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WO2000008023A1 - Piperidines tricycliques condensees a action anti-convulsive - Google Patents

Piperidines tricycliques condensees a action anti-convulsive Download PDF

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Publication number
WO2000008023A1
WO2000008023A1 PCT/EP1999/005586 EP9905586W WO0008023A1 WO 2000008023 A1 WO2000008023 A1 WO 2000008023A1 EP 9905586 W EP9905586 W EP 9905586W WO 0008023 A1 WO0008023 A1 WO 0008023A1
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WO
WIPO (PCT)
Prior art keywords
formula
hexahydropyrrolo
isoquinolin
disorders
compound
Prior art date
Application number
PCT/EP1999/005586
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English (en)
Inventor
Riccardo Novelli
Roderick Alan Porter
Original Assignee
Smithkline Beecham Plc
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Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO2000008023A1 publication Critical patent/WO2000008023A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
  • tricyclic/carboxamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the present invention provides a compound of formula (I) or a salt thereof or a solvate thereof
  • R 6 is hydrogen, phenylC ⁇ alkyl, or C galkyl
  • R 3 is hydrogen, halo, phenylCi _6alkyl, or Ci _6alkyl
  • A is a monocyclic aromatic carbocyclic or heterocyclic compound or a bicyclic carbocyclic or heterocyclic compound in which one ring is aromatic; m is 1 or 2; n is 1 or 2;
  • R 1 which may be at any position within the saturated ring system, is hydrogen or up to two substituents selected from fluoro or Ci _g alkyl;
  • R 2 is hydrogen or up to four substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C ⁇ . 6 alkyl, C ⁇ . 6 alkenyl, C j ⁇ alkynyl, Ci .gperfluoroalkyl, C3_gcycloalkyl, C3_ cycloalkyl-C ⁇ _4alkyl-, C ⁇ profession 6 alkylO-, C ⁇ alkylCO-, C 3 . 6 cycloalkylO-, C 3 .
  • R 3 is hydrogen, halogen, phenylCi _g alkyl, or C 1.5 alkyl; or R 3 and an R ⁇ are linked together to form a saturated or unsaturated carbocyclic or heterocyclic ring.
  • A When ring A is heterocyclic, A may be for example furanyl, thiophenyl, indolinyl or indazolinyl.
  • the ring A is typically optionally substituted phenyl or optionally substituted thiophenyl, preferably substituted phenyl.
  • alkyl groups including alkyl groups that are part of another moiety, may be straight chain or branched.
  • Aromatic rings, especially phenyl groups, including rings that are part of another moiety, may optionally be substituted with one or more independently selected halogen, C1 _g alkyl, C ⁇ _g alkoxy or Ci _g alkylcarbonyl groups.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo.
  • Suitable ⁇ , ⁇ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • heterocyclyl and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • a substituent for a heterocyclyl group is selected from halogen, (C ⁇ _ 6 )alkyl, aryl(C 1 _6)alkyl, (C ⁇ _ 6 )alkoxy, (C ⁇ _ 6 )alkoxy(C ⁇ _ 6 )alkyl, halo(C ⁇ _ 6)alkyl, hydroxy, amino, mono- and di-N-(C ⁇ _6)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ _6)alkylcarbonyl, aryloxycarbonyl, (C ⁇ _6)alkoxycarbonyl(C ⁇ _6)alkyl, aryloxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C ⁇ _6)alkylthio, (C ⁇ _6)alkylsulphinyl, (C ⁇ _ _
  • the compounds of formula (I) have one or more chiral carbon atoms and therefore may exist as enantiomers .
  • the present invention extends to each enantiomer and to mixtures thereof including racemates and diastereomers.
  • a suitable group of compounds of formula (I) have
  • R 1 as hydrogen, fluoro, methyl, ethyl or propyl
  • R2 as hydrogen or one or more of methyl, ethyl, rc-butyl, phenyl, wo-propyl, t- butyl, methoxy, ethoxy, n-propoxy, w ⁇ -propoxy, n-butoxy, phenoxy, benzyloxy, bromo, chloro, iodo, fluoro, nitro, cyano, acetyl, pivaloyl, wo-butyroyl, benzoyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, amino, acetylamino, methylthio, oxazolo, methylsulfonyl, n-propylsulfonyl, isopropylsulfonyl or dimethylsulfamoyl; R 3 as hydrogen, fluoro, methyl, ethyl or propyl.
  • R! is hydrogen
  • R2 is hydrogen or one or more of ethyl, methoxy, trifluoromethyl, cyano, chloro, fluoro.
  • Examples of compounds of formula (I) are: 3-(2-Chlorophenyl)-N-(l,2,3,5,6,10b-hexahydropyrrolo-[2,l-a]isoquinolin-9- yl)acrylamide;
  • these compounds When synthesised, these compounds may be isolated in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts.
  • the compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
  • the administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal or transdermal administration.
  • a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound.
  • Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to
  • 1000 mg for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
  • the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub- lingual, rectal, topical or parenteral (especially intravenous) composition.
  • a unit-dose composition such as a unit dose oral, including sub- lingual, rectal, topical or parenteral (especially intravenous) composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OC
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS), which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the present invention also provides a method of treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti- convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS), comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • R* A is R ⁇ as defined for formula (I) or a group convertible to R 1 ; with a compound of formula (HI)
  • R 2a and R 3a are independently R 2 or R 3 as defined for formula (I) or a group or groups convertible to R 2 or R 3 ;
  • A is as defined for formula (I), and L is
  • R 1A is R 1 as defined for formula (I) or a group convertible to R 1 ; with a compound of formula (V) or (VI)
  • R 2a and R ⁇ a are independently R 2 or R ⁇ as defined for formula (I) or a group or groups convertible to R 2 or R";
  • A is as defined for formula (I), and L is OH, acyloxy, or a halogen; and where required, converting an R 1 A , R 2a or R ⁇ a group to an R 1 , R 2 or R ⁇ group; converting one R*, R 2 or R° group to another R*, R 2 or R ⁇ group; converting a salt product to the free base or another pharmaceutically acceptable salt, or; converting a free base product to a pharmaceutically acceptable salt.
  • Conventional conditions for condensation of amines with carboxylic acids or active derivatives thereof, such as acid chlorides, may be used.
  • the amines and acids may be reacted in the presence of a mixture of ethyl(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formarnide.
  • Amines and acid chlorides may be reacted together in a suitable solvent such as ethyl acetate or tetrahydrofuran, in the presence of a base such as triethylamine.
  • the acid may be treated in solution with oxalyl chloride and then reacted with the amine or its hydrochloride.
  • reaction of a compound of formula (IV) with a compound of formula (V) or (VI) will, in the absence of a base such as triethylamine, result in formation of the hydrochloride salt of the compound of formula (I).
  • Hydrochloride salts can be obtained by also be obtained by passing HC1 gas into a solution of the free base, or adding a solution of HC1 in ether.
  • Conversions of an R 1 A , R 2A , R 3a or R 6a group to an R 1 , R 2 ,R 3 or R 6 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below.
  • Interconversion of one R , R ,R 3 or R 6 group to another typically arises when one compound of formula (I) is used as the precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
  • the compounds of formula (LI) and (IV) have chiral carbon atoms and therefore may exist as enantiomers. Accordingly the above process may produce compounds of formula (I) that are racemic mixtures. These mixtures may be separated or resolved by conventional procedures if individual enantiomers are required. Alternatively the starting materials may be selected to achieve a stereospecific reaction.
  • Compounds of formula (II) may be prepared from the corresponding hexahydro-pyrido/pyrollo-isoquinolines, firstly forming a nitro compound and then hydrogenating the nitro group to the amine.
  • the nitro group may be introduced by treating the hexahydro-pyrido/pyrollo-isoquinoline with concentrated sulfuric acid and adding potassium nitrate.
  • Hydrogenation of the nitro compound may be carried out by reaction with hydrogen at 50 psi in the presence of palladium/charcoal in a suitable solvent such as ethanol.
  • hexahydro-pyrido-isoquinoline starting materials may be prepared by analogous methods to those described in J. Pharm Bull, 1960, 8, 14.
  • Hexahydro-pyrrolo-isoquinolinylamines may be prepared by analogy to the methods disclosed in WO 97/17344 (Astra Aktibolag).
  • Hal is a halogen
  • the reactants may be heated in the presence of palladium acetate and triethylamine in a suitable solvent such as acetonitrile.
  • the acid of formula (ELI) can be reacted with the amine of formula (II) under conditions mentioned above for reaction of formulae (LI) and (EL), or converted to the acid chloride, for example by treatment with carbonyl chloride, and then reacted with the amine.
  • halo compounds of formula (VLI) are commercially available or can be prepared by standard methods.
  • compounds of formula (UL) are cinnamic acid derivatives.
  • Lithium aluminium hydride (5.42g) was stirred in diethyl ether (250ml). Dimethylphenylacetonitrile (13.8g) in diethyl ether (50ml) was added over 30 min at room temperature. When the addition was complete the reaction mixture was warmed to reflux for 3h, cooled (ice bath) and wet tetrahydrofuran CAREFULLY added. The mixture was subsequently quenched with water and 2N sodium hydroxide(l lml). The suspension was stirred for 30min, filtered, the organic phase isolated and dried (MgSO4). Solvent was removed at reduced pressure to give the title compound (13.8g) as an oil. MS m/z (API): 150 (MH+; 100%)
  • the amide D9 (lO.Og) in xylene (200ml) was treated with phosphorous pentoxide (25g) and phosphorous oxychloride (25g) subsequently added carefully.
  • the mixture was boiled for 7h. cooled and the solvent decanted.
  • the residue was dissolved in water, acidified with cone. HC1 and the aqueous phase washed with toluene.
  • the aqueous phase was basified with excess potassium carbonate, washed with toluene and treated with potassium iodide (20g).
  • the aqueous mixture was extracted with dichloromethane (x2), the combined organic phase dried (MgSO4) and solvent removed at reduced pressure to give after trituration with acetone the title compound as a brown solid (8.47g).
  • the iodide salt was converted to the nitrate salt by dissolving the iodide (9.4g) in acetonitrile (250ml). Silver nitrate (4.89g) in acetonitrile (100ml) was added dropwise over 30 min. The mixture was stirred for a further 30 min, filtered and solvent removed at reduced pressure to give after trituration with acetone the title compound (6.48g) as a colourless solid.
  • (+/-)-6,6-Dimethyl-l,2,3,5,6,10b-hexahydropyrrolo[2,l-a]-9-nitro-isoquinoline The compound Dl 1 (7.0g) was suspended in methanol and sodium borohydride (1.43g) added over lh. The mixture was stirred for a further lh after addition was complete, saturated potassium carbonate added and solvent removed at reduced pressure. The residue was extracted with dichloromethane (3 x 100ml), the organic phases were combined, dried (MgSO 4 ) and solvent removed at reduced pressure to give the title compound (5.17g) as a colourless solid.
  • the title compound compound (250g) was prepared from phenethylamine hydrochloride (200g) and 4-chlorobutyryl chloride (180g) according to the method of Description 9. MS m/z (API): 226, 228 (MH + ; 100%)
  • (+) 3-(2-Chlorophenyl)-N-(l,2,3,5,6,10b-hexahydropyrrolo-[2,l-a]isoquinolin- 9-yl)acrylamide hydrochloride The title compound (0.2 lg) was prepared from (+)l,2,3,5,6,10b- hexahydropyrrolo-[2,l-a]isoquinolin-9-amine (0.17g) D6 and 2-chlorocinnamic acid (0.20g) according to the method of Example 1
  • the acid D22 (0.12g) was converted to the acid chloride by treatment with oxalyl chloride (4ml) in dichloromethane (10ml) containing dimethylformamide (2 drop). The mixture was stirred for 2h at room temperature and solvent removed. The residue was dissolved in tetrahydrofuran (10ml) containing triethylamine (0.5mL) and 3-methylaninline lOOuL) added. The mixture was stirred for 16h. solvent removed at reduced pressure, the residue dissolved in dichloromethane (10ml) and washed with water. The organic phase was dried (MgSO4), and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 10%NH3/MeOH in dichloromethane 5:95) to give the title compound (0.069g) after conversion to the hydrochloride salt.
  • WO 92/22293 discloses compounds having anti- convulsant activity, including inter alia the compound tr ⁇ ns-(+)-6-acetyl-4S-(4- fluorobenzoylamino)-3 ,4-dihydro-2,2-dimethyl-2H- 1 -benzopyran-3R-ol (hereinafter referred to as Compound A). It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (SmithKline Beecham). The affinity of test compounds to the novel receptor site is assessed as follows.
  • Whole forebrain tissue is obtained from rats.
  • the tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4).
  • the homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.
  • To carry out the radioligand binding assay aliquots of tissue prepared as above (usually at a concentration of l-2mg protein/ml) are mixed with aliquots of [3H]-Compound A dissolved in buffer.
  • the final concentration of [3H]- Compound A in the mixture is usually 20nM.
  • the mixture is incubated at room temperature for 1 hour.
  • [3H]-Compound A bound to the tissue is then separated from unbound [3H]-Compound A by filtration through Whatman GF/B glass fibre filters. The filters are then washed rapidly with ice-cold buffer. The amount of radioactivity bound to the tissue trapped on the filters is measured by addition of liquid scintillation cocktail to the filters followed by counting in a liquid scintillation counter.
  • the affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H] -Compound A and tissue in the presence of a range of concentrations of the compound to be tested.
  • the decrease in the level of specific [3H]-Compound A binding as a result of competition by increasing concentrations of the compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.
  • the maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties 1.
  • anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
  • mice (naive male, Charles River, U.K. CD-I strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 300 mg kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC50) of the mice in a particular treatment group is determined by the ⁇ p and down' method of Dixon and Mood (1948)2.
  • Shock Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used.
  • Drugs are suspended in 1% methyl cellulose.

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Abstract

La présente invention concerne des composés représentés par la formule (I), ou bien des sels ou des solvats de ces composés, qui conviennent pour le traitement et la prophylaxie de l'épilepsie, de la migraine et autres troubles. Selon cette formule (I): X est CH ou N; P est -CH=CH- et Q est -NR6-, ou; P est -CH=CH- et Q est -NR6CH2-, ou; P est -NH- et Q est -R?3=CH-; R6¿ est hydrogène, phényle C¿1-6?alkyle ou alkyle en C1-6 R?3¿ est hydrogène, halo, phényle C¿1-6? alkyle ou alkyle en C1-6; A est un composé monocyclique aromatique carbocyclique ou hétérocyclique ou un composé bicyclique carbocyclique ou hétérocyclique dans lequel un noyau est aromatique; m vaut 1 ou 2; n vaut 1 ou 2; R?1¿ est hydrogène ou jusqu'à deux substituants pris dans fluoro ou alkyle en C¿1-6; R?2 est hydrogène ou jusqu'à quatre substituants pris dans halogène, NO¿2?, CN, N3, CF3O-, CF3S-, CF3CO-, trifluorométhyldiazirinyl, alkyle en C1-6, alcényle en C1-6, alkynyle en C1-6, perfluoroalkye en C1-6, cycloalkyle en C3-6, C3-6cycloalkyle C1-4alkyle-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyle C1-4alkylO-, C3-6cycloalkyle C1-4alkylCO-, phényle, phénoxy, benzyloxy, benzoyle, phényl-C1-4alkyle, C1-6alkylS-, C1-6 alkylSO2-, (C1-4alkyl)2NSO2-, (C1-4alkyl)NHSO2-, (C1-4alkyl)NCO-, oxyzolyl, (C1-4alkyl)NHCO- ou CONH2; ou -NR?4R5¿ou NHCOR4 où R4 est hydrogène ou alkyl en C¿1-4?; et R?5¿ est hydrogène, alkyle en C¿1-4?, formyle, -CO2C1-4 alkyle ou COC1-4 alkyle; ou deux groupes R?2¿ liés et formant un atome carbocyclique ou hétérocyclique, saturé ou insaturé, substitué ou non par -OH ou =O; R3 est hydrogène, halogène, phényle C¿1-6? alkyle ou alkyle en C1-6; ou R?3 et R2¿ liés l'un à l'autre forment un cycle saturé ou insaturé carbocyclique ou hétérocyclique.
PCT/EP1999/005586 1998-08-05 1999-08-03 Piperidines tricycliques condensees a action anti-convulsive WO2000008023A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9816986.5 1998-08-05
GBGB9816986.5A GB9816986D0 (en) 1998-08-05 1998-08-05 Novel compounds

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066411A2 (fr) * 2001-02-16 2002-08-29 Bayer Aktiengesellschaft Acides cinnamiques et derives d'acides cinnamiques a substitution polyhalogene et leur procede de production

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2160862A (en) * 1984-06-28 1986-01-02 Wyeth John & Brother Ltd Benzoquinolizines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2160862A (en) * 1984-06-28 1986-01-02 Wyeth John & Brother Ltd Benzoquinolizines

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066411A2 (fr) * 2001-02-16 2002-08-29 Bayer Aktiengesellschaft Acides cinnamiques et derives d'acides cinnamiques a substitution polyhalogene et leur procede de production
WO2002066411A3 (fr) * 2001-02-16 2002-11-21 Bayer Ag Acides cinnamiques et derives d'acides cinnamiques a substitution polyhalogene et leur procede de production
US6956129B2 (en) 2001-02-16 2005-10-18 Bayer Aktiengesellschaft Polyhalogen-substituted cinnamic acids and cinnamic acid derivatives and a process for the preparation of polyhalogen-substituted cinnamic acids and cinnamic acid derivatives
US7381832B2 (en) 2001-02-16 2008-06-03 Lanxess Deutschland Gmbh Polyhalogen-substituted cinnamic acids and cinnamic acid derivatives and a process for the preparation of polyhalogen-substituted cinnamic acids and cinnamic acid derivatives

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