WO2007138611A1 - Dérivés du 3-(hétérocyclyl)-n-(arylsulfonyl)indole en tant que ligands fonctionnels de la 5-ht6 - Google Patents

Dérivés du 3-(hétérocyclyl)-n-(arylsulfonyl)indole en tant que ligands fonctionnels de la 5-ht6 Download PDF

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WO2007138611A1
WO2007138611A1 PCT/IN2007/000059 IN2007000059W WO2007138611A1 WO 2007138611 A1 WO2007138611 A1 WO 2007138611A1 IN 2007000059 W IN2007000059 W IN 2007000059W WO 2007138611 A1 WO2007138611 A1 WO 2007138611A1
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Prior art keywords
indole
ethylpiperazin
chloro
compound
methylpiperazin
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PCT/IN2007/000059
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English (en)
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Venkata Satya Nirogi Ramakrishna
Vikas Shreekrishna Shirasath
Rama Sastri Kambhampati
Amol Dinkar Deshpande
Anand Vijaykumar Daulatbad
Santosh Vishwakarma
Venkateswarlu Jasti
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Suven Life Sciences Limited
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Publication of WO2007138611A1 publication Critical patent/WO2007138611A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to certain 3-(HeterocyclyI)-N-(arylsulfonyl)indole derivatives, their stereoisomers, their salts, their preparation and medicine containing them.
  • the present invention also relates to the process for preparing the compounds of general formula (I), their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the compounds of this invention bind selectively with high affinity to 5-HTg receptor.
  • compounds of general formula (I) of this invention are useful for treating diseases wherein activity of 5-HT (Serotonin) is modulated to obtain the desired effect.
  • the compounds of this invention are useful in the treatment of anxiety disorder, attention deficit disorder or obsessive-compulsive disorder and stroke or head trauma.
  • the compounds of general formula (I) of this invention are also useful to treat neurodegenerative disorders like Mild Cognitiive Impairment, Schiophrenia, Alzheimer's and Parkinson's disease.
  • the compounds of general formula (I) of this invention are also useful in the modulation of eating behaviour or obesity.
  • 5-HT receptor subtypes regulate the various effects of serotonin.
  • the 5-HTg receptor subtype was first cloned from rat tissue in 1993 (Monsma, F. J.;
  • the receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C, Biochemical Biophysical Research Communications, 1993, 193, 268-276).
  • GPCR G-protein coupled receptor
  • the receptor is found almost exclusively in the central nervous system (CNS) areas both in rats as well as in humans.
  • CNS central nervous system
  • In situ hybridization studies of 5-HTg receptor in rat brain using mRNA indicate principal localization in the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.;
  • 5-HT ⁇ receptor ligands Our understanding of the roles of 5-HT ⁇ receptor ligands is most advanced in two therapeutic indications in which this receptor is likely to have a major role: learning and memory deficits; and abnormal feeding behavior.
  • the exact role of the 5-HT 6 receptor is yet to be established in other CNS indications such as anxiety; although one 5-HT 6 agonist has reached Phase I clinical trials recently, the exact role of the receptor is still to be established and is the focus of significant investigation.
  • 5- HTg receptor ligands There are many potential therapeutic uses for 5- HTg receptor ligands in humans based on direct effects and on indications from available scientific studies. These studies include the localization of the receptor, the affinity of ligands with known in-vivo activity, and various animal studies conducted so far.
  • modulators of 5-HTg receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's.
  • the high levels of receptor found in structures such as the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens, and cortex suggests a role for the receptor in memory and cognition since these areas are known to play a vital role in memory (Gerard, C; Martres, M. - P.; Lefevre, K.; Miquel, M. C; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; EI Mestikawy, S., Brain Research, 1997, 746, 207-219).
  • 5-HTg ligands A related potential therapeutic use for 5-HTg ligands is the treatment of attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in children as well as adults.
  • ADD attention deficit disorders
  • 5-HTg antagonists appear to enhance the activity of the nigrostriata! dopamine pathway and ADHD has been linked to abnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R.
  • 5-HTg antagonists may attenuate attention deficit disorders. Further, recent in vivo studies in rats indicate that 5-HTg modulators may be useful in the treatment of movement disorders including epilepsy (Stean, T.; Routledge, C; Upton, N.,
  • a 5-HT ⁇ receptor-knockout mouse has been developed [Tecott, L.H. and Brennan, TJ.
  • mice that are homozygous for a disruption in the endogenous 5-HT 6 receptor gene have a phenotype of increased anxiety behavior that includes diminished investigation of foreign objects and elevation in stretched attend postures.
  • Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder.
  • GI gastrointestinal
  • 5-HTg receptor modulators i.e. ligands
  • diseases associated with a deficit in memory, cognition and learning such as Alzheimer's and attention deficit disorder
  • personality disorders such as schizophrenia
  • behavioral disorders e. g. anxiety, depression and obsessive compulsive disorders
  • motion or motor disorders e.g. anxiety, depression and obsessive compulsive disorders
  • motion or motor disorders e.g. anxiety, depression and obsessive compulsive disorders
  • Parkinson's disease and epilepsy e.g. anxiety, depression and obsessive compulsive disorders
  • diseases associated with neurodegeneration such as stroke or head trauma
  • withdrawal from drug addiction including addiction to nicotine, alcohol, and other substances of abuse.
  • the compounds which demonstrate a binding affinity for the 5-HTg receptor are earnestly sought both as an aid in the study of the 5-HTg receptor and as potential therapeutic agents in the treatment of central nervous system disorders, for example see Reavill C. and
  • 2-Substit ⁇ ted ti ⁇ ptamines agents with selectivity for 5-HT 6 serotonin receptors.
  • the preferred object of the invention to synthesize a potent selective 5-HTg receptor antagonist.
  • the present invention relates to a compound of the Formula (I), along with its stereoisomer or its salt with an inorganic or organic acid,
  • Ar represents any one group selected from phenyl, naphthyl, a monocyclic or bicyclic ring system, each of which may be further substituted by one or more independent substituents and those substituents are defined as Ri;
  • Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (C r C 3 )alkyI, halo(C r C 3 )alkyl, (C r C 3 )alkoxy, halo(C r C 3 )alkoxy, cyclo(Cj-C 6 )alkyl or cyclo(C 3 -C 6 )alkoxy; R 2 whenever present, represents hydrogen, (C r C 3 )alkyl or halo(C r C 3 )alkyl; R ⁇ and R4 represents either hydrogen or methyl.
  • the present invention also provides methods for preparing, compositions comprising, and methods for using Compounds of Formula (I).
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I), or individual stereoisomers, racemic or non-racemic mixture of stereoisomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with atleast one suitable carrier.
  • the invention relates to the use of a therapeutically effective amount of compound of formula (I), to manufacture a medicament, in the treatment or prevention of a disorder involving selective affinity for the 5-HTg receptor.
  • the invention further relates to the process for preparing compounds of formula (I).
  • Ar represents any one group selected from phenyl, naphthyl, a monocyclic or bicyclic ring system, each of which may be further substituted by one or more independent substituents and those substituents are defined as Ri;
  • R 1 represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (C r C 3 )alkyl, halo(C I -C 3 )alkyl, (Ci-C 3 )alkoxy, halo(C r C 3 )alkoxy, cyclo(C 3 -C 6 )alkyl or cyclo(C 3 -C 6 )alkoxy; R 2 whenever present, represents hydrogen, (C r C 3 )alkyl or halo(CVC 3 )alkyl; R 3 and R 4 represents either hydrogen or methyl.
  • halogen as used herein and in the claims (unless the context indicates otherwise) means atom such as fluorine, chlorine, bromine or iodine;
  • (C r C 3 )a1kyl as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl.
  • (Ci-C 3 )alkoxy as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes methoxy, ethoxy, propyloxy and iso-propyloxy.
  • halo(Ci-C 3 )alkyl as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes fluoromethyl, difluoroniethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like.
  • halo(C r C3)alkoxy as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from one to three carbon atoms and includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy and the like.
  • halo(Ci-C 3 )alkoxy as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkoxy radicals containing from one to three carbon atoms and includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy and the like.
  • cyclo(C 3 -C 6 )alkyl as used herein and in the claims (unless the context indicates otherwise) means cyclic and branched cyclic alkyl radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the cycloalkyl group may be substituted.
  • cyclo(C 3 -C 6 )alkoxy as used herein and in the claims (unless the context indicates otherwise) means cyclic and branched cyclic alkyl radicals containing from three to six carbon atoms and includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, the cycloalkoxy group may be substituted and the like.
  • monocyclic or bicyclic ring system is intended to mean both heteroaryl and heterocyclic rings.
  • Heteroaryl a 5 or 6 membered monocyclic aromatic or a fused 8 - 10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
  • Suitable examples of such monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyridyl.
  • fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl and the like.
  • Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above.
  • 5- to 7-membered heterocyclic ring is intended to mean a non aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Such rings may be parlially unsaturated.
  • Suitable examples of 5- io 7-uieinbered heterocyclic rings include piperidii ⁇ yl, letruhydr ⁇ yridmyl, pyrrolidinyl, m ⁇ rpholinyl, azepanyl, diazepanyl and piperazinyl.
  • a 5- to 7- membered heterocyclic ring, as described above, may be linked to the remainder of the molecule via a carbon atom or a suitable nitrogen atom.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e. g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • 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 stereoisomers as a rule are generally obtained as racemates that can be separated into the optically active isomers in a manner known per se.
  • the present invention relates to the D- form, the L-form and D,L- mixtures and in the case of a number of asymmetric carbon atoms, the diastereomeric forms and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • Those compounds of general formula (I) which have an asymmetric carbon and as a rule are obtained as racemates can be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • stereoisomers of compounds of general formula (I) may be prepared by one or more ways presented below: i) One or more of the reagents may be used in their optically active form. ii) Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process. The metal catalysts may be employed in the reduction process.
  • the metal catalyst may be Rhodium, Ruthenium, Indium and the like.
  • the chiral ligands may preferably be chiral phosphines (Principles of Asymmetric synthesis, J. E.
  • the mixture of stereoisomers may be resolved by conventional methods such as forming a diastereomeric salts with chiral acids or chiral amines, or chiral amino alcohols, chiral amino acids.
  • the resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography and the like, which is followed by an additional step of isolating the optically active product by hydrolyzing the derivative (Jacques et. al., "Enantiomers, Racemates and Resolution",
  • the mixture of stereoisomers may be resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases.
  • Chiral acids that can be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like.
  • Chiral bases that can be employed may be cinchona alkaloids, brucine or a basic amino group such as lysine, arginine and the like.
  • the present invention relates to all of these geometric isomers.
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e. g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with 1-6 equivalents of a base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium t-butoxide, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride and the like.
  • Solvents such as water, acetone, ether, THF, methanol, ethanol, t-butanol, dioxane, isopropanol, isopropyl ether or mixtures thereof may be used.
  • salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (e.g., water).
  • the present invention also provides a pioccsb f ⁇ i the Crude of u. compound of fonnula (I) or a pharmaceutically acceptable salt thereof, which comprises of the following route, wherein the key intermediate is synthesized by various methods known in literature.
  • the process of this invention includes contacting a compound of the following formula (a),
  • indole derivative with aryl sulfonyl chlorides, ArSO 2 Cl can take place in the presence of an inert organic solvent which includes, aromatic hydrocarbons such as toluene, o-, m-, p-xylene; halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole, and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; alcohols such as methanol, ethanol, n-propranol, n-butanol, tert-butanol and also DMF (N.N- dimethylformamide), DMSO (N.N-dimethyl sulfoxide ) and water.
  • aromatic hydrocarbons such as toluene, o-, m-,
  • Suitable bases are, generally, inorganic compounds such as alkali metal hydroxides and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal oxides and alkaline earth metal oxides, lithium oxide, sodium oxide, magnesium oxide and calcium oxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal amides and alkaline earth metal amides such as lithium amide, sodium amide, potassium amide and calcium amide; alkali metal carbonates and alkaline earth metal carbonates such as lithium carbonate and calcium carbonate; and also alkali metal hydrogen carbonates and alkaline earth metal hydrogen carbonates such as sodium hydrogen carbonate; organometallic compounds, particularly alkali-metal alkyls
  • reaction may be- effected in the presence of phase transfer catalyst such as tetra-n- butylammonium hydrogensulphate and the like.
  • phase transfer catalyst such as tetra-n- butylammonium hydrogensulphate and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He. Reaction times may vary from 1 to 24 hrs, preferably from 2 to 6 hours, whereafter, if desired, the resulting compound is continued into a salt thereof.
  • any one or more than one of the following steps can be carried out, i) converting a compound of the formula (I) into another compound of the formula (I) ii) removing any protecting groups; or iii) forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
  • halogenation, hydroxylation, alkylation and/or pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative as described earlier in detail.
  • Suitable amine protecting groups include sulphonyl (e. g. tosyl), acyl (e. g. acetyl, 2', 2', T- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e. g. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric or trifluoroacetic acid) or reductively (e. g.
  • Suitable amine protecting groups include trifluoroacetyl(-COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6- dimethoxybenzyl group(Ellman linker)', which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Process (iii) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parental (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such fo ⁇ ns as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of an aerosol spray from a pressurized container or a nebulizer, or from a capsule using a inhaler or insufflator.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas and the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the medicament for pressurized container or nebulizer may contain a solution or suspension of the active compound while for a capsule it preferably should be in the form of powder.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol formulations for treatment of the conditions referred to above e.g., migraine
  • each metered dose or "puff of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • An effective amount of a compound of general formula (I), or their derivatives as defined above can be used to produce a medicament, along with conventional pharmaceutical auxiliaries, carriers and additives.
  • Such therapy includes multiple choices: for example, administering two compatible compounds simultaneously in a single dose form or administering each compound individually in a separate dosage; or if required at same time interval or separately in order to maximize the beneficial effect or minimize the potential side-effects of the drugs according to the known principles of pharmacology.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT ⁇ 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, amyotrophic 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 amyotrophic 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 terms “treating”, “treat”, or “treatment” embrace all the meanings such as preventative, prophylactic and palliative.
  • “Therapeutically effective amount” is defined as 'an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (H) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein'.
  • the dose of the active compounds can vary depending on factors such as the route of administration, age and weight of patient, nature and severity of the disease to be treated and similar factors. Therefore, any reference herein to a pharmacologically effective amount of the compounds of general formula (I) refers to the aforementioned factors.
  • a proposed dose of the active compounds of this invention, for either oral, parenteral, nasal or buccal administration, to an average adult human, for the treatment of the conditions referred to above, is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • reaction scheme depicted herein provides potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Examples section For a more detailed description of the individual reaction steps, see the Examples section. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
  • specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. Commercial reagents were utilized without further purification. Room temperature refers to 25 - 30 0 C.
  • N-Acetyl-3-(4-ethyIpiperazin-l-yI)-5-bromo indole A mixture of 5-Bromo-l -acetyl indoxyl (4.6 g, 18.1 mM), titanium isopropoxide (13.12 g, 45.2 mM) and N-Ethyl piperazine (3.09 g, 27.1 mM) were stirred under nitrogen atmosphere for 4 hours at room temperature. Ethanol (20 mL) was charged to the suspension followed by the slow addition of sodium triacetoxy borohydride (8.08 g, 36.2 mM) in small portions. The progress of the reaction was monitored by TLC.
  • N-Acetyl-3-(4-ethyIpiperazin-l-yI)-5-bromoindole (4.6 g) technical material obtained as above was stirred with methanolic solution of 85 % potassium hydroxide (2.55 g, 3.87 mM in 46 mL of methanol) at reflux temperature. The progress of reaction was monitored by TLC. After completion of reaction, solvent was removed under vacuum. The residual mass was dissolved in 100 mL ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous magnesium sulfate. Solvent removal under vacuum yielded the desired product (3.7 g, 91 % yield).
  • Example 1 5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole: Sodium hydride (50 % suspension in mineral oil, 40.78 mg, 0.84 mM) was taken in 3 mL DMF in a round bottomed flask under nitrogen atmosphere at room temperature. To this mass under stirring was added a solution of 3-(4-ethylpiperazin-l-yl)-5-bromoindole (0.2 g, 0.65 mM) dissolved in 3 mL of DMF at RT. The mass was further stirred for 45 min.
  • Example 5 5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-mcthylpipcrazin-l-yl)-lII-i ⁇ dole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm "1 ): 2627, 2846, 1590, 1447, 1373, 1181, 1011,
  • Example 6 6-ChIoro-l-(4-fluorobenzenesuIfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 8 6-ChIoro-l-(4-isopropyIbenzenesulfonyI)-3-(4-methyIpiperazin-l-yI)-lH- indole:
  • Example 11 6-Chloro-l-(4-trifluoromethoxybenzenesulfonyl)-3-(4-methyIpiperazin-l- yl)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm "1 ): 2940, 2799, 1588, 1455; Mass (m/z): 474.3,
  • Example 13 6-Chloro-l-(4-fluorobenzenesulfonyl)-3-(4-methylpiperazin-l-yI)-lH- indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 16 5-ChIoro-l-(2-bromobenzenesulfonyI)-3-(4-ethyIpiperazin-l-yl)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 19 5-Chloro-l-(4-methylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH- indole: Using a similar procedure as given in the Example 1 and some n ⁇ -critical variations above derivative was prepared.
  • Example 20 5-Chloro-l-(4-fIuorobenzenesulfonyl)-3-(4-ethyIpiperazin-l-yI)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm "1 ): 2927, 2818, 1591, 1450; Mass (m/z). 421.9,
  • Example 21 5-BiOmo-l-(2,5-dimethoxybenzenesuIfonyl)-3-(4-ethyIpiperazin-l-yl)-lH- indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm "1 ): 2935, 2832, 1576, 1493; Mass (m/z): 508.3,
  • Example 26 6-Chloro-l-(4-trifluoromethoxybenzenesuIfonyl)-3-(4-ethylpiperazin-l-yI)- lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 28 6-Chloro-l-(4-bromobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole:
  • Example 30 ⁇ -Chloro-l- ⁇ -chlorobenzenesulfonyO-S- ⁇ -ethylpiperazin-l-yD-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 32 6-ChIoro-l-(3-trifluoromethyIbenzenesuIfo ⁇ yl)-3-(4-ethyl piperazin-1-yl)- lH-indole:
  • Example 36 6-Chloro-l-(2-bromobenzenesulfonyl)-3-(4-methyIpiperazin-l-yl)-lH- indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 40 l-(4-isopropylbenzenesulfonyO-3-(4-methylpiperazin-l-yI)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • Example 41 l-(4-Fluorobenzenesulfonyl)-3-(4-methylpiperazin-l-yl)-lH-indole: Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared.
  • the rats were housed in their single home cages for 28 days. During this period, the rats were either dosed orally or i.p., with a composition comprising a compound of formula (1) or a corresponding composition (vehicle) without the said compound (control group), once-a- day.
  • the rat is provided with ad libitum food and water.
  • Example 43 Tablet comprising a compound of formula (I):
  • Example 44 Composition for Oral Administration:
  • Example 45 Liquid oral formulation:
  • the ingredients were mixed to form a suspension for oral administration.
  • the active ingredient was dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride was then added with stirring to make the solution isotonic. The solution was made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
  • the ingredients were melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
  • cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: object recognition task model.
  • mice Four animals were, housed in each cage. Animals were, kept on 7.0 % food deprivation before one day and given water ad libitum throughout the experiment, and maintained on a 12 h light/dark cycle. Also the rats were habituated to individual arenas for 1 hour in absence of any objects.
  • Tl is the total time spent exploring the familiar objects (al + a2).
  • T2 is the total time spent exploring the familiar object and novel object (a3 +b).
  • the object recognition test was performed as described by Ennaceur, A., Delacour, J.,
  • Example 50 Chewing/Yawning/Stretching induction by 5-HT 6 R antagonists:
  • Rats Male Wistar rats weighing 200-250 g were used. Rats were given vehicle injections and placed in individual, transparent chambers for 1 h each day for 2 days before the test day, to habituate them to the observation chambers and testing procedure. On the test day, rats were placed in the observation chambers immediately after drug administration and observed continuously for yawning, stretching, and chewing behaviors from 60 to 90 min after drug or vehicle injections. 60 minutes prior to the drug administration Physostigmine, 0.1 mg/kg i.p. was administered to all the animals. Average number of yawns, stretches, and vacuous chewing movements during the 30 min observation period were recorded. Reference: (A) King M. V., Sleight A., J., Woolley M. L., and et. al.,
  • Example 51 Morris Water Maze Test: The water maze apparatus consisted of a circular pool (1.8 m diameter, 0.6 m high) constructed in black Perspex (TSE systems, Germany) filled with water (24 ⁇ 2 0 C) and positioned underneath a wide-angled video camera to track animal. The 10 cm 2 perspex platform, lying 1 cm below the water surface, was placed in the centre of one of the four imaginary quadrants, which remained constant for all rats. The black Perspex used in the construction of the maze and platform offered no intramaze cues to guide escape behavior. By contrast, the training room offered several strong extramaze visual cues to aid the formation of the spatial map necessary for escape learning.
  • An automated tracking system [Videomot 2 (5.51), TSE systems, Germany] was employed. This program analyzes video images acquired via a digital camera and an image acquisition board that determined path length, swim speed and the number of entries and duration of swim time spent in each quadrant of the water maze.
  • the training apparatus consisted of a chamber 300 mm in length, 260 mm wide, and 270 mm in height, constructed to established designs. The front and top were transparent, allowing the experimenter to observe the behavior of the animal inside the apparatus.
  • the chamber was divided into two compartments, separated by a central shutter that contained a small opening 50 mm wide and 75 mm high set close to the front of the chamber. The smaller of the compartments measured 9 mm in width and contained a low-power (6V) illumination source. The larger compartment measured 210 mm in width and was not illuminated.
  • 6V low-power
  • the floor of this dark compartment consisted of a grid of 16 horizontal stainless-steel bars that were 5 mm in diameter and spaced 12.5 mm apart.
  • a current generator supplied 0.75 mA to the grid floor, which was scrambled once every 0.5 s across the 16 bars.
  • a resistance range of 40-60 microohms was calculated for a control group of rats and the apparatus was calibrated accordingly.
  • An electronic circuit detecting the resistance of the animal ensured an accurate current delivery by automatic variation of the voltage with change in resistance.
  • Example 53 Binding assay for human 5-HT 6 receptor:
  • 5-HT fi Binding assay of compounds is tested according to the following procedures.
  • Receptor source Human recombinant expressed in HEK293 cells
  • Non-specific determinant Methiothepin mesylate - [0.1 ⁇ M]
  • Reactions were carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl 2 , 0.5 mM EDTA for 60 minutes at 37 0 C. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HT ⁇ binding site.
  • 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 ⁇ 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 ⁇ 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 500 ug/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 1 uM 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 Eppendorf tubes. The tubes were centrifuged for 5 min at 4° C, and the supernatants were stored at 4° C. until assayed.
  • 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 50 uL, peroxidase-Iabeled cAMP to the sample (100 uL) preincubated with the antiserum (100 uL) for 2 hours at 4° C.

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Abstract

La présente invention concerne des dérivés du 3-(hétérocyclyl)-N-(arylsulfonyl)indole de formule (I), utilisables pour traiter les affections du SNC liées à la fonction du récepteur de la 5-HTg. Les composés de la présente invention se lient sélectivement avec une affinité élevée au récepteur de la 5-HTg. L'invention concerne également les procédés de préparation de ces ligands et un médicament contenant ledit ou lesdits composés.
PCT/IN2007/000059 2006-05-30 2007-02-14 Dérivés du 3-(hétérocyclyl)-n-(arylsulfonyl)indole en tant que ligands fonctionnels de la 5-ht6 WO2007138611A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof

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US6187805B1 (en) * 1998-09-15 2001-02-13 Merck Sharp & Dohme Ltd. Indole and indoline derivatives as 5-HT6 selective ligands
EP1106605A1 (fr) * 1999-06-24 2001-06-13 Toray Industries, Inc. Antagonistes du recepteur adrenergique-alpha1b
WO2003013510A1 (fr) * 2001-08-07 2003-02-20 Smithkline Beecham P.L.C. 3-arylsulfonyl-7-piperazinyl- indols, -benzofurans et benzothiophenes a affinite avec les recepteurs 5-ht6 pour le traitement de troubles du snc
WO2005013974A1 (fr) * 2003-07-30 2005-02-17 Laboratorios Del Dr. Esteve S.A. Derives de 1-sulfonylindole, leur preparation et leur utilisation en tant que ligands de 5-ht6
WO2005066126A1 (fr) * 2003-12-23 2005-07-21 Eli Lilly And Company Composes modulateurs de cb1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6187805B1 (en) * 1998-09-15 2001-02-13 Merck Sharp & Dohme Ltd. Indole and indoline derivatives as 5-HT6 selective ligands
EP1106605A1 (fr) * 1999-06-24 2001-06-13 Toray Industries, Inc. Antagonistes du recepteur adrenergique-alpha1b
WO2003013510A1 (fr) * 2001-08-07 2003-02-20 Smithkline Beecham P.L.C. 3-arylsulfonyl-7-piperazinyl- indols, -benzofurans et benzothiophenes a affinite avec les recepteurs 5-ht6 pour le traitement de troubles du snc
WO2005013974A1 (fr) * 2003-07-30 2005-02-17 Laboratorios Del Dr. Esteve S.A. Derives de 1-sulfonylindole, leur preparation et leur utilisation en tant que ligands de 5-ht6
WO2005066126A1 (fr) * 2003-12-23 2005-07-21 Eli Lilly And Company Composes modulateurs de cb1

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
CN102869647A (zh) * 2010-01-05 2013-01-09 苏文生命科学有限公司 作为5-ht6受体配体的砜化合物
JP2013516458A (ja) * 2010-01-05 2013-05-13 スベン ライフ サイエンシズ リミティド ５−ｈｔ６受容体リガンドとしてのスルホン化合物
US9018231B2 (en) 2010-01-05 2015-04-28 Suven Life Sciences Limited Sulfone compounds as 5-HT6 receptor ligands
CN102869647B (zh) * 2010-01-05 2015-06-24 苏文生命科学有限公司 作为5-ht6受体配体的砜化合物
EA022043B1 (ru) * 2010-01-05 2015-10-30 Сувен Лайф Сайенсиз Лимитед Сульфоновые соединения в качестве лигандов 5-htрецептора
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof

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