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WO2000008006A2 - Composes pharmaceutiques - Google Patents

Composes pharmaceutiques Download PDF

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Publication number
WO2000008006A2
WO2000008006A2 PCT/GB1999/002560 GB9902560W WO0008006A2 WO 2000008006 A2 WO2000008006 A2 WO 2000008006A2 GB 9902560 W GB9902560 W GB 9902560W WO 0008006 A2 WO0008006 A2 WO 0008006A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
alkyl
compound
formula
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1999/002560
Other languages
English (en)
Other versions
WO2000008006A3 (fr
Inventor
Stephen Richard Baker
David Bleakman
John Goldsworthy
Patric James Hahn
Gunnar Erik Jagdmann
Shelley Hunnings Turkington
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co Ltd
Eli Lilly and Co
Original Assignee
Eli Lilly and Co Ltd
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co Ltd, Eli Lilly and Co filed Critical Eli Lilly and Co Ltd
Priority to EP99936874A priority Critical patent/EP1104413A2/fr
Priority to AU51845/99A priority patent/AU5184599A/en
Priority to CA002305406A priority patent/CA2305406A1/fr
Priority to JP2000563639A priority patent/JP2003510244A/ja
Publication of WO2000008006A2 publication Critical patent/WO2000008006A2/fr
Publication of WO2000008006A3 publication Critical patent/WO2000008006A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention relates to novel chemical compounds and their use as pharmaceuticals.
  • This invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I,
  • R x and R2 are each independently H or C ⁇ __g alkyl or ⁇ - ⁇ alkenyl or C3_]_Q cycloalkyl, or R1 and R ⁇ together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;
  • R 3 and R 4 are each independently H or C ⁇ __ alkyl or C3_ ⁇ _o cycloalkyl, R ⁇ and R ⁇ together with the carbon atom to which they are attached combine to form a C 4 _ 10 carbocyclic ring;
  • R5 and R ⁇ are each independently H or C ⁇ _ 6 alkyl, C ⁇ -6 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, a ino, C ⁇ _ 4 acyla ino and C ⁇ _ 6 alkylthio, C ⁇ - 6 alkylsulphone, or halo C ⁇ _ 6 alkylsulphone;
  • the compounds of the invention have been found to be active in tests indicative of their use in the treatment of diseases of the central nervous system such as neurological diseases, for example, neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.
  • diseases of the central nervous system such as neurological diseases, for example, neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.
  • a C ⁇ _ 6 alkyl group can be straight or branched chain, such as, for example, methyl, ethyl, propyl , isopropyl, butyl and isobutyl, and is preferably methyl.
  • a C 3 _ 6 alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds.
  • a c 3 _ ⁇ o cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C ⁇ - 6 alkyl, for example methyl, substituents , or can be a bicyclo-system as, for example, bicyclooctane .
  • a saturated heterocyclic ring of 4-10 atoms includes, a ring containing a further heteroatom in addition to the nitrogen to which they are attached, such as nitrogen and oxygen, for example, piperidino or morpholino.
  • a halo C ⁇ _ 6 alkylsulphone includes a C ⁇ _ 6 alkylsulphone substituted with halo atoms, for example trifluoromethylsulphone, or perfluoroethylsulphone .
  • a preferred group of compounds according to formula (I) is one in which R ⁇ and R ⁇ are independently trifluoromethyl or halo, especially bromo, chloro and fluoro, preferably when they are in position 3 and 4 in the phenyl ring.
  • Another preferred group is one which R ⁇ and R ⁇ are methyl
  • Particularly preferred compounds are compounds wherein R ⁇ is H or C ⁇ _ 3 alkyl, R 2 is H, R 3 and R 4 are methyl, R 5 and R are Chloro .
  • a further aspect of the invention relates to a compound of formula (I)
  • X is N or C, where X is C it can be bonded to its adjacent carbon by either a single or a double bond;
  • R! and R 2 are each independently H or C ⁇ _g alkyl or C3_g alkenyl or C3_ ] _ Q cycloalkyl, or R ⁇ and R 2 together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;
  • R 3 and R 4 are each independently H or C]__g alkyl or C3-.10 cycloalkyl, R 3 and R 4 together with the carbon atom to which they are attached combine to form a C carbocyclic ring;
  • R5 and R ⁇ are each independently H or C ⁇ - 6 alkyl, C ⁇ -6 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, amino, C ⁇ - 6 acylamino and C ⁇ -6 alkylthio, C ⁇ -6 alkylsulphone, or halo C ⁇ _ 6 alkylsulphone;
  • salts of the compounds of the invention can be prepared and such salts are included in the invention. They can be any of the well known acid addition salts.
  • Acid addition salts are preferably the pharmaceutically-acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example glycollic, maleic, fumaric, malic, tartaric, citric, salicyclic or o-acetoxybenzoic acids, or organic sulphonic acids, methane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2 -sulphonic acids,
  • salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, salts, or are useful for identification, characterisation or purification. It will be appreciated that the compounds of the invention can contain an asymmetric carbon atom as indicated by the asterisk in formula (I), and this gives rise to enantiomers .
  • the compounds can be prepared as racemates or as enantiomers, and individual enantiomers can be isolated from racemates by conventional techniques if so desired. Such racemates and individual enantiomers form part of the present invention.
  • the invention also includes a process for the production of compounds of the invention, which comprises a Strecker reaction of an arylpiperazine or piperidine ring with the corresponding cyanohydrin to give compound of formula (IV) , where X, R 3 , R 4 , R 5 and R 6 have the meaning given above, followed by elaboration of the side chain by partial hydrolysis of the corresponding nitrile with for example, hydrogen peroxide and an aqueous sodium hydroxide; or by hydrolysis to the acid of formula (V) followed by dehydrative coupling of the corresponding acid and amine with for example, 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride.
  • the compounds described above have pharmaceutical activity. They have been shown to possess affinity for glutamate receptors .
  • Excitatory amino acid or glutamate receptors are subdivided into two types, ionotropic and metabotropic .
  • Ionotropic glutamate receptors are intrinsic ligand gated ion channels that are composed of multiple subunit proteins forming multimeric complexes . Ionotropic glutamate receptors are selectively activated by the agonists N-methyl-D-asparate, AMPA, and kainate (Sommer B. And Seeburg P.H., Trends Pharmacol. Sci. 13: 291-296, 1993). Metabotropic glutamate receptors are a family of G-protein coupled receptors with novel molecular structure that are coupled to increases in phosphoinositide hydrolysis and decreases in cAMP formation.
  • the compounds of the present invention are active in a screen for activity in ionotropic receptors as described in more detail below.
  • the compounds of the invention are thus indicated for use in the treatment of neurological disorders such as acute neurodegenerative diseases, for example stroke, cerebral ischaemia and head and spinal cord trauma, and chronic neurodegenerative diseases such as, for example,
  • Alzheimer's disease, Parkinson's disease, Amyotropic lateral sclerosis, AIDS-induced dementia and Huntington's Chorea The compounds are also indicated for use as antipsychotic, anticonvulsant, analgesic and anti-emetic agents . They are also of potential use as anxiolytic and antidepressant agents .
  • the invention also includes a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically-acceptable diluent or carrier in association with a compound of formula (I) , or a pharmaceutically-acceptable salt thereof.
  • the compounds may be administered by various routes, for example, by the oral or rectal route, topically or parenterally, for example by injection, and are usually employed in the form of a pharmaceutical composition.
  • Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically-acceptable diluent or carrier.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed with a carrier which may, for example, be in the form of a capsule, sachet, paper or other container.
  • the carrier may be a solid, semi- solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, as a solid or in a liquid medium, ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders.
  • suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates , tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl- hydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Compositions in injectable form may, as it is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • each unit dosage form contains from 5 mg to 500 mg, for example, from 15 mg to 200 mg.
  • the term v unit dosage form' refers to physically discrete units suitable as unit dosages for human subjects and animals. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • the active compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg.
  • dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg.
  • the amount administered will be determined by the physician in the light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the reaction mixture was diluted with dichloromethane (800ml) and stirred with methanol-washed cation-exchange resin (Dowex 50WX8-100) (180g) for 4 hours.
  • the mixture was filtered over a pad of more ion-exchange resin (180g) on a glass sinter and then washed sequentially with (1) dichloromethane : methanol 1:1 (2) 15% ammoniacal methanol. Evaporation in vacuo of the ammoniacal wash gave a colourless solid (12.80g). Recrystallisation from absolute ethanol yielded the title compound as a white solid (4.56g). MS 318.0.
  • the aqueous phase was extracted three times with diethyl ether, and the combined ethere l extracts washed with (1) water (2) saturated sodium chloride solution; dried over magnesium sulphate, filtered and evaporated in vacuo .
  • the crude product was purified by flash chromatography on silica gel (eluant hexane 50% diethyl ether) to give 1- ( -butoxycarbonyl) -4- (3 , 4-dichlorophenyl) - 1 , 2 , 5 , 6-tetrahydropyridine as a viscous, colourless oil (1.56g) .
  • the suspension was concentrated in vacuo to a sludge, which was cooled (0°C) , filtered, and the solid rinsed with cold brine and set aside.
  • the filtrate was concentrated in vacuo to a sludge, cooled (0°C) , filtered, and the solid rinsed with cold brine and combined with the first batch. This was then taken up in methanol (25 mL) , diluted with 2-propanol (100 mL) , heated (50°C) , and filtered to remove inorganic salts.
  • the filtrate was concentrated in vacuo to afford sodium salt, which was taken up in water (30 mL) and treated with 0. IN HCL (75 mL) .
  • the reaction mixture was diluted with dichloromethane (600 mL) , treated with methanol-washed cation-exchange resin (Biorad AG50W-X8 sulfonic acid resin) (100 mg) , and agitated for 8 hours.
  • the mixture was filtered through a pad of cation-exchange resin (100 mg) and the resin washed with dichloromethane : methanol 1:1 (400 mL) to remove non-basic impurities.
  • the product was recovered by washing with 15% aqueous ammonia in methanol (3 X 400 mL) and concentrated in vacuo.
  • a tablet is prepared using the ingredients below:
  • Active Ingredient 250 Cellulose, microcrystalline 400
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • Tablets each containing 60 mg of active ingredient are made as follows: Active Ingredient 60 mg
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No . 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg medicament are made as follows : Active Ingredient 80 mg
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
  • Purified water to total 5 ml
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • HEK iGluR6 cells were obtained as described in Hoo, K.H. ; Nutt, S.; Fletcher, E. J.; Elliot, C . ; Korczak, B . ; Deverill, M. ; Rampersad, Y. ; Fantaske, R. P.; Kambo , R. K. Functional Expression and Pharmacological
  • the Culture Media was Dulbecco ' s Modified Eagle Media without Sodium Pyruvate, with 4500mg/L of Glucose, 1% of Penicillin/Streptomycin, (Gibco) , 10% of heat inactivated Foetal Calf Serum, (Seralab) and 500 ⁇ g/ml of Geneticin, (Gibco) .
  • Cells are loaded with 50 ⁇ l of 20 ⁇ M Fluo-3AM dye [Calbiochem or Molecular Probes) which was reconstituted to 3.54mM by addition of 20% F127 in DMSO (lmg Fluo - 3AM+221.2 ⁇ l 20% F127)] and 25 ⁇ l of stock in 5ml of HEPES buffer, (138 mM NaCl, ImM MgCl2 , 5mM CaC12 , lOmM Glucose, lOmM HEPES, 5mM KCl, pH to 7.4 with NaOH adjusted to 315 mOsm with NaCl) .
  • 20 ⁇ M Fluo-3AM dye Calbiochem or Molecular Probes
  • the 96 well plates were washed three times with HEPES (5CaNa) Solution, and 50 ⁇ l of Fluo-3AM dye were added to each well and they were incubated at room temperature for one hour. Then the well plates were washed twice with a buffer and they were left to stand in the second wash solution for 30min. Then the well plates were washed with buffer and they were replaced with 45 ⁇ l buffer. The fluorescence was measured with a 96 well plate fluorescence reader, Labsystems Fluoroskan II, at the Excitation wavelength of 485nM, and the Emission wavelength of 538nM to give basal reading.
  • the wash solution was removed and the well plates were preincubated for lOmin with 45 ⁇ l of a Buffer solution containing compound and l ⁇ M Concanavalin A solution.
  • the fluorescence was read to give the corresponding pre challenge values.
  • the Agonist Glutamate was added in a volume of 15 ⁇ l, at 400 ⁇ M to give a final concentration of lOO ⁇ M, and the fluorescence measurements were taken at 1, 3 and 5 min post challenge. The results were calculated as a percentage change of fluorescence from control challenged cells.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne une composition pharmaceutique correspondant à la formule (I): ou un sel pharmaceutiquement acceptable ou un ester de celle-ci, dans laquelle X, R?1, R2, R3, R4, R5 ou R6¿ ont des valeurs indiquées dans la spécification. Cette composition est utile dans le traitement des maladies du système nerveux central. L'invention concerne également un composé correspondant à la formule (I), un sel pharmaceutiquement acceptable ou un ester de celui-ci, qui sont utiles dans le traitement des maladies du système nerveux central.
PCT/GB1999/002560 1998-08-07 1999-08-04 Composes pharmaceutiques Ceased WO2000008006A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99936874A EP1104413A2 (fr) 1998-08-07 1999-08-04 Composes pharmaceutiques
AU51845/99A AU5184599A (en) 1998-08-07 1999-08-04 Pharmaceutical compounds
CA002305406A CA2305406A1 (fr) 1998-08-07 1999-08-04 Composes pharmaceutiques
JP2000563639A JP2003510244A (ja) 1998-08-07 1999-08-04 医薬化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9817197.8A GB9817197D0 (en) 1998-08-07 1998-08-07 Pharmaceutical compounds
GB9817197.8 1998-08-07

Publications (2)

Publication Number Publication Date
WO2000008006A2 true WO2000008006A2 (fr) 2000-02-17
WO2000008006A3 WO2000008006A3 (fr) 2000-08-03

Family

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PCT/GB1999/002560 Ceased WO2000008006A2 (fr) 1998-08-07 1999-08-04 Composes pharmaceutiques

Country Status (6)

Country Link
EP (1) EP1104413A2 (fr)
JP (1) JP2003510244A (fr)
AU (1) AU5184599A (fr)
CA (1) CA2305406A1 (fr)
GB (1) GB9817197D0 (fr)
WO (1) WO2000008006A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072709A1 (fr) * 2000-03-29 2001-10-04 Eli Lilly And Company Derives de naphtaline et leur utilisation pharmaceutique
WO2011000945A3 (fr) * 2009-07-03 2011-02-24 Nensius Research A/S Aminoalcamides pour une utilisation dans le traitement de maladies inflammatoires, dégénératives ou démyélinisantes du système nerveux central
CN107011288A (zh) * 2017-04-20 2017-08-04 齐鲁天和惠世制药有限公司 一种阿立哌唑中间体1‑(2,3‑二氯苯基)哌嗪盐酸盐的制备方法
WO2023172415A1 (fr) * 2022-03-07 2023-09-14 Firmenich Incorporated Compositions d'édulcorants

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435399A (en) * 1981-07-18 1984-03-06 Pfizer Inc. 2-Aryl-1-(imidazol-1-yl)-8-(4-piperazin-1-ylphenoxy) octan-2-ol antifungal agents
US4457931A (en) * 1982-09-27 1984-07-03 Selvi & C. S.P.A. Piperazine derivatives with anticholinergic and/or antihistaminic activity
GB2230780B (en) * 1989-04-22 1992-10-21 American Home Prod Tertiary alkyl functionalized piperazine derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
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WO2001072709A1 (fr) * 2000-03-29 2001-10-04 Eli Lilly And Company Derives de naphtaline et leur utilisation pharmaceutique
WO2011000945A3 (fr) * 2009-07-03 2011-02-24 Nensius Research A/S Aminoalcamides pour une utilisation dans le traitement de maladies inflammatoires, dégénératives ou démyélinisantes du système nerveux central
CN107011288A (zh) * 2017-04-20 2017-08-04 齐鲁天和惠世制药有限公司 一种阿立哌唑中间体1‑(2,3‑二氯苯基)哌嗪盐酸盐的制备方法
WO2023172415A1 (fr) * 2022-03-07 2023-09-14 Firmenich Incorporated Compositions d'édulcorants

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GB9817197D0 (en) 1998-10-07
JP2003510244A (ja) 2003-03-18
WO2000008006A3 (fr) 2000-08-03
EP1104413A2 (fr) 2001-06-06
CA2305406A1 (fr) 2000-02-17

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