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WO2007046112A1 - Derives de arylthioether tryptamine utiles en tant que ligands 5-ht6 fonctionnels - Google Patents

Derives de arylthioether tryptamine utiles en tant que ligands 5-ht6 fonctionnels Download PDF

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WO2007046112A1
WO2007046112A1 PCT/IN2006/000196 IN2006000196W WO2007046112A1 WO 2007046112 A1 WO2007046112 A1 WO 2007046112A1 IN 2006000196 W IN2006000196 W IN 2006000196W WO 2007046112 A1 WO2007046112 A1 WO 2007046112A1
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indole
ylmethyl
methyl
indol
chloro
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Venkata Satya Nirogi Ramakrishna
Rama Sastri Kambhampati
Vikas Shreekrishna Shirsath
Amol Dinkar Deshpande
Santosh Vishwakarma
Venkateswarlu Jasti
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Suven Life Sciences Ltd
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Suven Life Sciences Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to certain arylthioether tryptamine derivatives, their stereoisomers, their salts, their preparation and medicine containing them.
  • 5-HT 5-hydroxytryptamine
  • Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others.
  • 5 -HT receptor subtypes regulate the various effects of serotonin.
  • Known 5 -HT receptor family includes the 5 -HTj family (e.g. 5-HT 1A ), the 5-HT 2 family (e.g.5- HT 2 A), 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5- HT7 subtypes.
  • the 5-HTg receptor subtype was first cloned from rat tissue in 1993 (Monsma, F. J.;
  • the receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate c ⁇ clasc (Rual, M.; Trair ⁇ brt, E.; ⁇ rrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C, Biochemical Biophysical Research Communications, 1993, 193, 268-276).
  • GPCR G-protein coupled receptor
  • the receptor is found almost exclusively in the central nervous system (CNS) areas both in rat and in human.
  • 5-HTg receptor mRNA Lower levels of 5-HTg receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5- . HTg receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HTg receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor.
  • 5-HTg ligands There are many potential therapeutic uses for 5-HTg ligands in humans based on direct effects and on indications from available scientific studies. These studies include the localization of the receptor, the affinity of ligands with known in vivo activity, and various animal studies conducted so far. Preferably, antagonist compounds of 5-hg receptros are sought after as therapeutic agents.
  • One potential therapeutic use of modulators of 5-HTg receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's.
  • 5-HTg ligands A related potential therapeutic use for 5-HTg ligands is the treatment of attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults.
  • ADD attention deficit disorders
  • 5-HTg antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and because ADHD has been linked to abnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M., Journal of
  • 5-HTg antagonists may attenuate attention deficit disorders.
  • 5-HTg modulators may be useful in the treatment of movement disorders including epilepsy (Stean, T.; Routledge, C; Upton, N., British Journal of Pharmacology, 1999, 127 Proc. Supplement-131P; and Routledge, C; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M., British Journal of Pharmacology, 2000, 30 (7), 1606-1612).
  • GI gastrointestinal
  • WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WOO 1/32646 (all assigned to Glaxo SmithKline Beecham PLC) disclose a series of aryl sulphonamide and sulphoxide compounds as 5-HTg receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders. While some 5-HTg modulators have been disclosed, there continues to be a need for compounds that are useful for modulating 5- HT 6 .
  • Arylthioether tryptamine class of compounds has now been found which demonstrate 5-HTg receptor affinity, which may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders.
  • CNS central nervous system
  • the present invention relates to a compound of the Formula (I), along with its stereoisomer or its salt with an inorganic or organic acid,
  • Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as R 1 ;
  • Ar- for example may be,
  • Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (Ci-C 3 )alkyl, halo(d-C 3 )alkyl, (Ci-C 3 )alkoxy, haloCd-QOalkoxy, cyclo(C 3 -C 6 )alkyl or cyclo(C 3 -C 6 )alkoxy;
  • R 2 represents hydrogen, substituted or unsubstituted groups such as (Ci-C 3 )alkyl, (Ci-C 3 )acyl or BOC;
  • the present invention also provides methods for preparing, compositions comprising, and methods for using Compounds of Formula (I).
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I), or individual stereoisomers, racemic or non-racemic mixture of stereoisomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with atleast one suitable carrier.
  • the invention relates to the use of a therapeutically effective amount of compound of formula (I), in manufacture of a medicament, for the treatment or prevention of a disorders involving selective affinity for the 5-HTg receptor.
  • the invention further relates to the process for preparing compounds of formula (I), (v) Partial list of such compounds of general formula (I) is as follows:
  • the 5-hydroxytryptamine-6 (5-HTg) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its interesting distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting the said receptor.
  • arylthioether tryptamine derivatives of formula (I) demonstrate 5-HTg receptor affinity, along with its stereoisomer or its salt with an inorganic or organic acid,
  • Ar represents any one group selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, each of which may be further substituted by one or more independent substituents are defined as Ri; Ar- for example may be,
  • Ri represents one or multiple substitutions on the benzene ring, and includes a hydrogen, halogen, (d-C 3 )alkyl, halo(C r C 3 )alkyl, (C r C 3 )alkoxy, halo(Ci-C 3 )alkoxy, cyclo(C 3 -C 6 )alkyl or cyclo(C 3 -C6)alkoxy;
  • R 2 represents hydrogen, substituted or unsubstituted groups such as (Q- C 3 )alkyl, (Ci-C 3 )acyl or BOC;
  • a typical scheme may include following steps: STEP 1:
  • any one or more than one of the following steps can be carried out, i) converting a compound of the formula (I) into another compound of the formula (I) ii) removing any protecting group; or iii) forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.
  • tautomers, stereoisomers, geometric isomers and polymorphs are synthesized, either a mixture containing variable proportions is prepared wherein individual compounds can be isolated afterwards or elaborate procedure is applied to prepare a particular compound.
  • examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991).
  • Suitable amine protecting groups include sulphonyl (e. g. tosyl), acyl (e. g. acetyl, 2', 2', 2'- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e. g. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric or trifluoroacetic acid) or reductively (e. g. hydrogenolysis of a benzyl group or reductive removal of a 2 ⁇ 2 ⁇ T- trichloroethoxycarbonyl group using zinc in acetic acid) whichever is appropriate.
  • hydrolysis e. g. using an acid such as hydrochloric or trifluoroacetic acid
  • reductively e. g. hydrogenolysis of a benzyl group or reductive removal of a 2 ⁇ 2 ⁇ T- t
  • Suitable amine protecting groups include trifiuoroacetyl(-COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group(EUman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Process (iii) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • the pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parental (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of an aerosol spray from a pressurized container or a nebulizer, or from a capsule using a inhaler or insufflator.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas and the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the medicament for pressurized container or nebulizer may contain a solution or suspension of the active compound while for a capsule it preferably should be in the form of powder.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff' of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
  • An effective amount of a compound of general formula (I), or their derivatives as defined above can be used to produce a medicament, along with conventional pharmaceutical auxiliaries, carriers and additives.
  • Such therapy includes multiple choices: for example, administering two compatible compounds simultaneously in a single dose form or administering each compound individually in a separate dosage; or if required at same time interval or separately in order to maximize the beneficial effect or minimize the potential side-effects of the drugs according to the known principles of pharmacology.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HTg receptor antagonist is indicated, such as in the treatment of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances. Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances.
  • Parkinsonism amylotrophic lateral sclerosis, Alzheimer's disease, Attention deficit hyperactivity disorder (ADHD) and Huntington's disease.
  • schizophrenia means schizophrenia, schizophreniform, disorder, schizoaffective disorder and psychotic disorder wherein the term “psychotic” refers to delusions, prominent hallucinations, disorganized speech or disorganized or catatonic behavior. See Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington,
  • “Therapeutically effective amount” is defined as 'an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein'.
  • the dose of the active compounds can vary depending on factors such as the route of administration, age and weight of patient, nature and severity of the disease to be treated and similar factors. Therefore, any reference herein to a pharmacologically effective amount of the compounds of general formula (I) refers to the aforementioned factors.
  • a proposed dose of the active compounds of this invention, for either oral, parenteral, nasal or buccal administration, to an average adult human, for the treatment of the conditions referred to above, is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • the reaction scheme depicted herein provides potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • reaction mixture was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes and poured on to the ice water and compound was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound.
  • Lithium aluminium hydride (3.59 g, 89.8 mM) was taken in anhydrous tetrahydrofuran at ambient temperature (25 °C) and stirred well under nitrogen blanket. To this reaction mass was added a solution of Ethyl 5-fluoroindole-2-carboxylate (18.6 gm, 89.8 mM) dissolved in 130 ml of tetrahydrofuran slowly. The reaction was exothermic and temperature slowly went up to reflux.
  • the reaction mass was further maintained under reflux (60 - 65 0 C) for 3hrs, the reaction was monitored by TLC (the eluent system being n-hexane and ethyl acetate in 7:3 ratio and the product was more polar).
  • the mass was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes. Added 200 mL of ethyl acetate and stirred well.
  • the material was filtered through hyflow bed washed the bed with 50 mL ethyl acetate and layers separated. Aqueous layer was extracted with 2 x 100 mL of ethyl acetate.
  • reaction mass was cooled to 10 0 C and added dimethyl amine aqueous solution (36 %, 10 mL, 60 mM) drop- wise in 10 minutes.
  • the mass temperature was allowed to rise to 25 °C and maintained at that temperature under stirring for 2 hrs, while monitoring the reaction by TLC (the eluent system being n-hexane and ethyl acetate in 1 : 1 ratio and the product was more polar).
  • solvent ether was removed and added ice water (30 mL), stirred well and filtered the separated solids. The wet cake was dried under vacuum at 55 0 C for 3 hrs to yield 3.33 g (83 %) product.
  • Lithium aluminium hydride (1.67 g, 46.3 mM) was taken in anhydrous tetrahydrofuran (60 mlL) under nitrogen blanket and added portion- wise [(5-Fluoro-3-(2-N,N- dimethylaminooxalyl)indol-2-yl)methyl]phenylthioether (3.3 g, 9,26 mM) under stirring at ambient temperature (25 0 C). The mass temperature was raised to reflux (65 0 C) and maintained under reflux for 6 hours till completion of reaction (the reaction was monitored by TLC (the eluent system being chloroform and methanol in 9:1 ratio and the product was more polar).
  • Example 6 ⁇ 2-[2-(4-ChlorobenzenesulfonylmethyI)-4-chIoro-7-methyl-lH-indol-3- yl] ethyl ⁇ dimethy lamine.
  • Example 7 [2-(2-BenzenesuIfonylmethyI-lH-indol-3-yl)ethyl]dimethylamine hydrochloride.
  • Example 9 ⁇ 2-[2-(4-ChlorobenzenesulfonylmethyI-lH-indol-3-yl)]ethyl ⁇ dimethylamine Hydrochloride.
  • Example 10 ⁇ 2-[2-(4-FluorobenzenesuIfonyImethyI-5-fluoro-lH-indoI-3- yl)]ethyl ⁇ dimethylamine hydrochloride.
  • Example 14 ⁇ 2-[2-(4-ChIorobenzenesuIfonyImethyI-5-bromo-lH-indol-3- yl)]ethyl ⁇ dimethylamine hydrochloride. Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
  • Example 15 ⁇ 2-[2-(4-ChIorobenzenesulfonylmethyI-5-methoxy-lH-indoI-3-yI] yl)]ethyl ⁇ dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
  • Example 17 ⁇ 2-[2-(4-Methoxybenzenesulfonylmethyl-5-Fluoro-lH-indol-3-yI)]ethyl ⁇ dimethylamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
  • Example 20 [2-(2-BenzenesuIfonyImethyI-5-fluoro-lH-indoI-3-yI)]ethyI ⁇ diethyIamine Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
  • Example 36 2-(4-BromobenzenesuIfonylmethyl)-3-(4-ethylpiperazin-l-yImethyI)-5- chloro-lH-indole
  • Example 38 2-(4-ChlorobenzenesulfonyImethyI)-3-(4-methy-piperazin-l-ylmethyI)-5- chloro-lH-indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared.
  • Example 51 2-(BenzenesuIfonylmethyl)-3-(4-methylpiperazin-l-yImethyI)-5-fluoro-lH- indole Using essentially the same procedure described in example 3 and some non- critical variations the above derivative was prepared. LR.
  • Example 125 Food Intake Measurement (Behavioural Model).
  • mice Male Wistar rats (120-140 g) obtained from N. I. N. (National Institute of Nutrition, India) were used. The chronic effect of the compounds of general formula (I) on food intake in well-fed rats was then determined as follows. The rats were housed in their single home cages for 28 days. During this period, the rats were either dosed orally or i.p., with a composition comprising a compound of formula (1) or a corresponding composition (vehicle) without the said compound (control group), once-a-day. The rat was provided with ad libitum food and water. On 0, 1 st , 7 th , 14 th , 21 st and 28 th day the rat was left- with the pre-weighed amounts of food.
  • Example 126 Tablet comprising a compound of formula (I):
  • Example 127 Composition for Oral Administration
  • Example 128 Liquid oral formulation
  • Example 129 Parenteral Formulation
  • Example 130 Suppository Formulation
  • Example 131 Topical Formulation
  • Example 132 Object Recognition Task Model.
  • the cognition-enhancing properties of compounds of this invention were estimated using a model of animal cognition: the object recognition task model.
  • Male wistar rats (230 - 280 g) obtained from N. I. N. (National Institute of Nutrition, India) were used as an experimental animal.
  • Four animals were housed in each cage. Animals were kept on 20 % food deprivation before one day and given water ad libitum throughout the experiment, and maintained on a 12 h light/dark cycle. Also the rats were habituated to individual arenas for 1 hour in absence of any objects.
  • two identical objects plastic bottles, 12.5 cm height x 5.5 cm diameter
  • the same rats were placed in the same arena as they were placed in Tl trial.
  • Choice phase (T2) rats were allowed to explore the open field for 3 min. in presence of one familiar object (a3) and one novel object (b) (Amber color glass bottle, 12 cm high and 5 cm in diameter. Familiar objects presented similar textures, colors and sizes.
  • exploration of each object defined as sniffing, licking, chewing or having moving vibrissae whilst directing the nose towards the object at a distance of less than 1 cm) were recorded separately by stopwatch. Sitting on an object was not regarded as exploratory activity, however, it was rarely observed.
  • Tl was the total time spent exploring the familiar objects (al + a2).
  • T2 was the total time spent exploring the familiar object and novel object (a3 +b).
  • the object recognition test was performed as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats- Behavioral data, Behav. Brain Res., 31, 47-59. Some representative compounds have shown positive effects indicating the increased novel object recognition viz; increased exploration time with novel object and higher discrimination index.
  • Example 133 Chewing/Yawning/Stretching induction by 5HTgR antagonists.
  • Rats Male Wistar rats weighing 200-250 g were used. Rats were given vehicle injections and placed in individual, transparent chambers for 1 h each day for 2 days before the test day, to habituate them to the observation chambers and testing procedure. On the test day, rats were placed in the observation chambers immediately after drug administration and observed continuously for yawning, stretching, and chewing behaviors from 60 to 90 min after drug or vehicle injections. 60 minutes prior to the drug administration Physostigmine, 0.1 mg/kg i.p. was administered to all the animals. Average number of yawns, stretches, and vacuous chewing movements during the 30 min observation period were recorded.
  • the water maze apparatus consisted of a circular pool (1.8 m diameter, 0.6 m high) constructed in black Perspex (TSE systems, Germany) filled with water (24 ⁇ 2 0 C) and positioned underneath a wide-angled video camera to track animal.
  • the black Perspex used in the construction of the maze and platform offered no intramaze cues to guide escape behavior.
  • the training room offered several strong extramaze visual cues to aid the formation of the spatial map necessary for escape learning.
  • An automated tracking system [Videomot 2 (5.51), TSE systems, Germany] was employed.
  • This program analyzes video images acquired via a digital camera and an image acquisition board that determined path length, swim speed and the number of entries and duration of swim time spent in each quadrant of the water maze.
  • REFERENCE (1) Yamada N., Hattoria A., Hayashi T., Nishikawa T., Fukuda H. et. Al., Pharmacology, Biochem. And Behaviour, 2004, 78, 787-791.
  • Linder M. D. Hodges D. B., Hogan J. B., Corsa J. A., et al The Journal of Pharmacology and Experimental Therapeutics, 2003, 307 (2), 682-691.
  • Example 135 Passive avoidance:
  • the training apparatus consisted of a chamber 300 mm in length, 260 mm wide, and 270 mm in height, constructed to established designs. The front and top were transparent, allowing the experimenter to observe the behavior of the animal inside the apparatus.
  • the chamber was divided into two compartments, separated by a central shutter that contained a small opening 50 mm wide and 75 mm high set close to the front of the chamber. The smaller of the compartments measured 9 mm in width and contained a low-power (6V) illumination source. The larger compartment measured 210 mm in width and was not illuminated.
  • 6V low-power
  • the floor of this dark compartment consisted of a grid of 16 horizontal stainless-steel bars that were 5mm in diameter and spaced 12.5 mm apart.
  • a current generator supplied 0.75 mA to the grid floor, which was scrambled once every 0.5 s across the 16 bars.
  • a resistance range of 40-60 microohms was calculated for a control group of rats and the apparatus was calibrated accordingly.
  • An electronic circuit detecting the resistance of the animal ensured an accurate current delivery by automatic variation of the voltage with change in resistance.
  • Receptor source Human recombinant expressed in HEK293 cells
  • Radioligand [ 3 H]LSD (60-80 Ci/mmol)
  • Final ligand concentration [1.5 nM]
  • Non-specific determinant Methiothepin mesylate - [0.1 ⁇ M]
  • the antagonist property of the compounds at the human 5-HT 6 receptors was determined by testing their effect on cAMP accumulation in stably transfected HEK293 cells. Binding of an agonist to the human 5-HT 6 receptor will lead to an increase in adenyl cyclase activity. A compound that is an agonist will show an increase in cAMP production and a compound that is an antagonist will block the agonist effect.
  • Human 5-HT 6 receptors were cloned and stably expressed in HEK293 cells. These cells were plated in 6 well plates in DMEM/F12 media with 10 % fetal calf serum (FCS) and 500 ug/mL G418 and incubated at 37 0 C. in a CO 2 incubator.
  • the cells were allowed to grow to about 70 % confluence before initiation of the experiment.
  • the culture media was removed, and the cells were washed once with serum free medium (SFM).
  • SFM serum free medium
  • Two mL of SFM+IBMX media was added and incubated at 37 0 C for 10 min.
  • the media were removed and fresh SFM+IBMX media containing various compounds, and 1 uM serotonin (as antagonist) were added to the appropriate wells and incubated for 30 min.
  • the media were removed and the cells were washed once with 1 mL of PBS (phosphate buffered saline). Each well was treated with 1 mL cold 95 % ethanol and 5 mM EDTA (2:1) at 4 °C.
  • cAMP content was determined by EIA (enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (Amersham RPN 225). The procedure used was as described for the kit. Briefly, cAMP was determined by the competition between unlabeled cAMP and a fixed quantity of peroxidase-labelled cAMP for the binding sites on anti-cAMP antibody. The antibody was immobilized onto polystyrene microtitre wells precoated with a second antibody.
  • the reaction was started by adding 50 uL, peroxidase-labeled cAMP to the sample (100 uL) preincubated with the antiserum (100 uL) for 2 hours at 4° C. Following 1 hour incubation at 4° C, the unbound ligand was separated by a simple washing procedure. Then an enzyme substrate, trimethylbenzidine (1), was added and incubated at room temperature for 60 min. The reaction was stopped by the addition of 100 uL 1.0 M sulphuric acid and the resultant color read by a microtitre plate spectrophotometer at 450 nM within 30 minutes. In the functional adenylyl cyclase assay, some of the compound of this invention was found to be a competitive antagonist with good selectivity over a number of other receptors.

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  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne des dérivés d'aryilthioéther tryptamine représentés par la formule (I) utiles dans le traitement d'un trouble du système nerveux central lié au récepteur 5-HT6 ou du à ce dernier. Le profil pharmacologique de ces composés comprend une liaison à affinité élevée avec le récepteur 5-HT6 ainsi qu'une bonne sélectivité envers ledit récepteur. L'invention concerne également les stéréoisomères, les sels, les méthodes de préparation et les médicaments contenant lesdits dérivés d'aryilthioéther tryptamine.
PCT/IN2006/000196 2005-10-19 2006-06-09 Derives de arylthioether tryptamine utiles en tant que ligands 5-ht6 fonctionnels Ceased WO2007046112A1 (fr)

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IN1505/CHE/2005 2005-10-19
IN1505CH2005 2005-10-19

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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>
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US9359308B2 (en) 2011-11-23 2016-06-07 Portola Pharmaceuticals, Inc. Pyrazine kinase inhibitors
CN109187842A (zh) * 2018-11-13 2019-01-11 吕梁学院 一种沙棘中5-羟色胺提取检验与含量测定的方法
WO2023115166A1 (fr) * 2021-12-24 2023-06-29 Psylo Pty Ltd Composés

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10533001B2 (en) 2008-04-16 2020-01-14 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8501944B2 (en) 2008-04-16 2013-08-06 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8937070B2 (en) 2008-04-16 2015-01-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US9579320B2 (en) 2008-04-16 2017-02-28 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US9868729B2 (en) 2008-04-16 2018-01-16 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US11414410B2 (en) 2008-04-16 2022-08-16 Alexion Pharmaceuticals, Inc. Inhibitors of protein kinases
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>
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US9359308B2 (en) 2011-11-23 2016-06-07 Portola Pharmaceuticals, Inc. Pyrazine kinase inhibitors
CN109187842A (zh) * 2018-11-13 2019-01-11 吕梁学院 一种沙棘中5-羟色胺提取检验与含量测定的方法
WO2023115166A1 (fr) * 2021-12-24 2023-06-29 Psylo Pty Ltd Composés

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