WO2005066157A1 - 3-(pyrrolidine-3-l)indoles en tant que modulateurs du recepteur 5-ht6 - Google Patents

3-(pyrrolidine-3-l)indoles en tant que modulateurs du recepteur 5-ht6 Download PDF

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Publication number
WO2005066157A1
WO2005066157A1 PCT/IN2004/000431 IN2004000431W WO2005066157A1 WO 2005066157 A1 WO2005066157 A1 WO 2005066157A1 IN 2004000431 W IN2004000431 W IN 2004000431W WO 2005066157 A1 WO2005066157 A1 WO 2005066157A1
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indole
bromobenzenesulfonyl
methylpyrrolidin
methoxy
methyl
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PCT/IN2004/000431
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English (en)
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Venkateswarlu Jasti
Venkata Satya Nirogi Ramakrishna
Rama Sastri Kambhampati
Vikas Shreekrishna Shirsath
Nagaraj Kandikere Vishwottam
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Suven Life Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to 3-(Heterocyclic)indoles of the general formula (I) given below,
  • 5-HT receptors (Serotonin) (International Patent Publication WO 03/065046 A2), preferably those having discriminatory profile and strong affinity towards the particular receptor. Mediation of 5-ht 6 receptors has been proposed for treating various
  • CNS disorders CNS disorders, hematological disorders, eating disorders, diseases associated with pain, respiratory diseases, genito-urological disorders, cardio vascular diseases and cancer.
  • These compounds can be formulated into various dosage forms, whereby an effective amount could be delivered to the patient in need, either to obtain a therapeutic or diagnostic benefit.
  • R 1? R 2 , R 3 , J , R 5 , R ⁇ , 7, Re and R 9 may be same or different and each independently represent hydrogen, halogen, perhaloalkyl, perhaloalkoxy, hydroxy, (Ci-C 3 )alkyl, (C 3 -
  • C 5 cycloalkyl, (C ⁇ -C 3 )alkoxy, cyclo(C 3 -C 5 )alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, monoalkylamino, dialkylamino or thioalkyl;
  • R ⁇ .0 may represent either of hydrogen, halogen, perhaloalkyl, (C 1 -C 3 )alkyl, aryl or acyloxy;
  • Rii, R12, Ri3 and R 14 whenever possible, independently represent hydrogen, halogen, oxo, thio, perhaloalkyl, perhaloalkoxy, hydroxy, thiol or (C ⁇ -C 3 )alkyl. It is another object of this invention to provide compounds of the formula (I) which are useful as agonists, partial agonist or antagonists at the 5-ht receptor sub- types.
  • Ri, R 2 , R 3 and Ri independently represent hydrogen, halogen, perhaloalkyl, perhaloalkoxy, hydroxy, (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkoxy, cyclo(C 3 - C 5 )alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, monoalkylamino, dialkylamino or thioalkyl; Rio may represent either of hydrogen, halogen, perhaloalkyl, (C 1 -C 3 )alkyl, aryl or acyloxy; with 1 mole of a compound of general formula (HI),
  • R 5 , Re, R7, R 8 and R independently represent hydrogen, halogen, perhaloalkyl, perhaloalkoxy, hydroxy, (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl, (Ci-C 3 )alkoxy, cyclo(C 3 -C 5 )alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, monoalkylamino, dialkylamino or thioalkyl; and X is defined as either of-CH 2 -, -CO-, -S- or -S(O) !
  • the process may include one or more of the following steps: 1. converting a racemic compound of the formula (I) into substantially pure optically active form; or 2. converting one compound of the formula (I) into another; or 3. removing any protecting groups; or 4. forming a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention also provides a pharmaceutically acceptable composition comprising at-least one compound of formula (I) as defined in point (i) above or claim 1, in an effective amount along with suitable pharmaceutically acceptable adjuvant.
  • the present invention also provides use of one or more compounds defined in point (i) above or claim 1, or a composition comprising it to treat or prevent diseases related to CNS, eating, gastrointestine, blood, pain, respiration, genito-urinary, cardio vascular and cancer, wherein 5-Hydroxytryptamine receptor malfunction is involved.
  • the present invention further provides manufacturing a medicament in various dosage forms which contain at least one compound of formula (I).
  • CNS disorders wherein 5-ht receptors are involved and those which could be treated using compounds of this invention include psychosis, paraphrenia, anxiety, depression, mania, schizophrenia, schizophreniform disorders, migraine headache, drug addiction, convulsive disorders, personality disorders, hypertension, autism, post- traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, chronobiological abnormalities and circadian rhythms, cognitive memory disorders e.g.
  • Alzheimer's disease and age-related cognitive decline include ADHD (Attention Deficient Disorder/ Hyperactivity Syndrome), amylotrophic lateral sclerosis, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, panic attacks, and also disorders associated with spinal trauma and / or head injury such as hydrocephalus and also mild cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinsonism and Huntington's chorea.
  • GI Gastrointestinal disorders wherein 5-ht receptor is involved and such disorders which could be treated using compounds of this invention include LBS (Irritable bowel syndrome) or chemotherapy induced emesis.
  • Suitable groups represented by subtitutents like R l5 R 2 , R 3 , R 4 , R 5 , Rs, R , R 8 , R 9 , Rto, Ru, R 12 , R13 and R 14 may be selected from: halogen such as fluorine, chlorine, bromine or iodine; perhaloalkyl particularly perhalo(C 1 - C 3 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like; substituted or unsubstituted (C 1 -C 3 )alkyl group, such as methyl, ethyl, 2-chloroprop-l-yl, iso-propyl and the like
  • 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 R-isomer, S-isomer and R,S- mixtures and in the case of a number of asymmetric carbon atoms, the diastereomeric forms and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • Those compounds of general formula (I) which have an asymmetric carbon and as a rule are obtained as racemates can be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • stereoisomers of compounds of general formula (I) may be prepared by one or more ways presented below: i) One or more of the reagents may be used in their optically active form. ii) Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process. The metal catalysts may be employed in the reduction process. The metal catalyst may be Rhodium, Ruthenium, Indium and the like. The chiral ligands may preferably be chiral phosphines (Principles of Asymmetric synthesis, J. E.
  • the mixture of stereoisomers may be resolved by conventional methods such as forming 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 or neutralizing the derivative (Jacques et. al., "Enantiomers, Racemates and Resolution", Wiley Interscience, 1981).
  • 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 compound containing basic amino group such as lysine, arginine and the like.
  • 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.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of the formula (I) can be prepared.
  • the non-toxic acid addition salts include those having pharmacologically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benezenesulfonate, p-tolunesulfonate, palmoate and oxalate.
  • Pharmaceutically acceptable salts forming part of this invention are intended to define but not limited to the above list.
  • pharmaceutically acceptable salts of the compound of general formula (I) can be obtained by converting derivatives which have tertiary amino groups into the corresponding quarternary ammonium salts in the methods known in the literature by using quarternizing agents.
  • Possible quarternizing agents are, for example, alkyl halides such as methyl iodide, ethyl bromide and n-propyl chloride, including arylalkyl halides such as benzyl chloride or 2-phenylethyl bromide.
  • 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 acid mentioned as above in solvents such as water, alcohols, ethers, ethyl acetate, dioxane, DMF or a lower alkyl ketone such as acetone, or the mixtures thereof. Further the exceptional salts may be formed as intermediates during purification, preparation of other salts, or identification and characterization of compounds of formula (I) or intermediates involved in preparing compounds of formula (I).
  • the pharmaceutically acceptable salts of compounds of formula (I) may exist as solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate, and the like.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent preparation or crystalhzation, or adventitious to such solvent.
  • radio-labelled compounds related to general structure (I) can be prepared by incorporating isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, bromine and mTecnitium, exemplified by 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 18 F, 99m Tc, 31 P, S, 123 I and 125 I.
  • Isotopically labelled compounds of the present invention are popular in drug and/or substrate tissue distribution and target occupancy assays.
  • isotopically labelled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography).
  • Another aspect of the present invention comprises of a pharmaceutical composition, containing at least one of the compounds of general formula (I) as defined earlier, either in pure or impure forms forming an active ingredient, together with pharmaceutically employed carriers, auxiliaries and the like.
  • 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.
  • “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'.
  • 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 terms “treating”, “treat”, or “treatment” embrace all the meanings such as preventative, prophylactic and palliative.
  • 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 as well as the formulated medicaments prepared according to the present invention may in addition to at least one compound of formula formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racernate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt or a corresponding solvate, comprise further conventional auxiliary substances known to those skilled in the art, such as carriers, fillers, solvents, diluents, colouring agents, coating agents, matrix agents and/or binders.
  • auxiliary substances and the amounts thereof to be used are dependent on the intended route of administration, e.g. oral, rectal, intravenous, intraperitoneal, intramuscular, intranasal, buccal or topical route.
  • 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 (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.
  • Medicaments suitable for parenteral, topical or inhalatory administration may preferably be selected from the group consisting of solutions, suspensions, readily reconstitutable dry preparations and also sprays.
  • Suitable medicaments, e.g. medicaments for oral or percutaneous use may release the sulphonamide compounds of general formula (1) in a delayed manner, whereby the preparation of these delayed release medicaments is generally known to those skilled in the art.
  • Medicaments suitable for oral administration are for example, tablets, sugar- coated pills, capsules or multiparticulates, such as granules or pellets, optionally compressed into tablets, filled into capsules or suspended in a suitable liquid, solutions or suspensions.
  • Such the pharmaceutical compositions may have 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
  • 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.
  • 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.
  • Suitable delayed-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of
  • the medicament of the present invention may also have at least one enteric coating, which dissolves as a function of pH. Because of this coating, the medicament can pass through the stomach undissolved and the compounds of general formula I are only released in the intestinal tract.
  • the enteric coating preferably dissolves at a pH of between 5 and 7 Suitable materials and methods for the preparation of enteric coatings are also known to those skilled in the art Typically the pharmaceutical compositions and medicaments comprise 1 to 60 % by weight of one or more sulphonamide derivatives of general formula (1) and 40 to 99 % by weight of one or more excipients.
  • reaction schemes depicted below provide 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.
  • Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions.
  • Description 1 3-(lH-Indol-3-yI)-l-methylpyrrolidin-2,5-dione (Dl) Tetrahydrofuran (80mL), magnesium turnings (8.0 g, 0.33 moles) and iodine
  • the product was obtained in 87 % yield.
  • the compound obtained was identified by IR, NMR and mass spectral analyses as the title compound.
  • Example - 3 3-(4-Bromo-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-lH-indole: Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared, starting with D3. Mass (m/z): 277, 279 (M+3) + .
  • Example - 4 (R,S) l-Benzenesulfonyl-3-(l-methylpyrrolidin-3-yl)-lH-indole: A stirred solution of (R,S) 3-(l-Methylpyrrohdin-3-yl)-lH-indole (0.95 mmoles) in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzene sulfonyl chloride (1.09 mL, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L.
  • reaction mixture was quenched with 25 mL ice-cold water and diluted with 25 mL ethyl acetate.
  • the organic phase was separated, washed sequentially with water and brine, dried over anhydrous MgSO 4 and concentrated in vacuo.
  • the resultant residue was purified by flash chromatography (silica gel, EtOAc Hexane, 2/8 to 9/1) to afford the title compound as off-white foam, which was latter identified by IR, NMR and mass spectral data.
  • Example - 5 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-methylpyrroIidin-3-yl)-lH- indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 6 (R,S) l-(4-Fluorobenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-lH- indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 7 l-Benzenesulfonyl-3-(4-chloro-l-methyI-2,5 ⁇ dihydro-lH-pyrrol-3- yl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 8 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrroI-3-yl)-l-(4 ⁇ fluorobenzenesulfonyl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 10 (R,S) l-Benzoyl-3-(l-methyl-pyrrolidin-3-yl)-lH-indole: A stirred solution of (RS) 3 -(1 -Methylpyrrolidin-3 -yl)-l H-indole (8.95 moles) in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutesj treated with benzoyl chloride (1.16 g, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L.
  • Example - 11 l-(4-BromobenzenesulfonyI)-3-(4-Chloro-l-methyl-2,5- dihydro-lH-pyrrol-3-yl)-lH-indo!e: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 12 3-(4-Chloro-l-methyI-2,5-dihydro-lH-pyrrol-3-yl)-l-(4- methoxybenzenesulfonyl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 13 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-l-(2,4,5- trichlorobenzenesulfonyl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 14 l-(Benzenesulfonyl)-3-(4-chloro-l-methyl-2,5-dihydro-lH- pyrrol-3-yI)-5 ⁇ methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 15 3-(4-ChIoro-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-l-(4- fluorobenzenesulfonyl)-5-methoxy-lH-indoIe: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 16 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-l-(4- methoxybenzenesulfonyl)-5-methoxy-lH-indole: .
  • the above derivative was prepared.
  • Example - 17 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-l-(2,4,5- trichlorobenzenesulfonyl)-5-methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 18 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrrol-3-yl)-l-(4- isopropylbenzenesulfonyl)-5-methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 19 l-(2-Bromobenzenesulfonyl)-3-(4-Chloro-l-methyl-2,5- dihydro-lH-pyrrol-3-yl)- 5-methoxy-lH-indole Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 20 l-(4-Bromobenzenesulfonyl)-3-(4-Chloro-l-methyl-2,5- dihydro-lH-pyrrol-3-yl)- 5-methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 21 3-(4-Chloro-l-methyl-2,5-dihydro-lH-pyrrol-3 ⁇ yl)-l-(4- methylbenzenesulfonyl)-5-methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 22 l-(BenzenesuIfonyl)-3-(4-Chloro-l-ethyl-2,5-dihydro-lH- pyrrol-3-yl)- 5-methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 23 l-(4-Bromobenzenesulfonyl)-3-(4-ChIoro-l-methyl-2,5- dihydro-lH-pyrrol-3-yl)- 5-ethoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 24 4-Chloro-3-(4-chloro-l-methyl-pyrrolidin-3-yl)-l-(4- isopropyl-benzenesulfonyl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example - 25 (R > S) l-(2-Bromobenzenesulfonyl)-3-(l-ethylpyrrolidin-3- yl)-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 26 (R,S) l-(4-Isopropylbenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-5- methoxy-lH-indole Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 27 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l ⁇ methylpyrrolidin-3-yl)-5- methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 28 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-ethylpyrrolidin-3-yl)-5- methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 29 (R,S) l-(2-Bromobenzenesulfonyl) ⁇ 3-(l-methylpyrrolidin-3-yl)-4- methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 30 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l ⁇ methylpyrrolidin-3-yI)-6- methoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared. IR spectra (cm-1): 2775.43, 1364.11, 1175.41, 600.42; Mass (m/z): 449 (M+H) + , 451 (M+3) + ; 1H -NMR (ppm):
  • Example 31 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-methyIpyrrolidin-3-yl)-5- ethoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 33 (R,S) l-(4-Bromo-2-methoxybenzenesulfonyl)-3-(l-ethylpyrrolidin- 3-yl)-5-ethoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 34 (R,S) l-(4-methoxybenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-5- isopropoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared. R spectra (cm "1 ): 2925.64, 1373.37, 1175.11, 583.85; Mass (m/z): 429 (M+H) + .
  • Example 35 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-5- isopropoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 36 (R,S) l-(4-MethylbenzenesuIfonyl)-3-(l-methylpyrrolidin-3-yI)-5- isopropoxy-lH-indole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 37 (R,S) l-(4 ⁇ Bromobenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-5- isopropyl-lH-indole Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 38 (R,S) l-(2-BromobenzenesuIfony ⁇ )-3-(l-ethylpyrrolidin-3-yl)-lH-5- isopropoxyindole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 39 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-methylpyrrolidin-3-yl)-lH-5- cyclopentyloxyindole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 40 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l ⁇ methylpyrrolidin-3-yl)-lH-6- chloroindole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • Example 41 (R,S) l-(2-Bromobenzenesulfonyl)-3-(l-ethylpyrrolidin-3-yl)-lH-5- cyclopentyloxyindole: Using essentially the general procedure described in example 4 and some non- critical variations, the above derivative was prepared.
  • the ingredients are combined and granulated using a suitable solvent such as ethanol.
  • a suitable solvent such as ethanol.
  • the formulation is then dried and formed into tablets with an appropriate tablet machine.
  • Example 43 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.
  • the ingredients are mixed to form a suspension for oral administration.
  • the active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
  • the ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
  • Example 48 FOOD INTAKE MEASUREMENT.
  • Male Wistar rats (100-270 g) obtained from (National Institute of Nutrition, India) are used. The animals are acclimatized to the animal facility for atleast 7 days before they are subjected to any treatment. During this period the animals are housed (in groups of three) in translucid cages and provided with food and water ad libitum. At least 24 hours before the treatment starts, the animals are adapted to single-housing conditions.
  • the chronic effect of the compounds of general formula (I) on food intake in well-fed rats is then determined as follows.
  • the rats were housed in their single homecages for 28 days. After this period, the rats are orally dosed with a composition comprising a compound of formula (1) or a corresponding composition (vehicle) without said compound, once-a-day.
  • the rat is provided with ad libitum food and water. On 0, 7 th , 14 th , 21 st and 28 th" day the rat is left with preweighed food. Food intake and weight gain is measured.
  • Example 49 Binding assay for human 5HT6 receptor;
  • 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]
  • Reference compound Methiothepin mesylate
  • Positive control Methiothepin mesylate
  • Incubation conditions Reactions are carried out in 50 mM TRIS-HC1 (pH 7.4) containing 10 mM MgCl , 0.5 mM EDTA for 60 minutes at 37 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HT 6 binding site.

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Abstract

La présente invention concerne 3-indoles hétérocycliques de formule (I), ses stéréoisomères et sels. Dans ladite formule, les substituants tels que R, R1, R2, R3, R4, R10, R11, R12, R13, et R14 sont décrits dans la spécification. Ladite invention a aussi pour objet un procédé de préparation d'un composé de formule (I), une composition pharmaceutique contenant de tels composés et un procédé de conception d'un médicament. Ces composés sont, notamment, utilisés dans le traitement de divers troubles du système nerveux central, de troubles hématologiques, de troubles de l'alimentation, de troubles liés à la douleur, de maladie respiratoire, de troubles génito-urinaires, de maladies cardio-vasculaires et de cancer.
PCT/IN2004/000431 2004-01-02 2004-12-30 3-(pyrrolidine-3-l)indoles en tant que modulateurs du recepteur 5-ht6 WO2005066157A1 (fr)

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WO2008087123A2 (fr) * 2007-01-16 2008-07-24 Solvay Pharmaceuticals B.V. Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction
US20100041672A1 (en) * 2007-03-21 2010-02-18 Glaxo Group Limited Use of quinoline derivatives in the treatment of pain and irritable bowel syndrome
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8546431B2 (en) 2008-10-01 2013-10-01 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8697730B2 (en) 2007-10-26 2014-04-15 Panmira Pharmaceuticals, Llc 5-lipoxygenase activating protein (FLAP) inhibitor
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US9808455B2 (en) 2007-12-12 2017-11-07 Axovant Sciences Gmbh Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US10059691B2 (en) 2008-04-02 2018-08-28 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
WO2022120475A1 (fr) * 2020-12-07 2022-06-16 Mindset Pharma Inc. Dérivés d'amine-indole 3-cyclique utilisés en tant qu'agents sérotonergiques pour le traitement de troubles du système nerveux central
WO2023019368A1 (fr) * 2021-08-20 2023-02-23 Mindset Pharma Inc. Composés de 3-cycloamino-indole utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8841295B2 (en) 2005-11-04 2014-09-23 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US8710081B2 (en) 2005-11-04 2014-04-29 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
WO2008087123A3 (fr) * 2007-01-16 2008-11-27 Solvay Pharm Bv Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction
WO2008087123A2 (fr) * 2007-01-16 2008-07-24 Solvay Pharmaceuticals B.V. Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction
US20100041672A1 (en) * 2007-03-21 2010-02-18 Glaxo Group Limited Use of quinoline derivatives in the treatment of pain and irritable bowel syndrome
US8697730B2 (en) 2007-10-26 2014-04-15 Panmira Pharmaceuticals, Llc 5-lipoxygenase activating protein (FLAP) inhibitor
US9808455B2 (en) 2007-12-12 2017-11-07 Axovant Sciences Gmbh Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline
US10059691B2 (en) 2008-04-02 2018-08-28 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US10787437B2 (en) 2008-04-02 2020-09-29 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
US8546431B2 (en) 2008-10-01 2013-10-01 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US9663498B2 (en) 2013-12-20 2017-05-30 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic compounds and their application in pharmaceuticals
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US11304932B2 (en) 2015-07-15 2022-04-19 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
WO2022120475A1 (fr) * 2020-12-07 2022-06-16 Mindset Pharma Inc. Dérivés d'amine-indole 3-cyclique utilisés en tant qu'agents sérotonergiques pour le traitement de troubles du système nerveux central
WO2023019368A1 (fr) * 2021-08-20 2023-02-23 Mindset Pharma Inc. Composés de 3-cycloamino-indole utilisés en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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