0
18 75.0
19 9.0
20 12.0
21 124.0
22 22.0
5-HT6 Binding Ki
Comparative Examples (nM)
Clozapine 6.0
Loxapine 41.4
Bromocriptine 23.0
Methiothepin 8.3
Mianserin 44.2
Olanzepine 19.5 As can be seen from the results set forth above, the compounds of the present invention have a high degree of affinity for the 5-HT6 receptor.

Claims

WHAT IS CLAIMED IS:
A compound of formula I
Figure imgf000038_0001
(D
wherein
W is S02, CO, CONH, CSNH or (CH2)X;
X is 0, SOn or NR1X; Y is CR12 or N;
Z is CR13 or N with the proviso that when Y is N then
Z must be CR13; m and x are each independently 0 or an integer of 1,
2 or 3;
Figure imgf000038_0002
R± is halogen, CN, ORw, C02R15, CONR16R17, CNR18NR19R20 , S02NR21R22, SOpR23 or a C^-C8alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; R2 is H, CNR24NR25R26 or a C^Cgalkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R3, R4, R5, R6, R_, R8, R9, R28 and R2g are each independently H or an optionally substituted C - C6alkyl group; R10 is an optionally substituted C.,-C6alkyl, aryl or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2; Rxl is H or a C.,-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R12 and R13 are each independently H, halogen or a Cα- C6alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted; R14 is H, COR27 or a C^C^lkyl, C2-C6alkenyl, C2- C6alkynyl, aryl or heteroaryl group each optionally substituted; R15 and R27 are each independently H or a C.,-C6alkyl, C2-C6alkenyl , C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R16, R17, R18, Rw, R20, R2i, R25 and R26 are each independently H or an optionally substituted Cj-C^lkyl group; R21 and R22 are each independently H or a C.,-C6alkyl, aryl or heteroaryl group each optionally substituted; and R23 is an optionally substituted C1-C6alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 wherein W is S02.
3. The compound according to claim 1 or claim 2 wherein X is 0.
4. The compound according to any one of claims 1 to 3 wherein Q is an optionally substituted 3- pyrrolidinyl group.
5. The compound according to any one of claims 1 to 3 wherein R10 is an optionally substituted aryl or heteroaryl group.
6. The compound according to any one of claims 1 to 5 wherein Y is CR12.
7. The compound according to any one of claims 1 to 6 wherein Z is N.
8. The compound according to claim 1 selected from the group consisting of: 1- (phenylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indole;
4- (3-pyrrolidinyloxy) 1- (thien-2-ylsulfonyl) -lH-indole; 4-{ [4- (3-pyrrolidinyloxy) -lH-indol-1-yl] sulfonyl}aniline; 1- (1-naphthylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indole; 1- [ (5-chloro-l, 3-dimethyl-lH-pyrazol-4-yl) sulfonyl] -4- (3- pyrrolidinyloxy) -lH-indole;
1- (phenylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indazole; 1- (1-naphthylsulfonyl) -4- (3-pyrrolidinyloxy) -lH-indazole; 1- [ (2-chlorophenyl) sulfonyl] -4- (3-pyrrolidinyloxy) -1H- indazole; 1- [ (2-fluorophenyl) sulfonyl] -4- (3-pyrrolidinyloxy) -1H- indazole; 1- [3 , 4-dimethoxyphenyl) sulfonyl] -4- (3-pyrrolidinyloxy) - lH-indazole; 1- [ (5-chlorothien-2-yl) sulfonyl] -4- (3-pyrrolidinyloxy) - lH-indazole; N- (2-chloro-4-{ [4- (3-pyrrolidinyloxy) -lH-indazol-1- yl] sulfonyl}phenyl) acetamide; N- (4-{ [4- (3-pyrrolidinyloxy) -lH-indazol-ly} ] sulfonyl) - phenyl) acetamide; 8-{ [4- (3-pyrrolidinyloxy) -lH-indazol-1-yl] sulfonyl}- quinoline; 1- (1-naphthylsulfonyl) -4- (piperidin-4-yloxy) -lH-indazole; 1- (1-naphthylsulfonyl) -4- (piperidin-3-yloxy) -lH-indazole; 1- [ (5-chlorothien-2-yl) sulfonyl] -4- (piperidin-4-yloxy) - lH-indazole;
1- [ (5-chlorothien-2-yl) sulfonyl] -4- (piperidin-3-yloxy) - lH-indazole; 1- (phenylsulfonyl) -4- (piperidin-3- yloxy) -lH-indole; 4-{ [4- (piperidin-3-yloxy) -lH-indol-1-yl] sulfonyl}aniline; 1- (1-naphthylsulfonyl) -4- (piperidin-3-yloxy) -lH-indole; 1- (phenylsulfonyl) -4- (piperidin-4-yloxy) -lH-indole; 4-{ [4- (piperidin-4-yloxy) -lH-indol-1-yl] sulfonyl}aniline ; 1- (1-naphthylsulfonyl) -4- (piperidin-4-yloxy) -lH-indole; 1- (phenylsulfonyl) -5- (pyrrolidin-3-yloxy) -lH-indole; 1- (phenylsulfonyl) -6- (pyrrolidin-3-yloxy) -lH-indole;
1- (phenylsulfonyl) -6- (pyrrolidin-3-yloxy) -lH-indazole; 1- (phenylsulfonyl) -5- (pyrrolidin-3-yloxy) -lH-indazole; the stereoisomers thereof; and the pharmaceutically acceptable salts thereof .
9. A method for the treatment of a disorder of the central nervous system related to or affected by the 5- HT6 receptor in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I as claimed in any one of Claims 1 to 8; or a stereoisomer thereof or the pharmaceutically acceptable salts thereof .
10. The method according to claim 9 wherein said disorder is a motor disorder, anxiety disorder or cognitive disorder.
11. The method according to claim 9 wherein said disorder is schizophrenia or depression.
12. The method according to claim 10 wherein said disorder is Alzheimer's disease or Parkinson's disease.
13. The method according to claim 10 wherein said disorder is attention deficit disorder.
14. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I as claimed in any one of Claims 1 to 8; or a stereoisomer thereof or the pharmaceutically acceptable salts thereof .
15. The composition according to claim 14 having a formula I compound wherein X is 0; Q is an optionally substituted 3-pyrrolidinyl group and R10 is an optionally substituted aryl or heteroaryl group.
16. A process for the preparation of a compound of formula I which comprises one of the following:
a) reacting a compound of formula (B)
Figure imgf000043_0001
(B)
wherein , Q, X, Y, Z and Rx are as defined in claim 1, with an appropriate sulphonylating, acylating, carbamoylating, thiocarbamoylating, arylating or alkylating agent containing the group:
R10-W- where R10 is as defined above and W is S02, CO, CONH, CSNH or (CH2)x ; said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, to give a corresponding compound of formula (I) ; or b) removing a protecting group from a compound of formula (C) :
Figure imgf000043_0002
(C)
wherein m, W, X , Y, Z , R.^ and R10 are as defined in claim 1 , and
Figure imgf000043_0003
where P is a protecting group to give a corresponding compound of formula (I) wherein R2 is H; or c) alkylating a compound of formula (I) as defined in claim 1 wherein R2 is hydrogen with an alkylating agent of formula R2-L wherein L is a leaving group, such as halogen, and R2 is as defined in claim 1 excepting hydrogen to give a corresponding compound of formula (I) ; or d) converting a compound of formula (I) having a reactive substituent group to a different compound of formula I; or e) converting a basic compound of formula (I) to an acid addition salt or vice versa.
17. A method for the preparation of a compound of formula Ie
Figure imgf000044_0001
(Ie)
wherein
Figure imgf000044_0002
Y is CR12 or N;
Z is CR13 or N with the proviso that when Y is N then
Z must be CR13; m is 0 or an integer of 1, 2 or 3;
Figure imgf000045_0001
Rj is halogen, CN, OR14, C02R1S, CONR16R17, CNR18NR19R20 , S02NR21R22, SOpR23 or a C^-Cjalkyl, C2-C6alkenyl , C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; R2 is H, CNR24NR25R26 or a C.-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R3, R4, R5, R6, R7, R8, R9, R28 and R29 are each independently H or an optionally substituted C.,- C6alkyl group; R10 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2; R1 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl , C3- C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R12 and R13 are each independently H, halogen or a C^ C6alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted; Ri is H, COR27 or a C.-^alkyl, C2-C6alkenyl, C2-
C6alkynyl, aryl or heteroaryl group each optionally substituted; R15 and R27 are each independently H or a Cj-C8alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R16' R17' ^18' R19' R20' R24 ' R25 ^^ R26 arθ e^-Ch independently H or an optionally substituted Cx- Cβalkyl group; R21 and R22 are each independently H or a ^C^lkyl, aryl or heteroaryl group each optionally substituted; and R23 is an optionally substituted Cj-C8alkyl, aryl, or heteroaryl group which process comprises reacting a compound of formula XIX
Figure imgf000046_0001
(XIX)
wherein X, Y, Z, m and Q are as described hereinabove with a sulfonyl chloride, R10SO2Cl, wherein R10 is as described hereinabove in the presence of a base to give the desired compound of formula Ie .
PCT/US2002/012415 2001-04-20 2002-04-19 Heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands WO2002085892A1 (en)

Priority Applications (10)

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MXPA03009476A MXPA03009476A (en) 2001-04-20 2002-04-19 Heterocyclyloxy-, -thioxy- and -aminobenzazole derivatives as 5-hydroxytryptamine-6 ligands.
EA200301142A EA200301142A1 (en) 2001-04-20 2002-04-19 DERIVATIVES OF HETEROCYCLILOXY-, -TIOOXY-AND-AMINOBENZAZOL AS A LYHANDS OF 5-HYDROXITRIPTAMINE-6
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2005037834A1 (en) * 2003-10-20 2005-04-28 Biovitrum Ab NOVEL TETRAYDROSPIRO{PIPERIDINE-2,7’ -PYRROLO[3,2-b]PYRIDINE DERIVATIVES AND NOVEL INDOLE DERIVATIVES USEFUL IN THE TREATMENT OF 5-HT6 RECEPTOR -RELATED DISORDERS
WO2006038006A2 (en) * 2004-10-07 2006-04-13 Glaxo Group Limited 5-sulfonyl-1-piperidinyl substituted indole derivatives as 5-ht6 receptor antagonists for the treatment of cns disorders
WO2006076243A1 (en) * 2005-01-10 2006-07-20 Arena Pharmaceuticals, Inc. Processes for preparing 4-(phenoxy-5-methyl-pyrimidin-4-yloxy)piperidine-1-carboxylic acid derivatives and related compounds
JP2007523930A (en) * 2004-02-27 2007-08-23 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Piperidine derivatives
WO2007142905A2 (en) * 2006-06-01 2007-12-13 Wyeth 1-sulfonylindazolylamine and -amide derivatives as 5-hydroxytryptamine-6 ligands
WO2009034581A1 (en) * 2007-09-11 2009-03-19 Suven Life Sciences Limited Substituted indolyl compounds and their use as 5-ht6 ligands
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
CN105541693A (en) * 2014-07-08 2016-05-04 广东东阳光药业有限公司 Aromatic heterocyclic derivative and application thereof in medicines
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
CN111233736A (en) * 2020-03-16 2020-06-05 东莞市东阳光新药研发有限公司 Salts of heteroaromatic derivatives and use thereof
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ529631A (en) * 2001-06-07 2006-08-31 F Indole derivatives with 5-hydroxytryptamine (5-HT) 5-HT6 receptor affinity in the treatment of disorders of the CNS
AU2003201149A1 (en) * 2002-02-13 2003-09-04 Koninklijke Philips Electronics N.V. Integrated semiconductor optical device, method and apparatus for manufacturing such a device
DE602005011844D1 (en) * 2004-11-02 2009-01-29 Pfizer SULFONYLBENZIMIDAZOLDERIVATE
BRPI0606502A2 (en) * 2005-01-19 2009-06-30 Hoffmann La Roche compounds; process for the manufacture of compounds; pharmaceutical compositions; method for treating or preventing diseases that are associated with modulation of h3 receptors; method for treating or preventing obesity in a human or animal; method of treating or preventing type ii diabetes in a human or animal and uses of compounds
AU2006280091A1 (en) * 2005-08-15 2007-02-22 Wyeth Substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands
CA2619309A1 (en) * 2005-08-15 2007-03-22 Wyeth Azinyl-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands
MX2008012824A (en) * 2006-04-05 2008-10-15 Wyeth Corp Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands.
WO2007120596A1 (en) * 2006-04-12 2007-10-25 Wyeth DIHYDRO[1,4]DIOXINO[2,3-e]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS
US20090023925A1 (en) * 2007-06-28 2009-01-22 Wyeth N'-(2-halobenzylidene)sulfonylhydrazides as intermediates in the manufacture of arylsulfonylindazoles
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
WO2024032530A1 (en) * 2022-08-11 2024-02-15 江苏恩华药业股份有限公司 Aromatic heterocyclic cyclohexyl aminoalkyl piperidine derivative, preparation method and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050346A2 (en) * 1997-04-18 1998-11-12 Smithkline Beecham Plc Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders
WO1999047516A1 (en) * 1998-03-16 1999-09-23 Abdelmalik Slassi 3-(2-pyrrolidinylmethyl)-indole compounds having 5-ht6 affinity
WO2001002356A1 (en) * 1999-07-01 2001-01-11 Sankyo Company, Limited Indoline or tetrahydroquinoline derivatives

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3835291A1 (en) 1988-04-19 1989-11-02 Bayer Ag 1,3-DISUBSTITUTED PYRROLIDINES
GB9103862D0 (en) * 1991-02-25 1991-04-10 Glaxo Group Ltd Chemical compounds
US5578716A (en) * 1993-12-01 1996-11-26 Mcgill University DNA methyltransferase antisense oligonucleotides
JPH0940646A (en) 1995-07-27 1997-02-10 Yamanouchi Pharmaceut Co Ltd Condensed benzene ring derivative or its salt
WO2001005758A2 (en) * 1999-07-15 2001-01-25 Nps Allelix Corp. Indoles and indazoles for the treatment of migraine
DK1355904T3 (en) * 2000-12-22 2007-10-15 Wyeth Corp Heterocyclindazole and azaindazole Compounds as 5-Hydroxytryptamine-6 Ligands
TW593278B (en) * 2001-01-23 2004-06-21 Wyeth Corp 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
TW200401641A (en) * 2002-07-18 2004-02-01 Wyeth Corp 1-Heterocyclylalkyl-3-sulfonylindole or-indazole derivatives as 5-hydroxytryptamine-6 ligands
RU2347780C2 (en) * 2003-02-14 2009-02-27 Уайт Heterocyclyl-3-sulfonylindazoles as 5-hyroxytryptamine-6 ligands

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050346A2 (en) * 1997-04-18 1998-11-12 Smithkline Beecham Plc Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders
WO1999047516A1 (en) * 1998-03-16 1999-09-23 Abdelmalik Slassi 3-(2-pyrrolidinylmethyl)-indole compounds having 5-ht6 affinity
WO2001002356A1 (en) * 1999-07-01 2001-01-11 Sankyo Company, Limited Indoline or tetrahydroquinoline derivatives

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WO2003104193A1 (en) * 2002-06-05 2003-12-18 F. Hoffmann-La Roche Ag 1-sulfonyl-4-aminoalkoxy indole derivatives as 5-ht6-receptor modulators for the treatment of cns-disorders
US6774241B2 (en) 2002-06-05 2004-08-10 Roche Palo Alto Llc 1-sulfonyl-4-aminoalkoxy indole derivatives and uses thereof
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
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JP2006518385A (en) * 2003-02-14 2006-08-10 ワイス Heterocyclyl-3-sulfonylindazole as 5-hydroxytryptamine-6 ligand
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WO2004074243A3 (en) * 2003-02-14 2004-12-02 Wyeth Corp Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands
WO2005037834A1 (en) * 2003-10-20 2005-04-28 Biovitrum Ab NOVEL TETRAYDROSPIRO{PIPERIDINE-2,7’ -PYRROLO[3,2-b]PYRIDINE DERIVATIVES AND NOVEL INDOLE DERIVATIVES USEFUL IN THE TREATMENT OF 5-HT6 RECEPTOR -RELATED DISORDERS
JP2007523930A (en) * 2004-02-27 2007-08-23 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Piperidine derivatives
WO2006038006A2 (en) * 2004-10-07 2006-04-13 Glaxo Group Limited 5-sulfonyl-1-piperidinyl substituted indole derivatives as 5-ht6 receptor antagonists for the treatment of cns disorders
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EA014156B1 (en) * 2005-01-10 2010-10-29 Арена Фармасьютикалз, Инк. Process for preparing 4-(phenoxy-5-methyl-pyrimidin-4-yloxy)piperedine-1-carboxylicacid derivatives and related compounds
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US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
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