WO2009034581A1 - Composés indolyle substitués et leur utilisation en tant que ligands de 5-ht6 - Google Patents

Composés indolyle substitués et leur utilisation en tant que ligands de 5-ht6 Download PDF

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Publication number
WO2009034581A1
WO2009034581A1 PCT/IN2008/000280 IN2008000280W WO2009034581A1 WO 2009034581 A1 WO2009034581 A1 WO 2009034581A1 IN 2008000280 W IN2008000280 W IN 2008000280W WO 2009034581 A1 WO2009034581 A1 WO 2009034581A1
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amino
indole
benzenesulfonyl
piperidin
methyl
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PCT/IN2008/000280
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English (en)
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Nirogi Venkata Satya Ramakrishna
Anil Karbhari Shinde
Rama Sastri Kambhampati
Venkateswarlu Jasti
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Suven Life Sciences Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 novel substituted indolyl compounds of the formula (I), their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of above said novel compounds, their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • This invention also relates to the novel intermediates involved therein and process of their preparation.
  • 5-HT receptor subtypes regulate the various effects of serotonin.
  • 5-HT receptor family includes the 5-HT 1 family (e.g. 5-HT, A ), the 5-HT 2 family (e.g.5-HT 2A & 5-HT 2c ), 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 subtypes.
  • the 5-HT ⁇ receptor subtype was first cloned from rat tissue in 1993 (Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W., Sibley, D.R., Molecular Pharmacology, 1993, 43, 320- 327) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R., Journal of Neurochemistry, 1996, 66, 47-56).
  • the receptor is a G- protein coupled receptor (GPCR) positively coupled to adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C, Biochemical Biophysical Research Communications, 1993, 193, 268-276).
  • GPCR G- protein coupled receptor
  • the receptor is found almost exclusively in the central nervous system (CNS) areas both in rats as well as in humans.
  • 5-HT 6 receptor ligands Our understanding of the roles of 5-HT 6 receptor ligands is most advanced in two therapeutic indications in which this receptor is likely to have a major role: learning and memory deficits and abnormal feeding behaviour.
  • the exact role of the 5-HT 6 receptor is yet to be established in other CNS indications such as anxiety; although one 5-HT 6 agonist has reached Phase I clinical trials recently, the exact role of the receptor is still to be established and is the focus of significant investigation.
  • antagonist compounds of 5-HT 6 receptors are sought after as therapeutic agents.
  • modulators of 5-HT 6 receptor functions is in the enhancement of cognition and memory in human diseases such as Alzheimer's.
  • the high levels of receptor found in structures such as the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens and cortex suggests a role for the receptor in memory and cognition since these areas are known to play a vital role in memory (Gerard, C; Martres, M.P.; Lefevre, K.; Miquel, M. C; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; EI Mestikawy, S., Brain Research, 1997, 746, 207-219).
  • 5-HT ⁇ ligands A related potential therapeutic use for 5-HT ⁇ ligands is in the treatment of attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in children as well as adults.
  • ADD attention deficit disorders
  • ADHD Attention Deficit Hyperactivity Disorder
  • 5-HTe antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and ADHD has been linked to abnormalities in the caudate
  • 5-HT 6 antagonists may attenuate attention deficit disorders. At present, a few fully selective agonists are available.
  • 5-HT 6 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- 13 IP; and Routledge, C; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M., British Journal of Pharmacology, 2000, 30 (7), 1606-1612).
  • 5-HT 6 receptor modulators i.e. ligands
  • Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder.
  • GI gastrointestinal
  • GI gastrointestinal
  • 5-HT 6 receptor ligands as potential cognitive enhancers and antiobesity agents, gives elaborate discussion on evolution of 5-HT 6 ligands. It had summarized pharmacological tools and preclinical candidates used in evaluation of 5-HT O receptor in illnesses such as schizophrenia, other dopamine-related disorders and depression and to profile the neurochemical and electrophysiological effects of either blockade or activation of 5-HT 6 receptors. Furthermore, they have been used to characterize the 5-HT 6 receptor and to investigate its distribution.
  • Phenyl benzenesulfonamides are novel and selective 5-HT 6 antagonists: Identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-l- ylbenzenesulfonamide (SB-357134). Bioorg. Med. Chem. Lett. 11, 55- 58; Hirst, W.D. et al. (2003) Characterisation of SB-399885, a potent and selective 5-HT 6 receptor antagonist. 33 rd Annu. Meet. Soc. Neurosci. (Nov. 8-12, New Jersey), Abstract 576.7; Stadler, H. et al.
  • 5-HT 6 antagonists A novel approach for the symptomatic treatment of Alzheimer's disease. 37 th IUPAC Cong. Berlin, Abstract MM-7; Bonhaus, D. W. et al. (2002) Ro-4368554, a high affinity, selective, CNS penetrating 5-HT 6 receptor antagonist. 32 nd Annu. Meet. Soc. Neurosci., Abstract 884.5.; Beard, CC. et al. (2002) Preparation of new indole derivatives with 5-HT 6 receptor affinity. WO patent 2002098857].
  • Ro 63-0563 Potent and selective antagonists at human and rat 5-HT 6 receptors. Br. J. Pharmacol. 124, (556-562). Phase II antagonist candidate from GlaxoSmithKline, SB-742457 for the therapeutic indication of cognitive dysfunction associated with Alzheimer's disease [Ahmed, M. et al. (2003) Novel compounds. WO patent 2003080580], and the Lilly compound LY-483518 [Filla, S.A. et al. (2002) Preparation of benzenesulfonic acid indol-5-yl esters as antagonists of the 5-HT 6 receptor. WO 2002060871].
  • substituted indolyl compounds of formula (I) demonstrate very high 5-HT 6 receptor affinity. 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 or disorders affected by the 5-HTe receptor.
  • the present invention relates to novel substituted indolyl compounds of the formula (I), their derivatives, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • R represents hydrogen, (Ci-C 3 ) alkyl or (C 3 -C 6 ) cycloalkyl
  • R 1 , R. 2 and R 3 may be same or different and each independently represent hydrogen, halogen, (C r C 3 )alkyl, (C 3 -C 6 ) cycloalkyl, halo(C r C 3 )alkyl, (C r C 3 )alkoxy or halo (C 1 - C 3 )alkoxy;
  • R 4 represents hydrogen, (C r C 3 )alkyl, halo(C r C 3 )alkyl, aryl, aralkyl, (C 3 -C 6 ) cycloalkyl or t-butyloxy carbonyl; "m" represents 0 to 4;
  • n represents 0 to 5
  • p represents 0 to 5
  • the present invention relates to use of a therapeutically effective amount of compound of formula (I), to manufacture a medicament, in the treatment or prevention of a disorder involving selective affinity for the 5-HT 6 receptor.
  • the compounds of this invention are also useful in the treatment of various CNS disorders, hematological disorders, eating disorders, obesity, anxiety, depression, diseases associated with pain, respiratory diseases, gastrointestinal, cardiovascular diseases and cancer.
  • 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 at least one suitable carrier, diluents, adjuvants or excipients.
  • the invention relates to compositions comprising and methods for using compounds of Formula (I).
  • the invention relates to novel intermediates and process of their preparation of general formula (II) and (III), which are useful in the preparation of compounds of formula (I).
  • the invention relates to the use of a therapeutically effective amount of compound of formula (I), to manufacture a medicament, in the treatment or prevention of a disorder involving selective affinity for the 5-EfT 6 receptor.
  • the invention further relates to the process for preparing compounds of formula (I).
  • Halogen means fluorine, chlorine, bromine or iodine
  • (Ci-C 3 )alkyl means straight or branched chain alkyl radicals containing one to three carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl;
  • (Ci-C 3 )alkoxy means straight or branched chain alkyl radicals containing one to three carbon atoms and includes methoxy, ethoxy, propyloxy and iso-propyloxy;
  • Halo(C r C 3 )alkyl means straight or branched chain alkyl radicals containing one to three carbon atoms and includes fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like;
  • Halo(Ci-C 3 )alk ⁇ xy means straight or branched chain alkyl radicals containing one to three carbon atoms and includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy and the like;
  • Cyclo(C 3 -C 6 )alkyl means cyclic or branched cyclic alkyl radicals containing three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclo(C 3 -C 6 )alkyl methyl or cyclohexyl, which may be substituted or unsubstituted and optionally the substituents may be selected from halogen, (CVC3)alkyl or
  • Aryl means monocyclic aromatic ring system, which can optionally be substituted with hydrogen, halogen, (Ci-C 3 )alkyl, halo(C 1 -C 3 )alkyl, or halo (Ci-C 3 )alkoxy;
  • Aralkyl means benzyl or heterocyclylmethyl and the like;
  • 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.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, the mammal being treated therewith.
  • “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 (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein'.
  • treating embrace all the meanings such as preventative, prophylactic and palliative.
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis-trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e. g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated from one another by the usual methods or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to tautomeric forms and m ixtures thereof.
  • the stereoisomers as a rule are generally obtained as racemates that can be separated into the optically active isomers in a manner known per se.
  • the present invention relates to the D- form, the L-form and D 5 L - mixtures and in the case of a number of asymmetric carbon atoms, the diastereomeric forms and the invention extends to each of these stereo isomeric forms and to mixtures thereof including racemates.
  • stereoisomers of compounds of general formula (I) may be prepared by one or more ways presented below: i) One or more of the reagents may be used in their optically active form. ii) Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process.
  • the metal catalyst may be Rhodium, Ruthenium, Indium and the like.
  • the chiral ' ligands may preferably be chiral phosphines (Principles of Asymmetric synthesis, J. E. Baldwin Ed., Tetrahedron series, 14, 311-3.16).
  • the mixture of stereoisomers may be resolved by conventional methods such as forming diastereomeric salts with chiral acids or chiral amines or chiral amino alcohols, chiral amino acids.
  • the resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography and the like, which is followed by an additional step of isolating the optically active product by hydrolyzing the derivative (Jacques et. al., "Enantiomers, Racemates and Resolution", Wiley Interscience, 1981).
  • the mixture of stereoisomers may be resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases.
  • Chiral acids that can be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like.
  • Chiral bases that can be employed may be cinchona alkaloids, brucine or a basic amino acid such as lysine, arginine and the like.
  • the present invention relates to all of these geometric isomers.
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. ScL, 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids e. g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • the present invention includes, within its scope, all possible stoichiometric and non-stoichiometric forms.
  • the pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with 1-6 equivalents of a base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium t-butoxide, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride and the like. Solvents such as water, acetone, ether, THF, methanol, ethanol, t-butanol, dioxane, isopropanol, isopropyl ether or mixtures thereof may be used.
  • other salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form and if crystalline, may optionally be solvated, eg. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).
  • the process of this invention includes, contacting a compound of the following formula (a),
  • the above reaction is preferably carried out in a solvent such as tetrahydrofuran (THF), toluene, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using THF.
  • a solvent such as tetrahydrofuran (THF), toluene, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using THF.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be affected in the presence of a base such as potassium carbonate, sodium bicarbonate, sodium hydride or mixtures thereof and preferably using sodium hydride.
  • the reaction temperature may range from 20 0 C to 50 °C based on the choice of solvent and preferably
  • the key intermediate (a) is synthesized as described in preparations 4.
  • This key intermediate (a) may be commercially available or they may be prepared by conventional methods or by modification, using known process.
  • the process of this invention includes, contacting a compound of the following formula (b),
  • the above reaction is preferably carried out in a solvent such as ethanol, tetrahydrofuran (THF) 5 toluene, ethyl acetate, water, titanium isopropoxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using titanium isopropoxide and ethanol.
  • a solvent such as ethanol, tetrahydrofuran (THF) 5 toluene, ethyl acetate, water, titanium isopropoxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using titanium isopropoxide and ethanol.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • DME dimethyl ether
  • the reaction is carried by using reducing agents like sodium, sodium borohydride, sodium cyan
  • the reaction may be affected in the presence of a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, sodium hydride or mixtures thereof and preferably using sodium hydroxide.
  • a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, sodium hydride or mixtures thereof and preferably using sodium hydroxide.
  • the reaction temperature may range from 20 0 C to 45 0 C based on the choice of solvent and preferably at a temperature in the range from 25 0 C to 35 0 C.
  • the duration of the reaction may range from 4 to 10 hours, preferably from a period of 5 to 7 hours.
  • the key intermediate (b) is synthesized as described in preparations 10. This key intermediate (b) may be commercially available or they may be prepared by conventional methods or by modification, using known process. Scherae-3:
  • the above reaction is preferably carried out by using methanolic hydrochloric acid.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction temperature may range from 20 0 C to 40 °C and preferably at a temperature in the range from 25 °C to 35 0 C.
  • the duration of the reaction may range from 1 to 4 hours, preferably from a period of 0.5 to 3 hours.
  • the product, thus obtained, can be further derivatized to compounds (I) by methods described within.
  • the compound of formula (III) is converted into formula (I) by convenient derivatization.
  • the above reaction is preferably carried out by using methanolic hydrochloric acid.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction temperature may range from 20 0 C to 40 0 C and preferably at a temperature in the range from 25 0 C to 35 0 C.
  • the duration of the reaction may range from 1 to 4 hours, preferably from a period of 0.5 to 3 hours.
  • novel intermediate compound represented by the general formula (III) is prepared by the process as described in the specification.
  • the present invention also provides a process for the preparation of a novel intermediate of formula (II), which comprises of the following route:
  • the above reaction is preferably carried out in a solvent such as ethanol, tetrahydrofuran (THF), toluene, ethyl acetate, titanium isopropoxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using titanium isopropoxide and ethanol.
  • a solvent such as ethanol, tetrahydrofuran (THF), toluene, ethyl acetate, titanium isopropoxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl ether (DME) and the like or a mixture thereof and preferably using titanium isopropoxide and ethanol.
  • the reaction is carried by using reducing agents like sodium borohydride, sodium cyanoborohydride and the like or a mixture thereof and preferably using sodium cyanoborohydride.
  • the reaction may be affected in the presence of a base such as
  • the reaction temperature may range from 20 0 C to 45 0 C based on the choice of solvent and preferably at a temperature in the range from 25 0 C to 35 0 C.
  • the duration of the reaction may range from 4 to 10 hours, preferably from a period of 5 to 7 hours.
  • the key intermediate (b) is synthesized as described in preparations 10.
  • This key intermediate (b) may be commercial available or they may be prepared by conventional methods or by modification, using known process.
  • the present invention also provides a process for the preparation of a novel intermediate of formula (III), which comprises of the following route:
  • the reaction is carried by using reductive animation agents like sodium triacetoxy borohydride and sodium cyanoborohydride.
  • the reaction may be affected in the presence of a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate and sodium hydride.
  • the reaction temperature may range from 20 0 C to 45 0 C based on the choice of solvent and preferably at a temperature in the range from 25 0 C to 35 0 C.
  • the duration of the reaction may range from 2 to 6 hours, preferably from a period of 3 to 5 hours, wherein the key intermediate (II) is synthesized as described as earlier in specification
  • any one or more than one of the following steps can be carried out, i) Converting a compound of the formula (I) into another compound of the formula (I) ii) Removing any protecting groups; of Hi) Forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
  • Process (i) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution and ester hydrolysis or amide bond formation.
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2', 2', 2'- trichloroethoxycarbonyl, ben2yloxycarbonyl or t-butoxycarbonyl) and arylalkyl (eg. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric or trifluoroacetic acid) or reductively (e. g.
  • Suitable amine protecting groups include trifluoroacetyl, which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6- dimethoxybenzyl group (Ellman linker), which may be removed by acid catalyzed hydrolysis, for example with trifluoroacetic acid.
  • halogenation hydroxylation, alkylation and/or pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative as described earlier in detail.
  • the compounds of formula (I) in therapy they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (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 reconstirution 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.
  • 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 (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 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.
  • 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.
  • novel compounds of the present invention were prepared according to the following procedures, using appropriate materials and are further exemplified by the following specific examples.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and process of the following preparative procedures can be used to prepare these compounds.
  • Preparation 1 4-amino indole.
  • Preparation 9 4-Amino-l-(4'-FIuoro benzenesulfonyl)-lH-IndoIe.
  • l-(4-Fluoro benzenesulfonyl)-4-nitro- IH- indole (1.9 grams, 5.9 mmol) (obtained from preparation 8) dissolved in ethanol (30 mL) was taken in three neck round bottom flask (100 mL), equipped with condenser and thermometer socket. Add water (2 mL) at room temperature, and slowly heat the reaction mass to 40 0 C.
  • Iron powder (1.66 grams, 29.6 mmol) was added pinch wise to the above reaction mass, followed by the addition of concentrated hydrochloric acid (1 mL).
  • the above reaction mass was refluxed for a period of one hour and the progress of the reaction was monitored by thin layer chromatography.
  • the above reaction mass was cooled to room temperature and filtered through hy-flow bed. The filtrate was concentrated under reduced pressure and the residue was poured onto water (100 mL) and basified with 40% aqueous sodium hydroxide solution, and the product was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • concentrated hydrochloric acid (1 mL).
  • reaction mixture was diluted with ice water (200 mL) and filtered through hy-flow bed.
  • the bed was washed with ethyl acetate (50 mL) and the combined filtrate was basified with 10 % aqueous sodium hydroxide solution and extracted with (2 x 50 mL) ethyl acetate (2 x 50 mL).
  • the combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Example 1 l-(2'-Bromo benzenesulfonyl)-4-[N-(l-methyI piperidin-4-yI)] amino-lH- indole.
  • reaction mass was diluted with ice water (200 mL) and filtered through hy-flow bed. The bed was washed with ethyl acetate (50 mL) and the
  • Example 2 l-(2'-Bromo benzenesulfonyl)-4-[N-(piperidin-4-yl)] amino-lH-indole dihydrochloride.
  • Example 4 l-(2'-Bromo benzenesulfonyl)-4-[N-ethyl-N-(l-methyl piperidin-4-yl)] amino- lH-indole.
  • Example 5 4-[N-Ethyl-N-(l-methyl piperidin-4-yl)] amino-l-(4'-methyl benzenesulfonyl)- lH-indoIe.
  • Example 6 l-(2'-ChIoro benzenesuIfonyl)-4-[N-ethyl-N-(l-methyl piperidin-4-yI)] amino- lH-indoIe.
  • Example 7 l-(3'-Chlbrb be ⁇ ze ⁇ esulFonyl)-4-[N-(l-t-butyloxycarbonyI p ⁇ peridin-4-yI)-N- methyl] amino- lH-indole.
  • Example 8 4-[N-(l-t-Butyloxycarbonyl piperidin-4-yl)-N-methyl] amino-l-(4'-isopropyI benzenesulfonyl)-lH-indole.
  • Example 10 4-[N-(l-t-Butyloxycarbonyl piperidin-4-yl)-N-methyI] amino-l-(3' ⁇ trifluoromethyl benzenesulfonyl)-lH-indole.
  • Example 11 4-[N-(l-t-ButyIoxycarbonyl piperidin-4-yl)] amino-l-(3'-chloro benzenesuIfonyl)-lH-indole.
  • Example 12 l-(3'-Chloro benzenesulfonyI)-4-[N-methyl-N-(piperidin-4-yl)] amino-lH- indole dihydrochloride.
  • Example 14 l-(3'-Chloro benzenesulfonyl)-4-[N-(l-methyl piperidin-4-yI)] amino-lH- indole.
  • Example 15 l-(4'-FIuoro benzenesulfonyl)-4-[N-methyl-N-(piperidin-4-yl)] amino-lH- indole dihydrochloride.
  • Example 19 l-(4 '-Methyl be ⁇ zenesulfonyl)-4-[N ⁇ methyl-N-(l-methyl piperidin-4-yl)] amino- lH-indole.
  • Example 20 l-(2'-Chloro benzenesulfonyl)-4-[N-methyl ⁇ N-(l-methyl piperidin-4-yl)] amino-lH-indole.
  • Example 21 l-(4'-Fluoro benzenesulfonyI)-4-[N-methyI-N-(l-methyl piperidin-4-yl)] amino-lH-fnd ⁇ le.
  • Example 22 l-(3'-Ch!oro benzenesuIfonyl)-4-[N-methyl-N-(l-methyl piperidin-4-yl)] amino- lH-indole.
  • Example 24 l-(4'-Isopropyl benzenesulfonyl)-4-[N-methyl-N-(l-methyl piperidin-4-yl)] amino- lH-indoIe.
  • Example 25 l-(2'-Bromo benzenesulfonyl)-4-[N-methyl-N-(l-methyl piperidin-4-yl)] amino-lH-indole.
  • Example 26 l-(4'-Methoxy benzenesulfonyl)-4-[N-methyI-N-(l-methyI piperidin-4-yl)] amino-lH-indole.
  • Example 59 Tablet comprising a compound of formula (J)
  • the ingredients were combined and granulated using a solvent such as methanol.
  • the formulation was then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
  • Example 61 Liquid oral formulation
  • the ingredients were mixed to form a suspension for oral administration.
  • the active ingredient was dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride was then added with stirring to make the solution isotonic. The solution was made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane Filter and packaged under sterile conditions.
  • 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]
  • Reactions were carried out in 50 ⁇ M TRIS-HCl (pH 7.4) containing 10 ⁇ M MgCl 2 , 0.5 mM EDTA for 60 minutes at 37 0 C. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin 5-HT 6 binding site.
  • the antagonist property of the compounds at the human 5-HT ⁇ receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HT ⁇ receptor will lead to an increase in adenyl cyclase activity. A compound that is an agonist will show an increase in cAMP production and a compound that is an antagonist will block the agonist effect.
  • Human 5-HTe 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 ⁇ g/mL G418 'arid 'incubated' at 37 0 C in a CO 2 incubator. The cells were»allpwed 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 0 C for 10 minutes.
  • SFM serum free medium
  • SFM+IBMX media containing various compounds and 1 ⁇ M serotonin (as antagonist) were added to the appropriate wells and incubated for 30 minutes. 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 ⁇ M EDTA (2:1) at 4 0 C for 1 hour. The cells were then scraped and transferred into Eppendorf tubes. The tubes were centrifuged for 5 minutes at 4 0 C and the supernatants were stored at 4 0 C until assayed.
  • PBS phosphate buffered saline
  • cAMP content was determined by EIA (enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (Amersham RPN 225). The procedure used is as described for the kit. Briefly, cAMP is determined by the competition between unlabeled cAMP and a fixed quantity of peroxidase-labelled cAMP for the binding sites on anti-cAMP antibody. The antibody is immobilized onto polystyrene microtitre wells precoated with a second antibody. The reaction is started by adding 50 ⁇ L, peroxidase-labeled cAMP to the sample (100 ⁇ L) pre-incubated with the antiserum (100 mL) for 2 hours at 4 0 C. Following 1 hour incubation at 4 °C, the unbound ligand is separated by a simple washing procedure. Then an enzyme substrate, trimethylbenzidine (1), is added and incubated at room temperature for 60 minutes. The
  • mice Three to five animals were housed in each cage. Animals were kept fasted over night 10 and maintained on a 12 hours light/dark cycle. Three rats were dosed NCE (10 mg/Kg) orally and intravenously on day 0 and day 2
  • NCE compounds were quantified in plasma by validated LC-MS/MS method using solid phase extraction technique. NCE compounds were quantified in the calibration range of 2-2000 ng/ml in plasma. Study samples were analyzed using calibration samples in the batch and quality control samples spread across the batch.
  • Brain penetration was determined at steady state in rat.
  • male wistar nils 225 - 250 grams
  • halothane for surgical placement of jugular and femoral vein catheters.
  • the rats were housed in individual rat infusion cage connected with infusion components (Instech Solomon; Madison Meeting, PA. USA) and allowed free access to food and water
  • NCIi compound was dissolved in water and administered at a constant infusion rate (5 ml/kg/hr) over 6 -10 hours at a target dose rate of 1.0 mg free base/kg/h. Blood samples were removed during the latter part of the infusion to confirm steady-state blood concentrations, brain and blood was collected and estimated. Animals will be sacrificed to collect the plasma and brain tissue and was homogenized. Plasma and Brain was stored frozen at -20 0 C until analysis. The concentrations of the NCE compound in plasma and Brain were determined using LC-MS/MS method.
  • NCE compounds were quantified in plasma and brain homogenate by validated LC-MS/MS method using solid phase extraction technique. NCE compounds were quantified in the calibration range of 1-500 ng/mL in plasma and brain homogenate. Study samples were analyzed using calibration samples in the batch and quality control samples 1 spread across the batch. Extents of brain-blood ratio were calculated (Cb/Cp).
  • Example 69 Rodent Brain Micro dialysis Study for possible modulation of Neurotransmitters.
  • Group allocation Group 1 Vehicle (Water; 5 mL/kg; p.o.), Group 2: NCE (3 mg/kg; p.o.), Group 3: NCE (10 mg/kg; p.o.)
  • Rats were anesthetized with chloral hydrate and placed in Stereotaxic frame.
  • Guide cannula (CMA/12) was placed at AP: -5.2 mm, ML: +5.0 mm relative from bregma and DV: -3.8 mm from the brain surface according to the atlas of Paxinos and
  • a modified Ringer's solution comprised of: 1.3 ⁇ M CaC12 (Sigma), 1.0 ⁇ M MgCl 2 (Sigma), 3.0 ⁇ M KCl (Sigma), 147.0 ⁇ M NaCl (Sigma),
  • Microdialysis data were expressed as percent changes (Mean + S.E.M.) of baseline that was defined as the average absolute value (in fM/10 ⁇ L) of the four samples before drug administration. Effects of NCE (3 & 10 mg/kg) and Vehicle treatments were statistically evaluated by one-way ANOVA followed by Dunnett's multiple comparison tests. In all statistical measures, a p ⁇ 0.05 was considered significant. The Graph Pad Prism program statistically evaluated the data.
  • Example 70 Food Intake Measurement Male Wister rats (120-140 grams) obtained from N. I. N. (National Institute of
  • the rats were housed in single home cages for 28 days. During this period, the rats were either dosed orally or ip, with a composition comprising a compound of formula (1) or a
  • the rat is provided with ad libitum food and water.
  • the cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: the object recognition task model.
  • Male Wister rats (230 - 280 grams) obtained from N. I. N. (National Institute of
  • mice were used as experimental animals. 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 hours light/dark cycle. Also the rats were habituated to individual arenas for 1 hour in the absence of any objects.
  • Tl the rats were placed individually in the open field for 3 minutes, 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.
  • two identical objects plastic bottles, 12.5 cm height x 5.5 cm diameter
  • al and a2 yellow masking tape alone
  • the same rats were placed in the same arena as they were placed in Tl trial.
  • Tl is the total time spent exploring the familiar objects (al + a2).
  • T2 is the total time spent exploring the familiar object and novel object (a3 +b).
  • Some representative compounds have shown positive effects indicating the increased novel object recognition viz; increased exploration time with novel object and higher discrimination index.
  • 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°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:
  • Rats Male Wister rats weighing 200-250 grams were used. Rats were given vehicle injections and placed in individual, transparent chambers for 1 hour 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 minutes after drug or vehicle injections. 60 minutes prior to the drug administration Physostigmine, 0.1
  • the training apparatus consisted of a chamber 300 mm in length, 260 mm wide, and 270 mm in height, constructed to established designs. The front and top were transparent, allowing the experimenter to observe the behavior of the animal inside the apparatus.
  • the chamber was divided into two compartments, separated by a central shutter that contained a small opening 50 mm wide and 75 mm high set close to the front of the chamber. The smaller of the compartments measured 9 mm in width and contained a low-power (6V) illumination source. The larger compartment measured 210 mm in width and was not illuminated.
  • 6V low-power
  • the floor of this dark compartment consisted of " a grid of 16 horizontal stainless-steel bars that were 5 mm in diameter and spaced 12.5 mm apart.
  • a current generator supplied 0.75 mA to the grid floor, which was scrambled once every 0.5 seconds across the 16 bars.
  • a resistance range of 40-60 micro ohms 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.

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Abstract

La présente invention concerne de nouveaux composés indolyle substitués représentés par la formule (I), leurs dérivés, leurs stéréo-isomères, leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables les contenant. La présente invention concerne également un procédé de préparation desdits nouveaux composés, de leurs dérivés, de leurs stéréo-isomères, de leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables les contenant. L'invention concerne également les nouveaux intermédiaires mis en jeu dans ce procédé et leur procédé de préparation. Lesdits composés s'utilisent dans le traitement de divers troubles liés aux fonctions du récepteur 5HT-6.
PCT/IN2008/000280 2007-09-11 2008-05-02 Composés indolyle substitués et leur utilisation en tant que ligands de 5-ht6 WO2009034581A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093285B2 (en) * 2008-03-25 2012-01-10 Roche Palo Alto Llc Aminopiperidinyl derivatives and uses thereof
CN103420895A (zh) * 2012-05-18 2013-12-04 苏州爱斯鹏药物研发有限责任公司 一种4-氨基吲哚的制备方法
CN105541693A (zh) * 2014-07-08 2016-05-04 广东东阳光药业有限公司 芳杂环类衍生物及其在药物上的应用
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085892A1 (fr) * 2001-04-20 2002-10-31 Wyeth Derives d'heterocyclyloxy-, -thioxy- et aminobenzazol servant de ligands de 5-hydroxytryptamine-6
WO2005037834A1 (fr) * 2003-10-20 2005-04-28 Biovitrum Ab Nouveaux derives tetrahydrospiro{piperidine-2,7'-pyrrolo[3,2-b]pyridine et nouveaux derives indole utiles pour le traitement des troubles associes au recepteur 5-ht6

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085892A1 (fr) * 2001-04-20 2002-10-31 Wyeth Derives d'heterocyclyloxy-, -thioxy- et aminobenzazol servant de ligands de 5-hydroxytryptamine-6
WO2005037834A1 (fr) * 2003-10-20 2005-04-28 Biovitrum Ab Nouveaux derives tetrahydrospiro{piperidine-2,7'-pyrrolo[3,2-b]pyridine et nouveaux derives indole utiles pour le traitement des troubles associes au recepteur 5-ht6

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093285B2 (en) * 2008-03-25 2012-01-10 Roche Palo Alto Llc Aminopiperidinyl derivatives and uses thereof
CN103420895A (zh) * 2012-05-18 2013-12-04 苏州爱斯鹏药物研发有限责任公司 一种4-氨基吲哚的制备方法
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
CN105541693A (zh) * 2014-07-08 2016-05-04 广东东阳光药业有限公司 芳杂环类衍生物及其在药物上的应用
JP2017519798A (ja) * 2014-07-08 2017-07-20 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． 芳香族ヘテロ環誘導体及びその医薬的適用
EP3166924A4 (fr) * 2014-07-08 2017-11-15 Sunshine Lake Pharma Co., Ltd. Dérivés hétérocycliques aromatiques et leurs applications pharmaceutiques
AU2015286049B2 (en) * 2014-07-08 2018-03-01 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
CN105541693B (zh) * 2014-07-08 2018-10-16 广东东阳光药业有限公司 芳杂环类衍生物及其在药物上的应用

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