WO2007046112A1 - Arylthioether tryptamine derivatives as functional 5-ht6 ligands - Google Patents
Arylthioether tryptamine derivatives as functional 5-ht6 ligands Download PDFInfo
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- WO2007046112A1 WO2007046112A1 PCT/IN2006/000196 IN2006000196W WO2007046112A1 WO 2007046112 A1 WO2007046112 A1 WO 2007046112A1 IN 2006000196 W IN2006000196 W IN 2006000196W WO 2007046112 A1 WO2007046112 A1 WO 2007046112A1
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- WO
- WIPO (PCT)
- Prior art keywords
- indole
- ylmethyl
- methyl
- indol
- chloro
- Prior art date
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- -1 Arylthioether tryptamine derivatives Chemical class 0.000 title claims description 13
- 239000003446 ligand Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000000034 method Methods 0.000 claims abstract description 75
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 26
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- SNZXFRFQGXSSGN-UHFFFAOYSA-N phenylsulfanyloxysulfanylbenzene Chemical compound C=1C=CC=CC=1SOSC1=CC=CC=C1 SNZXFRFQGXSSGN-UHFFFAOYSA-N 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 16
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 16
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 16
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000005557 antagonist Substances 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 8
- 210000003169 central nervous system Anatomy 0.000 claims description 8
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
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- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
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- BKMPIBGQIHKXSF-UHFFFAOYSA-N 2-(benzenesulfonylmethyl)-5-chloro-3-[(4-methylpiperazin-1-yl)methyl]-1h-indole Chemical compound C1CN(C)CCN1CC(C1=CC(Cl)=CC=C1N1)=C1CS(=O)(=O)C1=CC=CC=C1 BKMPIBGQIHKXSF-UHFFFAOYSA-N 0.000 claims description 2
- AJZQVADVKJBGKM-UHFFFAOYSA-N 2-(benzenesulfonylmethyl)-5-fluoro-3-[(4-methylpiperazin-1-yl)methyl]-1h-indole Chemical compound C1CN(C)CCN1CC(C1=CC(F)=CC=C1N1)=C1CS(=O)(=O)C1=CC=CC=C1 AJZQVADVKJBGKM-UHFFFAOYSA-N 0.000 claims description 2
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- DZHHTCJAOBWWAE-UHFFFAOYSA-N 2-[(4-chlorophenyl)sulfonylmethyl]-3-[(4-ethylpiperazin-1-yl)methyl]-1h-indole Chemical compound C1CN(CC)CCN1CC(C1=CC=CC=C1N1)=C1CS(=O)(=O)C1=CC=C(Cl)C=C1 DZHHTCJAOBWWAE-UHFFFAOYSA-N 0.000 claims description 2
- GWHIUVLLYZVPLR-UHFFFAOYSA-N 2-[(4-methylphenyl)sulfanylmethyl]-3-[(4-methylpiperazin-1-yl)methyl]-1h-indole Chemical compound C1CN(C)CCN1CC(C1=CC=CC=C1N1)=C1CSC1=CC=C(C)C=C1 GWHIUVLLYZVPLR-UHFFFAOYSA-N 0.000 claims description 2
- ZXAHTGSGLJHJCG-UHFFFAOYSA-N 2-[2-(benzenesulfonylmethyl)-1h-indol-3-yl]-n,n-dimethylethanamine;hydrochloride Chemical compound Cl.N1C2=CC=CC=C2C(CCN(C)C)=C1CS(=O)(=O)C1=CC=CC=C1 ZXAHTGSGLJHJCG-UHFFFAOYSA-N 0.000 claims description 2
- ADJPTCONBRXLAF-UHFFFAOYSA-N 2-[2-(benzenesulfonylmethyl)-4-chloro-7-methyl-1h-indol-3-yl]-n,n-dimethylethanamine;hydrochloride Chemical compound Cl.N1C2=C(C)C=CC(Cl)=C2C(CCN(C)C)=C1CS(=O)(=O)C1=CC=CC=C1 ADJPTCONBRXLAF-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- 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 arylthioether tryptamine derivatives, their stereoisomers, their salts, their preparation and medicine containing them.
- 5-HT 5-hydroxytryptamine
- Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others.
- 5 -HT receptor subtypes regulate the various effects of serotonin.
- Known 5 -HT receptor family includes the 5 -HTj family (e.g. 5-HT 1A ), the 5-HT 2 family (e.g.5- HT 2 A), 5-HT 3 , 5-HT 4 , 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.;
- the receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate c ⁇ clasc (Rual, M.; Trair ⁇ brt, E.; ⁇ rrang, 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. 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.
- 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 receptros 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
- 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).
- GI gastrointestinal
- 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- HT 6 .
- Arylthioether tryptamine class of compounds has now been found which 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), along with its stereoisomer or its salt with an inorganic or organic acid,
- Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as R 1 ;
- Ar- for example may be,
- Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (Ci-C 3 )alkyl, halo(d-C 3 )alkyl, (Ci-C 3 )alkoxy, haloCd-QOalkoxy, cyclo(C 3 -C 6 )alkyl or cyclo(C 3 -C 6 )alkoxy;
- R 2 represents hydrogen, substituted or unsubstituted groups such as (Ci-C 3 )alkyl, (Ci-C 3 )acyl or BOC;
- the present invention also provides methods for preparing, compositions comprising, and methods for using Compounds of Formula (I).
- the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I), or individual stereoisomers, racemic or non-racemic mixture of stereoisomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with atleast one suitable carrier.
- the invention relates to the use of a therapeutically effective amount of compound of formula (I), in manufacture of a medicament, for the treatment or prevention of a disorders involving selective affinity for the 5-HTg receptor.
- the invention further relates to the process for preparing compounds of formula (I), (v) Partial list of such compounds of general formula (I) is as follows:
- the 5-hydroxytryptamine-6 (5-HTg) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its interesting distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting the said receptor.
- arylthioether tryptamine derivatives of formula (I) demonstrate 5-HTg receptor affinity, along with its stereoisomer or its salt with an inorganic or organic acid,
- Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
- Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (d-C 3 )alkyl, halo(C r C 3 )alkyl, (C r C 3 )alkoxy, halo(Ci-C 3 )alkoxy, cyclo(C 3 -C 6 )alkyl or cyclo(C 3 -C6)alkoxy;
- R 2 represents hydrogen, substituted or unsubstituted groups such as (Q- C 3 )alkyl, (Ci-C 3 )acyl or BOC;
- a typical scheme may include following steps: STEP 1:
- 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 group; or iii) forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
- tautomers, stereoisomers, geometric isomers and polymorphs are synthesized, either a mixture containing variable proportions is prepared wherein individual compounds can be isolated afterwards or elaborate procedure is applied to prepare a particular compound.
- examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991).
- Suitable amine protecting groups include sulphonyl (e. g. tosyl), acyl (e. g. acetyl, 2', 2', 2'- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e. g. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric or trifluoroacetic acid) or reductively (e. g. hydrogenolysis of a benzyl group or reductive removal of a 2 ⁇ 2 ⁇ T- trichloroethoxycarbonyl group using zinc in acetic acid) whichever is appropriate.
- hydrolysis e. g. using an acid such as hydrochloric or trifluoroacetic acid
- reductively e. g. hydrogenolysis of a benzyl group or reductive removal of a 2 ⁇ 2 ⁇ T- t
- Suitable amine protecting groups include trifiuoroacetyl(-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(EUman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
- Process (iii) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
- 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.
- the active compounds of the invention may be formulated for oral, buccal, intranasal, parental (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or a form suitable for administration by inhalation or insufflation.
- the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
- binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
- lubricants e.g., magnesium stearate, talc or silica
- disintegrants e.g., potato starch or sodium
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
- suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
- emulsifying agents e.g., lecithin or acacia
- non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
- the composition may take the form of tablets or lozenges formulated in conventional manner.
- the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such 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.
- 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.
- 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 mixture was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes and poured on to the ice water and compound was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound.
- Lithium aluminium hydride (3.59 g, 89.8 mM) was taken in anhydrous tetrahydrofuran at ambient temperature (25 °C) and stirred well under nitrogen blanket. To this reaction mass was added a solution of Ethyl 5-fluoroindole-2-carboxylate (18.6 gm, 89.8 mM) dissolved in 130 ml of tetrahydrofuran slowly. The reaction was exothermic and temperature slowly went up to reflux.
- the reaction mass was further maintained under reflux (60 - 65 0 C) for 3hrs, the reaction was monitored by TLC (the eluent system being n-hexane and ethyl acetate in 7:3 ratio and the product was more polar).
- the mass was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes. Added 200 mL of ethyl acetate and stirred well.
- the material was filtered through hyflow bed washed the bed with 50 mL ethyl acetate and layers separated. Aqueous layer was extracted with 2 x 100 mL of ethyl acetate.
- reaction mass was cooled to 10 0 C and added dimethyl amine aqueous solution (36 %, 10 mL, 60 mM) drop- wise in 10 minutes.
- the mass temperature was allowed to rise to 25 °C and maintained at that temperature under stirring for 2 hrs, while monitoring the reaction by TLC (the eluent system being n-hexane and ethyl acetate in 1 : 1 ratio and the product was more polar).
- solvent ether was removed and added ice water (30 mL), stirred well and filtered the separated solids. The wet cake was dried under vacuum at 55 0 C for 3 hrs to yield 3.33 g (83 %) product.
- Lithium aluminium hydride (1.67 g, 46.3 mM) was taken in anhydrous tetrahydrofuran (60 mlL) under nitrogen blanket and added portion- wise [(5-Fluoro-3-(2-N,N- dimethylaminooxalyl)indol-2-yl)methyl]phenylthioether (3.3 g, 9,26 mM) under stirring at ambient temperature (25 0 C). The mass temperature was raised to reflux (65 0 C) and maintained under reflux for 6 hours till completion of reaction (the reaction was monitored by TLC (the eluent system being chloroform and methanol in 9:1 ratio and the product was more polar).
- Example 6 ⁇ 2-[2-(4-ChlorobenzenesulfonylmethyI)-4-chIoro-7-methyl-lH-indol-3- yl] ethyl ⁇ dimethy lamine.
- Example 7 [2-(2-BenzenesuIfonylmethyI-lH-indol-3-yl)ethyl]dimethylamine hydrochloride.
- Example 9 ⁇ 2-[2-(4-ChlorobenzenesulfonylmethyI-lH-indol-3-yl)]ethyl ⁇ dimethylamine Hydrochloride.
- Example 10 ⁇ 2-[2-(4-FluorobenzenesuIfonyImethyI-5-fluoro-lH-indoI-3- yl)]ethyl ⁇ dimethylamine hydrochloride.
- Example 14 ⁇ 2-[2-(4-ChIorobenzenesuIfonyImethyI-5-bromo-lH-indol-3- yl)]ethyl ⁇ dimethylamine hydrochloride. Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
- Example 15 ⁇ 2-[2-(4-ChIorobenzenesulfonylmethyI-5-methoxy-lH-indoI-3-yI] yl)]ethyl ⁇ dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
- Example 17 ⁇ 2-[2-(4-Methoxybenzenesulfonylmethyl-5-Fluoro-lH-indol-3-yI)]ethyl ⁇ dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
- Example 20 [2-(2-BenzenesuIfonyImethyI-5-fluoro-lH-indoI-3-yI)]ethyI ⁇ diethyIamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
- Example 36 2-(4-BromobenzenesuIfonylmethyl)-3-(4-ethylpiperazin-l-yImethyI)-5- chloro-lH-indole
- Example 38 2-(4-ChlorobenzenesulfonyImethyI)-3-(4-methy-piperazin-l-ylmethyI)-5- chloro-lH-indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
- Example 51 2-(BenzenesuIfonylmethyl)-3-(4-methylpiperazin-l-yImethyI)-5-fluoro-lH- indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. LR.
- Example 125 Food Intake Measurement (Behavioural Model).
- mice Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, India) were used. The 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 i.p., with a composition comprising a compound of formula (1) or a corresponding composition (vehicle) without the said compound (control group), once-a-day. The rat was provided with ad libitum food and water. On 0, 1 st , 7 th , 14 th , 21 st and 28 th day the rat was left- with the pre-weighed amounts of food.
- Example 126 Tablet comprising a compound of formula (I):
- Example 127 Composition for Oral Administration
- Example 128 Liquid oral formulation
- Example 129 Parenteral Formulation
- Example 130 Suppository Formulation
- Example 131 Topical Formulation
- Example 132 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, 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.
- two identical objects plastic bottles, 12.5 cm height x 5.5 cm diameter
- 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.
- 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 was the total time spent exploring the familiar objects (al + a2).
- T2 was the total time spent exploring the familiar object and novel object (a3 +b).
- the object recognition test was performed as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats- Behavioral data, Behav. Brain Res., 31, 47-59. Some representative compounds have shown positive effects indicating the increased novel object recognition viz; increased exploration time with novel object and higher discrimination index.
- Example 133 Chewing/Yawning/Stretching induction by 5HTgR 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.
- REFERENCE (1) Yamada N., Hattoria A., Hayashi T., Nishikawa T., Fukuda H. et. Al., Pharmacology, Biochem. And Behaviour, 2004, 78, 787-791.
- Linder M. D. Hodges D. B., Hogan J. B., Corsa J. A., et al The Journal of Pharmacology and Experimental Therapeutics, 2003, 307 (2), 682-691.
- Example 135 Passive avoidance:
- the training apparatus consisted of a chamber 300 mm in length, 260 mm wide, and 270 mm in height, constructed to established designs. The front and top were transparent, allowing the experimenter to observe the behavior of the animal inside the apparatus.
- the chamber was divided into two compartments, separated by a central shutter that contained a small opening 50 mm wide and 75 mm high set close to the front of the chamber. The smaller of the compartments measured 9 mm in width and contained a low-power (6V) illumination source. The larger compartment measured 210 mm in width and was not illuminated.
- 6V low-power
- the floor of this dark compartment consisted of a grid of 16 horizontal stainless-steel bars that were 5mm in diameter and spaced 12.5 mm apart.
- a current generator supplied 0.75 mA to the grid floor, which was scrambled once every 0.5 s across the 16 bars.
- a resistance range of 40-60 microohms was calculated for a control group of rats and the apparatus was calibrated accordingly.
- An electronic circuit detecting the resistance of the animal ensured an accurate current delivery by automatic variation of the voltage with change in resistance.
- Receptor source Human recombinant expressed in HEK293 cells
- Radioligand [ 3 H]LSD (60-80 Ci/mmol)
- Final ligand concentration [1.5 nM]
- Non-specific determinant Methiothepin mesylate - [0.1 ⁇ M]
- the antagonist property of the compounds at the human 5-HT 6 receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HT 6 receptor will lead to an increase in adenyl cyclase activity. A compound that is an agonist will show an increase in cAMP production and a compound that is an antagonist will block the agonist effect.
- Human 5-HT 6 receptors were cloned and stably expressed in HEK293 cells. These cells were plated in 6 well plates in DMEM/F12 media with 10 % fetal calf serum (FCS) and 500 ug/mL G418 and incubated at 37 0 C. in a CO 2 incubator.
- the cells were allowed to grow to about 70 % confluence before initiation of the experiment.
- the culture media was removed, and the cells were washed once with serum free medium (SFM).
- SFM serum free medium
- Two mL of SFM+IBMX media was added and incubated at 37 0 C for 10 min.
- the media were removed and fresh SFM+IBMX media containing various compounds, and 1 uM serotonin (as antagonist) were added to the appropriate wells and incubated for 30 min.
- the media were removed and the cells were washed once with 1 mL of PBS (phosphate buffered saline). Each well was treated with 1 mL cold 95 % ethanol and 5 mM EDTA (2:1) at 4 °C.
- cAMP content was determined by EIA (enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (Amersham RPN 225). The procedure used was as described for the kit. Briefly, cAMP was determined by the competition between unlabeled cAMP and a fixed quantity of peroxidase-labelled cAMP for the binding sites on anti-cAMP antibody. The antibody was immobilized onto polystyrene microtitre wells precoated with a second antibody.
- the reaction was started by adding 50 uL, peroxidase-labeled cAMP to the sample (100 uL) preincubated with the antiserum (100 uL) for 2 hours at 4° C. Following 1 hour incubation at 4° C, the unbound ligand was separated by a simple washing procedure. Then an enzyme substrate, trimethylbenzidine (1), was added and incubated at room temperature for 60 min. The reaction was stopped by the addition of 100 uL 1.0 M sulphuric acid and the resultant color read by a microtitre plate spectrophotometer at 450 nM within 30 minutes. In the functional adenylyl cyclase assay, some of the compound of this invention was found to be a competitive antagonist with good selectivity over a number of other receptors.
Abstract
The present invention provides aryithioether tryptamine 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 good selectivity towards the said receptor. The present invention also includes the stereoisomers, the salts, methods of preparation and medicine containing the said aryithioether tryptamine derivatives.
Description
ARYLTHIOETHER TRYPTAMINE DERIVATIVES AS FUNCTIONAL 5-HT6 LIGANDS.
Field of Invention The present invention relates to certain arylthioether tryptamine 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 tiie 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 -HTj family (e.g. 5-HT1A), the 5-HT2 family (e.g.5- HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5- HT7 subtypes.
The 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 c}^clasc (Rual, M.; Trairϊbrt, E.; Λrrang, 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, 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 CAj, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HTg receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5- . HTg receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues.
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(1): 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 receptros 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 (1), 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 viva 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.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HTg receptor. It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HTg receptor. The preferred object of the invention to synthesize a potent selective 5-HTg receptor antagonist.
Summary of the Invention
Arylthioether tryptamine class of compounds has now been found which 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), along with its stereoisomer or its salt with an inorganic or organic acid,
Formula (I)
wherein Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as R1; Ar- for example may be,
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (Ci-C3)alkyl, halo(d-C3)alkyl, (Ci-C3)alkoxy, haloCd-QOalkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R2 represents hydrogen, substituted or unsubstituted groups such as (Ci-C3)alkyl, (Ci-C3)acyl or BOC; R3, R4, R3- and R4- independently may be either same or different, and represents hydrogen, halogen, perhaloalkyl; or R3 and R4, R3- and R4 represent =0, or a substituted or unsubstituted group selected from linear or branched (Ci-C3)alkylJ (C3-C6)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C6)alkoxy; optionally, R3 and R5 along with the intervening nitrogen and carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R5 and R5 represents hydrogen, (C]-C3)alkyl; optionally, R5 and R5 along with the nitrogen atom may form a 5, 6 or 7 membered 'cyclic structure'; 'n' is the number of carbon atoms, which may be either 0 or 1 and 'm' is the number of oxygen atoms attached to the sulfur atom, which may be either 0, 1 or 2.
The present invention also provides methods for preparing, compositions comprising, and methods for using Compounds of Formula (I). (ii) In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I), or individual
stereoisomers, racemic or non-racemic mixture of stereoisomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with atleast one suitable carrier. (iii) In another aspect, the invention relates to the use of a therapeutically effective amount of compound of formula (I), in manufacture of a medicament, for the treatment or prevention of a 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) Partial list of such compounds of general formula (I) is as follows:
[2-(2-Benzenesulfonylmethyl-5-fluoro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
[2-(2-Benzenesulfonylmethyl-5,7-difluoro-lH-indol-3-yl)ethyl]dimethylamine;
[2-(2-Benzenesulfonylmethyl-4-chloro-7-methyl-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl)-4-chloro-7-methyl-lH-indol-3- yl] ethyl} dimethylamine;
[2-(2-Benzenesulfonylmethyl-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
{2-[2-(4-Fluorobenzenesulfonylmethyl-lH-indoϊ-3-yl)]ethyl}dimethylamine;
{2-[2-(4-Chlorobenzenesulfonylmethyl-lH-indol-3-yl)]ethyl}dimethylamine hydrochloride; {2-[2-(4-Chlorobenzenesulfonylmethyl-5-fiuoro-lH-indol-3-yl)]ethyl}dimethylamine hydrochloride;
[2-(2-Benzenesulfonylmethyl-5-chloro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
2-(4-Chlorobenzenesulfonylmethyl)-5-Chloro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
[2-(2-Benzenesulfonylmethyl-5-bromo-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl-5 -bromo- lH-indol-3 -yl)] ethyl} dimethylamine hydrochloride; {2-[2-(4-Chlorobenzenesulfonylmethyl-5-methoxy-lH-indol-3- yl] ethyl} dimethylamine;
{2-[2-(2-bromobenzenesulfonylmethyl-5-methoxy-lH-indol-3- yl] ethyl} dimethylamine;
{2-[2-(4-Methoxybenzenesulfonylmethyl-5-Fluoro-lH-indol-3- yl]ethyl}dimethylamine;
{2-[2-(4-Methoxybenzenesulfonylmethyl-5-chloro-lH-indol-3-
yl]ethyl}dimethylamine;
{2-[2-(4-Methoxybenzenesulfonylmethyl-lH-indol-3-yl]ethyl}dimethylamine;
[2-(2-Benzenesulfonylmethyl-5-fluoro-lH-indol-3-yl)ethyl]diethylamine;
[2-(2-Benzenesulfonylmethyl- lH-indol-3 -yl)-ethyl] diethylamide; [3-(2-N3N-Diethylaminoethyl) indol-2-yl methyl]ρhenylthioether;
[5-Fluoro-3-(2-N,N-diethylaminoethyl) indol-2-yl methyljphenylthioether;
[(5-Fluoro-3-(4-N-Methylpiperazin-l-yl)ethyl)indol-2-yl)methyl]phenylthioether;
[2-(2-(4-Chlorobenzenesulfonyl)methyl-5,7-difluoro-indol-3-yl)ethyl]dimethylaniine;
[3-(4-N-Methylpiperazin-l-yl)ethylindol-2-yl methyl]phenylthioether; 2-(Benzenesixlfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-fluoro-lH- indole; 2-(4-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-fluoro-lH- indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole;
2-(2-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole; 2-(2-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-chloro-lH- indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH- indole; 2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH- indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-chloro-lH- indole;
2-(Benzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH-indole; 2-(Benzenesulfonylmethyl)-3 -(4-ethylpiperazin- 1 -ylmethyl)-5 -chloro- lH-indole;
2-(4-Metiiylbenzenesulfonylmethyl)-3-(4-methylpiperazin-lτylmethyl)-5-chloro-lH- indole;
2-(Benzenesulfonylmethyl)-3 -(4-meth.ylpiperazin- 1 -ylmethyl)-5 -bromo- lH-indole;
2-(Benzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-bromo-lH-mdole; 2-(4-Chlorobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
2-(4-Methylbenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole; 2-(4-Fluorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
{2-[2-(4-Methylbenzenesulfonylmethyl)-lH-indol-3-yl]ethyl}dimethylainine;
2-(4-Fluorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH- indole; 2-(Benzenesulfonylmethyl)-3 -(4-methylpiperazin- 1 -ylmethyl)-5 -Fluoro- lH-indole;
2-(4-Methylbenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-fluoro-lH- indole;
3-(4-Methylpiperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
5 -Bromo-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-p-tolylthiomethyl- lH-indole; 5 -Chloro-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-p-tolylthiomethyl- lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
3-(4-Methyl-piperazin- 1 -ylmethyl)-2-p-tolylthiomethyl- lH-indole; 3-(4-Ethyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5- Chloro-3-(4-methyl-piperazin-l-ylmet.hy1)-2-phenylthiomethyl-lH-mdole;
5- Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
5 -Fluoro-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-phenylthiomethyl- lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole; 5-Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-yhnethyl)-2-p-bromothiomethyl-lH-indole;
5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole;
5-Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole; 5-Fluoro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole;
5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiomethyl-lH-indole;
5-Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiomethyl-lH-indole;
5 -Fluoro-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-p -fluorothiomethyl- lH-indole; 5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiomethyl-lH-indole;
[(5 -Fluoro-3 -(2-N,N-dimethylaminooxalyl)indol-2-yl)methyl] phenylthioether;
[(5-Fluoro-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether; [(5-Chloro-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether; 4'-Chloro[(5-chloro-3-(2-N,N-dimethylaminoefthyl)indol-2- yl)methyl]phenylthioether; [(5-Chloro-3-(2-N3N-dimethylaminoethyl)indol-2-yl)methyl]-4'- methoxyphenylthioether;
4'-Chloro[(5-Fluoro-3-(2-N,N-dimethylaminoethyl)indol-2- yl)methyl]phenylthioether;
[(5-Methoxy-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether; [(5,7-Difluoro-3-(2-N,N-dimetliylaminoethyl)indol-2-yl)methyl]plienylthioetlier;
4'-Chloro[(5,7-difluoro-3-(2-N,N-dimethylaminoethyl)indol-2- yl)methyl]phenylthioether; and a pharmaceutically acceptable salt thereof. 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 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.
Surprisingly, it has now been found that arylthioether tryptamine derivatives of formula (I) demonstrate 5-HTg receptor affinity, along with its stereoisomer or its salt with an inorganic or organic acid,
Formula (I)
wherein Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (d-C3)alkyl, halo(CrC3)alkyl, (CrC3)alkoxy, halo(Ci-C3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R2 represents hydrogen, substituted or unsubstituted groups such as (Q- C3)alkyl, (Ci-C3)acyl or BOC; R3, R4, R3- and R4- independently may be either same or different, and represents hydrogen, halogen, perhaloalkyl; or R3 and R4, R3- and R4 represent =0, or a substituted or unsubstituted group selected from linear or branched (Ci-C3)alkyl, (C3- C6)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C6)alkoxy; optionally, R3 and R5 along with the intervening nitrogen and carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R5 and R5 represents hydrogen, (Ci-C3)alkyl; optionally, R5 and R5 along with the nitrogen atom may form a 5, 6 or 7 membered 'cyclic structure'; 'n' is the number of carbon atoms, which may be either 0 or 1 and 'm' is the number of oxygen atoms attached to the sulfur atom, which may be either 0, 1 or 2.
Also disclosed is a process to prepare a compound of formula (I), which comprises of contacting a compound of formula (iii), wherein all the substituents are as defined earlier for compound of formula (I) with suitable reagents to obtain the desired side-chain according to the established literature. For example, a typical scheme may include following steps: STEP 1:
STEP 2:
Alternatively,
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 group; or iii) forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
Wherever applicable tautomers, stereoisomers, geometric isomers and polymorphs are synthesized, either a mixture containing variable proportions is prepared wherein individual compounds can be isolated afterwards or elaborate procedure is applied to prepare a particular compound. In process (i), pharmaceutically acceptable salts may be prepared conventionally by reaction of the base with the appropriate acid or acid derivative as described earlier in detail or the thioether compounds where m = 0 can be converted to their oxidized derivatives with m = 1 or m = 2. m process (ii), examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991).
Suitable amine protecting groups include sulphonyl (e. g. tosyl), acyl (e. g. acetyl, 2', 2', 2'-
trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e. g. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric or trifluoroacetic acid) or reductively (e. g. hydrogenolysis of a benzyl group or reductive removal of a 2\ 2\ T- trichloroethoxycarbonyl group using zinc in acetic acid) whichever is appropriate. Other suitable amine protecting groups include trifiuoroacetyl(-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(EUman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
Process (iii) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parental (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such 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.
An effective amount of a compound of general formula (I), or their derivatives as defined above can be used to produce a medicament, along with conventional pharmaceutical auxiliaries, carriers and additives.
Such therapy includes multiple choices: for example, administering two compatible compounds simultaneously in a single dose form or administering each compound individually in a separate dosage; or if required at same time interval or separately in order to maximize the beneficial effect or minimize the potential side-effects of the drugs according to the known principles of pharmacology.
The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-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. 1H- NMR spectra were recorded at 400 MHz on a Bruker instrument. Deuterated chloroform (99.8 % D) was used as solvent. TMS was used as internal reference standard. Chemical shift values are expressed in parts per million i.e. (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,
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. The following Descriptions and Examples illustrate the preparation of compounds of the invention: Description 1: 2-HydroxymethyI-lH-Indole (Dl) lH-Indole-2-carboxylic acid ethyl ester (20 gm, 0.105 M) in THF (50 mL) was treated with cooled and stirred suspension of Lithium Aluminum Hydride (6.21 gm, 0.163 M) in THF (15 mL) slowly over the period of lhour. The reaction mixture was heated at reflux for 3 hours. After the completion of reaction, the reaction mixture was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes and poured on to the ice water and compound was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound.
Mass: 148 (M+H)+; NMR : 4.82 (2H, s), 6.40 - 6.40 (IH, d), 7.08 - 7.12 (IH, m), 7.16 - 7.25 (IH, m), 7.33 - 7.35 (IH, m), 7. 57 - 7.59 (IH, m), 8.35 (IH, bs). Description 2: 2- Phenylthiomethyl-lH-indole (D2) Tertahydrofuran (25 mL), Dl (2.0 g, 13.6 mM) and thiophenol (1.66 g, 15 mM) charged in a reaction flask equipped with magnetic stirrer, thermometer pocket, condenser arid CaCl2 guard tube. P-toulenesulfonic acid (0.55 g, 2.83 mM) was added in small portion to reaction mass. The mixture was heated at reflux for 4 hours. After the completion of reaction, the reaction mixture was poured on to the chilled caustic solution and compound was extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure. The residue
obtained was purified by flash chromatography using silica (ethyl acetate/ n-hexane, 0.3/9.7) to afford the compound, which was identified by IR, NMR, Mass spectral analyses as the title compound.
Mass: 240 (M+H)+; NMR: 4.27 (2H, s), 6.34 - 6.34 (IH, m), 7.07 - 7.32 (8H, m), 7.50 (IH, m), 8.22 (IH, bs).
Description 3: 2-HydroxymethyI-5-fluoroindole
Lithium aluminium hydride (3.59 g, 89.8 mM) was taken in anhydrous tetrahydrofuran at ambient temperature (25 °C) and stirred well under nitrogen blanket. To this reaction mass was added a solution of Ethyl 5-fluoroindole-2-carboxylate (18.6 gm, 89.8 mM) dissolved in 130 ml of tetrahydrofuran slowly. The reaction was exothermic and temperature slowly went up to reflux. The reaction mass was further maintained under reflux (60 - 65 0C) for 3hrs, the reaction was monitored by TLC (the eluent system being n-hexane and ethyl acetate in 7:3 ratio and the product was more polar). The mass was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes. Added 200 mL of ethyl acetate and stirred well. The material was filtered through hyflow bed washed the bed with 50 mL ethyl acetate and layers separated. Aqueous layer was extracted with 2 x 100 mL of ethyl acetate. The combined organic layer was washed with 2 x 30 mL of brine solution, dried over sodium sulfate, filtered and solvent removed under reduced pressure. Weight of the residual mass was 15 g. Mass: 166 (M+H); NMR: 3.78 (2H, s), 7.11 - 7.15 (2H, m), 7.50 (IH, s), 7.82 - 7.88 (2H, m). Description 4: [(5-FluoroindoI-2-yl)methyI]phenylthioether
2-Hydroxymethyl-5-fluoroindole (7.5 g, 45 mM) was taken in anhydrous THF, 60ml under nitrogen blanket. To this well stirred solution, thiophenol (7.49 g, 68 mM) was added at ambient temperature in a single lot. Cooled the mass to 20 0C and added p-toluene sulphonic acid (1.81 g, 9.5 mM) in small portions. Then the reaction mass was further stirred at ~25 0C for 3 hrs, while monitoring the reaction by TLC (the eluent system being n-hexane and ethyl acetate in 4:1 ratio and the product was less polar). After completion of the reaction, 40 % sodium hydroxide solution (60 mL) was added to the reaction mass and the product was extracted with 3 x 100 mL ethyl acetate. The combined organic layer was washed with 2 x 30 mL of brine solution, dried over sodium sulfate, filtered and solvent removed under reduced pressure. Weight of the residual mass was 11.2 g. It was purified by column chromatography using silica gel, eluting solvent system being 3 % ethyl acetate in n-hexane. The pure product obtained was about 2.95 g. Mass: 258.4 (M+H)+; NMR: 4.24 (2H, s), 6.29 (IH, s), 6.86 - 6.92 (IH, dt), 7.13 - 7.32 (7H, m), 8.21 (IH, s).
Example 1 : [(5-FIuoro-3-(2-N,N-dimethyIaminooxalyI)indol-2-yI)methyI]
phenylthioether
[(5-Fluoroindol-2-yl)methyl]phenylthioether (2.9 g, 11.2 mM) was taken in 30ml of diethyl ether, cooled the mass to 10 0C and added oxalyl chloride (1.57 g, 12.4 mM) drop-wise under stirring maintaining the mass temperature at 10 0C. After addition was complete, the mass temperature was allowed to reach ambient temperature (25 0C) and the mass was stirred for lhr at that temperature, while monitoring the reaction by TLC (the eluent system being n- hexane and ethyl acetate in 1:1 ratio and the product was more polar). Then the reaction mass was cooled to 10 0C and added dimethyl amine aqueous solution (36 %, 10 mL, 60 mM) drop- wise in 10 minutes. The mass temperature was allowed to rise to 25 °C and maintained at that temperature under stirring for 2 hrs, while monitoring the reaction by TLC (the eluent system being n-hexane and ethyl acetate in 1 : 1 ratio and the product was more polar). After completion of reaction, solvent ether was removed and added ice water (30 mL), stirred well and filtered the separated solids. The wet cake was dried under vacuum at 55 0C for 3 hrs to yield 3.33 g (83 %) product. Mass: 357.3 (M+H)+; NMR: 2.94 (3H, s), 3.11 (3H5 s), 4.53 (2H, s), 6.93 - 6.97 (IH3 dt, J = 9.0, 2.47), 7.16 - 7.30 (6H, m), 7.50 - 7.52 (IH, d, J = 9.24), 9.57 (IH, s). Example 2 : [(5-FIuoro-3-(2-N,N-dimethyIaminoethyl)indol-2- yl)methyl] phenylthioether
Lithium aluminium hydride (1.67 g, 46.3 mM) was taken in anhydrous tetrahydrofuran (60 mlL) under nitrogen blanket and added portion- wise [(5-Fluoro-3-(2-N,N- dimethylaminooxalyl)indol-2-yl)methyl]phenylthioether (3.3 g, 9,26 mM) under stirring at ambient temperature (25 0C). The mass temperature was raised to reflux (65 0C) and maintained under reflux for 6 hours till completion of reaction (the reaction was monitored by TLC (the eluent system being chloroform and methanol in 9:1 ratio and the product was more polar). The mass was cooled to 10 0C and added 10ml ice-cold water drop-wise (The quenching of the reaction mass was exothermic in nature). To the reaction mass thus obtained, added 50 mL ethyl acetate, stirred well, filtered the solids and washed the solids on the filter with 100 ml of ethyl acetate. Organic layer separated from the filtrate, washed with 2 x 30 ml of brine solution, dried over sodium sulfate, filtered and solvent removed under reduced pressure at 50 0C. Weight of the residual mass was 3.1 g. The pure product was was isolated by column chromatography on neutral alumina (activated), eluent being 20 % ethyl acetate in n-hexane. The yield of the product was 1.15 gm. Mass: 329.4 (M+H)+; NMR: 2.74 - 2.75 (6H, d, J = 5.04), 2.83 - 2.86 (2H, m), 2.90 - 2.97 (2H, m), 4.91 (2H, s), 6.86 - 6.92 (IH, dt), 7.11 - 7.15 (IH, dd), 7.16 - 7.20 (IH, q, J = 4.44), 7.21 - 7.30 (5H, m), 8.13 (IH, s).
Example 3 : [2-(2-Benzenesulfonylmethyl-5-fluoro-lH-indol-3-yl)-ethyI]dimethylamine
hydrochloride
[(5-Fluoro-3-(2-N,N-dimethylaminoefthyl)indol-2-yl)methyl]phenylthioether (1.15 g, 3.5 mM) was taken in chloroform (15 ml), added p-toluene sulfonic acid (0.66 g, 3.5 mM) at 25 0C. The mass was stirred for 1 hour and m-chloroperbenzoic acid (2.42 gm, 7.0 mM) was added in small portions at ambient temperature (25 0C). The mass temperature was maintained at 25 0C for 2.5 hrs under stirring till completion of reaction (the reaction was monitored by TLC). After completion of the reaction, the mass was cooled to 10 °C, pH adjusted to ~10.0 using aqueous ammonia solution and the product was extracted using 3 x 25 rriL of chloroform. The combined organic layer was washed with 2 x 15 ml of brine solution, dried over sodium sulfate, filtered and solvent removed under reduced pressure. The residual mass (1.8 g) obtained was purified by column chromatography using neutral alumina (activated), eluting solvent system being ethyl acetate. The pure product obtained was 230 mg. It was converted to hydrochloride salt in ethylacetate at ambient temperature using Iso-propanolol saturated with hydrochloride gas. Weight of the salt was 220 mg. Melting range (0C): 253.2-253.8 (dec); IR spectra (cm'1): 3152, 2921, 2608, 1630, 1307, 1155, 735, 688; Mass: 361.3 (M+H)+; NMR: 2.74 - 2.75 (6H, d, J = 5.04), 2.83 - 2.86 (2H, m), 2.90 - 2.97 (2H, m), 4.91(2H, s), 6.93 - 6.98 (IH, dt), 7.33 - 7.38 (IH, dd, J = 4.38), 7.41 - 7.44 (IH, dd, J = 8.88, 2.08), 7.60 - 7.64 (2H, m), 7.73 - 7.80 (3H, m), 10.38 (IH, s), 11.02 (IH, s). Example 4 : [2-(2-BenzenesuIfonylmethyl-5,7-difluoro-lH-indoI-3- yl)ethyl]dimethylamine
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (0C): 215.2 - 216.1; IR spectra (cm"1): 3336, 2984, 2929, 2727, 1585, 1344, 1151, 715, 687; Mass: 379.2 (M+H)+; NMR: 1.71 - 1.97 (2H, m), 2.16 (6H, s), 2.33 - 2.39 (2H, m), 4.51 (2H, m), 6.76 - 6.80 (IH, m), 6.89 - 6.92 (IH, dd, J = 8.88, 2.04), 7.44 - 7.48 (2H, t), 7.61 - 7.66 (3H, m), 8.77 (IH, s). Example 5 : [2-(2-BenzenesuIfonylmethyl-4-chloro-7-methyI-lH-indol-3- yl)ethyl] dimethylamine hydrochloride.
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (0C): 262.7 - 263.0 (dec); IR spectra (cm"1): 3157, 2939, 2577, 1616, 1300, 1152, 731; Mass: 391.2 (M+H)+; NMR: 2.35 (3H, s), 2.78 (6H, s), 3.09 - 3.13 (4H, m), 4.90 (2H, s), 6.87 - 6.89 (IH, d, J = 7.72), 6.93 - 6.95 (IH, d, J = 7.68), 7.62 - 7.66 (2H, t, J = 7.88), 7.76 - 7.80 (IH, t, J = 7.52), 7.84 - 7.86 (2H, d, J = 8.28), 10.34 (IH, s), 11.35 (IH, s).
Example 6 : {2-[2-(4-ChlorobenzenesulfonylmethyI)-4-chIoro-7-methyl-lH-indol-3- yl] ethyl} dimethy lamine.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 185.6 - 186.0; IR spectra (cm"1): 3355, 2961, 2859, 2774, 1578, 1388, 1147, 768; Mass: 425.1 (M+H)+; NMR: 2.2 - 2.3 (2H3 m), 2.33 (6H, s), 2.47(3H, s), 2.83 - 2.87 (2H, m), 4.62 (2H, s), 6.91 - 6.93 (IH, d, J = 7.48), 6.98 - 7.00 (IH5 d, J = 7.72), 7.43 - 7.47 (2H, m), 7.65 - 7.68 (2H, m), 8.71 (IH, m).
Example 7 : [2-(2-BenzenesuIfonylmethyI-lH-indol-3-yl)ethyl]dimethylamine hydrochloride.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 243.5 - 244.6 (dec); IR spectra (cm"1): 3226, 2959, 2621, 1619, 1301, 1147; Mass: 343.3 (MfH)+; NMR: 2.78 (6H, d, J = 4.76), 2.85 - 3.0 (4H, m), 4.90 (2H, s), 6.97 - 7.01 (IH, m), 7,08 - 7.12 (IH, m), 7.34 - 7.36 (IH, d, J = 7.84), 7.59 - 7.63 (3H, m), 7.73 - 7.77 (IH, m), 7.79 - 7.81 (2H, d, J = 8.08), 10.6 (IH, s), 11.09 (IH, s). Example 8 : {2-[2-(4-FluorobenzenesuIfonyImethyI-lH-indoI-3-yl)]ethyl} dimethylamine.
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 3390, 2917, 2710, 1590, 1315,
1147, 753, 655; Mass: 361.3 (M+H)+; NMR: 2.58 (6H, s), 2.63 - 2.68 (2H, m), 2.83 - 2.87 (2H, m), 4.67 (2H, s), 7.11 - 7.17,(3H, m), 7.23 - 7.25 (IH, m), 7.38 - 7.40 (IH, d, J = 7.84), 7.45 -
7.47 (IH, d, J = 7.88), 7.79 - 7.82 (2H, m), 8.74 (IH, s).
Example 9 : {2-[2-(4-ChlorobenzenesulfonylmethyI-lH-indol-3-yl)]ethyl} dimethylamine Hydrochloride.
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (0C): 216.5 - 217; IR spectra (cm" *): 3153, 2961, 2602, 1621, 1581, 1313, 1155, 713; Mass: 377.3 (M+H)+; NMR: 2.78 - 2.80 (6H, d, J = 4.8), 2.93 - 2.95 (2H, m), 3.01 - 3.05 (2H, m), 4.95 (2H, s), 7.0 - 7.04 (IH, m), 7.10 - 7.14 (IH, m), 7.36 - 7.38 (IH, d, J = 8.08), 7.61 - 7.63 (IH, d, J = 7.92), 7.71 - 7.73 (2H, m), 7.78 - 7.81 (2H, m), 10.30 (IH, s), 11.08 (IH, s). Example 10 : {2-[2-(4-FluorobenzenesuIfonyImethyI-5-fluoro-lH-indoI-3- yl)]ethyl}dimethylamine hydrochloride.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (0C): 254.7 - 255.1
(dec); IR spectra (cm"1): 3192, 2957, 2917, 2612, 1582, 1311, 1155; Mass: 395.2 (M+H)+; NMR: 2.77 - 2.78 (6H, d, J=4.8), 2.89 - 2.91 (2H, m), 2.98 - 3.02 (2H, m), 4.95 (2H, s), 6.93 - 6.99 (IH, dt), 7.35 - 7.37QH, dd, J = 4.56), 7.42 - 7.45 (IH, d, J = 8.96, 2.44), 7.69 - 7.73 (2H, m), 7.77 - 7.80 (2H, m), 10.27 (IH, s), 11.17 (IH, s). Example 11 : [2-(2-BenzenesulfonyImethyl-5-chloro-lH-indol-3-yI)ethyI]dimethylamine hydrochloride.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 250.5 - 252.2 (dec); IR spectra (cm'1): 3160, 2930, 2589, 1581, 1300, 1150, 605; Mass: 377.3 (M+H)+; NMR: 2.74 - 2.76 (6H, d, J = 4.76), 2.82 - 2.86 (2H, m), 2.90 - 2.95 (2H, m)
4.91 (2H, s), 7.0 - 7.11 (IH, dd, J = 8.72, 2.08), 7.37 - 7.39 (IH, d, J = 8.6), 7.59 - 7.64 (2H, m), 7.68 - 7.69 (IH, d, J = 1.88), 7.73 - 7.79 (3H, m), 10.27 (IH, s), 11.31 (IH, s). Example 12 : 2-(4-Chlorobenzenesulfonylmethyl)-5-ChIoro-lH-indol-3- yl)ethyl]dimethylamine hydrochloride: Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (0C): 263.0 - 263.5 (dec); IR spectra (cm"1): 3139, 2948, 2599, 1580, 1313, 1155, 763; Mass: 411.2 (M+H)+; NMR: 2.77 - 2.779 (6H, d, J = 3.64), 2.87 - 2.91 (2H, m), 2.99 - 3.0 (2H, m), 4.96 (2H, s), 7.09 - 7.12 (IH, dd, J = 8.64, 1.96), 7.36 - 7.39 (IH, d, J = 8.68), 7.69 - 7.80 (5H, m). Example 13 : [2-(2-Benzenesulfonylmethyl-S-bromo-lH-indol-3-yl)ethyl]dimethylamine hydrochloride.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 248.1 - 250.1 (dec); IR spectra (cm 1): 3153, 2931, 2579, 2458, 1582, 1298, 1150, 601; Mass: 421.2 (M+H)+; NMR: 2.73 - 2.75 (6H, d, J = 4.88), 2.82 - 2.88 (2H, m), 2.90 - 2.97 (2H, m)
4.92 (2H, s), 7.20 - 7.22 (IH, dd, J = 8.64, 1.8), 7.32 - 7.34 (IH, d, J - 8.64), 7.59 - 7.63 (2H, m), 7.73 - 7.82 (4H, m), 10.43 (IH, s), 11.33 (IH, s).
Example 14 : {2-[2-(4-ChIorobenzenesuIfonyImethyI-5-bromo-lH-indol-3- yl)]ethyl}dimethylamine hydrochloride. Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 262.7 - 263.3 (dec); IR spectra (cm'1): 3126, 2918, 2593, 2471, 1581, 1313, 1154, 762; Mass: 455.0 (M+H)+; NMR: 2.78 - 2.79 (6H, d, J = 3.64), 2.87 - 2.93 (2H, m), 2.98 - 3.04 (2H, m), 4.98 (2H, s), 7.22 - 7.24 (IH, dd, J = 8.64, 1.84), 7.34 - 7.36 (IH, d, J = 8.64), 7.70 -
7.74 (2H3 m), 7.77 - 7.81 (2H, m), 7.85 -7.86 (IH, d, J = 1.72), 10.27 (IH, s), 11.32 (IH, s).
Example 15 : {2-[2-(4-ChIorobenzenesulfonylmethyI-5-methoxy-lH-indoI-3-yI] yl)]ethyl}dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm'1): 2927, 2856, 1578, 1316, 1090, 1029; Mass: 407.5 (M+H)+; NMR: 2.39 - 2.46 (2H, m), 2.47 (6H, s), 2.71 - 2.75 (2H, m), 3.86 (3H, s), 4.61 (2H, s), 6.89 - 6.91 (2H, m), 7.26 -7.29 (IH, m,), 7.42 - 7.45 (2H, m), 7.66 - 7.68 (2H, m), 8.57 (IH, bs). Example 16 : {2-[2-(2-BromobenzenesulfonyImethyI-5-methoxy-lH-indoI-3-yI)]ethyl} dimethylamine
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm1): 3361, 1625, 1301, 1149, 772; Mass: 451.0 (M+H)+; NMR: 2.20 - 2.24 (2H, m), 2.30 (6H, s), 2.64 - 2.69 (2H, m), 3.81(3H, s), 4.88 (2H, s), 6.85 - 6.87 (IH, dd, J = 8.76, 2.36), 6.9 - 6.906 (IH, d, J = 2.2), 7.22 - 7.24 (IH, d, J = 8.76), 7.33 - 7.38 (IH, m), 7.4 - 7.46 (IH, m), 7.76 - 7.79 (IH, dd, J = 7.84), 7.87 - 7.89 (IH, dd, J = 7.84), 8.44 (IH, s). Example 17 : {2-[2-(4-Methoxybenzenesulfonylmethyl-5-Fluoro-lH-indol-3-yI)]ethyl} dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 197.1 - 198.5 (dec); IR spectra (cm"1): 3343, 2929, 1591, 1252, 1137, 527; Mass: 391.50 (M+H)+; NMR: 1.92 - 1.96 (2H, m), 2.18 (6H, s), 2.41 - 2.45 (2H, m), 3.82 (3H, s), 4.48 (2H, s), 6.85 - 6.9 (2H, m), 6.95 - 7.0 (IH, dt, J = 9.0, 2.4), 7.08 - 7.13.(1H, dd, J = 9.45, 2.28), 7.27 - 7.32 (IH, dd, J = 4.4), 7.5 - 7.55 (2H, m), 8.7 (IH, s). Example 18 : {2-[2-(4-MethoxybenzenesulfonylmethyI-5-chIoro-lH-indol-3- yl]ethyl}dimethylamine.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (°C): 191.5 - 193.6 (dec); IR spectra (cm"1): 3344, 2927, 1595, 1294, 1134, 800; Mass: 407.4, 409.6 (M+H)+; NMR: 1.89 - 1.93 (2H, m), 2.17 (6H, s), 2.36 - 2.42 (2H, m), 3.82 (3H, s), 4.48 (2H, s), 6.85 - 7.0 (2H, m), 7.15 - 7.18 (IH, dd, J = 8.64, 2.0), 7.28 - 7.3 (IH, d, J = 8.64), 7.41 - 7.42 (IH, d, J = 1.84), 7.49 - 7.51 (2H, m), 8.78 (IH, s).
Example 19 : {2-[2-(4-Methoxybenzenesulfonylmethyl-lH-indoI-3-yI)]ethyI} dimethylamine
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm"1): 3352, 2929, 1595, 1262, 1247, 1135, 660; Mass: 373.3 (M+H)+; NMR: 1.90 - 1.97 (2H, m), 2.17 (6H, s), 2.20 - 2.49 (2H, m), 3.82 (3H, s), 4.40 (2H, s), 6.83 - 6.88 (2H, m), 7.08 - 7.12 (IH, t, J = 7.8 Hz), 7.21 - 7.25 (IH, t, J = 7.72 Hz), 7.38 - 7.40 (IH3 d, J = 8.2 Hz), 7.46 - 7.48 (IH, d, J = 8.0 Hz), 7.50 - 7.53 (2H, m), 8.68 (IH, s). Example 20 : [2-(2-BenzenesuIfonyImethyI-5-fluoro-lH-indoI-3-yI)]ethyI}diethyIamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm"1): 3360, 2922, 1457, 1291, 1248, 1083, 612, 514; Mass: 389.3 (M+H)+; NMR: 0.95 - 0.99 (6H, t, J = 7.08 Hz), 2.10 - 2.16 (2H, m), 2.34 - 2.38 (2H, m), 2.45 - 2.50 (4H, q, J = 7.12 Hz), 4.52 (2H, s), 6.95 - 7.01 (IH, dt, J = 9.04, 2.48 Hz), 7.07 - 7.10 (IH, dd, J = 9.4, 2.36), 7.28 - 7.31 (IH, dd, J = 4.4), 7.41 - 7.47 (2H, m), 7.58 - 7.64 (3H, m), 8.64 (IH, s). Example 21 : [2-(2-BenzenesuIfonyImethyl-lH-indol-3-yl)]ethyI}diethylamine
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm"1): 3361, 2922, 1448, 1291, 1248, 1081, 654, 511; Mass: 371.5 (M+H)+; NMR: 0.96 - 0.99 (6H, t, J = 7.12 Hz), 2.10 - 2.2 (2H, m), 2.40 - 2.45 (2H, m), 2.49 - 2.51 (4H, q, J = 7.04 Hz), 4.54 (2H, s), 7.08 - 7.13 (IH, m), 7.21 - 7.25 (IH, m), 7.38 - 7.47 (4H, m), 7.58 - 7.76 (3H, m), 8.63 (IH, s). Example 22 : [3-(2-N, N-DiethylaminoethyI)indol-2-yImethyI]phenyIthioether
Using essentially the same procedure described in example 1 and 2 and some non-critical variations the above derivative was prepared. Melting point (°C): 75.23 (dec); IR spectra (cm"1): 3135, 2920, 2707, 1580, 1452, 1309, 1086, 736; Mass: 339.4 (M+H)+; 1H-NMR: 1.05 - 1.08 (6H, t, J = 7.12 Hz), 2.52 - 2.56 (2H, m), 2.60 - 2.65 (4H, q, J = 7.08), 2.75 - 2.80 (2H, m), 4.23 (2H, s), 7.05 - 7.11 (IH, m), 7.13 - 7.17 (IH, m), 7.20 - 7.30 (6H, m), 7.50 - 7.52 (IH, d, J = 7.8), 8.12 (IH, s). Example 23 : [5-Fluoro-3-(2-N,N-diethylaminoethyl)indoI-2-ylmethyl]phenylthio ether
Using essentially the same procedure described in example 1 and 2 and some non-critical variations the above derivative was prepared. Melting point (°C): 85.96 (dec); IR spectra (cm"1): 3415, 2970, 1584, 1482, 1235, 1086, 961; Mass: 357.4
(M+H)+; NMR: 1.03 - 1.07 (6H, t, J = 7.12 Hz), 2.48 - 2.52 (2H, m), 2.58 - 2.63 (4H, q, J = 7.12), 2.69 - 2.73 (2H, m), 4.21 (2H, s), 6.86 - 6.92 (IH, dt), 7.10 - 7.14 (IH, dd, J = 9.6), 7.16 - 7.19 (IH, dd, J = 4.36), 7.20 - 7.30 (5H, m), 8.1 (IH, s). Example 24 : [5-Fluoro-3-(4-N-Methylpiperazin-l-ylethyI)indol-2- ylmethyljphenylthioether
Using essentially the same procedure described in examples 1 and 2 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 3200, 2938, 2807, 1583, 1459, 1235, 1087, 960; Mass: 384.4 (M+H)+; 1H-NMR: 2.32 (3H, s), 2.36 - 2.41 (2H, m), 2.42 - 2.70 (8H, bs), 2.72 - 2.77 (2H, m), 4.2 (2H, s), 6.85 - 6.92 (IH, dt), 7.11 - 7.15 (IH, dd), 7.17 - 7.21 (IH, q, J = 4.40), 7.22 - 7.28 (5H, m), 8.54 (IH, s). Example 25 : [2-(2-(4-ChlorobenzenesuIfonyl)methyl-5,7-difluoro-indoI-3-yl)ethyl] dimethylamine
Using essentially the same procedures described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm"1): 3434, 2924, 1591, 1473, 1326, 1151, 1085, 813, 778, 763, 536; Mass: 413 (M+H)+; 1H-NMR: 2.0 - 2.07 (2H, m), 2.23 (6H, s), 2.44 - 2.50 (2H, m), 2.54 (2H, s), 6.74 - 6.82 (IH, dt, J = 9.12, 1.48), 6.91 - 6.95 (IH, dd, J = 8.84, 2.08), 7.42 - 7.45 (2H, m), 7.58 - 7.61 (2H, m), 8.85 (IH, s). Example 26 : [3-(4-N-Methylpiperazin-l-yIethyl)indoI-2-ylmethyI]phenylthioether
Using essentially the same procedure described in examples 1 and 2 and some non-critical variations the above derivative was prepared. IR spectra (cm"1): 3398, 2936, 2805, 1458, 1282, 1162, 740; Mass: 366 (M+H)+; NMR: 2.31 (3H, s), 2.38 - 2.42 (2H, m), 2.44 - 2.70 (8H, bs), 2.78 - 2.82 (2H, m), 4.22 (2H, s), 7.06 - 7.11 (IH, m), 7.14 - 7.18 (IH, m), 7.20 - 7.30 (6H, m), 7.50 - 7.52 (IH, d, J = 7.86), 8.15 (IH, s). Example 27 : 2-(BenzenesuIfonyImethyl)-3-(4-methyIpiperazin-l-ylmethyI)-lH-indole
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1145,
1256, 1301, 1457, 3340; Mass: 384 (M+H); NMR: 2.07 - 2.40 (HH, m), 3.08 (2H, s), 4.80 (2H, s), 7.09 - 7.23 (IH, m), 7.24 - 7.37 (IH, m), 7.40 - 7.44 (3H, m), 7.57 - 7.59 (2H, m), 7.63
- 7.65 (2H, m), 8.73 (IH, bs).
Example 28 : 2-(4-Bromobenzenesulfonyimethyl)-3-(4-methylpiperazin-l-ylmethyI)-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1149, 1260, 1313, 1456, 3377; Mass: 462 (M+H), 464 (M+H); NMR: 2.03 (3H, s), 2.08 - 2.41 (8H, m), 3.16 (2H, s), 4.78 (2H, s), 7.11 - 7.13 (IH, m), 7.24 - 7.26 (IH, m), 7.38 - 7.40 (IH, m), 7.47 - 7.49 (2H, m), 7.55 - 7.57 (2H, m), 7.59 - 7.61 (IH, m), 8.72 (IH, bs).
Example 29 : 2-(4-BromobenzenesulfonylmethyI)-3-(4-ethylpiperazin-l-ylmethyI)-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): 61.8; LR. (cm-1): 1150, 1268, 1313, 1453, 3392; Mass: 476 (M+H), 478 (M+H); NMR: 1.04 - 1.08 (3H, t), 2.11 - 2.46 (1OH, m), 3.17 (2H, s), 4.78 (2H, s), 7.11 - 7.13 (IH, m), 7.22 - 7.24 (IH, m), 7.38 - 7.40 (IH, m), 7.47 - 7.49 (2H, m), 7.54 - 7.57 (2H, m), 7.59 - 7.61 (IH, m), 8.72 (IH, bs). Example 30 : 2-(4-BromobenzenesulfonyImethyl)-3-(4-ethylpiperazin-l-yImethyI)-5- fluoro-lH-indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1162,1308, 1450, 3386; MASS: 494 (M+H), 496 (M+H); NMR: 1.06 - 1.10 (3H3 1), 2.08 - 2.42 (1OH, m), 3.13 (2H, s), 4.72 (2H, s), 6.97 - 7.01 (IH, m), 7.28 - 7.32 (2H, m), 7.47 - 7.49 (2H. m), 7.57 - 7.59 (2H, m), 8.75 (IH, bs). Example 31 : 2-(4-BromobenzenesuIfonyImethyI)-3-(4-methylpiperazin-l-ylmethyI)-5- fluoro-lH-indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1143,1315, 1455, 3364; Mass: 480 (M+H), 482 (M+H); NMR: 2.03 - 2.38 (HH, m), 3.12 (2H, s), 4.72 (2H, s), 6.98 - 7.01 (IH, m), 7.28 - 7.32 (2H, m), 7.47 - 7.49 (2H3 m), 7.57 - 7.59 (2H, d), 8.74 (IH, bs).
Example 32 : 2-(4-ChlorobenzenesuIfonylmethyl)-3-(4-ethylpiperazin-l-yImethyI)-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil;
I.R. (cm-1): 1146, 1261, 1315, 1450, 3377; Mass: 432 (M+H), 434 (M+H); NMR: 1.064-1.08 (3H, t), 2.03 - 2.22 (8H, m), 2.36 - 2.41 (2H, q), 3.49 (2H3 s), 4.78 (2H, s), 7.11 - 7.13 (IH, m), 7.22 - 7.24 (IH, m), 7.38 - 7.40 (3H, m), 7.55 - 7.61 (3H, m), 8.73 (IH, bs). Example 33 : 2-(4-ChIorobenzenesuIfonyImethyI)-3-(4-methylpiperazin-l-ylmethyI)-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1146, 1261, 1315, 1450, 3377; Mass: 418 (M+H), 420(M+H); NMR: 2.04 - 2.38 (HH, m), 3.15 (2H, s), 4.78 (2H, s), 7.11 - 7.13 (IH, m), 7.24 - 7.26 (IH, m), 7.38 - 7.40 (3H, m), 7.55 - 7.61 (3H, m), 8.72 (IH, bs). Example 34 : 2-(2-BromobenzenesuIfonyImethyI)-3-(4-methylpiperazin-l-ylmethyl)-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1161, 1261, 1311, 1446, 3271; Mass: 462 (M+H) 464 (M+H); NMR: 2.17 (3H, s), 2.26 - 2.38 (8H, m), 3.18 (2H, s), 4.84 (2H, s), 7.07 - 7.18 (IH, m), 7.26 (IH, m), 7.30 - 7.36 (3H, m), 7.42 - 7.45 (IH, m), 7.55 - 7.61 (2H, m), 8.90 (IH, bs). Example 35 : 2-(2-BromobenzenesuIfonyImethyI)-3-(4-ethylρiperazin-l-yImethyl)-lH- indole
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1160,
1261, 1311, 1447, 3377; Mass: 476 (M+H), 478 (M+H); NMR: 1.05 - 1.08 (3H, t), 2.35 - 2.41
(1OH, m), 3.30 (2H, s), 4.59 (2H, s), 7.06 - 7.08 (IH5 m), 7.18 - 7.26 (IH, m), 7.31 - 7.36 (3H, m), 7.41 (IH, m), 7.55 - 7.61 (2H, m), 8.90 (IH, bs);
Example 36 : 2-(4-BromobenzenesuIfonylmethyl)-3-(4-ethylpiperazin-l-yImethyI)-5- chloro-lH-indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1149, 1263, 1317, 1454, 3208; Mass: 510 (M+H), 512 (M+H); NMR: 1.04 - 1.08 (3H, t), 1.98 - 2.84 (10H, m), 3.11 (2H, s), 4.74 (2H, s), 7.17 - 7.20 (IH, dd, J = 8.6, 1.98 Hz), 7.29 - 7.31 (d, IH, J = 8.4 Hz), 7.46 - 7.48 (2H, m), 7.56 - 7.58 (3H, m), 8.83 (IH, bs). .
Example 37 : 2-(4-BromobenzenesuIfonyImethyI)-3-(4-methyIpiperazin-l-ylmethyl)-5- chloro-lH-indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1146, 1279, 1315, 1455, 3384; Mass: 496 (M+H), 498 (M+H); NMR: 2.02 - 2.39 (HH, m), 2.84 (2H, s), 4.74 (2H, s), 7.17 - 7.20 (IH, dd, J = 8.4, 2.0 Hz), 7.29 - 7.31 (IH, d, J = 9.2 Hz), 7.46 -7.48 (2H, m), 7.56 - 7.58 (3H, m), 8.76 (IH, bs). Example 38 : 2-(4-ChlorobenzenesulfonyImethyI)-3-(4-methy-piperazin-l-ylmethyI)-5- chloro-lH-indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range: Thick oil; LR: 1144, 1258, 1308, 1455, 3479; Mass: 452 (M+H)+, 454 (M+H)+; NMR: 2.04 - 2.43 (HH, m), 3.10 (2H, s), 4.74 (2H, s), 7.17 - 7.20 (IH, dd, J = 8.63, 1.94), 7.29 - 7.32 (IH, d, J = 8.64), 7.40 - 7.42 (2H, m), 7.52 - 7.58 (3H, m), 8.77 (IH, bs). Example 39 : 2-(4-ChlorobenzenesuIfonylmethyI)-3-(4-ethylpiperazin-l-ylmethyl)-5- chloro-lH-indoIe
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1148, 1261, 1314, 1449, 2963; Mass: 466 (M+H), 468 (M+2H); NMR: 1.09-1.13 (3H, t), 2.29 - 2.71 (1OH, m), 3.15 (2H, s), 4.70 (2H, s), 7.18 - 7.20 (IH, dd, J = 8.6, 2.04 Hz), 7.30 - 7.32 (IH, d, J = 8.64 Hz), 7.40 - 7.43 (2H, m), 7.55 - 7.58 (3H, m), 8.83 (IH, bs). Example 40 : 2-(Benzenesulfonylmethyl)-3-(4-methyIpiperazin-l-yImethyl)-5-chIoro-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C) 170.2; LR. (cm-1): 1141, 1257, 1353, 1446, 3478; Mass: 418 (M+H), NMR: 2.02 - 2.41 (HH, m), 3.02 (2H, s), 4.75 (2H, s), 7.16 - 7.18 (IH, dd, J = 8.6, 1.98 Hz), 7.29 - 7.31 (IH, d, J = 8.6 Hz), 7.41 - 7.45 (2H, m), 7.55 - 7.56 (IH, d, J = 1.88 Hz), 7.61 - 7.64 (3H, m), 8.79 (IH, bs). Example 41 : 2-(BenzenesulfonylmethyI)-3-(4-ethylpiperazin-l-yImethyl)-5-chIoro-lH- indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): 157; LR. (cm-1): 1137, 1248, 1342, 1448, 3359; Mass: 432 (M+H), 434 (M+H); NMR: 1.05 -
1.09 (3H, t), 2.07 - 2.42 (1OH, m), 3.04 (2H, s), 4.75 (2H, s), 7.16 - 7.18 (IH, dd, J = 8.64, 2.0 Hz), 7.29 - 7.31 (IH, d, J = 8.68 Hz), 7.42 -7.46 (2H, m), 7.55 - 7.55 (IH, d, J = 1.88), 7.61 - 7.64 (3H, m), 8.77 (IH, bs).
Example 42 : 2-(4-MethylbenzenesuIfonylmethyI)-3-(4-methyIpiperazin-l-ylmethyl)-5- chloro-lH-indole:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1167, 1253, 1305, 1464, 3339; Mass: 432 (M+H); NMR: 2.03 - 2.25 (HH, m), 2.36 (3H3 s), 3.067 (2H, s), 4.72 (2H, s), 7.16 - 7.18 (IH, dd, J = 8.5, 2.0 Hz), 7.21 - 7.23 (2H, d, J = 8.0 Hz), 7.29 - 7.31 (IH, d, J = 8.8 Hz), 7.49 - 7.51 (2H, m), 7.57 - 7.57 (IH, d, J = 2.0 Hz), 8.81 (IH, bs). Example 43 : 2-(BenzenesuIfonyImethyI)-3-(4-methylp.perazin-l-yImethyl)-5-bromo- lH-indoIe
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1167, 1283, 1346, 1451, 3367; Mass: 462 (M+H); NMR: 1.97 - 2.42 (HH, m), 3.01 (2H, s), 4.76 (2H, s), 7.24 - 7.26 (IH, m), 7.27 - 7.32 (IH, m), 7.42 - 7.45 (2H, m), 7.59 - 7.63 (3H, m), 7.71 - 7.72 (IH, d, J = 1.6 Hz), 8.78 (IH, bs). Example 44 : 2-(BenzenesulfonyImethyI)-3-(4-ethylpiperazin-l-yImethyl)-5-bromo-lH- indole:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): 179.6; I.R. (cm-1): 1167, 1247, 1305, 1448, 3361; Mass: 476 (M+H), NMR: 1.03 - 1.07 (3H, t), 2.00 -2.39 (1OH, m), 3.01 (2H, s), 4.77 (2H, s), 7.24 - 7.26 (IH, d, J = 8.4), 7.29 - 7.32 (IH, dd, J - 8.6, 1.8 Hz), 7.41 - 7.45 (2H, m), 7.59 - 7.63 (3H, m), 7.70 - 7.71 (IH, d, J = 1.6 Hz), 8.77 (IH, bs). Example 45 : 2-(4-ChIorobenzenesulfonylmethyI)-3-(4-ethylpiperazin-l-ylmethyI)-5- bromo-lH-indoIe:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; I.R. (cm-1): 1164, 1246, 1343, 1445, 3373; Mass: 510 (M+H), 512 (M+2H); NMR: 1.04 - 1.08 (3H, t), 1.98 - 2.46 (1OH, m), 3.10 (2H, s), 4.75 (s, 2H), 7.25 - 7.27 (IH, d, J = 8.6), 7.30 - 7.33 (IH, dd, J = 8.8, 1.6 Hz), 7.39 - 7.44 (2H, m), 7.52 - 7.55 (2H, m),
7.73 - 7.74 (IH, d), 8.78 (IH, bs).
Example 46 : 2-(4-ChIorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-yImethyI)-5- bromo -lH-indoIe:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1154, 1245, 1371, 1452, 3384; Mass: 496 (M+H), 498 (M+H); NMR: 2.02 - 2.30 (HH, m), 3.01(2H3 s), 4.75 (2H, s), 7.25 - 7.27 (IH, d, J = 8.8, 1.6 Hz), 7.30 - 7.33 (IH, dd, J = 8.4), 7.39 - 7.42 (2H3 m), 7.54 - 7.56 (2H, m), 7.74 - 7.746 (IH, d, J = 2.0 Hz), 8.80 (IH, bs).
Example 47 : 2-(4-MethylbenzenesuIfonyImethyl)-3-(4-methyIpiperazin-l-yImethyl)- 5- bromo -lH-indole:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1164, 1246, 1343, 1445, 3373; Mass: 476 (M+H), 478 (M+H); NMR: 2.04 (3H3 s), 2.17 - 2.56 (HH, m), 3.10 (2H, s), 4.73 (2H3 s), 7.22 - 7.27 (3H, m), 7.29 - 7.32 (IH, m), 7.50 - 7.52 (2H, d, J = 8.4 Hz), 7.72 - 7.72 (IH, d, J = 1.6 Hz), 8.87 (IH, bs). Example 48 : 2-(4-FIuorobenzenesulfonylmethyI)-3-(4-methyIpiperazin-l-yImethyl)-5- bromo-lH-indoIe:
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. Melting range (° C): Thick oil; LR. (cm-1): 1028, 1154, 1371, 1452; Mass: 480, 482 (M+H)+; NMR: 2.04 (3H, s), 2.17 - 2.56 (HH, m), 3.10 (2H, s), 4.73 (2H, s), 7.22 - 7.27 (3H, m), 7.29 - 7.32 (IH, m), 7.50 - 7.52 (2H, d, J = 8.4 Hz), 7.723 - 7.727 (IH, d, J = 1.6 Hz), 8.87 (IH, bs). Example 49 : {2-[2-(4-MethylbenzenesuIfonylmethyl)-lH-indol-3-yl]ethyl} dimethylamine.
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. IR spectra (cm"1): 3372, 2925, 1671, 1459, 1268, 1248, 1138, 713; Mass: 357.3 (M+H)+; NMR: 2.06 (3H5 s), 2.16 (6H, s), 2.35 - 2.39 (2H3 m), 2.43 - 2.47 (2H, m), 4.50 (2H, s), 7.08 - 7.12 (IH, t, J = 7.44 Hz), 7.19-7.28 (3H3 m), 7.38-7.40 (IH, d, J = 8.04), 7.46 - 7.49 (3H, m), 8.71(1H3 s).
Example 50 : 2-(4-FluorobenzenesuIfonylmethyl)-3-(4-methyIpiperazin-l-ylmethyI)-5- chloro -lH-indole
Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. LR. (cm-1): 1084, 1145, 1317, 1446, 2804, 3364; Mass: 436.2, 438.2 (M+H)+; NMR: 1.97 - 2.38 (HH, m), 3.38 (2H, s), 4.75 (2H, s), 7.09 - 7.13 (2H, m), 7.17 - 7.19 (IH, dd, J = 8.6, 2.0), 7.29 - 7.31 (IH, d, J = 8.6 Hz), 7.571 - 7.576 (IH, d, J = 1.88), 7.61 - 7.65 (2H, m), 8.81 (IH, s). Example 51 : 2-(BenzenesuIfonylmethyl)-3-(4-methylpiperazin-l-yImethyI)-5-fluoro-lH- indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. LR. (cm-1): 1084, 1168, 1286, 1450, 2803, 3372; Mass: 402.4, 404.5 (M+H)+; NMR: 1.97 - 2.41 (11H, m), 3.02 (2H, s), 4.74 (2H, s), 6.97 - 6.97 (IH3 m), 7.23 - 7.25 (IH, m), 7.28 - 7.31 (IH, m), 7.42 - 7.46 (2H, m), 7.61 - 7.65 (3H, m), 8.749 (IH3 s). Example 52 : 2-(4-MethyIbenzenesulfonyImethyI)-3-(4-methylpiperazin-l-ylmethyl)- 5- fluoro -lH-indole:
Using essentially the same procedure described in example 3 and some non-critical variations the above derivative was prepared. LR. (cm-1): 1084, 1157, 1287, 1452, 2794, 3411;
Mass: 416.5, 418.6 (M+H)+; NMR: 2.02 - 2.39 (14H3 m), 3.07 (2H, s), 4.71 (2H7 s), 6.94 - 6.99 (IH, m), 7.21 - 7.25 (3H, m), 7.27 - 7.30 (IH3 m), 7.50 - 7.52 (2H3 d, J = 8.24), 8.79 (IH, s).
Example 53 : 3-(4-MethyIpiperazin-l-yImethyI)-2-phenylthiomethyl-lH-indole
N-methyl piperzine (2.06 mM), 2 drops of water, acetic acid and 30% formaldehyde solution (2.06 mM) charged in a reaction flask and stirred on magnetic stirrer for 1 hour. D4 (1.88 mM) in dioxane was added to reaction mass and stirred further 3 - 4 hours. After the completion of reaction, the reaction mixture was poured on to the chilled caustic solution and compound was extracted with ethyl acetate (2 x 25 ml). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure. The residue obtained was purified by flash chromatography using silica (ethyl acetate/ TEA3 9.9/0.1) to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound. Mass: 352 (M+H)+; NMR: 2.26 (3H3 s), 2.38 - 2.50 (8H, bs), 3.5 (2H, s ), 4.35 (2H, s) 7.081 - 7.323 (8H, m), 7.64 -7.66 (IH3 m), 8.24 (IH3 bs).
Using essentially the same procedure described in Example 53 and some non-critical variations the following derivatives were prepared.
EXAMPLE 81 5-Cl 4'-Br CH3 464.3,466.3, 468 .3
EXAMPLE 82 5-Cl 4'-Cl CH3 420.3, 422.3
EXAMPLE 83 5-Cl 4'-F CH3 404.3, 406.3
EXAMPLE 84 5-Cl H C2H5 400.1,402.1
EXAMPLE 85 5-Cl 4'- CH3 C2H5 414.2,416.2
EXAMPLE 86 5-Cl 2'-Br C2H5 478.4, 480.3, 482 .3
EXAMPLE 87 5-Cl 4'-Br C2H5 478.4, 480.3, 482 .3
EXAMPLE 88 5-Cl 4'-Cl C2H5 434.4, 436.4
EXAMPLE 89 5-Cl 4'-F C2H5 418.3, 420.3
EXAMPLE 90 5-F H CH3 370.3
EXAMPLE 91 5-F 4'- CH3 CH3 384.5
EXAMPLE 92 5-F 2'-Br CH3 448.3,451.2
EXAMPLE 93 5-F 4'-Br CH3 448.3,451.2
EXAMPLE 94 5-F 4'-Cl CH3 404.2
EXAMPLE 95 5-F 4'-F CH3 388.1
EXAMPLE 96 5-F H C2H5 384.1
EXAMPLE 97 5-F 4'- CH3 C2H5 398.2
EXAMPLE 98 5-F 2'-Br C2H5 462.1,464.1
EXAMPLE 99 5-F 41- Br C2H5 462.1,464.1
EXAMPLE 100 5-F 4'-Cl C2H5 418.2
EXAMPLE 101 5-F 4'-F C2H5 402.1
EXAMPLE 102 5-MeO H CH3 382.3
EXAMPLE103 5-MeO 4'- CH3 CH3 396.5
EXAMPLE104 5-MeO 2'-Br CH3 460.3, 462.3
EXAMPLE 105 5-MeO 4'-Br CH3 460.3, 462.3
EXAMPLE 106 5-MeO 4'-Cl CH3 416.5,418.7
EXAMPLE 107 5-MeO 4'-F CH3 400.3
EXAMPLE 108 5-MeO H C2H5 396.2
EXAMPLE 109 5-MeO 4'- CH3 C2H5 410.2
EXAMPLE 110 5-MeO 2'-Br C2H5 474.3, 476.3
EXAMPLE 111 5-MeO 4'-Br C2H5 474.3, 476.3
EXAMPLE 112 5-MeO 4'-Cl C2H5 430.2, 432.2
EXAMPLE 113 5-MeO 4'-F C2H5 414.5
Using essentially the same procedure described in example 1 and 2 and some non-critical variations the following derivatives were prepared.
Example 125 : Food Intake Measurement (Behavioural Model).
Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, Hyderabad, India) were used. The chronic effect of the compounds of general formula (I) on food intake in 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 i.p., with a composition comprising a compound of formula (1) or a corresponding composition (vehicle) without the said compound (control group), once-a-day. The rat was provided with ad libitum food and water. On 0, 1st, 7th, 14th, 21st and 28th day the rat was left- with the pre-weighed amounts of food. Food intake and weight gain was measured on the routine basis. Also a food ingestion method was 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. Compounds have shown the statistically
significant decrease in food intake, when conducted in the above manner at the doses of either
10 mg/Kg, or 30 mg/Kg or both.
Example 126 : Tablet comprising a compound of formula (I):
The ingredients are combined and granulated using a solvent such as methanol. The formulation was then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine. Example 127 : Composition for Oral Administration
The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage. Example 128 : Liquid oral formulation
The ingredients are mixed to form a suspension for oral administration. Example 129 : Parenteral Formulation
The active ingredient was dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride was then added with stirring to make the solution isotonic. The solution was made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions. Example 130 : Suppository Formulation
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight. Example 131 : Topical Formulation
AU of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. was then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g. Example 132 : 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, hi the familiarization phase, (Tl), the rats were placed individually in the open field for 3 min., in which two identical objects (plastic bottles, 12.5 cm height x 5.5 cm diameter) covered in yellow masking tape alone (al and a2) were positioned in two adjacent corners, 10 cm. from the walls. After 24 hour of the (Tl) trial for long-term memory test, the same rats were placed in the same arena as they were placed in Tl trial. Choice phase (T2) rats were allowed to explore the open field for 3 min. in presence of one familiar object (a3) and one novel object (b) (Amber color glass bottle, 12 cm high and 5 cm in diameter. Familiar objects presented similar textures, colors and sizes. During the Tl and T2 trial, exploration of each object (defined as sniffing, licking, chewing or having moving vibrissae whilst directing the nose towards the object at a distance of less than 1 cm) were recorded separately by stopwatch. Sitting on an object was not regarded as exploratory activity, however, it was rarely observed. Tl was the total time spent exploring the familiar objects (al + a2). T2 was the total time spent exploring the familiar object and novel object (a3 +b). The object recognition test was performed as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats- Behavioral data, Behav. Brain Res., 31, 47-59. Some representative compounds have shown positive effects indicating the
increased novel object recognition viz; increased exploration time with novel object and higher discrimination index.
Example 133 : Chewing/Yawning/Stretching induction by 5HTgR 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. The representative examples 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. REFERENCE: (1) King M. V., Sleight A., J., Woolley M. L., and et. Al. Neuropharmacology, 2004, 47, 195-204. (2) Bentey J. C, Bourson A., Boess F. G., Fone K. C. F., Marsden C. A., Petit N., Sleight A. J., British Journal of Pharmacology, 1999, 126 (7), 1537-1542). Example 134 : 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. REFERENCE: (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. Example 135 : Passive avoidance:
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 mA to the grid floor, which was scrambled once every 0.5 s across the 16 bars. A resistance range of 40-60 microohms was calculated for a control group of rats and the apparatus was calibrated accordingly. An electronic circuit detecting the resistance of the animal ensured an accurate current delivery by automatic variation of the voltage with change in resistance. Experimental procedure:
This was 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 inhibitory stimulus was evaluated 24 h, 72 h and on 7 day post-training by returning the animal into the light chamber and recording their latency to enter the dark chamber, a criterion time of 300 s was employed.
Some of the compounds showed significant increase in latency to reach the dark zone, at 10 mg/Kg oral dose. REFERENCE: (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. Example 136 : Nova screen binding assay for human 5-HTg receptor.
Pharmacological data Compounds can be tested according to the following the procedures.
Materials and Methods:
Receptor source : Human recombinant expressed in HEK293 cells Radioligand : [3H]LSD (60-80 Ci/mmol) Final ligand concentration - [1.5 nM] Non-specific determinant : Methiothepin mesylate - [0.1 μM]
Reference compound : Methiothepin mesylate
Positive control : Methiothepin mesylate
Incubation conditions : Reactions were carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl2, 0.5 mM EDTA for 60 minutes at 37 0C. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin human-5HT6r 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). RESULTS:
Example 137 : cAMP assay
The antagonist property of the compounds at the human 5-HT6 receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HT6 receptor will lead to an increase in adenyl cyclase activity. A compound that is an agonist will show an increase in cAMP production and a compound that is an antagonist will block the agonist effect. Human 5-HT6 receptors were cloned and stably expressed in HEK293 cells. These cells were plated in 6 well plates in DMEM/F12 media with 10 % fetal calf serum (FCS) and 500 ug/mL G418 and incubated at 37 0C. in a CO2 incubator. The cells were allowed to grow to about 70 % confluence before initiation of the experiment. On the day of the experiment, the culture media was removed, and the cells were washed once with serum free medium (SFM). Two mL of SFM+IBMX media was added and incubated at 37 0C for 10 min. The media were removed and fresh SFM+IBMX media containing various compounds, and 1 uM serotonin (as antagonist) were added to the appropriate wells and incubated for 30 min. Following incubation, the media were removed and the cells were washed once with 1 mL of PBS (phosphate buffered saline). Each well was
treated with 1 mL cold 95 % ethanol and 5 mM EDTA (2:1) at 4 °C. for 1 hour. The cells were then scraped and transferred into Eppendorf tubes. The tubes were centrifuged for 5 min at 4 0C, and the supernatants were stored at 4 0C until assayed. cAMP content was determined by EIA (enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (Amersham RPN 225). The procedure used was as described for the kit. Briefly, cAMP was determined by the competition between unlabeled cAMP and a fixed quantity of peroxidase-labelled cAMP for the binding sites on anti-cAMP antibody. The antibody was immobilized onto polystyrene microtitre wells precoated with a second antibody. The reaction was started by adding 50 uL, peroxidase-labeled cAMP to the sample (100 uL) preincubated with the antiserum (100 uL) for 2 hours at 4° C. Following 1 hour incubation at 4° C, the unbound ligand was separated by a simple washing procedure. Then an enzyme substrate, trimethylbenzidine (1), was added and incubated at room temperature for 60 min. The reaction was stopped by the addition of 100 uL 1.0 M sulphuric acid and the resultant color read by a microtitre plate spectrophotometer at 450 nM within 30 minutes. In the functional adenylyl cyclase assay, some of the compound of this invention was found to be a competitive antagonist with good selectivity over a number of other receptors.
Claims
1. A compound having the formula (I)5 along with its stereoisomer or its salt with an inorganic or organic acid
wherein: Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (d-C3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R∑ represents hydrogen, substituted or unsubstituted groups such as (Ci-C3)alkyl, (Ci-C3)acyl or BOC; R3, R4, R3- and R4- independently may be either same or different, and represents hydrogen, halogen, perhaloalkyl; or R3 and R4, R3- and R4 represent =0, or a substituted or unsubstituted group selected from linear or branched (Ci-C3)alkyl, (C3-C6)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C6)alkoxy; optionally, R3 and R5 along with the intervening nitrogen and carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; . R5 and R5 represents hydrogen, (Ci-C3)alkyl; optionally, R5 and R5 along with the nitrogen atom may form a 5, 6 or 7 membered 'cyclic structure'; 'n' is the number of carbon atoms, which may be
either 0 or 1 and 'm' is the number of oxygen atoms attached to the sulfur atom, which may be either 0, 1 or 2.
2. A compound as claimed in claim- 1 wherein Ar is phenyl, naphthyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl or benzimidazolyl.
3. A compound as claimed in claim-1 wherein Ri is a hydrogen, halogen, perhaloalkyl, perhaloalkoxy, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, alkoxy(Ci-C3)alkoxy, hydroxy(Ci-C3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy.
4. A compound as claimed in claim-1 selected from among the following group:
[2-(2-Benzenesulfonylmethyl-5-fluoro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
[2-(2-Benzenesulfonylmethyl-5,7-difluoro-lH-indol-3-yl)ethyl]dimethylamine; [2-(2-Benzenesulfonylmethyl-4-chloro-7-methyl-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl)-4-chloro-7-methyl-lH-indol-3- yl] ethyl} dimethylamine;
[2-(2-Benzenesulfonylmethyl-lH-indol-3-yl)ethyl]dimethylamine hydrochloride; {2-[2-(4-Fluorobenzenesulfonylmethyl-lH-indol-3-yl)]ethyl}dimethylamine;
{2-L2-(4-Cblorobenzenesulfonylmethyl-lH-indol-3-yl)]θtliyl}diinethylαniine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl-5-fluoro-lH-indol-3-yl)]ethyl}dimethylamine hydrochloride; [2-(2-Benzenesulfonylmethyl-5-chloro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
2-(4-Chlorobenzenesulfonylmethyl)-5-Chloro-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
[2-(2-Benzenesulfonylmethyl-5-bromo-lH-indol-3-yl)ethyl]dimethylamine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl-5-bromo-lH-indol-3-yl)]ethyl}dimethylamine hydrochloride;
{2-[2-(4-Chlorobenzenesulfonylmethyl-5-methoxy-lH-indol-3- yl] ethyl} dimethylamine; {2-[2-(2-bromobenzenesulfonylmethyl-5-methoxy-lH-indol-3- yl] ethyl} dimethylamine;
{2-[2-(4-Methoxybenzenesulfonylmethyl-5-Fluoro-lH-indol-3- yl]ethyl} dimethylatnine;
{2-[2-(4-Methoxybenzenesulfonylmethyl-5-chloro-lH-indol-3- yl] ethyl} dimethylamine; {2-[2-(4-Methoxybenzenesulfonylmethyl-lH-indol-3-yl]ethyl}dimethylanτine;
[2-(2-Benzenesulfonylmetliyl-5-fluoro-lH-indol-3-yl)ethyl]diethylamine;
[2-(2-Benzenesulfonylmethyl-lH-indol-3-yl)-ethyl]diethylamine;
[3-(2-N,N-Diethylaminoethyl) indol-2-yl methyljphenylthioether;
[5-Fluoro-3-(2-N,N-dietiαylaminoethyl) indol-2-yl ttTLethyl]pnenylthioether; [(5-Fluoro-3-(4-N-Methylpiperazin-l-yl)ethyl)indol-2-yl)methyl]phenylthioether;
[2-(2-(4-Chlorobenzenesulfonyl)methyl-5,7-difluoro-indol-3-yl)ethyl]dimethylamine;
[3-(4-N-Methylpiperazin-l-yl)ethylindol-2-yl methyl]phenylthioether;
2-(Benzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-metb.ylpiperazin-l-ylmethyl)-lH-indole; 2-(4-Bromobenzenesiilfonylmethyl)-3-(4-ethylpiperazin-l-ylirιeth.yl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-fluoro-lH- indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-fluoro-lH- indole; 2-(4-Chlorobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperaziti-l-ylmethyl)-lH-indole;
2-(2-Bromobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-lH-indole;
2-(2-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-lH-indole;
2-(4-Bromobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-chloro-lH- indole;
2-(4-Bromobenzenesulfonylmeth.yl)-3-(4-methylpiperazin.-l-ylmethyl)-5-chloro-lH- indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH- indole; 2-(4-Chlorobenzenesulfonylmethyl)-3 -(4-ethylpiperazin- 1 -ylmethylJ-S-chloro- IH- indole;
2-(Benzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH-indole;
2-(Benzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-chloro-lH-indole;
2-(4-Methylbenzenesulfonylmethyl)-3 -(4-methylpiρerazin- 1 -ylmethyl)-5 -chloro-lH- indole;
2-(Benzenesulfonylmethyl)-3 -(4-methylpiperazin- 1 -ylmethyl)-5 -bromo-lH-indole;
2-(Benzenesulfonylmethyl)-3 -(4-ethylpiperazin- 1 -ylmethyl)-5 -bromo- lH-indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-ethylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
2-(4-Chlorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
2-(4-Methylbenzenesulfonylme1iιyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole;
2-(4-Fluorobenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-bromo-lH- indole; {2-[2-(4-Methylbenzenesulfonylmethyl)-lH-indol-3-yl]ethyl}dimethylamine;
2-(4-Fluorobenzenesxύfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-chloro-lH- indole;
2-(Benzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-fluoro-lH-indole;
2-(4-Methylbenzenesulfonylmethyl)-3-(4-methylpiperazin-l-ylmethyl)-5-fluoro-lH- indole;
3-(4-Methylpiperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5-Chloro-3-(4-metb.yl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-ylme1liyl)-2-p-tolylthiomethyl-lH-indole; 5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
3-(4-Methyl-piperazin- 1 -ylmethyl)-2-p-tolylthiomethyl- lH-indole;
3-(4-Ethyl-piperazin-l-ylmethyl)-2-p-tolylthiomethyl-lH-indole;
5- Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole; 5- Me1hoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiometliyl-lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-ylmethyl)-2-phenylthiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole;
5-Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole; 5-Methoxy-3-(4-methyl-piρerazin-l-ylmethyl)-2-p-bromothiomethyl-lH-indole;
5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole;
5 -Chloro-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-p-chlorothiomethyl- lH-indole;
5 -Fluoro-3 -(4-methyl-piperazin- 1 -ylmethyl)-2-p -chlorothiomethyl- lH-indole;
5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-chlorothiomethyl-lH-indole; 5-Bromo-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiomethyl-lH-indole;
5-Chloro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothioniethyl-lH-indole;
5-Fluoro-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiomethyl-lH-indole;
5-Methoxy-3-(4-methyl-piperazin-l-ylmethyl)-2-p-fluorothiometliyl-lH-indole;
[(5 -Fluoro-3 -(2-N,N-dimethylaminooxalyl)mdol-2-yl)methyl] phenylthioether;
[(5-Fluoro-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether;
[(5-Chloro-3-(2-N,N-dimethylaininoethyl)indol-2-yl)methyl]phenylthioether;
4'-Chloro[(5-chloro-3-(2-N,N-dimethylaminoethyl)indol-2- yl)methyl]phenylthioether;
[(5-Chloro-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]-4'- methoxyphenylthioether;
4'-Chloro[(5-Fluoro-3-(2-N,N-dimetliylaminoethyl)indol-2- yl)methyl]phenylthioether;
[(5-Methoxy-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether;
[(5,7-Difluoro-3-(2-N,N-dimethylaminoethyl)indol-2-yl)methyl]phenylthioether;
4'-Chloro[(5,7-difluoro-3-(2-N,N-dimethylammoethyl)indol-2- yl)methyl]phenylthioether; and a pharmaceutically acceptable salt thereof.
5. A process for preparing a compound of formula (I)
Formula (I)
wherein: Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (CrC3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy, halo(Ci-C3)alkoxy, cyclo(C3-C6)alkyl or cyclo(C3-C6)alkoxy; R2 represents hydrogen, substituted or unsubstituted groups such as (Ci-C3)alkyl, (Ci-C3)acyl or BOC; R3, R4, R3- and R4- independently may be either same or different, and represents hydrogen, halogen, perhaloalkyl; or R3 and R4, R3- and R4 represent =0, or a substituted or unsubstituted group selected from linear or branched (CrC3)alkyl, (C3-C6)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C6)alkoxy; optionally, R3 and R5 along with the intervening nitrogen and
10 carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R5 and R5 represents hydrogen, (Ci-C3)alkyl; optionally, R5 and R5 along with the nitrogen atom may form a 5, 6 or 7 membered 'cyclic structure'; 'n' is the number of carbon atoms, which may be either 0 or 1 and 'm' is the number of oxygen atoms attached to the sulfur atom, which may be either 0, 1 or 2;
1.5 which comprises of contacting a compound of formula (iii), wherein all substituents are as defined earlier for compound of formula (I) with reagents such as oxalyl chloride, followed by amine such as NHR5R5, N-(Ci-C2)alkylpiperazine derivative; and optionally reduction with Lithium aluminium hydride, and\or oxidation
to provide a compound of the formula (I) or its derivative.
6. A process for preparing a compound of formula (I) 5
Formula (I)
wherein: Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (d-C3)alkyl, halo(Ci-C3)alkyl, (d-C3)alkoxy, halo(Ci-C3)alkoxy, cyclo(C3-Cδ)alkyl or cyclo(C3-C6)alkoxy; R2 represents hydrogen, substituted or unsubstituted groups such as (Ci-C3)alkyl, (Ci-C3)acyl or BOC; R3, R4, R3- and R4- independently may be either same or different, and represents hydrogen, halogen, perhaloalkyl; or R3 and R4, R3- and R4 represent =0, or a substituted or unsubstituted group selected from linear or branched (Ci-C3)alkyl, (C3-C6)cycloalkyl, (Ci-C3)alkoxy, cyclo(C3-C6)alkoxy; optionally, R3 and R5 along with the intervening nitrogen and carbon atoms may form a 5, 6 or 7 membered 'cyclic structure'; R5 and R≤ represents hydrogen, (CrC3)alkyl; optionally, R5 and R5 along with the nitrogen atom may form a 5, 6 or 7 membered 'cyclic structure'; 'n' is the number of carbon atoms, which may be either 0 or 1 and 'm' is the number of oxygen atoms attached to the sulfur atom, which may be either 0, 1 or 2; which comprises of contacting a compound of formula (iii), wherein all substituents are as defined earlier for compound of formula (I) is treated with suitable reagents such as N-(Ci-C2)alkylpiperazine, or its equivalent along with a suitable aldehyde, under acidic
conditions; and optionally oxidation
(iii) 0) a.N-(Ci-C2)alky!piperazine or its derivative b. Formaldehyde c. Acetic acid.
to provide a compound of the formula (I) or its derivative.
7. A process for preparing a compound according to claim- 1, wherein if necessary, one or more than one of the following steps are carried out:
1. converting a compound of the formula (I) into another compound of the formula (I)
2. removing any protecting groups; or
3. forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
8. 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 4.
9. A method according to claim-8 wherein said disorder is an anxiety disorder, a cognitive disorder, or a neurodegenerative disorder
10. A method according to claim-8 wherein said disorder is Alzheimer's disease or Parkinson's disease.
11. A method according to claim-8 wherein said disorder is attention deficit disorder or obsessive compulsive disorder.
12. A method according to claim-8 wherein said disorder is stroke or head trauma.
13. A method according to claim-8 wherein said disorder is eating disorder or obesity.
14. 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 4.
15. A compound of formula (I), as defined in any one as claimed in claims 1 to 4 for use as a medicament.
16. Use of compound of formula (I), as defined in any one as claimed in claims 1 to 4 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.
17. A method for testing antagonists and antagonists with selectivity for the 5-HTg receptor comprising: administering a compound as claimed in 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.
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