WO2007020653A1 - Thioether derivatives as functional 5-ht6 ligands - Google Patents

Thioether derivatives as functional 5-ht6 ligands Download PDF

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Publication number
WO2007020653A1
WO2007020653A1 PCT/IN2005/000346 IN2005000346W WO2007020653A1 WO 2007020653 A1 WO2007020653 A1 WO 2007020653A1 IN 2005000346 W IN2005000346 W IN 2005000346W WO 2007020653 A1 WO2007020653 A1 WO 2007020653A1
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Prior art keywords
indole
dimethylaminoethylthio
methyl
alkyl
compound
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PCT/IN2005/000346
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French (fr)
Inventor
Venkata Satya Nirogi Ramakrishna
Vikas Shreekrishna Shirsath
Rama Sastri Kambhampati
Santosh Vishwakarma
Nagaraj Vishwottam Kandikere
Srinivasulu Kota
Venkateswarlu Jasti
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Suven Life Sciences Limited
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Publication of WO2007020653A1 publication Critical patent/WO2007020653A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • 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 thioether derivatives, their stereoisomers, their salts, their preparation and medicine containing them.
  • 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-HT ] family (e.g. 5-HTIA), the 5-HT 2 family (e.g.5- HT 2 A) 5 5-HT 3 , 5-HT4, 5-HT 5 , 5-HT 6 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).
  • GPCR G-protein coupled receptor
  • the receptor is found almost exclusively in the central nervous system (CNS) areas both in rat and in human.
  • 5-HTg receptor mRNA 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.
  • 5-HTg ligands there are many potential therapeutic uses for 5-HTg 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. Preferably, antagonist compounds of 5-hg receptors are sought after as therapeutic agents.
  • 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.
  • 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 both children and adults.
  • ADD attention deficit disorders
  • 5-HTg antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and because 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.
  • 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).
  • 5-HTg receptor modulators i.e. ligands
  • compounds which are 5-HTg receptor modulators may be useful for therapeutic indications including: the 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.
  • Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder.
  • GI gastrointestinal
  • Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder.
  • GI gastrointestinal
  • GI gastrointestinal
  • Thioether compounds of this invention has now been found to demonstrate 5-HTg receptor affinity, which may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders.
  • CNS central nervous system
  • the present invention relates to a compound of the Formula (I),
  • R 1 , R 3 and R 4 independently represents hydrogen, halogen, cyano, (C r C 3 )alkyl, ImIo(C]- C 3 )alkyl, thio(Ci-C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (C r C 3 )alkoxy, cyclo(C 3 -C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R 3 and R 4 may form a 5, 6 or 7 membered 'cyclic structure';
  • R 2 represents hydrogen, (Ci-C 3 )alkyl; halo(C r C 3 )alkyl and (Ci-C 3 )alkylthio;
  • R 5 and R5 independently represents hydrogen, (C r C 3 )alkyl, (C 3 )alkyl, (C 3 )alkyl, (C 3 )alky
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of atleast 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), in manufacture of a medicament, for the treatment or 1 prevention of disorders involving selective affinity for the 5 -HTg receptor.
  • the invention further relates to the process for preparing compounds of formula (I).
  • 35. 1 -(4-Isopropylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -ethoxy- 1 H- indole; 36. 1 -(2,4-Difluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -fluoro- IH- indole;
  • 70 l-(Benzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; 71. l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; 72. l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-mdole;
  • Ri represents hydrogen, halogen, cyano, (Ci- C 3 )alkyl, halo(C 1 -C 3 )alkyl, thio(Ci-C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 3 )alkoxy, cyclo(C 3 - C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R 2 represents hydrogen, (Ci-C 3 )alkyl; halo(Ci-C 3 )alkyl and (C r C 3 )alkylthio; R 5 and R 6 represents hydrogen, (C r C 3 )alkyl, (C 3 -C 7 )cycloalkyl; optionally R 5 and R?
  • R 7 and Rs represents hydrogen, (Ci-C 3 )alkyl; optionally, R 7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure.
  • R 7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure.
  • Ri represents hydrogen, halogen, cyano, (Cr C 3 )alkyl, halo(C 1 -C 3 )alkyl, thio(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (d-C 3 )alkoxy, cyclo(C 3 - C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R 2 represents hydrogen, (Ci-C 3 )alkyl; halo(Ci-C 3 )alkyl and (Ci-C 3 )alkylthio; R 5 and R 5 represents hydrogen, (C r C 3 )alkyl, (C 3 -C 7 )cycloalkyl; optionally R 5 and R 7 may form a 5, 6 or 7 membered 'cyclic structure'; R 7 and Rg represents hydrogen, (C
  • Ri, R 3 and R 4 independently represents hydrogen, halogen, cyano, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, thio(Ci-C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (C r C 3 )alkoxy, cyclo(C 3 -C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R 3 and R 4 together with the carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R 2 represents hydrogen, (Ci-C 3 )alkyl; halo(Ci-C 3 )alkyl and (C r C 3 )alkylthio.
  • the 5-hydroxytryptamine-6 (5-HTg) receptor is one of the most recent receptors to be identified by molecular cloning. Its has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor.
  • Ri , R 3 and Rt independently represents hydrogen, halogen, cyano, (C r C 3 )alkyl, halo(Ci-C 3 )alkyl, thio(d- C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (Ci-C 3 )alkoxy, cyclo(C 3 -C 7 )alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R 3 and R 4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C 3 )alkyl; halo(C !
  • R 5 and R 6 independently represents hydrogen, (Ci-C 3 )alkyl, (C 3 -C 7 )cycloalkyl; optionally R 6 and R 7 may form a 5, 6 or 7 membered 'cyclic structure'; R 7 and Rs represents hydrogen, (Ci-C 3 )alkyl; optionally, R 7 and Rs may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 1 or 2.
  • halogen as used herein and in the claims (unless the context indicates otherwise) means atom such as fluorine, chlorine, bromine or iodine;
  • (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 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, which may be further substituted.
  • 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, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroetliyl, difluoroethyl and the like.
  • halo(CrC 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 fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difiuoroethoxy and the like.
  • cyclo(C 3 -C 7 )alkyl as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain 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 7 )alkoxy as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from three to six carbon atoms and includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, the cycloalkoxy group may be substituted and the like.
  • Suitable "cyclic structures" formed by R 6 and R 7 , R 7 and R 8 wherever applicable may contain 3, 4, 5, 6 or 7 ring atoms as defined in the description, which may optionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally contain one or more double bonds and optionally contain combination of double bond and hetero atoms as described earlier.
  • cyclic structures examples include benzene, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like, which may be optionally substituted,
  • Suitable substituents on the "cyclic structure" as defined above include oxo, hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, (Ci-C 3 )alkyl, (Cr C 3 )alkoxy, thioalkyl, alkylthio, phenyl or benzyl groups.
  • 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 stereospecif ⁇ c 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 5 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 stereospecif ⁇ c or asymmetric synthesis.
  • stereoisomers of compounds of general formula (I) may be prepared by one or more ways presented below:
  • One or more of the reagents may be used in their optically active form.
  • 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 Ed., Tetrahedron series, 14, 311-316).
  • 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 (eg. water).
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises of following schemes:
  • 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.
  • 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, X, 2 ⁇ X- 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(EHman linker), which may be removed by acid catalysed hydrolysis, for example withtrifluoroacetic 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.
  • 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.
  • 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 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 forms 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 are preferably arranged so that 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.
  • the pharmaceutical 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.
  • 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-HTg receptor antagonist is indicated, such as in the treatment of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances. Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances.
  • Parkinsonism amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • schizophrenia means schizophrenia, schizophreniform, disorder, schizoaffective disorder and psychotic disorder wherein the term “psychotic” refers to delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington,
  • “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, (ii) 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.
  • the reaction scheme depicted herein provides potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • reaction reaction T.L.C.
  • the reaction mixture was cooled to 40 0 C. and the solvent was distilled under reduced pressure.
  • 100 mL of water was added and the mixture was extracted with ethyl acetate (50 mL x 3), then combined organic layer was washed with brine solution and dried over sodium sulphate and the organic solvents were removed under reduced pressure to obtain the title product.
  • reaction mixture was maintained at 20 - 25 °C for further 30 minutes.
  • TLC reaction-wise reaction
  • the excess of THF was distilled off and the concentrate was diluted with ice- water and extracted with ethyl acetate (4 x 10 mL).
  • the combined organic extracts were washed with cold water 25 mL, dried over sodium sulfate and evaporated under reduced pressure, below 50 °C.
  • the crude residue was purified by silica gel column chromatography using 30 % methanol in ethyl acetate as a mobile phase, to obtain the titled compound, which was identified by IR, NMR and mass spectral analyses.
  • mice Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, India) were used. fsThe chronic effect of the compounds of general formula (I) on food intake in well-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 Lp., 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.
  • the ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
  • Veegum K (Vanderbilt Co.) 1.0 g
  • the cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: the object recognition task model.
  • Male wistar rats (230 - 280 g) obtained from N. I. N. (National Institute of Nutrition, India) were used as an experimental animal.
  • Four animals were housed in each cage. Animals were kept on 20 % 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).
  • 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 comers, 10 cm. from the walls.
  • two identical objects plastic bottles, 12.5 cm height x 5.5 cm diameter
  • al and a2 yellow masking tape alone
  • the same rats were placed in the same arena as they were placed in Tl trial.
  • 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.
  • Ex. 101 Chewing/Yawning/Stretching induction by 5HTeR 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.
  • 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 black Perspex used in the construction of the maze and platform offered no intramaze cues to guide escape behavior.
  • 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
  • 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 5mm in diameter and spaced 12.5 mm apart.
  • a current generator supplied 0.75 niA 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.
  • Receptor source Human recombinant expressed in HEK293 cells
  • Non-specific determinant Methiothepin mesylate - [0.1 ⁇ M]
  • Incubation conditions Reactions are 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 is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HTg binding site.
  • Table 2 % Binding at 5-HT 6 (h) receptor at 100 nM concentration.

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Abstract

The present invention provides thioether derivatives of formula (I), useful in treatment of a CNS disorder related to or affected by the 5-HT6 receptor. Pharmacological profile of these compounds includes high affinity binding with 5-HT6 receptor along with selectivity towards the said receptor. The present invention also includes the stereoisomers, the salts, methods of preparation and medicine containing the said thioether derivatives.

Description

Thioether derivatives as functional S-HTg ligands.
Field of Invention;
The present invention relates to certain thioether derivatives, their stereoisomers, their salts, their preparation and medicine containing them. Background of the Invention „-•
Various central nervous system disorders such as anxiety, depression, motor disorders etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. 5 -HT receptor subtypes regulate the various effects of serotonin. Known 5 -HT receptor family includes the 5-HT] family (e.g. 5-HTIA), the 5-HT2 family (e.g.5- HT2A)5 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 rat and in human.
In situ hybridization studies of the 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,v 1995, 64, 1105-1111). Highest levels of 5-HTg receptor mRNA has been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus as well as CA], 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.
The high affinity of a number of antipsychotic agents for the 5-HTg receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting the said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HTg receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-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 C. Reavill and D. C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(l):104-109, Pharma Press Ltd.
There are many potential therapeutic uses for 5-HTg 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. Preferably, antagonist compounds of 5-hg receptors are sought after as therapeutic agents. 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 important structures in the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens, and cortex suggest 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 supported the potential cognition use (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). 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 neurochemicals known to be involved in 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 (I)3 23-26). Animal studies of memory and learning with a known selective 5-HTg antagonist found 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 both children and adults. Because 5-HTg antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and because 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. 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 human 5-HTg receptor is being 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).
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).
Taken together, the above studies strongly suggest that compounds which are 5-HTg receptor modulators, i.e. ligands, may be useful for therapeutic indications including: the 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.
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, B. L. Roth et al., J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley et al., Molecular Pharmacology, 1993, 43, 320-327, A. J. Sleight et al., Neurotransmission, 1995, 11, 1-5, and A. J. Sleight 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, Bentley et al., British Journal of Pharmacology, 1999, Suppl., 126, A64: 255; Wooley et al., Neuropharmacology, 2001, 41: 210-129; and WO 02/098878.
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 related prior art. These PCT applications and the references reported therein are all incorporated herein. 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- HT6.
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.
Summary of the Invention: Thioether compounds of this invention has now been found to demonstrate 5-HTg receptor affinity, which may be 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),
Figure imgf000005_0001
Formula (I) along with its stereoisomer or its salt with an inorganic or organic acid, wherein: R1, R3 and R4 independently represents hydrogen, halogen, cyano, (CrC3)alkyl, ImIo(C]- C3)alkyl, thio(Ci-C3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(CrC3)alkyl and (Ci-C3)alkylthio; R5 and R5 independently represents hydrogen, (CrC3)alkyl, (C3- C7)cycloalkyl; optionally R5 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and R8 represents hydrogen, (Ci-C3)alkyl; optionally, R7 and R8 may form a 3, 4, 5,
6 or 7 membered 'cyclic structure; "m" represents integer either 0, 1 or 2.
(ii) In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of atleast 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), in manufacture of a medicament, for the treatment or 1 prevention of disorders 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) It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HTg receptor.
(vi) Partial list of such compounds of general formula (I) is as follows:
1. l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole;
2. l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole; 3. l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole;
4. l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole;
5. l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- methoxy-lH- indole; 6. 1 -(4-Isopropylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio- lH-indole;
7. l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole;
8. l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole; 9. l-(4-Meiiiylbenzenesulfonyl)-2-methyl-3-dimethylamin.oethylthio-5-fluoro-lH- indole;
10. l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole; 11. l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole;
12. l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole;
13. l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole; 14. l-(4-Methoxybenzenesulfonyl)-2 -methyl -3 -dimethylaminoethylthio-5 -fmoro- 1 H- indole;
15. 1 -(4-Fluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -fluoro- 1 H- indole;
16. l-Benzenesulfonyl-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH-indole; 17. l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole;
18. 1 -(4-Fluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -bromo- IH- indole;
19. l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethyltlτio-5-bromo-lH- indole;
20. l-(4-Methoxybenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -bromo- IH- indole;
21. l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole; 22. l-Benzenesulfonyl-2-methyl-3-dimethylaminoethylthio-5-bromo-lH-indole;
23. l-(234-Difluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole;
24. l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole; 25. l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5- bromo- lH-indole;
26. l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl-lH-indole;
27. l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoetliylthio-5- trifluoromethyl-lH-indole;
28. l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-trifluoromethyl- lH-indole;
29. l-(4-Bromobenzenesulfonyl)-2-niethyl-3-Dimethylaminoethylthio-5-trifluoromethyl- lH-indole;
30. l-(2-Bromobenzenesulfonyl)-2-methyl-3-Dimethylanτinoeth.ylthio-5-trifluoromethyl- lH-indole;
31. l-(4-Methylbenzenesulfonyl)-2-methyl-3-Dimethylaminoethylthio-5-trifluoromethyl- lH-indole;
32. l-Benzenesulfonyl^-methyl-S-Dimethylaminoethylthio-S-trifluoromethyl-lH-indole;
33. 1 -(2,4-Difluorobenzenesulfbnyl) -2-methyl-3 -dimethylaminoethylthio-5 - trifluoromethyl-lH-indole;
34. l-(4-Medioxybenzenesulfonyl)-2-methyl-3-dimethylammoethylthio-5-eth.oxy-lH- indole;
35. 1 -(4-Isopropylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -ethoxy- 1 H- indole; 36. 1 -(2,4-Difluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -fluoro- IH- indole;
37. l-(5-Chloro-3-Methylbenzothiophen-2-yl-sulfonyl)-2-methyl-3- dimethylaminoethylthio-lH-indole;
38. l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro- lH-indole;
39. l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH- indole;
40. l-Benzenesulfonyl-2-methyl-3-dimethylamino ethylthio-5-methylthio-lH-indole;
41. l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- methylthio-lH-indole;
42. 1 -(4-Fluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methylthio- 1 H- indole;
43. 1 -(4-Bromobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methylthio- IH-
. indole; 44. l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH- indole;
45. l-(2-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH- indole;
46. l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole;
47. ^(S-Trifluoromethylbenzenesulfony^^-methyl-S-dimethylaminoethylthio-S-chloro- lH-indole;
48. l-(2,4-Difluorobenzenesulfonyl)-2-methyl-3-dimethylaniinoethylthio-5-methylthio- lH-indole;
49. l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-chloro-lH- indole;
50. l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoethylthio-5-chloro-lH- indole;
51. l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl- lH-indole; 52. l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-chloro-lH-indole;
53. 1 -(4-Isopropylbenzenesulfonyl)-3-dimethylaminoetliylthio-5 -chloro- lH-indole;
54. l-(4-Metlioxybenzenesulfonyl)-3-dimetliylaminoethylthio-5-bromo-lH-indole;
55. 1 -(4-Methoxybenzenesulfonyl)-3 -dimethylaminoethylthio-5 -chloro- 1 H-indole;
56. l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indole; 57. l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indole;
58. l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoetliylthio-5-bromo-lH- indole;
59. 1 -(2-Bromobenzenesulfonyl)-3 -dimethylaminoethylthio-5-methoxy- 1 H-indole;
60. l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indole; 61. l-(4-Fluorobenzenesnlfonyl)-3-dimethylaminoethylthio-5-metlioxy-lH-indole;
62. 1 -(Benzenesulfonyl)-3 -dimethylaminoethylthio-5 -methoxy- 1 H-indole;
63. l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole;
64. l-(4-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole;
65. l-(4-Methylbenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole; 66. l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indoIe;
67. l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole;
68. l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole;
69. l-(4-Methylbenzenesulfonyl)-3-dimethylaminoetliylthio-lH-mdole;
70. l-(Benzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; 71. l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; 72. l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-mdole;
73. 1 -(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio- lH-indole;
74. {2-[5-Bromo-l-(4-fluorobenzenesulphonyl)-lH-indole-3- sulphinyl]ethyl} dimethylamine; 75. {2-[l-(2-Bromobenzenesulphonyl)-lH-mdole-3-sulphinyl]ethyl}dimethylamine;
76. {2-[5-Bromo-l-(2-bromobenzenesulphonyl)-lH-indole-3-sulphinyl] ethyl} dimethylamine;
77. {2-[5-Bromo- 1 -(4-methoxybenzenesulphonyl) - 1 H-indole-3 -sulphinyl] ethyl} dimethylamine; 78. [2-[5-Bromo-l-(4-isopropylbenzenesulphonyl)-lH-indole-3-sulphinyl] ethyl} dimethylamine;
79. 1 -(4-Methoxybenzenesulfonyl)-3 -dimethylaminoethylthio-5 -fluoro- 1 H-indole ;
80. l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole;
81. l-(4-Bromobenzenesulfonyl)-3-dimethylaminoethyltliio-5-fluoro-lH-indole; 82. l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole;
83. {2-[5-Methoxy-l-(4-isopropylbenzenesulphonyl)-lH-indole-3- sulphinyl] ethyl} dimethylamine;
84. {2-[5-Methoxy-l-(2-Bromobenzenesulphonyl)-lH-indole-3- sulphinyl] ethyl} dimethylamine; 85. l-(2-Bromobenzenesulfonyl)-3-(N-methyltetrahydropyrrolidin-3-yl)thio-5-methoxy- lH-indole;
86. l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-6-chloro-lH-indole;
87. l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethylthio-6-chloro-lH-indole;
88. {2-[ 1 -(4-Methoxybenzenesulphonyl)- lH-indole-3 -sulphinyl] ethyl} dimethylamine ; 89. {2-[l-(4-Isopropylbenzenesulphonyl)-lH-indole-3-sulphinyl]ethyl}dimethylamine;
90. 1 -(4-Fluorobenzenesulfonyl)-3 -dimethylaminoethylthio-5 -fluoro- 1 H-indole;
91. {2-[l-(4-Methoxybenzenesulphonyl)-5-Methoxy-lH-indole-3- sulphinyl] ethyl} dimethylamine;
92. l-(2,4,5-Trichlorobenzenesulfonyl)-3-dimethylaminoethylthio-2-methyl-5-bromo- lH-indole;
93. l-(3-chlorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole;
94. 1 -(3-chlorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5,7-difluoro- 1 H- indole;
95. l-(l-naphthylsulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH-indole;
96. l-Cl-naphthylsulfony^-l-methyl-S-dimethylaminoethylthio-S-trifluoromethyl-lH- indole;
97. l-(2-naph.thylsulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole;
98. l-(2-naphthylsulfonyl)-2-methyl-3-dimethylaminoethylthio-4-meth.oxy-lH-indole;
99. {2-[5 -Bromo- 1 -(3 -chlorobenzenesulphonyl)- 1 H-indole-3 -sulphinyl] ethyl} dimethylamine;
100. {2-[5-ethoxy-l-(2-naphthylsulphonyl)-lH-indole-3-sulplimyl] ethyl} dimethylamine;
a stereoisomer thereof ; and a salt thereof.
(vii) The novel intermediate of the formula (c),
Figure imgf000011_0001
(c) along with its stereoisomer or its salt, wherein: Ri represents hydrogen, halogen, cyano, (Ci- C3)alkyl, halo(C1-C3)alkyl, thio(Ci-C3)alkyl, (C3-C7)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3- C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (CrC3)alkylthio; R5 and R6 represents hydrogen, (Cr C3)alkyl, (C3-C7)cycloalkyl; optionally R5 and R? may form a 5, 6 or 7 membered 'cyclic structure'; R7 and Rs represents hydrogen, (Ci-C3)alkyl; optionally, R7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure. (viii) The novel intermediate of the formula (f).
Figure imgf000011_0002
along with its stereoisomer or its salt, wherein: Ri represents hydrogen, halogen, cyano, (Cr C3)alkyl, halo(C1-C3)alkyl, thio(C1-C3)alkyl, (C3-C7)cycloalkyl, (d-C3)alkoxy, cyclo(C3- C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (Ci-C3)alkylthio; R5 and R5 represents hydrogen, (Cr C3)alkyl, (C3-C7)cycloalkyl; optionally R5 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and Rg represents hydrogen, (CrC3)alkyl; optionally, R7 and R8 may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 1 or 2.
(ix) The compound of formula (g)
Figure imgf000012_0001
wherein: Ri, R3 and R4 independently represents hydrogen, halogen, cyano, (Ci-C3)alkyl, halo(Ci-C3)alkyl, thio(Ci-C3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 together with the carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (CrC3)alkylthio.
Detailed Description of the Invention: The 5-hydroxytryptamine-6 (5-HTg) receptor is one of the most recent receptors to be identified by molecular cloning. Its has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor.
Surprisingly, it has now been found that thioether derivatives of formula (I) demonstrate 5-HTg receptor affinity,
Figure imgf000012_0002
along with its stereoisomer or its salt with an inorganic or organic acid, wherein: Ri , R3 and Rt independently represents hydrogen, halogen, cyano, (CrC3)alkyl, halo(Ci-C3)alkyl, thio(d- C3)alkyl, (C3-C7)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(C!-C3)alkyl and (Ci-C3)alkylthio; R5 and R6 independently represents hydrogen, (Ci-C3)alkyl, (C3-C7)cycloalkyl; optionally R6 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and Rs represents hydrogen, (Ci-C3)alkyl; optionally, R7 and Rs may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 1 or 2.
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 "(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 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, which may be further substituted.
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, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroetliyl, 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, difiuoroethoxy and the like.
The term "cyclo(C3-C7)alkyl" as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain 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-C7)alkoxy" as used herein and in the claims (unless the context indicates otherwise) means straight and branched chain alkyl radicals containing from three to six carbon atoms and includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, the cycloalkoxy group may be substituted and the like. Suitable "cyclic structures" formed by R6 and R7, R7 and R8 wherever applicable may contain 3, 4, 5, 6 or 7 ring atoms as defined in the description, which may optionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally contain one or more double bonds and optionally contain combination of double bond and hetero atoms as described earlier. Examples for the "cyclic structures" include benzene, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like, which may be optionally substituted,
Suitable substituents on the "cyclic structure" as defined above include oxo, hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, (Ci-C3)alkyl, (Cr C3)alkoxy, thioalkyl, alkylthio, phenyl or benzyl groups.
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 stereospecifϊc 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 D5L- 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 stereospecifϊc 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. ϋ) 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 Ed., Tetrahedron series, 14, 311-316). 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 the 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 (eg. water).
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises of following schemes:
Scheme 1; compounds of formula (I), wherein value for m is 0 (i) Contacting a compound of formula (a) :
Figure imgf000016_0001
(a) wherein substitutents such as Ri , R2 are as defined for compound of formula (I) with a amine of formula (b):
Figure imgf000016_0002
(b) wherein all the substitutents are as defined for the compound of formula (I); Lg is suitable leaving group such halogeno for example chloro, bromo or iodo; to produce a substituted indole thioether of the formula (c), wherein all of the substitutents are as defined earlier
Figure imgf000016_0003
(ii) treating a compound of formula (c), with arylsulfonyl derivatives of formula (d):
Figure imgf000017_0001
wherein all of the substitutents are as defined earlier, Lg is suitable leaving group such halogeno for example chloro, bromo or iodo; to obtain a compound of the formula (I) or its derivative.
Scheme 2; compounds of formula (I), wherein value for m is 1 or 2
Herein compounds of formula (I) having S-oxides i.e. may be prepared,
(i) oxidizing the sulfur in the side chain compound of formula (c) as described earlier, with suitable agents such as iodate salts of sodium, potassium and the like; to obtain compound (f) given below:
Figure imgf000017_0002
(f) wherein all of the substitutents are as defined earlier;
(Ii) treating a compound of the formula (f),wherein all of the substitutents are as defined earlier; Lg is suitable leaving group such halogeno for example chloro, bromo or iodo; with a compound of the formula (d),
Figure imgf000017_0003
wherein all of the substitutents as defined earlier, to obtain a compound of the formula
(I) or its derivative, wherein integer m has value either 1 or 2. Scheme 3: using thioindoxyl route: (i) Literature methods are reported for the preparation of indoxyls, for example,
WO2004048331 (Al)3 assigned to Suven Life Sciences. Similarly treating a substituted indole with various reagents a corresponding thioindoxyls can be prepared. A compound of general formula (g),
Figure imgf000018_0001
(g) wherein all of the substitutents are as defined earlier; with a amine of formula (b),
Figure imgf000018_0002
(b) wherein all of the substitutents are as defined earlier; Lg is suitable leaving group such halogeno for example chloro, bromo or iodo; provides a compound of the formula (I). Compounds obtained by the above method of preparation of the present invention can be transferred to 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, 0-alkylation, O- acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation, 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), 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, X, 2\ X- 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\ X- 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(EHman linker), which may be removed by acid catalysed hydrolysis, for example withtrifluoroacetic 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.
Numerous processes to prepare the intermediate of formula (a) can be found in literature. Some of them include US patent 4,059,583; Tetrahedron Letters, 51, 4465-66, 1969; Indian Journal of Chemistry, 2OB, 672-679, 1981. Compounds of the present invention may be synthesized by these synthetic routes that include processes analogous to those known in the chemical art, particularly in light of the description contained herein. Further various susbstitutions in indole ring can be achieved using modification of Fishcher indole synthesis.
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.
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. 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 forms 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. 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.
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-HTg receptor antagonist is indicated, such as in the treatment of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances. Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease. 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, (ii) 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. IH NMR spectra were recorded at 300 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 are reported 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, τt=triplet of triplets, m=multiplet. NMR, mass were corrected for background peaks. Specific rotations were measured at room temperature using the sodium D (589 nm). Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The following Descriptions and Examples illustrate the preparation of compounds of the invention. Intermediate 1: 5-Fluoro-3-dimethyIaminoethyIthio-lH-indole (intermediate (c))
S-(5-Fluoro-3-indolyl)isothiourea HI salt (intermediate (a)) (9 g, 26.7 mmoles) was dissolved in alkaline solution (I g NaOH in 20 mL ethanol) along with stirring and inert atmosphere. To the above reaction mixture, alcoholic solution of dimethylaminoethylchloride (36.1 mmoles) previously neutralised with Ig NaOH in 20 mL of ethanol was added. Additional alkali solution (1 g NaOH in 15 mL ethanol, 0.025 mmoles) was added and then the reaction mass was refluxed for 35 - 40 minutes. After completion of the reaction reaction (T.L.C.) the reaction mixture was cooled to 40 0C. and the solvent was distilled under reduced pressure. To this 100 mL of water was added and the mixture was extracted with ethyl acetate (50 mL x 3), then combined organic layer was washed with brine solution and dried over sodium sulphate and the organic solvents were removed under reduced pressure to obtain the title product.
The residue obtained was purified by flash chromatography (silica gel, EtOAc/TEA, 9.9/0.1) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound. Mass (m/e): 239(M+H)+
Intermediate 2: 5-Bromo-lH-indole-3-suIphinyIethyIdimethylamine (intermediate (f))
5-Bromo-3-dimethylaminoethylthio-lH-indole (3.65 mmole) dissolved in 35 mL methanol and 140 mL water was charged into a flask, cooled to 10 deg C. and sodium periodate (3.65 mmole) slowly under stirring in 15 minutes, maintaining the reaction mass at temperature below 25 deg C and the reaction was monitored by (TLC). After completion, the reaction mass was saturated with sodium sulphate and the product was extracted with dichloromethane (50 mL x 4). The combined organic layer was dried over sodium sulphate and the organic solvents were removed under reduced pressure to obtain the title product.
The residue obtained was purified by flash chromatography (silica gel, EtOAc/TEA, 9.9/0.1) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound. Mass (m/e) : 315, 317 (M+H)+ Ex. 1: l-(4-FIuorobenzenesuIfonyl)-2-methyI-3-dirnethylaminoethyIthio-lH-indole
A suspension of potassium hydride (1.2 mmoles, washed with hexane/THF mixture before use), in THF was stirred and cooled at 0 - 5 °C. To this cooled solution was added a solution of 2-methyl-3-dimethylaminoethylthio-lH-indole (0.8 mmoles), in THF, slowly, over 15 min. After completion of addition, the mixture was warmed to 25 - 30 0C and maintained for 2 hr. Then a solution of 4-Fluorobenzene sulfonyl chloride in THF (1.2 mmoles, in 2 mL of THF) was then added slowly to the above well stirred mixture under nitrogen atmosphere. The reaction mixture was maintained at 20 - 25 °C for further 30 minutes. After completion of reaction (TLC), the excess of THF was distilled off and the concentrate was diluted with ice- water and extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with cold water 25 mL, dried over sodium sulfate and evaporated under reduced pressure, below 50 °C. The crude residue was purified by silica gel column chromatography using 30 % methanol in ethyl acetate as a mobile phase, to obtain the titled compound, which was identified by IR, NMR and mass spectral analyses. IR spectra (cm"1): 1591, 1372, 1232, 1180; Mass (m/z): 393.3 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.36 (2H, m), 2.7-2.72 (2H, m), 2.74 (3H, s) 7.0-7.1 (2H, m), 7.3 (2H, m), 7.62-7.63 (IH, m), 7.78-7.81 (2H, m), 8.17-8.18 (IH, m). Ex. 2: l-(4-Bromobenzenesulfonyl)-2-methyI-3-dimethyIaminoethyIthio-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2969, 1574, 1373 1183; Mass (m/z): 453.2, 455.2(M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.32-2.35 (2H, m), 2.7-2.73 (2H, m), 2.74 (3H, s), 7.3-7.33 (2H, m), 7.54-7.56 (2H, m), 7.61-7.64 (3H, m), 8.15-8.18 (IH, m). Ex. 3: l-(4-BromobenzenesuIfonyI)-2-methyI-3-dimethyIaminoethylthio-5-methoxy-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2928, 1609, 1373, 1166, 794, 563; Mass (m/z): 483(M+H)+, 485(M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, m), 2.3-2.32 (2H, m), 2.68-2.72 (5H, m), 3.86 (3H, s), 6.9-6.93 (IH, dd, J = 9.08, 2.64 Hz), 7.07-7.078 (IH5 d, J = 2.56 Hz), 7.53-7.6 (4H, m), 8.04-8.06 (IH, d, J = 9.04 Hz). Ex. 4: l-(4-MethylbenzenesulfonyI)-2-methyl-3-dimethylaminoethyIthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2963, 2927, 1598, 1450, 1371, 1175; Mass (m/z): 389.5 (M+H)+; 1H-NMR (δ, ppm): 2.14 (6H, s), 2.31-2.35 (5H, m), 2.69- 2.73 (2H, m), 2.74 (3H, s), 7.19-7.31 (4H, m), 7.61-7.67 (3H, m), 8.19-8.21(1H, m). Ex. 5: l-(4-FluorobenzenesuIfonyl)-2-methyl-3-dimethylaminoethyIthio-5-methoxy-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2935, 2773, 1591, 1474, 1372, 1181, 684, 567; Mass (m/z): 423 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.34 (2H, m), 2.68-2.71 (5H, m), 3.86 (3H, s), 6.9-6.93 (IH, dd, J =9.08, 2.6 Hz), 7.06-7.1 (3H, m), 7.74-- 7.78 (2H, m), 8.05-8.07 (IH, d, J = 9.0 Hz). Ex. 6: l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2964, 1596, 1450, 1371, 1177;
Mass (m/z): 417.5 (M+H)+; 1H-NMR (δ, ppm): 1.18-1.2 (6H, d, I = 6.88 Hz), 2.13 (6H, s),
2.31- 2.35 (2H, m), 2.7-2.73 (IH, h, J = 7 Hz), 2.75 (3H, s), 2.87-2.91 (2H, m), 7.25-7.32 (4H, m), 7.62-7.63 (IH, m), 7.69-7.71 (2H, m), 8.21-8.23 (IH, m).
Ex. 7: l-(4-Isopropylbenzenesulfonyl)-2-methyI-3-dimethyIaminoethylthio-5-methoxy- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1609, 1474, 1370, 1167; Mass (m/z): 447.5 (M+H)+; 1H-NMR (δ, ppm): 1.182-1.189 (6H, d, J = 6.88), 2.13 (6H, s),
2.30- 2.34 (2H, m), 2.68-2.71 (2H, m), 2.72 (3H, s), 2.87-2.91(1H, m), 3.86 (3H, s), 6.9-6.93 (IH, dd, J = 9.0, 2.64 Hz), 7.07-7.08 (IH, d3 J = 2.56 Hz), 7.24-7.26 (2H, m), 7.65-7.67 (2H, m), 8.09-8.11 (IH, d, J = 9.04 Hz).
Ex. 8: l-(4-MethyIbenzenesuIfonyI)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1); 2933, 1609, 1474, 1369, 1167; Mass (raJz): 419.4(M+H)+, 1H-NMR (δ, ppm): 2.16 (6H, s), 2.34-2.37 (5H, m), 2.69-2.73, (5H, m), 3.86 (3H, s), 6.89-6.92 (IH, dd, J = 9.02, 2.62 Hz), 7.06-7.068 (IH, d, J = 2.58), 7.18-7.2 (2H, d, J = 8.09 Hz), 7.61-7.64 (2H, m), 8.07-8.09 (IH, d, J = 8.98 Hz). Ex. 9: l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2928, 1591, 1468, 1372, 1175,
1159; Mass (m/z): 407.4 (M+H)+, 1H-NMR (δ, ppm): 2.14 (6H, s), 2.3-2.33 (2H, m), 2.35 (3H, s), 2.67-2.7 (2H, m), 2.73 (3H, s), 7.00-7.03 (IH, m), 7.21-7.23 (2H, m), 7.27-7.29 (IH, m),
7.62-7.64 (2H, m), 8.13-8.16 (IH, m).
Ex. 10: l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethyIthio-S-fluoro-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2935, 1590, 1469, 1377, 1154;
Mass (m/z): 471.4, 473.4 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.35 (2H, m), 2.69-
2.7 (2H, m), 2.72 (3H, s) 7.0-7.06 (IH, m), 7.27-7.3 (IH, dd, J = 8.44, 2.64 Hz), 7.56-7.61 (4H, m), 8.1-8.13 (IH, m).
Ex. 11: l-(4-IsopropyIbenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2965, 1594, 1468, 1372, 1176;
Mass (m/z): 435.4 (M+H)+; 1H-NMR (δ, ppm): 1.19-1.2 (6H, d), 2.14 (6H, s), 2.3-2.34 (2H, m), 2.67-2.71 (2H, m), 2.73 (3H, s), 2.87-2.94 (IH, m), 7.0-7.05 (IH, m), 7.26-7.3 (3H, m), 7.66 -7.68 (2H, m), 8.14-8.18 (IH, m).
Ex. 12: l-(4-MethoxybenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2929, 1595, 1474, 1370, 1167; Mass (m/z): 435.5 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.32-2.36 (2H, m), 2.6-2.7 (2H, m), 2.72 (3H, s), 3.79 (3H, s), 3.86 (3H, s), 6.84-6.86 (2H, m), 6.89-6.92 (IH, dd, J = 9.04, 2.6
Hz), 7.06-7.07 (IH, d, J = 2.6 Hz)3 7.68-7.7 (2H, m), 8.07-8.099 (IH, d, J = 9.04 Hz).
Ex. 13: l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2972, 1593, 1496, 1370, 1265,
1166, 579, 552; Mass (m/z): 405.1 (M+H)+; 1H-NMR (δ, ppm): 2.1 (6H, s), 2.32-2.35 (2H, m),
2.69-2.73 (2H, m), 2.74 (3H,s), 3.79 (3H, s), 6.85-6.87 (2H, m), 7.28-7.31 (2H, m), 7.61- 7.62
(IH, m), 7.71-7.73 (2H, m), 8.19-8.21 (IH, m).
Ex. 14: l-(4-MethoxybenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1594, 1371, 1264, 1167;
Mass (m/z): 423.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.32-2.34 (2H, m), 2.68-2.71
(2H, m), 2.73 (3H,s), 3.8 (3H,s), 6.86-6.89 (2H, m), 7.0-7.05 (IH, m), 7.26-7.29 (IH, m), 7.69- 7.71 (2H, m), 8.13-8.16 (IH, m).
Ex. 15: l-(4-FIuorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2959, 1590, 1470, 1372, 1232, 1177; Mass (m/z): 411.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.35 (2H, m), 2.68-
2.71 (2H, m), 2.73 (3H, s), 7.0-7.07 (IH, m), 7.09-7.13 (2H, m), 7.28-7.3 (IH, dd), 7.76-7.79
(2H, m), 8.11-8.14 (IH, m).
Ex. 16: l-BenzenesuIfonyl-2-methyl-3-dimethylaminoethylthio-5-fluoro-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2928, 1590, 1467, 1372, 1244,
1159; Mass (m/z): 393.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.14 (6H, s), 2.3-2.34 (2H, m), 2.67-
2.71 (2H, m), 2.73 (3H, s), 7.01-7.07 (IH, m), 7.27-7.30 (IH, dd, J = 6.64, 2.64 Hz), 7.42-7.46
(2H, m), 7.54-7.56 (IH, m), 7.74-7.76 (2H, m), 8.13-8.17 (IH, m).
Ex. 17: l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2936, 1573, 1443, 1390, 1183;
Mass (m/z): 531, 533, 535 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.31-2.34 (2H, m), 2.69-
2.73 (5H5 m), 7.41-7.43 (IH, dd, J = 8.84, 2.0 Hz), 7.56-7.62 (4H, m), 7.76-7.77 (IH, d, J = 1.96 Hz), 8.03-8.05 (IH, d, J = 8.84 Hz). Ex. 18: l-(4-FluorobenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2927, 1591, 1180; Mass (m/z): 471.4, 473.4 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.31-2.35 (2H, m), 2.68-2.72 (5H, m), 7.1- 7.14 (2H, m), 7.4-7.43 (IH, dd, J = 8.88, 2.0 Hz), 7.76-7.80 (3H, m), 8.04-8.07 (d, IH, J = 8.84 Hz). Ex. 19: l-(4-IsopropyIbenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1595, 1443, 1177; Mass (m/z): 495.4, 497.4 (M+H)+ ; 1H-NMR (δ, ppm): 1.19-1.20 (6H, d), 2.14 (6H, s), 2.30-2.34 (2H, m), 2.68-2.71 (2H, m), 2.73 (3H, s), 2.87-2.94 (IH, m), 7.27-7.29 (2H, m), 7.39-7.42 (IH, dd, J = 8.84, 2.08 Hz), 7.66-7.69 (2H, m), 7.76-7.77 (IH, d, J= 2.0), 8.08-8.10 (IH, d, J = 8.84 Hz).
Ex. 20: l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole
Using essentially the same procedure described in example 1, and some 'non-critical variations the above derivative was prepared. IR spectra (cm"1): 2925, 1594, 1442, 1168; Mass (m/z): 483.3, 485.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.31-2.35 (2H, m), 2.68-2.71 (2H, m), 2.73 (3H, s), 3.8 (3H, s), 6.87-6.9 (2H, m), 7.38-7.41 (IH, dd, J = 8.84, 1.96 Hz), 7.69- 7.71 (2H, m), 7.75-7.76 (IH, d, J = 2.0 Hz), 8.06-8.09 (IH, d, J = 8.84 Hz). Ex. 21: l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethyIaminoethylthio-5-bromo-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2924, 1596, 1442, 1371, 1175, 744, 577; Mass (m/z): 467, 469 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.30-2.34 (2H, m), 2.36 (3H, s), 2.67-2.71 (2H, m), 2.73 (3H, s), 7.21-7.26 (2H, m), 7.39-7.41 (IH, dd, J = 8.84, 1.96 Hz), 7.63-7.65 (2H, m), 7.754-7.759 (IH, d, J = 1.96 Hz), 8.068-8.090 (IH, d, J = 8.88 Hz).
Ex. 22: l-Benzenesulfonyl-2-methyI-3-dimethylaminoethylthio-5-bromo-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2918, 1573, 1445, 1364, 1227,
1177, 750, 577; Mass (m/z): 453.2, 455.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.35 (2H, m), 2.68-2.72 (2H, m), 2.73 (3H, s), 7.4-7.47 (3H, m), 7.55-7.60 (IH, m), 7.74-7.77 (3H, m), 8.07-8.09 (IH5 d, J = 8.88 Hz). Ex. 23: l-(2,4-Difluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethyIthio-5-bromo-lH- indole
Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2926, 1602, 1436, 1377, 1229, 1181, 794, 538; Mass (m/z): 488.9, 491.0 (M+H)+ ; 1H-NMR (δ, ppm): 2.2 (6H, s), 2.37-2.41 (2H, m), 2.72-2.76 (5H, m), 6.81 (IH, m), 7.04 (IH, m), 7.5 (IH, dd, J = 8.8, 2.08 Hz), 7.78 - 7.81 (2H, m), 8.03 - 8.08(1H5 m). Ex. 24: l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1596, 1447, 1371, 1236,
1176, 778, 585; Mass (m/z): 463.2 (M+H)+ ; 1H-NMR (δ, ppm): 1.18-1.2 (6H, d), 2.15 (6H, m), 2.32-2.36 (2H, m), 2.54 (3H, s), 2.69-2.73 (5H, m), 2.88-2.91 (IH, m), 7.23-7.27 (3H, m), 7.513-7.517 (IH5 d, J = 1.88 Hz), 7.66-7.698 (2H, m), 8.11 - 8.14 (IH, s). Ex. 25: l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- bromo-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2923, 1574, 1449, 1377, 1233, 1183, 747, 592; Mass (m/z): 521, 523 (M+H)+ ; 1H-NMR (δ, ppm): 2.2 (6H, s), 2.38-2.42 (2H, m), 2.73 - 2.76 (5H, m), 7.43-7.45 (IH, dd, J = 6.8, 2.08 Hz), 7.59-7.63 (IH, t, J = 7.92 Hz), 7.771-7.776 (IH, d, J = 1.96 Hz), 7.82-7.88 (2H, m), 8.04-8.06 (IH, d, J = 8.88 Hz), 8.09 (IH, bs). Ex. 26: l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl-lH-indole Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1596, 1444, 1375, 1338,
1177, 794, 595; Mass (m/z): 485.4 (M+H)+ ; 1H-NMR (δ, ppm): 1.19-1.21 (6H, d, J = 6.92), 2.14 (6H, s), 2.32-2.36 (2H, m), 2.70-2.73 (2H, m), 2.77 (3H5 s), 2.91 (IH, m), 7.29-7.31 (2H, m), 7.55-7.57 (IH, dd, J = 8.84, 1.52 Hz), 7.69-7.72 (2H, m), 7.93 (IH, s), 8.31-8.34 (IH, d, J = 8.76 Hz).
Ex. 27: l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl-lH-indole
Using essentially Hie same procedure described in example 1, and some non-critical variations the above derivative was prepared, IR spectra (cm"1): 2942, 1595, 1443, 1373, 1338, 1262, 1169, 792, 592; Mass (m/z): 473.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.33-2.36 (2H, m), 2.7-2.73 (2H, m), 2.76 (3H, s), 3.81 (3H, s), 6.88-6.92 (2H, m), 7.54-7.56 (IH, dd, J = 8.8, 1.48), 7.72-7.76 (2H, m), 7.92 (IH, s), 8.3-8.32 (IH, d, J = 8.76 Hz). Ex. 28: l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1592, 1494, 1376, 1338, 1262, 1182, 795, 592; Mass (m/z): 461.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.33-2.37 (2H, m), 2.71-2.74 (2H, m), 2.76 (3H, s), 7.12-7.16 (2H, m), 7.56-7.588 (IH, dd, J = 8.8, 1.52 Hz), 7.93 (IH, s), 7.80-7.84 (2H, m), 8.28-8.30 (IH, d, J = 8.76 Hz). Ex. 29: l-(4-Bromobenzenesulfonyl)-2-methyl-3-Dimethylaminoethylthio-S- . trifluoromethyl-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2927, 1574, 1444, 1376, 1338,
1184, 794, 603; Mass (m/z): 521, 523.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.34-2.37 (2H, m), 2.71-2.73 (2H, m), 2.75 (3H, s), 7.61 (5H, m), 7.93 (IH, s), 8.27-8.34 (IH, d, J = 8.0
Hz).
Ex. 30: l-(2-BromobenzenesulfonyI)-2-methyI-3-DimethylaminoethyIthio-5- trifluoromethyl-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1574, 1447, 1373, 1338,
1179, 794, 596; Mass (m/z): 521, 523.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.18 (6H, s), 2.37-2.41
(2H5 m), 2.62 (3H, s), 2.74-2.78 (2H, m), 7.47-7.52 (3H, m), 7.68-7.72 (IH, dd), 7.98 (IH, bs), 8.03-8.06 (2H, m).
Ex. 31 : l-(4-MethyIbenzenesulfonyI)-2-methyl-3-Dimethylaminoethylthio-5- trifluoromethyl-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2928, 1597, 1444, 1374, 1338,
1176, 793, 592; Mass (m/z): 457.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H3 s), 2,31-2.35 (2H, m), 2.36 (3H, s), 2.69-2.73 (2H, m), 2.76 (3H, s), 7.23-7.26 (2H, m), 7.54-7.567 (IH, dd, J = 8.76 Hz), 7.66-7.68 (2H, d, J = 8.36 Hz), 7.92 (IH, s), 8.3-8.32 (IH, d, J = 8.76 Hz).
Ex. 32: l-Benzenesulfonyl^-methyl-S-Dimethylaminoethylthio-S-trifluoromethyl-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2947, 1553, 1449, 1375, 1341, 1175, 729, 600; Mass (m/z): 443.4 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H5 s), 2.32-2.35 (2H, m), 2.70-2.73 (2H, m), 2.76 (3H, s), 7.45-7.49 (2H3 m), 7.55-7.59 (2H, m), 7.78-7.80 (2H, m), 7.931 (IH, s), 8.31-8.33 (IH, d, J = 8.76 Hz).
Ex. 33: l-(2,4-DifluorobenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5- trifluoromethyl-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2926, 1603, 1432, 1379, 1338, 1181, 795, 594; Mass (m/z): 479.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.19 (6H, s), 2.39-2.42 (2H5 m), 2.74 (3H, s), 2.75-2.78 (2H, m), 2.91 (IH, m), 6.84-6.87 (IH, m), 7.06 (IH, m), 7.49- 7.52 (IH, dd, J = 8.76, 1.4 Hz), 7.95 (IH, s), 8.03-8.05 (IH, d, J = 8.76 Hz), 8.1-8.12 (IH, m). Ex. 34: l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethyIaminoethylthio-5-ethoxy-lH- indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2967, 1594, 1464, 1368, 1264, 1181, 804, 575; Mass (m/z): 449.3 (M+H)+ ; 1H-NMR (δ, ppm): 1.42-1.45 (3H, t), 2.17 (6H, s), 2.35-2.39 (2H, m), 2.69-2.73 (5H, m), 3.79 (3H, s), 4.04-4.11 (2H, q), 6.83-6.87 (2H, m), 6.89-6.92 (IH, dd, J = 9.08, 2.52 Hz), 7.04-7.05 (IH, d, J = 2.52 Hz), 7.67-7.7 (2H, m), 8.06- 8.09 (IH, d). Ex. 35: l-(4-IsopropyIbenzenesuIfonyI)-2-methyl-3-dimethylaminoethylthio-5-ethoxy-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2965, 1609, 1464, 1370, 1175, 681, 583; Mass (m/z): 461.3 (M+H)+ ; 1H-NMR (δ, ppm): 1.18-1.19 (6H, d), 1.42-145 (3H, t), 2.13 (6H, s), 2.31-2.34 (2H, m), 2.67-2.71 (2H, m), 2.72 (3H, s), 2.87-2.90 (IH, m), 4.06- 4.11 (2H,q), 6.89-6.92 (IH, m, J = 9.12, 2.56 Hz), 7.06-7.07 (IH, d, J = 2.56 Hz), 7.24-7.26 (2H, m), 7.65-7.68 (2H, m), 8.08-8.10 (IH, d, J = 9.08 Hz).
Ex. 36: l-(2,4-DifluorobenzenesuIfonyI)-2-methyl-3-dimethylaminoethylthio-5-fIuoro-lH- indole
Using essentially the same procedure described in example 1 , and some non-critical variations the above derivative was prepared. IR spectra (cm 1): 2924, 1602, 1469, 1377, 1182, 684, 539; Mass (m/z): 429.4 (M+H)+; 1H-NMR (δ, ppm): 2.19 (6H, s), 2.39-2.42 (2H, m), 2.72 (3H, s), 2.73-2.76 (2H, m), 6.8-6.87 (IH, m), 6.95-7.0 (IH, m), 7.01-7.07 (IH, m), 7.29-7.33 (IH, dd, J = 8.48 Hz), 7.86-7.89 (IH, m), 8.05-8.06 (IH, m). Ex. 37: l-(5-Chloro-3-Methylbenzothiophen-2-yI-suIfonyI)-2-methyI-3- dimethylaminoethylthio-lH-indoIe Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2961, 2925, 1510, 1451, 1372, 1232, 1175, 651, 578, 547; Mass (m/z): 479.2 (M+H)+; 1H-NMR (δ, ppm): 2.14 (6H, s), 2.36- 2.39 (2H5 m), 2.6 (3H, s), 2.73-2.77 (2H, m), 2.79 (3H, s), 7.3-7.32 (2H, m), 7.4-7.43 (IH, dd, J = 8.68, 2.04 Hz), 7.62-7.64 (IH5 d, J = 8.8 Hz), 7.65-7.66 (IH, m), 7.72-7.72 (IH3 d, J = 1.88 Hz), 8.14-8.16 (IH, m). Ex. 38: l-(3-TrifluoromethylbenzenesulfonyI)-2-methyI-3-dimethylaminoethylthio-S- fluoro-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2954, 2925, 1592, 1468, 1377, 1326, 1182, 832, 670, 560; Mass (m/z); 461.5 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31- 2.35 (2H, m), 2.68-2.72 (2H, m), 2.74 (3H, s), 7.06-7.09 (IH, m), 7.28-7.31 (IH, dd, J = 8.4, 2.6 Hz), 7.57-7.61 (IH5 1, J = 7.92 Hz), 7.81-7.83 (IH, d, J = 7.88 Hz), 7.86-7.88 (IH5 d, J = 7.96 Hz), 8.07 (IH5 s), 8.11-8.15 (IH5 m). Ex. 39: l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH- indole Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2927, 145O5 1376, 1233, 1180, 748, 589; Mass (m/z): 443.4 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H5 s), 2.33-2.37 (2H, m), 2.71-2.75 (2H5 m), 2.76 (3H, s), 7.31-7.35 (2H5 m), 7.57-7.59 (IH, t5 J = 7.92 Hz), 7.63-7.65 (IH5 m), 7.79-7.81 (IH, d), 7.88-7.91 (IH5 d), 8.1 (IH5 s), 8.17-8.19 (IH, m). Ex. 40: l-Benzenesulfonyl-2-methyl-3-dimethylamino ethyIthio-5-methylthio-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1595, 1447, 1371, 1234,
1183, 802, 583; Mass (m/z): 421 (M+H)+; 1H-NMR (δ, ppm): 2.15 (6H, s), 2.31-2.34 (2H, m),
2.68-2.7 (2H5 m), 2.72 (3H, s), 7.23-7.24 (IH, d), 7.41-7.45 (2H, m), 7.51-7.55 (2H, m), 7.74 - 7.77 (2H5 m), 8.11-8.13 (IH, d, J = 8.74 Hz).
Ex. 41 : l-(3-TrifluoromethyIbenzenesulfonyl)-2-methyl-3-dimethyIaminoethylthio-5- methylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1608, 1448, 1376, 1326, 1180, 802, 577; Mass (m/z): 488.8 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H5 s), 2.31-2.35 (2H, m), 2.54 (3H,s), 2.69-2.73 (2H, m), 2.74 (3H5 s), 7.27-7.28 (IH5 dd5 J = 1.88 Hz), 7.51-7.51 (IH5 d5 J = 1.88 Hz), 7.56-7.60 (IH5 1), 7.80-7.82 (IH, d, J = 7.88 Hz)5 7.86-7.88 (IH5 d5 J = 8.0 Hz)5 8.07-8.09 (2H, m). Ex. 42: l-(4-FluorobenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole
Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm'1); 2924, 1591, 1447, 1372, 1231, 1180, 767, 580; Mass (m/z): 439 (M+H)+; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.32-2.35 (2H, m), 2.54 (3H, s), 2.69-2.73 (5H, m), 7.08-7.13 (2H, m), 7.24-7.26 (IH, dd), 7.5-7.51 (IH, d, J = 1.88 Hz), 7.76-7.8 (2H, m), 8.08-8.10 (IH, d, J = 8.76 Hz). Ex. 43: l-(4-BromobenzenesuIfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2964, 1573, 1446, 1372, 1233, 1182, 770, 573; Mass (m/z): 499.1, 501.1 (M+H)+; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.31-2.35 (2H, m), 2.54 (3H, s), 2.69-2.73 (5H, m), 7.23-7.24 (IH, dd, J = 1.92 Hz), 7.50- 7.50 (IH, d, J = 1.88 Hz), 7.55-7.62 (4H, m), 8.06-8.08 (IH, d, J = 8.76 Hz). Ex. 44: l-(4-MethylbenzenesuIfonyI)-2-methyI-3-dimethylaminoethyIthio-5-methylthio- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2924, 1596, 1447, 1370, 1235,
1175, 668, 581; Mass (m/z): 434.9 (M+H)+; 1H-NMR (δ, ppm): 2.21 (6H, s), 2.35 (3H, s), 2.42- 2.46 (2H, m), 2.54 (3H, s), 2.72 (3H, s), 2.73-2.77 (2H, m), 7.2-7.28 (3H, m), 7.48-7.49
(IH, d, J = 1.88 Hz), 7.63-7.67 (2H, m), 8.1-8.12 (IH, d, J = 8.76 Hz).
Ex. 45: l-(2-Bromobenzenesulfonyl)-2-methyI-3-dimethyIaminoethyIthio-5-methyIthio- lH-indole Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2923, 1572, 1448, 1369, 1235, 1177, 764, 582; Mass (m/z): 499.3, 501.3 (M+H)+; 1H-NMR (δ, ppm): 2.22 (6H, s), 2.44-2.48 (2H, m), 2.54 (3H, s), 2.62 (3H, s), 2.76-2.80 (2H, m), 7.15-7.18 (IH, dd, J = 8.76, 1.96 Hz), 7.43- 7.47 (2H, m), 7.56-7.56 (IH, d, J = 1.88 Hz), 7.67-7.69 (IH, dd), 7.78-7.82 (IH, d), 7.88- 7.91 (IH5 dd).
Ex. 46: l-(4-Methoxybenzenesulfonyl)-2-methyI-3-dimethyIaminoethylthio-5-methyIthio- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2922, 1594, 1445, 1369, 1262, 1167, 796, 580; Mass (m/z): 451.3 (M+H)+; 1H-NMR (δ, ppm): 2.24 (6H, s), 2.47-2.51 (2H, m), 2.54 (3H3 s), 2.72 (3H, s), 2.75-2.79 (2H3 m), 3.8 (3H, s), 6.85-6.89 (2H, m), 7.23-7.24
(IH3 dd3), 7.48 (IH3 d3 J = 1.88), 7.6-7.72 (2H3 m), 8.1-8.12 (IH3 d, J = 8.68 Hz).
Ex. 47: l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- chloro-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 293I3 1576, 1445, 1377, 1326, 1181, 789, 575; Mass (m/z): 477 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.33-2.37 (2H3 m), 2.70-2.74 (2H3 m), 2.74 (3H3 s), 7.29-7.31 (IH, dd, J = 8.8, 2.2 Hz), 7.58-7.62 (2H, m), 7.82- 7.88 (2H3 m), 8.08-8.12 (2H, m). Ex. 48: l-(2,4-DifluorobenzenesulfonyI)-2-methyl-3-dimethylaminoethylthio-5-methylthio- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2926, 1602, 1435, 1375, 1180, 770, 539; Mass (m/z): 457 (M+H)+; 1H-NMR (δ, ppm): 2.21 (6H, s), 2.41-2.44(2H, t), 2.52 (2H3 m), 2.73 (3H3 s), 2.74-2.78 (2H, t), 6.80-6.85 (IH, m), 7.02-7.03 (IH, m), 7.17-7.19 (IH3 dd, J = 8.76, 1.92 Hz), 7.52-7.53 (IH, d, J = 1.88 Hz),7.80-7.83 (IH, d, J = 8.7 Hz), 8.04 (IH, m). Ex. 49: l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-chloro-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm."1): 2928, 1597, 1445, 1371, 1176, 762, 580; Mass (m/z): 423.I3 425 (M+H)+ ; 1H-NMR (δ, ppm): 2.15 (6H3 s), 2.31-2.33 (2H3 1), 2.36 (3H3 s)3 2.68-2.71 (2H, m), 2.72 (3H3 s), 7.21-7.25 (2H, m), 7.27-7.28 (IH, dd, J = 2.16 Hz), 7.59-7.59 (IH3 d, J = 2.12 Hz), 7.63-7.65 (2H, m)3 8.11-8.14 (IH3 d, J = 8.8 Hz).
Ex; 50: l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethyIaminoethyIthio-5-chloro-lH- indole
Using essentially the same procedure described in example I3 and some non-critical variations the above derivative was prepared. IR spectra (cm."1): 2942, 1573, 1443, 1383, 13268, 1177, 792, 595; Mass (m/z): 463.1 (M+H)+; 1H-NMR (δ, ppm): 2.2 (6H3 s), 2.47-2.51 (2H3 m), 2.87-2.9 (2H, m), 7.33-7,36 (IH, dd), 7.59-7.64 (3H, m), 7.82-7.84 (IH5 d), 7.90-7.92 (IH, d, J = 8.84 Hz), 8.01-8.03 (IH, d), 8.14 (IH, s). Ex. 51: l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethyIaminoethylthio-5- trifluoromethyl-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2925, 161 I3 1443, 1381, 1326, 1181, 795, 593; Mass (m/z): 511.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.16 (6H, s), 2.37-2.39 (2H, m), 2.72-2.76 (2H, m), 2.78 (3H, s), 7.5-7.64 (2H, m), 7.84-7.94 (3H, m), 8.126 (IH, s), 8.28- 8.30 (IH5 (I, J = 8.76 Hz).
Ex. 52: l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-chIoro-lH-indoIe Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2940, 1573, 1443, 1376, 1285, 1176, 762, 592; Mass (m/z): 473, 475.3, 477.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.24 (6H, s), 2.49- 2.52 (2H, m), 2.86-2.89 (2H, m), 7.20-7.23 (2H, m), 7.42-7.46 (IH, m), 7.49-7.55 (IH, m), 7.56- 7.58 (IH, d, J = 8.76 Hz), 7.69 (2H5 m), 7.85 (lH,s), 8.18-8.21 (IH, dd, J = 7.92, 1.68 Hz).
Ex. 53: l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-chloro-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2963, 1596, 1442, 1375, 1385, 1173, 794, 592; Mass (m/z): 437.3, 439 (M+H)÷ ; 1H-NMR .(δ, ppm): 1.18-1.20 (6H5 d), 2.23 (6H, s), 2.46-2.50 (2H, m), 2.84-2.87 (2H, m), 2.89-2.92 (IH5 m), 7.28-7.32 (3H, m), 7.60- 7.61 (IH5 d, J = 2.0 Hz)5 7.63 (IH, s), 7.76-7.78 (2H, m), 7.91-7.93 (IH5 d, J = 8.80 Hz). Ex. 54: l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2969, 1594, 1439, 1373, 1265, 1164, 750, 586; Mass (m/z): 469.24, 471.2 (M+H)+; 1H-NMRXS, ppm): 2.22 (6H, s), 2.44-2.48 (2H5 m), 2.82-2.86 (2H5 m), 3.80 (3H, s), 6.88-6.90 (2H, m), 7.42-7.45 (IH, dd, J = 8.76, 1.96 Hz)5 7.60 (IH, s), 7.76-7.77 (IH5 d5 J = 1.84 Hz)5 7.77-7.80 (2H5 m), 7.84-7.86 (IH5 d, J = 8.80 Hz). Ex. 55: l-(4-MethoxybenzenesuIfonyl)-3-dimethylaminoethylthio-5-chloro-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm1): 2927, 1594, 1441, 1374, 1265, 1165, 8044, 587; Mass (m/z): 425.3, 427.2 (M+H)+; 1H-NMR1(S, ppm): 2.2 (6H, s), 2.45-2.48 (2H, m), 2.83-2.86 (2H5 m), 3.8 (3H, s), 6.88-6.9, (2H, m), 7.28-7.31 (IH5 dd, J = 8.8, 2.0 Hz)5 7.60-7.61 (IH5 d, J = 1.96 Hz), 7.62 (IH, s), 7.80 (2H, m), 7.89-7.91 (IH5 d, J = 8.72 Hz).
Ex. 56: l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethyIthio-5-bromo-lH-indoIe
Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2963, 1595, 1439, 1375, 1284, 1172, 776, 591; Mass (m/z): 481.1, 483.1 (M+H); 1H-NMR (δ, ppm): 1.18-1.20 (6H, d)r 2.22 (6H5 s)5 2.45-2.48 (2H, t), 2.83-2.85 (2H, t), 2.87-2.92 (IH5 m), 7.28-7.30 (2H, m), 7.43-7.46
(IH, dd, J = 8.8, 1.92 Hz), 7.61 (IH, s), 7.76-7.77 (3H5 m), 7.86-7.88 (IH, d, J = 8.76 Hz). Ex. 57: l-(2-BromobenzenesulfonyI)-3-dimethyIaminoethylthio-5-bromo-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2941, 1571, 1442, 1376, 1285,
1176, 756, 592; Mass (m/z): 517.1, 519.1, (M+H)+ ; 1H-NMR (δ, ppm): 2.24 (6H3 s), 2.49-2.53 (2H, m), 2.86-2.89 (2H, m), 7.37-7.38 (IH, dd, J = 1.92 Hz), 7.44-7.46 (IH, dt), 7.51-7.53
(2H, m), 7.67-7.68 (IH, dd), 7.82- 7.83 (IH, d, J =1.84 Hz), 7.84 (IH, s), 8.19-8.21 (IH, dd, J
= 7.96, 1.68 Hz).
Ex. 58: l-(3-TrifluoromethylbenzenesulfonyI)-3-dimethylaminoethylthio-5-bromo-lH- indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2942, 1569, 1441, 1383, 1283,
1177, 752, 692, 594; Mass (m/z): 507.2, 509.2 (M+H)+; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.47- 2.50 (2H, m), 2.86-2.90 (2H, m), 7.47-7.50 (IH, dd, J = 8.8, 1.92 Hz), 7.58 (IH, s), 7.60-7.64 (IH, t, J = 7.88), 7.78-7.785 (IH, d, J =1.76 Hz), 7.82-7.87 (2H, m), 8.01-8.03 (IH, d, J = 7.96 Hz), 8.14 (IH, bs).
Ex. 59: l-(2-BromobenzenesuIfonyI)-3-dimethyIaminoethylthio-5-methoxy-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2940, 1610, 1469, 1372, 1212,
1166, 851, 597; Mass (m/z): 469.2, 471.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.24 (6H, s), 2.51-2.55 (2H, m), 2.87-2.91 (2H, m), 3.84 (3H, s), 6.86-6.88 (IH, dd, J = 9.16, 2.4 Hz), 7.1-7.11 (IH, d, J = 2.52), 7.4-7.48 (2H, m), 7.53-7.55 (IH, d, J = 9.0 Hz), 7.65-7.67 (IH, dd, J = 7.86, 1.24
Hz), 7.8 (IH, s), 8.11-8.13 (IH, dd, J = 7.92, 1.68 Hz).
Ex. 60: l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2941, 1590, 1377, 1241, 1179,
777, 584; Mass (m/z): 457 (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.45-2.49 (2H, m), 2.84-
2.88 (2H, m), 7.11-7.15 (2H, m), 7.44-7.47 (IH, dd, J = 8.76, 1.92 Hz), 7.57 (IH, s), 1.71-1.1%
(IH, d, J = 8.80 Hz), 7.83-7.85 (IH, d, J = 8.8 Hz), 7.86-7.9 (2H, m).
Ex. 61: l-(4-FluorobenzenesulfonyI)-3-dimethylaminoethylthio-5-methoxy-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2962, 1585, 1443, 1375, 1303,
1183, 854, 586; Mass (m/z): 409 (M+H)+; 1H-NMR (δ, ppm): 2.22 (6H, s), 2.46-2.50 (2H, m),
2.85 - 2.89 (2H, m), 3.83 (3H, s), 6.95-6.98 (IH, dd, J = 9.04, 2.0 Hz), 7.04-7.049 (IH, d, J =
2.48 Hz), 7.08-7.12 (2H, m), 7.52 (IH, s), 7.85-7.88 (3H, m). Ex. 62: l-(Benzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2941, 1610, 1470, 1371, 1213, 1165, 851, 603; Mass (m/z): 391 (M+H)+; 1H-NMR-(S, ppm): 2.22 (6H, s), 2.46-2.49 (2H, m), 2.84 -2.88 (2H, m), 3.83 (3H, s), 6.94-6.97 (IH, dd, J = 9.0, 2.52 Hz), 7.04-7.046 (IH, d, J = 2.48), 7.41-7.45 (2H, m), 7.52-7.54 (IH, m), 7.56 (IH, s), 7.83-7.86 (2H, m), 7.87-7.89 (IH, d, J = 9.0 Hz). Ex. 63: l-(4-MethoxybenzenesuIfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2942, 1594, 1469, 1370, 1213,
1164, 680, 595; Mass (m/z): 421.2 (M+H)+ ; 1H-NMR (δ,. ppm): 2.22 (6H, s), 2.45-2.49 (2H, m), 2.83-2.87 (2H, m), 3.79 (3H, s), 3.83 (3H, s), 6.85-6.88 (2H, m), 6.93-6.96 (IH, dd, J = 9.0, 2.52 Hz), 7.04-7.048 (IH, d, J = 2.48 Hz), 7.55 (IH, s), 7.76-7.79 (2H, m), 7.85-7.88 (IH, d, J = 9.0 Hz). Ex. 64: l-(4-BromobenzenesuIfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2938, 1609, 1477, 1373, 1210,
1165, 854, 619; Mass (m/z): 469.2, 471.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.46-2.5 (2H, m), 2.85-2.89 (2H, m), 3.83 (3H, s), 6.95-6.98 (IH, dd, J = 9.0, 2.52 Hz), 7.03-7.04 (IH, d, J = 2.52 Hz), 7.5 (IH, s), 7.55-7.57 (2H, m), 7.68-7.7 (2H, m), 7.84-7.86 (IH, d).
Ex. 65: l-(4-Methylbenzenesulfonyl)-3-dimethyIaminoethyIthio-5-methoxy-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2941, 1610, 1470, 1371, 1213,
1165, 851, 677, 596; Mass (m/z): 405.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.22 (6H, s), 2.33 (3H, s), 2.45 -2.49 (2H, m), 2.83-2.87 (2H, m), 3.83 (3H, s), 6.93-6.96 (IH, dd, J = 8.96, 2.48 Hz),
7.03- 7.04 (IH, d, J = 2.52 Hz), 7.2-7.22 (2H, d, J = 8.12 Hz), 7.55 (IH, s), 7.71-7.73 (2H, m),
7.85 -7.88 (IH, d, J = 9.04 Hz).
Ex. 66: l-(4-IsopropyIbenzenesulfonyl)-3-dimethylaminoethyIthio-5-methoxy-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2963, 1610, 1469, 1372, 1213,
1166, 851, 597; Mass (m/z): 433.3 (M+H)+ ; 1H-NMR (δ, ppm): 1.17-1.19 (6H, d, J = 6.96), 2.22 (6H, s), 2.46-2.49 (2H, m), 2.84-2.92 (3H, m), 3.83 (3H, s)3 6.94-6.97 (IH5 dd, J = 9.0, 2.52 Hz), 7.04-7.05 (IH, d, J = 2.48), 7.25-7.28 (2H, m), 7.57 (IH, s), 7.75-7.78 (2H3 m), 7.88- 7.90 (IH, d, J = 9.04 Hz). Ex. 67: l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2941, 1594, 1479, 1371, 1264, 1167, 758, 587; Mass (m/z): 391.4 (M+H)+ ; 1H-NMR (δ, ppm): 2.22 (6H, s), 2.47-2.50 (2Ht m), 2.85-2.89 (2H, m), 3.79 (3H, s), 6.87-6.89 (2H, m), 7.28-7.35 (2H, m), 7.6 (IH, s), 7.61- 7.63 (IH, d), 7.81-7.99 (3H, m). Ex. 68: l-(4-FluorobenzenesuIfonyl)-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2941, 1591, 1493, 1375, 1240, 1180, 837, 577; Mass (m/z): 379.3 (M+H)+ ; 1H-NMR .(δ, ppm): 2.23 (6H, s), 2.47-2.51 (2H, m), 2.87-2.91 (2H, m), 7.09-7.13 (2H, m), 7.3-7.37 (2H, m), 7.56 (IH, s), 7.6- 7.64 (IH, d), 7.88 -7.92 (2H, m), 7.96-7.98 (IH, d, J = 8.2 Hz). Ex. 69: l-(4-MethyIbenzenesulfonyI)-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2930, 1597, 1444, 1371, 1265,
1174, 711, 587; Mass (m/z): 375.3 (M+H)+ ; 1H-NMR -(S, ppm): 2.22 (6H, s), 2.34 (3H, s), 2.46- 2.50 (2H, m), 2.85-2.89 (2H, m), 7.21-7.36 (4H3 m), 7.6 (IH, s), 7.61-7.63 (IH, b), 7.75- 7.77 (2H, m), 7.97-7.99 (IH, bd, J = 8.28 Hz).
Ex. 70: l-(Benzenesulfonyl)-3-dimethylaminoethylthio-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2938, 1604, 1446, 1372, 1265,
1175, 730, 594; Mass (m/z): 361.3 (M+H)+ ; Η-NMR.(ppm): 2.22 (6H, s), 2.47-2.51 (2H, m), 2.87 -2.90 (2H, m), 129-1Λ6 (5H, m), 7.55 (IH, s), 7.60-7.62 (IH, bd), 7.87-7.89 (2H, m), 7.9- 8.0 (IH, bd). Ex. 71: l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethyIthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1596, 1444, 1373, 1265, 1174, 945, 651, 590; Mass (m/z): 403.4 (M+H)+; 1H-NMR (δ, ppm): 1.18-1.19 (6H, d, J = 6.96 Hz), 2.22 (6H, s), 2.47-2.51 (2H, m), 2.8-2.91 (3H, m), 7.27-7.36 (4H, m), 7.61 (IH, s), 7.62 - 7.64 (IH, d), 7.7-7.8 (2H, m), 7.9-8.01(1H, d, J = 8.28 Hz).
Ex. 72: l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2943, 1609, 1443, 1380, 1326, 1178, 728, 595; Mass (m/z): 429.1 (M+H)+ ; 1H-NMR (δ, ppm): 2.2 (6H, s), 2.48-2.52 (2H, m), 2.88-2.95 (2H, m), 7.32-7.39 (2H5 m), 7.56 (2H, m), 7.6-7.64 (2H, m), 7.79-7.82 (IH, bd),
7.98-8.0 (IH, d), 8.16 (IH, bs). Ex. 73: l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2939, 1634, 1445, 1372, 1263,
1177, 74I3 586; Mass (rα/z): 439.2, 441.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.24 (6H, s), 2.52-2.55 (2H, m), 2.89-2.92 (2H, m), 7.26-7.30 (2H, m), 7.62-7.70 (2H5 m), 7.64-7.68 (3H, m), 7.85
(IH, s), 8.18-8.20 (IH, dd, J = 7.9, 1.7 Hz).
Ex. 74: {2-[5-Bromo-l-(4-fluorobenzenesuIphonyl)-lH-indole-3-sulphinyl] ethyljdimethylamine
Using essentially the same procedure described in example 1, and intermediate (f) the above derivative was prepared. IR spectra (cm"1): 2945, 1590, 1439, 1382, 1241, 1183, 746, 586; Mass (m/z): 473.2, 475.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.27 (6H, s), 2.51-2.56 (IH, m), 2.8- 2.83 (IH, m), 3.1-3.32 (IH, m), 3.33-3.38 (IH, m), 7.16-7.21 (2H, m), 7.51-7.54 (IH, dd, J = 8.88, 1.88 Hz), 7.88-7.90 (IH, d, J = 8.88, 1.88), 7.93-7.95 (2H, m), 7.96 (IH, s), 7.97- 7.98 (IH, d, J = 1.84 Hz). Ex. 75: {2-[l-(2-BromobenzenesuIphonyl)-lH-indoIe-3-sulphinyl]ethyl}dimethyIamine -
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2926, 1573, 1446, 1376, 1265, 1181, 741, 586; Mass (m/z): 455.1, 457.1 (M+H)+ ; 1H-NMR .(δ, ppm): 2.29 (6H, s), 2.58-2.64 (IH, m), 2.84-2.87 (IH, m), 3.2-3.25 (IH, m), 3.35-3.4 (IH, m), 7.31-7.33 (2H, m), 7.47-7.56 (2H, m), 7.68-7.70 (2H, m), 7.83-7.88 (IH, m), 8.2 (IH, s), 8.3-8.32 (IH, dd, J = 7.96, 1.6 Hz).
Ex. 76: {2-[5-Bromo-l-(2-bromobenzenesulphonyl)-lH-indole-3-suIphinyl] ethyl}dimethylamine
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2920, 1567, 1441, 1378, 1285, 1180, 752, 576; Mass (m/z): 532.9, 534.9 (M+H)+ ; 1H-NMR (δ, ppm): 2.28 (6H, s), 2.57-2.59 (IH, m), 2.81-2.84 (IH, m), 3.15-3.18 (IH, m), 3.36-3.41, (IH, m), 7.43-7.44 (IH, m), 7.49- 7.49 (IH, m), 7.56-7.58 (2H, m), 7.69-7.71 (IH, dd, J = 6.72, 1.16 Hz), 8.04- 8.05 (IH, d, J = 1.8), 8.16 (IH, s), 8.29-8.31 (IH, dd, J = 7.96, 1.68 Hz). Ex. 77: {2-[5-Bromo-l-(4-methoxybenzenesuIphonyl)-lH-indoIe-3-sulphinyl] ethyl}dimethylamine
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2945, 1593, 1439, 1377, 1267,
1167, 749, 574; Mass (m/z): 485.2, 487.2 (M+H)+ ; 1H-NMR ,(δ, ppm): 2.27 (6H, s), 2.51-2.56 (IH, m), 2.78-2.81 (IH, m), 3.11-3.16 (IH, m), 3.33-3.38 (IH, m), 3.83 (3H, s), 6.91-6.94 (2H, m), 7.48-7.51 (IH3 dd, J = 8.92, 1.88 Hz), 7.84-7.87 (2H3 m), 7.88-7.90 (IH, d, J = 8.92), 7.97 (IH, s), 7.98-7.99 (IH, d, J = 1.88 Hz).
Ex. 78: [2-[5-Bromo-l-(4-isopropyIbenzenesuIphonyI)-lH-indole-3-sulphinyl] ethyljdimethylamine Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1595, 1439, 1378, 1285, 1175, 776, 655, 592; Mass (m/z): 497.3, 499.3 (M+H)+; 1H-NMR (δ, ppm): 1.20-1.22 (6H, d), 2.26 (6H5 s), 2.53-2.54 (IH, m), 2.78-2.81 (IH3 m), 2.93-2.99 (IH3 m), 3.36-3.37 (IH3 m), 4.11-4.13 (IH3 m), 7.32-7.35 (2H3 bd3 J = 8.48 Hz)3 7.50-7.53 (IH3 dd, j = 8.92, 1.92 Hz), 7.81-7.83 (2H, m), 7.92-7.94 (IH3 d, J = 8.92 Hz), 7.97 (IH3 s), 8.00 (IH, d, J = 1.84 Hz). Ex. 79: l-(4-MethoxybenzenesuIfonyI)-3-dimethyIaminoethyIthio-5-fluoro-lH-indole
Using essentially the same procedure described in example I3 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2962, 1594, 1463, 1372, 1164, 589; Mass (m/z): 409.4 (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H3 s), 2.47-2.51 (2H, m), 2.83- 2.87 (2H, m), 3.81 (3H3 s), 6.88-6.90 (2H, m), 7.04-7.10 (IH, dt), 7.27-7.29 (IH, dd), 7.64 (IH, s), 7.79-7.81 (2H, m), 7.90-7.94 (IH, m). Ex. 80: l-(4-IsopropylbenzenesuIfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole
Using essentially the same procedure described in example I5 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1463, 1375, 1173, 856, 594; Mass (m/z): 421.3 (M+H)+; 1H-NMR^, ppm): 1.17-1.20 (6H, d), 2.22 (6H, s), 2.45-2.49 (2H, m), 2.83-2.87 (2H, m), 2.87-2.92 (IH, m), 7.06-7.11 (IH, dt), 7.25-7.31 (3H, m), 7.65 (IH, s), 7.75-7.80 (2H, m), 7.92-7.96 (IH, m). Ex, 81 : l-(4-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2946, 1463, 1375, 1159, 857, 576; Mass (m/z): 457.3 (M+H)+ , 459.3 (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.46-2.50 (2H, m), 2.85-2.88 (2H, m), 7.07-7.12 (IH, dt), 7.27-7.30 (IH, dd), 7.58-7.62 (3H3 m), 7.69- 7.73 (2H, m), 7.89-7.93 (IH, m). Ex. 82: l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethyIthio-5-fluoro-lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2925, 1463, 1160, 857, 788, 595; Mass (m/z): 457.2 (M+H)+, 459.2 (M+H)+ ; 1H-NMR .(δ, ppm): 2.24 (6H, s), 2.49-2.53 (2H, m), 2.85-2.89 (2H, m), 6.97-7.03 (IH, dt), 7.33-7.36 (IH, dd), 7.42-7.46 (IH, dt), 7.49- 7.54 (IH, dt), 7.58-7.62 (IH, dd), 7.67-7.7 (IH, dd), 7.89 (IH, s), 8.17-8.19 (IH, dd). Ex. 83: {2-[5-Methoxy-l-(4-isopropylbenzenesulphonyl)-lH-indoIe-3- sulphinyl]ethyl}dimethylamine
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2964, 1469, 1375, 1173, 667, 596; Mass (m/z): 449.3; 1H-NMR (δ, ppm): 1.19- 1.21 (6H, d), 2.26 (6H, s), 2.53-2.55 (IH/ m), 2.78-2.81 (IH, m), 2.90-2.93 (IH, m), 3.15-3.19 (IH, m), 3.34-3.37 (IH, m), 3.82 (3H, s), 7.0-7.03 (IH, dd), 7.24-7.27 (IH, d), 7.30-7.34 (2H, m), 7.80-7.84 (2H, m), 7.93-7.96 (2H, m).
Ex. 84: {2-[5-Methoxy-l-(2-bromobenzenesulphonyl)-lH-indole-3-suIphinyI] ethyl}dimethylamine
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2973, 1652, 1470, 1375, 1175, 1029, 769, 598; Mass (m/z): 485.2, 487.2 (M+H)+ ; 1H-NMRXa, ppm): 2.29 (6H, s), 2.59-2.6 (IH, m), 2.82-2.85 (IH, m), 3.19-3.22 (IH, m), 3.38-3.43 (IH, m), 3.82 (3H, s), 6.92-6.94 (IH, dd), 7.3-7.31 (IH, d, J = 2.44 Hz), 7.43-7.49 (IH, dt), 7.52-7.54 (IH, dd), 7.56-7.59 (IH, d), 7.68-7.72 (IH, dd), 8.14 (IH, s), 8.24-8.26 (IH, dd).
Ex. 85: l-(2-Bromobenzenesulfonyl)-3-(N-methyltetrahydropyrrolidin-3-yl)thio-5- methoxy-lH-indoIe
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2960, 1470, 1373, 1260, 1168,
1026, 801, 596; Mass (m/z): 481.1 (M+H)+, 483.1 (M+H)+ ; 1H-NMR (δ, ppm): 1.85-1.95 (IH, m), 2.27-2.36 (IH, m), 2.48 (3H, s), 2.60-2.64 (IH, m), 2.78-2.85 (IH, m), 2.92-2.99 (IH, m),
3.2-3.27 (IH, m), 3.66-3.74 (IH, m), 3.85 (3H,s), 6.87-6.90 (IH, dd), 7.09-7.71 (IH, dd), 7.40-
7.45 (IH, dt), 7.48-7.51 (IH, dd), 7.52-7.54 (IH, d), 7.67-7.69 (IH, dd), 7.88 (IH, s), 8.16 - 8.19 (IH, dd).
Ex. 86: l-(4-MethoxybenzenesulfonyI)-3-dimethylaminoethylthio-6-chloro- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2966, 1594, 1497, 1374, 1265, 1167, 809, 673, 579; Mass (m/z): 425.1, (M+H)+; 427.2 (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.48-2.52 (2H, m), 2.84-2.88 (2H, m), 3.81 (3H5 s), 6.9-6.93 (2H, m), 7.24-7.27 (IH, dd), 7.51-7.54 (IH, d), 7.57 (IH, s), 7.80-7.83 (2H5 m), 7.99-8.01 (IH5 d). Ex. 87: l-(4-FIuorobenzenesulfonyl)-3-dimethyIaminoethylthio-6-chloro- lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm4): 2964, 1591, 1494, 1379, 1241, 1179, 954, 673, 539; Mass (m/z): 413.2, (M+H)+ ; 415.1 (M+H)+; 1H-NMR (δ, ppm): 2.22 (6H, S)5 2.47-2.50 (2H, m), 2.86-2.89 (2H, m), 7.13-7.17 (2H, m), 7.26-7.29 (IH, dd), 7.53-7.55
(2H, m), 7.89-7.92 (2H, m), 7.9-8.01 (IH, d).
Ex. 88: {2-[l-(4-MethoxybenzenesuIphonyl)-lH-indole-3-sulphinyl]ethyl}dimethylamine
Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2924, 1593, 1374, 1168, 1093,
701, 569; Mass (m/z): 407.3; 1H-NMR-(S, ppm): 2.28 (6H, s), 2.55-2.57 (IH, m), 2.83 -2.86
(IH, m), 3.17-3.2 (IH, m), 3.32-3.37 (IH5 m), 3.82 (3H, s), 6.91-6.93 (2H, m), 7.3- 7.32 (IH, m), 7.39-7.41 (IH, m), 7.78-7.80 (IH, d), 7.86-7.88 (2H, m), 7.99 (IH, s), 8.01- 8.03 (IH, d).
Ex. 89: {2-[l-(4-Isopropylbenzenesulphonyl)-lH-indole-3-sulphinyI]ethyI}dimethyIamine Using essentially, the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2963, 1595, 1376, 1176, 1091,
755, 590; Mass (m/z): 419.3; 1H-NMR (δ, ppm): 1.19-1.21 (6H, d), 2.29 (6H, s), 2.53- 2.6
(IH, m), 2.82-2.95 (2H, m), 3.17-3.24 (IH, m), 3.33-3.41 (IH, m), 7.29-7.33 (3H, m), 7.4-
7.43 (IH, m), 7.79-7.86 (3H, m), 7.99 (IH, s), 8.05-8.07 (lH,d). Ex. 90: l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole
Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2961, 1590, 1463, 1378, 1293,
1180, 1159, 857, 683, 589; Mass (m/z): 397.2, (M+H)+ ; 1H-NMR (δ, ppm): 2.23 (6H, s), 2.47-
2.51 (2H, m), 2.85-2.88 (2H, m), 7.07-7.17 (3H, m), 7.27-7.31 (IH, dd), 7.61 (IH, s), 7.87- 7.95 (3H, m).
Ex. 91: {2-[l-(4-MethoxybenzenesuIphonyI)-5-Methoxy-lH-indole-3- sulphinyl]ethyl}dimethylamine Using essentially the same procedure described in example 74, and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 2974, 1655, 1374, 1167, 1092, 688, 592; Mass (m/z): 437.3; 1H-NMR ,(δ, ppm): 2.27 (6H, s), 2.53 - 2.55 (IH, m), 2.78 -2.82
(IH, m), 3.15-3.18 (IH, m), 3.34-3.38 (IH, m), 3.82 (6H, s), 6.9-6.93 (2H, m), 6.99- 7.02 (IH, dd), 7.23-7.24 (IH, d), 7.82-7.86 (2H, m), 7.89-7.92 (2H, m).
Ex. 92: l-(2,4,5-Trichlorobenzenesulfonyl)-3-dimethylaminoethylthio-2-methyl-5-bromo- lH-indole Using essentially the same procedure described in example 1, and some non-critical variations the above derivative was prepared. IR spectra (cm'1): 2963, 1441, 1376, 1260, 1179;
Mass (m/z): 555.9 (M+H)+, 556.9 (M+H)+ ; 1H-NMR (δ, ppm): 2.21 (6H, s), 2.39-2.42 (2H, m), 2.65 (3H3 s), 2.73-2.77 (2H, m), 7.35-7.38 (IH, dd), 7.54 (IH, s), 7.71-7.74 (IH, d), 7.81-
7.82 (IH, d), 8.24 (IH, s). Ex. 93: Food Intake Measurement (Behavioural Model).
Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, Hyderabad, India) were used. fsThe chronic effect of the compounds of general formula (I) on food intake in well-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 Lp., 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 rat is left with the pre-weighed amounts of food. Food intake and weight gain is 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.
Ex. 94: Tablet comprising a compound of formula (I):
Ingredient % wt./wt
Compound of invention 5 mg
Lactose 60 mg
Crystalline cellulose 25 mg
K 90 Povidone 5 mg
Pregelatinised starch 3 mg
Colloidal silicon dioxide l mg
Magnesium stearate l mg
Total weight per tablet 100 mg
The ingredients are combined and granulated. The formulation is then dried and formed into tablets with an appropriate tablet machine. Ex. 95: Composition for Oral Administration
Ingredient % wt./wt. Compound of invention 20.0 % Lactose 79.5 % Magnesium stearate 0.5 %
The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
Ex. 96: Liquid oral formulation
Ingredient Amount
Compound of invention 1.0 g
Methyl paraben 0.15 g
Propyl paraben 0.05 g '
Granulated sugar 25.5 g
Sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
Flavoring 0.035 g
Colorings 0.5 g
Distilled water q.s. to lOO ml
The ingredients are mixed to form a suspension for oral administration. Ex. 97: Parenteral Formulation
Ingredient % wt./wt.
Compound of invention 0.25 g
Sodium Chloride qs to make isotonic
Water for inj ection to 100 ml
The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is 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. Ex. 98: Suppository Formulation
Ingredient % wt. /wt.
Compound of invention ϊ .0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight. Ex. 99: Topical Formulation
All of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.
Ingredients Grams
Compound of invention 0.2-2 g
Span 60 2 g
Tween 60 2 g
Mineral oil 5 g
Petrolatum 1O g
Methyl paraben 0.15 g
Propyl paraben 0.05 g
BHA (butylated hydroxy anisole) 0.01 g
Water 100 ml
Ex. 100: Object Recognition Task Model.
The cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: the 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 20 % 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 comers, 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. Ex. 101: Chewing/Yawning/Stretching induction by 5HTeR 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.
Some compounds demonstrated 40 - 60 % increase in the stretching, yawning and chewing behaviors in comparison with the vehicle treated groups, at 1 mg/Kg, 3 mg/Kg, 10 mg/Kg and 30 mg/Kg. REFERENCES:
1. King M. V., Sleight A., J., Woolley M. L., and et. Al. Neuropharmacology, 2004, 47, 195-204.
2. Bentey J. C, Boivrson 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). Ex. 102: Water Maze:
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.
REFERENCES:
1. Yamada N., Hattoria A., Hayashi T., Nishikawa T., Fukuda H. et. Al., Pharmacology, Biochem. And Behaviour, 2004, 78, 787-791.
2. 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.
Ex. 103: Passive avoidance Apparatus
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 5mm in diameter and spaced 12.5 mm apart. A current generator supplied 0.75 niA 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 carried 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 irihibitory 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. Some of the compounds showed the significant increase in latency to reach the dark zone, at 10 mg/Kg oral dose.
REFERENCES:
1. Callahan P. M., Ilch C. P., Rowe N. B., Tehim A., Abst. 776.19.2004, Society for neuroscience, 2004.
2. Fox G. B., Connell A. W. U., Murphy K. J., Regan C. M., Journal of Neurochemistry, 1995, 65, 6, 2796-2799.
Ex. 104: Novascreen binding assay for human 5HT6 receptor.
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 are 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 is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HTg binding site.
Literature Reference: Monsma F. J. Jr., et al., Molecular Cloning and Expression of Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs. MoI. Pharmacol. (43): 320-327 (1993). Table 1: Ki values at 5-HT6 (h) receptor.
Figure imgf000048_0001
Table 2: % Binding at 5-HT6 (h) receptor at 100 nM concentration.
Figure imgf000048_0002

Claims

We claim:
1. A compound having the formula (I),
Figure imgf000049_0001
Formula (I) along with its stereoisomer or its salt with an inorganic or organic acid, wherein: Ru R3 and R4 independently represents hydrogen, halogen, cyano, (Ci-C3)alkyl, halo(Ci-C3)alkyl, thio(Q- C3)alkyl, (C3-C7)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (Ci-C3)alkylthio; R5 and Rδ independently represents hydrogen, (CrC3)alkyl, (C3-C7)cycloalkyl; optionally R5 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and Rs represents hydrogen, (Ci-C3)alkyl; optionally, R7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 0, 1 or 2.
2. The compound according to claim 1, wherein "m" is integer having value 0.
3. The compound according to claim 1, wherein "m" is integer having value 1.
4. The compound according to claim 1, wherein "m" is integer having value 2.
5. The compound according to claim 1, selected from among the following: l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole; l-(4-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole; 1 -(4-Bromobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methoxy- IH- indole; l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole;
1 -(4-Fluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5- methoxy- 1 H- indole; l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoetliylthio-lH-indole; l-(4-Isopropylbenzenesulfonyl)-2-metliyl-3-dimethylaminoethylthio-5-methoxy-lH- indole; l-(4-Meώylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole; l-(4-MeiJiylbenzenesulfonyl)-2-methyl-3-dimetliylaminoetliylthio-5-fluoro-lH-indole; 1 -(4-Bromobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -fluoro- lH-indole; l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimeth.ylaminoethylthio-5-fluoro-lH- indole; l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methoxy-lH- indole; l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoeth.ylthio-lH-indole; l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaniinoeth.ylthio-5-fluoro-lH- indole; l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethyltliio-5-fluoro-lH-indole; l-Benzenesulfonyl^-methyl-S-dimethylaminoethylthio-S-fluoro-lH-indole; 1 -(4-Bromobenzenesulfonyl) -2-methyl-3 -dimethylaminoetliylthio-5 -bromo- 1 H-indole; l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylammoethylthio-5-bromo-lH-mdole; l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole; l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH- indole; l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-bromo-lH-indole; l-Benzenesulfonyl^-methyl-S-dimethylaminoethylthio-S-bronio-lH-indole;
1 -(2,4-Difluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -bromo- IH- indole; l-(4-Isopropylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH- indole; l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoetliylthio-5- bromo- lH-indole;
1 -(4-Isopropylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -trifluoromethyl- lH-indole; l-(4-Metlαoxybenzenesvιlfonyl)-2-methyl-3-dimethylammoethylthio-5-trifluoromethyl- lH-indole;
1 -(4-Fluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -trifluoromethyl- lH-indole; l-(4-Bromobenzenesulfonyl)-2-methyl-3-Dimethylaminoethylthio-5-trifluoromethyl- lH-indole; l-(2-Bromobenzenesιdfonyl)-2-methyl-3-Dimethylamino6tlιylthio-5-trifluoromethyl- lH-indole; l-(4-Metiiylbenzenesulfonyl)-2-methyl-3-Dimethylaminoethylthio-5-trifluorometliyl- lH-indole; l-Benzenesulfonyl^-methyl-S-Dimethylaminoethyltliio-S-trifluoromethyl-lH-indole; l-(2,4-Difluorobenzenesiϊlfonyl)-2-methyl-3-dimethylammoethylthio-5- trifluoromethyl- lH-indole; l-(4-Methoxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-eth.oxy-lH- indole;
1 -(4~Isopropylbenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -ethoxy- IH- indole;
1 -(2,4-Difluoroberizenesulfbnyl) -2-methyl-3 -dimethylaminoethylthio-5 -fluoro- 1 H- indole; l-(5-Chloro-3-Methylbenzothiophen-2-yl-sulfonyl)-2-methyl-3- dimethylaminoethylthio- lH-indole; l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-fluoro- lH-indole;
1 -(3 -Trifluor omethylbenzenesulf onyl) -2-methyl-3 -dimethylaminoethylthio- 1 H-indole ; l-Benzenesulfonyl-2-methyl-3-dimethylamino ethylthio-5-methylthio-lH-indole; l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5- methylthio-lH-indole; l-(4-Fluorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH- indole; 1 -(4-Bromobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methylthio- IH- indole; l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methyltlύo-lH- indole; l-(2-Bromobenzenesulfonyl)-2-methyl-3-dimethylaminoethyltliio-5-methylthio-lH- indole; l-(4-Metlioxybenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-methylthio-lH- indole; l-(3-Triflvιorometliylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-chloro- lH-indole; 1 -(2,4-Difluorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methylthio- IH- indole; l-(4-Methylbenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5-chloro-lH-indole; ^(S-Trifluoromethylbenzenesulfony^-S-dimethylaminoetliylthio-S-chloro-lH-indole; l-(3-Trifluoromethylbenzenesulfonyl)-2-methyl-3-dimetliylaminoethylthio-5- trifluoromethyl-lH-indole; l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-chloro-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-dimethylaniinoethylthio-5-chloro-lH-indole; l-(4-Methoxybenzenesulfonyl)-3-dimefthylaminoethylthio-5-bromo-lH-indole; l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-5-cb.loro-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-bromo-lH-indole; l-(2-Bromobenzenesulfonyl)-3-dimethylaminoetliyltliio-5-bromo-lH-indole; l-(3-Trifluoromethylbenzenesulfonyl)-3-dimeth.ylaminoethylthio-5-bromo-lH-indole; l-(2-Bromobenzenesnlfonyl)-3-dimethylaminoethylthio-5-metlioxy-lH-mdole; l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoethyltliio-5-bromo-lH-indole; l-(4-Fluorobenzenesulfonyl)-3-dimethylaminoetliylthio-5-metlioxy-lH-mdole; 1 -(Benzenesulfonyl)-3 -dimethylaminoethylthio-5 -methoxy- 1 H-indole; l-(4-Methoxybenzenesulfonyl)-3-dimeth.ylaminoethylthio-5-methoxy-lH-indole; l-(4-Bromobenzenesulfonyl)-3-dimethylaminoetliylthio-5-methoxy-lH-indole; l-(4-Methylbenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-methoxy-lH-indole; l-(4-Metb.oxybenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; l-(4-Flιιorobenzenesulfonyl)-3-dimethylaminoetliylthio-lH-indole; l-(4-Methylbenzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; l-(Benzenesulfonyl)-3-dimethylaminoethylthio-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethyltliio-lH-indole; l-(3-Trifluoromethylbenzenesulfonyl)-3-dimethylaminoethyltliio-lH-mdole; l-(2-Bromobenzenesulfonyl)-3-dimethylaminoetliylthio-lH-indole;
{2-[5 -Bromo- 1 -(4-fluorobenzenesulphonyl)- lH-indole-3- sulphinyl] ethyl} dimethylamine;
{2-[l-(2-Bromobenzenesulphonyl)-lH-indole-3-sulphinyl]ethyl}dimethylamine; {2-[5-Bromo-l-(2-bromobenzen6Sulphonyl)-lH-indole-3-sulphinyl] ethyl} dimethylamine;
{2-[5 -Bromo- 1 -(4-methoxyb enzenesulphonyl)- lH-indole-3 -sulphinyl] ethyl} dimethylamine; [2-[5-Bromo-l-(4-isopropylbenzenesulphonyl)-lH-indole-3-sulphinyl] ethyl} dimethylamine; l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole; l-(4-Isopropylbenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole; l-(4-Bromobenzenes\ilfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole; l-(2-Bromobenzenesulfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole;
{2-[5-Methoxy-l-(4-isopropylbenzenesulphonyl)-lH-indole-3- sulphinyl]ethyl} dimethylamine;
{2-[5 -Methoxy- 1 -(2-Bromob enzenesulphonyl)- lH-indole-3 - sulphinyl]ethyl} dimethylamine; 1 -(2-Bromobenzenesulfbnyl) -3 -(N-methyltetrahydropyrrolidin-3 -yl)thio-5 -methoxy- lH-indole; l-(4-Methoxybenzenesulfonyl)-3-dimethylaminoethylthio-6-chloro-lH-indole; l-(4-Fluorobenzenesυlfonyl)-3-dimethylaminoethylthio-6-chloro-lH-indole; {2-[l-(4-Methoxybenzenesulphonyl)-lH-indole-3-sulphinyl]ethyl}dimethylamine; {2-[l-(4-Isopropylbenzenesulphonyl)-lH-indole-3-sulphinyl]ethyl}dimethylamine; l-(4-Fluorobenzenesμlfonyl)-3-dimethylaminoethylthio-5-fluoro-lH-indole;
{2-[l-(4-Methoxybenzenesulphonyl)-5-Methoxy-lH-indole-3- sulphinyl] ethyl} dimethylamine; l-(2,4,5-Trichlorobenzenesulfonyl)-3-dimethylaminoethylthio-2-methyl-5-bromo-lH- indole;
1 -(3 -chlorobenzenesulfonyl)-2-methyl-3 -dimethylaminoethylthio-5 -methoxy- IH- indole; l-(3-chlorobenzenesulfonyl)-2-methyl-3-dimethylaminoethylthio-5,7-difluoro-lH- indole;
Figure imgf000053_0001
l-(l-naphthylsulfonyl)-2-methyl-3-dimethylaminoethylthio-5-trifluoromethyl-lH- indole; l-(2-naphthylsulfonyl)-2-methyl-3-dimethylaminoethylthio-lH-indole; l-(2-naphthylsulfonyl)-2-methyl-3-dimethylaininoethyltliio-4-inethoxy-lH-indole;
{2-[5-Bromo- 1 -(3 -chlorobenzenesulphonyl)- lH-indole-3 -sulphinyl] etliyl} dimethylamine;
{2-[5-ethoxy-l-(2-naphthylsulphonyl)-lH-indole-3-sulphinyl] ethyl} dimethylamine; a stereoisomer thereof ; and a salt thereof.
6. 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 claims 1 to 5.
7. The method according to claim 6 wherein said disorder is an anxiety disorder, a cognitive disorder, or a neurodegenerative disorder.
8. The method according to claim 6 wherein said disorder is Alzheimer's disease or Parkinson's disease.
9. The method according to claim 6 wherein said disorder is attention deficit disorder or obsessive compulsive disorder.
10. The method according to claim 6 wherein said disorder is stroke or head trauma.
11. The method according to claim 6 wherein said disorder is eating disorder or obesity.
12. 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 claims 1 to 5.
13. A compound of formula (I), as defined in any one of claims 1 to 5 for use as a medicament.
14. Use of compound of formula (I), as defined in any one of Claims 1 to 5 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.
15. A method for testing antagonists 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.
16. A process for the preparation of a compound of formula (I),
Figure imgf000055_0001
along with its stereoisomer or its salt with an inorganic or organic acid, wherein: R1, R3 and R4 independently represents hydrogen, halogen, cyano, (Ci-C3)alkyl, halo(C]-C3)alkyl, thio(Ci-C3)alkyl, (C3-C7)cycloalkyl, (C1-C3)BIkOXy5 cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (d-C3)alkyl; halo(CrC3)alkyl and (CrC3)alkylthio; Rs and R5 independently represents hydrogen, (Ci-C3)alkyl, (C3- C7)cycloalkyl; optionally R5 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and Rg represents hydrogen, (d-C3)alkyl; optionally, R7 and Rs may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 0, 1 or 2, said process comprising contacting a compound of general formula (a) wherein: R1 and R2 are as defined above
Figure imgf000055_0002
(a) (b) (C)
with an amine of formula (b) wherein R5, R5, R7 and R8 are as defined above; Lg is suitable leaving group such as chloro, bromo or iodo, to produce a compound of the formula (c), wherein m, Ri, R2, R5, Rs, R7 and Rs are as defined above; and further treating the compound (c) with arylsulfonyl derivative of the formula (d) as defined earlier Compound of formula (T)
Figure imgf000056_0001
(c) (Φ
wherein Ri, R3, and R4 are as defined in claim- 1; and Lg is suitable leaving group such halogeno for example chloro, brorαo or iodo, provides a compound of the formula (I) or its derivative wherein Ri, R2, R3, R4, R5, Re, R7, and Rs are as defined in claim- 1.
17. A process for the preparation of a compound of formula (I)
Figure imgf000056_0002
along with its stereoisomer or its salt with an inorganic or organic acid, wherein: Ri, R3 and R4 independently represents hydrogen, halogen, cyano, (Ci-C3)alkyl, halo(Ci-C3)alkyl, thio(CrC3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (Ci-C3)alkylthio; R5 and R5 independently represents hydrogen, (Ci-C3)alkyl, (C3- C7)cycloalkyl; optionally Rg and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and R8 represents hydrogen, (Ci~C3)alkyl; optionally, R7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 0, 1 or 2, said process comprising said process comprises of oxidizing sulfur in the side chain compound of formula (c), wherein Ri, R2, R5, Rg, R7 and Rg are as defined above to obtain compound (f)
Figure imgf000057_0001
(C) (*)
wherein m, Ri5 R2, R5, R5, R7 and R8 are as defined above and treating compound of formula (f) with arylsulfonyl of the formula (d),
Compound of formula (T)
Figure imgf000057_0002
wherein R1, R3 and R4 are as defined above; and Lg is suitable leaving group such as chloro, bromo or iodo, to obtain a compound of the formula (I) or its derivative wherein value for m is 1 or 2; Ri, R2, R3, R4, R5, R5, R7, and R8 are as defined above.
18. A process for the preparation of a compound of formula (I),
Figure imgf000057_0003
along with its stereoisomer or its salt with an inorganic or organic acid, wherein: Ri, R3 and R4 independently represents hydrogen, halogen, cyano, (Ci-C3)alkyl, halo(C]-C3)alkyl, thio(CrC3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or R3 and R4 may form a 5, 6 or 7 membered 'cyclic structure'; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (CrC3)alkylthio; R5 and R6 independently represents hydrogen, (CrC3)alkyl, (C3- C7)cycloalkyl; optionally R6 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and R8 represents hydrogen, (Ci-C3)alkyl; optionally, R7 and R8 may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 0, 1 or 2, said process comprising treating compounds of formula (g), wherein Ri, R2, R3 and R4 are as defined above; with an amine of formula (b).
Compound of formula (I)
Figure imgf000058_0001
wherein R5, R65 R7 and Rs are as defined above; Lg is suitable leaving group such as chloro, bromo or iodo; provides a compound of the formula (I) or its derivative wherein value for m is 1 or 2; Ri, R2, R3, R4, R5, R5, R7, and Rs are as defined in claim- 1.
19. A process for preparing a compound according to claim 1, optionally further including
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.
20. A novel intermediate compound of formula (c)
Figure imgf000058_0002
(c) along with its stereoisomer or its salt, wherein: Rx represents hydrogen, halogen, cyano, (CrC3)alkyl, halo(d-C3)alkyl, thio(CrC3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3-C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R2 represents hydrogen, (Ci-C3)alkyl; halo(Ci-C3)alkyl and (CrC3)alkylthio; R5 and R6 independently represents hydrogen, (Ci-C3)alkyl, (C3-C7)cycloalkyl; optionally R6 and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and R8 represents hydrogen, (Cr C3)alkyl; optionally, R7 and R8 may form a 3, 4, 5, 6 or 7 membered 'cyclic structure',
21. A novel intermediate compound of formula (f)
Figure imgf000059_0001
(i) and its stereoisomer or its salt, wherein: Ri represents hydrogen, halogen, cyano, (CV
C3)alkyl, halo(Ci-C3)alkyl, thio(CrC3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3- C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; R2 represents hydrogen, (CVC3)alkyl; halo(Ci-C3)alkyl and (CVC3)alkylthio; R5 and R6 independently represents hydrogen, (Ci-C3)alkyl, (C3-C7)cycloalkyl; optionally Re and R7 may form a 5, 6 or 7 membered 'cyclic structure'; R7 and R8 represents hydrogen, (Q-Cyalkyl; optionally R7 and Rg may form a 3, 4, 5, 6 or 7 membered 'cyclic structure; "m" represents integer either 1 or 2.
22. A novel intermediate compound of formula (g)
Figure imgf000059_0002
(g) wherein: Ri, R3 and R4 independently represents hydrogen, halogen, cyano, (d-C3)alkyl, halo(Ci-C3)alkyl, thio(CrC3)alkyl, (C3-C7)cycloalkyl, (CrC3)alkoxy, cyclo(C3- C7)alkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl; or two adjacent groups like R3 and R4 together with the adjoining carbon atoms may form a 5, 6 or 7 membered 'cyclic structure; R2 represents hydrogen, (CVC3)alkyl; halo(C]-C3)alkyl, (CV C3)alkylthio and (d-C3)alkoxy.
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