EP0724578A1 - Derives amines servant d'antagonistes des canaux a calcium - Google Patents

Derives amines servant d'antagonistes des canaux a calcium

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Publication number
EP0724578A1
EP0724578A1 EP94929536A EP94929536A EP0724578A1 EP 0724578 A1 EP0724578 A1 EP 0724578A1 EP 94929536 A EP94929536 A EP 94929536A EP 94929536 A EP94929536 A EP 94929536A EP 0724578 A1 EP0724578 A1 EP 0724578A1
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EP
European Patent Office
Prior art keywords
formula
compound
alk
propyl
galkyl
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.)
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Application number
EP94929536A
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German (de)
English (en)
Inventor
David Gwyn Cooper
Ronald Joseph King
Thomas Henry Brown
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0724578A1 publication Critical patent/EP0724578A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D295/08—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 singly bound oxygen or sulfur atoms
    • C07D295/084—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61P25/08—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
    • A61P25/28—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D295/12—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 singly or doubly bound nitrogen atoms
    • C07D295/125—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to amine derivatives, more particularly aryloxy-, arylthio-, and aroyl-alkylamino compounds having a heteroatom in the alkyl portion, to processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of ischaemic stroke.
  • Stroke is reportedly the third most common cause of death in the developed world.
  • Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
  • British Patent No. 924961 describes, as intermediates for the preparation of anti- nematodal agents, compounds of formula R. W .CH2.CH2.NXY, wherein R is phenyl optionally substituted by inter alia halogen, alkyl or alkoxy, X and Y are inter alia alkyl, or NXY represents a pyrrolidino, piperidino or morpholino group and W is a straight saturated chain containing up to 16 carbon atoms and 1 to 3 non-adjacent oxygen atoms.
  • the present invention therefore provides, in a first aspect, a compound of formula
  • R.1 and R ⁇ each independently represent: hydrogen, C ⁇ galkyl, C3_gcycloalkyl, C3_gcycloalkylC _4alkyl, arylC ⁇ alkyl, C2-6hydroxyalkyl or R3R 4 NC2-6_lkyl (where R ⁇ and R 4 independently represent H or C ⁇ _4alkyl) or NR--R represents a saturated heterocyclic ring containing 4 to 9 ring members, one of which may optionally be a further heteroatom selected from O, S or NR* ⁇ (where
  • R5 is H, C ⁇ alkyl or arylC1.4a.kyl), which ring may optionally be substituted by one or two substituents selected from Cj.galkyl and C ⁇ alkoxy;
  • X represents O, S or NR6 (where R ⁇ is hydrogen, C1.4a._kyl or arylC1.4a._kyl);
  • n is 2 to 5
  • m is 1 to 5 (providing that when m is 1, Y represents a bond)
  • Ar represents phenyl optionally substituted by 1-3 substituents selected from halo, Ci.galkyl, Ci.galkoxy, C ⁇ _2alkylenedioxy e.g.
  • Y 1 is Y 2 (CH2) r where r is 0 or 1 and Y 2 is O, S or NR where R? is hydrogen or C ⁇ _4_lkyl, Z is (CH2.
  • S or -CH CH-, s is 0, 1 or 2 or Ar is the corresponding tricyclic dehydro ring system; or a pharmaceutically acceptable salt thereof for use as a therapeutic agent.
  • the invention provides the use of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions where a calcium antagonist is required.
  • Compounds of formula (I) and their pharmaceutically acceptable salts are preferably used in the manufacture of a medicament for the treatment of conditions related to the accumulation of calcium in the brain cells of mammals.
  • n and m preferably are independently from 2 to 4 such that the total of n + m is from 4 to 8.
  • n + m is preferably 7 and when Y is other than a bond n + m is preferably 6.
  • Y preferably represents oxygen.
  • X preferably represents oxygen or NR -*; R6 preferably represents hydrogen.
  • Alk* and Alk 2 preferably independently represent CH2 or when branched, HXCH ) or C(CH3>2.
  • A is oxygen q is preferably zero and p is preferably zero or 1.
  • p + q is preferably 1 or 2.
  • p and q are preferably both zero.
  • tricyclic heteroaryl groups examples include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine.
  • the tricyclic moiety can be linked to the remainder of formula (I) via any suitable ring atom.
  • Suitable substituents for Ph, and tricyclic heteroaryl groups include, for example, 1 to 3 substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1.4a.kyl
  • Ar is phenyl mono-substituted by phenoxy, benzyl, benzyloxy, benzoyl, halobenzoyl or halo; phenyl disubstituted by halo; or Ar is 2-dibenzofuranyl.
  • Ar is phenyl substituted by benzyl, benzoyl, fluorobenzoyl or benzyloxy.
  • the substituent is preferably at the 3- or 4- position of the phenyl ring.
  • Ci.galkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Ci.galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as isopropyl, t-butyl, or sec-pentyl.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts may be used for example in the isolation of a final product and are included within the scope of this invention.
  • the compounds of formula (I) may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. Certain compounds of formula (I) are believed to be novel. Thus, in a further aspect the invention provides novel compounds of formula (IA):
  • A represents -CH2CH2-;
  • reduction of a compound wherein A and/or Y represent C O to a compound wherein A and/or Y represent -CH2-; followed if desired by salt formation.
  • the reaction between a compound of formula (II) and a compound of formula (HI) can be carried out under standard conditions.
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methane- sulphonyloxy or p-toluene sulphonyloxy.
  • reaction may be effected in the absence or presence of solvent such as dimethylformamide or methylethylketone optionally in the presence of a base such as sodium hydride or potassium carbonate and at a temperature in the range 0 to 200°C.
  • solvent such as dimethylformamide or methylethylketone
  • a base such as sodium hydride or potassium carbonate
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • This reaction may optionally be effected in the presence of a solvent such as tetrahydrofuran.
  • the reaction of a compound of formula (IV) with a compound of formula (V) according to process (b) may be effected in conventional manner, for example using excess amine as solvent or alternatively using an organic solvent, such as ethanol or dimethylformamide.
  • the leaving group L 2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction may be carried out in the presence of a base such as potassium carbonate, sodium hydride or potassium t- butoxide or an excess of amine may be employed.
  • reductive amination of an aldehyde (X) may be effected using a reducing agent such as sodium cyanoborohydride in the presence of a compound of formula (V), according to procedures well known in the art. It will be appreciated that when X represents NH the nitrogen atom should preferably be protected for example as described below.
  • reaction of compounds (XI) and (XII) may be effected in an analogous manner to process (a) described above.
  • Reduction of a pyridinium derivative (XIII) according to process (0 may be effected for example by hydrogenation, using a noble metal catalyst such as palladium on charcoal, platinum or platinum oxide (Adam's catalyst), suitably in a solvent such as an alcohol e.g. ethanol.
  • L 2 may be halogen or a sulphonic acid residue such as a tosylate or mesylate and the reaction may be carried out under standard conditions in a solvent such as dimethylformamide, optionally in the presence of a base eg sodium hydride.
  • a base eg sodium hydride.
  • L 2 should be fluoro, such that the compound (XV) is a fluoro- substituted aryl compound, and the reaction is preferably effected in the presence of a strong base such as sodium hydride, and in a polar organic solvent such as dimethylsulphoxide or dimethylformamide.
  • Interconversion reactions according to process (h) may be carried out using standard methods.
  • a compound of formula (II) can be prepared under standard alkylation conditions by reacting a compound of formula (XVI) :
  • L and L 2 are preferably selected so that the compound of formula (V) reacts selectively with L 2 .
  • L is suitably hydroxy and L 2 is suitably halo.
  • Compounds of formula (HI) are commercially available or may be prepared using standard procedures well known in the art, for example using methods analogous to those described for process (a).
  • a compound of formula (IV) may be prepared by Friedel-Craft acylation of a compound HAr with an acylating agent of the formula L 2 (CH2) n X(CH2) m C(O)Hal, where Hal represents a halogen atom such as bromo or chloro. It will be appreciated that when X represents NH, nitrogen protection should preferably be employed. The carbonyl group in the resulting compound of formula (IV) may if desired subsequently be reduced.
  • Compounds of formula (V) and (XVI) are commercially available or may be prepared by standard methods. Compounds of formula (VI) may be prepared according to general processes (a) and (b) described herein employing an appropriate amide corresponding to formula (II) or (V).
  • Compounds of formula (VTI) may be prepared by acylation of a compound of formula (V) for example with an appropriate acid chloride or ester, which may itself be prepared from a compound of formula (III) by reaction with an appropriate, commercially available bromoalkyl ester or acid, followed if necessary or desired by conversion to an acid chloride.
  • a compound (VII) may be prepared by a method analogous to process (a).
  • Amides of formulae (VHI) and (IX) may be prepared for example by reaction of a corresponding carboxylic acid or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula ArY(CH2) m (R ⁇ ) H or R 1 R 2 N(CH 2 ) n (R 6 )NH respectively.
  • An aldehyde of formula (X) may be prepared for example by reduction of the corresponding nitrile using a reducing agent such as diisobutyl aluminium hydride, in the presence of an inert solvent such as toluene. Conveniently reductive amination of the aldehyde is carried out in situ, i.e. the compound of formula (I) is obtained from the nitrile in a one-pot reaction without isolation of the intermediate aldehyde.
  • the nitrile may itself be prepared by reacting a compound of formula (IV) wherein L 2 is halo with potassium cyanide.
  • Compounds (X) may also be prepared by other standard procedures such as reduction of an ester or oxidation of an alcohol.
  • Compounds of formula (XI) may be prepared by methods analogous to any of processes (a) - (d) described herein. Alternatively a compound (XI) may be obtained by catalytic hydrogenation of a corresponding compound of formula (I) wherein Ar represents a benzyloxyphenyl group. This therefore provides a further method of converting a compound of formula (I) to a different compound of formula (I).
  • Suitable protecting groups include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t- butoxycarbonyl or benzyloxycarbonyl.
  • An aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis.
  • a compound of formula (I) When a compound of formula (I) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
  • the invention also encompasses any novel intermediates described herein, in particular those of formulae (II), (IV), (VI), (VII), (V ⁇ l), (IX) and (XII).
  • Compounds of the invention have been found to exhibit high calcium influx blocking activity, for example in neurons.
  • the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head or spinal injury, AIDS -related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the invention also provides a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head or spinal injury, AIDS -related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceuucal compositions adapted accordingly. Parenteral administration is generally preferred.
  • the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent e.g. cremophore.
  • a cyclodextrin or a solubilising agent e.g. cremophore.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0J mg and 100 mg, preferably between 0J mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day.
  • the total daily dosage by oral administration could be in the range 1 to 2000 mg and the total daily dosage by parenteral administration could be in the range OJ to 400 mg.
  • the compounds may be administered for a period of continuous therapy, for example for a week or more.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination or concurrently with one or more other therapeutic agents, for example a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator; an excitatory amino acid antagonist such as an NMDA antagonists; a free radical inhibitor; or a calpain inhibitor.
  • a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator
  • an excitatory amino acid antagonist such as an NMDA antagonists
  • a free radical inhibitor such as an NMDA antagonists
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCl2, 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a rundown corrected control value.
  • Block by 20 ⁇ M drug was assessed 3 minutes after drug application.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
  • Suspending agent e.g. Xanthan gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • Preparation 7 3-(4-Benzylphenoxy)propylamine hydrochloride
  • the product from Preparation 6 (7.5g), hydrazine hydrate (7.5ml) and ethanol (250ml) were heated at reflux until all the solid had dissolved and heating was continued for a further 30 minutes.
  • the cooled mixture was filtered and the filtrate was evaporated.
  • the residue was dissolved in hot ethanol (150ml) and treated with concentrated hydrochloric acid (10ml). The resulting solution was allowed to cool and the precipitate was collected to give the title compound as a white solid which was used without further purification.
  • N-[3-(3,4-Dichlorophenoxy)propyl]-N-[3-(l-piperidino)propyl]amine dihydrochloride A mixture of 3-(3,4-dichlorphenoxy)propylamine (2.2g), 80% sodium hydride (0.6g), 1- (3-chloropropyl)piperidine hydrochloride (1.98g) and dimethylformamide (30ml) was stirred under nitrogen at 60°C for 36 hours. The mixture was treated with water and extracted with ether. The ether layer was washed with dilute sodium hydroxide solution and brine, dried over sodium sulphate and the solvent removed.
  • N- ⁇ 3-[4-(4-Fluorobenzoyl)phenoxy]propyl ⁇ -N-[3-(l-piperidino)propyl]amine dihydrochloride A mixture 1-piperidinopropylamine (0.426g), 80% sodium hydride (0.072g), and dimethylformamide (10ml) was stirred under argon at 40°C for 0.5hours. The resulting solution was treated with 4-(3-bromopropyloxy)-4'-fluorobenzophenone (l.Og) and then stirred under argon at 60°C for 18 hours.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés répondant à la formule (I), dans laquelle R1 et R2, indépendamment l'une de l'autre, représentent hydrogène, alkyle C¿1-8?, cycloalkyle C3-8, cycloalkyle C1-8alkyleC1-4, arylalkyle C1-4, hydroxyalkyle C2-6, ou R?3R4¿N alkyleC¿2-6? (où R?3 et R4¿ indépendamment l'un de l'autre représentent H ou alkyle C¿1-4?), ou NR?1R2¿ représente un hétérocylce saturé renfermant de 4 à 9 éléments de cycle, dont l'un est éventuellement un hétéroatome supplémentaire choisi parmi O, S et NR?5 (où R5¿ représente H, alkyle C¿1-4?, ou arylalkyle C1-4), ce cycle étant évenutellement substitué par un ou deux substituants choisis parmi alkyle C1-6 et alcoxy C1-6; X représente O, S ou NR?6 (où R6¿ représente hydrogène, alkyleC¿1-4? ou arylalkyle C1-4); Y représente O, S, C=O ou une liaison; n est compris entre 2 et 5; on est compris entre 1 et 5 (à condition que si m est 1, Y représente une liaison) et Ar représente phényle éventuellement substitué par 1 à 3 substituants choisis parmi halo, alkyle C1-8, alcoxy C1-8, alkylènedioxy C1-2, par exemple méthylènedioxy, trifluorométhyle, trifluorométhyloxy, ou par un groupe Ph(Alk?1)¿pA(Alk2)q- où Ph représente phényle éventuellement substitué, A représente une liaison, O, S, -C=O, ou CH=CH, Alk?1 et Alk2¿, indépendamment l'une de l'autre, représentent alkyle C¿1-4? linéaire ou ramifié, et p et q, indépendamment l'un de l'autre, représentent 0 ou 1, à condition que la longueur de -(Alk?1)¿pA(Alk2)q- ne dépasse pas 5 atomes, ou Ar représente un groupe hétéroaryle tricyclique éventuellement substitué (a), où Y1 représente Y2(CH2)r où r vaut 0 ou 1 et Y2 représente O, S ou NR7 où R7 représente hydrogène ou alkyle C¿1-4?, Z représente (CH2)s ou -CH=CH-, S vaut 0, 1 ou 2 ou Ar représente le système cyclique déshydrocyclique correspondant; et leurs sels pharmaceutiquement acceptables; utilisables comme agents athérapeutiques, par exemple dans le traitement des accès ischémiques.
EP94929536A 1993-10-22 1994-10-11 Derives amines servant d'antagonistes des canaux a calcium Withdrawn EP0724578A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9321812 1993-10-22
GB939321812A GB9321812D0 (en) 1993-10-22 1993-10-22 Pharmaceuticals
PCT/EP1994/003358 WO1995011240A1 (fr) 1993-10-22 1994-10-11 Derives amines servant d'antagonistes des canaux a calcium

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EP0724578A1 true EP0724578A1 (fr) 1996-08-07

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EP (1) EP0724578A1 (fr)
JP (1) JPH09504014A (fr)
AU (1) AU7855394A (fr)
GB (1) GB9321812D0 (fr)
WO (1) WO1995011240A1 (fr)
ZA (1) ZA948232B (fr)

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HU226635B1 (en) * 1995-01-23 2009-05-28 Asubio Pharma Co Piperidine and piperazine derivatives, medicines containing them as active ingredient and their use
US5891885A (en) * 1996-10-09 1999-04-06 Algos Pharmaceutical Corporation Method for treating migraine
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
WO2000021550A2 (fr) * 1998-10-13 2000-04-20 President And Fellows Of Harvard College Methodes et compositions de traitement des maladies neurodegeneratives
JP4904948B2 (ja) 2006-07-04 2012-03-28 住友化学株式会社 中間体アルコール化合物の製造方法
AU2016275764B8 (en) 2015-06-11 2021-03-04 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof

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BE588558A (fr) * 1959-03-13 1960-09-12
US3239520A (en) * 1961-11-20 1966-03-08 Nl Combinatie Chem Ind N-(monocarbocyclic aryloxy-lower alkyl)-n' (diloweralkyl, or heterocyclic)-lower alkylene diamines
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DE3418271A1 (de) * 1984-05-17 1985-11-21 Dr. Karl Thomae Gmbh, 7950 Biberach Neue benzazepinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
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ZA948232B (en) 1996-04-22
GB9321812D0 (en) 1993-12-15
JPH09504014A (ja) 1997-04-22
AU7855394A (en) 1995-05-08
WO1995011240A1 (fr) 1995-04-27

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