WO2007138611A1 - 3-(heterocyclyl)-n-(arylsulfonyl)indole derivatives as functional 5-ht6 ligands - Google Patents

3-(heterocyclyl)-n-(arylsulfonyl)indole derivatives as functional 5-ht6 ligands Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
indole
ethylpiperazin
chloro
compound
methylpiperazin
Prior art date
Application number
PCT/IN2007/000059
Other languages
French (fr)
Inventor
Venkata Satya Nirogi Ramakrishna
Vikas Shreekrishna Shirasath
Rama Sastri Kambhampati
Amol Dinkar Deshpande
Anand Vijaykumar Daulatbad
Santosh Vishwakarma
Venkateswarlu Jasti
Original Assignee
Suven Life Sciences Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suven Life Sciences Limited filed Critical Suven Life Sciences Limited
Publication of WO2007138611A1 publication Critical patent/WO2007138611A1/en

Links

Classifications

    • 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.

Abstract

The present invention provides 3-(Heterocyclyl)-N-(arylsulfonyl)indole derivatives of formula (I), which are useful in treatment of CNS disorders that are related to 5-HTg receptor function. The compounds of this invention bind selectively with high affinity to 5-HTg receptor. The present invention also discloses the methods of preparation of these ligands and medicine containing the said compound/s.

Description

3-(HETEROCYCLYL)-N-(ARYLSULFONYL)INDOLE DERIVATIVES AS
FUNCTIONAL 5-HTg LIGANDS
Field of Invention:
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. Thus, 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. Specifically, 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. 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. 5-HT receptor subtypes regulate the various effects of serotonin. Known 5-HT receptor family includes the 5-HTi family (e.g. 5-HT]A), the 5-HT2 family (e.g.5- HT2A)= 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5- HT7 subtypes.
The 5-HTg receptor subtype was first cloned from rat tissue in 1993 (Monsma, F. J.;
Shen, Y.; Ward, R. P.; Hamblin, M. W., Molecular Pharmacology, 1993, 43, 320-327) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R., Journal of Neurochemistry, 1996, 66, 47-56). 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). The receptor is found almost exclusively in the central nervous system (CNS) areas both in rats as well as in humans. 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.;
Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M., Neuroscience, 1995, 64, 1105-1 I I I). Highest levels of 5-HTg receptor mRNA has been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus as well as CAj, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HTg 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- HTg receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues, so it is possible that new therapeutic agents targeted towards 5- HT6 receptors might have relatively few peripheral side-effects.
Our understanding of the roles of 5-HTβ 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-HT6 receptor is yet to be established in other CNS indications such as anxiety; although one 5-HT6 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. 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.
The high affinity of number of antipsychotic agents towards 5-HTg receptor, the localization of its mRNA in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. 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 the said receptor. REF : Sleight, AJ. et al. (1997) 5-HT6 and 5- HT7 receptors: molecular biology, functional correlates and possible therapeutic indications, Drug News Perspect. 10, 214-224.
Monstna FJ. et al. (1993) and Kohen, R. et al. (2001) have shown that several tricyclic antidepressant compounds, such as aniitryptiline, and atypical antidepressant compounds, such as mianserin, have high affinity for the 5-HT6 receptor. These findings have led to the hypothesis that the 5-HT6 receptor is involved in the pathogenesis and/or treatment of affective disorders. Rodent models of anxiety-related behavior yield conflicting results about the role of the 5-HT6 receptor in anxiety. Treatment with 5-HT6 receptor antagonists increases seizure threshold in a rat maximal electroconvulsive-shock test [Stean, T. et al. (1999) Anticonvulsant properties of the selective 5-HT6 receptor antagonist SB-271046 in the rat maximal electroshock seizure threshold test. Br. J. Pharmacol. 127, 131P; Routledge, C. et al. (2000) Characterization of SB-271046: a potent, selective and orally active 5-HT (6) receptor antagonist. Br. J. Pharmacol. 130, 1606-1612]. Although this indicates that 5-HT6 receptors might regulate seizure threshold, the effect is not as pronounced as that of known anticonvulsant drugs.
At present, a few fully selective agonists are available. The Wyeth agonist WAY-
181187 (SAX-187, 12) is currently in Phase I trials to target anxiety [Cole, D.C. et al. (2005)
Discovery of a potent, selective and orally active 5-HT6 receptor agonist, WAY-181187. 230th
ACS Natl. Meet. (Aug 28-Sept 1, Washington DC), Abstract MEDI 17.] International Patent Publication WO 03/066056 Al reports that antagonism of 5-HTg receptor could promote neuronal growth within the central nervous system of a mammal. Another International Patent Publication WO 03/065046 A2 discloses new variant of human 5- HTg receptor, and proposes that 5-HTg receptor is associated with numerous other disorders.
Early studies examining the affinity of various CNS ligands with known therapeutic utility or a strong structural resemblance to known drugs suggests a role for 5-HTg ligands in the treatment of schizophrenia and depression. For example, clozapine (an effective clinical antipsychotic) has high affinity for the 5-HTg receptor subtype. Also, several clinical antidepressants have high affinity for the receptor as well and act as antagonists at this site (Branchek, T. A.; Blackburn, T. P., Annual Reviews in Pharmacology and Toxicology, 2000, 40, 319-334).
One potential therapeutic use of 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). The ability of known 5-HTg receptor ligands to enhance cholinergic transmission also supports the potential cognition use (Bentey, J. C; Boursson, A.; Boess, F. (J.; K.one, F. C; Marsden, C. A.; Petit, N.; Sleight, A. J., British Journal of Pharmacology, 1999, 126 (7), 1537-1542).
Studies have found that a known 5-HTg selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT. This selective elevation of certain neurochemicals is noted during memory and cognition, strongly suggests a role for 5-HTg ligands in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal of Pharmacology, 2000, 130 (1), 23-26). Animal studies of memory and learning with a known selective 5-HTg antagonist have some positive effects
(Rogers, D. C; Hatcher, P. D.; Hagan, J. J. Society of Neuroscience, Abstracts, 2000, 26, 680). 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. As 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. M., Journal of Neuroscience, 1998, 18(15), 5901-5907), 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.,
British Journal of Pharmacology, 1999, 127 Proc. Supplement-131P; and Routledge, C;
Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.;
Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M., British Journal of Pharmacology, 2000, 30 (7), 1606-1612).
A 5-HTβ receptor-knockout mouse has been developed [Tecott, L.H. and Brennan, TJ.
(2000) Serotonin 5-HTβ receptor knockout mouse. US patent 6,060,642.]. Transgenic mice that are homozygous for a disruption in the endogenous 5-HT6 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. See for example, Roth, B. L.; ct al.. Journal of Pharmacology and Experimental Therapeulios, 1994, 268, pages 1403-1412;
Sibley, D. R.; et al., Molecular Pharmacology, 1993, 43, 320-327, Sleight, A. J.; et al., Neurotransmission, 1995, 11, 1-5; and Sleight, A. J.; et al., Serotonin ID Research Alert, 1997,
2(3), 115-118. Furthermore, the effect of 5-HTg antagonist and 5-HTg antisense oligonucleotides to reduce food intake in rats has been reported thus potentially in treatment of obesity. See for example, Bentey, J. C; Boursson, A.; Boess, F. G.; Kone, F. C; Marsden, C. A.; Petit, N.; Sleight, A. J., British Journal of Pharmacology, 1999, 126 (7), 1537-1542); Wooley et al., Neuropharmacology, 2001, 41 : 210-129; and WO 02/098878.
Various studies suggest for possible role for 5-HTg receptor modulators, i.e. ligands, in treatment of diseases associated with a deficit in memory, cognition and learning such as Alzheimer's and attention deficit disorder; the treatment of personality disorders such as schizophrenia; the treatment of behavioral disorders, e. g. anxiety, depression and obsessive compulsive disorders; the treatment of motion or motor disorders such as Parkinson's disease and epilepsy; the treatment of diseases associated with neurodegeneration such as stroke or head trauma; or 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
Rogers D. C, Current Opinion in Investigational Drugs, 2001, 2(l):104-109, Pharma Press Ltd.
Recently a review by Holenz, Jo" rg and et.al., Drug Discovery Today, 11, 7/8, April
2006, Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents, gives elaborate discussion on evolution of 5-HT6 ligands. It had summarized pharmacological tools and preclinical candidates used in evaluation of 5-HT6 receptor in illnesses such as schizophrenia, other dopamine-related disorders and depression, and to profile the neurochemical and electrophysiological effects of either blockade or activation of 5-HT6 receptors. Furthermore, they have been used to characterize the 5-HT6 receptor and to investigate its distribution. So far several clinical candidates form the part of indole-type structures and are closely related structurally to the endogenous ligand 5-HT, for example compounds by Glennon, R.A. et al. 2-Substitιιted tiγptamines: agents with selectivity for 5-HT6 serotonin receptors., J. Med. Chem. 43, 1011-1018, 2000; Tsai, Y. et al. Nl-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists, Bioorg. Med. Chem. Lett. 10, 2295-2299, 2000; Demchyshyn L. et al., ALX-1161: pharmacological properties of a potent and selective 5-HT6 receptor antagonist., 31st Annu. Meet. Soc. Neurosci. (Nov 10-15), Abstract 266.6, 2001; Slassi, A. et al. Preparation of 1- (arylsulfonyl)-3-(tetrahydropyήdinyl)indoles as 5-HT6 receptor inhibitors and WO 200063203, 2000; and Mattsson, C. et al., Novel, potent and selective 2-alkyl-3-(l,2,3,6-tetrahydropyridin- 4-yl)-lH-indole as 5-HT6 receptor agonists, XVIIth International Symposium on Medicinal Chemistry, 2002; Mattsson, C. et al., 2-Alkyl-3-(l,2,3,6-tetrahydropyridin-4-yl)-lH-indoles as novel 5-HT6 receptor agonists, Bioorg. Med. Chem. Lett. 15, 4230-4234, 2005]
Structure -functionality relationships are described in the section on indole-like structures (and in a receptor-modeling study in which Pullagurla et al. claim different binding sites for agonists and antagonists [Pullagurla, M.R. et al. (2004) Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors. Bioorg. Med. Chem. Lett. 14, 4569- 4573]. Most antagonists that are reported form part of the monocyclic, bi cyclic and tricyclic aryl-piperazine classes [Bromidge, S.M. et al. (1999) 5-Chloro-N-(4-methoxy-3- ρiρerazin-l-ylphenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046): A potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J. Med. Chem. 42, 202-205; Bromidge, S.M. et al. (2001) Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-l- ylbenzenesulfonamide (SB-357134). Bioorg. Med. Chem. Lett. 1 1, 55- 58; Hirst, W.D. et al. (2003) Characterisation of SB-399885, a potent and selective 5-HT6 receptor antagonist. 33rd Annu. Meet. Soc. Neurosci. (Nov. 8-12, New Orleans), Abstract 576.7; Stadler, H. et al. (1999) 5-HTe antagonists: a novel approach for the symptomatic treatment of Alzheimer's disease. 37th IUPAC Cong. .Berlin, Abstract MM-7; Bonhaus, D. W. et al. (2002) Ro-4368554, a high affinity, selective, CNS penetrating 5-HT6 receptor antagonist. 32nd Annu. Meet. Soc. Neurosci., Abstract 884.5.; Beard, CC. et al. (2002) Preparation of new indole derivatives with 5-HT6 receptor affinity. WO patent 2002098857]
The aryl-sulfonyl structure-containing class of 5-HT6 receptor ligands (Holenz, J. et al. (2005) Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. J. Med. Chem. 48, 1781-1795; Sleight, AJ. et al. (1998) Characterization of Ro 04-6790 and Ro 63-0563: Potent and selective antagonists at human and rat 5-HT6 receptors. Br. J. Pharmacol. 124, 556-562) advanced are the Phase II antagonist candidate from GlaxoSmithKline, SB-742457 for the therapeutic indication of cognitive dysfunction associated with Alzheimer's disease [Ahmed, M. et al. (2003) Novel compounds. WO Publication No. 2003080580], and the Lilly compound LY-483518 [Filla, S.A. et al. (2002) Preparation of benzenesulfonic acid indol-5-yl esters as antagonists of the 5-HT6 receptor. WO patent 2002060871]. SB-271046, the first 5-HT6 receptor antagonist to enter Phase I clinical development, has been discontinued (probably because of low penetration of the blood-brain barrier). In addition, the selective 5-HT6 receptor antagonist SB-271046 is inactive in animal tests related to either positive or negative symptoms of schizophrenia [Pouzet, B. et al. (2002) Effects of the 5-HT6receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol. Biochem. Behav. 71, 635-643].
International Patent Publications WO 2004/055026 Al, WO 2004/048331 Al, WO 2004/048330 Al and WO 2004/048328 A2 (all assigned to Suven Life Sciences Limited) describes the related prior art. Further WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WOO 1/32646 (all assigned to Glaxo SmithKline Beecham PLC) disclose a series of aryl sulphonamide and sulphoxide compounds as 5-HTg receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders. While some 5-HTg modulators have been disclosed, there continues to be a need for compounds that are useful for modulating 5-HTg. 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-HTg 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-HTg receptor. It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HTg receptor.
The preferred object of the invention to synthesize a potent selective 5-HTg receptor antagonist.
Summary of the Invention:
3-(Heterocyclyl)-N-(arylsulfonyl)indole class of compounds has now been found which demonstrate high 5-HTg receptor binding affinity, which may be further used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders. (i) The present invention relates to a compound of the Formula (I), along with its stereoisomer or its salt with an inorganic or organic acid,
Figure imgf000008_0001
Formula (T)
wherein: 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;
Figure imgf000008_0002
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (CrC3)alkyI, halo(CrC3)alkyl, (CrC3)alkoxy, halo(CrC3)alkoxy, cyclo(Cj-C6)alkyl or cyclo(C3-C6)alkoxy; R2 whenever present, represents hydrogen, (CrC3)alkyl or halo(CrC3)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).
(ϋ) In another aspect, 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.
(iii) In another aspect, 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.
(iv) In another aspect, the invention further relates to the process for preparing compounds of formula (I).
(v) Partial list of such compounds of general formula (D is as follows:
1 -(4-Fluorobenzenesul fonyl)-3-(4-methylpiperazin- 1 -y I)- 1 H-indole; . 1 -(2-Bromobenzenesulfonyl)-3-(4-methylpiperazin- 1 -yl)- 1 H-indole; l-(3-Chlorobenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-lH-indole; l-(4-Isopropylb.enzenesulfonyl)-3-(4-methylpiperazin-l- yl)-l H-indole; l-(4-Fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indoIe; l-(2,5-Dimethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole; 1 -(2-Bromobenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole; l-(4-Trifluoromethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole; l-(4-Methylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
1 -(4-Isopropylbenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole; l-(4-Fluorobenzenesulfonyl)-5-methoxy-3-(4-methylpiperazin-l-yl)-lH-indole; l-(2-BiOmobenzenesulfonyl)-5-methoxy-3-(4-methylpiperazin-l-yl)-lH-xndole; l-(3-Chlorobenzenesulfonyl)-5-methoxy-3-(4-methylpiperazin-l- yl)-lH-indole;
I -(H-IsopropylbeήzenesulfonylVS-methoxy-S-f^-methylpipcraxin- 1 - yl)- 1 TT-indolc; l-(4-Fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-5-methoxy-lH-indole; l-(2,5-Dimethoxybenzenesulfonyl)-3-(4-ethylρiperazin-l-yl)-5-methoxy-lH-indole; l-(2-BrυiiiυbBnzenesulfυiiyl)-j-(4-ethylpipei-azin-l-yl)-5-methoxy-lH-iudole;
3-(4-Ethylpiperazin-l-yl)-5-methoxy-l-(4-trifluoromethoxybenzenesulfonyl)-lH-indole;
3-(4-Ethylpiperazin-l-yl)-l-(4-Methylbenzenesulfonyl)-5-methoxy-lH-indole;
3-(4-Ethylpiperazin- 1 -yl)- 1 -(4-isopropylbenzenesulfonyl)-5-methoxy- 1 H-indole;
5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-lH-indole; 5-Bromo- 1 -(2-bromobenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole;
5-Bromo- 1 -(3-chlorobenzenesulfonyl)-3 -(4-methylpiperazin- 1 - yl)- 1 H-indole; 5-Bromo-l -(4-isopropylbenzenesulfonyl)-3-(4-methylpiperazin~l - yl)-l H-indole;
5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
5-Bromo-l-(2,5-dimethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l -yl)-l H-indole;
5-Bromo- 1 -(2-bromobenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole; 5-Bromo-l -(4-trifIuoromethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
5-Bromo-l-(4-methylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole;
5-Bromo-l-(4-isopropylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole;
6-Chloro-l-(4-fluoiObenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
6-Chloro-l-(4-methoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole; 6-Chloro- 1 -(4-isopropylbenzenesulfonyl)-3-(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro-l-(3-trifluoromethylbenzenesulfonyl)-3-(4-methyl piperazin-l-yl)-l H-indole;
6-Chloro- 1 -(4-methoxybenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-trifluoromethoxybenzenesuIfonyI)-3-(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-methylbenzenesulfonyl)-3-(4-methylpiperazin- 1 -yl)- 1 H-indole; 6-Chloro- 1 -(4-fluorobenzenesulfonyl)-3-(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(2-bromobenzenesulfonyl)-3-(4-ethy lpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-isopropylbenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
5-ChIoro-l -(2-bromobenzenesulfonyl)- 3 -(4-ethy lpiperazin- 1 -yl)- 1 H-indole;
5-Chloro-l-(4-isopropylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole; 5 -Chloro- 1 -(3-chlorobenzenesulfony l)-3 -(4-ethy lpiperazin- 1 -yl)- 1 H-indole;
5-Chloro- 1 -(4-methylbenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
5-Chloro- 1 -(4-fluorobenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-trifluoromethoxybenzenesulfonyl)-3-(4-ethylρiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(benzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole; 6-Chloro- 1 -(4-bromobenzenesulfonyl)-3 -(4-ethy lpiperazin- 1 -yl)- 1 H-indole;
6-Chloro-l-(l-Naphthylsulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indυle;
6-Chloro- 1 -(3 -chlorobenzenesulfony l)-3 -(4-ethy lpiperazin- 1 -yl)- 1 H-indole;
6-Chloro-l-(2,5-dimethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
6-Chloro-l-(3-trifluoromethylbenzenesulfonyl)-3-(4-ethyl piperazin-l-yl)-l H-indole; 6-Chloro- 1 -(4-methylbenzenesulfonyl)-3 -(4-ethy lpiperazin- 1 -y I)- 1 H-indole; a stereoisomer thereof ; and a salt thereof. Detailed Description of the Invention:
Surprisingly, it has now been found that 3-(Heterocycly])-Nl-(arylsulfonyl)indole derivatives of formula (I) demonstrate very high 5-HTg receptor affinity,
Figure imgf000011_0001
Formula (I)
wherein: 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;
Figure imgf000011_0002
R1 represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (CrC3)alkyl, halo(CI-C3)alkyl, (Ci-C3)alkoxy, halo(CrC3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R2 whenever present, represents hydrogen, (Cr C3)alkyl or halo(CVC3)alkyl; R3 and R4 represents either hydrogen or methyl.
Each group of compound (I) is explained below. Each term used herein is defined to have meanings described below in either case of a single or a joint use with other terms, unless otherwise noted.
The term "halogen" as used herein and in the claims (unless the context indicates otherwise) means atom such as fluorine, chlorine, bromine or iodine;
The term "(CrC3)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.
The term "(Ci-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 methoxy, ethoxy, propyloxy and iso-propyloxy.
The term "halo(Ci-C3)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.
The term "halo(CrC3)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.
The term "halo(Ci-C3)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.
The term "cyclo(C3-C6)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.
The term "cyclo(C3-C6)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. The term "monocyclic or bicyclic ring system" is intended to mean both heteroaryl and heterocyclic rings.
The term "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. Suitable examples of such 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.
The term 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 piperidiiϊyl, letruhydrυμyridmyl, pyrrolidinyl, mυrpholinyl, 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.
The term "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. In the case of the compounds of general formula (I) having an asymmetric carbon atom 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. However, it is also possible to employ an optically active compound from the start, a correspondingly optically active or diastereomeric compound then being obtained as the final compound.
The 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.
Baldwin F.d., Tetrahedron series, 14, 311-310). iii) 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",
Wiley Interscience, 1981). iv) 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. In the case of the compounds of general formula (I) containing geometric isomerism 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.
In addition to pharmaceutically acceptable salts, other 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 fυi the pieptiraLion 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),
Figure imgf000015_0001
(a)
wherein all substitutents are as described earlier, with aryl sulphonyl compound of formula ArSO2Cl, wherein Ar is as defined for the compounds of formula (I), in presence of inert solvent at suitable temperature to obtain a compound of formula (I), which if required may be derivatized further. Our previous patent application WO 2004/048330 Al gives more details on the reaction conditions and reagents useful in the said interconversions of the compounds of foπnula (I). The reaction of indole derivative with aryl sulfonyl chlorides, ArSO2Cl, 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. The preferred list of solvents includes DMSO, DMF, acetonitrile and THF. Mixtures of these in varying ratios can also be used. 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 such as methyl lithium, butyl lithium, phenyl lithium; alkyl magnesium halides such as methyl magnesium chloride, and alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and di- methoxymagnesium, further more organic bases e.g. triethylamine, triisopropylamine, and N- methylpiperidine, pyridine. Sodium hydroxide, Sodium methoxide, Sodium ethoxide, potassium hydroxide potassium carbonate and triethylamine are especially preferred. Suitably the reaction may be- effected in the presence of phase transfer catalyst such as tetra-n- butylammonium hydrogensulphate and the like. The inert atmosphere may be maintained by using inert gases such as N2, 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.
Compounds obtained by the above method of preparation of the present invention can be transformed into another compound of this invention by further chemical modifications of well-known reaction such as oxidation, reduction, protection, deprotection, rearrangement reaction, halogenation, hydroxylation, alkylation, alkylthiolation, demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-suIfonylation, coupling reaction using transition metals and the like. If necessary, 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.
In process (i), 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.
In process (ii) examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991). 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. hydrogenolysis of a benzyl group or reductive removal of a 2', 2', T- trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other 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. In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, 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.
For oral administration, 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). The tablets may be coated by methods well known in the art. 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).
For buccal administration, 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 foπns as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively,, 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.
For intranasal administration or administration by inhalation, 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. In the case of a pressurized aerosol, 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 (made, for example, from gelatin) 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) in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 μg 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.
The phrase "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.
The term "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.
For illustrative purposes, the reaction scheme depicted herein provides potential routes for synthesizing the compounds of the present invention as well as key intermediates. 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. Although 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. In addition, 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 0C. Melting points are uncorrected. IR spectra were taken using KBr and in solid state. Unless otherwise stated, all mass spectra were carried out using ESI conditions. 1H NMR spectra were recorded at 400 MHz on a Bruker instrument. Deuterated chloroform (99.8 % D) was used as solvent. TMS was used as internal reference standard. Chemical shift values are expressed in parts per million (δ) values. The following abbreviations are used for the multiplicity for the NMR signals: s=singlet, bs=broad singlet, d=doublet, t=triplet, q=quartet, qui-quintet, h=heptet, dd=double doublet, dt=double triplet, tt=triplet of triplets, m-=multiplet. NMR, mass were corrected for background peaks. Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions.
The following examples illustrate the preparation of compounds of the invention.
Description 1: 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. After completion of the reaction 100 mL, cold- water added to the reaction mass and the separated solids were filtered. The inorganic solids on the filter were washed with ethyl acetate till colourless filtrate was obtained. The filtrate was basified with aqueous ammonia. The organic layer was separated, washed with brine solution and dried the organic layer on anhydrous magnesium sulfate. Solvent removal under vacuum gave 4.6 g oily technical product (yield: 72 %). Technical material was directly taken for next step without any purification. Description 2: 3-(4-Ethylpiperazin-l-yl)-5-bromo indole:
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). Column purification from silica gel, 100 - 200 mesh size using ethyl acetate containing 1 % triethyl amine as eluent afforded the pure product in 51 % yield. Mass (m/z): 308.2, 310.2 (M+H)+; 1H-NMR (δ ppm): 1.13 - 1.16 (3H, t, J = 7.20), 2.49 - 2.55 (2H, q, J = 7.24), 2.69 (4H, bs), 3.11 (4H, bs), 6.753 - 6.759 (IH, d, J = 2.44), 7.17 - 7.19 (IH, d, J = 8.6), 7.24 - 7.26 (IH, dd, J = 8.68, 2.0), 7.73 (IH, bs), 7.75 - 7.76 (IH, d, J = 1.6). 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. A solution of 4 - fluorobenzenesulloiiyl chloride (178 mg, 0.91 mM) in 2 ml DMF was added to the above reaction mass and the mass was further stirred for 2 hr at RT. The progress of reaction was monitored by TLC. After completion of the reaction the reaction mass was quenched on to water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with 1 x 10 ml brine solution, dried over anhydrous sodium sulfate and solvent removed under vacuum to get 310 mg of syrupy product. The product was purified by column chromatography using 100-200 mesh silicagel, the eluent system being ethyl acetate and n-hexane in 8:2 ratio to obtain 130 mg of pure product. IR spectra (cm'1): 2928, 2819,
1590, 1447; Mass (m/z): 466.2, 468.2 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.16 (3H, t, J = 7.16), 2.48 - 2.53 (2H, q, J = 7.04), 2.66 (4H, bs), 3.08 (4H, bs), 6.93 (IH, s), 7.04 - 7.10 (2H, m),
7.40 - 7.42 (IH, dd, J = 8.80, 1.88), 7.62 - 7.624 (IH, d, J = 1.84), 7.77 - 7.81 (2H, m), 7.87 -
7.89 (I H, d, J = 8.78).
Example 2: 5-Bromo-l-(2-bromobenzeπesulfonyl)-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. IR spectra (cm"'): 2956, 2790, 1574, 1369; Melting range (0C):
146.2 - 147.4; Mass (m/z): 512, 514, 516 (M+H)+; 1H-NMR (δ ppm): 2.38 - 2.40 (3H, s), 2.67
(4H, bs), 3.12 (4H,bs), 7.21 (IH, s), 7.32 - 7.34 (IH, dd, J = 8.82, 1.89), 7.35 - 7.4 (IH, dt, J = 7.56, 1.83), 7.40 - 7.45 (IH, dt, J = 7.55, 1.38), 7.60 - 7.62 (IH, d, J = 8.8), 7.65 - 7.66 (IH, d,
J = 1.45), 7.67 - 7.68 (I H, t, J = 2.12), 7.93 - 7.95 (IH, dd, J = 7.78, 1.83).
Example 3: 5-Bromo-l-(3-chlorobenzenesulfonyI)-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): 2839, 2793, 1583, 1443, 1376; Melting range
(0C): 116 - 122.7; Mass (m/z): 468.3, 470.3, 472.4 (M+H)+; 1H-NMR (δ ppm): 2.38 (3 H, s),
2.64 (4H, bs), 3.08 (4H, bs), 6.93 (IH, s), 7.34 - 7.36 (IH, t, J = 8.0), 7.41 - 7.48 (IH, dd, J =
8.84, 1.92), 7.47 - 7.50 (IH, m), 7.625 - 7.629 (IH, d, J = 1.84), 7.63 - 7.66 (IH, m), 7.77 -
7.78 (IH, t, J = 1.88), 7.87 - 7.89 (IH, d, J = 8.8) Example 4: 5-Bromo-l-(4-isopropyIbenzenesuIfonyl)-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): 2962, 2797, 1585, 1447, 1372, 1173, 1107,
776, 592; Mass (m/z): 476, 478 (M+H)+; 1H-NMR (δ ppm): 1.17 - 1.19 (6H, d, J = 6.92), 2.37 (3 H, s), 2.62 (4H, bs), 2.85 - 2.91 (IH, sept, J = 6.92), 3.07 (4H, bs), 6.98 (IH, s), 7.22 - 7.25
(2H, in), 7.V) - 7 1 1 (1 TT, ήή, J = 8.8, 1.88), 7.611 - 7.616 (III, d, J - l.δ'1), 7.68 7.71 (2H, m), 7.90 - 7.92 (IH, d, J = 8.8).
Example 5: 5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-mcthylpipcrazin-l-yl)-lII-iπdole: 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,
798; Mass (m/z): 452, 454 (M+H)+; 1H-NMR (δ ppm): 2.39 (3H, s), 2.65 (4H, bs), 3.08 (4H, bs), 6.94 (IH, s), 7.05 - 7.10 (2H, m), 7.40 - 7.43 (IH, dd, J = 4.8, 1.88), 7.612- 7.616 (IH, d,
J = 1.8), 7.78 - 7.82 (2H, m), 7.87 - 7.89 (IH, d, J = 8.8).
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. IR spectra (cm"1): 2934, 2819, 1590, 1372; 1H-NMR (δ ppm): Mass (m/z): 422.4, 424.4 (M+H)+; 1.11- 1.15 (3 H, t, J = 7.24), 2.47 - 2.53 (2H, q, J = 7.12), 2.65 (4H, bs), 3.09, (4H, bs), 6.91 (IH, s), 7.07 - 7.11 (2H, m), 7.18 - 7.21 (IH, dd, J = 8.52, 1.88), 7.40 - 7.42 (IH, dd, J = 8.48), 7.80 - 7.83 (2H, m), 8.033 - 8.038 (IH, d, J = 1.76). Example 7: 6-Chloro-l-(4-niethoxybenzenesulfonyI)-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. IR spectra (cm"1): 2968, 2818, 1593, 1367; Mass (m/z): 434.6
(M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.24), 2.47 - 2.52 (2H, q, J = 7.2), 2.64 (4H,' bs), 3.07 (4H, bs), 3.79 (3H, s), 6.84 - 6.87 (2H, m), 6.94 (IH, s), 7.16 - 7.19 (IH, dd, J = 8.44, 1.84), 7.39 - 7.41 (IH, d, J = 8.48), 1.12 - 1.16 (2H, m), 8.044 - 8.049 (IH, d, J = 1.76).
Example 8: 6-ChIoro-l-(4-isopropyIbenzenesulfonyI)-3-(4-methyIpiperazin-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): 2963, 2797, 1595, 1458; Mass (m/z): 432.3, 434.4 (M+H)+; 1H-NMR (δ ppm): 1.18 - 1.2 (6H, d, J = 6.92), 2.36 (3H, s), 2.61 - 2.62 (4H, bs), 2.88 - 2.90 (IH, m), 3.05 - 3.1 (4H, bs), 6.96 (IH, s), 7.17 - 7.19 (IH, dd, J = 8.44, 1.84), 7.24 - 7.26 (2H, m), 7.39 - 7.42 (IH, d, J = 8.48), 7.7 - 7.73 (2H, m), 8.064 - 8.069 (IH, d, J = 1.72).
Example 9: 6-Chloro-l-(3-trifluoromethylbenzenesuIfonyl)-3-(4-methyI piperazin-1- 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): 458.2, 460.2 (M+H)+; 1H-NMR (δ ppm): 2.36 (3 H, s), 2.59 - 2.62 (4H, t, J = 4.56), 3.06 - 3.08 (4H, t, J = 4.60), 6.92 (IH, s), 7.20 - 7.23 (IH, dd, J = 8.48, 1.80), 7.40 - 7.42 (IH, d, J = 8.48), 7.55 - 7.59 (IH, t, J = 7.92), 7.77 - 7.79 (IH, d, J - 7.84), 7.95 - 7.97 (IH, d, J = 8.0), 8.055 - 8.059 (IH, d, J = 1.88), 8.07 (IH, s).
Example IU: 6-ChIoiO-l-(4-methoxyben/eii[e!iulfυiij'l)-3-(4-iiιeUiylpiperaziπ-l-yl)-lil- indolc:
Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm"1): 2963, 2799, 1594, 1455; Melting range (0C): 159.1 - 162.1 Mass (m/z): 420.1, 422.1; (M+H)+; 1H-NMR (δ ppm): 2.36 (3H, s), 2.59 - 2.61 (4H, t, J = 4.44), 3.06 - 3.08 (4H, t, J = 4.32), 3.79 (3H, s), 6.85 - 6.88 (2H, m), 6.94 (IH, s), 7.16 - 7.19 (IH, dd, J = 8.48, 1.88), 7.38 - 7.41 (IH, d, J = 8.48), 7.72 - 7.76 (2H, m), 8.041 - 8.046 (IH, d, J = 1.8). 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,
476.1 ; (MB-H)+; 1H-NMR (δ ppm): 2.36 (3H, s), 2.59 - 2.62 (4H, t, J = 4.4), 3.06 - 3.09 (4H, t,
J = 4.48), 6.9 (I H, s), 7.2 - 7.25 (3H, m), 7.41 - 7.43 (IH, d, J = 8.52), 7.83 - 7.87 (2H, m), 8.045 - 8.049 (1H, d, J = 1.72).
Example 12: 6-ChIoro-l-(4-methylbenzenesulfonyl)-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. IR spectra (cm"1): 2939, 2799, 1587, 1455; Mass (m/z): 404.3, 406.3 (M+H)+; 1H-NMR (δ ppm): 2.34 (3H, s), 2.36 (3H, s), 2.58 - 2.64 (4H, bs), 3.40 - 3.90 (4H, bs), 6.94 (IH, s), 7.16 - 7.21 (3H, m), 7.38 - 7.40 (IH, d5 J = 8.48), 7.67 - 7.69 (2H, m), 8.043 - 8.047 (IH, dd, J = 1.80). 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. IR spectra (cm"1): 2939, 2799, 1590, 1493; Mass (m/z): 408.3, 410.2 (M+H)+; 1H-NMR (δ ppm): 2.36 (3H, s), 2.59 - 2.61 (4H, t, J = 4.52), 3.06 - 3.08 (4H, t, J = 4.0), 6.91 (IH, s), 7.07 - 7.11 (2H, m), 7.19 - 7.21 (IH, dd, J = 8.44, 1.84), 7.40 - 7.42 (IH, d, J = 8.48), 7.81 - 7.84 (2H, m), 8.034 - 8.039 (IH, d, J = 1.8). Example 14: 6-Chloro-l-(2-bromobenzenesulfonyl)-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): 2969, 2817, 1588, 1371; Mass (m/z): 482.2,
484.2, 486.2 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.16 (3 H, t, J = 7.24), 2.49 - 2.54 (2H, q, J =
7.2), 2.67 (4H, bs), 3.13 (4H, bs), 7.18 - 7.21 (2H, m), 7.36 - 7.44 (2H, m), 7.46 - 7.48 (IH, d, J = 8.44), 7.66 - 7.69 (IH, dd, J = 7.792, 1.3), 7.764 - 7.768 (IH, d, J = 1.74), 7.91 - 7.93 (IH, dd, J = 7.85, 7.94).
Example 15: 6-Chloro-l-(4-isopropylbenzenesulfonyl)-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): 2964, 2812, 1586, 1368; Mass (m/z): 446,5,
44S.4 (M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.24), 1.18 - 1.2 (6H, d, J = 6.95),
2.47 - 2.52 (2H, q, J = 7.19), 2.64 (4H, bs), 2.85 - 2.92 (IH, sep., J = 6.90),.3.09 (4H, bs), 6.95
(IH, s), 7.17 - 7.19 (IH, dd, J - 8.43, 1.82), 7.24 - 7.26 (2H, m), 7.40 - 7.42 (IH, d, J = 8.52),
7.70 - 7.73 (2H, m), 8.06 - 8.07 (IH, d, J = 1.76). 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. Mass (m/z): 482.2, 484.2, 486.3 (M+H)+; 1H-NMR (δ ppm): 1.13 - 1.16 (3H, t, J = 7.21), 2.5 - 2.55 (2H, q, J = 7.18), 2.68 (4H, bs), 3.13 (4H, bs), 7.18 — 7.21 (IH, dd, J = 8.82, 2.04), 7.23 (IH, s), 7.35 - 7.39 (IH, dt, J = 7.64, 1.93), 7.4 - 7.44 (I H, dt, J = 7.49, 1.3), 7.52 - 7.525 (IH, d, J = 2.0), 7.65 - 7.67 (2H, in), 7.92 - 7.9 (IH, dd, J = 7.74, 1.81). Example 17: 5-Chloro-l-(4-isopropylbenzenesulfonyI)-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. IR spectra (cm'1): 2964, 2818, 1595, 1450; Mass (m/z): 446.8,
448.8 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.15 (3H, t, J = 7.19), 1.17 - 1.19 (6H, d, J = 6.92), 2.48 - 2.53 (2H, q, J = 6.87), 2.65 (4H, bs), 2.84 - 2.89 (IH, sep., J •= 6.92), 3.08 (4H, bs), 6.99 (IH, s), 7.22 - 7.28 (3H, m), 7.45 - 7.46 (IH, d, J = 2.03), 7.68 - 7.70 (2H, m), 7.95 - 7.97 (IH, d, J = 8.84). Example 18: 5-Chloro-l-(3-chlorobenzenesulfonyl)-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. IR spectra (cm"1): 2963, 2925, 1584, 1376; Mass (m/z): 438.4,
440.4, 442.4 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.16 (3H, t, J = 7.19), 2.49 - 2.54 (2H, q, J =
7.16), 2.66 (4H, bs), 3.08 (4H, bs), 6.94 (IH, s), 7.28 - 7.30 (IH, dd, J = 8.91, 1.94), 7.32 - 7.36 (IH, t, J = 7.98), 7.47 - 7.49 (2H, m), 7.63 - 7.65 (IH, m), 7.77 (IH, m), 7.92 - 7.94 (IH, d, J = 8.88).
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 nυπ-critical variations above derivative was prepared. IR spectra (cm'1): 2926, 2818, 1596, 1450; Mass (m/z): 418.4, 420.3 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.15 (3H, t, J = 7.18), 2.33 (3H, s), 2.48 - 2.65 (2H, q, J = 7.19), 2.65 (4H, bs), 3.08 (4H, bs), 6.98 (IH, s), 7.16 - 7.18 (2H, m), 7.24 - 7.27 (IH, m), 7.44 - 7.45 (IH, d, J = 1.89), 7.64 - 7.66 (2H, m), 7.93 - 7.95 (IH, d, J = 8.8). 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,
423.9 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.15 (3H, t, J = 7.20), 2.48 - 2.53 (2H, q, J = 7.12), 2.65 (4H, bs), 3.08 (4H, bs), 6.94 (IH, s), 7.04 - 7.09 (2H, m), 7.26 - 7.29 (IH, dd, J = 8.88, 1.96), 7.462 - 7.467 (IH, d, J = 2.0), 7.77 - 7.81 (2H, m), 7.92 - 7.94 (IH, d, J = 8.8). 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,
510.2 (M+H)+; 1H-NMR (δ ppm): 1.14 - 1.18 (3H, t, J = 7.15), 2.54 (2H, q), 2.71 (4H, bs), 3.11 (4H, bs), 3.60 (3H, s), 3.81 (3H5 s), 6.78 - 6.80 (IH, d, J = 9.08), 7.01 - 7.04 (IH, dd, J = 9.03, 3.14), 7.09 (I H, s), 7.31 - 7.34 (IH, dd, J = 8.8, 1.8), 7.55 - 7.56 (IH, d, J = 3.3), 7.64 - 7.645 (1 H, d, J = 1.8), 7.67 - 7.69 (1 H, d, J = 8.8).
Example 22: 5-Bromo-l-(2-bromobenzenesulfonyI)-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. IR spectra (cm"1): 2928, 2819, 1677, 1448; Mass (m/z): 526.3, 528.2, 530.1 (M+H)+; 1H-NMR (δ ppm): 1.10 - 1.17 (3H, t, J = 7.16), 2.52 - 2.53 (2H, q), 2.68
(4H, bs), 3.13 (4H, bs), 7.21 (IH, s), 7.31 - 7.34 (IH, dd, J = 8.84, 1.88), 7.35 - 7.40 (IH, dt, J
= 7.56, 1.84), 7.40 - 7.45 (IH, dt, J = 7.68, 1.56), 7.60 - 7.62 (IH, d, J = 8.80), 7.65 - 7.68
(2H, m), 7.93 - 7.97 (IH, dd, J = 7.80, 1.84).
Example 23: 5-Bromo-l-(4-trifluoromethoxybenzenesulfonyl)-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): 2928, 2821, 1587, 1448; Mass (m/z): 532.3,
534.3 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.16 (3H, t, J = 6.76), 2.50 - 2.52 (2H, q), 2.66 (4H, bs), 3.09 (4H, bs), 6.93 (IH, s), 7.20 - 7.22 (2H, d), 7.41 - 7.44 (IH, dd, J - 8.84, 1.92), 7.631 - 7.636 (IH, d, J = 2.20), 7.81 - 7.83 (2H, m), 7.88 - 7.90 (IH, d, J = 8.80).
Example 24: 5-Bromo-l-(4-methylbenzenesulfonyl)-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. IR spectra (cm"1): 2926, 2820, 1676, 1448; Mass (m/z): 462.3,
464.5 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.16 (3H, t, J = 7.20), 2.33 (3H, s), 2.50 - 2.55 (2H, q, J = 7.16), 2.67 (4H, bs), 3.08 (4H, bs), 6.96 (IH, s), 7.17 - 7.19 (2H, d, J = 8.16), 7.38 - 7.40 (IH, dd, J = 8.84, 1.92), 7.601- 7.605 (IH, d, J = 1.88), 7.64 - 7.66 (2H, d, J = 8.32), 7.88 - 7.90 (IH, d, J = 8.84). Example 25: 5-Bromo-l-(4-isopropylbenzenesulfonyl)-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. IR spectra (cm"1): 2964, 2818, 1596 1448; Mass (m/z): 490.3,
492.6 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.15 (3H, t, J = 7.20), 1.17 - 1.19 (6H, d, J = 6.96), 2.48 - 2.53 (2H, q, J = 7.08), 2.65 (4H, bs), 2.84 - 2.88 (IH, m), 3.49 (4H, bs), 6.98 (IH, s), 7.22 - 7.26 (2H, m), 7.39 - 7.41 (IH, dd, J = 8.8, 1.92), 7.61 - 7.62 (IH, d, J = 1.76), 7.68 -
7.70 (2H, m), 7.90 - 7.92 (1 H, d, J = 8.84).
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. IR spectra (cm"1): 2930, 2791, 1601, 1441; Mass (m/z): 488.2, 490.5 (M-HH)+; 1H-NMR (δ ppm): 1.1 1 - 1.15 (3H, t, J = 7.20), 2.47 - 2.52 (2H5 q, J = 7.20), 2.64 (4H, bs), 3.09 (4H, bs), 6.91 (IH, s), 7.20 - 7.26 (3H, m), 7.42 - 7.44 (IH, d, J = 8.48), 7.83 - 7.87 (2H, m), 8.04 - 8.05 (IH, d, J = 1.7). Example 27: 6-Chloro-l-(benzenesulfonyl)-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. IR spectra (cm"1): 2968, 2817, 1587, 1447; Mass (m/z): 404, 406 (M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.24), 2.47 - 2.52 (2H, q, J = 7.20), 2.64 (4H, bs), 3.09 (4H, bs), 6.95 (IH, s), 7.17 - 7.20 (IH, dd, J = 8.48, 1.84), 7.39 - 7.44 (3H, m), 7.51 - 7.55 (IH, m), 7.79 -7.81 (2H, m), 8.05 - 8.06 (IH, d, J = 1.8).
Example 28: 6-Chloro-l-(4-bromobenzenesulfonyl)-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. IR spectra (cm"1): 2971, 2820, 1572, 1424; Mass (m/z): 482.2,
484.2, 486.3 (M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.24), 2.47 - 2.52 (2H, q, J = 7.24), 2.64 (4H, bs), 3.08 (4H, bs), 6.89 (IH, s), 7.19 - 7.21 (IH, dd, J = 8.44, 1.84), 7.40 - 7.42 (IH, d, J = 8.48), 7.53 - 7.56 (2H, m), 7.63 - 7.66 (2H, m), 8.023 - 8.028 (IH, d, J = 1.76). Example 29: 6-Chloro-l-(l-Naphthylsulfonyl)-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. IR spectra (cm"1): 2936, 2814, 1589, 1450; Mass (m/z): 454.4, 456.7 (M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3 H, t, J = 7.20), 2.47 - 2.52 (2H, q, J = 7.20), 2.64 (4H, bs), 3.09 (4H, bs), 7.14 - 7.17 (IH, dd, J = 8.8, 1.8), 7.18 (IH, s), 7.40 - 7.42 (IH, d, J = 8.53), 7.-18 - 7.50 (IH, t, J = -1.12), 7.54 - 7.65 (2H, m), 7.87 7.88 (2H, m), 7.95 7.97 (I H, dd, 7.44, 0.8), 8.02 - 8.04 (IH, d, J = 8.23), 8.73 - 8.75 (IH, d, J = 8.66). Example 30: δ-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. IR spectra (cm"1): 2968, 2817, 1588, 1372; Mass (m/z): 438.5, 440.2, 442.6 (M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.20), 2.47 - 2.53 (2H, q, J = 7.24), 2.65 (4H, bs), 3.10 (4H, bs), 6.91 (IH, s), 7.20 - 7.22 (IH, dd, J = 8.52, 1.88), 7.34 - 7.38 (IH, t, J = 7.96), 7.41 - 7.44 (IH, d, J = 8.48), 7.48 - 7.52 (IH, m), 7.66 - 7.69 (IH, m), 7.78 - 7.79 (IH, t, J = 1.88), 8.02 - 8.03 (IH, d, J = 1.76). Example 31: 6-Chloro-l-(2,5-dimethoxybenzenesuIfonyl)-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. IR spectra (cm'1): 2965, 2807, 1585, 1492; Mass (m/z): 464.5, 466.5 (M+H)+; 1H-NMR (δ ppm): 1.12 - 1.15 (3H, t, J = 7.15), 2.48 - 2.53 (2H, q, J = 7.25), 2. (4H, bs), 3.10 (4H, bs), 3.62 (3H, s), 3.82 (3H, s), 6.79 - 6.81 (IH, d, J = 9.04), 7.02 - 7.05 (2H, m), 7.15 - 7.18 (IH, dd, J = 8.44, 1.9), 7.42 - 7.44 (IH, d, J = 8.48), 7.54 - 7.55 (IH, d, J = 3.15), 7.881 - 7.886 (1 H, d, J = 1.77).
Example 32: 6-ChIoro-l-(3-trifluoromethyIbenzenesuIfoπyl)-3-(4-ethyl piperazin-1-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): 2930, 2815, 1376, 1326; Mass (m/z): 472.5, 474.5 (M+H)+; 1H-NMR (δ ppm): 1.11 -1.15 (3H5 1, 7.16), 2.47 - 2.52 (2H, q, J = 7.12), 2.64 (4H, bs), 3.09 (4H, bs), 6.91 (IH, s), 7.20 - 7.23 (IH, dd, J = 8.41, 1.70), 7.40 - 7.42 (IH, d, J = 8.55), 7.55 - 7.59 (IH, t, J = 7.90), 7.77 - 7.79 (IH, d, J = 7.76), 7.95 - 7.97 (IH, d, J = 8.0), 8.05 - 8.07 (2H, m).
Example 33: 6-Chloro-l-(4-methylbenzenesulfonyl)-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. IR spectra (cm"1): 2968, 2818, 1588; Mass (m/z): 418.5, 420.4
(M+H)+; 1H-NMR (δ ppm): 1.11 - 1.15 (3H, t, J = 7.21), 2.34 (3H, s), 2.47 - 2.52 (2H, q, J =
7.18), 2.64 (4H, bs), 3.08 (4H, bs), 6.94 (IH, s), 7.16 - 7.20 (3H, m), 7.38 - 7.40 (IH, d, J =
8.48), 7.67- 7.69 (211, d, J - 8.36), 8.044 - 8.048 (HI, d, J - 1.71).
Example 34: 6-ChIoro-l-(2,5-dimethoxybenzenesulfonyl)~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): 2965, 2807, 1585, 1492; Mass (m/z): 450.2, 452.2 (M+H)+; 1H-NMR (δ ppm): 2.37 (3H, s), 2.60 - 2.62 (4H, bs), 3.10 (4H, bs), 3.62 (3H, s), 3.82 (3H, s), 6.79 - 6.81 (IH, d, J = 9.04), 7.02 - 7.05 (2H, m), 7.15 - 7.18 (IH, dd, J = 8.44, 1.9), 7.42 - 7.44 (IH, d, J = 8.48), 7.54 - 7.55 (IH, d, J = 3.15), 7.881 - 7.886 (IH, d, J = 1.77). Example 35: o-Chloro-l^S-chlorobenzenesulfonyO-S^-methylpiperazin-l-yO-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): 2936, 2799, 1372, 1178; Mass (m/z): 424.2, 426.1, 428.2 (M+H)+; 1H-NMR (δ ppm): 2.37 (3H, s), 2.60 - 2.62 (4H, bs), 3.07 - 3.09 (4H, bs), 6.91 (IH, s), 7.20 - 7.22 (IH, dd, J = 8.50, 1.82), 7.345 - 7.38 (IH, t, J = 7.99, 7.47), 7.41 - 7.43 (IH, d, J = 8.49), 7.48 - 7.51 (IH, m), 7.66 - 7.69 (IH, m), 7.78 - 7.79 (IH, t, J = 1.86,
1.90), 8.032 - 8.036 (IH, d, J = 1.78).
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. IR spectra (cm"1): 2937, 2798, 1371, 1178; Mass (m/z): 468.2, 470.2, 472.3 (M+H)+; 1H-NMR (δ ppm): 2.37 (3H, s), 2.62 - 2.64 (4H, bs), 3.27 - 3.29 (4H, bs), 7.18 (IH, s), 7.19 - 7.21 (IH, dd, J = 8.54, 1.82), 7.36 - 7.48 (3H, m), 7.66 - 7.69 (IH, dd, = 7.76, 1.33), 7.765 - 7.769 (IH, d, J= 1.8), 7.91 - 7'.93 (IH, dd, J = 7.84, 1.1). Example 37: 6-Chloro-l-(4-bromobenzenesulfonyl)-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. IR spectra (cm"1): 2937, 2798, 1371, 1178; Mass (m/z): 468.2, 470.2, 472.3 (M+H)+; 1H-NMR (δ ppm): 2.36 (3H, s), 2.59 - 2.62 (4H, bs), 3.06 - 3.08 (4H, bs), 6.89 (IH, s), 7.19 - 7.21 (IH, dd, J = 8.5, 1.84), 7.40 - 7.42 (IH, d, J = 8.46), 7.53 - 7.57 (2H, m), 7.64 - 7.67 (2H, m), 8.022 - 8.026 (IH, d, J = 1.72). Example 38: l-(3-chlorobenzenesulfonyl)-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. IR spectra (cm"1): 2930, 2792, 1373, 1177; Mass (m/z): 390.2, 392.3 (M+H)+; 1H-NMR (δ ppm): 2.37 (3H, s), 2.61 - 2.64 (4H, bs), 3.12 - 3.08 (4H, bs), 6.93 (IH, s), 7.21 - 7.36 (3H, m), 7.50 - 7.52 (IH, d, J = 7.84), 7.65 - 7.67 (IH, m), 7.86 - 7.79 (IH, t , 1.92,1.80 ), 8.003 - 8.023 (IH, d, J = 8.32). Example 39: l-(4-methyIbenzenesulfonyl)-3-(4-methylpiperazin-l-y[)-lH-indoIe:
Using a similar procedure as given in the Example 1 and some non-critical variations above derivative was prepared. IR spectra (cm"1): 2938, 2797, 1367, 1173; Mass (m/z): 370.3
(M-HH)+; 1H-NMR (δ ppm): 2.31 (3H, s), 2.37 (3H, s), 2.61 - 2.63 (4H, bs), 3.10 (4H, bs), 6.96
(IH, s), 7.14 - 7.32 (4H, m), 7.47 - 7.49 (IH, d, J = 7.88), 7.66 - 7.68 (2H, dd, J = 8.36), 8.01 -
8.03 (IH, d , J - 8.32).
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. IR spectra (cm"1): 2963, 2799, 1368, 1174; Mass (m/z): 398.3 (M-HH)+; 1H-NMR (δ ppm): 1.16 - 1.18 (6H, d, J = 8), 2.37 (3H, s), 2.61 - 2.63 (4H, bs), 2.83 - 2.90 (IH, sep., J = 8), 3.11 (4H, bs), 6.98 (IH, s), 7.19 - 7.23 (3H, m), 7.29 - 7.33 (IH, m), 7.49 - 7.51 (IH, d, J = 7.87), 7.70 - 7.73 (2H, dd), 8.03 - 8.05 (IH, d, J = 8.32). 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. IR spectra (cm"1): 2962, 2798, 1366, 1 173; Mass (m/z): 374 (M+H)+; 1H-NMR (δ ppm): 2.38 (3H, s), 2.62 - 2.65 (4H, bs), 3.11 (4H, bs), 6.93 (IH, s), 7.02 - 7.07 (2H, m), 7.22 - 7.26 (I H, m), 7.30 - 7.32 (IH, m), 7.49 - 7.51 (IH, d, J = 7.88), 7.79 - 7.83 (2H, m), 8.00 - 8.02 (I H, d, J = 8.32). Example 42: Food Intake Measurement::
Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, Hyderabad, India) were used. The chronic effect of the compounds of general formula (I) on food intake in weil-fed rats was then determined as follows.
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.
On 0, 1st, 7th, 14th, 21st and 28th day the rats were left with the pre- weighed amounts of food. Food intake and weight gain were measured on the routine basis. Also a food ingestion method is disclosed in the literature (Kask et al., European Journal of Pharmacology, 414, 2001, 215-224, and Turnball et. Al., Diabetes, vol 51, August, 2002, and some in-house modificatins.). The respective parts of the descriptions are herein incorporated as a reference, and they form part of the disclosure.
Some representative compounds have shown the statistically significant decrease in food intake, when conducted in the above manner at the doses of either 10 mg/Kg, or 30 mg/Kg or both. Example 43: Tablet comprising a compound of formula (I):
Figure imgf000029_0001
The ingredients were combined and granulated using a solvent such as methanol. The formulation was then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine. Example 44: Composition for Oral Administration:
Figure imgf000030_0001
The ingredients were mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage. Example 45: Liquid oral formulation:
Figure imgf000030_0002
The ingredients were mixed to form a suspension for oral administration.
Example 46: Parenteral Formulation:
Figure imgf000030_0003
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.
Example 47: Suppository Formulation:
Figure imgf000030_0004
Figure imgf000031_0001
The ingredients were melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
Example 48: Topical Formulation:
Figure imgf000031_0002
All of the ingredients, except water, were combined and heated to about 60° C with stirring. A sufficient quantity of water at about 60° C was then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g. Example 49: Object Recognition Task Model:
The cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: object recognition task model.
Male wistar rats (230 - 280 g) obtained from N. I. N. (National Institute of Nutrition, Hyderabad, India) were used as an experimental animal.
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.
One group of 12 rats received vehicle (1 mL/Kg) orally and another set of animals received compound of the formula (I) either orally or i.p., before one hour of the familiar (Tl) and choice trial (T2). The experiment was carried out in a 50 x 50 x 50 cm open field made up of acrylic. In the familiarization phase, (Tl), the rats were placed individually in the open field for 3 min., in which two identical objects (plastic bottles, 12.5 cm height x 5.5 cm diameter) covered in yellow masking tape alone (al and a2) were positioned in two adjacent corners, 10 cm. from the walls. After 24 hour of the (Tl) trial for long-term memory test, the same rats were placed in the same arena as they were placed in Tl trial. Choice phase (T2) rats were allowed to explore the open field for 3 min. in presence of one familiar object (a3) and one novel object
(b) (Amber color glass bottle, 12 cm high and 5 cm in diameter. Familiar objects presented similar textures, colors and sizes. During the Tl and T2 trial, exploration of each object (defined as sniffing, licking, chewing or having moving vibrissae whilst directing the nose towards the object at a distance of less than 1 cm) were recorded separately by stopwatch.
Sitting on an object was not regarded as exploratory activity, however, it was rarely observed.
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.,
1988, A new one-trial test for neurobiological studies of memory in rats- Behavioral data,
Behav. Brain Res., 31, 47-59.
Some representative compounds have shown positive effects indicating the increased novel object recognition viz; increased exploration time with novel object and higher discrimination index
Example 50: Chewing/Yawning/Stretching induction by 5-HT6R antagonists:
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.,
Neuropharmacology, 2004, 47, 195-204. (B) Bentey J. C, Bourson A., Boess F. G., Fone K. C.
F., Marsden C. A., Petit N., Sleight A. J., British Journal of Pharmacology, 1999, 126 (7),
1537-1542).
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 ± 20C) and positioned underneath a wide-angled video camera to track animal. The 10 cm2 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.
Reference: (A) Yamada N., Hattoria A., Hayashi T., Nishikawa T., Fukuda H. et. Al., Pharmacology, Biochem. And Behaviour, 2004, 78, 787-791. (B) Linder M. D., Hodges D. B., Hogan J. B., Corsa J. A., et al The Journal of Pharmacology and Experimental Therapeutics, 2003, 307 (2), 682-691. Example 52: Passive avoidance Test:
Animals were trained in a single-trial, step through, light-dark passive avoidance paradigm. 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. 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. Experimental procedure:
This was canned out as described previously (Fox et al., 1995). Adult male Wistar rats weighing 200-230 g were used. Animals were brought to the laboratory 1 h before the experiment. On the day of training, animals were placed facing the rear of the light compartment of the apparatus. The timer was started once the animal has completely turned to face the front of the chamber. Latency to enter the dark chamber was recorded (usually < 20 s), and having completely entered the dark compartment an inescapable foot shock of 0.75 mA for 3 s was administered to the animal. Animals were then returned to their home cages. Between each training session, both compartments of the chamber were cleaned to remove any confounding olfactory cues. Recall of this inhibitory stimulus was evaluated 24 h, 72 h and on 7 day post-training by returning the animal into the light chamber and recording their latency to enter the dark chamber, a criterion time of 300 s was employed.
Reference: (A) Callahan P. M., llch C. P., Rowe N. B., Tehim A., Abst. 776.19.2004, Society for neuroscience, 2004. (B) Fox G. B., Connell A. W. U., Murphy K. J., Regan C. M., Journal ofNeurochemistry, 1995, 65, 6, 2796-2799.
Example 53: Binding assay for human 5-HT6 receptor:
5-HTfi Binding assay of compounds is tested according to the following procedures.
Materials and Methods:
Receptor source : Human recombinant expressed in HEK293 cells
Radioligand : [3H]LSD (60-80 Ci/mmol)
Final ligand concentration - [1.5 nM]
Non-specific determinant : Methiothepin mesylate - [0.1 μM]
Reference compound : Methiothepin mesylate
Positive control : Methiothepin mesylate Incubation conditions:
Reactions were carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl2, 0.5 mM EDTA for 60 minutes at 37 0C. 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 - 5HTό binding site.
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000035_0001
Literature Reference: Monsma F. J. Jr., et a]., Molecular Cloning and Expression of Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs. MoI. Pharmacol. (43): 320-327 (1993). Example 54: cAMP assay:
The antagonist property of the compounds at the human 5-HT6 receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HTβ 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-HTβ 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 CO2 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. 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. 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. Following 1 hour incubation at 4° C, the unbound ligand is separated by a simple washing procedure. Then an enzyme substrate, trimethylbenzidine (1), is added and incubated at room temperature for 60 min. The reaction is stopped by the addition of 100 uL 1.0 M sulphuric acid and the resultant color read by a microtitre plate spectrophotometer at 450 nM within 30 minutes.
In the functional adenylyl cyclase assay, some of the compound of this invention was found to be a competitive antagonist with good selectivity over a number of other receptors including other serotonin receptors such as 5-HTiA and 5-HT7.

Claims

We claim:
1. A compound having the formula (I),
Figure imgf000037_0001
Formula (I)
wherein: 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;
Figure imgf000037_0002
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (CrC3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R2 whenever present, represents hydrogen, (CrC3)alky1 or halo(CrC3)alkyl; R3 and R4 represents either hydrogen or methyl.
2. A compound of Claim-1 wherein Ar is phenyl, naphthyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl or benzimidazolyl.
3. A compound of Claim-1 wherein R1 is a hydrogen, halogen, perhaloalkyl, perhaloalkoxy, (CrC3)alkyl, halo(CrC3)alkyl, (C,-C3)alkoxy, halo(C1-C3)alkoxy, alkoxy(C!-C3)alkoxy, hydroxy(CrC3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy.
4. A compound of Claim-1 wherein R2 represents hydrogen, (CrC3)alkyl or halo(Cr C3)alkyl.
5. A compound of Claim-1 wherein both R3 and R4 represents hydrogen.
6. The compound, according to claim-1, selected from among the following group: 1 -(4-Fluorobenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole; 1 -(2-Bromobenzenesulfonyl)-3 -(4-methylpiperazin- 1 -y I)- 1 H-indole; l-(3-Chlorobenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-lH-indole; l-(4-Fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole; l-(2,5-Dimethoxybenzenesulfonyl)-3-(4-ethyIpiperazin-l-yl)-l H-indole; l-(2-Bromobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
1 -(4-Trifluoromethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l -yl)-l H-indole; l-(4-Methylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
1 -(4-Isopropylbenzenesulfonyl)-3-(4-ethylpiperazin- 1 -y I)- 1 H-indole; l-(4-FIuorobenzenesuIfonyl)-5-methoxy-3-(4-methylpiperazin-l-yl)-lH-indole; l-(2-Bromobenzenesulfonyl)-5-methoxy-3-(4-methylpiρerazin-l-yl)-lH-indole; l-(3-Chlorobenzenesulfonyl)-5-methoxy-3-(4-methylpiperazin-l- yl)-l H-indole; l-(4-Isopropylbenzenesulfonyl)-5-methoxy-3-(4-methylpiperazin-l- yl)-l H-indole; l-(4-FluorobenzenesulfonyI)-3-(4-ethyIpiperazin-l-yi)-5-methoxy-l H-indole;
1 -(2,5-Dimethoxybenzenesulfony])-3 -(4-ethylpiperazin- 1 -yl)-5 -methoxy- 1 H-indole; 1 -(2-Bromobenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)-5-methoxy- 1 H-indole;
3-(4-Ethylpiperazin- 1 -yl)-5-methoxy- 1 -(4-trifluoromethoxybenzenesulfonyl)- 1 H-indole;
3-(4-Ethylpiperazin- 1 -yl)- 1 -(4-Methylbenzenesulfonyl)-5-methoxy- 1 H-indole;
3-(4-Ethylpiperazin- 1 -yl)- 1 -(4-isopropylbenzenesulfonyl)-5-methoxy- 1 H-indole;
5-Bromo- 1 -(4-fluorobenzenesulfonyl)-3-(4-methylpiperazin- 1 - yl)- 1 H-indole; 5-Bromo-l -(2-bromobenzenesulfonyl)-3-(4-methylpiperazin- 1 -yl)-l H-indole;
5-Bromo-l-(3-chlorobenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-l H-indole;
5-Bromo-l-(4-isopropylbenzenesulfonyl)-3-(4-methylpiperazin-l- yl)-l H-indole;
5-Bromo-l-(4-fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
5-Bromo-l-(2,5-dimethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole; 5-Bromo- 1 -(2-bromobenzenesulfonyl)-3 -(4-ethylpiperazin- 1 -y I)- 1 H-indole;
5-Bromo- 1 -(4-trifluoromethoxybenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
5-Bromo- 1 -(4-methylbenzenesulfonyl)-3-(4-ethyIpiperazin- 1 -yl)- 1 H-indole;
5-Bromo-l-(4-isoρropylbenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
6-Chloro- 1 -(4-fluorobenzenesulfony l)-3 -(4-ethylpiperazin- 1 -yl)- 1 H-indole; 6-Chloro- 1 -(4-methoxybenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-isopropylbenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(3-trifluoromethylbenzenesulfonyl)-3-(4-methyl piperazin- 1 -yl)- 1 H-indole;
6-Chloro-l-(4-methoxybenzenesulfonyl)-3-(4-methylpiperazin-l-yl)-lH-indole;
6-Chloro- 1 -(4-trifluoromethoxybenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole; 6-Chloro- 1 -(4-methylbenzenesulfony l)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-fluorobenzenesulfonyl)-3 -(4-methylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(2-bromobenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole; 6-Chloro- 1 -(4-isopropy lbenzenesul fonyl)-3 -(4-ethyl piperazin- 1 -yl)- 1 H-indole;
5-Chloro-l-(2-bromobenzenesulfonyl)- 3-(4-ethylρiperazin-l-yl)-lH-indole;
5-Chloro- 1 -(4-isopropylbenzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
5-Chloro- 1 -(3-chlorobenzenesuIfony I)-3 -(4-ethyIpiperazin- 1 -yl)- 1 H-indole; 5-ChloiO-l-(4-methylbenzenesulfony])-3-(4-ethylpiperazin-l-yl)-l H-indole;
5-Chloro-l-(4-fluorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole;
6-Chloro-l-(4-trifluoromethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole;
6-Chloro- 1 -(benzenesulfonyl)-3-(4-ethylpiperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-bromobenzenesulfonyi)-3-(4-ethy lpiperazin- 1 -yl)- 1 H-indole; 6-Chloro-l -(I -Naphthylsu]fonyl)-3-(4-ethylpiperazin-l -yl)-l H-indole;
6-Chloro-l-(3-chlorobenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-l H-indole;
6-Chloro-l-(2,5-dimethoxybenzenesulfonyl)-3-(4-ethylpiperazin-l-yl)-lH-indole;
6-Chloro- 1 -(3-trifluoromethylbenzenesulfonyl)-3-(4-ethyl piperazin- 1 -yl)- 1 H-indole;
6-Chloro- 1 -(4-methyIbenzenesulfonyl)-3-(4-ethylρiperazin- 1 -yl)- 1 H-indole; astereoisomer thereof ; and a salt thereof.
7. A process to prepare a compound of formula (I), as claimed in claim-1, wherein the said process comprises of contacting a compound of formula (a)
Figure imgf000039_0001
00 wherein all substitutents are as defined for the compound of formula (I) in claim-1, with aryl sulphonyl compound of formula ArSO2Cl, wherein Ar is as defined for the compound of formula (I) in claim-1, in presence of an appropriate base and inert solvent at suitable temperature to obtain a compound of formula (T).
8. A process for preparing a compound of formula (I) according to claim-1, wherein if necessary, one or more of the following steps are carried out:
1. converting a compound of the formula (I) into another compound of the formula (I)
2. removing any protecting groups; or
3. forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
9. A method for the treatment of a disorder of the central nervous system related to or affected by the 5-HTg receptor, in a patient in need thereof, which comprises providing to said patient a therapeutically effective amount of a compound of formula (I) as defined in any one of claim- 1 to claim-6.
10. The method according to claim-9 wherein the said disorder is a motor disorder, anxiety disorder, a cognitive disorder, or a neurodegenerative disorder.
11. The method according to claim-10 wherein the said disorder is selected from a group consisting of: attention deficit disorder; obsessive compulsive disorder; withdrawal from drug, alcohol or nicotine addiction; schizophrenia and depression.
12. The method according to claim-9 wherein the said disorder is Alzheimer's disease or Parkinson's disease.
13. The method according to claim-9 wherein the said disorder is attention deficit disorder or obsessive compulsive disorder.
14. The method according to claim-9 wherein the said disorder is stroke or head trauma.
15. The method according to claim-9 wherein the said disorder is eating disorder or obesity.
16. A pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and, -an effective amount of a compound of formula (I) as defined in any one of claim- 1 to claim-6.
17. A compound of formula (I), as defined in any one of claim- 1 to claim-6 for use as a medicament.
18. Use of compound of foπnula (I), as defined in any one of Claim- 1 to Claim-6 in the manufacture of a medicament for the treatment of a disorder of the central nervous system related to or affected by the 5-HTg receptor.
19. A method for testing agonists and antagonists with selectivity for the 5-HTg receptor comprising: administering a compound of claim-1 and observing said animals' responses; and comparing said responses to control animals; and administering other compounds of unknown activity to said experimental animals.
PCT/IN2007/000059 2006-05-30 2007-02-14 3-(heterocyclyl)-n-(arylsulfonyl)indole derivatives as functional 5-ht6 ligands WO2007138611A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN923CH2006 2006-05-30
IN923/CHE/2006 2006-05-30

Publications (1)

Publication Number Publication Date
WO2007138611A1 true WO2007138611A1 (en) 2007-12-06

Family

ID=38195718

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000059 WO2007138611A1 (en) 2006-05-30 2007-02-14 3-(heterocyclyl)-n-(arylsulfonyl)indole derivatives as functional 5-ht6 ligands

Country Status (1)

Country Link
WO (1) WO2007138611A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010032258A1 (en) 2008-09-17 2010-03-25 Suven Life Sciences Limited Aryl sulfonamide amine compounds and their use as 5-ht6 ligands
WO2011083487A1 (en) 2010-01-05 2011-07-14 Suven Life Sciences Limited Sulfone compounds as 5-ht6 receptor ligands
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

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 (en) * 1999-06-24 2001-06-13 Toray Industries, Inc. Alpha1b-adrenergic receptor antagonists
WO2003013510A1 (en) * 2001-08-07 2003-02-20 Smithkline Beecham P.L.C. 3-arylsulfonyl-7-piperazinyl- indoles, -benzofurans and -benzothiophenes with 5-ht6 receptor affinity for treating cns disorders
WO2005013974A1 (en) * 2003-07-30 2005-02-17 Laboratorios Del Dr. Esteve S.A. 1-sulfonylindole derivatives, their preparation and their use as 5-ht6 ligands
WO2005066126A1 (en) * 2003-12-23 2005-07-21 Eli Lilly And Company Cb1 modulator compounds

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 (en) * 1999-06-24 2001-06-13 Toray Industries, Inc. Alpha1b-adrenergic receptor antagonists
WO2003013510A1 (en) * 2001-08-07 2003-02-20 Smithkline Beecham P.L.C. 3-arylsulfonyl-7-piperazinyl- indoles, -benzofurans and -benzothiophenes with 5-ht6 receptor affinity for treating cns disorders
WO2005013974A1 (en) * 2003-07-30 2005-02-17 Laboratorios Del Dr. Esteve S.A. 1-sulfonylindole derivatives, their preparation and their use as 5-ht6 ligands
WO2005066126A1 (en) * 2003-12-23 2005-07-21 Eli Lilly And Company Cb1 modulator compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010032258A1 (en) 2008-09-17 2010-03-25 Suven Life Sciences Limited Aryl sulfonamide amine compounds and their use as 5-ht6 ligands
WO2011083487A1 (en) 2010-01-05 2011-07-14 Suven Life Sciences Limited Sulfone compounds as 5-ht6 receptor ligands
CN102869647A (en) * 2010-01-05 2013-01-09 苏文生命科学有限公司 Sulfone compounds as 5-ht6 receptor ligands
JP2013516458A (en) * 2010-01-05 2013-05-13 スベン ライフ サイエンシズ リミティド Sulfone compounds as 5-HT6 receptor ligands
US9018231B2 (en) 2010-01-05 2015-04-28 Suven Life Sciences Limited Sulfone compounds as 5-HT6 receptor ligands
CN102869647B (en) * 2010-01-05 2015-06-24 苏文生命科学有限公司 Sulfone compounds as 5-ht6 receptor ligands
EA022043B1 (en) * 2010-01-05 2015-10-30 Сувен Лайф Сайенсиз Лимитед Sulfone compounds as 5-htreceptor ligands
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

Similar Documents

Publication Publication Date Title
EP1919896B1 (en) Aminoaryl sulphonamide derivatives as functional 5-ht6 ligands.
US8470830B2 (en) 5-(heterocyclyl)alkyl-N-(arylsulfonyl)indole compounds and their use as 5-HT6 ligands
US8003670B2 (en) Aminoalkoxy aryl sulfonamide compounds and their use as 5-HT6 ligands
EP2121602B1 (en) 4-(heterocyclyl)alkyl-n-(arylsulfonyl) indole compounds and their use as 5-ht6 ligands
WO2007138611A1 (en) 3-(heterocyclyl)-n-(arylsulfonyl)indole derivatives as functional 5-ht6 ligands
WO2007020653A1 (en) Thioether derivatives as functional 5-ht6 ligands
WO2009034581A1 (en) Substituted indolyl compounds and their use as 5-ht6 ligands
EP1948166B1 (en) Carbazole derivatives as functional 5-ht6 ligands

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07736524

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07736524

Country of ref document: EP

Kind code of ref document: A1